Gaetano J. Scuderi

Retrograde ejaculation after anterior lumbar interbody fusion using rhBMP-2: a cohort controlled study

BACKGROUND CONTEXT The commercially available growth factor recombinant bone morphogenic protein-2 (rhBMP-2) used in spinal fusion has been associated with numerous adverse reactions, including inflammatory reactions in soft tissue, heterotopic bone formation, radiculitis, osteolysis, and cage or graft subsidence. The original Food and Drug Administration Summary of anterior lumbar interbody fusion (ALIF) reported 12 retrograde ejaculation (RE) events (8%) in the rhBMP-2 groups compared with (1.4%) in the control group. It had been debated whether this finding was related to rhBMP-2 use. PURPOSE To compare the incidence of RE after ALIF in patients with and without rhBMP-2 use. STUDY DESIGN Retrospective analysis of prospectively gathered outcomes data on consecutive subjects having ALIF with and without rhBMP-2 use. PATIENT SAMPLE Male patients with lumbar spondylosis or spondylolisthesis having ALIF of the lowest one or two lumbar levels with and without rhBMP-2. OUTCOME MEASURE Report of RE as a new finding after ALIF. METHODS From the comprehensive outcome database at a high-volume university practice, male subjects having ALIF for one- (L5/S1) or two-level (L4/L5, L5/S1) lumbar fusion were identified. Retrograde ejaculation events were recorded and comparative incidence compared. RESULTS The two groups were comparable for age and additional procedures performed. There were 69 L5/S1 ALIFs performed with rhBMP-2 and 174 ALIFs performed without rhBMP-2 during the study period. Of those, 24 and 64 were two-level ALIFs performed with and without rhBMP-2, respectively. There were five RE events (7.2%) reported in the rhBMP-2 group and 1 (0.6%) in the control group. Comparing single-level L5/S1 ALIF, there was a 6.7% and 0% rate of RE in the rhBMP-2 versus control groups, respectively. At 1 year after surgery, three of six affected subjects reported resolution of the RE. CONCLUSION This study confirms previous reports of a higher rate of RE in ALIF procedures using rhBMP-2. This may be an important consideration in subjects concerned with sterility after surgery.

Diagnostic Utility of Cytokine Biomarkers in the Evaluation of Acute Knee Pain

BACKGROUND The diagnosis of clinically important meniscal tears of the knee remains challenging, and it is unknown why only some injuries become painful. The role of inflammatory cytokines in generating pain following meniscal injury remains unclear. This study aimed to investigate the cytokine profile in patients with acute knee pain believed to be secondary to meniscal damage. METHODS This prospective cohort study included thirty-two patients without rheumatoid arthritis who had knee pain for less than six months, with either an acute or insidious onset, and elected to have arthroscopic treatment after nonoperative management had failed. Twenty-three of these patients elected to have the contralateral, nonoperatively treated knee lavaged at the time of arthroscopy. Fifteen asymptomatic control subjects also contributed samples of knee joint fluid, for a total of seventy samples from forty-seven subjects. Lavage of the operatively treated, contralateral, and control knees was performed with the patient under regional anesthesia prior to arthroscopy, if applicable, by the infusion of sterile saline solution into the knee followed by the immediate withdrawal into a syringe. The concentrations of seventeen inflammatory cytokines and chemokines were measured with use of a multiplexed immunoassay panel. Preoperative magnetic resonance imaging findings and cytokine assay results were compared with intraoperative findings. RESULTS Multivariate analysis of variance detected significantly greater concentrations of interferon gamma (IFN-gamma); interleukins 2, 4, 6, 10, and 13 (IL-2, IL-4, IL-6, IL-10, and IL-13); monocyte chemotactic protein-1 (MCP-1); and macrophage inflammatory protein-1 beta (MIP-1beta) in fluid samples from painful knees than in samples from nonpainful knees. Correlation analysis demonstrated a significant positive correlation between patient-reported pain scores and concentrations of IL-6 (Spearman rho = 0.7), MCP-1 (rho = 0.8), MIP-1beta (rho = 0.6), and IFN-gamma (rho = 0.6). These four cytokines also demonstrated a positive correlation with each other (rho = 0.5 to 0.7). The presence of IFN-gamma, IL-6, MCP-1, or MIP-1beta performed as well as magnetic resonance imaging in the prediction of intraoperative findings. CONCLUSIONS Intra-articular concentrations of four inflammatory cytokines IFN-gamma, IL-6, MCP-1, and MIP-1beta correlated to pain in patients with symptomatic meniscal tears in the knee but were markedly lower in asymptomatic normal knees and in asymptomatic knees with meniscal tears. These cytokines may be involved in the generation of pain following meniscal injury.

Predictors of outcome in patients with chronic back pain and low-grade spondylolisthesis

Study Design. Retrospective case series. Objectives. To determine the factors influencing symptom relief after uninstrumented posterolateral spinal fusion with or without decompression in adult patients with chronic back pain and previously asymptomatic low‐grade isthmic spondylolisthesis. Summary of Background Data. The role of previously asymptomatic low‐grade isthmic spondylolisthesis in chronic adult low back pain is unclear. Operative intervention in this setting is controversial. Methods. Twenty‐four consecutive adult patients with chronic low back pain and low‐grade isthmic spondylolisthesis first detected during routine work‐up of new onset low back pain underwent spinal fusion with or without decompression. The influence of active workers compensation or litigation claims, radicular pain, concomitant laminectomy, age, gender, fusion to L4, intervertebral disc bulge, and pseudarthrosis were investigated. Results. All 13 patients involved in workers compensation claims or pending litigation had fair or poor results. Nine of 11 patients without such issues had good or excellent results. Although the strong association of workers compensation with poor results made it difficult to assess the importance of other risk factors, the data suggest that good results may be more likely in patients with radiculopathy who undergo laminectomy. Conclusions. This investigation, although limited by a number of factors including small sample size and retrospective, unblinded review, suggests that active workers compensation and litigation issues are associated strongly with poor results of operative management for chronic low back pain in adult patients with low‐grade spondylolisthesis.

Platelet-rich plasma increases matrix metalloproteinases in cultures of human synovial fibroblasts.

BACKGROUND The effect of platelet-rich plasma on chondrocytes has been studied in cell and tissue culture. Less attention has been given to the effect of platelet-rich plasma on nonchondrocytic cell lineages within synovial joints, such as fibroblast-like synoviocytes, which produce cytokines and matrix metalloproteinases (MMPs) that mediate cartilage catabolism. The purpose of the present study was to determine the effect of platelet-rich plasma on cytokines and proteases produced by fibroblast-like synoviocytes. METHODS Platelet-rich plasma and platelet-poor plasma from harvested autologous blood were prepared with a commercially available system. Fibroblast-like synoviocytes were treated with platelet-rich plasma, platelet-poor plasma, recombinant PDGFββ (platelet-derived growth factor ββ), or phosphate-buffered saline solution and incubated at 37°C for forty-eight hours. The concentrations of IL-1β (interleukin-1β), IL-1RA (IL-1 receptor antagonist), IL-6, IFN-γ (interferon-γ), IP-10 (interferon gamma-induced protein 10), MCP-1 (monocyte chemotactic protein-1), MIP-1β (macrophage inflammatory protein-1β), PDGFββ, RANTES, TNF-α (tumor necrosis factor-α), VEGF (vascular endothelial growth factor), MMP-1, MMP-3, and MMP-9 in the culture medium were determined by multiplex immunoassay. RESULTS Platelet-rich plasma cultured in medium contained multiple catabolic mediators in substantial concentrations, including MMP-9 (15.8 ± 2.3 ng/mL) and MMP-1 (2.5 ± 0.8 ng/mL), as well as proinflammatory mediators IL-1β, IL-6, IFN-γ, IP-10, MCP-1, MIP-1β, RANTES, and TNF-α in concentrations between 20 pg/mL and 20 ng/mL. Platelet-poor plasma contained significantly lower concentrations of these compounds. Platelet-rich plasma was used to treat human fibroblast-like synoviocytes, and the resulting concentrations of mediators were corrected for the concentrations in the platelet-rich plasma alone. Compared with untreated fibroblast-like synoviocytes, synoviocytes treated with platelet-rich plasma exhibited significantly greater levels of MMP-1 (363 ± 94.0 ng/mL, p = 0.018) and MMP-3 (278 ± 90.0 ng/mL, p = 0.018). In contrast, platelet-poor plasma had little effect on mediators secreted by the synoviocytes. PDGFββ-treated fibroblast-like synoviocytes exhibited a broad proinflammatory cytokine response at four and forty-eight hours. CONCLUSIONS Platelet-rich plasma was shown to contain a mixture of anabolic and catabolic mediators. Synoviocytes treated with platelet-rich plasma responded with substantial MMP secretion, which may increase cartilage catabolism. Synoviocytes responded to PDGF with a substantial proinflammatory response.

Cytokine Profiling in Acute Anterior Cruciate Ligament Injury

PURPOSE To evaluate the presence and relative concentrations of cytokines, known to be involved in the inflammatory cascade, in acute anterior cruciate ligament (ACL) injury. METHODS We evaluated an extensive cytokine profile in synovial fluid from 12 patients with acute ACL injury undergoing arthroscopy compared with 15 control subjects using a BioPlex assay (Bio-Rad Laboratories, Hercules, CA) to measure the concentration of 17 inflammatory cytokines. RESULTS In patients with acute ACL injury compared with asymptomatic control subjects, the following cytokines were identified at significantly increased concentrations (P < .001, Mann-Whitney U test) compared with control samples: interleukin 6 (105 ± 72 v 0 ± 0 pg/ml), interferon γ (1,544 ± 608 v 9 ± 7.5 pg/ml), macrophage inflammatory protein 1β (16 ± 3.8 v 0.3 ± 0.2 pg/ml), and monocyte chemotactic protein 1 (35 ± 13 v 0.5 ± 0.4 pg/ml). There was no case of a cytokine exhibiting increased levels in asymptomatic compared with symptomatic knee samples. CONCLUSIONS This investigation identified 4 specific cytokines (interleukin 6, interferon γ, monocyte chemotactic protein 1, and macrophage inflammatory protein 1β) out of a panel of 17 inflammatory molecules for which the levels were consistently elevated in the context of ACL injury compared with non-painful, non-acutely injured knees in a volunteer population. LEVEL OF EVIDENCE Level IV, prognostic case series.

Long-term clinical manifestations of retained bullet fragments within the intervertebral disk space.

A retrospective review of 12 patients who were victims of penetrating trauma with a bullet or bullet fragments lodged within the intervertebral disk space was conducted. The objective of the review was to evaluate the potential systemic effects of lead resorption at long-term follow-up. Literature regarding the potential for lead toxicity due to retained bullet fragments within the intervertebral disk space is lacking. Between January 1969 and June 1993, a total of 238 patients with a gunshot wound to the spine were identified. Twelve of the 238 were found to have a bullet or bullet fragments within the intervertebral disk space. All patients were fully screened for evidence of plumbism. The average age at time of gunshot injury was 35.8 years; the average time for follow-up was 7.8 years. One of the 12 patients showed clinical evidence of plumbism. The patient subsequently underwent a partial laminectomy and diskectomy with excision of the bullet fragments. The patients complaints, specific for plumbism, resolved 2 months postoperatively. We conclude that patients with retained lead-based bullet fragments in the intervertebral disk should be educated about the rare potential for plumbism due to partial bullet fragment resorption and that long-term observation for this disorder is recommended.

Pseudarthrosis after postoperative wound infection in the lumbar spine.

This retrospective investigation attempts to define the incidence of fusion success after postoperative infection after a posterior lumbar fusion, as well as which risk factors may adversely affect arthrodesis after successful debridement. At an average follow-up of 37 months, 18 of 29 patients (62.1%) had a successful arthrodesis. Eighty-seven percent of patients whose fusion excluded the sacrum had a solid arthrodesis, compared with only 36% of those fusions including the sacrum. The fusion rate in female patients was 33.3%, compared with 82.4% in male patients. The rate of fusion with allograft bone was 17.2 versus 83.3% with autograft bone. Female sex, the use of allograft bone, and extension of the fusion mass to the sacrum significantly increase the incidence of nonunion after a postoperative deep spinal wound infection.

Cytokine assay of the epidural space lavage in patients with lumbar intervertebral disk herniation and radiculopathy.

Introduction Lumbar disk herniation may result in a radiculopathic pattern of symptoms. Consideration for a primary biochemical inducement of pain over a mechanical mechanism is a contemporary topic of spinal research. However, the exact pathomechanism by which a degenerative intervertebral disk leads to neural inflammation and pain has not been determined. Using modern techniques of chemical analysis, biochemical markers can be identified which participate in the degenerative cascade, and possibly with the onset of pain. The purpose of this research is to identify potential biochemical markers through a novel technique of epidural space lavage that may be helpful in understanding the pathogeneses of pain in the presence of intervertebral disk degeneration and herniation. Methods Fifty consecutive patients with acute radiculopathy secondary to a symptomatic herniated lumbar intervertebral disk or spinal stenosis, and who were indicated for epidural steroid injection were identified. Additionally, 3 volunteers with no history of back pain or radiculopathy volunteered to undergo epidural lavage. After needle insertion, a lavage followed by fluid aspiration of the epidural space at the level of the disc herniation, in the case of the symptomatic patients, was performed using normal saline, before the instillation of corticosteroids. The fluid samples were frozen at −20°C until analysis. A biochemical evaluation for a battery of cytokines was undertaken (IL-1β, IL-1ra, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p40, IL-13, IL-15, IL-17, TNF-α, IFN-α, IFN-γ, GM-CSF, MIP-1alpha, MIP-1β, IP-10, MIG, Eotaxin, RANTES, and MCP-1, and neuropeptides) using high-resolution multiplex bead immunoassays and enzyme-linked immunosorbent assay (ELISA). Additionally, polyacrylamide gel electrophoresis was carried out to verify the presence of serum proteins. Results Despite the presence of amino acids/serum proteins in the epidural lavage fluid, none of the aforementioned mediators were isolated in a quantifiable concentration using the ELISA techniques with >5 pg/mL resolution. Discussion The current proteomics array technology was not able to detect critical levels of biochemical markers present in the epidural space through the mentioned lavage technique. This lack of detection could be due to the absence of the factors in this environment or the inability of the technique to obtain or detect factors which may be present. Conclusion Although a novel approach, the current study was unable to identify the presence of a series of inflammatory peptides in the epidural lavage of patients with symptomatic radicular pain due to herniated disc disease. We recommend alternative experimental designs than the one we pursued for definitively identifying potential sources of pain generators.

Cytokine expression in the epidural space: a model of noncompressive disc herniation-induced inflammation.

Study Design. Animal study. Objective. Development of an animal model for the study of biochemical changes that occur in the epidural space after intervertebral disc herniation. Summary of Background Data. Although strong evidence for an inflammatory component exists, the biochemical processes underlying pain after disc herniation remain unknown. Methods. Epidural lavage was performed in 48 rats after L5 dorsal root ganglion exposure at baseline and 3, 6, or 24 hours after placement of autologous nucleus pulposus (NP) (N = 15), saline (N = 15), or NP + an interferon-&ggr; antibody (anti-IFN-&ggr;; N = 18) directly onto the dorsal root ganglion. Multiplex assays quantifying interleukin (IL)-1&agr;, IL-1&bgr;, IL-2, IL-4, IL-6, IL-10, tumor necrosis factor &agr; (TNF-&agr;), IFN-&ggr;, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were performed. NP (N = 7) was also analyzed for these cytokines by placing NP into saline and measuring the relative concentration. Results. Cytokines measured low at baseline (0–100 pg/mL) in all groups. Compared with saline, NP application caused IL-6 elevation, peaking at T = 3 hours, that was prevented by anti-IFN-&ggr;. NP induced elevation of TNF-&agr;, peaking at T = 24 hours and was prevented by anti-IFN-&ggr;. IFN-&ggr; was elevated after NP at T = 3 hours and T = 24 hours. IL-1&agr; was similar after saline versus NP. The concentrations of IL-1&bgr; and IL-10 were elevated at T = 3 hours, 6 hours, and 24 hours in all groups without between-groups difference. The level of IL-4 peaked at T = 3 hours in the NP group and was different than saline and NP + anti-IFN-&ggr; groups, but the time effect was insignificant. There was no change for GM-CSF. The concentration of cytokines measured in normal NP was less than 2 pg/mL for all cytokines except TNF-&agr;. Conclusion. In this model of acute noncompressive disc herniation, NP caused the elevation of epidural IL-6, TNF-&agr;, and IFN-&ggr;—all attenuated by IFN-&ggr; blockade. IL-1&bgr; and IL-10 were both significantly elevated by saline alone and their response was not prevented by IFN-&ggr; blockade. This model may prove useful for the study of the biochemical processes by which NP induces inflammation-induced nerve root irritation and radiculopathic pain.

Epidural Interferon Gamma-Immunoreactivity: A Biomarker for Lumbar Nerve Root Irritation

Study Design. Prospective observational cohort. Objective. Correlate epidural inflammatory cytokines with the clinical response to epidural steroid injection in patients with lumbar nerve root irritation. Summary of Background Data. Some back pain syndromes are thought to be associated with activation of inflammatory pathways and others may be associated with primary mechanical derangements. Human studies providing detailed evidence for the primary inflammatory causation, which may be best treated with anti-inflammatory strategies, are lacking. There are currently no accurate diagnostic tests to predict the response to epidural steroid injection or surgical intervention in back pain and sciatica syndromes. Methods. Forty-seven consecutive patients with lumbar degenerative changes and low back and/or leg pain were prospectively enrolled. An epidural lavage was performed, followed by injection of marcaine/depo-medrol. Subjects scored their pain before and 3 months after the procedure. The immunoreactivity of an array of cytokines was measured in lavage samples and compared with clinical response to the therapeutic injection. Ten subjects underwent repeat epidural lavage sampling 3 months after the steroid injection. Results. Interferon gamma (IFN&ggr;) was the most consistently detected cytokine. IFN&ggr;-immunoreactivity also highly correlated with reported reduction of pain 3-months after the epidural steroid injection. In subjects reporting significant pain relief (>50%) from the injection, mean [IFN&ggr;] was significantly greater compared with patients experiencing no significant relief. The IFN&ggr;-immunoreactivity in repeat lavage samples decreased to trace residual concentrations in patients who reported pain relief from the steroid injection. Conclusion. The presence of epidural IFN&ggr;-immunoreactivity corresponding to >10 pg/mL predicted significant pain relief after epidural steroid injection with >95% accuracy. These results suggest that IFN&ggr; may be part of a biochemical cascade triggering pain in sciatica; IFN&ggr;-immunoreactivity may aid as a biomarker for predicting the response to steroid therapy and/or surgical intervention, and may serve as a future therapeutic target.