European Spine Journal (2019) 28:2579–2587 https://doi.org/10.1007/s00586-019-06108-9 ORIGINAL ARTICLE Disc infammation and Modic changes show an interaction efect on recovery after surgery for lumbar disc herniation Niek Djuric1 · Xiaoyu Yang1 · Raymond W. J. G. Ostelo2,3 · Sjoerd G. van Duinen4 · Geert J. Lycklama à Nijeholt5 · Bas F. W. van der Kallen4 · Wilco C. Peul1,5 · Carmen L. A. Vleggeert‑Lankamp1 Received: 30 January 2019 / Revised: 18 July 2019 / Accepted: 7 August 2019 / Published online: 22 August 2019 © The Author(s) 2019 Abstract Purpose To study the interaction between Modic changes (MC) and infammation by macrophages in the disc, in relation to clinical symptoms before and after discectomy for lumbar disc herniation. Methods Disc tissue was embedded in parafn and stained with haematoxylin and CD68. Subsequently, tissue samples were categorized for degree of infammation. Type of MC was scored on MRI at baseline. Roland Disability Questionnaire (RDQ) score and visual analogue scale for back pain and leg pain separately were considered at baseline and 1-year follow- up post-surgery. Main and interaction efects of MC and infammation were tested against clinical outcome questionnaires. In addition, this analysis was repeated in bulging and extruded discs separately. Results Disc material and MRI’s of 119 patients were retrieved and analysed. Forty-eight patients demonstrated mild infammation, 45 showed moderate infammation, and 26 showed considerable infammation. In total, 49 out of 119 patients demonstrated MC. Grade of disc infammation did not associate with the presence of MC. At baseline, no main or interaction efects of MC and infammation were found on the clinical scores. However, during follow-up after discectomy, signifcant interaction efects were found for RDQ score: Only in patients with MC at baseline, patients remained signifcantly more disabled (3.2 points p = 0.006) if they showed considerable disc infammation compared to patients with mild infammation. The additional analysis showed similar results in extruded discs, but no signifcant efects in bulging discs. Conclusions An interaction efect of MC and disc infammation by macrophages is present. Only in patients with MC, those with considerable infammation recover less satisfactory during follow-up after surgery. Graphic abstract These slides can be retrieved under Electronic Supplementary Material. Table 5 Key points Post-hoc test for the main effects of inflammation on the VAS leg score and interaction effects on the RDQ and VAS leg score during the one-year follow-up. Take Home Messages Table 4B shows which subgroups explain the main / interaction effect found in Table 4A. mean RDQ and VAS leg scores are compared between different degrees of inflammation, separately for patients in the entire population (n = 97) and with and without Key words: Sciatica, inflammation, macrophage, Roland disability Modic Changes type 2 (MC2) (n = 96). Values are means ±SE, and p values, which are corrected for mulple tesng according to questionnaire, disc pathology, Modictype 2 changes Bonferroni (15 tests). Inflammaon in the Mild Moderate Considerable mild vs mild vs moderate vs 1. The clinical effects of Inflammation in lumbar disc herniation enre populaon (N = 46) (N =44) (N=27) moderate considerable considerable depends on the presence of Modicchanges. 1. Only in patients with Modictype 2 changes, considerable disc • VAS leg 14.1 ±1.2 7.8 ±1.2 9.7 ±1.5 p = 0.004 p = 1.000p = 0.390 inflammation associates with a higher RDQ score during follow-up Inflammaon in paents Mild Moderate Considerable mild vs mild vs moderate vs after surgery. without MC: (N = 31) (N =25) (N=14) moderate considerable considerable 2. Both ModicChanges and inflammation seem to play a significant • RDQ 4.5 ±0.4 4.0 ±0.4 3.4 ±0.6 p = 1.000 p = 1.000 p = 1.000 role in the rate of recovery after surgery for lumbar disc 16.7 ±1.4 8.2 ±1.5 6.4 ±2.0 p <0.001 p <0.001 p = 1.000 herniations. 2. Only in patients without Modicchanges, disc inflammation leads • VAS leg to less leg pain during follow-up after surgery Inflammaon in paents Mild Moderate Considerable mild vs mild vs moderate vs with MC2: (N = 15) (N =19) (N=12) moderate considerable considerable • RDQ 3.6 ±0.6 3.8 ±0.6 6.8 ±0.7 p = 1.000 p = 0.009 p = 0.019 3. At baseline, no associations or interactions were found between 11.4 ±1.9 7.5 ±1.9 13.1 ±2.4 p = 1.000 p = 1.000 p = 0.975 Modictype 2, inflammation and RDQ/VAS scores. • VAS leg Djuric N, Yang X, Ostelo RWJG, van Duinen SG, Lycklama àNijeholt GJ, van der Djuric N, Yang X, Ostelo RWJG, van Duinen SG, Lycklama àNijeholtGJ, van der Djuric N, Yang X, Ostelo RWJG, van Duinen SG, Lycklama àNijeholt GJ, van der KallenBFW, Peul WC, Vleggeert-Lankamp CLA (2019)Disc inflammation and Modic Kallen BFW, Peul WC, Vleggeert-LankampCLA (2019)Disc inflammation and Modic Kallen BFW, Peul WC, Vleggeert-LankampCLA (2019)Disc inflammation and Modic changes show an interaction effect on recovery after surgery for lumbar disc herniation. changes show an interaction effect on recovery after surgery for lumbar disc herniation. changes show an interaction effect on recovery after surgery for lumbar disc herniation. Eur Spine J; Eur Spine J; Eur Spine J; Keywords Sciatica · Infammation · Macrophage · Roland disability questionnaire · Modic type 2 changes Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s0058 6-019-06108 -9) contains supplementary material, which is available to authorized users. Extended author information available on the last page of the article Vol.:(0123456789)1 3 2580 European Spine Journal (2019) 28:2579–2587 Introduction Materials and methods Patients with lumbar disc herniation often sufer from radic- Hypothesis ular pain symptoms, the origin of which is not fully under- stood. Even though a part can be explained by mechanical A signifcant interaction efect is expected between disc compression of the nerve root, infammation also seems infammation and MC on the clinical symptoms: Patients to play a major role. Disc infammation may occur if the with MC will sufer from a high degree of infammation, nucleus pulposus herniates into the epidural space. This may while patients without MC will beneft from infammation. induce a foreign-body reaction accompanied by neovascu- In addition, we expect this efect to be clearer in extruded larization and macrophage infltration [1]. discs as compared to bulging discs. Macrophages may subsequently induce a resorption process by excreting matrix metalloproteases [2], inducing apoptosis and degrading collagen fbres [3]. This so-called Study population functional infammation response can explain spontaneous regression in herniation size [4]. On the other hand, they This retrospective study was performed using participants can also excrete pro-infammatory cytokines such as IL-6, from the Sciatica Trial [13], a multicenter RCT with 283 IL8 and TNF-alpha, which have been associated with exac- patients who sufered from sciatica for 6–12 weeks and had a erbation of the pain symptoms, the so-called painful infam- disc herniation as assessed by means of MRI. A total of 141 mation response [5–7]. This discrepancy in infammation patients were randomized to surgery, and 125 patients actu- response is refected in the inconsistent fndings regarding ally underwent surgery (16 recovered before surgery could the correlation between the presence of macrophages in be performed). The other 142 patients were randomized to herniated disc material and clinical symptoms [8, 9]. As of prolonged conservative care, of which 55 patients under- today, it remains unknown what factors are of infuence on went surgery within 1 year, with a mean time to surgery of the type of infammation response that patients experience. 15 weeks after randomization. Thus, in the frst year after Nevertheless, the degree of infammation can be infuenced randomization, a total of 180 patients underwent surgery by specifc characteristics of the disc. For example, extruded for sciatica. Out of the 180 patients, 120 disc samples were discs, which are more exposed to the systemic circulation, available for analysis. Missing samples were due to multiple tend to have a higher degree of infammation as compared reasons: not collected during surgery, got lost after surgery, to bulging discs [4]. Therefore, the type of disc herniation not preserved properly, or got lost after preservation. All sur- should not be neglected when the characteristics of disc geries were performed between November 2002 and Febru- infammation are studied. ary 2005. The protocol, which included analysis of the disc Modic changes (MC), also known as vertebral endplate material, was approved by the medical ethics committees at signal changes (VESC) on MRI, are often seen in patients all participating hospitals. with lumbar disc herniation [10] and have been proposed to associate with slowing the recovery rate in patients that Histological analysis sufer from a herniated disc [11]. In addition, Dudli (2017) introduced the suggestion that MC represent the effect of crosstalk between bone marrow and the intervertebral Disc material of all operated patients was collected and fxed disc [12]. Hence, changes in the vertebral endplate, like in 4% formaldehyde solution after surgery and was subse- infammatory dysmyelopoiesis and upregulation in neuro- quently stored for future analysis. For the purpose of this trophic factors, may induce the presence of diferent types retrospective study, samples were embedded in blocks of of macrophages, which may interact with the infammation parafn and stained with CD68 to evaluate infammation response in the disc. By doing so, possibly, MC represent by macrophages. A detailed description of the protocol was a shift in the above-mentioned infammation reaction from published in our previous work [14].