Nerve Injury CSF Biomarker for Degenerative Disc Disease-Related Low Back Pain

spinal tap
spinal tap
The cerebrospinal fluid of patients with vs without intervertebral disc degeneration with and without low back pain was shown to differentially express proteins involved in inflammation and nerve injury.

The cerebrospinal fluid (CSF) of patients with vs without intervertebral disc degeneration (DD) with and without low back pain (LBP) was shown to differentially express proteins involved in inflammation and nerve injury. In addition, differentially expressed CSF proteins linked to nerve injury are associated with DD-related chronic LBP, but not with non-painful DD. These study results were published in The Journal of Pain.1

While intervertebral DD may account for chronic LBP in some patients, DD can also be related to normal aging and is found in nearly one-third of individuals without LBP.2 As a result, magnetic resonance imaging (MRI) cannot distinguish between DD related to LBP and non-painful DD. In addition, patients with LBP frequently complain of radiating pain, but nerve compression is seldom detected on MRI. Thus, the pathogenesis of painful DD likely involves factors that cannot be identified with imaging.

Protein expression in CSF has been shown to be altered with lumbar disc herniation, a subset of DD.3 The authors of the current study therefore hypothesized that proteomic analysis of the CSF of patients with DD may lead to the identification of proteins involved in the pathogenesis of LBP resulting from DD.

Researchers, led by Tony K.Y. Lim, PhD and Laura S. Stone, PhD, from the Alan Edwards Centre for Research on Pain at McGill University in Montreal, Canada, performed a proteomic screen in healthy individuals (n=25), patients with DD and LBP (n=15), and patients with DD but no associated LBP (n=13). From this analysis, 2 proteins were selected for further analysis. Cystatin C, which is associated with inflammation, was expressed at higher levels in the CSF of participants with DD with and without LBP compared with healthy controls, and hemopexin, which is linked to nerve injury, was more abundantly expressed in the CSF of individuals with DD and LBP than in the CSF of patients with nonpainful DD.

Enzyme-linked immunosorbent assay (ELISA) analysis confirmed that cystatin C concentrations in the CSF were significantly higher in patients with non-painful DD vs healthy controls (P <.05). While CSF cystatin C levels did not correlate with pain intensity or disability, they were associated with DD severity as measured by the Thompson scale (P =.04). Hemopexin levels measured with ELISA were higher in the CSF of patients with painful DD than in that of healthy controls (P <.01), but no difference was found between participants with nonpainful DD and controls. Hemopexin levels were associated with pain intensity (as measured on a visual analog scale, P =.01), disability (P =.01), and DD severity (P =.008).

Summary and Applicability

MRI studies cannot differentiate between painful DD and painless DD. Researchers analyzed protein expression in the CSF of healthy individuals, patients with DD but no related LBP, and patients with DD-associated LBP. CSF levels of inflammation-related Cystatin C were associated with DD severity (but not with pain or disability), suggesting an inflammatory process in DD, and CSF levels of hemopexin were associated with DD severity, pain, and disability, pointing to nerve injury as a possible contributor to LBP arising from DD.

“Our data suggests that nerve damage may be involved even when the pain is just in the back region and that treatments targeting neuronal excitation that would be used for neuropathic pain might be useful even for pain that is localized just to the back. Perhaps combinations of different types of treatments might give the best results,” Dr Stone told Clinical Pain Advisor.

“Our study only infers nerve damage from the pattern of changes in expression; we have no direct evidence. Future studies need to confirm the presence of a neuropathic component directly,” she added.

Study Limitations 

Proteomic analysis of CSF does not allow for the identification of low abundance proteins since only the most abundantly expressed proteins were selected for analysis. Thus, low-abundance proteins could not be evaluated in this study.

In addition, the number of study participants was low in all groups.

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  1. Lim TKY, Anderson KM, Hari P, et al. Evidence for a role of nerve injury in painful intervertebral disc degeneration: A cross-sectional proteomic analysis of human cerebrospinal fluid [published online June 23, 2017]. J Pain. doi:10.1016/j.jpain.2017.06.002
  2. Jensen MC, Brant-Zawadzki MN, Obuchowski N, Modic MT, Malkasian D, Ross JS. Magnetic resonance imaging of the lumbar spine in people without back pain. N Engl J Med. 1994;331(2):69-73. doi:10.1056/NEJM199407143310201
  3. Liu XD, Zeng BF, Xu JG, Zhu HB, Xia QC. Proteomic analysis of the cerebrospinal fluid of patients with lumbar disk herniation. Proteomics. 2006;6(3):1019-1028. doi:10.1002/pmic.200500247