S. P. F. Hughes

SENSORY AND SYMPATHETIC INNERVATION OF THE VERTEBRAL ENDPLATE IN PATIENTS WITH DEGENERATIVE DISC DISEASE

We obtained intervertebral discs with cartilage endplates and underlying cancellous bone at operation from patients with degenerative disc disease and then used immunohistochemical techniques to localise the nerves and nerve endings in the specimens. We used antibodies for the ubiquitous neuronal protein gene product 9.5 (PGP 9.5). Immunoreactivity to neuropeptide Y was used to identify autonomic nerves and calcitonin gene-related peptide (CGRP) and substance P to identify sensory nerves. Blood vessels were identified by immunoreactivity with platelet-endothelial cell-adhesion molecule (CD31; PECAM). In a control group with no known history of chronic back pain, nerve fibres immunoreactive to PGP 9.5 and neuropeptide Y were most closely related to blood vessels, with occasional substance P and CGRP immunoreactivity. In patients with severe back pain and markedly reduced disc height, proliferation of blood vessels and accompanying nerve fibres was observed in the endplate region and underlying vertebral bodies. Many of these nerves were immunoreactive to substance P or CGRP, and in addition, substance P- and CGRP-immunoreactive nociceptors were seen unrelated to blood vessels. Quantification by image analysis showed a marked increase in CGRP-containing sensory nerve fibres compared with normal control subjects. We speculate that a chemotactic response to products of disc breakdown is responsible for the proliferation of vascularity and CGRP-containing sensory nerves found in the endplate region and vertebral body adjacent to degenerate discs. The neuropeptides substance P and CGRP have potent vasodilatory as well as pain-transmitting effects. The increase in sensory nerve endings suggests increase in blood flow, perhaps as an attempt to augment the nutrition of the degenerate disc. The increase in the density of sensory nerves, and the presence of endplate cartilage defects, strongly suggest that the endplates and vertebral bodies are sources of pain; this may explain the severe pain on movement experienced by some patients with degenerative disc disease.

Geometrical dimensions of the lower lumbar vertebrae – analysis of data from digitised CT images

Abstract The precise dimensions of the lumbar vertebrae and discs are critical for the production of appropriate spinal implants. Unfortunately, existing databases of vertebral and intervertebral dimensions are limited either in accuracy, study population or parameters recorded. The objective of this study is to provide a large and accurate database of lumbar spinal characteristics from 126 digitised computed tomographic (CT) images, reviewed using the Picture Archiving Communication System (PACS) coupled with its internal measuring instrumentation. These CT images were obtained from patients with low back pain attending the spinal clinic at the Hammersmith Hospitals NHS Trust. Measurements of various aspects of vertebral dimensions and geometry were recorded, including vertebral and intervertebral disc height. The results from this study indicated that the depth and width of the vertebral endplate increased from the third to the fifth lumbar vertebra. Anterior vertebral height remained the same from the third to the fifth vertebra, but the posterior vertebral height decreased. Mean disc height in the lower lumbar segments was 11.6 ± 1.8 mm for the L3/4 disc, 11.3 ± 2.1 mm for the L4/5, and 10.7 ± 2.1 mm for the L5/S1 level. The average circumference of the lower endplate of the fourth lumbar vertebra was 141 mm and the average surface area was 1492 mm2. An increasing pedicle width from a mean of 9.6 ± 2.2 mm at L3 through to 16.2 ± 2.8 mm at L5 was noted. A comprehensive database of vertebral and intervertebral dimensions was generated from 378 lumbar vertebrae from 126 patients measured with a precise digital technique. These results are invaluable in establishing an anthropometric model of the human lumbar spine, and provide useful data for anatomical research. In addition this is important information for the scientific planning of spinal surgery and for the design of spinal implants.

Motion characteristics of the lumbar spine in the normal population.

Study Design The present study investigated the dynamic motion characteristics of the lumbar spine in the normal population using a potentiometric analysis system. Objectives To assess the ability of a triaxial potentiometric analysis system to measure dynamic motion in the lumbar spine, and to use this system to form a database of dynamic motion characteristics from which normal parameters of motion and the factors affecting this motion could be defined. Summary of Background Data Spinal motion has been studied using a variety of different methods, the majority of which have been limited either in terms of reliability, accuracy, or invasiveness and many have been only of a static nature. There has been no previous study into the normal dynamic motion characteristics of the lumbar spine. Methods The accuracy of the system was determined by a series of tests against a callbrated engineering mill, and the reliability of the system was assessed on 10 subjects with repeated measurements over a 3-day period. Values of range of motion and angular velocity were obtained from 203 normal subjects during flexion and extension, lateral flexion, and rotation. Results The results of the calibration testing revealed excellent accuracy, and it was shown that the system was repeatable. Initial analysis of the results indicated that sex differences did exist with men having 58.4° of flexion and women having 53.4°. Age appeared to have an influence on motion, and a gradual reduction was seen with each decade (P < 0.0001), with the 20–29-year age range having 59.5° mean flexion, the 30–39-year group having 58.1°, the 40–49-year group having 53.7°, the 50–60-year group having 57.5°, and the 60–70-year group having 45.9°. Multiple regression techniques revealed that only a few factors are important with respect to motion and that these varied according to the characteristic being defined. Conclusions Range of motion tended to be affected by age and sex, whereas velocity was only affected by distance moved, with occupation and body mass index having little or no influence on the motion. The factors identified could only account for a small proportion of the variation seen, suggesting that it is difficult to predict the motion characteristics with any degree of sensitivity.

The vascular response to fracture micromovement

Micromovement has been shown to promote the healing of experimental fractures, but its role in the clinical management of fractures with soft-tissue injury is less certain. In a 2-mm transverse osteotomy of the ovine tibia held in an instrumented external fixator, axial interfragmentary displacement was quantified in vivo for six weeks after osteotomy. Group I (n = 11) had an axial fixation stiffness of 460 N/mm and Group II (n = 12) had a stiffness of 238 N/mm. With a 25% difference in micromovement, a fourfold change in corticomedullary blood flow was observed at two weeks after osteotomy (p < 0.01). Although by six weeks mechanical properties in torsion were similar, there were marked differences in the periosteal cross-sectional perimeter, area, and intracortical porosity that complemented the hemodynamic changes. The early vascular response is very sensitive to the initial mechanical environment, and appears to precede and determine the organization of osteogenesis. Further understanding of this relationship may prove to be of direct clinical relevance in the augmentation of healing of devascularized diaphyseal fractures.

BACK PAIN AND DISABILITY AFTER LUMBAR LAMINECTOMY: IS THERE A RELATIONSHIP TO MUSCLE RETRACTION?

OBJECTIVE:Preliminary studies have suggested that prolonged retraction of the paraspinal muscle during spinal surgery may produce ischemic damage. We report the continuous measurement of intramuscular pressure (IMP) during decompressive lumbar laminectomy and its relationship to subsequent back pain and disability. METHODS:Twenty patients undergoing two-level decompressive lumbar laminectomy for lumbar canal stenosis were recruited. Back pain and disability were assessed by use of the Visual Analog Score (VAS), Oswestry Disability Index (ODI), and Short-Form 36 (SF-36) Health Survey. During surgery, IMP was recorded continuously from the multifidus muscle by use of a pressure transducer. The intramuscular perfusion pressure (IPP) was estimated as the difference between the patients mean arterial pressure and IMP. RESULTS:Two muscle retractors were used: the Norfolk and Norwich (n = 10) and the McCulloch (n = 10). The mean duration of deep muscle retraction was 62.7 ± 8 minutes (range, 19–133 min). On application of deep muscle retraction, there was a rapid and sustained increase in IMP (P < 0.001), and overall, the calculated mean IPP approached 0 mm Hg or less during this period (P < 0.001). On release of deep muscle retraction, there was a rapid decrease in IMP to preoperative levels. The IPP was greater with the Norfolk and Norwich than the McCulloch retractor (P < 0.001). Compared with preoperative values, there was a decrease in ODI (P < 0.001) and VAS for back pain (P < 0.001) at discharge and 4 to 6 weeks and 6 months after surgery. In addition, there was a decrease in SF-36 scores at 6 months compared with preoperative values (P < 0.001). Total duration of muscle retraction greater than 60 minutes was associated with worse VAS scores for back pain and ODI and SF-36 scores for disability at 6 months after surgery (P < 0.05). There was no relationship between the VAS, ODI, and SF-36 scores and other parameters measured, including the mean IPP, retractor type, operating surgeon, and wound length. CONCLUSION:The McCulloch retractor generates a higher IMP than the Norfolk and Norwich retractor. However, postoperative improvement in VAS, ODI, and SF-36 scores in these patients was associated with a shorter duration of muscle retraction and not the degree of IMP or IPP generated. In this respect, periodic relaxation of the paraspinal muscle retractors during surgery to allow muscle perfusion may help to reduce postoperative back pain and disability.

The pathogenesis of degeneration of the intervertebral disc and emerging therapies in the management of back pain

This article reviews the current knowledge of the intervertebral disc (IVD) and its association with low back pain (LBP). The normal IVD is a largely avascular and aneural structure with a high water content, its nutrients mainly diffusing through the end plates. IVD degeneration occurs when its cells die or become dysfunctional, notably in an acidic environment. In the process of degeneration, the IVD becomes dehydrated and vascularised, and there is an ingrowth of nerves. Although not universally the case, the altered physiology of the IVD is believed to precede or be associated with many clinical symptoms or conditions including low back and/or lower limb pain, paraesthesia, spinal stenosis and disc herniation. New treatment options have been developed in recent years. These include biological therapies and novel surgical techniques (such as total disc replacement), although many of these are still in their experimental phase. Central to developing further methods of treatment is the need for effective ways in which to assess patients and measure their outcomes. However, significant difficulties remain and it is therefore an appropriate time to be further investigating the scientific basis of and treatment of LBP.

The evaluation of the surgical management of nerve root compression in patients with low back pain: Part 1: the assessment of outcome.

Study Design. This was a prospective study investigating the outcome of decompression surgery using validated measures of outcome. Objectives. To investigate the outcome of lumbar decompressive surgery in the initial postoperative year period in terms of function, disability, general health, and psychological well-being. Summary of Background Data. The majority of studies investigating the outcome of lumbar decompression surgery have been retrospective and have not used validated measures of outcome. This limits their interpretation and usefulness. Methods. Eighty-four patients undergoing lumbar spinal stenosis surgery were recruited into this study. Patients were assessed by use of validated measures of outcome including the Oswestry Disability Index and the Short Form SF-36 General Health Questionnaire before surgery and 6 weeks, 6 months, and 1 year after surgery. Results. A significant reduction in pain (P < 0.001) was observed at the 6-week postoperative stage; this did not change at the subsequent assessment stages. Only some of the SF-36 categories were sensitive to change. The subcategories that were sensitive to change were physical function (P < 0.05), bodily pain (P < 0.001), and social function (P < 0.05). Improvements were observed in these categories at the 6-week and 6-month reviews. A gradual reduction in the Oswestry Disability Index was observed with time, with changes principally being observed between the 6-week and 6-month review and the 6-week and 1-year review stages (P < 0.05). Minimal changes were observed in the psychological assessments with time. The outcome of surgery could not be predicted reliably from psychological, functional, or pain measures. Conclusions. The visual analogue pain scales, the Oswestry Disability Index, and certain categories of the SF-36 Questionnaire, namely bodily pain and physical and social function, appeared to be the most sensitive outcome measures, with significant improvements occurring at the 6-week and 6-month reviews.

The use of interventional open MRI to assess the kinematics of the lumbar spine in patients with spondylolisthesis.

Study Design. Open interventional MRI techniques were used to investigate the intervertebral mobility of the lumbar spine in subjects with isthmic and degenerative spondylolisthesis. The findings were compared with those in a published database of subjects with no history of low back pain. Objective. To investigate patterns of intervertebral mobility in subjects with spondylolisthesis to determine the level of spinal instability in this population. Summary of Background Data. Subjects with spondylolisthesis have been considered to present with a special form of spinal instability. Consequently, this condition is frequently managed by spinal fusion. However, confusion exists regarding whether there is excessive motion at the level of the defect. Methods. For this study, 29 subjects presenting to spinal clinics with spondylolisthesis (15 isthmic and 14 degenerative) were recruited and compared with an existing database of control subjects. The motion characteristics of these subjects in flexed and extended positions were investigated using interventional open MRI of known precision. In all the subjects, the level of resting pain, the grade of slip, and the level of the defect were noted. Results. No mobility differences, in terms of both angular and translational motion, were found between the subjects with spondylolisthesis and those with no history of low back pain, suggesting that subjects with spondylolisthesis do not present with either instability or hypermobility. Conclusion. A spondylolytic defect does not lead to detectable instability or hypermobility in the lumbar spine.

Aseptic Loosening Of Total Hip Replacement: Macrophage Expression Of Inducible Nitric Oxide Synthase And Cyclo-oxygenase-2, Together With Peroxynitrite Formation, As A Possible Mechanism For Early Prosthesis Failure

Aseptic loosening is a major cause of failure of total hip arthroplasty. The adverse tissue response to prosthetic wear particles, with activation of cytokine and prostanoid production, contributes to bone loss around the implants. We have investigated the possibility that inducible nitric oxide synthase (iNOS) and cyclo-oxygenase-2 (COX-2) are expressed in macrophages in the pseudomembrane at the bone-implant interface, thereby contributing to the periprosthetic bone resorption. We also assessed whether peroxynitrite, a nitric oxide (NO)-derived oxidant associated with cellular injury, is generated in the membrane. Enzymatic activity of iNOS was measured using the arginine-citrulline assay technique and prostaglandin E2 (PGE2), as an indicator of COX-2 activity, was measured using an enzyme immunoassay. Cellular immunoreactivity for iNOS, nitrotyrosine (a marker of peroxynitrite-induced cellular injury) and COX-2 was assessed by quantitative peroxidase immunocytochemistry while immunofluorescence methods were used for subsequent co-localisation studies with CD68+ macrophages. The presence of calcium-independent iNOS activity and PGE2 production was confirmed in the homogenised interface membrane. Immunocytochemistry showed that periprosthetic CD68+ wear-debris-laden macrophages were the most prominent cell type immunoreactive for iNOS, nitrotyrosine and COX-2. Other periprosthetic inflammatory and resident cell types were also found to immunolocalise nitrotyrosine thereby suggesting peroxynitrite-induced protein nitrosylation and cellular damage not only in NO-producing CD68+ macrophages, but also in their neighbouring cells. These data indicate that both iNOS and COX-2 are expressed by CD68+ macrophages in the interface membrane and peroxynitrite-induced cellular damage is evident in such tissue. If high-output NO and peroxynitrite generation were to cause macrophage cell death, this would result in the release of phagocytosed wear debris into the extracellular matrix. A detrimental cycle of events would then be established with further phagocytosis by newly-recruited inflammatory cells and subsequent NO, peroxynitrite and prostanoid synthesis. Since both NO and PGE2 have been implicated in the induction and maintenance of chronic inflammation with resulting loss of bone, and peroxynitrite in the pathogenesis of disease states, they may be central to the pathogenesis of aseptic loosening.

Nitric oxide in fracture repair: DIFFERENTIAL LOCALISATION, EXPRESSION AND ACTIVITY OF NITRIC OXIDE SYNTHASES

Our aim was to investigate whether nitric oxide synthase (NOS) isoforms, responsible for the generation of NO, are expressed during the healing of fractures. To localise the sites of expression compared with those in normal bone we made standardised, stabilised, unilateral tibial fractures in male Wistar rats. Immunostaining was used to determine the precise tissue localisation of the different NOS isoforms. Western blotting was used to assess expression of NOS isoform protein and L-citrulline assays for studies on NOS activity. Control tissue was obtained from both the contralateral uninjured limb and limbs of normal rats. Immunohistochemistry showed increased expression of endothelial NOS (eNOS) to be strongest in the cortical blood vessels and in osteocytes in the early phase of fracture repair. Western blot and image analysis confirmed this initial increase. Significantly elevated calcium-dependent NOS activity was observed at day 1 after fracture. Inducible NOS (iNOS) was localised principally in endosteal osteoblasts and was also seen in chondroblasts especially in the second week of fracture healing. Western blotting showed a reduction in iNOS during the early healing period. Significantly reduced calcium-independent NOS activity was also seen. No neuronal NOS was seen in either fracture or normal tissue. Increased eNOS in bone blood vessels is likely to mediate the increased blood flow recognised during fracture healing. eNOS expression in osteocytes may occur in response to changes in either mechanical or local fluid shear stress. The finding that eNOS is increased and iNOS reduced in early healing of fractures may be important in their successful repair.