Dural Ossification in Ossification of
the Ligamentum Flavum

N. Muthakumar, M.Ch., Department of Neurosurgery,
Madurai Medical College, Madurai, India

The author set out to highlight one of the underrecognized and underreported aspects of ossification of the ligamentum flavum, primarily dural ossification, and to discuss the incidence, radiologic signs, causes, and surgical and prognostic implications of dural ossification. 

OLF is increasingly recognized as a cause of myelopathy and one of the surgical pitfalls in the management of this condition is ossification of the dura mater.  Preoperative identification of ossified dura mater would be helpful to the surgeon in order to properly plan the surgery and to appropriately counsel the patients regarding surgical risks. 

CT and MR  imaging were utilized to identify radiologic signs of dural ossification. 
The author notes that one of the important surgical pitfalls in the management of OLF is dural involvement by the ossified yellow ligament.  The author notes that radiologic signs of dural ossification have not been described. Dural ossification when occurring in association with OLF has not been described. When dural ossification can be anticipated by preoperative radiologic signs, the surgeon can be prepared to deal with dural laceration during surgery and if necessary modify the surgical techniques accordingly. 

The author reports a series of 20 patients with OLF, 8 of whom had intraoperative evidence of dural ossification as well, and who also had sustained dural laceration during surgery.  Among these 8 patients, 7 were found to have had radiologic evidence of dural involvement.  The author notes that MR  images of these patients demonstrated features suggestive of dural involvement in axial images of the involved levels.  These images consisted of an isodense to slightly hyperdense center sandwiched between hypodensities produced by the ossification.  In the remaining 3 patients with CT evidence of dural ossification, there were no signs on the MRI suggestive of dural ossification. All patients who had dural lacerations during surgery underwent either primary suturing of the dural laceration when possible or duroplasty with autologous fascia.  A CSF was encountered in 4 of these 7 patients.  If a water-type repair cannot be made, then a fascial patch  is sutured to the dura on one side, and on the other side where the dural margin could not be made out, the fascia was tucked in and tissue glue was applied.   One patient  developed a profuse CSF leak in the postoperative period and resulted in fulminant meningitis, which was controlled with difficulty.

The author notes that ossification of the yellow ligament is a slowly progressing condition  causing myelopathy.  It commonly affects the lower thoracic spine, especially T9 to T12. The prevalence of this disease is high among Japanese.  Asymptomatic OLF is common in Japan with incidence of this radiographic finding being as high as 6.2% in males and 4.8% in females patients. 

A study from Japan noted that individuals with incidentally discovered OLF on lateral radiographs were asymptomatic and did not have evidence of ossification of the posterior longitudinal ligaments, diffuse idiopathic skeletal hyperostosis, and degenerative osteoarthritis.  They note that OLF is being increasingly reported around the world.  They state that the cause of OLF itself remains unknown.  It is believed that ossification of spinal ligaments is due to both intrinsic and extrinsic factors.  With abnormal metabolism of growth hormone, calcitonin, and glucose, obesity and specific genetic backgrounds have been proposed intrinsic factors.  Mechanical stress to the spinal ligaments has been considered one of the important extrinsic factors.  In pretensile strength, the thoracic ligamentum flavum predisposes it to ossifications. 

The author cited an additional study from Japan noting dural adhesions in 62% of their patients with OLF. In their series, dural adhesions represented deleterious factors for preoperative and short-term postoperative neurologic status but not for long-term neurologic outcome. 

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Neck Muscle Load Distribution in Lateral, Frontal & Rear-End Impacts: A 3-Dimensional Finite Element Analysis

S. Hedenstierna, Ph.D., et. al, Division of Neuronic Engineering,
School of Technology & Health, Royal Institute of Technology, Stockholm, Sweden, and MEA Forensic Engineers and Scientists, Ltd., Richmond, VC, Canada. 
Spine, vol. 34, no. 24, pp. 2626-2633

A finite element model with solid element musculature was used to simulate frontal, lateral, and rear-end vehicle impacts at 4 peak accelerations.  The peak cross-sectional forces, internal energies, and effective strains were calculated for each muscle and impact configuration. The computer load distribution was compared with experimental EMG data. 
The objective for this study was to quantify passive muscle loads in non-active cervical muscles during impacts of various directional energy. 

The authors reported that load distribution in the cervical muscles varied with load directions.  Peak sectional forces, internal energies, and strains increased in most muscles with increasing impact acceleration.  The dominant muscles identified by the model for each direction for splenius capitis, levator scapulae, and sternocleidomastoid in lateral impacts; splenius capitis and trapezoid in frontal impacts; and SCM, rectus capitis posterior minor, and hyoids in rear-end impacts.  This corresponded with the most active muscles identified by EMG reportings, although within these muscles the distribution of forces and EMG levels were not the same. 

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“Ultra-Structural Analysis on Lumbar Disc Herniation Using Surgical Specimens:
Role of Neovascularization of Macrophages in Herniated Discs”

Shigeru Kobayashi, et. al
Spine, 2009; 34: 655-662

The authors point out that much remains unclear about the indication for surgery in lumbar disc herniation, primarily because of our inadequate understanding of the mechanisms responsible for the improvement or disappearance of symptoms with conservative therapy.  They further point out, however, that with the development of diagnostic imaging techniques, such as CT and MRI, these technologies provide a non-invasive means of observing changes in the hernia mass over time. 

They quote a 10-year follow-up study in which lumbar disc herniation in patients who either underwent surgery or received conservative treatment that surgery produced a better outcome after 1 and 3 years but there was no significant difference between these groups after 6 to 10 years.  They reviewed different studies, noting that regression was observed in a substantial percentage of patients with time and conservative care and they also found that these studies revealed that many patients with disc herniation do not require surgery but instead can improve with conservative therapy alone. 

They studied the mechanisms  responsible for the spontaneous regression of lumbar disc herniation by examining the herniated tissue collected at operation from patients with lumbar disc herniation. 

They observed that capillaries that invade the hernia and macrophages derived from monocytes migrating out of these capillaries are important factors in the regression of the herniated disc. Macrophages contain lysosomes filled with collagen-degrading enzymes that break down substances after phagocytosis, whereas primarily lysosymes are secreted by these cells and break down intracellular substances, such as collagen.  Both of these mechanisms are closely involved in the regression of herniation. 

They further observed that the inflammatory response that occurs around hernia tissue in the epidural space is believed to play an important role in herniated disc resorption.  They also observed that this inflammatory response may have a harmful effect on the adjacent nerve root. They therefore recommend that control of the inflammatory reaction is an important challenge when treating patients with disc herniations.  They report that this inflammatory reaction may cause adhesions between the lesion and the nerve root, which may then produce the mobility of the nerve root during movement of the legs. This can lead to severe tension or compression on the nerve root and can cause disturbance of infra-radicular blood flow and breakdown of the blood-nerve barrier resulting in infra-radicular inflammatory changes such as edema and demyelination.  They also note, however, that the inflammatory response that occurs around hernia tissue in the epidural space is believed to play an important role in herniated disc resorption, although it may also produce adhesions between the hernia mass and the nerve root. Therefore, they find that the challenge at this point is to control the inflammatory reaction when treating patients with disc herniation. 

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“Embryonic Stem Cells Used for Disc Regeneration
in an In Vivo Model of Disc Degeneration”

Ramiro Perez de la Torre, M.D., et. al
Spine Journal 8 (2008, 1S-191S)

Proceedings of the 23rd Annual Meeting of
the North American Spine Society,
October 15-18, 2008.

The authors began this study with the understanding that there is currently no therapy available to repair or restore degenerated intervertebral discs.  They do note that embryonic stem cells can potentially grow indefinitely in vitro and differentiate into a variety of cell types.  They found that the use of embryonic stem cells would be an appropriate alternative to commonly used sources for deriving cells of various lineage for therapeutic purposes.  They stated that the origin of the intervertebral disc was the notochordal cell.  They also reported that terminally differentiated chondrocytes displace this cell and as a result of reduced proteoglycan production and as water loss occurs from the disc, this causes degeneration of the disc.  Their goal with this study was to learn more about the potential of murine embryonic stem cells and their capacity to differentiate into notochordal cells in an in vivo rabbit model in which there is disc degeneration.  They observed viable new cartilage forming as well as notochordal cell growth, and utilizing fluorescent analysis, this revealed viable chondrocytes with experimental discs implanted in embryonic stem cells.  They also reported that there was no inflammatory response as evidence of cell mediated immune response. 

They concluded that the use of embryonic stem cells injected into degenerative discs can develop a new notochordal cell population and that by the use of xenograft implanted mouse cells in an immune competent rabbit, this can result in a lack of immune response and result in an immunologic sanctuary within the intervertebral disc. 

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Adeno-Associated Gene Transfer to the Rabbit Intervertebral Disc: In Vivo Evaluation of a Novel Gene Regulation System
E. Westrick, C. Pacek, L. Taylor, G. Sowa et al
UPMC selected articles 2008, (21-23)

The research team created this study to evaluate a novel gene regulation system in vivo, and hypothesized that transgene expression would not occur in the absence of the activator ligand. 

They note that the promise of gene therapy for intervertebral disc degeneration has been strengthened to recent success utilizing growth factors TGF-B, BMP-2, and that patient safety was of paramount importance as misdirected injections have potentially toxic implications. 

They therefore stated that the evaluation of controlled systems for regulation of gene expression is necessary.  They introduced the Rheo Switch system, which utilizes an inducible promoter that only allows transgene transcription in the presence of an activator ligand.  They stated that previous in vitro studies demonstrated efficient transfection and strict dose dependent control on adeno-associated viral vector containing this novel control system and a marker gene green fluorescent protein.  

They performed this study on white rabbits and they injected both non-degenerated at L2-3 and L3-4 and degenerated L4-5 discs with a precision threader plunger syringe utilizing a 30-gauge needle.  Each rabbit received either 1.5 x 10”, P/15 ml per disc or 108, T/15 ml per disc of AAV Rheo Switch-GFP.  One group of rabbits received the injection without an activator drug and the second group of rabbits did not receive intradiscal viral injections but treated for five days with subcutaneous injections of activator ligand.  The injected discs, adjacent discs L1-2 and L5-6 dura, spinal cord, liver, brain, and a vertebral body sample were harvested.  Frozen tissues were analyzed for the presence of GFP (which was the activator ligand).  They utilized fluorescent microscopy and immunohistochemical staining. 

No activator ligand was evident in discs from rabbits that received only virus or only activator ligand.  Increasing activator ligand (GFP) expression was seen with higher viral concentrations. They found no GFP expression evident in the adjacent discs, spinal cord, dura, bone, liver or brain samples. 

The authors found that this study demonstrated efficient viral transfection and dose dependant control of a novel gene regulation system in vivo.  No transgene expression was evident in the absence of an activator ligand.  Thus, this technology has great potential to improve the safety of gene therapy for intervertebral disc degeneration.  They found that further studies were necessary, however, to determine the duration of gene expression after activator ligand cessation and also to determine efficacy in degenerated discs.

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The Twin Spine Study: Contributions to a Changing View of Disc Degeneration

Disc degeneration has been commonly viewed over much of the last century as a result of aging wear and tear from mechanical insults and injuries.  Thus, prevention strategies in research in lumbar degenerative changes and associated clinical conditions focused largely on mechanical factors as primary causes using an injury model.  The Twin Spine Study, a research program on the etiology and pathogenesis of disc degeneration has contributed to a substantial revision of this view of determinants of lumbar disc degeneration.  The authors stated that among the most significant findings regarding this study were a substantial influence of heredity on lumbar disc degeneration and the identification of the first gene forms associated with disc degeneration.  Conversely, despite extraordinary discordance between twin siblings and occupational and leisure time physical loading conditions throughout adulthood, surprisingly little effect on disc degeneration was observed.  Studies on the effects of smoking on twins with large discordance in smoking exposure demonstrated an increase in disc degeneration associated with smoking, but this was small.  No evidence was found to suggest that exposure to whole-body vibration through motorized vehicles leads to accelerate a disc degeneration in these well-controlled studies.  More recent results indicate that the effect of anthropometric factors, such as body weight, and muscle strength on disc degeneration, although modest, appear in this work to be greater than those of occupational physical demands.  In fact, some indications are found that routine loading may actually have some benefits to the disc. 

The authors note that there have been more than 30 studies of genes associated with disc degeneration and related pathology.  They found that among 23 studied genes, including aggrecan (AGC), collagen (COL), vitamin D receptor (VDR), inflammatory (IL), degradative (MMB), and some other genes, 17 have been associated with disc degeneration or related pathology in at least one study.  They stated that there is reasonable evidence suggesting association of disc degeneration with the VDR gene, and the COL9A2, and with the COL9A3 gene.  They stated that at this point, however, the findings indicate that each gene has only modest affects. 

They stated that the main phenotype was quantitative CSF-adjusted disc signal, in addition to the typical qualitative ordinal scores of disc height narrowing and bulging in 579 MZ and DZ twin subjects.  Analyses yielding associations of lumbar disc signal bulging and disc height narrowing with the AGC1 gene.  Disc signal was also associated with COL9A1 and COL1A1 genes, and interleukin genes, IL1RL2 and IL18R1.  Some of these findings support those of earlier analyses whereas others await replication. 

The authors noted further that disc degeneration and back pain are clearly not synonymous and the association between the two is routinely debated.  They stated if disc degeneration does influence back pain problems and both have a substantial genetic component, disc degeneration may be one pathway to which the genes influence back pain. 

The authors further note that in contrast, less than 5% of the variants in back pain outcomes explained by environmental factors was due to the same environmental factors influencing disc height narrowing.  They stated that a question would arise if some of the particular environmental physical loading exposure served primarily to exacerbate symptoms rather than cause the underlying pathology.  They also stated that it was important to note that a little overlap was found between environmental factors influencing pain reporting and disc narrowing, environmental factors do appear to have a substantial role in disc height narrowing as do genes.

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