## 4 Discussion
From the results of our study as well, it can be suggested that high-intensity change (HIC) in the protruding NP on T2-weighted MRI might be another predictive factor for the improvement of leg pain. The combination of occupancy rate and HIC of the protruding NP might serve as patient selection criteria, to achieve a higher response to chemonucleolysis with condoliase. We also obtained insightful information from patients who did not see an improvement or had aggravation of low back and/or leg pain after chemonucleolysis and underwent disectomy. Two patients underwent surgical intervention within 3 months and were excluded from the above analysis (foraminal LDH associated with spondylolisthesis and a patient with recurrent LDH after full-endoscopic disectomy). Six of the 34 patients underwent surgical intervention after 3 months of follow-up. Among the patients, eight required surgical intervention and two each had recurrent LDH, protrusion type LDH, and small sub-ligamentous extrusion type of LDH. The size of the  
Figure 7: Representative images of an 18-year-old man with large LDH. Preoperative sagittal (**a**) and axial (**d**) T2-weighted magnetic resonance imaging (MRI) showing sub-ligamentous LDH at L4/5. Sagittal (**b**) and axial (**e**) MRI taken 3 months after chemonucleolysis showing reduction of LDH. Sagittal (**c**) and axial (**f**) MRI taken 6 months after chemonucleolysis showing significant reduction in size. protruded NPs did not change after chemonucleolysis. For recurrent LDH, scar formation following a previous surgery might affect the penetration of condoliase and shrinkage of the NP. The pre- and postoperative spinal canal occupancy ratio did not change in these eight patients. Therefore, recurrent LDH, protrusion type of LDH, and small sub-ligamentous extrusion type of LDH should be excluded from the indication for chemonucleolysis with condoliase. We also pathologically examined the removed disc material and confirmed the preservation of the cartilaginous endoplate. Furthermore, we compared pathologic tissues obtained from patients (32-year-old man) who underwent surgery 3 months after condoliase injection and the similar-aged patients (32-year-old man) in whom condoliase was not injected. Decrease of toluidine blue staining in the intercellular space of condoliase injection indicates the degradation of glycosaminoglycans (chondroitin sulfate, keratan sulfate, and hyaluronic acid), which is a main component of the nucleus pulposus. However, chondrocyte necrosis was scarcely observed in both specimens (Figure 8). This finding strongly supports the safety of condoliase against the surrounding normal tissues. With respect to low back pain, [PERSON] et al. reported that there was no significant difference in the treatment group compared with the placebo group in terms of improvement at 3 months after administration [26]. In our study as well, there was no significant improvement 3 months after administration. However, comparison between the G and P groups with low back pain revealed that there was a significant difference in age. However, eight patients (four male, four female) in their teens were included in this study; the G group was statistically younger than the P group. Eight teenagers showed a good improvement of both low back pain and leg pain (mean improvement rate of NRS score of low back pain and leg pain \(\geq\)50% 3 months after the administration was 67.5% and 87.5%, respectively). We speculate that one of the reasons for the high efficacy in teenaged cases is the high water content in the nucleus pulposus (the content is predicted to be more abundant in  
Figure 8: Micrographs of the nucleus pulposus obtained from patients who underwent surgery 3 months after condoliase injection (**A**,**B**) and the similar-aged patients in whom condoliase was not injected (**C**,**D**). Staining: (**A**,**C**) hematoxylin and eosin; (**B**,**D**) toluidine blue. Magnification of microscope: (**A**–**D**) \(\times\)20.  
younger patients than that in elder patients).