August 2019 Edition. Volume XIX

A sad truth of life is that we are often unappreciative of important things until they are lost. Our most precious asset is our intact nervous system. To experience the  impairment of nervous system function, even transiently, provides all of us with a healthy respect for the importance of its integrity.

Human brains, spinal cords, and spinal nerves are protected externally by the armor of the skull and spinal column and internally by the meningeal membranes (the meninges). The thickest of these, the dura mater, serves as a tough barrier to protect the more fragile arachnoid and pial membranes. It is these diaphanous and delicate membranes which upport as well as assist in nourishing neural tissue. Cerebrospinal fluid is created in the spinal subarachnoid space and then flows over the surface of the brain where it is reabsorbed into the circulatory system. The subarachnoid space is the most delicate and fragile structure in the human body. This fragility allows only a slight tolerance for insult. The subarachnoid space is the true “salum sanctorum” of the human body.

Epidural Injection 03 80pDespite these facts the subarachnoid space is a highly traveled medical roadway for many purposes including administration of epidural steroids, spinal anesthesia, myelography, spinal diagnostic taps, intra-thecal catheters for drug infusion, etc. The sensitivity of the subarachnoid space to foreign body substances was well demonstrated by an epidemic of permanent paralysis relating to spinalanesthesia in the United States in the 1950s. This was before the advent of disposable syringes and needles. It was subsequently determined that the etiology of these disastrous complications was a chemical meningitis caused by the presence of minuteparticles of simple detergent remaining in the syringes after cleaning. Even today the medical insurance rates relating to performance of spinal anesthesia remain high because of this past experience. What have we learned from this history? Actually not much.

The sanctity of the subarachnoid space was severely tested during the 20th century. The desire to radiographically outline this area of the body for diagnostic purposes ledto the introduction of air myelography by Dandy in 1919. This was subsequently followed by the introduction of a number of substances which included thorium dioxide (Thorotrast) which, unlike air, provided excellent x-ray images. Thorium’s major liability turned out to be its radioactivity and long half-life. The risks associated with its use did not become evident until many years had passed. It was only when clinicians began to investigate the epidemic of resulting malignant brain and spinal cord tumors that the connection was made at which time Thorotrast “fell into disuse.”

Lipiodol replaced Thorotrast as a myelographic agent in the 1920s. This oil based chemical was, however, recognized as being highly neurotoxic soon afterwards. This finding was vividly documented by neurosurgeon Eric Oldberg who published an editorial on Lipiodol in1940 entitled :


OldbergEric“Anyone who has had perforce to dig about in the soggy mess which is the cauda equina of some unfortunate in whom five or ten cubic centimeters of lipiodol had been optimistically injected a year or two previously will understand this statement. Not only is the original disease still present, but a chronic, adhesive, chemical inflammation of the caudal roots has been engrafted upon it.”


InflamExudateShown to the left is a operative photograph where the dura mater has been opened in the lumbar area to demonstrate a severe inflammatory reaction.  In the case shown the inflammatory reaction was due to infectious meningitis.  The white area reflects inflammatory cell response.  The pathology is similar to that observed and described by Dr. Oldberg when he opened the dura following lipiodol myelography.
The desire to find a more acceptable alternative to Lipiodol led, in the 1940s, to the introduction of the oil-ester based chemical iophendylate (Pantopaque, Myodil). “With the assurance from the initial experimental studies that it was “safe” Steinhausen and associates, in 1942, advocated the routine use of iophendylate for spinal myelography.   In sad truth iophendylate was never shown to be “safe”, particularly in experimental animals. The neurotoxicity of iophendylate turned out to be only slightly less than Lipiodol.  It took a period of almost 50 years and about 5 million iophendylate myelograms before this fact even began to enter into the awareness of the medical profession at-large . Even as we enter a new millennium there still exists scant understanding or general knowledge regarding this subject. This has been due, in large part, to a failure in releasing known adverse animal experimental data as well as other phenomena.

Early concerns regarding iophendylate were expressed, however, in some medical communities throughout the world. This was particularly so in Sweden where the quest to develop water-soluble alternatives to iophendylate was initiated in the late 1940s.  As opposed to the toxic effects of the oil based chemicals the side-effects of the water soluble alternatives tended to be immediate, and were, at first, quite drastic consisting of severe pain, spasm (sometimes violent), seizures and hypotension. Today’s non-ionic water soluble myelographic agents represent a major advance in decreasing patient risk but still introduce foreign body substances into the subarachnoid space.

Due to the development of high resolution non-invasive MRI scanning (and digital MRI myelography) there is now a much reduced need for myelography. When water-soluble dyes are used appropriately their risk is low and the benefit to the patient can be high. When they are used inappropriately (wrong agent, wrong concentration, etc.) they continue to have the potential of being highly toxic to the tissues of the nervous system. The unknown factor in all cases of introducing a foreign body substances into the subarachnoid space is the nature of any given individual’s auto immune response to it. Examples of this phenomenon abound in medicine. Most are familiar, as with the anaphylactic potential of penicillin and more are now becoming aware of the allergic potential of other common substances including household cleaners, latex, etc.

The adverse sequela relating to the introduction of foreign body substances into the body’s “salum sactorum” remains a game of chance for the patient. When the reactions are of an acute nature (i.e. the wrong concentration of a water-soluble contrast agent) the resulting nerve injury can be similar, in clinical signs and symptoms, to those resulting from the body’s exposure to environmental nerve gas or the ingestion of neurotoxins. The picture is often that of transient, or permanent, neurologic dysfunction and/or incapacitation. The present lack of information and general education regarding these issues is appalling. It means that there is a lack of informed consent for the patient and also precludes the possibility of patient pre-treatment with medications which can be effective in preventing the serious known potential adverse side-effects.

Today the most serious example of the dumping of toxic chemicals into the subarachnoid space relates to the widely unappreciated potentially serious complications of inadvertently depositing toxic substances (i.e. steroids containing glycols or ionic contrast media) from the common practice of epidural steroid injection intended to relieve back pain. Many cases of incapacitating adhesive arachnoiditis secondary to chemical meningitis have now been observed as a result of this procedure.  This has now become one of the most common reasons for patients to bring medical-legal suits against their physicians for not having warned them in advance about such risks (and often discovering, in the process, that their physicians were also ignorant regarding these serious potential complications).

When medical use of intrathecal drugs is deemed reasonable (and associated with true informed consent) the risk versus benefit determination must then be made by an informed patient.  For example:

The intrathecal injection of methotrexate, an antimetabolite, has been advocated by some in the treatment of certain neoplastic disorders. Its use however has been associated with acute chemical meningitis characterized by headache, back pain, nuchal rigidity, and fever.  In addition sub-acute myelopathy has been seen associated with paraparesis/ paraplegia, and leukoencephalopathy.  The latter is a condition which produces destruction of the myelin sheaths which cover nerve fibers. The symptoms of this process can include confusion, irritability, somnolence, dementia, ataxia, seizures, and coma. Leukoencephalopathy can be progressive and fatal.

Recent medical reports indicate that intrathecal injection of preservative-free methylprednisolone may be helpful in managing the disabling pain of post-herpetic neuralgia.  In situations such as this it is extremely important that those concerned have some awareness of the sanctity of the subarachnoid space and the possible associated liabilities before “jumping” into such a therapeutic regimen.

In Summary

While there are, in today’s world, patients who require the placement of foreign body substances into their subarachnoid spaces for diagnostic and therapeutic purposes associated informed consent is mandatory, but often absent.  Under all circumstances non-invasive alternatives should be employed first.  A important medical goal is to make, in the future, invasion of the subarachnoid space totally obsolescent.

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