On May 19, 1942 William Van Wagenen, a neurosurgeon at the University of Rochester medical school, gave a presentation before the Harvey Cushing Society in New York City on the subject of Pantopaque® myelography. Dr. Van Wagenen had been trained by Harvey Cushing and was the first president of the Harvey Cushing Society founded in 1931 to honor this pioneering neurosurgeon. Dr. Van Wagenen’s talk antedated, by over 6 months, an address by one of his colleagues, radiologist Theodore Steinhausen, also on Pantopaque® myelography. On August 3, 2002, at a deposition, it was declared that the May 19, 1942 Van Wagenen presentation did not include the animal experimental studies previously performed at the University of Rochester.
After over 60 years this issue is difficult to clarify; but the point is a mute one. Van Wagenen concluded, on the basis of human clinical study that Pantopaque® produced “chemical meningitis” and Steinhausen stated, on the basis of animal studies, that Pantopaque was “safe.” The conclusions drawn by these two gentlemen regarding the safety and efficacy of Pantopaque®, the myelographic agent being studied, differed dramatically. Because of the importance of the Van Wagenen presentation in better understanding later deceptive practices the full text continues to be presented below:
Steinhausen declared, on the basis of his review of the animal research data, that Pantopaque® was “safe.” Van Wagenen found that the same agent produced a variable “chemical meningitis” and that the chemical reactions observed were “fairly great and probably greater than than it is with Lipiodol” upon his review of the same animal research study. Van Wagenen pointed out that both Pantopaque® and Lipiodol were of use in examining the subarachnoid space for “small lesions.” This observation is consistent with the original use of small amounts of Lipiodol as a means of locating spinal tumors. How Pantopaque® then graduated to become a routine agent for full-column myelography has been documented by Suzanne Parisian. This review of the Pantopaque® saga by an ex-FDA physician makes clear that the process by which this myelographic agent came into use was clearly negligent. The continuing cover-up of this negligence has resulted in condemning many patients, throughout the world, to serious chemical meningitis and lifetimes of severe and unremitting pain. Because the message has not yet been publicly disclosed the grim problem of chemical meningitis due to ill-advised epidural steroid administration continues to be a global public health epidemic.
Full-Text of the Van Wegenen
(Abstract of paper read by Dr. P. Van Wagenen at the New York Meeting of the Harvey Cushing Society, May 19, 1942.)
CLINICAL REPORT ON THE USE OF PANTOPAQUE
(Ethyl Iodophenylundecylate): A New Contrast Medium for
Visualization of the Subarachnoid Spaces
by William P. Van Wagenen, M.D.
(From the Department of Surgery Neurosurgical Division, School of Medicine and Dentistry, The University of Rochester, Rochester, New York)
This preparation has been used in 30 cases where space-displacing masses within the spinal canal were suspected. The majority of these masses proved to be ruptures of the nucleus pulposus or related lesions. PANTOPAQUE would seem to have certain definite advantages over the use of Lipiodol.
First, it is more fluid, more miscible with spinal fluid than Lipiodol.
Second, there is little, if any tendency of the preparation to break up into bubbles and create artefacts.
Thirdly, it tends to get into the spaces of Jacot and the various subarachnoid spaces more easily than Lipiodol and there are fewer false and erroneous conclusions regarding apace-displacing masses.
Fourth, the ease of removal through a lumbar puncture needle is considerably greater than Lipiodol.
Fifth, it is a slowly absorbable preparation.
Sixth, a lesser amount is needed for study of the subarachnoid space, 2 to 3 cc. being sufficient.
We have not as yet asked patients to return for follow-up in order to note the degree of absorbability at this date. The chemical meningitis created by the presence of this preparation varies a: good deal from time to time. It is distinctly the impression that when this preparation is introduced in a closed space, such as created by a spinal cord tumor, that the chemical reaction is fairly great and probably greater than it is with Lipiodol. The degree of headache and other meningeal signs created by this preparation varies a good deal also. A very decided impression is gained that the preparation should be removed in part or entirely after the examination is over. The impression is gained that the increased mobility is a handicap in examining the subarachnoid apace for evidences of small lesions in the cervical and thoracic regions. For these regions Lipiodol is preferred.
The technique for use of the preparation is as follows: The patient is placed in the prone position on the tilt fluoroscopic table. A lumbar puncture is, done usually between L 3 and L 4. At times a blanket is placed beneath the, abdomen to give a little added separation of spinous processes. Three cubic centimeters of the warmed preparation are injected after a specimen of spinal fluid has been aspirated. The needle is pushed forward until it appears to lie near the ventral part of the subarachnoid sac. A sterile dressing is placed over the needle, the fluoroscopy carried out and the preparation aspirated at the end of the procedure.
Intrathecal Injection of Ethyl Iodophenylundecylate in Dogs
In the development of ethyl iophenylundecylate as a contrast medium for myelography upwards of 150 dogs have been injected intrathecally with different types of liquid iodine organic compounds. Through this large experience, which has extended from 1936 until the present, the procedure has been standardized somewhat. It is essential that the dogs be free of distemper, or any suspicion of distemper and that the operator be experienced before the results are significant. The animals used in the assay should be held under observation for at least three weeks and should preferably weigh 15-20 kilograms. Rectal temperatures should be taken daily for three days prior to the injection, or until the temperature isconstant. The reading on the last day is taken arbitrarily as the reference temperature.
Prier to the injection, the dogs are anesthetized either by intraperitoneal injection of Bivipal or by intravenous injection of Nembutal. The hair is closely clipped over a wide area of the back of the skull and the cervical spine. The clipped area is then thoroughly scrubbed with soap and water. Next, using sterile technique, the prepared site is cleansed with 70% alcohol, painted with tincture of iodine, and again cleansed with 70% alcohol. The prepared area may, if desired, be draped with sterile towels.
An assistant, gripping the nose of the dog, sharply flexes the head on the chest. This manouever makes the cisterna magna more accessible by widening the distance between the atlas and the foramen magnum. Observing sterile technique, the operator then determines the location of the occipital protuberance and the position of the spine of the second cervical vertebra. At a point midway between these two landmarks a 20-gauge lumbar puncture the ligamentum nuchae needle and into the cistern. Great care must be taken as the cistern is entered to prevent damage to the medulla. When the subarachnoid space has been entered, the trochar of the needle is removed and a 5 cc. sterile syringe attached. Slightly more spinal fluid is removed than contrast medium to be injected. The pressure within the spinal canal should be sufficientlygreat to make the removal easy. After the spinal fluid has been removed, the syringe containing it is disengaged and a second sterile syringe containing ethyl iodophenylundecylate or other medium is attached to the needle. The injection is made slowly, the syringe is then disengaged, and the trochar put back in place. The needle is quickly removed and the dog’s head extended to aid in preventing escape of spinal fluid from the puncture wound. The animal is then placed for several hours with his head on a support so that it is well above the plane of the body.
Direct trauma of the cord by the needle and escape of spinal fluid from the canal are to be guarded against. Accidental perforation of a blood vessel in the dura frequently occurs and all animals from which a bloody spinal fluid is obtained should be discarded. Similarly, animals in which trauma is suspected should be disregarded. An experienced operator can usually get excellent results in four out of six dogs.
Following recovery from anesthesia the animal should be observed forfood consumption, gait changes, evidence of cord bladder and symptoms of chemical meningitis as evidenced by outcry when the head is quickly tent or the neck palpated. Rectal temperatures should be taken for the period of a week during which the animal should be given opportunity to exercise freely since the maximum effects of a myelographic medium becomes evident only when unrestricted exercise is permitted.
Dogs injected intrathecally with ethyl iodophenylundecylate are usually in better clinical condition than control animals injected with iodized poppy-seed oil. This is brought out in the two series of experiments summarized in Tables I and II, the adverse effects of the media, such as gait disturbances, etc., are collectively described under the heading “Chemical Meningitis.” Subsequent to those experiments it was noted that although dogs tolerate ethyl iodophenylundecylate better than iodized poppyseed oil in the doses given nevertheless, ethyl iodophenylundecylate produces a mild fever that is not produced by iodized poppyseed oil. This fever may be as high as 2.0C and may last for several days. A typical fever curve for a dog injected intrathecally with ethyl iodophenylundecylate is given in Chart I, and typical data showing extent, and duration of fever with a group of dogs injected with ethyl iodophenylundecylate are collected in Table III
Ethyl iodophenylundecylate is absorbed from the spinal canals of dogs in about a year provided the dose is not larger than 3 cc. The rate of absorption appears to be affected by the position that the medium occupies in the subarachnoid space and doubtless is slowest in the region of the cauda equina.
In dogs both. ethyl iodophenylundecylate and iodized poppyseed oil are encysted shortly after intrathecal injection. Because of its greater fluidity, ethyl iodophenyl undecylate forms smaller globules in the subarachnoid space, and accordingly the cysts are smaller. The reaction about the two kinds .of cysts is essentially that of tissue to a foreign body, but the amount of irritation produced is greater with ethyl iodophenylundecylate This is seen in the illustrative sections shown in Plate I and II both of which are selected to show the maximum damage that occurs in dogs Plate I is a photomicrograph of a section taken from the cord of a dog sacrificed 45 days after injection of ethyl iodophenylundecylate. The cysts are smaller than those shown in Plate II which is taken from an animal injected with iodized poppyseed oil
And killed at 100 days. It is evident that the walls of the cysts are made up of thin layers of fibrous tissue, in which small numbers of mononuclear cells and phagocytes are present together with a few polymorphonuclear cells. The detail is shown better in Plate III which is a high power magnification of a portion of a section from the dog injected with ethyl iodophenylundecylate. The dilation of the central cana1 in the iodized poppyseed oil section (Plate I) is due to hydrocephalus, two cases of which were seen in a series of nine dogs. One similar case of hydrocephalus has been observed with ethyl iodophenylundecylate in. a series of 55 dogs. As the content of the cysts are absorbed the damaged area becomes smaller and smaller and, with ethyl iodophenylundecylate, are difficult to locate after a period of a year.
The mortality of the experimental dogs was relatively low, both with iodized poppyseed oil and with ethyl iodophenylundecylate . In the poppyseed oil series only one dog out of 14 died, and autopsy showed that a subarachnoid hemorrhage as the cause of death. In contrast, with ethyl iodophenylundecylate 3 dogs died out of to experimental group of 55. One of these deaths was due to peritonitis, but two were referable to damage to the medulla on injection of the contrast media.
As shown in Tables I-III, the level at which the two contrast media were injected varied from 0.19-0.48 g./kg. or from 7 to 10 times the amount that is usually used in myelography in man. The toxic effects, such as they were, seemed to bear no relation to the dosage; however, a larger series of experiments might bring out such a relationship.
Summary: Intrathecal injection of ethyl iodophenylundecylate in doses up to 0.48 g./ kg. in dogs produces a slight fever of short duration, but otherwise does not effect the clinical behavior of the animal. After a short period of time, the drug is encysted and about these cysts there is mild foreign body reaction. As the cystic contents are absorbed, the tissue slowly returns to normal in a period of about one year. In contrast, iodized poppyseed oil does not produce fever, but frequently does cause a diminution in the activity of the animal; the drug is encysted and these cysts are essentially unchanged during the life of the animal.