**4. Discussion**

DISH is a systemic condition characterized by ossification of ligaments and entheses throughout the body. Considered to be mostly an asymptomatic condition, DISH was largely ignored by clinicians and researchers until the 1990s. However, it is now known that DISH can sometimes result in specific symptoms, including back pain [14], stiffness [15], reduced range of articular motion [4] and dysphagia [16]. Notably, energy cannot be distributed over multiple segments in patients with DISH. Therefore, even minor trauma can lead to an unstable spinal fracture. A retrospective study [17,18] reviewed 289 patients with

DISH-related spinal fractures and demonstrated that these fractures frequently resulted in spinal cord injury and were sometimes associated with mortality. That study also found that the diagnosis was often delayed, leading to unexpected impairment of neurologic status, especially in patients with a thoracolumbar fracture. Therefore, it is important to recognize the presence of this pathology and the associated risks even after minor trauma, given that DISH creates longer bony lever arms, which increase spinal instability at the fracture site when a fracture occurs.

Patients with cervical OPLL often have ossification of other spinal ligaments, including the ligamentum flavum, anterior longitudinal ligament, and the interspinous and supraspinous ligaments. In earlier studies [4,19–22], 25–50% of patients with cervical OPLL had DISH. A previous retrospective study by our group [10] revealed that DISH was distributed primarily in the middle thoracic spine in younger patients but could extend to the cervical and/or lumbar spine in older patients. Toyoda et al. [23] reported that the prevalence of DISH increased with age in whole-spine radiographs of 345 patients in whom spinal surgery was required. Older patients in the present study also had a more severe DISH grade. Although a further longitudinal study is needed, the evidence to date suggests that ossification of the anterior longitudinal ligament might progress gradually from the thoracic spine to the cervical spine and lumbar spine with aging.

DISH has been recognized to be not only a structural abnormality in the human thoracic spine but also a result of metabolic syndrome. Okada et al. [24] compared subjects with and without DISH and demonstrated that the prevalence of metabolic syndrome was significantly higher in patients with DISH than in those without DISH (28.9% vs. 16.0%). Furthermore, using abdominal CT, Lantsman et al. [25] showed that areas of visceral fat were larger in patients with DISH than in healthy controls. Although there were no significant associations in terms of the prevalence of DM between patients with and without DISH or among the three grades in the present study, the onset and extent of DISH may be associated with a systemic metabolic disorder.

This prospective multicenter study is the first to investigate subjective outcomes in patients with cervical OPLL according to DISH status. Although we collected patientreported outcomes for activities of daily living, we found no DISH-related differences in patients with cervical OPLL. These findings are consistent with the opinion of some clinicians that DISH should be considered a state rather than a disease [26]. DISH may be present not only by itself but can also accompany ossification of other spinal ligaments that often lead to spinal cord disorders [13,27]. Therefore, in the present study, to reduce selection bias in this regard, we enrolled only patients with cervical OPLL. Therefore, we believe that DISH does not directly impair neurologic status or quality of life.

Several studies have investigated the association between presence of DISH and physical pain. Mata et al. [28] compared clinical symptoms in 56 patients with DISH, 43 control patients with lumbar spondylosis, and healthy volunteers and demonstrated that patients with DISH were more likely to report a history of upper extremity pain, medial epicondylitis of the elbow, enthesitis of the patella or heel, and dysphagia than were patients with lumbar spondylosis. They also reported that neck rotation and thoracic movements were more limited in the patients with DISH than in the patients with spondylosis or the healthy controls, and lumbar movement was more restricted in the patients with DISH than in the healthy controls. However, the findings of a similar study were contradictory. Schlapbach et al. [29] demonstrated that the radiological findings for DISH were not associated with an increased frequency of back pain and had no clinical relevance. Moreover, Holton et al. [30] randomly collected data for 298 elderly men from a surveillance cohort of 5995 men and demonstrated that the frequency of LBP was reduced in 126 men with DISH compared with 172 men without DISH based on North American Spine Society questionnaires for back and neck pain. We have also shown that patients with continuous OPLL are less likely to have neck pain than those with other types of ossification in which the cervical spine has more mobility than in continuous OPLL [27]. Similarly, the present study revealed that the prevalence of neck pain decreased with increasing DISH grade. Given that patients

with DISH are often found to have ossification of other spinal ligaments, the structural change caused by DISH alone cannot always explain their clinical status. Indeed, in this study, there was a significant increase in the OP-index value with increasing DISH grade, which may be a confounding factor. However, the present findings sugges<sup>t</sup> that segmental motion at unstable intervertebral levels rather than bony bridging segments is likely to cause pain and that neck pain is likely to be less severe in patients with a more severely ankylosed spine (DISH grade 3) than in those with a less restricted spine. Therefore, DISH localized in the thoracic spine (grade 1) may create overload at the cervical and lumbar spine and lead to neck pain and LBP.

This study has several limitations. First, it was a cross-sectional cohort study of a specific disease and not population-based. Second, the study was not longitudinal and thus cannot reach conclusions on causality. Third, the presence of DISH was evaluated only on reconstructed sagittal CT images with no review of bony bridges at the lateral portion of the intervertebral segments. Fourth, we could not determine whether mobility of the segmen<sup>t</sup> adjacent to DISH affects neck pain or LBP. Fifth, the JOA-CMEQ could not evaluate pain states in detail. Further studies are required in the general population to clarify these clinical questions and eliminate confounding factors in terms of each spinal ligament. However, despite these limitations, we believe that our findings provide important information on the clinical features of DISH in patients with cervical OPLL.
