THE IATROGENIC ASPECT OF ADHESIVE ARACHNOIDITIS

It is recognised that arachnoiditis most commonly arises from medical procedures such as surgery, myelograms and epidural injections. Clinically significant adhesive arachnoiditis is, however, a relatively rare adverse effect.

When it was originally described over 100 years ago, it was predominantly a disease of the thoracic spine, due to infections such as tuberculosis. However, nowadays, it is most common in the lumbar region, and also seen in the cervical region, whereas thoracic arachnoiditis is now uncommon. This trend is the result of the influence of iatrogenic causes.

Surgery tends to cause localised arachnoiditis, whereas chemical insults such as myelograms and epidural injections give rise to a more diffuse picture, due to their spread in the cerebrospinal axis.

The introduction of myelograms earlier this century heralded an upsurge in severe diffuse adhesive arachnoiditis. Air myelograms were the first, and these led on to Thorotrast, which was highly toxic due to its radioactive nature. No- one knows how many people were damaged by it, but the numbers were undoubtedly in the thousands.

Oil-based contrast agents such as Myodil (Pantopaque) were introduced after very cursory pre-clinical trials. They were highly toxic and caused incidence of serious adverse effects as frequent as 74%([10]). These have been well documented by many authors ([11]). Water-soluble agents such as Omnipaque (Iohexol) have since replaced Pantopaque. These are less toxic, but still capable of serious and lasting side-effects, of which arachnoiditis is one ([12]). Metrizamide (Amipaque) is particularly linked with risk of seizures and neuropsychiatric disturbance. ([13]) In 1997, H.R. 738 was introduced as a Bill in the House of Representatives, concerning “Myelogram-Related Arachnoiditis Amendments” calling for discontinuance of the use of Pantopaque, Amipaque, Omnipaque and Isovue. (See under Diagnostic Tests.)

Since the withdrawal of oil-based myelography, Depo-Medrol is the principal cause of adhesive arachnoiditis in the Western world. Dr. Burton maintains that almost all cases of clinically significant adhesive arachnoiditis are caused by Depo-Medrol.

Depo-Medrol (Depomedrone) is a steroid preparation administered epidurally or intrathecally in the treatment of Failed Back Surgery Syndrome (FBSS).

The rationale for its use is that the steroid (methylprednisolone) is an anti-inflammatory agent. Although in itself beneficial, the drug is in a solution that contains preservatives such as polyethylene glycol (also used in antifreeze). Other preparations such as Kenalog use benzyl alcohol. It should be noted that alcohol is a recognised cause of toxic neuropathy, so adverse reactions are unsurprising.

Wood ([14]) studied the effects of injections of methylprednisolone acetate into rat sciatic nerves. Nerves treated with either the steroid or its vehicle showed damage, including collagen (scar) formation and demyelination.

The manufacturers, Upjohn, stated in 1981 that “we would advise against the epidural/extradural routes of administration because of possible adverse reactions”. However, this specific recommendation was withdrawn from the data sheet in 1997.

However, Kenalog, another steroid drug used in epidural injections, has “not recommended for administration via the epidural route” on the data sheet from the manufacturers, Bristol Myers Squibb.

The drug remains unlicensed for use around the spine, the use being left to the individual doctor’s discretion and clinical judgement. Its use in UK is extensive and epidural steroid injection (ESI) is practised by a variety of clinicians including GPs and specially trained physiotherapists.

Currently, literature on Depo-medrol states that it is contraindicated for intrathecal administration and that it contains benzyl alcohol, which is potentially toxic when administered locally to neural tissue.

Most patients who have had adverse effects from the drug say they would NOT have had the injection if they had known it was not licensed for use around the spine. Many of them say that they are significantly worse since receiving the drug.

Nelson ([15]) maintains that "the epidural space is not wholly separate from the subdural and/or subarachnoid space" and that the spaces are "not only contiguous, but continuous". He therefore concludes that epidural delivery of drugs may not guarantee that the substance will remain isolated in the epidural space. Moreover, he cites a 2.5% risk of inadvertent injection directly into the subarachnoid space. The Mackinnon studies on rats ([16]) showed that a variety of injectable steroids may damage peripheral nerves if injected intraneurally. Furthermore, the NHMRC report ([17]) from 1994 shows that the risk of dural puncture is, on average, “at least 5%”. The authors also warn, “particular care must be taken if attempting an epidural injection in patients previously treated by spinal surgery. Complete obliteration of the epidural space occurs following decompressive laminectomy and in such cases an attempted epidural injection carries a very high risk of dural tap.”

Byrod and Olmarker ([18]) found evidence that the potential barrier properties of the dura/arachnoid “seem less than effective” for preventing substances in the epidural space from reaching the endoneural space of nerve roots.

It is also important to note that several authors have questioned the efficacy of epidural steroid injections (ESI) in treating disc prolapse, lumbar stenosis or FBSS. Rosen et al ([19]) concluded in 1988, “overall results were poor”, with only approximately 50% of patients receive temporary relief, whilst long-term relief occurs in less than 25% of patients. Anderson and Mosdal ([20]) found that epidural steroid injection was “useless” in patients with long-lasting complaints and previous disc operations. This finding was also seen in the study by Cuckler et al ([21]), which failed to demonstrate ESI efficacy, with the authors also raising the issue of published reports of “serious complications”. More recently, in 1997, Carette et al ([22]) studied patients with prolapsed nucleus pulposus and found that epidural steroid “offers no significant functional benefit, nor does it reduce the need for surgery,” although there may be short-term improvement in pain and sensory deficit. Ringsdal et al ([23]) proposed that “future correctly designed studies are necessary to clarify whether the injection should be a supplement to the established treatment of low back pain and sciatica,” as they found that previous studies showed conflicting results. The NHMRC report suggests that ESI are of greater use in sciatica when there is a substantial inflammatory component (especially if acute) but are less useful if there is a predominantly compressive radiculopathy .The AHCPR Clinical Practice Guideline ([24]) clearly states that “Epidural injections are invasive and pose rare but serious potential risks. There was no evidence that epidural steroids are effective in treating acute radiculopathy.” These papers demonstrate that there remains a question about the benefit of ESI, which at best tends to be temporary (less than 6 months) and thus the risks seem to outweigh the benefits and call into question the advisability of continuing use of this form of treatment.

Epidural anaesthetics are another group of drugs implicated in causing arachnoiditis. (See below). Vandermeulen ([25]) includes arachnoiditis as a “mishap”… “solely due to … epidural anaesthesia”. Haisa et al ([26]) state that lumbar adhesive arachnoiditis should be considered for differential diagnosis of back and leg pain after epidural anaesthesia.

Furthermore, epidural anaesthesia may cause subarachnoid cysts or cavities, which are also recognised complications of arachnoiditis. (See below)

If the epidural space is already compromised by disc herniation, stenosis or epidural fibrosis, the risk is greater. Yuen et al ([27]) state that neurological complications “ may be more severe in the presence of spinal stenosis”.

Rocco et al ([28]) in a study of pressure gradients in the epidural space, concluded that as resistance to inflow of fluid was significantly higher in the diseased epidural space, “spread of anesthetics might be difficult to predict”.

In 1955, Hurst conducted studies on monkeys ([29]), which demonstrated that a wide range of chemicals, when introduced into the CSF, produced an immediate pathological

response, which “proceeds steadily to its termination”. The early stages are asymptomatic, but after a latent period, the clinical picture is then one of “severe and progressive signs and symptoms”. This is similar to the picture in arachnoiditis, and therefore all short-term studies (which make up the majority of the evidence concerning

safety of ESI) will fail to address the issue of arachnoiditis, which tends to occur after an indeterminate interval following exposure.

Chymopapain, an enzyme that has been used for chemonucleosis in treatment of prolapsed discs, also has been implicated in causing epidural fibrosis ([30]) and animal

studies show severe nerve damage if injected into the nerve sheath ([31]). In fact, one paper suggests use of intrathecal chymopapain for use as a model for chemically induced spinal cord injury. ([32])

Table of Contents

Introduction
THE SCALE OF THE PROBLEM
ARACHNOIDITIS OR EPIDURAL FIBROSIS?
NOMENCLATURE
THE INFLAMMATORY NATURE OF ADHESIVE ARACHNOIDITIS
PATHOLOGY
CLASSIFICATION
CAUSES
THE IATROGENIC ASPECT OF ADHESIVE ARACHNOIDITIS
NEXT: PRESERVATIVES IN SPINAL INJECTIONS
PROGNOSIS
THE SYNDROMIC NATURE OF SYMPTOMS IN ADHESIVE ARACHNOIDITIS (Warning: LONG)
COMPLICATIONS OF ADHESIVE ARACHNOIDITIS
DIFFERENTIAL DIAGNOSIS
CLINICAL ASSESSMENT
DIAGNOSTIC TESTS
TREATMENT OPTIONS (Warning: LONG)
MULTIPLE CHEMICAL SENSITIVITY
LOOKING TO THE FUTURE
APPENDIX I: AUTOIMMUNE ASPECTS
APPENDIX II: SYRINGOMYELIA
ADDENDUM - May 2000
REFERENCES