Abstract
Introduction
This study aimed to evaluate the efficacy of condoliase injection therapy (CIT) for lateral lumbar disc herniation (LLDH).
Methods
This retrospective study included 157 of 180 enrolled patients (70 males, 87 females; mean age: 52.6±16.9 years). These patients were divided into two groups (group L: LLDH, group M: medial LDH [subligamentous and transligamentous]). From baseline to 1 year after injection (final follow-up), leg pain was assessed using the visual analog scale (VAS) and the Japanese Orthopedic Association (JOA) scoring for CIT's clinical efficacy of CIT. Radiography and magnetic resonance imaging conducted before and 3 months after the injection were assessed. Patients with a VAS improvement of ≥50% at the final follow-up were defined as responders. The responder and nonresponder LLDH groups were also compared.
Results
Groups L and M showed comparable responder rates (75.0% and 77.4%, respectively) (P=0.80). VAS and JOA scores at 1 year showed no significant differences between the groups (P=0.82 and 0.80, respectively). VAS score at 1 month after injection reduced considerably in the responder group compared with that in the nonresponder group (19.7 vs. 66.0, P<0.01) and continued to decrease at the last follow-up (3.5 vs. 52.0, P<0.001). Nonresponders had significantly lower disc heights after 3 months. However, intervertebral instability, alignment, and disc degeneration did not differ between the responders and nonresponders.
Conclusions
The response rate of CIT for LLDH was comparable to that for medial LDH. Therefore, CIT is an effective treatment for LLDH.
Keywords: lumbar disc herniation, lateral lumbar disc herniation, medial lumbar disc herniation, condoliase injection therapy, response rate
Introduction
In the 1980s and the 1990s, chemonucleolysis using chymopapain was reported to be effective in treating patients with lumbar disc herniation (LDH) in Europe and the United States1-3). However, serious adverse events, such as neurologic deterioration or anaphylactic reactions, have been reported because of the low substrate specificity of chymopapain. Therefore, this treatment had decreased by the end of the 1990s. Alternatively, chondroitin sulfate ABC endolyase (condoliase) is a pure mucopolysaccharidase with high substrate specificity for chondroitin sulfate and hyaluronic acid, which are glycosaminoglycans of proteoglycans abundant in the nucleus pulposus4,5). In contrast to chymopapain, condoliase does not have protease activity and can induce chemonautolysis without disturbing the nerve and ligament tissue6).
In 2018, Matsuyama and Chiba7,8) first reported the effectiveness of condoliase injection therapy (CIT) for LDH. Subsequently, several reports showing CIT's effectiveness and safety of CIT have been published9,10). Although the efficacy of CIT has been demonstrated for medial lumbar disc herniation (MLDH), its efficacy for lateral lumbar disc herniation (LLDH) is unknown. LLDH compresses the nerve root in the narrow radicular foramen, thereby directly compressing the dorsal radicular ganglion; hence, patients with LLDH may manifest more severe clinical symptoms11). If CIT does not shrink the disc in LLDH, the pain may not improve; therefore, its effectiveness remains unknown.
The efficacy of CIT for LLDH has yet to be reported. Thus, the aims of this study were to clarify (1) the therapeutic efficacy of CIT for LLDH, (2) whether CIT for LLDH is as effective as that for MLDH, and (3) factors in patient background and clinical course associated with successful CIT for LLDH. We hypothesized that CIT could reduce pain for LLDH, but the responder rate in LLDH was lower than that in MLDH because of severe pain.
Materials and Methods
Study design and setting
This was a single-center retrospective study. After obtaining approval from our ethics committee, we reviewed the data of patients who received CIT for LDH recorded from October 2018 onward in our hospital. The inclusion criteria were as follows: 1) age >18 years, 2) unilateral leg pain with or without back pain, and 3) neurologic signs consistent with nerve root compression on magnetic resonance imaging (MRI). Conversely, the exclusion criteria were as follows: 1) cauda equina syndrome, 2) severe and progressive motor deficits, 3) multiple lesions, and 4) less than 3 months of follow-up. Of 180 consecutive patients, 23 were excluded from the study. Thus, 157 consecutive patients were included in the analysis. Among them, 24 had LLDH. Table 1 lists the patient demographics. The included patients were then divided into two groups: the LLDH group (group L) and the MLDH group (group M [subligamentous and transligamentous]). For LLDH, a selective nerve root block was performed in all patients after confirming that the clinical symptoms expected at the disc level were consistent with the patient's chief complaint. The LLDH group included patients whose clinical symptoms were consistent with reproducible pain at the nerve root block. The clinical efficacy, including the response rate between these groups, was then compared (Fig. 1). Patients in the nonresponder group were offered surgical or conservative treatment, and those who choose conservative treatment were followed up with medication, lumbar disc block, and nerve root block.
Table 1.
Comparison of Demographics between Patients with LLDH and Those with MLDH.
| Group L
N=24 |
Group M
N=133 |
P value | |
|---|---|---|---|
| Age, y, mean (SD) | 64.1 (13.1) | 50.6 (16.7) | <0.001*2 |
| Sex, male/female, n | 9/15 | 61/72 | 0.51 |
| BMI, kg/m2, mean (SD) | 25.7 (4.5) | 23.8 (3.7) | 0.06 |
| Herniated disc level, n (%) | 0.78 | ||
| L1/2 | 0 (0.0) | 1 (0.8) | |
| L2/3 | 0 (0.0) | 4 (3.0) | |
| L3/4 | 3 (12.5) | 10 (7.6) | |
| L4/5 | 10 (41.7) | 61 (46.2) | |
| L5/S | 11 (45.8) | 56 (42.4) | |
| Required surgery, n (%) | 6 (25.0) | 23 (17.3) | 0.39 |
| Follow-up periods, months (SD) | 10.4 (9.0) | 7.7 (6.8) | 0.10 |
| Duration of leg pain (month), (SD) | 6.3 (8.7) | 5.6 (9.2) | 0.74 |
| Allergy (%) | 0.68 | ||
| Skin rash | 2 (11.1) | 9 (6.8) | |
| Anaphylactic reaction | 0 (0.0) | 0 (0.0) | |
| Posterior intervertebral angle >5°, n (%) | |||
| Pre-condoliase injection | 1 (5.3) | 8 (6.5) | 1.00 |
| 3 months after condoliase injection | 2 (11.8) | 18 (16.2) | 1.00 |
| Vertebral translation >3 mm, n (%) | |||
| Pre-condoliase injection | 4 (18.2) | 10 (7.9) | 0.23 |
| 3 months after condoliase injection | 4 (22.2) *1 | 11 (9.8) | 0.22 |
| Pfirrmann classification, n (%) | |||
| Pre-condoliase injection | 0.16 | ||
| II | 1 (4.2) | 10 (7.6) | |
| III | 11 (45.8) | 84 (63.6) | |
| IV | 12 (50.0) | 36 (27.3) | |
| V | 0 (0.0) | 2 (1.5) | |
| 3 months after condoliase injection | 0.17 | ||
| II | 0 (0.0) | 6 (4.8) | |
| III | 7 (29.2) | 59 (47.2) | |
| IV | 16 (66.7) | 57 (45.6) | |
| V | 1 (4.2) | 3 (2.4) | |
| VAS for leg pain, mm (SD) | |||
| Baseline | 84.3 (19.5) | 74.6 (22.2) | 0.05 |
| 1 month | 31.3 (33.9) | 31.1 (26.3) | 0.97 |
| 3 months | 21.4 (29.4) | 19.5 (26.1) | 0.75 |
| Last follow-up | 17.6 (33.3) | 16.3 (24.6) | 0.82 |
| Responders, n (%) | 18 (75.0) | 103 (77.4) | 0.80 |
| ΔVAS (last follow-up to baseline) mm (SD) | |||
| Overall | 66.7 (37.0) | 56.8 (33.5) | 0.19 |
| Responders | 79.7 (19.2) | 69.5 (22.3) | 0.07 |
| JOA score | |||
| Baseline | 18.2 (2.7) | 19.6 (2.3) | 0.01*2 |
| Last follow-up | 25.4 (3.9) | 25.6 (4.0) | 0.80 |
| Δ JOA score (last follow-up to baseline) | |||
| Overall | 7.2 (4.0) | 6.0 (3.6) | 0.180 |
| Responders | 8.5 (2.9) | 7.2 (2.9) | 0.08 |
Group L, patients with lateral lumbar disc herniation (LLDH); Group M, patients with medial lumbar disc herniation (MLDH); SD, standard deviation; BMI, body mass index; VAS, visual analog scale; JOA, Japanese Orthopedic Association
*1: Percentage in 23 patients where follow-up was possible
*2: P<0.05
Figure 1.
A flowchart showing patient inclusion. L, group with lateral lumbar disc herniation; M, group with medial lumbar disc herniation.
CIT procedure
Under local anesthesia, patients were placed in the prone position and a 21-gage disc puncture needle was inserted from the affected side under fluoroscopic guidance. After the needle tip was confirmed to be positioned at the center of the disc, 1 mL of solution containing 1.25 U/mL condoliase was injected. All patients were closely monitored for 1 h after the injection. The patient was discharged without prophylactic antibiotics after no anaphylactic reactions or worsening of neurological symptoms was confirmed.
Clinical assessments
Leg pain was assessed using the visual analog scale (VAS) at baseline and at 1 month, 3 months, and 1 year (final follow-up) after CIT. The Japanese Orthopedic Association (JOA) score12) was determined at baseline and final follow-up. If the patient was asymptomatic and refused to return to the hospital, the date of the last visit was used as the endpoint. Patients with a VAS improvement of ≥50% at the final follow-up were defined as responders.
Radiographic assessments
Lumbar radiography in the standing position and MRI were performed before and 3 months after CIT. We then measured the rates of spondylolisthesis (defined as >3 mm vertebral translation based on the lateral lumbar radiograph, posterior intervertebral angle >5°)10) on a lateral flexion radiograph and lumbar lordosis on the lateral radiograph. Using MRI, we evaluated intervertebral disc degeneration (defined as one or more grade progression in the Pfirrmann classification)13), herniation type (subligamentous extrusion, transligamentous extrusion, or lateral), and the reduction in disc herniation. Moreover, two spine surgeons assessed the reduction in herniation.
Statistical analysis
Data are presented as numbers and percentages for categorical variables and as means and standard deviations for continuous variables. We used Fisher's exact test to analyze categorical variables and Mann-Whitney U test for continuous variables. All statistical tests were conducted using EZR software version 1.40 (Jichi Medical School, Tochigi, Japan14)) with the significance level set at P<0.05.
Results
Efficacy of condoliase
The responder rate was 75% in group L and 77.4% in group M, with no statistically significant difference (P=0.80). The VAS scores 1 year after CIT were also not significantly different between groups L and M (17.6 and 16.3, respectively; P=0.82). The JOA score was significantly lower in group L at baseline (18.2 vs. 19.6, P=0.01), but both groups were comparable at the final observation (L, 25.4; M, 25.6; P=0.80) (Fig. 2). In terms of changes in VAS and JOA scores, both responders tended to show greater improvement in group L than in group M (ΔVAS scores: 79.7 vs. 69.5, P=0.07; ΔJOA scores: 8.5 vs. 7.2, P=0.08). Moreover, the incidence of allergy or progression to spondylolisthesis and disc degeneration was not significantly different between the two groups (Table 1).
Figure 2.
Changes in VAS scores of leg pain in group L and group M at 1, 3, and 12 months after CIT. VAS, visual analog scale; CIT, condoliase injection therapy; L, group with lateral lumbar disc herniation; M, group with medial lumbar disc herniation.
Comparison between the responders and nonresponders in LLDH
Compared with nonresponders, responders showed significantly reduced VAS scores 1 month after injection (19.7 vs. 66.0, P<0.01). Three months after the injection, the VAS scores decreased further (6.3 vs. 66.7, P<0.001) and continued to decline at the last follow-up (3.5 vs. 52.0, P<0.001) (Table 2) (Fig. 3). Regarding radiographic parameters, the nonresponders had a significantly lower disc height than the responders 3 months after CIT, although the difference was not significant before CIT (Table 3). However, other parameters, including intervertebral instability, alignment, hernia reduction, and disc degeneration, showed no significant differences between the responders and nonresponders.
Table 2.
Comparison of Demographics between Responders and Nonresponders in LLDH.
| Responders
N=18 |
Nonresponders
N=6 |
P value | |
|---|---|---|---|
| Age, y, mean (SD) | 65.1 (14.3) | 61.2 (9.2) | 0.54 |
| Sex, male/female, n | 7/11 | 2/4 | 1.00 |
| BMI, kg/m2, mean (SD) | 25.5 (4.8) | 26.0 (4.0) | 0.85 |
| Herniated disc level, n (%) | 0.84 | ||
| L3/4 | 2 (11.1) | 1 (16.7) | |
| L4/5 | 7 (38.9) | 3 (50.0) | |
| L5/S | 9 (50.0) | 2 (33.3) | |
| Type of hernia | 0.67 | ||
| Foraminal | 11 (61.1) | 3 (50.0) | |
| Extraforaminal | 7 (38.9) | 3 (50.0) | |
| Follow-up periods, months (SD) | 10.8 (10.2) | 9.2 (3.5) | 0.71 |
| Duration of leg pain, month (SD) | 5.1 (6.3) | 10.4 (14.4) | 0.24 |
| Allergy (%) | |||
| Skin rash | 2 (11.1) | 0 (0.0) | 1.00 |
| Anaphylactic reaction | 0 (0.0) | 0 (0.0) | 1.00 |
| LBP after CIT, n (%) | 4 (22.2) | 3 (50.0) | 0.31 |
| VAS for leg pain, mm (SD) | |||
| Baseline | 83.2 (19.8) | 87.5 (19.9) | 0.65 |
| 1 month | 19.7 (23.9) | 66.0 (37.5) | <0.01* |
| 3 months | 6.3 (10.6) | 66.7 (17.5) | <0.001* |
| Last follow-up | 3.5 (6.4) | 52.0 (46.0) | <0.001* |
SD, standard deviation; BMI, body mass index; LBP, low back pain; VAS, visual analog scale
*P<0.05
Figure 3.
Changes in VAS scores of leg pain between nonresponders and responders in LLDH at 1, 3, and 12 months after CIT. VAS, visual analog scale; CIT, condoliase injection therapy; LLDH, lateral lumbar disc herniation
Table 3.
Comparison of Radiographic Parameters between Responders and Nonresponders in LLDH.
| Responders
N=18 |
Nonresponders
N=6 |
P value | |
|---|---|---|---|
| Posterior intervertebral angle >5, n (%) | |||
| Pre-condoliase injection | 1 (5.9) | 1 (16.7) | 0.46 |
| 3 months after condoliase injection | 1 (7.1*1) | 1 (16.7) | 0.33 |
| Vertebral translation >3, n (%) | |||
| Pre-condoliase injection | 3 (17.6) | 1 (16.7) | 0.30 |
| 3 months after condoliase injection | 3 (17.6) | 1 (16.7) | 0.30 |
| Pfirrmann classification, n (%) | |||
| Pre-condoliase injection | 1.00 | ||
| II | 1 (5.6) | 0 (0.0) | |
| III | 8 (44.4) | 3 (50.0) | |
| IV | 9 (50.0) | 3 (50.0) | |
| 3 months after condoliase injection | 0.10 | ||
| III | 7 (38.9) | 0 (0.0) | |
| IV | 11 (61.1) | 5 (83.3) | |
| V | 0 (0.0) | 1 (16.7) | |
| Reduction of herniation, n (%) | 15 (83.3) | 3 (50.0) | 0.14 |
| Disc height, mm (SD) | |||
| Pre-condoliase injection | 8.3 (2.3) | 7.2 (1.2) | 0.29 |
| 3 months after condoliase injection | 7.1 (1.8) | 5.4 (1.7) | <0.05*2 |
| ΔDisc height, mm (SD) | 1.1 (1.0) | 1.9 (0.8) | 0.13 |
| LL (L1–S1), °(SD) | |||
| Pre-condoliase injection | 29.3 (10.1) | 27.9 (6.6) | 0.76 |
| 3 months after condoliase injection | 30.2 (8.4) | 31.0 (8.1) | 0.85 |
| ΔLL (L1–S1), °(SD) | −0.9 (5.5) | −3.0 (2.5) | 0.38 |
| LLL (L4–S1), °(SD) | |||
| Pre-condoliase injection | 21.5 (7.2) | 23.9 (5.3) | 0.45 |
| 3 months after condoliase injection | 20.9 (6.7) | 24.3 (4.9) | 0.26 |
| ΔLLL (L4–S1), °(SD) | 0.6 (4.3) | −0.38 (4.9) | 0.65 |
LL, lumbar lordosis; LLL, low lumbar lordosis; SD, standard deviation
*1: Percentage in 17 patients where follow-up was possible
*2: P<0.05
Case presentation
A 37-year-old woman with L5/S LLDH presented with right lower extremity pain, suggesting the distribution of nerve root compression (Fig. 4A). After 8 months of ineffective conservative treatment, CIT was administered. The VAS score for leg pain significantly improved from 100 mm at baseline to 0 mm 3 months after CIT, and MRI showed hernia reduction (Fig. 4B).
Figure 4.
Representative case: A 37-year-old woman with L5/S LLDH. Baseline sagittal, axial, and parasagittal (A) T2-weighted magnetic resonance images showing extraforaminal herniation at L5/S. Axial and parasagittal (B) MRI taken 3 months after CIT showing significant reduction in disc herniation. LLDH, lateral lumbar disc herniation; CIT, condoliase injection therapy; MRI, magnetic resonance imaging
Discussion
To the best of our knowledge, this study is the first to evaluate the clinical outcomes of CIT for LLDH. Contrary to our hypothesis, the responder rate in group L (75.0%) was comparable to that in group M (77.4%). Group L also showed more improvement in leg pain than group M. The VAS score was significantly lower in responders in group L at 1 month after injection than in nonresponders and continued to decrease until the last follow-up. Thus, CIT was effective not only for MLDH but also for LLDH.
A phase III clinical trial showed that CIT was effective in 72.0% of patients at 13 weeks and 79.0% of patients at 52 weeks after injection7). In another study, 33 of 42 patients (76.2%) achieved pain relief at 3 months after injection5). The criteria for determining efficacy were the same for both this study and the previous studies7), with a threshold of at least 50% improvement in VAS score for leg pain. In the current study, the response rate for LLDH was 75%, which was comparable to that in previous studies that included only MLDH; thus, CIT was also beneficial for LLDH.
Epidemiologically, patients with LLDH may present with severer clinical symptoms, such as severe radicular pain, compared with those with MLDH11). LLDH compresses the nerve root in the narrow radicular foramen, causing direct compression of the dorsal radicular ganglion. Although our study results showed no significant difference, pain tended to improve more in patients with LLDH than in those with MLDH after CIT. Although disc reduction has been reported in MLDH7), our results suggest that CIT also reduced disc height in patients with LLDH.
Banno et al. reported that CIT's influencing factors such as the history of herniotomy, spondylolisthesis, and posterior intervertebral angle below 5° are associated with reduced effectiveness10). In another study, symptom duration before CIT was significantly longer in nonresponders than in responders15,16). In the current study, no significant factors influenced the difference between responders and nonresponders in group L, and factors related to treatment response may differ between LLDH and MLDH.
In the radiographic assessment of patients with LLDH, the disc height decreased in both responders and nonresponders after CIT but was significantly lower in nonresponders. There were no significant differences in the other parameters. Additionally, due to dehydration, the intervertebral disc height after injection decreased17), and this phenomenon was observed in patients with LLDH. Despite the seemingly stronger effect of the injection in patients with greater height reduction, the height was significantly reduced among nonresponders. In LLDH, foraminal stenosis associated with disc height reduction may have exacerbated nerve root compression, thereby failing to improve the pain; nevertheless, the cause of the leg pain improvement was unclear. Further studies with long-term follow-up are necessary.
Surgery is often the treatment of choice when LLDH is refractory to conservative treatment of choice18-20). However, surgical treatments are invasive, and complications have been reported21-24). Evidence of CIT's efficacy for LLDH remains limited, but favorable results have been reported for MLDH7-9,15,25). CIT is a simple procedure that does not require hospitalization and is less expensive than surgery. As mentioned, our study results suggest that CIT is effective against LLDH, comparable to MLDH, and may be a minimally invasive treatment for LDH.
Nevertheless, our study had some limitations that should be acknowledged. First, it was retrospective in design and had a relatively small sample size. Second, the follow-up period in this study was relatively short. Despite these limitations, this study showed that the efficacy of CIT for LLDH is comparable to that of MLDH.
Conclusion
The response rate of CIT for LLDH (75.0%) was comparable to that for MLDH. Nevertheless, patients with LLDH tended to show more improvement in pain than those with MLDH. Furthermore, CIT for LLDH reduced pain in responders at an early stage after the injection. Therefore, CIT is a novel and beneficial treatment option for LLDH.
Conflicts of Interest: The authors declare that there are no relevant conflicts of interest.
Sources of Funding: None
Ethical Approval: The study was approved by the Institutional Review Board of Anjo Kosei Hospital (IRB approval No. R21-029).
Informed Consent: As all clinical and radiological interventions are routine assessments and this is a retrospective study design, informed consent specific to the current study was waived.
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