Introduction

Chemonucleolysis is a medical procedure that involves the dissolving of the gelatinous cushioning material in an intervertebral disc by the injection of an enzyme such as chymopapain. In 1956, Thomas⁷ injected papain into the vein of a rabbit’s ear, observed the floppiness of that ear (compared with the erect state of the control ear), and confirmed softening of the cartilage attributable to papain.

Chemonucleolysis with chymopapain was introduced by Smith and Brown^8,9 in 1964 as an effective therapy for some types of intervertebral disc herniation. However, because of the protein nature of chymopapain, anaphylactic reactions and neurotoxicity have limited the use of this therapy. Although it has demonstrated long-term success rates between 66% and 88%,^10,11 a controlled study initiated by the US Food and Drug Administration¹² (FDA) found chymopapain no more effective than placebo. Though it has become commercially unavailable in the US, it is still widely used outside of the US.

Two enzymes have been described as effective when used in vivo: chymopapain, which catalyzes the hydrolytic cleavage of glycosaminoglycans from proteoglycan aggregates in the disc, and collagenase, which splits the type 2 collagen fibers with relative particularity. The basic collagenase enzyme synthesized by Clostridium histolyticum consists of varied subenzymes that split the collagen fibers at different locations. The purified collagenase is relatively specific for type 2 collagen, seen mainly in the nucleus pulposus, which consists of 15–20% collagen in its dry weight. Wittenberg et al.¹³ did a 5-year clinical follow-up assessment of a prospective, randomized study of chemonucleolysis using chymopapain (4000 IU) or collagenase (400 ABC units). At 5 years, good and excellent results were observed in 72% of the chymopapain group and 52% of the collagenase group.

If conservative treatment in patients with recurrent disc herniation after chemonucleolysis fails, surgery is usually recommended. Historically, a second injection was considered contraindicated because of the fear of allergic or anaphylactic reactions. Schweigel and Berezowskyj¹⁴ suggested a second injection of chymopapain generally is contraindicated. They observed five major anaphylactic reactions in a review of 35 patients. Due to the high incidence of anaphylaxis, they considered repeat use of chymopapain to be an unacceptable alternative to surgery until a definitive test for chymopapain sensitivity is available.

Sutton¹⁵ did not observe an anaphylactic reaction when patients were premedicated with histamine receptor blockers. The effect of histamine, released by the immunoglobulin E mediated mast cells, will be blocked. Van de Belt et al.¹⁶ reviewed 85 patients who received a second injection of chymopapain because of a recurrent disc herniation between 1980 and 1996. All patients were pretreated for 3 days with H₁ and H₂ receptor blockers. Immediate sensitivity reactions were not seen. Four type 1 and one type 2 reactions were seen after the second injection, and no other complications were seen.

Age can be a factor in choosing patients for chemonucleolysis. Patients older than 60 years may lack sufficient mucoprotein in the offending disc to be hydrolyzed. Patients younger than 20 years have not been studied as frequently as older patients, but 80–90% satisfactory results are reported even though stiffness of the back may persist for a year or more. Single-level involvement with leg pain greater than back pain, corroborative physical findings, and imaging studies represent the ideal chemonucleolysis candidate.¹⁷ A successful intervention depends on the chymopapain reaching the mucoprotein of the herniated nucleus pulposus to hydrolyze it, so there must not be a sequestrated fragment surrounded by fibrosis or a posterior ligament defect closed by fibrosis to prevent the enzyme reaching an extrusion. If the offending herniation is primarily composed of annular tissue, its collagenous content will not be reduced by chymopapain. Spinal stenosis, whether central or lateral, may be exacerbated by chemonucleolysis rather than helped. Deburge et al.¹⁸ reported lateral recess stenosis in 16 patients and two cases of sequestrated discs in 38 patients who had not been successfully treated with chymopapain.

For the diagnosis of disc abnormalities, MRI is superior to CT scan However, MRI is not as effective in the diagnosis of bony lesions, which makes CT scan essential in the preoperative evaluation of chemonucleolysis. With CT scan, information regarding chronic degenerative disc abnormalities, such as lateral recess stenosis and facet hypertrophy, as well as bony spurs and calcified discs, may be obtained. If a soft protrusion is demonstrated without spinal stenosis on CT scan, the success rate is expected to be better (Table 85.1).¹⁹

Table 85.1 Contraindications for chemonucleolysis

Complications

Between 1982 and 1991, 121 adverse events in 135 000 patients were reported to the FDA and investigated. Seven cases of fatal anaphylaxis, 24 infections, 32 bleeding problems, 32 neurological events, and 15 miscellaneous occurrences were found. The overall mortality rate was 0.019%.¹⁷ A major disadvantage of chemonucleolysis is the occurrence of back spasm, which can be quite severe in approximately 10% of patients.¹⁷ Comparing the complications of laminectomy reported by Ramirez and Thisted.⁴ in 1989 with those of chemonucleolysis, Nordby et al.¹⁷ reported that he found anaphylaxis to be unique to chemonucleolysis; infection occurred 17 times as often with laminectomy as with chemonucleolysis, neurologic and hemorrhagic events six times as often with laminectomy, and mortality rates incidental to the procedures occurred three times as frequently with laminectomy. Other potential complications include overdecompression, disc collapse, or instability of the motion segment. These side effects can result from excess ‘digestion’ of disc material. More serious complications have been reported, including lumbar subarachnoid hemorrhage and paraplegia. When chymopapain is inadvertently injected into the subarachnoid space, a cauda equina syndrome results.²⁰ Wittenberg et al.¹³ reported cauda equina syndrome in two patients using collagenase. A case of acute transverse myelitis (ATM) was observed 21 days after an injection in 1982, and an additional five cases were subsequently reported to the FDA.²¹ Since no case of ATM has occurred in nearly 60 000 cases since 1984, an association between ATM and chemonucleolysis probably does not exist. Consequently, as of 1992, the FDA approved removing even the mention of ATM from the detailed chymopapain package Full Prescribing Information.²¹

Long-term results

Following chemonucleolysis, relief of leg pain is immediate; however, in up to 30% of patients, maximal relief of symptoms may take up to 6 weeks. There are some specific measures that can be utilized during chemonucleolysis to reduce the incidence of low back pain which includes infiltrating the needle track with local anesthetic and the use of antiinflammatory medications after the procedure.²²

A prospective, placebo-controlled, double-blind, multicenter, crossover trial of 88 patients demonstrated a 73% success rate in the chemonucleolysis group and a 42% success rate in the placebo group The failures in the placebo group later underwent chemonucleolysis and had a 90% success rate.²³ The primary end point for considering a patient a failure was if the patient had pain severe enough to consider another intervention for treatment.

Nordby et al.¹⁷ reported that in a 7–10-year follow-up of 3130 patients with chemonucleolysis, overall satisfactory results were reported from 71–93% among the 13 contributors for an average of 77%. The use of chymopapain has been greater in Europe and Australia than in the United States since the acute transverse myelitis scare, and intrathecal complications have been rare there. A combined long-term report of 1736 patients in 1992 from the United Kingdom, France, and Germany showed good to excellent results of 66–84%, with an overall average of 75.3%. A prospective, randomized, controlled trial comparing automated percutaneous lumbar discectomy (APLD) to chemonucleolysis for the treatment of sciatic pain reported a 1-year outcome of 66% success in the chemonucleolysis group and 37% in the APLD group.²⁴

The most compelling evidence that chemonucleolysis is a safe and effective treatment for herniation of the nucleus pulposus is found in well-designed and conducted prospective, randomized, double-blind studies in the United States and Australia.²⁵ One of these double-blind studies has been carried through for 10 years without code break or loss of follow-up. Success persisted in 77% of patients with chemonucleolysis compared with only 38% for the placebo group (p=0.004). Only six of the patients with chemonucleolysis had required laminectomy compared with 14 in the placebo group (p=0.028).

Launois et al.²⁶ reported the success rate at 1 year for chemonucleolysis at 88% and for laminectomy at 76%. Chemonucleolysis continued to be superior to surgery after an additional year. In a 9–11-year prospective, randomized study comparing patients with these two methods, Wilson et al.²⁷ concluded that ‘surgically treated patients that had done well initially deteriorated with time, whereas those who did well following chemonucleolysis maintained a successful outcome in the long-term cost savings.’ A major consideration in cost savings is the absence of epidural scarring or adhesive arachnoiditis with chemonucleolysis, thus avoiding the frequent ‘failed back syndrome’ seen with laminectomy, which has become an ever-increasing health and economic burden.²⁸ When the results of surgery after chemonucleolysis failure were compared with the results from microdiscectomies performed without prior injections, slightly more good and excellent results were observed in the primary surgery patients.²⁹

Other authors such as McCulloch and MacNab³⁰ stated that open surgery was easier after prior chemonucleolysis.

Norton³¹ obtained very poor results in patients treated either surgically or with chymopapain. All of his patients were claiming workmen’s compensation. Others have shown that on treatment with chymopapain such patients do not respond as well as those who are more highly motivated and covered by private insurance.

Nordby and Wright³² reported that 45 studies were analyzed, some including comparisons of chemonucleolysis to open laminectomy/discectomy and others to percutaneous discectomy. Individual success rates exceeded 60%, whereas cohort total averaged 76%. In studies comparing chemonucleolysis with open discectomy, success rate averaged 76.2% as compared with 88% for open surgery. In two other studies, percutaneous discectomy was less successful than chemonucleolysis. Where included, duration of hospitalization showed less time and thus less costs for chemonucleolysis. Return to work compilations showed time off slightly less for chemonucleolysis than for laminectomy.

Wittenberg et al.¹³ reported a 5-year clinical follow-up assessment of a prospective, randomized study of chemonucleolysis using chymopapain (4000 IU) or collagenase (400 ABC units); patients in the chymopapain group started work in the same job an average of 8 weeks after injection, whereas patients in the collagenase group returned to work after an average of 11 weeks.

Kim et al.¹⁹ reported that three thousand patients with herniated lumbar disc were treated with chemonucleolysis between 1984 and 1999 and found that the clinical success rate in their series was 85%. The patient group with the chief complaint of leg pain achieved a better clinical outcome than the patient group with low back pain (88% versus 59%), and a positive straight leg raising test was strongly correlated with good clinical outcome. Patients manifesting a soft, protruded disc had a better outcome than those manifesting diffuse bulging disc. Other prognostic factors favoring a good outcome were young age, short duration of symptoms, and no bony spur or calcification on radiological study.

Revel et al.³³ conducted a randomized clinical trial to compare the results of automated percutaneous discectomy with those of chemonucleolysis in 141 patients with sciatica caused by a disc herniation; 69 underwent automated percutaneous discectomy and 72 were subjected to chemonucleolysis. The principal outcome was the overall assessment of the patient 6 months after treatment. Treatment was considered to be successful by 61% of the patients in the chemonucleolysis group compared with 44% in the automated percutaneous discectomy group. At 1-year follow-up, overall success rates were 66% in the chemonucleolysis group and 37% in the automated percutaneous group. Within 6 months of treatment, 7% of the patients in the chemonucleolysis group and 33% in the discectomy group underwent subsequent open surgery. The complication rates of both treatment groups were low, with the exception of a high rate of low back pain in the chemonucleolysis group (42%). In another prospective study, 22 patients with painful disc herniations were randomized either to chemonucleolysis or APLD; at 2 years the chemonucleolysis-treated patients were significantly better, based upon outcomes as measure with the Oswestry Disability Index, back pain and leg pain recurrence.³⁴

The combination of low-dose chemonucleolysis with 500 IU chymopapain followed by an automated percutaneous nucleotomy of the cervical spine has been performed. A follow-up of at least 1 year of the first 22 patients showed in 19 patients good or excellent results. In one patient a fair result was obtained and in two patients the symptoms were unchanged.³⁵

Introduction

In 1975, Hijikata et al.² performed the first percutaneous discectomy using modified pituitary rongeurs. A decade later in 1985, Onik and colleagues²⁴ developed the nucleotome, an automated suction shaver that allows for the performance of an automated percutaneous lumbar discectomy (APLD). The shaver functioned by drawing the nucleus pulposus into a small cutting port and eliminated a portion of the nucleus via a reciprocating ‘guillotine-like’ blade. APLD utilized a 20.3 cm needle inserted through a 2.8 mm diameter cannula. Onik and Helms³⁶ reported an 85% success rate independent of the amount of disc material removed. It is believed that the removal of nuclear material from the center of the disc results in disc decompression. Ultimately, it is believed this decreases pressure transmitted through the rent in the anulus to the herniation. This results in decreased pressure on the affected nerve.

Indications

Different morphological and pathophysiological parameters are used to define criteria for selecting candidates for APLD. Some clinicians stress the value of CT discography. Mochida and Arima³⁷ demand the absence of perforation of the posterior longitudinal ligament and degenerative canal stenosis detected by CT or MRI along with other clinical guidelines including age and disturbance of innervated muscles.

APLD is efficacious for patients whose herniations are still contained by the anulus or the posterior longitudinal ligament. Patients with sequestered fragments are not candidates because there is no biomechanical mechanism by which that fragments would be resorbed. MRI can be extremely helpful in excluding obviously migrated fragments and large disc extrusions.³⁶ An absolute contraindication of APLD is the migration of a disc fragment. When small degrees of migration are present (3 mm or less) the possibility of a good result from APLD is not precluded. The success rate for APLD is about 43% in those patients who had fragments that migrated more than 3 mm from the disc space. In a study by Carragee and Kim examining outcomes of open discectomy, it had been shown that herniations larger than 6 mm generally did well with discectomy, whereas smaller herniations were associated with a poor outcome (26% success).³⁸ These studies suggest that patients with smaller herniations are ideal candidates for APLD and probably with other techniques that effect percutaneous disc decompression.

A CT discogram is the most definitive procedure for selecting patients for APLD which demonstrate complete tears of the anulus and posterior longitudinal ligament. A CT discogram also allows the assessment of the size of the rent in the anulus that is communicating with the herniation. Besides the characterization of the herniation on imaging studies, patients should clinically have the symptoms of radiculopathy.³⁶ APLD is not a procedure for those patients with vague or equivocal symptoms or simply a bulging disc. APLD can be an excellent procedure for patient who has had a reherniation at the site level of previous disc surgery. These patients who are reoperated at the same level obtain lower success rates, as well as being exposed to a much higher morbidity due to lack of tissue planes caused by epidural fibrosis. APLD takes a posterolateral course that avoids the epidural space and does not create epidural fibrosis. Mirovsky and Neuwirth³⁹ reported 10 patients with lumbar disc reherniation at the same level as a previously open operation with follow-up of 2.5 years They report that 70% of their patients showed complete or significant pain relief avoiding reoperation. Sixty percent showed motor deficit improvement. Failure was primarily relegated to those with spinal stenosis or segmental instability.

Onik et al.⁴⁰ reported that patients whose herniations occur in the lateral location beyond the intervertebral foramen are candidates for APLD. Such patients are difficult to treat with the traditional interlaminar approach of microdiscectomy, which requires the removal of all or a large portion of the facet. APLD showed excellent results in those patients because the percutaneous discectomy instrumentation drives over the herniation itself. The poor results occurred in patients with concomitant stenosis.⁴¹

ALPD can be the procedure of choice for those patients suspected of infectious discitis. The first principles of treatment for disc space infection are to make the diagnosis and isolate the organism. Diagnosis may be delayed because patient’s complaints are relatively non-specific. Imaging studies may direct one to the diagnosis, but tissue must be obtained for the confirmation and isolation of the organism. APLD biopsy is a minimally invasive procedure for obtaining sufficient material for histological analysis and culture. The rate of secondary surgical intervention may be reduced if infected disc material is removed by percutaneous biopsy; however, surgical treatment is indicated in all patients who develop neurological deficits as well as in the presence of epidural or retroperitoneal abscess.⁴² Gebhard and Brugman⁴³ reported a case in which nucleotome was used to remove 5 ml of disc material and the disc space was irrigated with 75 ml of normal saline containing cefazolin, the patient reported immediate relief of his back and thigh pain. Fouquet et al.⁴⁴ obtained bacteriologic diagnosis in only nine of 25 patients biopsied with a Mazabraud trocar. Krodel et al.⁴⁵ reported seven positive cultures of 15 patients who underwent needle biopsy. Yu et al.⁴⁶ described two cases in which automated biopsy was used to diagnose unusual infections include Candida discitis and tuberculosis.

Percutaneous discectomy has been used also in the treatment of cervical disorders. Theron et al.,⁴⁷ in 1992, reported preliminary experience in 23 cases. All patients complained of neck pain or brachialgia due to single, soft herniated disc at a single level; the success rate was 80%. They later reported 78 treated cases, including 68 with follow-up of at least 6 months and overall success rate of 70.6%, and no complication was reported (Table 85.2).

Table 85.2 Contraindications for APLD