Key points
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Ossification of the posterior longitudinal ligament (OPLL) is a hyperostotic condition of the spine associated with severe neurologic deficits. The incidence is higher in East Asians.
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OPLL is a multifactorial disease caused by a combination of environmental and genetic factors.
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Six susceptibility loci have been identified by a large-scale genome-wide association study among Japanese. Further study identified RSPO2 as a susceptibility gene for OPLL.
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In addition to the old classification based on plain radiograph, new classification systems using computed tomography have been proposed.
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Surgical indication for patients with OPLL is determined by the presence of neurological symptoms. The surgical method is determined by careful evaluation of the images, considering both efficacy and surgical complications.
Acknowledgments
The authors thank Ms. Maya Ueda for drawing the illustrations used in this chapter.
Introduction
Ossification of the posterior longitudinal ligament (OPLL) is a hyperostotic condition of the spine associated with severe neurologic deficits ( Fig. 12.1 ) [ , ]. The disease entity of OPLL has been widely recognized after a report from Japan in 1960 [ ], although it was first described by Key in 1838 [ ]. In 1975, the Ministry of Health, Labor, and Welfare of Japan designated OPLL as an intractable disease and started a research project because the high prevalence of OPLL among the Japanese was recognized. Since then, many studies on OPLL have been conducted mainly in Japan [ ]. This chapter briefly reviews the current concept of OPLL, including genetic background and imaging phenotypes as well as clinical aspects.
Epidemiology
There are many reports that the frequency of cervical OPLL varies between races. The incidence is higher among East Asians, including Japanese, than Caucasians. The frequency of cervical OPLL has been reported to be approximately 3% (1.9%–4.3%) in a plain X-ray survey of Japanese subjects [ ]. In a computed tomography (CT) study, the frequency of cervical OPLL was reported to be 6.3% with the definition of OPLL as thickness of 2 mm or more [ ]. Surveys using CT in South Korea and the eastern part of China showed that the prevalence of cervical OPLL was 5.7% [ ] and 4.1% [ ], respectively. A CT-based survey in the United States reported a racial difference in the prevalence of OPLL; 4.8% in Asians, 3.2% in Native Americans, 2.1% in Africans, 1.9% in Hispanics, and 1.3% in Caucasians [ ]. The incidence of thoracic OPLL is lower than that of the cervical one, the prevalence ranging from 1.6% to 1.9% in CT among Japanese patients [ , ]. The patients with cervical OPLL often show a tendency of hyperostosis in the ligament of the whole spine ( Fig. 12.2 ).
OPLL occurs in the 30s and prevalence increases in the 50s and older [ , , ]. Gender differences exist in the prevalence of OPLL. Cervical OPLL is more common among men, with a reported gender ratio of 1.8–2.5: 1 [ , ]. On the other hand, thoracic OPLL is more common among women, with a gender ratio of 1: 1.4–3.1 [ , , ].
Etiology and pathogenesis
The pathogenesis of OPLL is poorly understood. However, multifactorial etiologies have been suggested with the involvement of both environmental and genetic factors [ ]. As there are racial differences in the prevalence of OPLL, one of the causes of OPLL is thought to be the life environment. Many studies have hypothesized that dietary habits, comorbidities, and mechanical factors are involved in the occurrence and incidence of OPLL in addition to the genetic background [ ]. The nongenetic factors for OPLL include age, diabetes mellitus, obesity, diet, exercise, and mechanical stimulation [ ]. Plasma pentosidine levels, higher femoral neck bone mineral density, and the presence of diffuse idiopathic skeletal hyperostosis are also associated with OPLL [ ].
Genetic factors
It is obvious that OPLL has a strong genetic background. This is supported by family and twin studies, and HLA haplotype analysis [ ]. A study with 347 OPLL families reported an OPLL prevalence of 26% among parents and 29% among siblings of the OPLL probands [ ]. In 24 families with OPLL, a high prevalence of OPLL was found in the sibs who shared identical HLA haplotypes [ ].
The reported OPLL-related genes include FGF2, FGFR1, BMP2, BMP4, BMP9, VKORC1, TGF-β1, ENPP1, TGFBR2, COL17A1, PTCH1, BID, COL6A1, COL1A2, IL15RA, TLR5, 20p12, RUNX2, ACE, ESR1, ESR2, HLA haplotype, AHSG, RXRB, IL-1β, VDR, TGF-β3, etc. [ ]. To identify susceptibility gene(s) for OPLL, Nakajima et al. conducted a GWAS using 8265 Japanese subjects in collaboration with The Investigation Committee on the Posterior Longitudinal Ligament [ ]. They successfully genotyped 616,496 SNPs on autosomes and 12,228 SNPs on X chromosome. By a whole-genome imputation using the GWAS data followed by a replication study using additional 7017 subjects, they identified six susceptibility loci for OPLL [chromosome: 20p12.3 (SNP ID: rs2423294), 8q23.1 (rs374810), 12p11.22 (rs1979679), 12p12.2 (rs11045000), 8q23.3 (rs13279799), 6p21.1 (rs927485)]. The most significantly associated SNP in the GWAS locus was rs374810, which was located in the chondrocyte promoter region of RSPO2 (encoding R-spondin 2) [ ]. They further identified RSPO2 as a susceptibility gene for OPLL. R-spondin 2 is a secreted agonist of canonical Wnt-β-catenin signaling. RSPO2 was decreased in the early stage of chondrocyte differentiation. R-spondin 2 inhibited the expression of genes encoding early chondrocyte differentiation markers by activating Wnt-β-catenin signaling [ ].
Clinical manifestations
Clinical symptoms of OPLL
Most patients with cervical OPLL are asymptomatic with mild complaints such as neck pain and paresthesia [ ]. Decreased neck motion is also a possible complaint of patients with cervical OPLL. On the other hand, OPLL has been recognized as one of the main causes of myelopathy/radiculopathy especially in the East Asian countries [ ]. Symptomatic patients often complain about the clumsiness of the hands, gait dysfunction, or bladder/rectal disturbance in addition to numbness in the peripheral parts of the extremities. When performing a physical examination, the physician should assess both the Romberg and tandem gait tests to identify early signs of gait or balance dysfunction. Brisk reflexes, as well as clonus, may be present in the upper and lower extremities. Pathologic reflexes such as the Hoffman reflex and the inverted radial reflex suggest an upper motor neuron lesion. A hyperactive scapulohumeral reflex can be seen with cord compression above C3 [ ]. Dysdiadochokinesia or difficulty with rapid supination and protonation of the hand can be also found in myelopathy patients. In some cases of OPLL, the patient may complain of radicular symptoms and may demonstrate radicular signs such as a positive Spurling test. Therefore, the symptom is very similar to cervical spondylotic myelopathy, and physicians need to diagnose with radiograph, CT, or magnetic resonance imaging (MRI) carefully (see Chapter 5 ). Moreover, it should be considered whether neurological symptoms correspond to the imaging findings including vertebral levels and neural compression.
Imaging phenotypes
To date, no imaging phenotype of OPLL has been shown to be associated with a particular genotype. In addition, diagnosis or prognosis of OPLL cannot be made from biomarkers in blood or urine. Therefore, the diagnosis of this disease is made by focusing on the ossification of the ligament. CT images can help to classify the type of cervical and thoracic OPLL and have been associated with higher intraobserver reliability than radiographs [ ].
Classic classification of OPLL
Cervical OPLL can be diagnosed by plain X-ray, and the ossification is classified into four types according to the Investigation Committee on OPLL of the Japanese Ministry of Health and Welfare: continuous type, segmental type, mixed type, and localized or circumscribed type ( Fig. 12.3 ) [ , ]. The continuous type is a long lesion extending over several vertebral bodies and the intervening disc spaces (see Chapter 6 ). The segmental type involves ossification behind each vertebral body. The mixed type is a combination of continuous and segmental types. The localized or circumscribed type is mainly located behind the intervertebral disc space without the involvement of the vertebral body [ , ]. The segmental type is most common, occurring in 37% of patients with cervical OPLL. The continuous, mixed, and localized/circumscribed types occurred in 27%, 29%, and 8%, respectively [ ].
Thoracic OPLL is further subclassified as flat or beak type ( Fig. 12.4 ). The beak type is a segmental OPLL with a sharp protrusion behind the disk space. The flat type is either continuous or mixed OPLL with a flat shape [ ].
New classification of OPLL using CT
CT is effective when diagnosis by plain X-ray is difficult, especially for the lower cervical and thoracic spine. The Japanese Committee for Clinical Practice Guidelines for OPLL recognizes that small ossified lesions are not OPLL if they are apparently unrelated to neurological symptoms and are visible for the first time on CT [ ].
On the other hand, Epstein examined CT scans of the cervical spine in Caucasians and noted hypertrophy of the posterior longitudinal ligament with punctuate calcification. This finding was described as OPLL [ ]. Early OPLL often originates opposite multiple disc spaces in patients in their mid-40s, proving difficult to discern from disc disease and early spondylosis alone. Plain MRI studies reveal a diffusely hyperintense PLL, whereas gadolinium-enhanced MRI revealed uniformly enhancement of PLL while disc herniations would alternatively remain hypointense (see Chapter 8 ). Furthermore, the ubiquitous retrovertebral extension seen on these examinations further points to early OPLL rather than disc disease [ ].
Ossification may be discontinued on detailed examination with CT (reconstructed image) even if it looks continuous in a plain X-ray lateral image. Also, the ossification may not be continuous with the posterior border of the vertebral body. Such ossification forms are called “nonbridge” type, and it is speculated that a dynamic factor is involved [ ]. Subcommittee members of the Investigation Committee on the Ossification of the Spinal Ligaments of the Japanese Ministry of Public Health and Welfare proposed three new classification systems of cervical OPLL based on CT imaging: A, B, and axial [ ]. Classification A comprises two lesion types: bridge and nonbridge ( Fig. 12.5A ) [ ]. Classification B requires examiners to describe all vertebral and intervertebral levels where OPLL exits in the cervical spine ( Fig. 12.5B ). Then, connection or disconnection of OPLL is expressed as follows: ① A dot (“.”) is applied when the OPLL lesion is disconnected, similar to the segmental type in the X-ray classification; ② A slash (“/”) is applied when the OPLL lesion is beyond the intervertebral level, without any bridge formation to the adjacent vertebral body; ③ A bar (“–”) is applied when the OPLL lesion is beyond the intervertebral level, with bridge formation to the adjacent vertebral body; ④ A circle (“〇”) is applied at the level of the vertebral body when the OPLL lesion is not attached to the vertebral body (level number is circled). This means that if the OPLL lesion is fused with the vertebral body, the circle is not applied at the level of the vertebral body [ ]. Axial classification comprises central and lateral lesions identified on axial CT images ( Fig. 12.5C ) [ ].
A multicenter study examining whole-spine CT (reconstructed sagittal image) in Japan revealed that cervical OPLL was closely associated with systemic ossification tendencies [ ]. In a series of studies, Kawaguchi et al. recorded the distribution of OPLL at each vertebral body and intervertebral disc level and defined the number of levels at which OPLL was present as the ossification index (OP index) ( Fig. 12.6 ) [ ]. It has been proposed to categorize the cervical OP index into three grades: Grade 1, 0–5; Grade 2, 6–9; Grade 3, 10–14. Moreover, patients with a whole spine OP index ≥20 were deemed to have severe OPLL ( Fig. 12.6 ) [ , ]. In addition to the OP-index, the sum of the intervertebral segments showing ossification of the anterior longitudinal ligament (OA index) was proposed ( Fig. 12.6 ) [ , ]. They found that 56.2% of patients with cervical OPLL had coexisting ossified lesions in the thoracolumbar spine [ ]. Moreover, the number of levels with OPLL and the incidence of OPLL in the thoracolumbar region increased with increasing cervical OP grade [ ]. This new evaluation system allows for a quantitative assessment of ossifying ligaments and may reflect better the genetic predisposition. The combination of genotyping and phenotyping, which reflects a tendency of ossification, may lead to a complete understanding of the pathogenesis of OPLL in the future.
Natural course of OPLL and imaging risk factor of myelopathy
Ossification is often progressive during the natural course of the disease. Among 218 patients with an average follow-up of almost 7 years, the incidence of longitudinal progression was 41.3% and the incidence of thickness progression was 26.1% [ ].
In a CT-based evaluation, 41 patients were followed on average for approximately 2 years with the mean ossification volume of 2047.4 ± 1437.3 mm 3 at baseline and 2201.0 ± 1524.1 mm 3 in the final examination. The mean annual rate of lesion increase was 4.1 ± 2.7%. Younger age was the only significant predictor of OPLL progression ( R 2 = 0.23; P = .001) in multivariate linear regression analysis [ ]. In another CT study, Choi et al. followed up 60 patients for at least 24 months (mean 29.6 months) and detected evidence of OPLL progression. Progression of cervical OPLL was associated with younger age, involvement of multiple levels, and mixed-type morphology, while OPLL masses that were contiguous with the vertebral body and had trabecular formation were less likely to progress [ ].
The most significant problem with OPLL is the development of myelopathy caused by ossification rather than ossification itself. However, asymptomatic OPLL were found in 11% of individuals in their 60s [ ] and that 71% of cases with asymptomatic cervical vertebrae did not develop myelopathy over 30 years [ ]. Therefore, OPLL does not always lead to the development of myelopathy ( Fig. 12.7 ). When the occupation ratio of the ossified ligament in the spinal canal is 60% or more and the effective anterior–posterior diameter of the spinal canal is 6 mm or less, such criteria are risk factors for the development of myelopathy even under static conditions ( Fig. 12.8 ) [ ]. In addition, Matsunaga et al. clarified that more laterally deviated OPLL fragments on axial CT resulted in higher rates of myelopathy as compared with those that were located centrally [ ] ( Fig. 12.5C ). Also, dynamic factors may play an important role in the development of cervical myelopathy and radiculopathy in OPLL especially with mixed- or segmental-type [ , ].
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