Introduction
Adjacent segment disease (ASD) is a major long-term complication of posterior lumbar interbody fusion (PLIF), characterized by degenerative changes at spinal levels adjacent to the fused segments, often impairing the quality of life [1]. ASD may be radiographic (defined by imaging findings without symptoms) or symptomatic (presenting with new pain or neurological symptoms) [1]. The primary mechanism underlying ASD is believed to involve mechanical stress concentration at the cranial adjacent level, resulting from altered spinal biomechanics after rigid fusion [1,2]. The reported incidence of symptomatic ASD after lumbar fusion ranges from approximately 5%–18% within 5–10 years after surgery [1]. Identified risk factors include advanced age, obesity, preexisting degeneration, and the use of rigid fusion constructs [3,4]. Recently, ligamentum flavum (LF) hypertrophy at adjacent levels has been recognized as an important contributor to symptomatic ASD [5].
The LF, which spans the posterior and lateral aspects of the spinal canal, is primarily composed of elastic fibers (approximately 80% elastin and 20% collagen under normal conditions) [6]. In lumbar spinal stenosis, the LF becomes pathologically thickened due to fibrosis, decreased elastin content, and increased collagen deposition [7,8]. Fibrosis is a major driver of LF hypertrophy in spinal stenosis [9], and in vitro and in vivo studies have shown that mechanical stress promotes LF fibrosis [10,11]. Recent single-cell analyses have shown that hypertrophied LF harbors heterogeneous, profibrotic cell populations, including higher proportions of fibroblasts, alpha-smooth muscle actin (α-SMA)-positive myofibroblasts, and macrophages than normal LF [12]. This cellular heterogeneity suggests that LF thickening results from fibrotic remodeling rather than uniform hypertrophy of a single cell type [13], implying that hypertrophied LF may exhibit altered responsiveness to mechanical stress.
Moreover, diffuse LF hypertrophy across multiple spinal levels, particularly at L2/3, which is typically thinner than L4/5, has been reported to indicate a genetic or systemic predisposition [14–17]. Thus, preoperative identification of significant LF thickening at L2/3 may reflect an inherent susceptibility that influences tissue responses to mechanical stress [16,17].
Based on these insights, this retrospective study aimed to investigate whether preoperative LF hypertrophy at the cranial adjacent level promotes postoperative progression, and whether LF hypertrophy at L2/3, previously proposed as a marker of genetic susceptibility, is associated with progressive hypertrophy at the cranial adjacent level following PLIF.
Materials and Methods
Ethical considerations
This study was conducted in accordance with the principles of the Declaration of Helsinki. The study protocol was approved by the Institutional Review Board (Teikyo University Ethical Review Board for Medical and Health Research Involving Human Subjects, approval number: 19-174-3). Written informed consent was obtained from all participants.
Patients
We retrospectively reviewed medical records of 202 consecutive patients with lumbar spinal canal stenosis who underwent PLIF at Teikyo University Hospital between January 2014 and November 2023. Patients were excluded if they had undergone PLIF for ASD (n=6), concomitant decompression at the cranial adjacent level (n=20), had spondylolysis (n=2), degenerative scoliosis with a Cobb angle of ≥20° (n=2), postoperative infection (n=1), or had incomplete data (n=120). After applying these criteria, 51 patients (26 men and 25 women) who underwent computed tomography (CT) examinations both preoperatively and at 1 year postoperatively were included in the analysis (Fig. 1).
Among the 151 excluded patients, the most common reason for exclusion was incomplete data, largely related to institutional policy. Specifically, between January 2014 and March 2018, 1-year postoperative CT evaluation was not routinely performed, leading to the exclusion of 70 of 83 patients (84%) during this period. After reinforcement of the postoperative imaging protocol in April 2018, the exclusion rate decreased to 50 of 119 patients (42%) through November 2023. To account for potential selection bias, all reasons for exclusion were documented, and temporal trends in exclusion rates were analyzed. Furthermore, baseline characteristics were compared between included and excluded patients, with results presented in Supplement 1.
Radiological evaluation
Radiological assessments at the cranial level adjacent to the fused segments included LF thickness, disc height, rotatory displacement, laminar inclination, facet degeneration, disc degeneration, vacuum phenomenon, and Modic changes. Additionally, LF thickness at L2/3, lumbar lordosis, and pelvic incidence were evaluated.
LF thickness at L2/3 was treated an indicator of inherent or genetic predisposition and analyzed as an independent variable, regardless of the fusion level. Fusion-related factors, including the number of fused segments and the cranial adjacent level, were entered as separate covariates in the statistical model.
X-ray
Preoperative standing lateral radiographs in flexion and extension were obtained for all patients. Rotatory displacement at the cranial adjacent level of the fused vertebrae was measured using functional standing lumbar radiographs [18]. Laminar inclination [19], lumbar lordosis, and pelvic incidence were also measured on standing lateral lumbar radiographs.
CT
LF thickness at the cranial adjacent level was measured preoperatively and 1 year postoperatively using a slightly modified method based on previous reports [14,20]. Specifically, LF thickness was measured at 4 points (medially and laterally on both sides) on axial CT images at the disc level, and the mean value was used for analysis (Fig. 2). The change in LF thickness between the preoperative and 1-year postoperative scans was also calculated. All LF measurements were performed once by a single experienced spine surgeon using a standardized protocol. Formal inter- or intra-rater reliability testing was not conducted.
Statistical analyses
To assess potential selection bias, baseline characteristics were compared between included and excluded patients to identify any systematic differences. Changes in LF thickness at the cranial adjacent level before and 1 year after surgery were compared using a paired t-test. Correlations between preoperative LF thickness (at the cranial adjacent level or L2/3) and postoperative changes in LF thickness were examined. Because no validated CT-based threshold exists for defining LF hypertrophy progression, the postoperative change in LF thickness at the cranial adjacent level was dichotomized at the sample median. Patients were thereby classified into progression and non-progression groups for exploratory screening of potential risk factors. Radiological and clinical variables were compared between these two groups. Demographic variables included age, sex, and body mass index (BMI). Continuous variables were compared using the Student t-test or Wilcoxon rank-sum test, and categorical variables were analyzed using the chi-square or Fisher exact test, as appropriate. We also compared patient characteristics related to LF thickness at L2/3 between those whose cranial adjacent level was L2/3 and those with other adjacent levels. To minimize information loss from dichotomization, univariate analyses were first performed using linear regression, followed by multivariable regression with backward elimination. Multicollinearity among explanatory variables was assessed using variance inflation factor (VIF) values. Sensitivity analyses using ridge and least absolute shrinkage and selection operator (LASSO) regression were additionally performed to verify the robustness of the results. All analyses were conducted using the JMP Student Edition ver. 18.0 (SAS Institute Inc., Cary, NC, USA). Two-tailed p-values <0.05 were considered statistically significant.
Results
There were no significant differences in baseline characteristics between included and excluded patients (Supplement 1).
LF hypertrophy
At the cranially adjacent level, LF thickness increased significantly from 3.4±0.8 mm preoperatively to 4.0±1.1 mm at 1 year postoperatively (p<0.0001, paired t-test) (Fig. 3). The preoperative LF thickness at the cranial adjacent level was positively correlated with its postoperative change (r=0.31, p<0.05) (Fig. 4). Notably, preoperative LF thickness at L2/3 showed an even stronger positive correlation with postoperative change in LF thickness at the adjacent level (r=0.47, p<0.001) (Fig. 5).
In a subgroup analysis, LF thickness at L2/3 was compared between patients whose cranial adjacent level was L2/3 and those with other adjacent levels. No significant difference was observed between the two groups (Supplement 2).
Between-group comparisons and regression analyses
Table 1 presents the demographic and surgical characteristics of the LF hypertrophy progression and non-progression groups. No significant differences were found between these two groups in terms of sex, age, BMI, number of fused levels, or cranial adjacent level.
Table 2 summarizes preoperative radiographic parameters. The preoperative LF thickness at the cranial adjacent level and L2/3 were significantly greater in the LF hypertrophy progression group than in the non-progression group (p<0.05 and p<0.01, respectively). No significant differences were observed regarding disc height, rotatory displacement, laminar inclination, facet joint degeneration, disc degeneration, vacuum phenomenon, Modic change, lumbar lordosis, or pelvic incidence. In the multivariable linear regression analysis with backward elimination, LF thickness at L2/3 and facet joint degeneration were retained in the final model, both showing significant positive associations with postoperative LF thickening. The model yielded an R2 of 0.30 (adjusted R2=0.27) and an Akaike information criterion of 84.05. VIF analysis indicated substantial multicollinearity among explanatory variables; however, sensitivity analyses using ridge and LASSO regression produced consistent results (Tables 3–5).
Discussion
This study conducted a longitudinal, quantitative assessment of LF thickness at the cranial adjacent level following PLIF. The final multivariable model identified preoperative LF thickness at L2/3 and facet joint degeneration as significant predictors of postoperative LF thickening. These findings suggest that preoperative LF thickness at L2/3 reflects an inherent predisposition to hypertrophy, whereas facet joint degeneration likely indicates mechanical stress at the adjacent level. Both factors have clear clinical relevance.
LF thickness at the cranial adjacent intervertebral level increased significantly 1 year postoperatively compared with the preoperative measurement. Excessive mechanical stress is known to develop at the disc immediately cranial to the fusion site [1,2], and the accelerated LF thickening observed in some patients may be explained by the cellular mechanisms identified in recent studies. Single-cell analyses have demonstrated that hypertrophied LF is enriched with myofibroblasts [12], which are key mediators of fibrosis. These myofibroblasts likely play a pivotal role in shaping the response of LF to the altered biomechanics after fusion. Myofibroblasts differ from quiescent fibroblasts in that they possess contractile α-SMA fibers, enabling them to sense and generate mechanical tension within the extracellular matrix. Consequently, patients with a predisposed LF (harboring more myofibroblastic cells or primed fibrogenic pathways), may exhibit heightened responsiveness to mechanical stress. Following fusion, this predisposition could amplify fibrotic remodeling, resulting in disproportionate LF hypertrophy at the adjacent level.
Interestingly, preoperative LF thickness at L2/3 showed a strong association with postoperative LF hypertrophy at the cranial adjacent level, suggesting that thickening at this upper level reflects a constitutional or systemic predisposition rather than a purely biomechanical process. Previous imaging studies support this interpretation, as LF at L2/3 is normally thinner than at lower lumbar levels [14,15], and patients with thickened LF at L2/3 frequently exhibit diffuse hypertrophic LF across multiple segments [17]. A recent clinical classification of lumbar stenosis similarly defined a “ligamentous stenosis” subtype characterized by diffuse LF thickening [16], representing a distinct phenotype of generalized LF hypertrophy. Systemic factors may also contribute to this phenotype; for example, insulin resistance has been linked to multilevel LF hypertrophy in lumbar stenosis [25]. Consistent with these reports, our subgroup analysis demonstrated that preoperative LF thickness at L2/3 was not affected by whether the cranial adjacent level included L2/3, supporting its role as an independent marker of genetic or systemic predisposition. Collectively, these findings suggest that LF thickness at L2/3 may serve as a useful surrogate marker for identifying patients at higher risk of adjacent level LF hypertrophy after fusion, thereby facilitating risk stratification and targeted postoperative surveillance.
This study aimed to identify predictors of postoperative LF hypertrophy rather than to directly evaluate the development of ASD. Accordingly, LF hypertrophy should be viewed as a potential risk indicator for ASD, meriting close follow-up, rather than as an independent predictor of ASD.
Some limitations of this study should be considered. First, the sample size was relatively small (n=51). Second, the relatively high exclusion rate raises the possibility of selection bias. Most exclusions were due to incomplete data arising from the institutional imaging policy before 2018; following protocol revision, the exclusion rate markedly declined. Comparison of baseline characteristics between included and excluded patients revealed no significant differences, consistent with a missing-at-random mechanism (Supplement 1). Nonetheless, selection bias related to missing data cannot be entirely excluded. Third, the follow-up duration was limited to 1 year. Previous reports have shown that approximately 20% of patients who develop ASD exhibit progressive LF hypertrophy within 2 years postoperatively [26]. Our analysis, therefore, represents an exploratory effort to identify early predictors rather than long-term outcomes. Extended follow-up studies are needed to confirm these findings and assess their relationship with clinical ASD and reoperation rates. Fourth, the choice of imaging modality represents a limitation. Although MRI offers superior soft-tissue contrast, postoperative MRI following PLIF is frequently compromised by implant-related artifacts, hindering clear visualization of the LF at the cranially adjacent level. Therefore, CT was used for postoperative evaluation. Previous studies have shown that CT-based measurements of lumbar LF thickness are feasible and that CT-derived ligament width and thickness closely approximate cadaveric anatomic dimensions [27]. The high spatial resolution of CT enhances structural delineation and measurement precision; however, its use limits direct comparability with MRI-based investigations. Fifth, all measurements were performed only once by a single surgeon, without formal inter- or intra-rater reliability testing. Although a standardized protocol and four-point averaging were employed to minimize random error, some degree of measurement variability cannot be excluded.
Conclusions
Preoperative LF thickness at L2/3 and the presence of facet joint degeneration at the cranial adjacent level were independently associated with postoperative progression of LF hypertrophy at the cranial adjacent level following PLIF. These findings suggest that both inherent (genetic or systemic) predisposition and mechanical stress may contribute to LF hypertrophy at adjacent levels after lumbar fusion.
PDF Links
PubReader
ePub Link
XML Download
Full text via DOI
Download Citation
Supplement
