Human Leukocyte Antigen: Probable Site on Genome

Multiple studies increasingly document a genetic correlation among OPLL, diffuse idiopathic skeletal hyperostosis (DISH), and ossification of other ligaments—ossification of the yellow ligament (OYL) and ossification of the anterior longitudinal ligament (OALL).^7,8 In evaluation of 91 sibling pairs of patients with OPLL in 53 Japanese families, the genetic locus for OPLL was found near the human leukocyte antigen (HLA) site on chromosome 6-p. In patients with DISH, 50% have concurrent OPLL and test positive for HLA.⁹ In the Chinese population, another susceptibility gene, COL6A1, appears to represent a “common susceptibility gene” for both OYL and OPLL.¹⁰

Autosomal Dominant Inheritance

An autosomal dominant mode of inheritance is supported by genetic and epidemiologic data from patients with OPLL. OPLL is found in 26.15% of parents and 28.89% of siblings of patients with OPLL, a finding that supports a likely autosomal dominant transmission.¹¹ A 53% expression rate of OPLL is observed in patients with two concurrent HLA strands compared with 24% with one strand, which further supports this hypothesis.⁸ Autosomal recessive transmission has been suggested when 56% of a patient’s siblings with both HLA haplotypes were symptomatic with OPLL, whereas those with only one HLA haplotype were not.¹² Two additional unique genetic factors were identified in 18 patients with OPLL compared with 51 age-matched controls: BamHI 10.0/10.0 kb and HindIII 19.0/19.0 kb genotypes.^7,13

Other Contributing Factors (Hormones and Proteins)

Genetically modulated hormones and proteins also appear to contribute to the expression of OPLL. Increased concentrations of growth hormone receptors and activins have been shown to enhance OPLL expression/progression.^14,15 Elevated concentrations of bone morphogenetic proteins have resulted in increased osteogenesis in originally nonossified ligaments of OPLL patients (347 families, 1030 relatives).¹⁵ In a more recent study, bone morphogenetic protein 2 (BMP-2) additionally positively correlated with the extent of OPLL progression.¹⁶ Insulin was also correlated with OPLL onset/progression in people with non–type 1 diabetes via direct and indirect stimulation of BMP-2 within the ligament.¹⁷ Fibronectin, a glycoprotein that plays a role in the development of bony tissues, was also found to be significantly elevated in patients with OPLL or OYL.¹⁸

Posterior Longitudinal Ligament

The PPL, comprised of collagen fibers with elastin densely concentrated at its center, originates at the base of the clivus and extends to the sacrum. It is attached to each disc anulus, where it is widest, and is narrowest at each midvertebral level; it is 1 to 2 mm thick centrally, thinning out laterally.

Hypertrophied and Ossified Posterior Longitudinal Ligament

Hypertrophy of the PPL is first attributed to fibroblastic hyperplasia followed by increased collagen deposition. The subsequent formation of ossification centers is attributed to progressive mineralization and cartilaginous ingrowth. These centers eventually coalesce, leading to OPLL characterized by mature Haversian canals actively engaged in bone marrow production. OPLL enlarges an average of 0.4 mm per year in its anterior-posterior dimension, and longitudinal expansion occurs at a rate of 0.67 mm per year.

In Vitro Characteristics of Cultured Posterior Longitudinal Ligament in Patients with Ossification of the Posterior Longitudinal Ligament

In patients with OPLL, the PPL is osteogenic.^7,8,13–15 Immunohistochemical evaluation of PPL cells for patients undergoing anterior cervical decompression for cervical disease revealed “up-regulation of proliferating cell nuclear antigen” in patients with OPLL.¹⁹ This finding of increased osteogenicity of the PPL was also confirmed in myelopathic patients with OPLL in North America.²⁰ Collecting supernatants of PPL obtained intraoperatively from patients with OPLL compared with non-OPLL control patients (with spondylosis) revealed increased osteocalcin synthesis in the OPLL patients. The quantity of osteocalcin induced was determined by incubating these PPL cells with 1.25(OH)₂ and vitamin D₃ for 72 hours in serum-free medium.²¹ Those with OPLL grew to confluence, whereas those with spondylosis alone did not respond to vitamin D₃ priming.

Early Disease

OPLL represents a continuum of maturation that starts with hypertrophy of the PPL and ends with frank ossification.^1,4,6,22 Early OPLL usually originates opposite multiple interspaces in patients in their mid 40s and is often misdiagnosed as multiple disc herniations. However, unlike disc herniations, OPLL begins with retrovertebral extension that can be seen on enhanced MRI studies performed with gadolinium (Gd)-DTPA and as punctate CT-documented ossification. Too often, patients undergo multilevel anterior discectomy and fusion procedures where the PPL is ignored, leading to many retained disc fragments, and in early OPLL, leaving patients with continued symptomatology.

Classic Disease

There are four classic types of mature/classic OPLL²³ (Figs. 88-7 and 88-8). The segmental variant (39%), located behind the vertebral bodies, does not cross the intervening disc spaces. The continuous type (27%) extends from vertebra to vertebra, traversing the disc spaces. The mixed form (29%) simultaneously includes both continuous and segmental elements with “skip” areas. The “other” form (5%) is localized to the disc spaces, with limited degrees of rostral and caudal retrovertebral extension.

FIGURE 88-7 The midline sagittal two-dimensional CT study (soft tissue image) documents the “mixed” type of ossification of the posterior longitudinal ligament (OPLL). The continuous form of OPLL extends behind the C2-5 vertebral bodies, ending at the C5-6 caudal disc space. Dorsal to the C2 body, the double-layer sign indicative of dural penetrance is most clearly visualized. Observe the hypodense space (representing the dura) separating the C2 vertebral body from the linear ossification that represents intradural OPLL.

FIGURE 88-8 The parasagittal two-dimensional CT (bone-window) shows classic “segmental” ossification of the posterior longitudinal ligament (OPLL) located along the entire dorsal length of the C4 and C5 vertebral bodies. Also, observe the double-layer sign signified by the hypodense dura visualized between the dorsal aspect of the vertebral bodies and the hyperdense intradural OPLL.

Myelopathy Scales

Two major myelopathy scales are used worldwide: the Nurick scale and the Japanese Orthopaedic Association (JOA) scale.

Radiography

Based on lateral 6-foot plain radiographs, the normal anteroposterior dimension of the cervical spinal canal should measure 17 mm between the C3-7 levels. In absolute stenosis, the canal is narrowed to 10 mm or less, whereas with relative stenosis, the canal measures between 10 and 13 mm. The extent of OPLL is readily described by the occupancy ratio, which is determined by dividing the thickness of the measured ossified lesion by the anterior/posterior developmental canal diameter. If the ratio is greater than 40%, the risk of myelopathy increases.²

Computer-assisted measurements based on plain radiographs may be used to follow the postoperative progression of OPLL.³⁰ In a multicenter study, lateral radiographs taken immediately as well as 1 and 2 years following posterior decompressions were assessed (131 patients). All radiographs were transformed into digital images and compared. Over 2 years, there was a 56.5% rate of progression, occurring more often in younger patients with the mixed and continuous forms of OPLL.

Magnetic Resonance Imaging

MRI examinations, particularly T1- and T2-weighted MRI studies, performed with and without contrast (Gd-DTPA) demonstrate the spinal column, spinal cord, nerve roots, intrinsic cord disease, and extrinsic cord compression from the occiput through the cervicothoracic junction in the transaxial, coronal, and sagittal planes. On noncontrast MRI studies, hypertrophied PPL often appears opposite multiple disc spaces, demonstrated by accompanying retrovertebral extension appearing slightly hyperintense and enhancing with Gd-DTPA. Classic OPLL is identified on 50% of T1-weighted MRI studies by a hyperintense signal, reflecting the presence of fat within mature Haversian canals actively engaged in bone marrow production. MRI examinations may also help identify disc herniations (hypointense masses) that occur in 81% of cases in conjunction with segmental OPLL.³¹

Ossified OPLL, which appears hypointense on MRI studies, may lead to an underestimation of the true extent of the OPLL and should therefore be combined with plain radiographic and CT-based studies to document the true degree of cord compression more accurately. In a multicenter study, 156 OPLL patients from 16 institutions were followed an average of 10.3 years with plain radiographs, MRI, and CT studies.³² Of interest, all 39 patients with OPLL occupying greater than 60% of the anteroposterior diameter of the spinal canal were myelopathic, whereas only 49% with OPLL occupying less than 60% of the spinal canal were myelopathic.

Intrinsic cord swelling/edema, myelomalacia, and gliosis produce hyperintense signals on T2-weighted MRI scans and are considered poorer prognostic signs for cervical spondylotic myelopathy (CSM) compared with OPLL.^31,33 Despite the 43% incidence of increased preoperative cord signals on MRI studies that failed to resolve postoperatively, patients with OPLL exhibited better outcomes compared with those with CSM. Dynamic MRI studies may also prove useful in demonstrating “dynamic” compression preoperatively and residual cord compromise postoperatively.

Magnetic Resonance Angiography

Measurement of the interpedicular distance on preoperative CT scans typically dictates the medial/lateral dimension of the surgical trough to be created. It may therefore vary from an average of 14 mm in the Japanese population to 18 to 20 mm in the North American population. Therefore, patients undergoing multilevel anterior corpectomy with fusion (ACF) may benefit from preoperative magnetic resonance angiography studies if the vertebral artery appears to be following an unusually tortuous course. Occasional arterial loops may appear superficially, lateral to the anterior vertebral body margin, extending ventrally as they course between the individual foramen transversarium. Alternatively, loops may be aberrantly medially located lateral to the spinal canal.

The management of vertebral artery injuries is controversial. Direct surgical repair of an injured vessel is often difficult and carries substantial risks, whereas the advent of newer interventional neuroradiologic techniques provides a preferred “endovascular” solution. For injuries that are less than 6 hours old, transient vessel tamponade may be immediately followed by acute stent placement. In those injuries that are more than 6 hours old, endovascular trapping with coils may be performed. Both endovascular alternatives avoid the risk of delayed reopening of the vessel, prevent pseudoaneurysm formation, and limit the potential for cephalad clot propagation and cranial embolization.

Computed Tomography

Noncontrast CT, intravenous-enhanced contrast CT, two-dimensional and three-dimensional reconstructed CT, and myelo-CT studies directly demonstrate punctate ossification characteristic of early OPLL or frank ossification typical of classic OPLL (Fig 88-9; see also Figs. 88-7 and 88-8). CT studies also demonstrate degenerative changes adjacent to levels of prior surgery.³³ (Double-dose intravenous contrast-enhanced CT images may increase resolution of lateral or foraminal root pathology, helping to differentiate postoperative scar [enhancing] from new disc pathology [nonenhancing]). Two-dimensional and three-dimensional noncontrast CT reconstructed images provide a sagittal overview of the extent of cord compression without incurring the risk associated with myelo-CT studies. In particular, younger patients with OPLL and normal-sized spinal cords are at greater risk for acute deterioration following myelography compared with older individuals with OPLL and significant underlying cord atrophy.

FIGURE 88-9 At the mid-C6 vertebral level, the transaxial CT (soft tissue window) scan documents both the single-layer and C signs produced by ossification of the posterior longitudinal ligament located centrally and toward the right side of the spinal canal.

Myelo-Computed Tomography Studies

Myelo-CT studies are now rarely performed, because combined MRI/CT studies are extremely accurate and avoid myelography’s inherent risks of precipitating neurologic deterioration. Dorsally and dorsolaterally, myelo-CT studies (dynamic, static) demonstrate shingling of the lamina, OYL, OPLL, spondylosis, and disc pathology contributing to significant cord compression/stenosis. Postoperatively, myelo-CT studies also confirm whether the posterior decompression has been adequate or if further possible anterior surgery is warranted. Following open-door laminoplasty performed in OPLL patients, there was less dorsal shift of the cord but greater cord expansion, the latter factor positively correlating with outcome.³⁸

Studies Documenting Fusion Following Multilevel Anterior Cervical Surgery

Fusion criteria, documented on static and two-dimensional CT studies performed immediately postoperatively and repeated at 3, 6, and 12 months postoperatively included (1) the presence of bony trabeculation, (2) lack of bony lucency at the fibula strut allograft/vertebral body interface, and (3) ingrowth of bone centrally into the fibula. Dynamic radiographs additionally revealed (1) less than 3.5 mm of translation, (2) less than 5 degrees of angulation, and (3) less than 1 mm of motion demonstrated between the tips of adjacent spinous processes. An additional criterion for fusion following multilevel ACF performed with fibula strut allograft consists of cephalad or caudad bony ingrowth from the vertebral end plate into the central canal.³⁹ Eighteen patients with OPLL had, on average, a 2.9-level ACF performed with fresh-frozen fibula strut allografts, accompanied by C2-T1 posterior wiring and fusion (PWF). CT documentation of bony ingrowth and other signs of fusion were observed in 17 (94%) of 18 patients (ingrowth documented utilizing 500–900 Hounsfield units). Bony ingrowth doubled from 3 to 6 months postoperatively, increasing both rostrally (1.5–3.5 mm) and caudally (2.1–4.6 mm). Although early bony ingrowth signaled progression toward fusion, its absence was not pathognomonic for a failure to fuse as observed in the one patient.

Studies Documenting Posterior Fusion

When posterior fusions are performed, whether utilizing wiring techniques (facet wiring, rod-eyelet-cable fusion constructs), lateral mass screws, or pedicle screws, the dynamic radiographic criteria enumerated previously should be met. In such cases, two-dimensional coronal and sagittal CT-based studies should demonstrate continuity between (1) bone graft and underlying laminae and (2) continuity of bone graft and fusion across facet joints.