Continuing experience with chemonucleolysis.

Chemonucleolysis using chymopapain is the least invasive technique used to treat a herniated lumbar pulposus. After 37 years of clinical experience, multiple clinical trials, a national multicenter, double-blind study mandated by the Food and Drug Administration, and heated controversy in the scientific community, the injection of chymopapain to treat herniated discs has (in appropriately selected patients) proven as successful as laminectomy, with fewer complications and the advantage of considerable cost savings.

Long-term follow-up review of patients who underwent laminectomy for lumbar stenosis: a prospective study.

OBJECT: Decompressive laminectomy for stenosis is the most common operation performed in the lumbar spine in older patients. This prospective study was designed to evaluate long-term results in patients with symptomatic lumbar stenosis. METHODS: Between January 1984 and January 1995, 170 patients underwent surgery for lumbar stenosis (86 patients), lumbar stenosis and herniated disc (61 patients), or lateral recess stenosis (23 patients). The male/female ratio for each group was 43:43, 39:22, and 14:9, respectively. The average age for all groups was 61.4 years. For patients with lumbar stenosis, the success rate was 88.1 % at 6 weeks and 86.7% at 6 months. For patients with lumbar stenosis and herniated disc, the success rate was 80% at 6 weeks and 77.6% at 6 months, with no statistically significant difference between the two groups. For patients with lateral recess stenosis, the success rate was 58.7% at 6 weeks and 63.6% at 6 months; however, the sample was not large enough to be statistically significant. One year after surgery a questionnaire was sent to all patients; 163 (95.9%) responded. The success rate in patients with stenosis had declined to 69.6%, which was significant (p = 0.012); the rate for patients with stenosis and herniated disc was 77.2%; and that for lateral recess stenosis was 65.2%. Another follow-up questionnaire was sent to patients 1 to 11 years after surgery (average 5.1 years); 146 patients (85.9%) responded, 10 (5.9%) were deceased, and 14 (8.2%) were lost to follow-up review. At 1 to 11 years the success rate was 70.8% for patients with stenosis, 66.6% for those with stenosis and herniated disc, and 63.6% for those with lateral recess stenosis. Eleven patients who underwent reoperation were included in the group of patients whose surgeries proved unsuccessful, regardless of their ultimate outcome. There was no statistically significant difference in outcome between 1 year and 1 to 11 years with respect to stenosis, stenosis with herniated disc, and lateral recess stenosis. CONCLUSIONS: In conclusion, long-term improvement after laminectomy was maintained in two-thirds of these patients.

Postchemonucleolysis discectomy versus repeat discectomy: a prospective 1- to 13-year comparison.

This long-term prospective study evaluates the clinical results of subsequent laminectomy in 103 consecutive patients who initially underwent chemonucleolysis (CNL) or laminectomy for lumbar disc herniation. Between 1981 and 1994, 53 patients who had received CNL initially and then underwent laminectomy and 50 patients treated initially with laminectomy underwent a repeat laminectomy. Clinical assessment at 6 weeks showed a success rate of 80.8% for post-CNL laminectomy and 78% for repeat laminectomy. At 6 months, the success rate for patients treated with CNL was 86% versus 78.7% for laminectomy. At 12 months, the overall success rate for the CNL group was 80.4% versus 83.3% for the laminectomy group, but in patients who had not obtained relief from the first procedure the success rate for the second procedure was higher for the post-CNL patients. A questionnaire was sent to all patients for 1- to 13-year follow-up review. The average follow-up period was 6.6 years for post-CNL laminectomy and 5.2 years for repeat laminectomy. The long-term success rate (81.8%) was higher in the post-CNL group compared to 64.4% in the repeat laminectomy group. Seven patients in the post-CNL group and nine in the repeat laminectomy group had undergone a third operation. When these originally successfully treated patients were reassigned after unsuccessful outcomes, the success rate for the CNL groups was 72.7%, versus 51.1% in the laminectomy group (p = 0.049). Employment rates were 80% for patients with CNL (21.8% changed jobs) and 76.3% for patients undergoing laminectomy (48.3% changed jobs) (p = 0.036). In conclusion, patients who underwent laminectomies after receiving CNL had significantly better long-term results than those who had repeat laminectomies.

Chemonucleolysis.

Even with a history of controversy and troubling complications, chymopapain has endured the test of time to show 30 years of clinical success in the treatment of herniated nucleus pulposus. Strict attention to indications, contraindications, and technique ensures safety and efficacy of treatment. A trend to decreased dosage may result in less postinjection spasm. Between 1982-1991, 121 adverse events in 135,000 patients were reported to the Food and Drug Administration and investigated. Seven cases of fatal anaphylaxis, 24 infections, 32 bleeding problems, 32 neurologic events, and 15 miscellaneous occurrences were found. Overall mortality rate was 0.019%. All categories were of lesser incidence than complications with laminectomy. Long-term results show that improvement after chemonucleolysis is maintained, whereas the outcome after laminectomy is reported to deteriorate with time. Cost savings with chemonucleolysis over laminectomy are largely a matter of shorter hospitalization. A protocol for cervical chemonucleolysis is being developed in the United States after good results have been shown in Spain and France. Other enzymes continue under investigation, but chymopapain remains the standard to which they are compared.

Lumbar chymopapain nucleolysis.

Chemonucleolysis with chymopapain is indicated in the majority of patients who are candidates for surgery for intractable sciatica due to herniated nucleus pulposus. It is safer, as effective, and cheaper than standard surgical discectomy, providing that patients are well selected and the procedure is properly performed. Because the indication for chemonucleolysis is not limited to contained discs, it has proved to be more effective than percutaneous discectomy. At present, of all percutaneous methods, lumbar chymopapain nucleolysis is the only procedure that has withstood the test of time. It is an attractive alternative to surgical discectomy and should be presented for consideration to patients who meet the criteria for the procedure.

Chemonucleolysis versus laminectomy. A cohort comparison of effectiveness and charges.

STUDY DESIGN: A prospective cohort study was done comparing 100 consecutive chemonucleolysis patients with 100 consecutive laminectomy patients. OBJECTIVES: The effectiveness and cost of chymopapain chemonucleolysis was compared with that of laminectomy to manage herniated lumbar discs. SUMMARY OF BACKGROUND DATA: Although the efficacy of chemonucleolysis has been established, controversy regarding the relative benefits of chemonucleolysis and laminectomy continues to arise. The relative cost-effectiveness of the two procedures has not been evaluated previously in a cohort study. METHODS: Patients in both treatment groups were of comparable age, height and weight, and worker's compensation status. Patients with migrated disc were not considered for chemonucleolysis. Improvement in pain, paresthesia, straight-leg raising, reflexes, motor loss, and sensory function, self-reported overall improvement, ability to maintain employment, and charge of treatment were used to measure treatment success. RESULTS: Clinical assessment after 6 weeks showed 92% of laminectomy patients compared with 82% of chemonucleolysis patients compared with 82% of chemonucleolysis patients had successful results (P = 0.058). Chemonucleolysis patients had greater improvement in numbness (P = 0.014) and sensory and motor functions (P = 0.002). After 6 months, 88% of chemonucleolysis patients and 85% of laminectomy patients had successful results, with a greater improvement in sensory status of chemonucleolysis patients and 82% of laminectomy patients had successful results, and more chemonucleolysis patients than laminectomy results, the average charge savings for chemonucleolysis patients was +5365 when chemonucleolysis was performed instead of laminectomy. CONCLUSION: This study shows that chemonucleolysis is an effective as laminectomy in appropriately selected patients but at lower charge and can contribute substantially to reducing short-and long-term health costs.

Disk-caused nerve compression in patients with acute low-back pain: diagnosis with MR, CT myelography, and plain CT.

Ninety-five patients with acute low-back and radicular pain underwent magnetic resonance (MR) imaging and either plain computed tomography (CT) (n = 32) or CT myelography (n = 63) for diagnosis of herniated nucleus pulposus-caused nerve compression (HNPNC). Patients were followed up for at least 6-12 months. Fifty-six patients underwent surgery, and 39 received conservative treatment. Receiver operating characteristic (ROC) analysis was performed on correlation of results of blinded image reading with "true" diagnoses determined by an expert panel [corrected]. Results in subgroup analysis for ROC curve areas were MR, 0.84, versus plain CT, 0.86; MR, 0.81, versus CT myelography, 0.83; and MR, 0.82, versus findings with both CT techniques, 0.85. Results indicate no statistically significant difference in diagnostic accuracy of HNPNC among the three modalities. Thus, factors of cost, radiation dose, and invasiveness influence selection of modality. On the basis of accuracy findings, the authors suggest that MR should replace CT myelography because of the invasiveness of myelography but that MR should not replace plain CT because plain CT is equally accurate and much less costly.

Deoxyribonucleoside triphosphate pools and thymidine chemosensitization in human T-cell leukemia.

Thymidine kills cells by depleting dCTP stores. The present experiments tested whether deoxycytidine, by replenishing dCTP pools, could prevent thymidine cytotoxicity and thymidine's enhancement of carboplatin killing in two human T-cell acute leukemia cell lines. MOLT3 and JM cells were exposed to combinations of thymidine, deoxycytidine, and carboplatin and then assessed for survival, the magnitude of thymidine-carboplatin chemosensitization, and changes in deoxyribonucleoside triphosphate pools. For both cell lines, deoxycytidine (up to 144.5 micrograms/ml x 24 h) completely restored dCTP pools but only partially protected against thymidine cytotoxicity (100-1000 micrograms/ml x 24 h) and thymidine-carboplatin sensitization (up to 60 micrograms carboplatin/ml during the last hour of thymidine). This contrasts with complete protection in prior studies using other cell types. Thymidine alone markedly increased dTTP and dGTP pools and decreased dCTP; dATP pools underwent a sharp decline which has not been observed before in any cell line. In subsequent studies 0.0336-137.3 micrograms deoxyadenosine/ml partially prevented cytotoxicity and carboplatin sensitization by 300 micrograms thymidine/ml. Together, deoxycytidine and deoxyadenosine completely prevented thymidine-carboplatin sensitization even though dATP and dCTP pools were not entirely returned to normal. These findings are discussed in regard to the unusual sensitivity of T-cell malignancies to thymidine toxicity, mechanisms of cytotoxicity and chemosensitization by thymidine, and the possibility of thymidine selectively sensitizing T-cell malignancies to killing by alkylating agents.

A 1- to 4-year follow-up review of treatment of sciatica using chemonucleolysis or laminectomy.

To help clarify the comparative effects of chemonucleolysis and discectomy, the author studied 178 consecutive patients with sciatica who did not respond to conservative treatment. None had previously undergone laminectomy or chemonucleolysis or had spinal stenosis. All received postmyelography computerized tomography (CT) and, if the radiological interpretation was that of an extruded migrated disc, a laminectomy was performed; otherwise, the patient was given a choice of the two procedures. Of the 178 patients, 106 underwent chemonucleolysis and 72 laminectomy. Workers' compensation was being paid to 21.6% of the chemonucleolysis patients and 20.8% of the laminectomy patients. Postoperatively, substantial improvement was noted in 82.7% of the chemonucleolysis patients and 92.5% of the laminectomy patients at 6 weeks and in 92.8% of the chemonucleolysis patients and 89.7% of the laminectomy patients at 6 months. The majority of patients in both groups had improved neurological signs. Follow-up questionnaires at 1 to 4 years postoperatively revealed an overall success rate of 86.5% for chemonucleolysis patients and 83.8% for laminectomy patients. In patients not receiving workers' compensation, 90.1% of the chemonucleolysis patients and 88.6% of the laminectomy patients had a successful outcome; in those receiving workers' compensation, 69.6% of the chemonucleolysis patients and 60.0% of the laminectomy patients had a successful outcome. No statistically significant differences in improvement rate in neurological symptoms or signs were identified between the two procedures. Overall, 85.1% of the chemonucleolysis patients and 78.5% of the laminectomy patients were employed at follow-up review. To achieve optimum results and eliminate noncandidates for chemonucleolysis, routine use of postmyelography CT is recommended. When properly used, chymopapain chemonucleolysis is an acceptable alternative to surgical discectomy.

Neonatal intracranial choriocarcinoma.

A 1-month-old infant died from extensive intracerebral hemorrhage due to a metastatic choriocarcinoma to the brain that presumably originated in the placenta. The clinical course was characterized by hyperbilirubinemia, repeated episodes of seizures, and intracranial hemorrhage. A computed tomographic scan revealed a large vascular mass in the left parieto-occipital region and a small lesion in the left frontal lobe. The placenta was expelled during the delivery and was not examined. In view of the high level of maternal human chorionic gonadotropic hormone and the autopsy finding of metastasis, we presumed that the mass was a metastatic choriocarcinoma that had originated in the maternal placenta. To our knowledge, only one previous instance of this phenomenon has been reported.

Sensitization of C6 glioma to carboplatin cytotoxicity by hyperthermia and thymidine.

Thymidine (a nucleoside metabolite) and 41.8 degrees C hyperthermia were used to sensitize C6 glioma cells to carboplatin cytotoxicity in vitro. Clinically achievable thymidine concentrations (0, 200, 400, or 1000 micrograms/ml X 24 hours) significantly enhanced carboplatin killing. Clinically achievable hyperthermia exposures (40.5 or 41.8 degrees C X 1 hour) also enhanced carboplatin killing; 41.8 degrees C was more effective than was 40.5 degrees C. Thymidine and 41.8 degrees C hyperthermia together enhanced carboplatin killing significantly more than did the thymidine-carboplatin or hyperthermia-carboplatin combinations. These results illustrate the concept of 'combination chemosensitization' for simultaneously addressing the divergent drug resistance mechanisms of malignant gliomas.

Radiosensitization of C6 glioma by thymidine and 41.8 degrees C hyperthermia.

The cytotoxic, antiproliferative, and radiosensitizing effects of thymidine (a nucleoside metabolite) were studied using the C6 glioma cell line in vitro. Radiosensitization by a combination of thymidine and 41.8 degrees C hyperthermia was also evaluated. Thymidine concentrations above 100 micrograms/ml completely inhibited C6 proliferation while concentrations of 100 to 1000 micrograms/ml (for up to 24 hours) decreased C6 cell survival to as little as 7.4% compared to untreated control cells. Radiosensitivity was enhanced by the administration of thymidine alone (400 micrograms/ml x 24 hours before irradiation); sensitization by 41.8 degrees C hyperthermia alone (1 hour ending immediately before irradiation) was less pronounced. Thymidine and hyperthermia together produced greater radiosensitization than did heat alone or thymidine alone. These data support the further investigation of thymidine as a neuro-oncology radiosensitizer.

Signs and symptoms after chemonucleolysis. A detailed evaluation of 214 worker's compensation and noncompensation patients.

The effectiveness of chemonucleolysis was examined in a retrospective study of 214 consecutive patients with herniated lumbar discs. All patients were candidates for surgery. All underwent myelography, and most had computed tomography (CT) scans. The clinical status of patients was assessed at 6 weeks and at 6 months, and evaluation was made from responses of the patients to a questionnaire at 1 year. Evaluation at 1 year demonstrated that the results of chemonucleolysis were successful for 181 patients (84.6%). Of the 172 patients who received no worker's compensation, the procedure was successful for 90.7%. Of 42 with worker's compensation, the success rate was 59.5%. After chemonucleolysis, most patients showed neurologic improvement. Data comparing neurologic symptoms and signs between compensation and noncompensation patients are presented. This is the first report of objective data after chemonucleolysis in these two groups. A discussion on the morbidity and mortality of chemonucleolysis is included, along with a comparison of cost between chemonucleolysis and laminectomy.

Anticonvulsive and convulsive effects of lidocaine: comparison with those of phenytoin, and implications for mechanism of action concepts.

The anticonvulsive action of lidocaine was tested in mice against a series of convulsants, and its profile of action compared with that of phenytoin. Both agents antagonized seizures induced by ouabain or glutamate (injected i.c.b.), effects attributable to reduction of the sodium conductance of neuronal membranes. Lidocaine and phenytoin were relatively ineffective against convulsants that act on synaptic chloride channels via the GABA-ionophore receptor complex. At higher dose levels, both lidocaine and phenytoin are excitatory within limited ranges. Lidocaine-induced seizures were potentiated by phenytoin, and antagonized by chlordiazepoxide, phenobarbital, valproate, trimethadione and muscimol, but not by ethosuximide. This profile of action is similar to that of bicuculline, suggesting that lidocaine may bind to the GABA recognition site and to another site in the GABA-ionophore receptor complex. Phenytoin-induced excitation was antagonized by chlordiazepoxide, less effectively by phenobarbital or trimethadione, only minimally by valproate, and not by trimethadione or muscimol. Phenytoin is known to bind to picrotoxin and benzodiazepine receptor sites; these findings suggest that it may be excitatory at one or both of these sites.

Effects of anticonvulsants on K+-induced excitation and on penicillin-induced seizures.

Excitation induced in mice by intracerebral injection of KCl was antagonized by prior i.p. injection of phenytoin, chlordiazepoxide or phenobarbital, but was not significantly affected by muscimol, valproate, ethosuximide or trimethadione. In contrast, seizures induced by intracerebral injection of benzyl penicillin were antagonised by chlordiazepoxide, phenobarbital, valproate, ethosuximide and trimethadione, but not by phenytoin or muscimol. Implications with regard to mechanisms of action of the anticonvulsants and of penicillin are discussed.

Chymopapain chemonucleolysis: correlation of diagnostic radiographic factors and clinical outcome.

The therapeutic response to treatment of lumbar disk herniation with chymopapain chemonucleolysis is significantly influenced by the criteria used for patient selection. Although careful clinical selection of patients reduces the frequency of treatment failure, some patients do not achieve satisfactory relief of pain with chemonucleolysis. In an attempt to identify objective pretreatment radiographic findings that might refine selection criteria and further reduce the failure rate of chemonucleolysis, a retrospective correlation of pretreatment radiographs and clinical responses was made of 200 consecutive chemonucleolysis patients. Marked improvement in sciatica occurred in 79.9% and 79.3% of patients at early and late follow-up, respectively. There was a significantly higher response rate, however, in patients who had definite radiographic evidence of focal disk herniation and in those patients with definite radiographic evidence of nerve-root compression (marked nerve-root deviation, nerve-root flattening or edema, root-sleeve amputation) by disk material. Those patients with a preinjection disk height greater than the mean had a slightly better response rate (91.1%) than those whose disk height was smaller than the mean (80.0%). Most cases of treatment failure could be attributed to an incorrect radiographic diagnosis, treatment of patients with equivocal diagnostic studies, the presence of "free" disk fragments, and causes of nerve-root compression unresponsive to chymopapain.

Chymopapain chemonucleolysis: CT changes after treatment.

Chymopapain chemonucleolysis is now used extensively in this country to treat lumbar disk herniation. Despite increasing experience in patient selection, there continue to be patients who do not respond to treatment and require diagnostic reevaluation. Interpretation of postchemonucleolysis computed tomographic (CT) scans in these patients requires a knowledge of the CT changes that normally occur after treatment with chemonucleolysis. To define these temporal changes, a prospective CT evaluation was performed of 29 treated interspaces in 26 patients who returned for routine postchemonucleolysis follow-up. Despite a successful clinical response in 17 of 21 patients, changes in the size, location, shape, homogeneity, and density of the disk herniation were uncommon at the 6 week follow-up. In 24 treated interspaces, the most common changes at 6 week CT follow-up were the development of vacuum phenomenon in three (12.5%) and a slight decrease in the size of two (8.3%) disk herniations. A successful response was noted in 17 of 21 patients scanned at 6 month follow-up, with five (22.7%) of 22 injected interspaces exhibiting vacuum phenomenon and 13 (59.1%) interspaces showing an observable decrease in the size of the disk herniation. Early improvement of sciatica after chemonucleolysis often occurs without a change in the size of the disk herniation and may be mediated by chymopapain-induced disk-space narrowing. Continued improvement may be accompanied by both a decrease in the disk height and a reduction in the size of the disk protrusion.

Efficacy of chymopapain chemonucleolysis. A long-term review of 105 patients.

A 9- to 12-year follow-up review was conducted in 105 of 124 patients who were treated with chymopapain chemonucleolysis for herniated lumbar disc. The data were obtained from responses to a questionnaire. Seventy-nine patients (75.2%) reported marked improvement, six (5.7%) had slight improvement, and 20 (19.0%) had no improvement. Of the 87 patients not receiving workman's compensation, 70 patients (80.5%) had marked improvement; four (4.6%) had slight improvement; and 13 (14.9%) had no improvement. Of the 18 compensation cases, nine patients (50.0%) had marked improvement; two patients (11.1%) had slight improvement; and seven patients (38.9%) had no improvement. These results are comparable to those reported for surgical discectomy, and confirm that chymopapain chemonucleolysis is an alternative to surgery.