Accepted Manuscript Predicting Epidural Steroid Injections with Lab Markers and Imaging Techniques Benoy V. Benny, M.D Monika Yogesh Patel, MD PII:
S1529-9430(14)00377-5
DOI:
10.1016/j.spinee.2014.04.003
Reference:
SPINEE 55852
To appear in:
The Spine Journal
Received Date: 16 October 2013 Revised Date:
16 March 2014
Accepted Date: 8 April 2014
Please cite this article as: Benny BV, Patel MY, Predicting Epidural Steroid Injections with Lab Markers and Imaging Techniques, The Spine Journal (2014), doi: 10.1016/j.spinee.2014.04.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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First Author: Benoy V. Benny, M.D Baylor College of Medicine Medical Center Department of Physical Medicine and Rehabilitation McNair Campus 7200 Cambridge St, Suite 10C Houston, TX 77030 713-798-6198
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Title: Predicting Epidural Steroid Injections with Lab Markers and Imaging Techniques
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Corresponding Author and Second Author: Monika Yogesh Patel, MD University of Texas Health Science Center at Houston and Baylor College of Medicine Department of Physical Medicine and Rehabilitation 1333 Moursund Ave Houston, TX, 77030 713-799-5033
[email protected] Acknowledgement Statement Copyediting services were performed by Wanda Reese, Medical Writer/Editor Consultant Jade Medical Communications Group 12021 Wilshire Blvd., #296 Los Angeles, CA 90025 424-653-6195
[email protected] ACCEPTED MANUSCRIPT
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Predicting Epidural Steroid Injections with Lab Markers and Imaging Techniques Abstract:
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Background Context: Epidural steroid injections (ESI) have been used for a number of years in
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the treatment of radicular pain caused by nerve root impingement or stenosis following failed
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conservative treatments with oral medications, physical therapy, and life style modifications.
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Purpose: Evaluation of predictive tools for epidural steroid injection outcomes in treating
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radicular pain.
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Study design: A comprehensive, systematic review of the prognostic accuracy of certain
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predictive methods used to determine epidural steroid injection outcomes.
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Methods: Fifty articles were obtained via the Pubmed database, using keywords and cross
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referencing works cited. Inclusion criteria included patients with radicular pain; analysis of a
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specific prediction tool; and outcomes measured by improvement in pain and/or function.
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Exclusion criteria included literature review articles and animal or cadaver studies. Eight articles
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studying imaging techniques or lab markers as prediction tools underwent quality evaluation and
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evidence classification based on the 2011 American Academy of Neurology Clinical Practice
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Guideline Process Manual. The authors received no institutional or private funding for this
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literature review.
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Results: For patients with radicular pain, there is insufficient evidence to either support or refute
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the prognostic accuracy of spinal stenosis seen on imaging in determining epidural steroid
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outcomes (two Class IV studies). It is possible that low grade nerve root compression as seen on
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lumbar MRIs, does predict short term reduction in pain after transforaminal epidural steroid
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injection (TFESI) (Class II and Class III studies). For patients with lumbar radicular pain, there
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is both insufficient and conflicting evidence that either supports or refutes prognostic accuracy of
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hs-CRP in determining epidural steroid outcomes (two Class III studies). It is probable IFN-y
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>10pg/mL from epidural lavage is predictive of short term pain reduction following lumbar
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epidural steroid injection (ESI) (single Class I study). There is insufficient evidence that either
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supports or refutes prognostic accuracy of fibronectin-aggrecan complex from epidural lavage to
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determine epidural steroid outcome (single Class IV study).
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Conclusions: Predictive tools for ESI outcomes such as nerve root compression grading and
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inflammatory markers, particularly, elevated IFN-y from epidural lavage fluid, seem promising
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in the future. At this time, future research is needed with a larger sample size, broader spectrum
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of patients and a more defined system of outcome measurements at standardized follow-up time
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periods before practice recommendations can be made.
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Introduction:
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Epidural steroid injections have been used for a number of years in the treatment of radicular pain caused by nerve root impingement or stenosis after conservative treatments with
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oral medications, physical therapy and life style modifications have failed¹. The management of
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lumbar radicular pain with a corticosteroid epidural injection was first recorded in 1952². It
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became increasingly popular in the late 1990s, and showed an increase of 121% from 1998 to
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2005 in the United States Medicare population³.
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This procedure involves corticosteroid injection with or without a local anesthetic at the
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site of pathology, which may be in the cervical, thoracic or lumbar spine. The mechanism of
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action is not completely understood, but it is believed that corticosteroids reduce inflammation
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by inhibiting the synthesis and/or release of proinflammatory mediators resulting in a reduction
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of pain symptoms³.
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There are three main techniques for reaching the epidural space: an intralaminar,
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transforaminal and caudal approach. There is variability in efficacy for each of the three
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techniques. Manchikanti et al developed practice guidelines based on a systematic review in
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2009 and determined the level of evidence based on the United States Preventative Services Task
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Force4. Caudal ESI has Level I evidence for short and long-term relief in managing chronic low
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back and lower extremity pain secondary to lumbar disc herniation and/or radiculitis and
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discogenic pain without disc herniation or radiculitis4. Intralaminar ESI has Level II-2 evidence
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for blind lumbar intralaminar epidural injections for short-term relief in managing chronic low
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back and lower extremity pain secondary to lumbar disc herniation and/or radiculitis4. The
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evidence is Level III for blind lumbar intralaminar epidural injections in managing low back pain
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of spinal stenosis and chronic low back pain of discogenic origin without disc herniation or
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radiculitis4. The level of evidence for lumbar TFESIs is Level II-1 for short-term relief and
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Level II-2 for long-term relief in managing chronic low back and lower extremity pain4.
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Although the literature has shown that ESIs are efficacious, and that pain relief results can vary, this article aims to review and identify predictive tools that may help identify patients
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with improved pain relief or function after receiving ESI.
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Methods:
A Pubmed literature search was performed using the keywords epidural steroid
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injections, outcomes, prediction, back pain, radiculopathy. In addition, the reference lists of the
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articles searched were reviewed to identify articles that may have been initially missed. The
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search included English-language articles and covered publications ranging from 1987 to 2012.
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There were 50 records initially identified (see Figure 1). The search was further narrowed by
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using inclusion criteria of 1) radicular pain symptoms; 2) specific prediction tool studied; 3) ESI
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as the primary intervention; and 4) preferred outcome measurement of improvement in pain or
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function. There were 38 articles that met these inclusion criteria. The prediction measurement
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investigated could be classified into seven broad topics: imaging findings, lab markers, clinical
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exam findings, epidural technique, electrodiagnostic findings, discogram, and chronic opioid use.
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However, only single articles were found analyzing electrodiagnostic findings, discogram, or
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chronic opioid as individual prediction tools and therefore were excluded. As epidural technique
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and clinical exam findings have been extensively reviewed in the literature, these predictive tools
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were not included in this review. Additionally, all literature review articles were excluded.
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There were eight remaining articles included in the review; four retrospective studies analyzing
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imaging findings, and four prospective studies analyzing lab markers. ESI techniques included
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transforaminal, intralaminar and caudal approaches. All outcome measurements were short term,
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within three months of ESI.
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Methods used to assess the quality and strength of evidence were performed using the
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2011 American Academy of Neurology Clinical Practice Guideline Process Manual for
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prognostic accuracy5 (see Table 1). Articles are graded from strongest level of evidence, Class I
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to weakest level of evidence, Class IV. To meet Class I criteria, an article must be a cohort
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survey with prospective data collection, include a broad spectrum of persons at risk for
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developing the outcome; outcome measurement is objective or determined without knowledge of
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risk factor status; defined inclusion criteria; and contain risk factor and outcome measurements
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of at least 80% of enrolled subjects 5. To meet Class II criteria, article must be a cohort study
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with retrospective data collection or case-control study; inclusion criteria must be defined; and at
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least 80% of enrolled subjects have both the risk factor and outcome measured; include a broad
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spectrum of persons with and without the risk factor and the outcome; the presence of the risk
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factor and outcome are determined objectively or without knowledge of one another5. To meet
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Class III criteria, article must be a cohort or case control study, include a narrow spectrum of
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persons with or without disease, and the presence of the risk factor and outcome determined
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objectively, without knowledge of the other or by different investigators5. To meet Class IV
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criteria, article did not include persons at risk for the outcome, did not include persons with and
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without the risk factor, included undefined or unaccepted measures of risk factor or outcomes; no
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measures of association or statistical precision presented or calculable5.
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Classification of recommendations was linked to the strength of evidence found in the articles reviewed using the 2011 American Academy of Neurology Clinical Practice Guideline
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Process Manual5 (see Table 2). Classification is graded from strongest level of recommendation,
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Level A, to weakest level of recommendation, Level U. Level A recommendations must have at
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least two consistent Class I studies5,6,7. A Level A recommendation is established as predictive
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for the given condition in the specific population5,6,7. A Level B recommendation requires at
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least one Class I study or two consistent Class II studies5,6,7. A Level B recommendation is
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established as probably predictive for the given condition in the specific population5,6,7. A Level
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C recommendation must have at least one Class II study or two consistent Class III studies5,6,7.
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A Level C recommendation is established as possibly predictive for the given condition in the
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specific population5,6,7. A Level U recommendation has inadequate or conflicting data5,6,7. A
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Level U recommendation is established as a treatment predictor but unproven given current
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knowledge5,6,7.
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The rationale for using the American Academy of Neurology Clinical Practice Guideline
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Process Manual for this review is based on its utilization for 56 evidenced based reviews
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published by the American Academy of Neurology available on the National Guideline
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Clearinghouse public resource for evidence-based clinical practice guidelines5,6. In particular,
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Schellinger et al performed a literature review utilizing the American Academy of Neurology
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Clinical Practice Guideline Process Manual to classify the level of evidence of prognostic
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articles 5,6,7.
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Results:
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Imaging as a Predictive Tool:
Fish et al performed a retrospective study reviewing MRIs for disk herniation, nerve root
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compromise, neuroforaminal narrowing or central canal stenosis in patients with cervical
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radiculopathy who received a cervical intralaminar epidural injection from C7-T18. The same
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physician performed all injections and one radiologist reviewed all of the MRIs. However, there
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was a small number of patient (N=32), without strong power. There was only one patient with
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discal herniation and authors were unable to yield conclusive results. Additionally, there were
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no covariants such as additional treatment accounted for, no standardized follow-up time period,
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and patients lost to follow-up were excluded. Therefore it was graded as a Class IV study.
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Campbell et al retrospectively studied CT scan for canal diameter that underwent non-
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fluoroscopic guided intralaminar ESI and then correlated it with undergoing surgical
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decompression9. There was no significant difference in the functional limitations, demographics
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and comorbidities between subjects. However there was no defined level of ESI performed and
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no functional or pain evaluation tool measured. Therefore it was graded as a Class IV study.
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Paiden et al performed a retrospective study evaluating contrast dispersal patterns of
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transforaminal steroid injections at a single level performed in patients with lumbar
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radiculopathy10. Outcome was measured using the numeric pain scale. There were clear
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outcome measures and reporting of number of drop outs. However, there was no standardization
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of contrast volume, small number of subjects (N=38), but only 17 of these patients had MRIs
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available for review, and no clear definition of participant baseline characteristics. Therefore it
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was graded as a Class III study. Ghahreman et al reviewed patients with radicular pain who
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underwent TFESI and attempted to correlate it with MRI grading of discal herniation and nerve
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root compression11. The interventionalist was blinded to outcome, clear outcome measurements
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were defined, and number lost to follow-up was reported. However, subjects were combined
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into high-grade and low-grade compression groups to compensate for low numbers in treatment
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groups. Therefore it was graded as a Class II study (see Table 3).
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Lab markers as a predictive tool:
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In patients with discal herniation it is presumed that the nucleus pulposus herniation causes an inflammatory cascade. Golish et al studied fibronectin-aggrecan complex from
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epidural lavage fluid as a predictive tool of functional improvement after caudal epidural steroid
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injection12. The SF-36, a well validated clinical instrument of function, was used. There was
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also a strong power reported. However, there was no standardized follow-up time period for
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outcome measurement, multiple levels were injected, no reported dropout rate, and relevant
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baseline characteristics were not similar between subjects. Therefore, it was considered a Class
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IV study. Park et al studied hs-CRP as a marker of pain relief after TFESI13. Strong power and
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clear outcomes were reported. However, there was no reporting of dropout rate, covariants, or
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acuity of symptoms. Patient spectrum was limited by including only male participants.
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Therefore it was considered a Class III study. In addition, Ackerman et al studied hs-CRP as a
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predictor of pain response in patients with MRI findings of discal herniation who received
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lumbar ESI every two weeks for a maximum of three times14. A control group was established,
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where patient baseline demographics were reported, however, patient spectrum was limited by
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including only male participants. Also, patients who had radicular symptoms lasting more than
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six weeks after initial lumbar ESI were excluded causing a selection bias, no dropout rate
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reported, and each participant received a different number of injections. Therefore it was
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considered a Class III study. Scuderi et al studied IFN-y from epidural lavage fluid as a
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predictor of pain relief after a lumbar epidural steroid injection performed at the level of
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suspected pathology15. There was strong power and reporting of dropout rate. There were
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similar baseline subject characteristics; however, there was a larger proportion with herniated
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discs per MRI. Author also reported a technical limitation in the collection and assay of
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inflammatory cytokines. This was considered a Class I study (see Table 4 and Table 5).
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Conclusions:
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Imaging as a Predictive Tool:
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There were four retrospective articles reviewed for determination of imaging as a
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predictive tool. Based on the Ghahreman and Paiden studies, their review of the grade of nerve
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root compression seen on lumbar MRI predicts short term reduction in pain after TFESI (Class
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II and Class III studies)10,11. For patients with radicular pain, low grade nerve root compression
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in the lumbar spine evaluated by MRI imaging is possibly predictive of short term (less than two
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month) reduction in pain relief after receiving a lumbar TFESI (Level C)10,11. Fish and
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Campbell’s studies reviewed imaging findings of spinal stenosis as outcome prediction tools, but
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had conflicting results8.9. Fish did not have a significant number of patients with discal
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herniation in the small subjects studied, and concluded spinal stenosis did correlate with
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reduction in the neck disability index after cervical intralaminar injection for patients with
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cervical radicular pain (Class IV study)8. Campbell reviewed CT spinal canal dimensions to
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predict decompressive surgery within the following two years after receiving a series of blind
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lumbar intralaminar ESI, and found it was not predictive of ESI response (Class IV study)9.
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Based on the Fish and Campbell studies, there is insufficient evidence that spinal stenosis seen
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on imaging can predict improved outcome after ESI (Level U)8,9.
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Lab Markers as a Predictive Tool:
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There were four prospective articles reviewed for determination of lab markers as a
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predictive tool. Park and Ackerman’s studies reviewed hs-CRP as a predictive tool of pain relief
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following lumbar ESI in male participants and had conflicting results13, 14. Park performed
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fluoroscopic guided lumbar TFESI at the level of foraminal stenosis on MRI and did not find hs-
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CRP predictive of pain relief at four weeks follow-up period (Class III study)13. Ackerman
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performed up to three intralaminar ESI’s with MRI findings of discal herniation and concluded
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patients with higher hs-CRP levels at baseline predicted less pain relief after ESI at six weeks
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follow-up (Class III study)14. However, there was selection bias by excluding patients with
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elevated hs-CRP due to cardiac reasons, and persistent radicular pain symptoms six weeks after
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receiving three consecutive ESI’s. Based on Park and Ackerman’s studies, there is insufficient
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evidence that hs-CRP can predict short term pain relief following lumbar ESI short (Level U)13,
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improved function in patients with radicular symptoms after receiving a caudal ESI, and found
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significant improvement in function at mean follow-up period of 6.4 weeks; however, outcome
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measurement did not have a standardized follow-up period (Class IV study)12. Based on the
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Golish study, there is insufficient evidence fibronectin- aggrecan complex predicts short term
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functional improvement after caudal ESI (Level U) 12. Scuderi studied inflammatory cytokines
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from epidural lavage fluid and found IFN-y >10pg/mL predictive of 50% reduction of VAS at 3
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months follow-up after lumbar ESI 15. It is highly likely IFN-y >10pg/mL from epidural lavage
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predicts short term pain reduction after lumbar epidural steroid injection (single Class I study)15.
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Based on the Scuderi study, in patients with radicular pain, IFN-y >10pg/mL from epidural
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lavage fluid is probably predictive of short term pain reduction after lumbar ESI (Level B)15.
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However, it may be difficult and expensive to assay epidural lavage fluid in a clinical setting,
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which limits the utility of IFN-y as a predictive tool of ESI outcome.
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Further Research:
Further research involving larger sample sizes, similar patient demographics, defined
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outcome measurements and standardized follow-up time periods need to be performed.
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Additionally, a standardized number of injections and approach techniques need to be performed
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to adequately compare results to further develop treatment guidelines.
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33. Trief PM, Grant W, Fredrickson B. A prospective study of psychological predictors of lumbar surgery outcome. Spine (Phila Pa 1976). 2000;25 (20):2616–21. PMID: 11034646
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34. Ghahreman A, Ferch R, Bogduk N. The efficacy of transforaminal injection of steroids for the treatment of lumbar radicular pain. Pain Med. 2010 Aug;11(8):1149-68. PMID: 20704666
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35. Cicala RS, Turner R, Moran E, Henley R, Wong R, Evans J. Methylprednisolone acetate does not cause inflammatory changes in the epidural space. Anesthesiology. 1990 Mar;72(3):556-8. PMID: 2310038
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36. Riew KD, Yin Y, Gilula L, Bridwell KH, Lenke LG, Lauryssen C, Goette K. The effect of nerveroot injections on the need for operative treatment of lumbar radicular pain. A prospective,
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randomized, controlled, double-blind study. J Bone Joint Surg Am. 2000 Nov;82-A(11):1589-93. PMID: 11097449 37. Carette S, Leclaire R, Marcoux S, Morin F, Blaise GA, St-Pierre A, Truchon R, Parent F, Levésque J, Bergeron V, Montminy P, Blanchette C. Epidural corticosteroid injections for sciatica due to herniated nucleus pulposus. N Engl J Med. 1997 Jun 5;336(23):1634-40. PMID: 9171065
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39. Buttermann GR. Lumbar disc herniation regression after successful epidural steroid injection. J Spinal Disord Tech. 2002 Dec;15(6):469-76. PMID: 12468973
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48. Manchikanti L, Hirsch JA, Smith HS. Evidence-based medicine, systematic reviews, and guidelines in interventional pain management: Part 2: Randomized controlled trials. Pain Physician 2008; 11:717-773. PMID: 19057624
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51. Manchikanti L, Datta S, Smith HS, Hirsch JA. Evidence-based medicine, systematic reviews, and guidelines in interventional pain management: Part 6. Systematic reviews and meta-analyses of observational studies. Pain Physician 2009; 12:819-850. PMID: 19787009
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52. Manchikanti L, Pampati V, Rivera JJ, Beyer C, Damron KS, Barnhill RC. Caudal epidural injections with sarapin or steroids in chronic low back pain. Pain Physician. 2001 Oct;4(4):32235. PMID: 16902678
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53. Nelemans PJ, deBie RA, deVet HC, Sturmans F. Injection therapy for subacute and chronic benign low back pain. Spine (Phila Pa 1976). 2001 Mar 1;26(5):501-15. PMID:11242378
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54. Hayashi N, Weinstein JN, Meller ST, Lee HM, Spratt KF, Gebhart GF. The effect of epidural injection of betamethasone or bupivacaine in a rat model of lumbar radiculopathy. Spine (Phila Pa 1976) 1998; 23:877-885. PMID: 9580954
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Table 1: Rating scheme for the Strength of Evidence5,6,7 Classification of Evidence for Prognostic Accuracy Class I
- Cohort survey with prospective data collection
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- Includes a broad spectrum of persons at risk for developing the outcome - Outcome measurement is objective or determined without knowledge of risk factor status - Also required: a. Inclusion criteria defined
Class II
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b. At least 80% of enrolled subjects have both the risk factor and outcome measured
- Cohort study with retrospective data collection or case-control study. Study meets criteria a and b (see Class I)
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- Includes a broad spectrum of persons with and without the risk factor and the outcome - The presence of the risk factor and outcome are determined objectively or without knowledge of one another Class III
- Cohort or case control study
- Narrow spectrum of persons with or without the disease
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- The presence of the risk factor and outcome are determined objectively, without knowledge of the other or by different investigators
- Did not include persons at risk for the outcome
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- Did not include patients with and without the risk factor - Undefined or unaccepted measures of risk factor or outcomes - No measures of association or statistical precision presented or calculable
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Class IV
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Table 2: Rating Scheme for the Strength of the Recommendations5,6,7 Classification of Recommendations
Established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for
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Level A
the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.)*
Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given
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Level B
condition in the specified population. (Level B rating requires at least one Class I study or two consistent Class
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II studies.)
Possibly effective, ineffective or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)
Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven.
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*In exceptional cases, one convincing Class I study may suffice for an "A" recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and the lower limit of the confidence interval
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is > 2).
ACCEPTED MANUSCRIPT Hypothesis
Study Design
Inclusion
Exclusion
Intervention(s)
Outcome(s)
Analysis
Conclusion
Strengths
Limitations
To determine which type of MRI findings predispose a patient to respond favorably to a CESI
Retrospective N=32 patients Single center 2002-2004
Cervical radiculopathy Failed conservative treatment Previous MRI
Lost follow-up Incomplete surveys Complications of ESI
Positive MRI Negative MRI Disk herniation Nerve root compromise Neuroforaminal stenosis Central canal stenosis Cervical epidural steroid injection at C7-T1 level intralaminar approach.
Neck Disability Index (NDI), taken day of procedure and at follow-up visit mean time 26.9 weeks
Regression analysis, p6 Mild opioids and muscle relaxants for pain control Control Group: 15 patients without disc herniation and sciatica
Prior treatment with in the last 6 weeks with steroids or NSAIDS Elevated hs-CRP secondary to coronary artery disease Radicular symptoms present 6 weeks after first LESI
At least 18 yo MRI showing nerve compression PE of nerve root irritation Psychological distress
Lumbar spine surgery Steroid use in last 90 days Inflammatory/ immunological disease process diabetes Motor weakness were recommended to have surgical decompression.
Lumbar ESI every two weeks for a maximum of three injection. Prior to injection, CBC, hs-CRP, and ESR were drawn MRI results: Disc protrusion, Disc prolapsed with annual tear Disc extrusion Sequestered disc Epidural lavage and samples taken at closest involved nerve root, followed by LESI 10 Patients agreed to repeat lavage at 3 months
Acute onset Lasting 2 weeks or more Positive Physical Exam findings Lumbar MRI with HNP correlating to PE findings Unilateral Lumbar radicular pain without pain in the back Radiographic signs of foraminal stenosis, Duration of symptoms 2-24 months,
Analysis Power 84%, for N=26. t-test, Wilcoxon rank sum test, KolmogorovSmirnov test, and two by two contingency table analysis, ROC analysis comparing SF-36 score and molecular complex data. Mann-whitney Utest to compare within VAS and hsCRP. Type I error