Three-dimensional imaging analysis for the diagnosis of dural ossification in thoracic ossification of the ligamentum flavum: a multicenter study

Introduction

Ossification of the ligamentum flavum (OLF) presents as a pathological replacement of the ligamentum flavum with hypertrophic lamina bone and has been recognized as the main cause of thoracic spinal stenosis and myelopathy (1-4). Due to the progression of OLF and its poor response to conservative therapy, surgical decompression is generally considered to be the best treatment option (5). Potential sequelae of chronic OLF are the compression and subsequent ossification of the dura mater, resulting in an inseparable osseous fusion between the ligamentum flavum and the dura mater (1,6,7). For surgeons, unforeseen dural ossification (DO) may increase the risk of intraoperative complications, such as cerebrospinal fluid (CSF) leakage and spinal cord injury (3,7-9). Preoperative diagnosis of DO assists surgeons in making comprehensive preparations for the surgical procedure. Although the incidence of DO in patients with OLF is as high as 43.4%, the accurate diagnosis of DO has presented a difficult problem for surgical management (8,10). Radiological studies regarding OLF-DO are relatively rare, and the diagnostic accuracy of imaging signs still needs to be improved (11,12). Furthermore, there are variations in how the slices through tissues are obtained based on the spinal curvature, especially for the upper or middle thoracic spine, which might lead to deviations in the results of conventional measurement methods (13-16). Therefore, most of the current findings can only be applied to the lower thoracic spine, despite nearly 50% of DOs being located in the upper and middle segments (9,12,14,15).

Combining previous studies and clinical observations, we find that DO frequently occurs in the segment with the most severe compression on sagittal computed tomography (CT) images (17,18). Moreover, axial images illustrate that DO is often observed on multiple slices and not just on a single slice (6,8,19,20). Therefore, we speculate that the formation of DO is associated with the severity of OLF compression of the dura mater and the contact area of the OLF and the dura mater. Considering that OLF compression is not a 2-dimensional (2D) problem and is rather a 3D problem (14,21,22), a novel 3D imaging analysis based on CT scans was used in the present study. This may correct the measurement deviation caused by spinal curvature with multiplanar reconstruction (MPR). We sought to test this hypothesis by using the 3D imaging analysis and evaluate its superiority in diagnosing DO in the whole thoracic spine over the conventional measurement methods. We present the following article in accordance with the STARD reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-22-418/rc).

Methods

Patients

This retrospective study analyzed 397 consecutive patients who underwent laminectomy for thoracic OLF in four institutions (Shanghai Changzheng Hospital, Shanghai Zhabei Central Hospital, Weifang Traditional Chinese Medicine Hospital, and Suzhou Municipal Hospital) between May 2014 and April 2019. Thoracic OLF diagnosis was based on the patient’s medical history, clinical symptoms, and radiological information. Neurological deterioration was considered the indication for surgical treatment. The exclusion criteria were as follows: (I) a history of spinal trauma, tumor, deformity, or surgery; (II) accompanying thoracic ventral compressive lesions; (III) diffuse idiopathic skeletal hyperostosis; and (IV) incomplete or ambiguous data.

Intraoperative evidence of DO included the following: (I) obvious fusion of the ossified dura and OLF; (II) the occurrence of dural tears and CSF leakage during resection due to adhesion of the ossified dura and OLF; and (III) OLF and ossified dura found in the resected ossified mass. According to intraoperative evidence of DO, these patients were divided into non-DO and DO groups (Figure 1). The patients’ clinical characteristics were recorded, including sex, age, body mass index (BMI), diabetes mellitus (DM), hypertension (HTN), the number of ossified segments, and the segment of maximum compression. This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and was approved by and registered with the institutional review board of Shanghai Changzheng Hospital. The requirement for individual informed consent for this retrospective analysis was waived.

Figure 1 Patient screening and classification flowchart. OLF, ossification of the ligamentum flavum; CSF, cerebrospinal fluid.

Radiological measurements

Preoperative CT images of the thoracic spine obtained using a Philips Brilliance 256-slice CT (Philips Healthcare, Amsterdam, The Netherlands) or Siemens 64-detector CT (Siemens Healthcare. Erlangen, Germany) were available for all 114 patients. The following imaging parameters were used for CT scanning: 120 kVp/50 mAs, slice thickness 1 mm, slice interval 1 mm, matrix 512×512 pixels, collimation 128×0.625 mm, duration 0.5 s, and standard resolution algorithms with iDose4 iterative reconstruction. All CT images were assessed by 3 independent and well-experienced observers with more than 6 years of experience in the practice of spinal surgery who were blinded to the grouping and medical information of all included patients. Each observer measured all radiological parameters 3 times and recorded the mean values of the 3 measurements.

To investigate the relationship between DO and the severity and range of OLF compression of the dura mater, a 3D occupying ratio (OR) was used based on multidimensional imaging analysis software, which could assess OLF compression from the coronal, axial, and sagittal views. Preoperative CT images with Digital Imaging and Communication in Medicine (DICOM) data were imported into Mimics software 19.0 (Materialise, Inc., Leuven, Belgium) for measurement of the 3D OR.

To evaluate the 3D imaging analysis and conventional measurement methods in the diagnosis of DO, the 1D OR and 2D OR, as the most accurate diagnostic indicators of OLF-DO in previous studies, were compared with the 3D OR (12,15). The diagnostic values of DO among the 1D, 2D, and 3D ORs were compared in the upper, middle, lower, and whole thoracic spine. As the conventional measurement methods, the 1D and 2D ORs were measured using IMPAX 6.0 software (AGFA, Inc., Mortsel, Belgium). The detailed measurement methods are described in the following sections.

1D OR

The OLF thickness was defined as the maximum thickness of the unilateral ossified mass (Figure 2A). The spinal canal distance was defined as the distance from the lamina to the midpoint of the posterior vertebral wall (Figure 2B). The bilateral ORs were measured, and the larger value was considered the 1D OR. The 1D OR was calculated using the following formula: 1D OR = OLF thickness/spinal canal distance × 100%.

Figure 2 Measurement of the 1D OR. The 1D OR was calculated as follows: OLF thickness/spinal canal distance × 100%. (A) In the axial view, the OLF thickness was defined as the maximum thickness of the unilateral ossified mass (red arrow). (B) In the axial view, the spinal canal distance was defined as the distance (red arrow) from the lamina to the midpoint of the posterior vertebral wall (black line). 1D, 1-dimensional; OR, occupying ratio; OLF, ossification of the ligamentum flavum.

2D OR

The available canal area was defined as the available cross-sectional area of the narrowest spinal canal (Figure 3A). The normal canal area was measured as the cross-sectional area of the spinal canal with the widest distance between the pedicles and no ossification at the same segment (Figure 3B). The 2D OR was calculated using the following formula: 2D OR = (1 – available canal area/normal canal area) × 100%.

Figure 3 Measurement of the 2D OR. The 2D OR was calculated as follows: (1 – available canal area/normal canal area) × 100%. (A) In the axial view, the available canal area was defined as the available cross-sectional area of the narrowest spinal canal (red polygon). (B) In the axial view, the normal canal area was defined as the cross-sectional area of the spinal canal with the widest distance between the pedicles and no ossification in the same segment (red polygon). 2D, 2-dimensional; OR, occupying ratio.

3D OR

The procedures of 3D measurement using Mimics software comprised the following 5 steps. (I) The initial outline of the normal spinal canal was identified using the Multiple slice editor and Interpolation button. (II) In the pedicle region, the outline of the normal spinal canal could be determined directly. In the region without pedicles, the cross-sectional contour of the spinal canal with the widest distance and no ossification between the pedicles at the same segment was defined as the boundary of the normal spinal canal (Figure 4A-4D). Therefore, the outline of the normal spinal canal was determined manually using Edit Mask. (III) The OLF mass was initially segmented by a threshold value of bone (226–1,751 HU). Based on the initial segmentation, the segment of maximum compression was chosen by Crop Mask. (IV) The outline of the OLF was further determined manually by using Edit Mask (Figure 4A-4D). Additionally, the outline of the OLF mass was limited to the outline of the normal spinal canal. (V) After 3D renderings were reconstructed based on the outlines, the Mask 3D Preview pattern was chosen, and the volume of the OLF mass outside of the spinal canal was further removed manually by using Edit Mask (Erase) (Figure 4E). Finally, the 3D models of the OLF and spinal canal were obtained (Figure 4F).

Figure 4 Measurement of the 3D OR using the Mimics software. The outlines of the OLF mass (yellow) and involved spinal canal (green) were confirmed manually by using Edit Mask (Draw and Erase) on the (A) coronal, (B) axial, and (D) sagittal views. (B,C) The cross-sectional contour of the spinal canal (red) with the widest distance between the pedicles at the same segment was defined as the boundary of the normal spinal canal in the region without pedicles. (E) 3D renderings of the OLF mass and spinal canal were reconstructed based on the outlines. The volume of the OLF mass (yellow) outside of the spinal canal (green) were then removed manually by using Edit Mask (Erase). (F) The ultimate 3D model was obtained, and the 3D OR (OLF volume/normal canal volume × 100%) was calculated automatically. 3D, 3-dimensional; OR, occupying ratio; OLF, ossification of the ligamentum flavum.

The 3D OR was calculated as follows: 3D OR = OLF volume/normal canal volume × 100%. The OLF volume was defined as the volume of ossified mass at the segment of maximum compression. The normal canal volume was defined as the volume of the spinal canal corresponding to the measured OLF (the top and bottom of the normal spinal canal were consistent with the top and bottom of the measured OLF).

Statistical analysis

MedCalc 19.0 (MedCalc Software Ltd, Inc., Ostend, Belgium) software was used for statistical analysis. Univariate analysis was performed to compare related variables between the DO and non-DO groups by independent t-test for continuous variables and chi-square tests for categorical variables. The reproducibility and reliability of the measurements were assessed by intraclass and interclass correlation coefficients, respectively. Receiver operating characteristic (ROC) curve analysis was performed to determine the optimal cutoff value of the 3D OR for distinguishing between patients with DO and those without DO. A comparison of the diagnostic value of the radiological parameters was performed based on the areas under the ROC curves (AUC) by z test. The level of statistical significance was set at a P value of 0.05

Results

After filtering, 283 patients were excluded and 114 patients were enrolled in this study (Figure 1). These patients were divided into the non-DO group (n=60) and the DO group (n=54). Table 1 demonstrates that no significant differences in age (P=0.23), sex (P=0.54), BMI (P=0.39), DM (P=0.19), HTN (P=0.33), number of involved segments (P=0.40), or segments of maximum compression (P=0.61) distribution were found between the non-DO and DO groups. Most parts of the segments of maximum compression were located in the lower thoracic spine (T9–T12) (62.3%), while the remaining parts were in the upper and middle thoracic spine (T1–T8; 37.7%).

OLF compression and DO

The 3D OR in the DO group (50.9%±7.9%) was significantly higher than that in the non-DO group (30.8%±7.5%; P<0.01). The intraclass and interclass correlation coefficients were 0.94 and 0.90, respectively, demonstrating almost perfect agreement. Table 2 shows that the 3D OR had a relatively high diagnostic accuracy for DO in the whole thoracic spine (T1–T12; 92.6% sensitivity, 90.0% specificity, and 91.2% diagnostic coincidence rate). The optimal cutoff point for the 3D OR was measured at 40.0% by the maximum of the Youden index.

Comparison of the diagnostic value

The ROC curves of radiographic parameters in the whole thoracic spine (T1–T12) are illustrated in Figure 5. The 3D OR [AUC =0.98; 95% confidence interval (CI): 0.93–0.99] indicated a statistically higher diagnostic value for DO in the whole thoracic spine compared with the 1D OR (AUC =0.81; 95% CI: 0.73–0.88; P<0.01) and 2D OR (AUC =0.87; 95% CI: 0.79–0.92; P<0.01; Table 3). Additionally, the 2D OR had a higher diagnostic coincidence rate compared with the 1D OR despite the lack of statistical difference in their diagnostic values (P=0.18).

Figure 5 ROC curves of the 1D, 2D, and 3D ORs. ROC, receiver operating characteristic; 1D, 1-dimensional; 2D, 2-dimensional; 3D, 3-dimensional; OR, occupying ratio.

As shown in Tables 4,5, the 3D OR demonstrated a statistically higher and more stable diagnostic value than did the 1D OR and 2D OR regardless of whether it was applied in the upper and middle thoracic spine (T1–T8) or lower thoracic spine (T9–T12). Conversely, the diagnostic values of 1D OR and 2D OR in the upper and middle thoracic spine were markedly lower than those in the lower thoracic spine.

Clinical feasibility

As shown in Table 2 and Figure 6, there was an obvious overlap between the DO and non-DO patients near the optimal cutoff value of 40% (from 37% to 43%). None of the DO patients had a 3D OR of <37% (100% sensitivity), while only 1 patient without DO had a 3D OR of >43% (98.3% specificity). This indicated that DO could be entirely excluded when the 3D OR was <37%, and could almost be diagnosed if the 3D OR was >43%. Therefore, the 3D OR was divided into 3 zones to maximize the clinical feasibility: the safe zone (<37%), vague zone (37–43%), and ossification zone (>43%).

Figure 6 Distribution of the 3D OR in the whole thoracic spine for the diagnosis of DO in patients with OLF. 3D, 3-dimensional; OR, occupying ratio; DO, dural ossification; OLF, ossification of the ligamentum flavum.

Discussion

The major findings of this study were as follows. First, DO was significantly associated with the severity and range of OLF compression of the dura mater, and the 3D OR may be used as an indicator of DO in the whole thoracic spine. Second, the 3D OR demonstrated a statistically higher and more stable diagnostic value than did the 1D OR and 2D OR in the upper and middle thoracic spine (T1–T8), the lower thoracic spine (T9–T12), and the whole thoracic spine (T1–T12). Third, to maximize clinical feasibility, the 3D OR was divided into 3 zones: the safe zone (<37%), vague zone (37–43%), and ossification zone (>43%).

If the probability of DO could not be foreseen preoperatively, the risk of surgical complications, especially CSF leakage and spinal cord injury, would increase considerably (9). Although imaging signs such as the “comma sign” and “tram track sign” have been proposed for the diagnosis of DO, their misdiagnosis rates were reported to be 38.9%. Therefore, it might be necessary to develop a novel diagnostic method. In this study, we first proposed that the formation of DO was associated with the severity of OLF compression of the dura mater and the contact area of the OLF and the dura mater. However, it is difficult to simultaneously assess the severity and range of compression based only on the 1D or 2D radiological parameters (14,21). Our previous study found that the 3D OR could precisely reflect the oppressive state of OLF from multiple dimensions and thus predict the clinical grade of thoracic myelopathy (14). Herein, we introduce the 3D OR to test this hypothesis and report whether it could be used as an indicator to identify DO in patients with OLF.

The univariate analysis indicated that the 3D OR in the DO group was significantly higher than that in the non-DO group, which suggested an association between the formation of DO and the severity and range of OLF compression. In the early stage of OLF, ossification usually grows from the capsular portion to the laminar portion (6). Furthermore, there is only mild spinal stenosis and no DO. With the progression of OLF, the ossification enlarges anteriorly toward the dura mater, thereby aggravating the severity of compression, resulting in deformation of the dura mater (23). At the same time, ossification also expands superiorly and inferiorly, thus enlarging the range of OLF compression of the dura mater (24). This increases the contact area of relative movement between the OLF and the dura mater (25). When the severity of OLF horizontal compression of the dura mater and their vertical contact area develops to a certain degree, DO might occur. Consistent with our hypothesis, the optimal cutoff point of the 3D OR was measured at 40.0%. ROC curve analysis indicated that the 3D OR had a high diagnostic value (92.6% sensitivity, 90.0% specificity, and 91.2% diagnostic coincidence rate) and could serve as a critical indicator for distinguishing between OLF patients with and without DO.

Considering that the formation of DO with OLF compression is a slowly progressive process, a single cutoff value might not correctly distinguish between DO and non-DO in OLF. In our study, there was an obvious overlap between patients with DO and those without DO near the 40% cutoff value (from 37–43%). However, none of the patients with DO had a 3D OR of <37%, while only 1 patient without DO had a 3D OR of >43%. For clinical feasibility, the 3D OR was divided into 3 zones: the safe zone (<37%), vague zone (37–43%), and ossification zone (>43%). For patients with OLF in the ossification zone, surgeons must realize the presence of DO and develop a normalized preoperative design that should contain a low-risk surgical procedure, proper management of the ossified thecal sac, and a rescue plan for CSF leakage after resection. For those in the vague zone, DO might be immature or may already exist. Thus, it is necessary to combine with other diagnostic methods, such as imaging signs, to further identify the presence of DO. For those in the safe zone, early surgical intervention is recommended to decrease the incidence of DO-related complications.

To our knowledge, this is the first study to compare the diagnostic value of radiographic parameters from 1D to 3D for DO. After analyzing 39 patients with OLF, Zhou et al. proposed that a unilateral spinal canal occupational rate (1D OR) could serve as an indicator of DO, reporting a 76.0% sensitivity and 91.0% specificity (12). In addition, Yu et al. reported a cross-sectional area OR (2D OR) that had 92.6% sensitivity and 96.6% specificity for the diagnosis of DO after analyzing 56 patients with OLF (15). However, comparing the sensitivity or specificity alone, rather than a statistical comparison, is insufficient to determine whether these parameters are helpful in diagnosing DO (14,26). Furthermore, a small sample size could produce a type II error in the diagnostic model. Therefore, we analyzed 114 patients with OLF from 4 institutions and used the z test for comparison between independent ROC curves of these parameters (27). The 3D OR showed a statistically higher diagnostic value for DO in the whole thoracic spine compared with the 1D OR and 2D OR. A combination of factors might have contributed to this result and thus each part of the thoracic spine was investigated in detail.

DO in the upper and middle thoracic spine was previously reported to account for 33–46% of all DO cases. However, few studies have focused on the diagnostic efficacy of the conventional measurement methods for DO in T1–T8. Our results indicated that the diagnostic value of 1D OR and 2D OR in T1–T8 was markedly lower than that in T9–T12. Due to a large curvature variation between each segment in the upper and middle thoracic spine, it would be clinically wrong to perform these calculations without MPR. In contrast, this issue might be avoided by using the 3D imaging analysis. To correctly determine the radiological parameters, the 2D MPR can be reconstructed at an arbitrary angle or plane to achieve the appropriate orthogonal alignment based on a spinal section (14,28). This could explain why the 3D OR demonstrated a statistically higher and more stable diagnostic value for DO than did the 1D and 2D OR in T1–T8.

To eliminate the impact of MPR on the diagnostic value, these radiological parameters were further compared in the lower thoracic spine (T9–T12). Our results indicated that the 3D OR had a higher diagnostic value for DO in T9–T12 compared to that of the 1D and 2D parameters (P<0.01). Additionally, the 2D OR showed a higher diagnostic coincidence rate compared with the 1D OR, but this difference was not statistically significant. In fact, the 1D OR could only assess the degree of unilateral compression of OLF (9). Although the 2D OR could reflect the degree of bilateral compression, it could not assess the range of compression (14). Several radiographic parameters have been linked to OLF compression in previous studies, including the sagittal, coronal, and axial dimensions, which highlights the inadequacy of assessment from only a single dimension (9,12-14,29-31). In contrast, the 3D OR could make up for this owing to its comprehensive assessment of OLF compression from multiple dimensions.

This study has several limitations that should be noted. First, although our study included the largest sample size in the literature on the diagnosis of DO to date, its design was retrospective in nature. Therefore, a larger prospective study is needed to verify our findings. Second, our measurement method required manual operations in some key procedures, which might have inevitably produced human errors. However, the results still indicated that the 3D OR measurement method showed strong reproducibility and reliability. Third, the 3D imaging analysis based on Mimics software requires greater time and effort compared to the conventional measurement methods. Thus, further research is needed to simplify the operating steps and minimize human error in the future.

Conclusions

DO was significantly associated with the severity of OLF compression of the dura mater and the contact area of the OLF and the dura mater. The 3D OR could be used as a critical diagnostic indicator for identifying DO in the whole thoracic spine and showed superiority over the conventional radiological parameters. Classification of the 3D OR could maximize its clinical feasibility, thereby helping surgeons to decrease the incidence of DO-related surgical complications.

Acknowledgments

Funding: This study was supported by the National Natural Science Foundation of China (No. 81802218).

Footnote

Reporting Checklist: The authors have completed the STARD reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-22-418/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-22-418/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and was approved by and registered with the institutional review board of Shanghai Changzheng Hospital. The requirement for individual informed consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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