LETTER TO THE EDITOR
1111n_DPTA: A Safe Radiopharmaceutical for Cisternography Editor, RADIOLOGY Dear Sir: The recent report by Jayabalan, et al. (1) concludes that the aseptic meningitis which they observed in three patients following 111In_DTPA cisternographic examinations was due to unknown cause. Furthermore, they report that the samples of the lots of commercial 111In_DTPA were tested for pyrogens with negative test results. They therefore concluded that bacterial endotoxin was not the cause, thus implying that the 111In_DTPA may itself occasionally be toxic in cerebrospinal fluid. Two independent studies (2, 3) of this same problem present strong evidence that the contrary conclusion is true, that bacterial endotoxin is indeed the cause of aseptic meningitis or the febrile responses that have been observed after the intrathecal administration of cisternographic agents. The radiopharmaceuticals in all these studies were tested and found to be nonpyrogenic by U.S. Pharmacopeia criteria, and in most cases Limulus test results were also obtained and confirmed the results of the older U.S.P. rabbit test. The conflicting conclusions stem from the way the different investigators have applied the Limulus test. The end point of the Limulus test is usually selected to give the same results as the U.S.P. rabbit test. This is done so that it can be applied to the testing of drugs which are to be administered intravenously. The usual end point for intravenous drug studies is to observe whether or not the test sample is gelled at a given point in time. Depending upon the strength of the particular lot of lysate, the gelation time is selected. Usually this time is between 20 and 30 minutes. The selection of the end point to obtain equivalency of the two methods was established by Cooper et al. (4). This equivalency has been incorporated into the instructions accompanying commercially supplied Limulus lysate kits. Indeed, by following these instructions, test results were usually negative for 111In-DTPA, and indicated that if the radiopharmaceutical was administered intravenously, the agent would not cause pyrogen responses in patients. The Limulus method, however, can be used to detect much lower levels of endotoxin. One way to do this is to simply observe the test tube for a longer period of time. * When this is done, endotoxin levels can be found that are too low to cause a pyrogen reaction if administered intravenously, but which can cause adverse reactions when injected intrathecally. Jayabalan et al. cited Limulus test results which were applicable only to making a comparison of whether or not the levels of endotoxin contamination were at the level which would give a positive result by the U.S.P. method. Endotoxin con-
Table I:
Adverse Reactions to Cisternography*
Year
No. of Reported Reactions
1971 1972 1973 1974 1975
30 23 9 4 0
* H. L. Atkins, Chairman, Subcommittee on Adverse Reactions to Radiopharmaceuticals, Society of Nuclear Medicine (3).
tamination, unlike sterility, is usually a continuous variable. For this reason, I suggest that the results of Jayabalan et al. are not inconsistent with the conclusions drawn by the other investigators. Our original results (2) showing a correlation between endotoxin contamination and aseptic meningitis or febrile response, and our original conclusion that man is more sensitive to pyrogens when they are administered intrathecally, have been confirmed and extended by the more recent report of Cooper and Harbert (3). In fact, the latter investigators have concluded that endotoxin is at least a thousand times more toxic on a milligram basis when administered intrathecally than intravenously. Thus, a more sensitive end point must be used when the Limulus test is applied to cisternographic agents. It is currently accepted by most manufacturers of cisternographic agents that the U.S.P. pyrogen test is insufficiently sensitive for intrathecal radiopharmaceuticals, and that these agents should be tested using the Limulus lysate method with more sensitive end-point criteria. Since the manufacturers of radiopharmaceuticals have begun to use more stringent criteria, the incidence of adverse reactions to radioisotopic cisternography has sharply declined (5). The data in TABLE I show that the number of adverse reactions dropped from a high of 30 in 1971 to 0 in 1975. This decreased incidence of adverse reactions to cisternography is even more significant when we consider that the total number of· cisternograms has increased significantly during this same period, including cisternograms performed with 111In_DTPA. Therefore, I suggest that we need not be alarmed by the report of Jayabalan et al. In contrast to their conclusions, I further suggest that currently available 111In_DTPA is a safe radiopharmaceutical for cisternography. Other considerations (6) indicate that 111In_DTPA is probably the most ideal radiopharmaceutical for this purpose, Hence, its use is to be encouraged.
Buck A. Rhodes, Ph.D. Professor of Diagnostic Radiology and Pharmacy Practice TheUniversity of Kansas Medical Center Kansas City, Kansas
* More recently, Dr. Jayabalan prolonged the Limulus test to 60 minutes. He has had no unsatisfactory results from material evaluatedby the Limulus amebocyte test observed at 60 minutes. Editor
749
750
LETTER TO THE EDITOR
REFERENCES 1. Jayabalan V, White D, Bank M: Adverse reactions (aseptic meningitis) from 111In_DTPA clsternographic examinations. Radiology 115:403-405, May 1975 2. Rhodes BA, Kamanetz GS, Wagner HN Jr: The use of LlmuIus testing to reduce the incidence of adverse reactions to cisternographic agents. Neurology (Minneap) 24:810-812, Sep 1974 3. Cooper JF, Harbert JC: Endotoxin as a cause of aseptic
June 1976
meningitis after radionuclide cisternography. J Nucl Med 16:809813, Sap 1975 4. Cooper JF, Levin J, Wagner HN Jr: Quantitative comparison of in vitro and in vivo methods for the detection of endotoxin. J Lab Clin Med 78:138-148, Jul1971 5. Atkins HL: Registry of adverse reactions to radiopharmaceuticals. Private communication, J_sn 1976 6. Hosain F, Som P: Chelated 1111n: an ideal radiopharmaceutical for cisternography. Br J RadioI45:677-679, Sep 1972
1111n_DPTA: A Safe Radiopharmaceutical for Cisternography Editor, RADIOLOGY Dear Sir: The recent report by Jayabalan, et al. (1) concludes that the aseptic meningitis which they observed in three patients following 111In_DTPA cisternographic examinations was due to unknown cause. Furthermore, they report that the samples of the lots of commercial 111In_DTPA were tested for pyrogens with negative test results. They therefore concluded that bacterial endotoxin was not the cause, thus implying that the 111In_DTPA may itself occasionally be toxic in cerebrospinal fluid. Two independent studies (2, 3) of this same problem present strong evidence that the contrary conclusion is true, that bacterial endotoxin is indeed the cause of aseptic meningitis or the febrile responses that have been observed after the intrathecal administration of cisternographic agents. The radiopharmaceuticals in all these studies were tested and found to be nonpyrogenic by U.S. Pharmacopeia criteria, and in most cases Limulus test results were also obtained and confirmed the results of the older U.S.P. rabbit test. The conflicting conclusions stem from the way the different investigators have applied the Limulus test. The end point of the Limulus test is usually selected to give the same results as the U.S.P. rabbit test. This is done so that it can be applied to the testing of drugs which are to be administered intravenously. The usual end point for intravenous drug studies is to observe whether or not the test sample is gelled at a given point in time. Depending upon the strength of the particular lot of lysate, the gelation time is selected. Usually this time is between 20 and 30 minutes. The selection of the end point to obtain equivalency of the two methods was established by Cooper et al. (4). This equivalency has been incorporated into the instructions accompanying commercially supplied Limulus lysate kits. Indeed, by following these instructions, test results were usually negative for 111In-DTPA, and indicated that if the radiopharmaceutical was administered intravenously, the agent would not cause pyrogen responses in patients. The Limulus method, however, can be used to detect much lower levels of endotoxin. One way to do this is to simply observe the test tube for a longer period of time. * When this is done, endotoxin levels can be found that are too low to cause a pyrogen reaction if administered intravenously, but which can cause adverse reactions when injected intrathecally. Jayabalan et al. cited Limulus test results which were applicable only to making a comparison of whether or not the levels of endotoxin contamination were at the level which would give a positive result by the U.S.P. method. Endotoxin con-
Table I:
Adverse Reactions to Cisternography*
Year
No. of Reported Reactions
1971 1972 1973 1974 1975
30 23 9 4 0
* H. L. Atkins, Chairman, Subcommittee on Adverse Reactions to Radiopharmaceuticals, Society of Nuclear Medicine (3).
tamination, unlike sterility, is usually a continuous variable. For this reason, I suggest that the results of Jayabalan et al. are not inconsistent with the conclusions drawn by the other investigators. Our original results (2) showing a correlation between endotoxin contamination and aseptic meningitis or febrile response, and our original conclusion that man is more sensitive to pyrogens when they are administered intrathecally, have been confirmed and extended by the more recent report of Cooper and Harbert (3). In fact, the latter investigators have concluded that endotoxin is at least a thousand times more toxic on a milligram basis when administered intrathecally than intravenously. Thus, a more sensitive end point must be used when the Limulus test is applied to cisternographic agents. It is currently accepted by most manufacturers of cisternographic agents that the U.S.P. pyrogen test is insufficiently sensitive for intrathecal radiopharmaceuticals, and that these agents should be tested using the Limulus lysate method with more sensitive end-point criteria. Since the manufacturers of radiopharmaceuticals have begun to use more stringent criteria, the incidence of adverse reactions to radioisotopic cisternography has sharply declined (5). The data in TABLE I show that the number of adverse reactions dropped from a high of 30 in 1971 to 0 in 1975. This decreased incidence of adverse reactions to cisternography is even more significant when we consider that the total number of· cisternograms has increased significantly during this same period, including cisternograms performed with 111In_DTPA. Therefore, I suggest that we need not be alarmed by the report of Jayabalan et al. In contrast to their conclusions, I further suggest that currently available 111In_DTPA is a safe radiopharmaceutical for cisternography. Other considerations (6) indicate that 111In_DTPA is probably the most ideal radiopharmaceutical for this purpose, Hence, its use is to be encouraged.
Buck A. Rhodes, Ph.D. Professor of Diagnostic Radiology and Pharmacy Practice TheUniversity of Kansas Medical Center Kansas City, Kansas
* More recently, Dr. Jayabalan prolonged the Limulus test to 60 minutes. He has had no unsatisfactory results from material evaluatedby the Limulus amebocyte test observed at 60 minutes. Editor
749
750
LETTER TO THE EDITOR
REFERENCES 1. Jayabalan V, White D, Bank M: Adverse reactions (aseptic meningitis) from 111In_DTPA clsternographic examinations. Radiology 115:403-405, May 1975 2. Rhodes BA, Kamanetz GS, Wagner HN Jr: The use of LlmuIus testing to reduce the incidence of adverse reactions to cisternographic agents. Neurology (Minneap) 24:810-812, Sep 1974 3. Cooper JF, Harbert JC: Endotoxin as a cause of aseptic
June 1976
meningitis after radionuclide cisternography. J Nucl Med 16:809813, Sap 1975 4. Cooper JF, Levin J, Wagner HN Jr: Quantitative comparison of in vitro and in vivo methods for the detection of endotoxin. J Lab Clin Med 78:138-148, Jul1971 5. Atkins HL: Registry of adverse reactions to radiopharmaceuticals. Private communication, J_sn 1976 6. Hosain F, Som P: Chelated 1111n: an ideal radiopharmaceutical for cisternography. Br J RadioI45:677-679, Sep 1972
