Pathomechanism of Ligamentum Flavum Hypertrophy: A Multidisciplinary Investigation Based on Clinical, Biomechanical, Histologic, and Biologic Assessments

Study Design. A multidisciplinary study involving clinical, histologic, biomechanical, biologic, and immunohistologic approaches. Objective. To clarify the pathomechanism of hypertrophy of the ligamentum flavum. Summary of Background Data. The most common spinal disorder in elderly patients is lumbar spinal canal stenosis, causing low back and leg pain, and paresis. Canal narrowing, in part, results from hypertrophy of the ligamentum flavum. Although histologic and biologic literature on this topic is available, the pathomechanism of ligamentum flavum hypertrophy is still unknown. Methods. The thickness of 308 ligamenta flava at L2/3, L3/4, L4/5, and L5/S1 levels of 77 patients was measured using magnetic resonance imaging. The relationships between thickness, age, and level were evaluated. Histologic evaluation was performed on 20 ligamentum flavum samples, which were collected during surgery. Trichrome and Verhoeff-van Gieson elastic stains were performed for each ligamentum flavum to understand the degree of fibrosis and elastic fiber status, respectively. To understand the mechanical stresses in various layers of ligamentum flavum, a 3-dimensional finite element model was used. Von Mises stresses were computed, and values between dural and dorsal layers were compared. There were 10 ligamenta flava collected for biologic assessment. Using real-time reverse transcriptase polymerase chain reaction, transforming growth factor (TGF)-β messenger ribonucleic acid expression was quantitatively measured. The cellular location of TGF-β was also confirmed from 18 ligamenta flava using immunohistologic techniques. Results. The ligamentum flavum thickness increased with age, however, the increment at L4/5 and L3/4 levels was larger than at L2/3 and L5/S1 levels. Histology showed that as the ligamentum flavum thickness increased, fibrosis increased and elastic fibers decreased.This tendency was more predominant along the dorsal side. Von Misses stresses revealed that the dorsal fibers of ligamentum flavum were subjected to higher stress than the dural fibers. This was most remarkably observed at L4/5. The largest increase in ratio observed between the dorsal and dural layer was approximately 5-fold in flexion at L4/5 in flexion. Expression of TGF-β was observed in all ligamenta flava, however, the expression decreased as the ligamentum flavum thickness increased. Immunohistochemistry showed that TGF-β was released by the endothelial cells, not by fibroblasts. Conclusions. Fibrosis is the main cause of ligamentum flavum hypertrophy, and fibrosis is caused by the accumulation of mechanical stress with the aging process, especially along the dorsal aspect of the ligamentum flavum. TGF-β released by the endothelial cells may stimulate fibrosis, especially during the early phase of hypertrophy.