Nuclear Medicine
Adverse Reactions (Aseptic Meningitis) from 111lndium-OTPA Cisternographic Examinations 1 Vemblaserry Jayabalan, M.D., Dennis White, M.D., and Morris Bank, Ph.D. Cisternographic examinations have become a relatively common procedure in the evaluation of patients with suspected communicating hydrocephalus. Adverse reactions to radiopharmaceuticals are relatively uncommon, particularly with the commonly used agents such as lllln-DTPA and 169Yb-DTPA. Adverse reactions after lumbar intrathecal instillation of lllln_DTPA in three patients are described. INDEX TERMS: reactions
Cisternography • Cisterns,
subarachnoid. Meningitis. Aadionuclides,
Radiology 115:403-405, May 1975
APPROXIMATELY 70 cisternographic examinations have
K been performed in the radiology department at Hurley Hospital in the past two and a half years. Initially a few examinations were carried out with 1311-RIHSA (radioiodinated human serum albumin), and occasionally 169Yb_DTPA (diethylenetriaminepentaacetic acid) was utilized. The majority of examinations were performed with 111In-DTPA, supplied by Diagnostic Isotopes, Inc. The radiopharmaceutical was supplied in sterile single-dose vials, calibrated for the day of the examination. The activity of 111In_DTPA was usually in the range of 500/-Lei. No adverse reactions to the various radiopharmaceuticals were noted in 67 of the 70 examinations, but aseptic meningitis developed in three patients following intrathecal administration of 111In_DTPA. Only one other instance of adverse reaction to intrathecal administration of 111In_DTPA is recorded in the literature (21). The manufacturer of 111In-DTPA, Diagnostic Isotopes, Inc., was unaware of any adverse reactions except those mentioned above (23). CASE REPORTS CASE I: K. P., a 23-year-old, right-handed, single woman, was known to have centerencephalic grand mal epilepsy controlled by phenobarbital. She had flexion contractures of the hands and feet. On admission vital signs were normal. Complete blood count (CBC) was normal with a white blood count (WBC) of 5,500/mm 3 and a normal differential. Cerebrospinal fluid obtained before intrathecal administration of lllln_DTPA revealed a clear fluid with three monocytes and protein of 54 mg/ 100 ml. About five hours later, following intrathecal administration of 500 ,uCi of lllln_DTPA, the patient became febrile and vomiting, myoclonic jerks, grand mal seizures and nuchal rigidity developed. This was controlled with Valium and phenobarbital. Lumbar puncture performed the next day showed a clear, colorless fluid, color index 80, no sugar, and protein 44 mg/
100 ml, WBC 3/mm 3 , monocytes 100 %, red blood count (RBC) 750/mm 3 . Her temperature during the day varied between 99.2° and 102.4° F (37.3°-39.1° C). The next day the patient was still febrile with the temperature ranging between 99.2° and 101.8° F (37.3°-38.8° C). She had occasional vomiting. Complete blood count showed a WBC of 9,600/ mm 3 with a differential of basophils 1, segmented cells 65, bands 14, lymphocytes 17, monocytes 3. On the third day the patient was still febrile with an average temperature of 99° F (37.2° C). Complete blood. count showed a WBC of 4,200/mm 3 with a differential of 60 % monocytes and 40 % polymorphonuclear cells. Cerebrospinal fluid obtained the same day revealed a slightly xanthochromatic fluid with color index of 88, protein 84 mg/100 ml, sugar 56 mg/100 ml, WBC 322/mm 3 , monocytes 58 %, polymorphonuclear cells 42 %. After the fourth day the patient returned to an afebrile state and was asymptomatic. During this period no antibiotics were administered. The patient received parenteral fluids and medication in the form of phenobarbital and Valium. CASE II: J. S., a 1-year-old girl, underwent cisternography performed with 250 ,uCi of l11In_DTPA. About four hours following the procedure signs and symptoms of meningeal reaction similar to those of CASE I developed. Cerebrospinal fluid findings and peripheral blood picture were similar. This patient also made an uneventful recovery. No antibiotics were administered. CASE III: In K. D., a 74-year-old white man, cerebrospinal fluid obtained before the introduction of 500 ,uCi of 111In-DTPA revealed clear, colorless fluid, protein 70 mg/100 ml, glucose 76 mg/100 ml, WBC 10/mm3 , 100% monocytes, RBC 2/mm 3 . Two hours following cisternography the patient became febrile with a temperature of 99.4° F (37.4° C), pulse 100/min., and shivering and headache. On the third day neck rigidity, spiking fever, and positive Kernig's sign developed.. Lumbar puncture revealed an opening pressure of 190 mm H~ and a slightly xanthochromatic fluid. By the seventh hospital day the temperature returned to normal and the patient became asymptomatic.
In all three cases the cerebrospinal fluid obtained at various times was submitted to bacteriological examinations, including smears and cultures for aerobic and an-
1 From the Department of Radiology (V. J., Chief, Division of Nuclear Medicine; D. W., Radiologist; M. B., Physicist), Hurley Hospital, Flint, Mich. Accepted for pUblication in November 1974. dk
403
404
May
VEMBLASERRY JAYABALAN AND OTHERS
aerobic organisms. All tests were negative. The lumbar puncture tray was examined bacteriologically and proved negative. The vials and residual radiopharmaceuticals remaining in the vials were also subjected to bacteriological examinations with negative results. Diagnostic Isotopes, Inc. performed the following tests on samples from two of the three batches of 1111n_ DTPA that were used: (a) Rabbit Pyrogen Test, (b) LimuIus Amebocyte Lysate Endotoxin Test, (c) ATI Sterilometers Test, (d) Bacillus Steamothermophilus Indicator Test (11-13, 17, 18). All these tests were reported to be negative. The three examinations were performed in the same room under identical conditions and were carried out over a two-week period. The lumbar punctures in patients K. P. and J. S. were performed by the same physician. All the cisternographic examinations from which no adverse reactions developed were also performed under identical conditions. DISCUSSION
The symptoms and signs of meningeal reaction developed between two and six hours following intrathecal administration of 111In-DTPA and persisted from four to six days. All three patients recovered with symptomatic treatment without the administration of antibiotics. Review of the literature indicates that there have been previous reports of aseptic meningitis developing in patients undergoing cisternographic examinations. When 1311-albumin or 99mTc-albumin was used, these reactions were attributed to the albumin (1, 2, 15, 16) and possible hypersensitivity to the albumin. The possibility that these reactions were secondary to the presence of pyrogens was also raised. It was suggested that routine tests for pyrogens were insensitive and less sensitive than the human thecal membranes (13). It was postulated that more sensitive tests for pyrogens such as the Limulus Amebocyte Lysate Endotoxin Test would be more helpful (11, 12, 17, 18). Other possibilities include trauma from the lumbar puncture itself (19, 20), contamination of the thecal space by the antiseptic preparation used in preparing the skin at the time of lumbar puncture, use of nondisposable lumbar puncture equipment that may be contaminated, idiosyncrasy of the patients, and chemical reactions to the various ingredients contained in the radiopharmaceuticals. Since the availability of chelated radiopharmaceuticals such as 111In-DTPA and 169'Yb-DTPA, the frequency of adverse reactions has been extremely low. Only a few cases of adverse reactions following intrathecal administration of 111In_DTPA are known to us (21,23). We are not aware of any adverse reactions having occurred after 169Yb_DTPA administration. As in the recorded cases of aseptic meningitis following 111In-DTPA injection, we were also unable to iso-
1975
late any contaminating organisms in the cerebrospinal fluid or in the residual radiopharmaceuticals. More sensitive tests for pyrogens in the form of Limulus Amebocyte Lysate Endotoxin Test were also negative. Cisternographic examinations are performed on the request and referral by a neurologist or neurosurgeon. The lumbar puncture and intrathecal instillation of the radiopharmaceuticals are performed by a neurologist, neurosurgeon or neuroradiologist experienced in these procedures. In spite of these precautions, adverse reactions, although rare, may occur. CONCLUSION
Cisternography is a fairly common procedure performed in patients suspected of having communicating hydrocephalus. It provides valuable information to the neurosurgeon on the advisability of shunting in these patients. At the present time the most preferred agent for cisternographic examination is 111In-DTPA. Adverse reaction to this radiopharmaceutical has been rare. It is possible that milder forms of reactions such as headaches are unnoticed. The cause for these reactions is unknown at present. The adverse reactions are usually a form of aseptic meningitis and usually resolve without sequelae. ACKNOWLEDGMENTS: Thanks are expressed to Dr. M. Levine and Dr. R. Ouyang for permission to use material from their cases; and to Mr. Anthony J. Kale, microbiologist at Hurley Hospital, for the culture studies; and to Diagnostic Isotopes, Inc., New Jersey, for the pyrogen tests performed. Department of Radiology Hurley Hospital Flint, Mich. 48502
REFERENCES 1. Nicol CF: A second case of aseptic meningitis following isotope cisternography using 1-131 human serum albumin. Neurology 17:199-200, Feb 1967 2. Detmer DE, Blacker HM: A case of aseptic meningitis secondary to intrathecal injection of 1-131 human serum albumin. Neurology 15:642-643, Jul 1965 3. Lathrop P: An epidemiologic investigation of chemical meningitis. Ph.D. Dissertation. Berkeley, University of California,
1968 4. Barnes B, Fish M: Chemical meningitis as a complication of isotope cisternography. Neurology 22:83-91, Jan 1972 5. Goldman WW Jr, Sanford JP: An "epidemic" of chemical meningitis. Am J Med 29:94-101, Jul 1960 6. Paddison RM, Alpers BJ: Role of intrathecal detergents in pathogenesis of adhesive arachnoiditis. Arch Neurol Psychiat 71: 87-100, Jan 1954 7. Joseph SI, Denson JS: Spinal anesthesia, arachnoiditis, and paraplegia. JAMA 168:1330-1333, 8 Nov 1958 8. Gibbons RB: Chemical meningitis following spinal anesthesia. JAMA 210:900-902,3 Nov 1969 9. Winkelman NW: Neurologic symptoms following accidental intraspinal detergent injection. Neurology 2:284-291, Jul-Aug 1952 10. Jenicek JA: Aseptic meningitis following lumbar epidural block: case report. Anesthesiology 16:464-465, May 1955 11. Levin J, Tomasulo PA, Oser RS: Detection of endotoxin in human blood and demonstration of an inhibitor. J Lab Clin Mad 75: 903-911, Jun 1970 12. Levin J, Bang FB: Clottable protein in Limu/us: its localiza-
Vol. 115
ADVERSE REACTIONS FROM 111IN_DTPA CISTERNOGRAPHY
tion and kinetics of its coagulation by endotoxin. Thromb Diath Haemorrh 19:186-197,31 Mar 1968 13. Cooper JF, Levin J, Wagner HN: New, rapid in vitro test for pyrogen in short-lived radiopharmaceuticals. J Nucl Med 11:31 0, 1970 14. Atkins HL, Hauser W, Richards P, et al: Adverse reactions to radiopharmaceuticals. J Nucl Med 13:232-233, Mar 1972 15. Harbert JC, Cooper J: Aseptic meningitis following isotope cisternography (letter to ed). J Nucl Med 13:778, Oct 1972 16. Oldham RK, Staab EV: Aseptic meningitis following the intrathecal injection of radioiodinated serum albumin. Radiology 97: 317-321, Nov 1970 17. Cooper JF, Levin J, Wagner HN Jr: Quantitative comparison of in vitro and in vivo methods for the detection of endotoxin. J Lab elin Med 78: 138-148, Jul 1971
405
Nuclear Medicine
18. Cooper JF, Hochstein HD, Seligmann EB Jr: The Limulus test for endotoxin (pyrogen) in radiopharmaceuticals and biologicals. Bull Parenter Drug Assoc 26:153-162, Jul-Aug 1972 19. Reynolds KE, Wilson G: Aseptic meningitis following diagnostic lumbar puncture; indications for lumbar puncture and complications secondary to it. JAMA 102: 1460-1462, 5 May 1934 20. Austin DA, Sokolowski JW Jr: Postlumbar puncture chemical meningitis. New York J Med 68:2444-2446, Sep 1968 21. Alderson PO, Siegel BA: Adverse reactions following "'InDTPA cisternography. J Nucl Med 14:609-611, Aug 1973 22. Messert B, Rieder MJ: RISA cisternography. Study of spinal fluid changes associated with intrathecal RISA injection. Neurology 22:789-792, Aug 1972 23. Personal communication: Mr. Dutt, Diagnostic Isotope, Inc., New Jersey
Adverse Reactions (Aseptic Meningitis) from 111lndium-OTPA Cisternographic Examinations 1 Vemblaserry Jayabalan, M.D., Dennis White, M.D., and Morris Bank, Ph.D. Cisternographic examinations have become a relatively common procedure in the evaluation of patients with suspected communicating hydrocephalus. Adverse reactions to radiopharmaceuticals are relatively uncommon, particularly with the commonly used agents such as lllln-DTPA and 169Yb-DTPA. Adverse reactions after lumbar intrathecal instillation of lllln_DTPA in three patients are described. INDEX TERMS: reactions
Cisternography • Cisterns,
subarachnoid. Meningitis. Aadionuclides,
Radiology 115:403-405, May 1975
APPROXIMATELY 70 cisternographic examinations have
K been performed in the radiology department at Hurley Hospital in the past two and a half years. Initially a few examinations were carried out with 1311-RIHSA (radioiodinated human serum albumin), and occasionally 169Yb_DTPA (diethylenetriaminepentaacetic acid) was utilized. The majority of examinations were performed with 111In-DTPA, supplied by Diagnostic Isotopes, Inc. The radiopharmaceutical was supplied in sterile single-dose vials, calibrated for the day of the examination. The activity of 111In_DTPA was usually in the range of 500/-Lei. No adverse reactions to the various radiopharmaceuticals were noted in 67 of the 70 examinations, but aseptic meningitis developed in three patients following intrathecal administration of 111In_DTPA. Only one other instance of adverse reaction to intrathecal administration of 111In_DTPA is recorded in the literature (21). The manufacturer of 111In-DTPA, Diagnostic Isotopes, Inc., was unaware of any adverse reactions except those mentioned above (23). CASE REPORTS CASE I: K. P., a 23-year-old, right-handed, single woman, was known to have centerencephalic grand mal epilepsy controlled by phenobarbital. She had flexion contractures of the hands and feet. On admission vital signs were normal. Complete blood count (CBC) was normal with a white blood count (WBC) of 5,500/mm 3 and a normal differential. Cerebrospinal fluid obtained before intrathecal administration of lllln_DTPA revealed a clear fluid with three monocytes and protein of 54 mg/ 100 ml. About five hours later, following intrathecal administration of 500 ,uCi of lllln_DTPA, the patient became febrile and vomiting, myoclonic jerks, grand mal seizures and nuchal rigidity developed. This was controlled with Valium and phenobarbital. Lumbar puncture performed the next day showed a clear, colorless fluid, color index 80, no sugar, and protein 44 mg/
100 ml, WBC 3/mm 3 , monocytes 100 %, red blood count (RBC) 750/mm 3 . Her temperature during the day varied between 99.2° and 102.4° F (37.3°-39.1° C). The next day the patient was still febrile with the temperature ranging between 99.2° and 101.8° F (37.3°-38.8° C). She had occasional vomiting. Complete blood count showed a WBC of 9,600/ mm 3 with a differential of basophils 1, segmented cells 65, bands 14, lymphocytes 17, monocytes 3. On the third day the patient was still febrile with an average temperature of 99° F (37.2° C). Complete blood. count showed a WBC of 4,200/mm 3 with a differential of 60 % monocytes and 40 % polymorphonuclear cells. Cerebrospinal fluid obtained the same day revealed a slightly xanthochromatic fluid with color index of 88, protein 84 mg/100 ml, sugar 56 mg/100 ml, WBC 322/mm 3 , monocytes 58 %, polymorphonuclear cells 42 %. After the fourth day the patient returned to an afebrile state and was asymptomatic. During this period no antibiotics were administered. The patient received parenteral fluids and medication in the form of phenobarbital and Valium. CASE II: J. S., a 1-year-old girl, underwent cisternography performed with 250 ,uCi of l11In_DTPA. About four hours following the procedure signs and symptoms of meningeal reaction similar to those of CASE I developed. Cerebrospinal fluid findings and peripheral blood picture were similar. This patient also made an uneventful recovery. No antibiotics were administered. CASE III: In K. D., a 74-year-old white man, cerebrospinal fluid obtained before the introduction of 500 ,uCi of 111In-DTPA revealed clear, colorless fluid, protein 70 mg/100 ml, glucose 76 mg/100 ml, WBC 10/mm3 , 100% monocytes, RBC 2/mm 3 . Two hours following cisternography the patient became febrile with a temperature of 99.4° F (37.4° C), pulse 100/min., and shivering and headache. On the third day neck rigidity, spiking fever, and positive Kernig's sign developed.. Lumbar puncture revealed an opening pressure of 190 mm H~ and a slightly xanthochromatic fluid. By the seventh hospital day the temperature returned to normal and the patient became asymptomatic.
In all three cases the cerebrospinal fluid obtained at various times was submitted to bacteriological examinations, including smears and cultures for aerobic and an-
1 From the Department of Radiology (V. J., Chief, Division of Nuclear Medicine; D. W., Radiologist; M. B., Physicist), Hurley Hospital, Flint, Mich. Accepted for pUblication in November 1974. dk
403
404
May
VEMBLASERRY JAYABALAN AND OTHERS
aerobic organisms. All tests were negative. The lumbar puncture tray was examined bacteriologically and proved negative. The vials and residual radiopharmaceuticals remaining in the vials were also subjected to bacteriological examinations with negative results. Diagnostic Isotopes, Inc. performed the following tests on samples from two of the three batches of 1111n_ DTPA that were used: (a) Rabbit Pyrogen Test, (b) LimuIus Amebocyte Lysate Endotoxin Test, (c) ATI Sterilometers Test, (d) Bacillus Steamothermophilus Indicator Test (11-13, 17, 18). All these tests were reported to be negative. The three examinations were performed in the same room under identical conditions and were carried out over a two-week period. The lumbar punctures in patients K. P. and J. S. were performed by the same physician. All the cisternographic examinations from which no adverse reactions developed were also performed under identical conditions. DISCUSSION
The symptoms and signs of meningeal reaction developed between two and six hours following intrathecal administration of 111In-DTPA and persisted from four to six days. All three patients recovered with symptomatic treatment without the administration of antibiotics. Review of the literature indicates that there have been previous reports of aseptic meningitis developing in patients undergoing cisternographic examinations. When 1311-albumin or 99mTc-albumin was used, these reactions were attributed to the albumin (1, 2, 15, 16) and possible hypersensitivity to the albumin. The possibility that these reactions were secondary to the presence of pyrogens was also raised. It was suggested that routine tests for pyrogens were insensitive and less sensitive than the human thecal membranes (13). It was postulated that more sensitive tests for pyrogens such as the Limulus Amebocyte Lysate Endotoxin Test would be more helpful (11, 12, 17, 18). Other possibilities include trauma from the lumbar puncture itself (19, 20), contamination of the thecal space by the antiseptic preparation used in preparing the skin at the time of lumbar puncture, use of nondisposable lumbar puncture equipment that may be contaminated, idiosyncrasy of the patients, and chemical reactions to the various ingredients contained in the radiopharmaceuticals. Since the availability of chelated radiopharmaceuticals such as 111In-DTPA and 169'Yb-DTPA, the frequency of adverse reactions has been extremely low. Only a few cases of adverse reactions following intrathecal administration of 111In_DTPA are known to us (21,23). We are not aware of any adverse reactions having occurred after 169Yb_DTPA administration. As in the recorded cases of aseptic meningitis following 111In-DTPA injection, we were also unable to iso-
1975
late any contaminating organisms in the cerebrospinal fluid or in the residual radiopharmaceuticals. More sensitive tests for pyrogens in the form of Limulus Amebocyte Lysate Endotoxin Test were also negative. Cisternographic examinations are performed on the request and referral by a neurologist or neurosurgeon. The lumbar puncture and intrathecal instillation of the radiopharmaceuticals are performed by a neurologist, neurosurgeon or neuroradiologist experienced in these procedures. In spite of these precautions, adverse reactions, although rare, may occur. CONCLUSION
Cisternography is a fairly common procedure performed in patients suspected of having communicating hydrocephalus. It provides valuable information to the neurosurgeon on the advisability of shunting in these patients. At the present time the most preferred agent for cisternographic examination is 111In-DTPA. Adverse reaction to this radiopharmaceutical has been rare. It is possible that milder forms of reactions such as headaches are unnoticed. The cause for these reactions is unknown at present. The adverse reactions are usually a form of aseptic meningitis and usually resolve without sequelae. ACKNOWLEDGMENTS: Thanks are expressed to Dr. M. Levine and Dr. R. Ouyang for permission to use material from their cases; and to Mr. Anthony J. Kale, microbiologist at Hurley Hospital, for the culture studies; and to Diagnostic Isotopes, Inc., New Jersey, for the pyrogen tests performed. Department of Radiology Hurley Hospital Flint, Mich. 48502
REFERENCES 1. Nicol CF: A second case of aseptic meningitis following isotope cisternography using 1-131 human serum albumin. Neurology 17:199-200, Feb 1967 2. Detmer DE, Blacker HM: A case of aseptic meningitis secondary to intrathecal injection of 1-131 human serum albumin. Neurology 15:642-643, Jul 1965 3. Lathrop P: An epidemiologic investigation of chemical meningitis. Ph.D. Dissertation. Berkeley, University of California,
1968 4. Barnes B, Fish M: Chemical meningitis as a complication of isotope cisternography. Neurology 22:83-91, Jan 1972 5. Goldman WW Jr, Sanford JP: An "epidemic" of chemical meningitis. Am J Med 29:94-101, Jul 1960 6. Paddison RM, Alpers BJ: Role of intrathecal detergents in pathogenesis of adhesive arachnoiditis. Arch Neurol Psychiat 71: 87-100, Jan 1954 7. Joseph SI, Denson JS: Spinal anesthesia, arachnoiditis, and paraplegia. JAMA 168:1330-1333, 8 Nov 1958 8. Gibbons RB: Chemical meningitis following spinal anesthesia. JAMA 210:900-902,3 Nov 1969 9. Winkelman NW: Neurologic symptoms following accidental intraspinal detergent injection. Neurology 2:284-291, Jul-Aug 1952 10. Jenicek JA: Aseptic meningitis following lumbar epidural block: case report. Anesthesiology 16:464-465, May 1955 11. Levin J, Tomasulo PA, Oser RS: Detection of endotoxin in human blood and demonstration of an inhibitor. J Lab Clin Mad 75: 903-911, Jun 1970 12. Levin J, Bang FB: Clottable protein in Limu/us: its localiza-
Vol. 115
ADVERSE REACTIONS FROM 111IN_DTPA CISTERNOGRAPHY
tion and kinetics of its coagulation by endotoxin. Thromb Diath Haemorrh 19:186-197,31 Mar 1968 13. Cooper JF, Levin J, Wagner HN: New, rapid in vitro test for pyrogen in short-lived radiopharmaceuticals. J Nucl Med 11:31 0, 1970 14. Atkins HL, Hauser W, Richards P, et al: Adverse reactions to radiopharmaceuticals. J Nucl Med 13:232-233, Mar 1972 15. Harbert JC, Cooper J: Aseptic meningitis following isotope cisternography (letter to ed). J Nucl Med 13:778, Oct 1972 16. Oldham RK, Staab EV: Aseptic meningitis following the intrathecal injection of radioiodinated serum albumin. Radiology 97: 317-321, Nov 1970 17. Cooper JF, Levin J, Wagner HN Jr: Quantitative comparison of in vitro and in vivo methods for the detection of endotoxin. J Lab elin Med 78: 138-148, Jul 1971
405
Nuclear Medicine
18. Cooper JF, Hochstein HD, Seligmann EB Jr: The Limulus test for endotoxin (pyrogen) in radiopharmaceuticals and biologicals. Bull Parenter Drug Assoc 26:153-162, Jul-Aug 1972 19. Reynolds KE, Wilson G: Aseptic meningitis following diagnostic lumbar puncture; indications for lumbar puncture and complications secondary to it. JAMA 102: 1460-1462, 5 May 1934 20. Austin DA, Sokolowski JW Jr: Postlumbar puncture chemical meningitis. New York J Med 68:2444-2446, Sep 1968 21. Alderson PO, Siegel BA: Adverse reactions following "'InDTPA cisternography. J Nucl Med 14:609-611, Aug 1973 22. Messert B, Rieder MJ: RISA cisternography. Study of spinal fluid changes associated with intrathecal RISA injection. Neurology 22:789-792, Aug 1972 23. Personal communication: Mr. Dutt, Diagnostic Isotope, Inc., New Jersey
