Ossification of the Posterior Longitudinal Ligament and Other Enthesopathies

Published on 26/03/2015 by admin

Filed under Neurosurgery

Last modified 26/03/2015

Print this page

rate 1 star rate 2 star rate 3 star rate 4 star rate 5 star
Your rating: none, Average: 0 (0 votes)

This article have been viewed 2582 times

CHAPTER 282 Ossification of the Posterior Longitudinal Ligament and Other Enthesopathies

Background and Epidemiology

The enthesopathies are conditions that result in progressive inflammation of the tendons and ligaments of the axial or appendicular skeleton (or both) and subsequent degeneration and calcification. Major disorders included among the enthesopathies are ossification of the posterior longitudinal ligament (OPLL), ossification of the anterior longitudinal ligament (OALL), ossification of the ligamentum flavum (OLF), and diffuse idiopathic skeletal hypertrophy (DISH). Ankylosing spondylitis (AS) is an enthesopathy that is marked by inflammatory erosion of the joints of the spine (facets, intervertebral disks) with ensuing ossification and autofusion. Among the enthesopathies, OPLL is of particular concern to neurosurgeons and orthopedic spine surgeons because the progressive hypertrophy and subsequent calcification of the posterior longitudinal ligament within the spinal canal confer a risk for spinal cord compression and neurological compromise.

OPLL is characterized by growth of the posterior longitudinal ligament with the development of ossification centers and eventual calcification and mature ectopic bone formation. OPLL was first reported in 1838; however, the disorder gained recognition in the 1960s when brought to attention by the Japanese spine surgery community. OPLL is a relatively common cause of cervical myelopathy in middle-aged and elderly Japanese and is therefore believed to occur with higher frequency in the Asian population. Epidemiologic studies have revealed the prevalence of OPLL in asymptomatic Japanese adults to be 2.0% as opposed to 0.95% in Koreans and 0.17% to 0.20% in white individuals.1 OPLL thus represents a major public health problem in East Asia.

Recently, better understanding of OPLL with improved radiographic imaging suggests that it may be more prevalent in even the non-Japanese population. A computed tomography (CT) and magnetic resonance imaging (MRI) study revealed that in symptomatic patients with myelopathy or radiculopathy, OPLL or some variant may be identified in as many as 25% of U.S. patients as compared with 27% of Japanese patients.2 However, this study probably reflected a bias, with the higher proportion of OPLL patients being due to referral patterns.

Because it is believed that North American Indians are originally descended from humans who migrated across the Bering Strait, North American Hispanics may have a higher prevalence of OPLL than the general North American population, in whom cervical spondylotic myelopathy is frequently encountered. Recent study of OPLL variants found the distribution of compressive morphologies to be similar to that reported in East Asians.3

Pathophysiology

The posterior longitudinal ligament is normally 1 or 2 mm thick and courses along the dorsal aspect of the vertebral bodies from the axis, where it is continuous with the tectorial membrane, to the sacrum. The ligament is broader at the intervertebral disk spaces, where it adheres to the anulus fibrosus, than along the vertebral bodies. The ligament consists of a superficial layer that spans several levels and a deeper layer that connects adjacent bodies.

The underlying cause of OPLL is still unclear but is believed to be influenced by several genetic and environmental factors. Pathophysiologically, OPLL follows a progressive evolutionary process. Initially, the posterior longitudinal ligament undergoes degenerative changes with subsequent tissue hyperplasia, fibrocartilaginous cell proliferation, and subsequent ligamentous hypertrophy. Endochondral bone growth leads to collagen deposition and mineralization and the formation of punctate ossification centers. As the ossification centers coalesce, mature lamellar bone with haversian canals results and leads to active bone marrow production and frank ossification. With severe OPLL, the dura may become incorporated in the ossification process.

Genetic Factors

Familial surveys and genetic studies reveal that OPLL has a strong hereditary component with an autosomal dominant pattern of inheritance. OPLL occurs in 26% of parents and 29% of siblings of patients in whom OPLL is diagnosed.4 Genetic linkage analysis reveals an association between the HLA haplotype and OPLL. Patients with two concurrent HLA strands have a 53% rate of expression of OPLL as opposed to a 24% rate in those with only one concurrent strand.5

Further genetic analysis of 91 sibling pairs of patients with OPLL suggests that the genetic locus for OPLL may be situated close to the HLA region on chromosome 6p.6,7 Patients with DISH, who commonly have OPLL, also test positive for the same HLA antigen. The COL11A2 gene, which is located within the class II major histocompatibility complex region of chromosome 6, is believed to be the gene responsible for OPLL. Patients with OPLL have a significantly higher incidence of genetic abnormalities in the COL11A2 region.8 COL11A2 encodes the α2 chain of type XI collagen, which is a minor collagen in the cartilage matrix and may be involved in controlling the growth of type II collagen. Overproduction of type XI collagen has been seen in histologic studies of some surgical specimens of OPLL.9

Other genetic loci associated with OPLL include the collagen 6A1 gene (COLA1). COLA1 is located on chromosome 21q, and genome-wide linkage and linkage disequilibrium analysis of 142 affected sibling pairs has identified this gene locus as the candidate gene for the pathogenesis of OPLL.10 COLA1 encodes the α1 chain of type VI collagen.11 Overproduction of type VI collagen may serve as a scaffold for chondrocyte infiltration and endochondral bone growth.

The animal model of OPLL, the tiptoe walking (ttw) mouse, demonstrates progressive calcification of spinal ligaments. A single-base mutation in the nucleotide pyrophosphate gene (NPPS) is thought to be responsible for the development of ligament ossification in this model. NPPS encodes for a protein that inhibits the mineralization and calcification of cartilaginous tissue. Loss of the NPPS protein may cause unregulated ossification of the spinal ligaments. In humans, NPPS has three isoforms, with NPP1 being located on chromosome 6. A single-base polymorphism in NPP1 is more common in patients with cervicothoracic OPLL than in those with only cervical OPLL, perhaps indicative of more severe and progressive disease.12

Growth Factors

The posterior longitudinal ligament in patients with OPLL demonstrates an enhanced potential for osteogenesis, thus suggesting that intrinsic growth factors may be integral in the pathogenesis of OPLL. Bone morphogenetic proteins (BMPs) are a class of growth factors involved in the induction of new bone formation. The nonossified ligaments of OPLL patients and their relatives are found to have elevated concentrations of BMP.13 Histologic evaluation of OPLL surgical specimens demonstrates the presence of BMP-2 in the ossified matrix, chondrocytes, and fibroblasts in cartilaginous areas adjacent to the OPLL.14,15 Furthermore, BMP-2 mRNA was isolated from the spinal ligaments of patients with OPLL and not from control subjects.15 Zinc finger protein 145, a regulator of BMP expression and an early initiator of osteoblastic differentiation, is also upregulated in OPLL patients. Comparatively, the MSX2 gene, which expresses a protein that inhibits osteoblastic differentiation and mineralization of fibroblasts, is downregulated in OPLL patients.

Other growth factors associated with OPLL include transforming growth factor-β, which is present in the ossified matrix and chondrocytes in cartilaginous tissue adjacent to OPLL. Osteocalcin synthesis, which reflects the osteoblastic phenotype of cells, is observed in the supernatant of the posterior longitudinal ligament of patients with OPLL and not from patients with non-OPLL cervical spondylosis.16 Insulin-like growth factor, connective tissue growth factor, parathyroid hormone, platelet-derived growth factor, retinoid, estrogens, and interleukin-1 are also associated with the pathogenesis of OPLL.

Metabolic Factors

OPLL is associated with a high incidence of adult-onset obesity and impaired glucose tolerance.17,18 Among 535 patients with OPLL, 28% were diabetic and 18% qualified as borderline diabetic.19 In patients with known OPLL, the extent of ossification is significantly correlated with the fasting serum insulin level.17 In a study from the Japan Collaborative Epidemiological Study Group for Evaluation of Ossification of the Posterior Longitudinal Ligament of the Spine Risk,20 adult-onset obesity and non–insulin-dependent diabetes were identified as independent risk factors for OPLL. When 69 eligible patients with OPLL were compared with control patients without spinal disorders matched for age and gender, the OPLL group had a significantly higher proportion of patients with diabetes and a higher body mass index.

From the same study, additional dietary habits associated with increased risk for the development of OPLL included frequent consumption of pickled foods. Alternatively, diets rich in chicken and soy products were correlated with a decreased risk for OPLL. No association between cigarette or alcohol consumption and OPLL was observed. Other reports have suggested that hypoparathyroidism and hypophosphatemic rickets are related to a higher incidence of OPLL.19

Other Enthesopathies

The enthesopathies are characterized by progressive inflammation of tendons and ligaments and their association with bone. OPLL is of primary concern to neurosurgeons and orthopedic spine surgeons because of the location of the posterior longitudinal ligament within the spinal canal and the risk for cord compression with hypertrophy and calcification. Other major spinal enthesopathies include DISH, OALL, and OLF. DISH is an ossifying condition that affects the axial and appendicular skeleton and is commonly also known as ankylosing hyperostosis. With spinal involvement, the anterolateral vertebral column is primarily affected. DISH most commonly occurs in adults, and it affects 3% of those older than 40 years and 15% of those older than 65 years.21,22 Because ossification occurs outside the spinal canal, patients are generally asymptomatic; however, an extensive calcified cervical mass may cause dysphagia or thoracic outlet syndrome and require surgical resection.23 DISH and OPLL may be genetically linked, with the same HLA antigen that tests positive in patients with OPLL occurring in those with DISH as well. Fifty percent of patients with DISH concurrently have OPLL, whereas 24% of those with OPLL also demonstrate DISH.19

AS is an immune-mediated inflammatory condition that results in progressive erosion of the intervertebral disks and apophyseal joints. Joint destruction is eventually replaced by ankylosis and subsequent autofusion of the spine. Patients with AS also suffer from diffuse osteoporosis, which leads to an increased susceptibility to fractures after minor trauma and a high risk for spinal deformity. AS is genetically linked to the HLA-B27 antigen. OPLL reportedly occurs in 3.5% to 29% of patients with AS.24,25 AS, an important entity for those concerned with spinal disease, is discussed separately in Chapter 284.

Clinical Findings

OPLL most commonly occurs in the cervical spine of middle-aged or elderly adults and is uncommon in children and adolescents. The frequency of OPLL begins to increase after the age of 40, and most patients are initially seen in the sixth decade. It predominantly affects the cervical spine, with 70% of cases occurring in this region, and generally affects two to four levels. The remaining 30% of cases are generally divided between the upper thoracic and upper lumbar regions. Cervical OPLL occurs in twice as many males as females; however, thoracic OPLL is more frequent in women.

Clinically, OPLL may be asymptomatic, but when symptoms do develop, patients have signs and complaints consistent with myelopathy or radiculopathy. Patients may have neck pain, paresthesias, radicular pain, motor weakness, and hand dyscoordination. With severe disease, long-tract signs such as spasticity, gait disturbance, and bowel and bladder dysfunction arise. Neurological deficits occur secondary to direct mechanical compression of the spinal cord as a result of the OPLL lesion occupying space within the spinal canal. Compression also causes perturbed vascular flow with subsequent spinal cord ischemia. Ventral stenosis may lead to greater loss in the corticospinal tracts with progressive motor dysfunction. Chronic injury may result in gliosis and myelomalacia of the spinal cord. Generally, symptoms follow a slow, insidious course; however, in the setting of even minor trauma with hyperextension of the neck, patients may have acute spinal cord injury.

The cervical myelopathy attributable to OPLL is classified according to either the Nurick grade or the Japanese Orthopedic Association (JOA) score. The Nurick classification is composed of six grades (0 to 5) based on the severity of radiculopathy and myelopathy. A patient who is neurologically intact or has only mild radiculopathy is grade 0; grade 6 correlates with severe myelopathy or quadriplegia. The JOA classification is a 17-point composite score in which points are assigned based on hand and leg motor function, upper and lower extremity sensory function, trunk sensory function, and bladder continence.26 A modification of the JOA score incorporates a manual muscle test of shoulder and elbow strength, and a western modification has also been developed because the scoring of upper extremity function is based in part on the ability to use chopsticks.

Diagnosis

OPLL is diagnosed by the presence of an ossified ligament on radiographic imaging. It is often identified on lateral plain radiographs as a longitudinal hyperdense area of calcification along the dorsal margin of the vertebral body. Based on lateral radiographs, OPLL is classified into one of four subtypes (Fig. 282-1A to D). The continuous type is characterized by a single contiguous ossified ligament that spans two or more adjacent vertebrae. The segmental type is the most common form and has fragmented lesions located behind the vertebral bodies that do not cross the disk space. The mixed type is a combination of both continuous and segmental lesions. Rarely, OPLL is a localized variant that is confined to only the area posterior to the disk space.

Lateral plain films are used to determine the occupying ratio and the space available for the spinal cord (SAC). The occupying ratio is the maximum anteroposterior thickness of the ossified ligament divided by the diameter of the spinal canal at the corresponding level. An occupying ratio of greater than 40% is associated with a high risk for myelopathy. In a clinical series of patients with OPLL, Matsunaga and colleagues found that all patients with greater than 60% stenosis suffered myelopathy.27 Alternatively, in patients with less than 60% stenosis, there was no correlation between the occupying ratio and Nurick grade. The SAC is determined by measuring the anteroposterior distance between the dorsal aspect of the ossified lesion and the posterior margin of the lamina at a constant tube-to-film distance of 150 cm. In one clinical series, all patients with a SAC of less than 6 mm had myelopathy, whereas no patients with a SAC of 14 mm or greater demonstrated myelopathy.28 For patients with a SAC of between 6 and 14 mm, there was no correlation between SAC and the degree of neurological compromise.

Additional imaging modalities such as CT and MRI may facilitate the diagnosis and management of OPLL. CT is particularly helpful for better characterizing the morphology of the ossified lesion in cross section, identifying potential dural involvement, and improving visualization of the cervicothoracic junction. CT axial and reconstructed images and CT myelography may facilitate the detection of thoracic OPLL or OLF. MRI is useful for imaging the spinal cord and nerve roots; however, differentiation of OPLL from conventional cervical spondylosis may not be possible. Although early OPLL with bone marrow and fat within the ligament may appear as hyperintense foci, mature OPLL lesions generally appear hypointense on MRI. MRI, however, may demonstrate evidence of changes in spinal cord signal indicative of edema, gliosis, or myelomalacia. The presence of these imaging findings serves as an indirect measure of neurological status and may facilitate treatment planning and assessment of patient prognosis.

Natural History

The natural history of OPLL is characterized by slowly progressive and variable growth of the ossified lesion. In a 2-year radiographic follow-up study of 13 patients with OPLL managed conservatively, the growth rate of the ossified lesion varied highly from patient to patient; however, mean growth was 4.07 mm longitudinally and 0.67 mm in thickness per year.29 The natural history clinically appears to be dependent on the initial neurological status at diagnosis. Matsunaga and coworkers studied 167 patients in whom OPLL was diagnosed and treated conservatively for an average of 11 years.28 Of the 140 patients who were initially asymptomatic, in only 18% did myelopathy subsequently develop during the study period. Alternatively, of the 27 patients who were initially myelopathic and refused to undergo surgery, 44% experienced worsening of their neurological status during the study period. Of all 167 patients managed conservatively, myelopathy either developed or worsened in only 22% despite the fact that 42% demonstrated radiographic growth of their ossified lesion during the study period.

In a subsequent study with a minimum of 10 years’ follow-up, Matsunaga and associates evaluated 304 patients with OPLL who were managed conservatively for 10 to 30 years.27 Of the patients who were initially asymptomatic, only 17% became myelopathic during the study period. The Kaplan-Meier estimate of the myelopathy-free rate in patients without myelopathy at initial evaluation was 71% at 30 years. Of patients who were myelopathic initially, however, 64% deteriorated neurologically during the follow-up period. Radiographic evaluation revealed that patients with minimal stenosis on initial assessment rarely progressed to greater than 60% stenosis during follow-up examination. The results of these studies suggest that in only a small percentage of patients in whom OPLL is diagnosed and is initially asymptomatic will myelopathy eventually develop during their lifetime.

Management

Conservative management of patients with OPLL is reserved for those who are asymptomatic and who radiographically demonstrate a small degree of stenosis. Additionally, nonoperative management may be appropriate for patients with advanced age or significant medical comorbidities, those who are poor surgical candidates, or those who have severe chronic neurological deficits that are presumably irreversible. MRI evidence of spinal cord myelomalacia may facilitate assessment of the prognosis for neurological recovery with surgical intervention. Conservative treatment consists of oral nonsteroidal agents, epidural steroid injections, and potentially a cervical orthosis for patients with neck pain.

Surgical decompression is indicated for patients with myelopathic or radicular findings such as paresthesias, radicular pain, motor weakness, hand dyscoordination, gait disturbance, spasticity, and bowel or bladder dysfunction. Early treatment of mild to moderate myelopathy, especially in younger patients, may prevent the development of severe irreversible neurological deficits. Patients with mild symptoms but who have a SAC of less than 6 mm, an occupying ratio of greater than 40%, or MRI evidence of changes in spinal cord signal may also be considered candidates for surgical decompression.

Severely compromised patients, however, may not benefit from surgical treatment. In a study of patients with a minimum of 10 years’ follow-up, surgery was no more effective than conservative measures in patients with a poor Nurick grade 5 (wheelchair bound or bedridden).27 Surgical decompression proved better than conservative management only in patients with a moderate Nurick grade 3 or 4 (able to ambulate with assistance but unable to work). However, this lack of improvement may be due to the spinal cord already being permanently damaged from traumatic compression or ischemia. Additionally, posterior surgery alone instituted in severely compromised states may not provide adequate neural decompression.

Some contend that prophylactic surgery may be indicated in younger patients with mild symptoms but severe stenosis radiographically. With a longer life expectancy, younger patients have a greater risk of suffering even minor cervical trauma that may result in permanent neurological injury. Patients with a narrowed SAC of less than 10 mm have a higher risk for the development of myelopathy after trauma, with up to 23% of patients with OPLL becoming acutely or increasingly symptomatic after a minor event.30 In a study of patients with OPLL manifested as acute cervical cord injury, the level of the injury was frequently at the caudal edge of the ossified lesion, probably secondary to hyperextension of the neck with minor trauma.31

Once the decision to proceed with surgical intervention is made, an appropriate surgical approach must be selected. A variety of anterior and posterior procedures have been described for direct or indirect decompression of the spinal cord in the setting of OPLL (Fig. 282-2). Anterior cervical approaches consist of direct decompression by either surgical resection or “floating” of the ossified lesion, along with reconstruction of the anterior spinal column and fusion. Posterior cervical approaches achieve indirect decompression by increasing SAC through either laminectomy or laminoplasty without directly addressing the ossified lesion. Even though several studies have failed to demonstrate any significant difference in outcome between anterior and posterior surgery,3235 anterior approaches are associated with longer operative time, increased blood loss, and more frequent complications.35

Anterior Surgery

Anterior procedures for cervical OPLL allow definitive resection or mobilization of the ossified lesion and direct decompression of the spinal cord (Fig. 282-3A to I); however, they are frequently complicated by significant epidural bleeding, leakage of cerebrospinal fluid from ossified dural involvement, and potential injury to the spinal cord or nerve roots. Alternatively, an anterior floating method has been described in which a generous corpectomy is performed laterally such that the transverse dimensions extend at least 20 to 25 mm.34,36 Particular attention is directed toward identifying the uncinate processes to demarcate the extent of lateral resection. Once the ossified lesion is released at its lateral, cranial, and caudal margins with the use of a high-speed drill and a diamond bur, the calcified plaque rises ventrally to decompress the spinal cord. With the anterior floating method, the ossified lesion is not resected but instead is allowed to migrate anteriorly into the corpectomy defect. After decompression, either by resection of the OPLL or with the anterior floating method, anterior strut grafting with or without instrumentation is performed. Other complications described with anterior decompression include graft dislodgement, pseudarthrosis, and C5 nerve root palsy.