- Email: [email protected]
Urological Complications Following Chemonucleolysis
0022-5347 /85/l336-l065$D2.00/0
Vo!. 133, June Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright© 1985 by The Williams & Wilkins Co.
UROLOGICAL COMPLICATIONS FOLLOWING CHEMONUCLEOLYSIS B. BERKSON, M. G. ZAKHARY, M. L. PRIMACK AND R. FIRFER From the Division of Urology, Louis A. Weiss Memorial Hospital and University of Illinois School of Medicine, Chicago, Illinois
ABSTRACT
Urinary complications following chemonucleolysis have not been reported in the urological literature. We report a case of urinary retention, perineal hypoesthesia and penile dysesthesia following L5 to Sl chemonucleolysis with chymopapain and review the literature in this area. Chemonucleolysis was described by Smith and Brown as a chemical dissolution of the nucleus pulposus by the intradiskal injection of the enzyme, chymopapain, a proteolytic enzyme derived from the fruit Carica papaya. 1 • 2 Clinical trials of chemonucleolysis were begun in July 1963 in humans suffering from sciatica secondary to herniated nucleus pulposus. 1 In 1974 the drug was under clinical investigation in the United States. The Food and Drug Administration withdrew the investigation in 1975 because of concerns about its efficacy. A new clinical trial subsequently was done in Illinois with a purified form of chymopapain, which led to approval by the Food and Drug Administration in April 1983. Several complications have been reported secondary to the use of chymopapain. We present a case of urological interest.
except for a small free fragment in the extradural spinal canal at the SI level. Final diagnosis was hyporeflexic type bladder neuropathy secondary to chemonucleolysis. The patient was discharged from the hospital on intermittent catheterization. A month later the patient began to void voluntarily with a residual urine of less than 30 cc. However, he noticed dyspareunia at this time, which was secondary to extreme hyperesthesia of the glans penis. Urinalysis and urine culture were negative. Physical examination of the genitalia was normal. The glandular hyperesthesia became progressively worse for several weeks and then improved slowly. The perineal hypoesthesia also resolved eventually. DISCUSSION
CASE REPORT
A 59-year-old white man presented with a history of low backache, as well as pain and numbness of the left leg and foot. There were no urological complaints. Examination revealed left buttock pain on 60-degree hip flexion, tenderness over the left sciatic notch, and hyperesthesia of the lateral aspect of the left leg and foot. A metrizamide myelogram demonstrated asymmetry of the L4 and L5 facets, with bulging of the L4 and L5 disk, and herniated nucleus pulposus to the left at the L5 to 81 level. Electromyography and nerve conduction studies were normal. On February 3, 1984 the patient underwent a lumbar diskogram through a lateral approach under general anesthesia with iothalmate meglumine. Then, chemonucleolysis was performed with 3,000 units chymopapain dissolved in 1.5 ml. sterile water, and injected at the disk between the L5 and Sl vertebrae. Immediately following the procedure the symptoms improved significantly. However, generalized hives, pruritus, marked hypertension and chills developed 6 hours after disk injection and the patient was unable to void. The allergic reaction responded well to medical treatment. The bladder was catheterized intermittently with several unsuccessful trials at voiding during the following 5 days. Urological evaluation then was obtained. No obstructive uropathic condition was seen at cystoscopy. The bulbocavernosus reflex was intact. Urodynamic evaluation revealed an increased bladder capacity (800 cc) with a decreased intravesical voiding pressure (10 to 12 cm. water). Bladder sensation was intact with a first desire to void at 175 cc. Sphincter electromyography and urethral pressure profilometry were normal. Administration of 5 mg. bethanechol subcutaneously resulted in a 10 cm. increase in resting intravesical pressure. At that time the patient also began to complain of perineal hypoesthesia. A neurological consultation was obtained but no other neurological deficit could be detected. A computerized tomography scan of the lumbar spine on February 8 failed to demonstrate any change from the initial myelogram findings Accepted for publication February 27, 1985.
The most dramatic complication of chemonucleolysis is acute anaphylactic reaction, which usually occurs within 15 minutes after injection. The reported incidence is 0.2 to 1 per cent. 3- 7 Hiroshi reported on a 48-year-old man who had transverse myelitis and urinary retention 3 weeks after chemonucleolysis with chymopapain. 7 This case also was reported among 25 other cases of complications, including cerebral hemorrhage, paraplegia/paraparesis, seizure, Guillain-Barre syndrome and hemiparesis.8 Among these patients 5 presented with neurogenic bladder dysfunction in association with the neurological disorder. Several theories have been postulated to explain the complications. Smith and Brown reported a case of thoracic paraplegia following chemonucleolysis for left sciatica in which hemorrhagic arachnoiditis was found on exploration of the spinal cord. 2 This condition was attributed to hemorrhage and retained contrast medium in the subarachnoid space. Sussman reported 2 other instances of paraplegia following chymopapain administration but failed to document the level of paralysis. 9 Serum radioimmunoassay studies for chymopapain immunoreactive protein have revealed that therapeutic intradiskal injection of 4 to 12 mg. chymopapain results in peak plasma levels at 24 hours, followed by a gradual decrease during 1 week. 10 Decreasing plasma levels corresponded to increasing concentrations of antichymopapain immunoreactive protein. Kapsalis and associates studied 1,263 patients, including 12 who had had an anaphylactic reaction. 11 While 7 of the 12 patients had antichymopapain antibodies of the IgE class 60 who did not have an anaphylactic reaction had similar antibodies. Other factors believed to contribute to reported complications are malpositioning of the intradiskal needle, intrathecal injection of chymopapain, or the effect of chymopapain and/or the myelogram contrast medium. 12· 13 Thrombosis of the anterior spinal artery by an autoimmune mechanism was suggested by Abramsky and Teitelbaum to explain transverse myelitis after chemonucleolysis. 14 To our knowledge we present the only case in which the urological complications are the only presentation, with no
1065
1066
BERKSON AND ASSOCIATES
other neurological deficit. Whether any of these theories explain our case remains unknown. We believe that the urologist should be aware of the potential of neurogenic bladder dysfunction developing after chemonucleolysis, as well as the possibility of hyperesthetic and hypoesthetic conditions of the genitalia and perineum. Further investigations are necessary to explain the etiology behind these complications. REFERENCES 1. Smith, L.: Enzyme dissolution of the nucleus pulposus in humans. J.A.M.A., 187: 137, 1964. 2. Smith, L. and Brown, J. E.: Treatment of lumbar intervertebral disc lesions by direct injection of chymopapain. J. Bone Joint Surg., 49: 502, 1967. 3. Graham, C. E.: Chemonucleosis: a double blind study comparing chemonucleosis with intra discal hydrocortisone: in the treatment of backache and sciatica. Clin. Orthop., 11 7: 179, 1976. 4. McCulloch, J. A.: Chemonucleolysis for relief of sciatica due to a herniated intervertebral disc. Canad. Med. Ass. J., 124: 879, 1981. 5. Watts, C.: Complications of chemonucleolysis for lumbar disc disease. Neurosurgery, 1: 2, 1977. 6. Wiltse, L. L., Widell, E. R., Jr. and Yuan, H. A.: Chymopapain chemonucleolysis in lumbar disk disease. J.A.M.A., 231: 474, 1975.
7. Eguro, H.: Transverse myelitis following chemonucleolysis: report of a case. J. Bone Joint Surg., 65A: 1328, 1983. 8. Update on the Safety and Efficacy of Chymodiactin (chymopapain). Northbrooke, Illinois: Smith Laboratories, Inc., March 15, 1984. 9. Sussman, B. J.: Inadequacies and hazards of chymopapain injections as a treatment of intervertebral disc disease. J. Neurosurg., 42: 389, 1975. 10. Kapsalis, A. A., Stern, I. J. and Bornstein, I.: The fate of chymopapain injected of therapy of intervertebral disc disease. J. Lab. Clin. Med., 83: 532, 1974. 11. Kapsalis, A. A., Stern, I. J. and Bornstein, I.: Correlation between hypersensitivity to parenteral chymopapain and the presence of IgE anti-chymopapain antibody. Clin. Exp. Immunol., 33: 150, 1978. 12. Kelley, R. E., Daroff, R. B., Sheremata, W. A. and McCormick, J. R.: Unusual effects of metrizamide lumbar myelography. Constellation of aseptic meningitis, arachnoiditis, communicating hydrocephalus, and Guillain-Barre syndrome. Arch. Neurol., 37: 588, 1980. 13. Peroutka, S. J., Ullrich, C. G., Fisher, R. S., Suss, R. A. and Brooks, B. R.: Transient areflexia and quadriplegia following metrizamide myelography. Letter to the Editor. Ann. Neurol., 12: 406, 1982. 14. Abramsky, 0. and Teitelbaum, D.: The autoimmune features of acute transverse myelopathy. Ann. Neurol., 2: 36, 1977.
Vo!. 133, June Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright© 1985 by The Williams & Wilkins Co.
UROLOGICAL COMPLICATIONS FOLLOWING CHEMONUCLEOLYSIS B. BERKSON, M. G. ZAKHARY, M. L. PRIMACK AND R. FIRFER From the Division of Urology, Louis A. Weiss Memorial Hospital and University of Illinois School of Medicine, Chicago, Illinois
ABSTRACT
Urinary complications following chemonucleolysis have not been reported in the urological literature. We report a case of urinary retention, perineal hypoesthesia and penile dysesthesia following L5 to Sl chemonucleolysis with chymopapain and review the literature in this area. Chemonucleolysis was described by Smith and Brown as a chemical dissolution of the nucleus pulposus by the intradiskal injection of the enzyme, chymopapain, a proteolytic enzyme derived from the fruit Carica papaya. 1 • 2 Clinical trials of chemonucleolysis were begun in July 1963 in humans suffering from sciatica secondary to herniated nucleus pulposus. 1 In 1974 the drug was under clinical investigation in the United States. The Food and Drug Administration withdrew the investigation in 1975 because of concerns about its efficacy. A new clinical trial subsequently was done in Illinois with a purified form of chymopapain, which led to approval by the Food and Drug Administration in April 1983. Several complications have been reported secondary to the use of chymopapain. We present a case of urological interest.
except for a small free fragment in the extradural spinal canal at the SI level. Final diagnosis was hyporeflexic type bladder neuropathy secondary to chemonucleolysis. The patient was discharged from the hospital on intermittent catheterization. A month later the patient began to void voluntarily with a residual urine of less than 30 cc. However, he noticed dyspareunia at this time, which was secondary to extreme hyperesthesia of the glans penis. Urinalysis and urine culture were negative. Physical examination of the genitalia was normal. The glandular hyperesthesia became progressively worse for several weeks and then improved slowly. The perineal hypoesthesia also resolved eventually. DISCUSSION
CASE REPORT
A 59-year-old white man presented with a history of low backache, as well as pain and numbness of the left leg and foot. There were no urological complaints. Examination revealed left buttock pain on 60-degree hip flexion, tenderness over the left sciatic notch, and hyperesthesia of the lateral aspect of the left leg and foot. A metrizamide myelogram demonstrated asymmetry of the L4 and L5 facets, with bulging of the L4 and L5 disk, and herniated nucleus pulposus to the left at the L5 to 81 level. Electromyography and nerve conduction studies were normal. On February 3, 1984 the patient underwent a lumbar diskogram through a lateral approach under general anesthesia with iothalmate meglumine. Then, chemonucleolysis was performed with 3,000 units chymopapain dissolved in 1.5 ml. sterile water, and injected at the disk between the L5 and Sl vertebrae. Immediately following the procedure the symptoms improved significantly. However, generalized hives, pruritus, marked hypertension and chills developed 6 hours after disk injection and the patient was unable to void. The allergic reaction responded well to medical treatment. The bladder was catheterized intermittently with several unsuccessful trials at voiding during the following 5 days. Urological evaluation then was obtained. No obstructive uropathic condition was seen at cystoscopy. The bulbocavernosus reflex was intact. Urodynamic evaluation revealed an increased bladder capacity (800 cc) with a decreased intravesical voiding pressure (10 to 12 cm. water). Bladder sensation was intact with a first desire to void at 175 cc. Sphincter electromyography and urethral pressure profilometry were normal. Administration of 5 mg. bethanechol subcutaneously resulted in a 10 cm. increase in resting intravesical pressure. At that time the patient also began to complain of perineal hypoesthesia. A neurological consultation was obtained but no other neurological deficit could be detected. A computerized tomography scan of the lumbar spine on February 8 failed to demonstrate any change from the initial myelogram findings Accepted for publication February 27, 1985.
The most dramatic complication of chemonucleolysis is acute anaphylactic reaction, which usually occurs within 15 minutes after injection. The reported incidence is 0.2 to 1 per cent. 3- 7 Hiroshi reported on a 48-year-old man who had transverse myelitis and urinary retention 3 weeks after chemonucleolysis with chymopapain. 7 This case also was reported among 25 other cases of complications, including cerebral hemorrhage, paraplegia/paraparesis, seizure, Guillain-Barre syndrome and hemiparesis.8 Among these patients 5 presented with neurogenic bladder dysfunction in association with the neurological disorder. Several theories have been postulated to explain the complications. Smith and Brown reported a case of thoracic paraplegia following chemonucleolysis for left sciatica in which hemorrhagic arachnoiditis was found on exploration of the spinal cord. 2 This condition was attributed to hemorrhage and retained contrast medium in the subarachnoid space. Sussman reported 2 other instances of paraplegia following chymopapain administration but failed to document the level of paralysis. 9 Serum radioimmunoassay studies for chymopapain immunoreactive protein have revealed that therapeutic intradiskal injection of 4 to 12 mg. chymopapain results in peak plasma levels at 24 hours, followed by a gradual decrease during 1 week. 10 Decreasing plasma levels corresponded to increasing concentrations of antichymopapain immunoreactive protein. Kapsalis and associates studied 1,263 patients, including 12 who had had an anaphylactic reaction. 11 While 7 of the 12 patients had antichymopapain antibodies of the IgE class 60 who did not have an anaphylactic reaction had similar antibodies. Other factors believed to contribute to reported complications are malpositioning of the intradiskal needle, intrathecal injection of chymopapain, or the effect of chymopapain and/or the myelogram contrast medium. 12· 13 Thrombosis of the anterior spinal artery by an autoimmune mechanism was suggested by Abramsky and Teitelbaum to explain transverse myelitis after chemonucleolysis. 14 To our knowledge we present the only case in which the urological complications are the only presentation, with no
1065
1066
BERKSON AND ASSOCIATES
other neurological deficit. Whether any of these theories explain our case remains unknown. We believe that the urologist should be aware of the potential of neurogenic bladder dysfunction developing after chemonucleolysis, as well as the possibility of hyperesthetic and hypoesthetic conditions of the genitalia and perineum. Further investigations are necessary to explain the etiology behind these complications. REFERENCES 1. Smith, L.: Enzyme dissolution of the nucleus pulposus in humans. J.A.M.A., 187: 137, 1964. 2. Smith, L. and Brown, J. E.: Treatment of lumbar intervertebral disc lesions by direct injection of chymopapain. J. Bone Joint Surg., 49: 502, 1967. 3. Graham, C. E.: Chemonucleosis: a double blind study comparing chemonucleosis with intra discal hydrocortisone: in the treatment of backache and sciatica. Clin. Orthop., 11 7: 179, 1976. 4. McCulloch, J. A.: Chemonucleolysis for relief of sciatica due to a herniated intervertebral disc. Canad. Med. Ass. J., 124: 879, 1981. 5. Watts, C.: Complications of chemonucleolysis for lumbar disc disease. Neurosurgery, 1: 2, 1977. 6. Wiltse, L. L., Widell, E. R., Jr. and Yuan, H. A.: Chymopapain chemonucleolysis in lumbar disk disease. J.A.M.A., 231: 474, 1975.
7. Eguro, H.: Transverse myelitis following chemonucleolysis: report of a case. J. Bone Joint Surg., 65A: 1328, 1983. 8. Update on the Safety and Efficacy of Chymodiactin (chymopapain). Northbrooke, Illinois: Smith Laboratories, Inc., March 15, 1984. 9. Sussman, B. J.: Inadequacies and hazards of chymopapain injections as a treatment of intervertebral disc disease. J. Neurosurg., 42: 389, 1975. 10. Kapsalis, A. A., Stern, I. J. and Bornstein, I.: The fate of chymopapain injected of therapy of intervertebral disc disease. J. Lab. Clin. Med., 83: 532, 1974. 11. Kapsalis, A. A., Stern, I. J. and Bornstein, I.: Correlation between hypersensitivity to parenteral chymopapain and the presence of IgE anti-chymopapain antibody. Clin. Exp. Immunol., 33: 150, 1978. 12. Kelley, R. E., Daroff, R. B., Sheremata, W. A. and McCormick, J. R.: Unusual effects of metrizamide lumbar myelography. Constellation of aseptic meningitis, arachnoiditis, communicating hydrocephalus, and Guillain-Barre syndrome. Arch. Neurol., 37: 588, 1980. 13. Peroutka, S. J., Ullrich, C. G., Fisher, R. S., Suss, R. A. and Brooks, B. R.: Transient areflexia and quadriplegia following metrizamide myelography. Letter to the Editor. Ann. Neurol., 12: 406, 1982. 14. Abramsky, 0. and Teitelbaum, D.: The autoimmune features of acute transverse myelopathy. Ann. Neurol., 2: 36, 1977.