December 2017 Edition. Volume XVII

A Myelography Retrospective: From Innovative Technique to Obsolescent Technology

DandyPneumoThe technique of myelography was born when the ventricular system of the brain was accidentally visualized on a post-traumatic skull x-ray performed by Luckett in 1913. His original film is shown to the left. Myelography, is an invasive diagnostic test in which a substance, radio-opaque on x-ray, is placed in the subarachnoid space for diagnostic purposes. By definition, all contrast materials, including air, used for this purpose are “foreign bodies.”  The first physician to apply air myelography for ventriculography and air encephalography was Johns Hopkins neurosurgeon Walter Dandy who initiated his work in 1918.  Because air was difficult to visualize a search for alternatives began soon afterwards.  In 1932 thorium dioxide (Thorotrast®) was first introduced.  This substance appeared, at first to be ideal for the purpose of myelography (as well as other radiologic studies). Were it not for the fact that Thorotrast was radioactive it would have been an acceptable contrast media for its time.  Unfortunately for patients it turned out to be a highly toxic radioactive substance.  It was only 20-30 years after its introduction that the medical profession began to suspect that the sudden and unusually high incidence of malignancies involving the brain and spinal cord (as well as adhesive arachnoiditis) might be related to thorium dioxide’s radioactivity. At this point this myelographic agent “fell into disuse.”  It is unfortunate that the neurotoxicity of thorium dioxide was never officially documented during the first part of the 20th century.  Because of this oversight history continued to repeat itself with other neurotoxic myelographic agents.

The list of neurotoxic myelographic agents is not long, but distinguished, in the annals of medical disasters.  At the top of this list are the oil-based myelographic substances. These include Lipiodol (iodinated poppy-seed oil), Halogenol (brominated sesame-seed oil), Campiodol (iodinated rape-seed oil), and Pantopaque®/ Myodil® (ethyl iophenylundecylate).  At the height of the popularity of oil myelography about 450,000 myelograms were being performed in the United States on a yearly basis (at least an equal number elsewhere in the world). Pantopaque® was originally introduced as a means of locating spinal tumors.  It’s initial use involved placing a small quantity (i.e. 1-2ccs) of the oil dye in the cisterna magna at the base of the skull and observing where, in the spinal canal, the block was present.  How Pantopaque® and Myodil® then became utilized for routine full-column myelography to diagnose herniated discs is, in itself, a remarkable tale.  Part of this tale included claims by some who touted safety, when they knew that the opposite was true.  Suffice it to point out that starting in the 1940’s clinicians and medical publications of the period began to attempt to sound the alarm and identify the association of oil myelography with severe nerve scarring and the other associated adverse clinical sequela.

It is noteworthy that, to date, none of the oil myelographic substances have ever been “officially” acknowledged to be toxic. In regard to iophendylate the fact that it dissolved rubber, linoleum and even organic substances as inert as styrofoam didn’t seem to bother anyone and these oils continued to be injected into the subarachnoid space throughout the world.  Yet, there were those who tried to spread the alarm.  Particularly descriptive were the words of neurosurgeon Eric Oldberg in 1940.  Despite these forewarnings oil myelography generally continued unabated in the United States until the early 1980s when it finally “fell into disuse.”

Astonishingly, oil myelography, when it finally “fell into disuse” did not do so because of its well documented toxicity.  It “fell into disuse” because of its poor performance as a myelographic agent (which was known from the start).  The point has been occasionally made that American clinicians had no choice but to use iophendylate for myelography from the 1940s to the 1980s.  In 1944 Francis Murphey, then a U.S. Army neurosurgeon and co-founder of the Semmes Murphey Clinic in Memphis, Tennessee initially believed that Pantopaque® was an acceptable myelographic agent.  After the end of World War II both Francis Murphey and R. Eustace Semmes discontinued the use of Pantopaque® in their clinic because of the toxicity which began to be apparent by that time.  The diagnosis of disc herniation was then made, at their clinic, on the basis of the patient’s examination without the use of myelography.

Similar concerns regarding Pantopaque®/ Myodil®  developed in many other counties. Concerned radiologists in Scandinavia began the search, in the 1940s, for safer alternatives.  What makes their effort all the more remarkable was that they were among the few to dismiss the claims by Steinhausen et al in 1942 that the oil-esterundecylate Pantopaque® was “safe” (when clearly it was not).

Water-Soluble Myelography

It must be recognized today that the effort by Scandinavian radiologists to develop safer alternatives was quite a valiant endeavor because the first of the water-soluble agents were highly irritating to the subarachnoid space and produced serious acute patient problems.  Acute inflammation, hypotension, spasms (often violent enough to fracture vertebrae), seizures and even death occurred.  Because of these early adverse reactions ionic water-soluble myelography was often performed under general anesthesia to control the above complications.

Over time, newer, and less toxic non-ionic agents were then introduced thus allowing increased safety and efficacy. The first non-ionic approved for myelography was metrizamide introduced in 1979.  A listing of the most popular of the water-soluble agents follows:


Ionics
Methiodal Sodium (Abrodil, Conturex, Myotrast)
Diatrozoate Meglumine  (Conray)
Iodamide Meglumine (Renovue)
Iothalmate Meglumine
Ioxitalamate Meglumine (Telebrix)
Iocarmate Meglumine (Dimer-X)


Non-Ionics
Metrizamide (Amipaque, Nycomed)
Iohexal (Omnipaque)
Iopamidol* (Imipamiro, Iopamivon, Isovue, Iopamiro, Niopam, Solutrast)

Iopamidol was introduced in Italy and in Germany in 1981 as the first commercially available non-ionic water-soluble contrast medium approved for myelography. Over 110 million units have been sold worldwide and 3,000 scientific publications have been generated regarding its use, yet, the following warning generated continues to be displayed:

* 1997  Bracco Diagnostics, Inc. USA and Italy IOPAMIDOL INJECTION, USP NOT FOR INTRATHECAL USE WARNINGS: Severe Adverse Events – Inadvertent Intrathecal Administration Serious adverse reactions have been reported due to the inadvertent intrathecal administration of iodinated contrast media that are not indicated for intrathecal use. These serious adverse reactions include: death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema. [Burton Report® italics] Special attention must be given to insure that this drug product is not inadvertently administered intrathecally.http://www.iopamidol.com/product/bula.htm


All oil and water soluble contrast agents are foreign body substances in the sub-arachnoid space.  Some are more toxic than others. Many patients have chosen death as being is preferable to a lifetime of agony from adhesive arachnoiditis.  Yet, all medicine is practiced on a “risk versus benefit” basis.  But, the key question is “how can this be carried out?” if the physicians themselves are ignorant of the risks and are thus unable to provide the patient with “informed consent”?

Other intangibles relate to human error and the introduction of the wrong agent or the right agent at a incorrect concentration. Serious and even fatal complications relating to the introduction of water soluble contrast agents into the subarachnoid space are known, but only rarely documented from the scientific standpoint, because of the need to obtain and test cerebrospinal fluid samples soon after the procedure. These neurologic injuries represent an important segment of “hospital errors” which are typically not well addressed.

Summary  


Oil myelography was gradually replaced by water soluble contrast agent myelography and, in recent years, by non-invasive CT and MRI imaging.  Because the incidence and prevalence of the neurotoxic complications of oil myelography was never officially studied it is simply not known how many patients developed severe incapacitation and disability directly related to the introduction of this material into the subarachnoid space.

One point, however, is crystal clear, of the at least 5 million patients who underwent oil myelography in the United States during the 20th century not a single case ever involved true informed consent  on the part of the patient in regard to the real risks of this procedure prior to it being carried out.

The Continuing Concern  


Since its inception, the Burton Report® has attempted to point out that:

The human subarachnoid space is a poor depository for foreign body substances (this means ANY foreign body substance).  Myelography has been an important diagnostic tool in the 20th century but it is invasive and few patients have ever been provided with true informed consent regarding the known, and well documented potential liabilities.  Even lumbar puncture can cause spinal fluid leakage producing disability and even death from meningitis.  Rarely are patients told this.  Myelography, in the 20th century, due to the routine use of highly toxic agents, particularly  the oil substances, has produced a world-wide public health disaster whose full magnitude is still not appreciated by many and may never be accurately documented.

Even the safest myelographic agent can be a disaster for any given patient.  Given the realities of the medical environment the potential for mistake and/or misadventure (wrong agent/ wrong concentration/ wrong approach) there is always the chance of error causing permanent patient problems.  The fact that any given patient can have an idiosyncratic (personal adverse effect) reaction to any of the myelographic substances only raises the ante of concern.  In the 21st century there remains little justification for invasive myelography because of advances in noninvasive body imaging.  The world will be a great deal better off when myelography, as a test, becomes obsolete and only of historic interest.

 

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