•
Neuroradiology
Lumbar Radiculography with Metrizamide A Nonionic Water-Soluble Contrast Medium 1 Ingar O. Skalpe, M.D., and Per Amundsen, M.D. Six hundred lumbar radiculographies were performed with metrizamide in 581 patients. Excellent radiographs were obtained in almost all cases. The adverse effects were minor and no serious complications occurred. The authors consider metrizamide superior to other water-soluble contrast media in present use from both toxicological and radiological points of view. INDEX TERMS:
Contrast Media, comparative studies. Metrizamide • Myelography, con-
trast media Radiology 115:91-95, Apri/1975
•
•
f~\HOH
controversial subjects in neuroradiology concerns the use of contrast media in the subarachnoid space. Thus, in Scandinavia and other European countries the water-soluble contrast medium methiodal sodium was until recently considered "the medium of choice" for examination of the lumbar subarachnoid space. This medium is not used in the United States and other English-speaking countries, where the oily medium Pantopaque (ethyl iodophenylundecylate) is preferred. An illustrative example of the difference in opinions is the fact that the Swedish health authorities have forbidden the use of the last-named. The drawbacks of both methiodal sodium and ethyl iodophenylundecylate are obvious. The local irritative properties of methiodal sodium make spinal anesthesia necessary. Therefore, this medium can be used only below the conus of the spinal cord. Both acute and long-term complications are reported with this medium (3,4, 22, 23, 24, 27, 30). With a proper technique, however, the complication rate is low and the diagnostic accuracy is satisfactory (6). The most important indication for lumbar radiculography is suspected disk herniation. There· is general agreement that this diagnosis is made with higher accuracy with a water-soluble medium than with ethyl iodophenylundecylate because the former medium gives better filling of the root sleeves. Another disadvantage with Pantopaque is that it is slowly resorbed from the subarachnoid space. Although most radiologists try to withdraw it at the end of the examination, a complete withdrawal is seldom achieved, and the small residual amount might therefore exert an irritative effect through the years. Reports on severe complications claimed to be due to arachnoiditis caused by ethyl iodophenylundecylate have appeared, as summarized by Di Chiro and Fisher (14). However, many radiologists consider these obvious drawbacks to be outweighed by its advantages. NE OF THE MOST
O
H~ ~H
CO
CH3CO~O~COCH3 CYH 3 I
Fig. 1.
Structural formula for metrizamide.
It has a low acute toxicity and can be used for examination of the entire spinal subarachnoid space. The introduction of meglumine iothalamate (Conray Meglumin) and later its dimer, meglumine iocarmate (Dlmer-X), seemed to change the situation in favor of water-soluble contrast agents (1,2,8, 13,29). A major disadvantage of methiodal sodium was eliminated, since both media could be used without spinal anesthesia. It soon appeared, however, that these media were not ideal for subarachnoid use. Most authors reported clonic convulsions in the lower extremities after lumbar radiculography with meglumine iothalamate and meglumine iocarmate (1,2,21,29,31,32). Due to this spasmogenic effect the media should be used only below the conus of the spinal cord. Recent reports on adhesive arachnoiditis occurring as a long-term effect after use of these media have also precluded their general acceptance (3, 7, 22, 23, 30). With adequate doses and a proper technique, however, many authors claim that both meglumine iothalamate and meglumine iocarmate are safe media for lumbar radiculography. A new principle for the synthesis of water-soluble contrast agents was suggested by Almen in 1969 (5).
1 From the Department of Neuroradiology, Ulleval Hospital, Oslo, Norway. Accepted for publication in October 1974. Additional articles on the use of metrizamide will be found on pages 59 and 237 of this issue.
91
ah
92
INGAR
O.
April 1975
SKALPE AND PER AMUNDSEN
Table I:
Age and Sex Distributions in 600 Lumbar Radiculographies with Metrizamide Women
Age (yr.) 10-19 20-29 30...:39 40-49 50-59 60-69 70-
TH XII
Totals
Men
Total
4
5
9
18 21 63 68 20
52 76 121
70 97 184 169 65
101 45
2
4
6
196
404
600
Table II: Dose (ml) and Concentration (mg Iodine i'er ml) of Metrizamide in 600 Lumbar Radiculographies Dose --... Concentration --...
~~10~
~-15~
119
170
170
200
153* 270
26 87
17 41
113
58
Women Men
1 5
Total
6
---
423
* One patient received 10 ml/200 mg iodine per ml. Table III:
Adverse Effects After Lumbar Radiculography with Metrizamide Dizziness
Pain Numbness
Headache
Nausea
Women Men
78 (40%) 109 (27%)
33 (17%) 44 (11%)
35 (18%) 37 (9%)
37 (19%) 70 (17%)
Total
187 (31%)
77 (13%)
72 (12%)
107 (18%)
-----
Fig. 2. Lumbar radiculography with 10 ml metrizamide (170 mg iodine per ml). Lateral position, horizontal beam direction. A. Good filling of the root sleeves on the right side. B. No filling of the root sleeve of the fifth lumbar root on the left side (arrowhead). Minor indentation in the contrast column at the same level. Findings indicate disk herniation. C. Contrast material is transported to the subarachnoid space in the conus region by lowering the head end of the table.
an extremely low toxicity and a remarkably low irritative effect on the central nervous system when introduced into the subarachnoid spaces in experimental animals (28).2 The pilot clinical studies with metrizamide were carried out in four medical centers working in close contact. The results of these preliminary clinical studies indicated that it was the best of the hitherto known watersoluble contrast media used in the subarachnoid space (15, 19, 33, 34). In this communication, we present our experience with this new water-soluble medium in 600 consecutive lumbar radiculographies. Special attention was paid to its possible adverse effects, since this is one of the main problems with the use of positive contrast media in the subarachnoid spaces. MATERIAL
He advocated the use of nonionic compounds in order to decrease the osmolarity of water-soluble contrast agents, since the hypertonicity was responsible for some of the adverse effects of these media (10, 18). Based upon Alrnen's proposal, a series of nonionic compounds were synthesized in the research laboratories of Nyegaard & Co., Oslo, Norway. One of these substances, metrizamide (Fig. 1), was found to be promising in preliminary studies. It was therefore chosen for further studies. More than three years intensive laboratory studies with a view to pharmacology, toxicology, and physiology preceded its use in humans. On the basis of these studies metrizamide was found to have
Six hundred lumbar radicufographies were carried out in 581 patients from June 1972 through February 1974. The patients were referred with a clinical diagnosis of lumbar disk herniation. From June 1972 to September 1973 women of fertile age were excluded, but later there was no selection. The sex distribution is given in TABLE I. METHODS
The first 100 examinations were performed by an ex2 It should be pointed out that the Food and Drug Administration of the United States has not yet accepted metrizamide.
LUMBAR RADICULOGRAPHY WITH METRIZAMIDE
Vol. 115
perienced neuroradiologist; the last 500 were carried out as routine procedures mainly by residents with varying experience in neuroradiology. No premedication was given. The spinal puncture was performed with a 22gauge needle with the patient on his side. The dose and concentration of contrast medium are shown in TABLE II. The position of the contrast medium was checked by television screening. In 134 patients the agent was allowed to pass above the tenth thoracic vertebra in order to include the conus region in the examination. In the others the contrast medium was not allowed to pass above this level. Usually the upper limit was at T 12L 1 . The radiologic technique was otherwise approximately the same as had been used with methiodal sodium (6, 27). Most of the patients were examined in the lateral position with horizontal beam direction, but in some radiographs were also obtained in prone or supine position with a vertical beam direction. After the examination the patients were kept supine in bed with the upper end elevated 10° for 24 hours. Sixty-five were placed in the prone position for one hour, whereafter they were placed in the supine position with the bed horizontal. In the first series of 100 patients a: complete neurologic examination was carried out by the same neurologist before the radiculography and 24 hours later. A series of other procedures, including electroencephalography and cerebrospinal fluid examinations were also performed, and the results recorded before and after radiculography in this part of the study (33). In the last 500 patients a questionnaire regarding the adverse effects expected to follow the radiculography was sent to the referring department. The physician in charge of the patient was asked to answer the questions and return the questionnaire when the patient was discharged or operated upon. RESULTS Radiologic Findings: Excellent films with good filling of the root sleeves to the level of T 12 L 1 were obtained in almost all cases (Fig. 2). Opacification of the subarachnoid space in the conus region was easy to achieve with a horizontal beam direction and the patient on his side (Fig. 2,q. Demonstration of the conus itself could be obtained with a vert ical beam direction and the patient either supine or prone (Fig. 3). However, this was technically difficult in some cases because the contrast medium was diluted with cerebrospinal fluid when it was transported up into the conus region. Adverse Effects (TABLE III): The frequency of headache, nausea, and dizziness was higher in women than in men. The headache was moderate to minor in most patients, usually lasting a few hours, but in a few it lasted for several days. This headache usually appeared in the erect position and vanished when the patient lay down. The frequency of headache was the same (31 % ) in the patients in whom the contrast medium was al-
93
Neuroradiology
Fig. 3. Opacificat ion of the conus region with delineation of the conus (arrowheads) and the cauda equlna. Subtraction technique.
lowed to rise above T 10 and in those in whom it had been kept below this level during the examination. Increase in dose and iodine concentration did not affect the frequency of headache in the men in the present series, while the women had a significantly higher frequency (p < 0.05) after 15 ml with a concentration of 200 mg iodine/ml than after 10 ml metrizamide with a concentration of 170 mg iodine/ml (59 and 32%, respectively). The frequency of headache was 63 % in the patients placed in the horizontal position shortly after radiculography. Nausea and dizziness represented minor complaints in most of the patients , but a few, vomited repeatedly for several hours. The most frequent other complaint was pain in the buttocks and thighs of another character than the usual sciatic pain, often associated with a feeling of stiffness or numbness in the leg muscles. A few patients complained of transitory micturition disturbances in the evening on the day of radiculography. This was probably due to the fact that they were
94
INGAR
O. SKALPE
asked to urinate while lying in their beds. The next day when they were allowed to go to the toilet, no difficulties with the urination occurred. A slight-to-moderate increase in the white cell count occurred in 21 of 29 patients in whom a repeat spinal puncture was performed six to 48 hours after the radlculoqraphy (33). Three patients with increased white cell count in the cerebrospinal fluid were reexamined two weeks to four months later, and the counts were normal in all three. Transitory changes in the EEG recordings occurred in 13 of 79 patients examined 24 hours after the radiculography (24). Nineteen of the patients in the present series were examined twice, three because the first contrast medium injection was made subdurally. In the other 16 the root sleeves could be studied at both examinations. The interval between the examinations was less than two months in six patients and more than two months in 10. No changes indicating adhesive arachnoiditis were found. DISCUSSION
Metrizamide gave the same excellent quality of radiographs as did meglumine iothalamate and meglumine iocarmate. A major advantage of metrizamide compared with these media, however, was the marked reduction of spasmogenic effects. Thus, in spite of the high doses and high iodine concentrations used in many patients in the present series, and in spite of the fact that the conus region was included in the examination in many patients, no convulsions were seen. The introduction of meglumine iothalamate and later meglumine iocarmate for lumbar radiculography increased the interest in possible adverse effects following such examinations. It has been shown that after administration of both these media approximately one third of the patients complain of headache and many complain of nausea and dizziness (31, 32). However, it should be noted that a similar frequency of headache is reported after diagnostic lumbar puncture (35). The same tendency of higher frequency of headache in women than in men which was found after radiculography with meglumine iothalarnate (31), meglumine iocarmate (32), and metrizamide is also found after diagnostic lumbar puncture (35). In many patients in the present series the headache had the same character as a postlumbar puncture headache, that is, it was present only when the patient was in the erect position and vanished when he lay down. The increased frequency of headache seen after increasing the dose and iodine concentration in the women in the present series, however, indicates that the contrast medium is also responsible for the headache in some patients. The same conclusion may be drawn from the fact that the frequency of headache seems to increase when the patients lie prone for one hour after the radiculography and then are placed su-
AND PER AMUNDSEN
April 1975
pine with the bed horizontal. This procedure was expected to reduce the leakage of cerebrospinal fluid and thus probably reduce the frequency of headache (12). The same observation was recently made by Bettinger and Sondheimer (9) who found that headache was twice as common after ethyl iodophenylundecylate myelography in patients who remained prone as in patients who maintained a supine position following the examination. It should also be noted that these authors reported an overall incidence of headache following ethyl iodophenylundecylate myelography of 27 per cent, approximately the same frequency as is reported with water-soluble contrast media. Evaluation of increase in the patients' usual sciatic pain was difficult on the basis of the questionnaires. Probably such increase was in most cases due to the withdrawal of analgesics prior to radiculography and unusual movements during the examination. However, many patients complained of pain of another character than their sciatic pain, usually located in the buttocks and thighs. This pain was often associated with a feeling of stiffness or numbness in the leg muscles. These symptoms are most probably due to irritative effects of the contrast medium. In most of the cases the adverse effects described above might be reduced by suitable drugs. In the present series the use of drugs was restricted, since we wanted a complete registration of the adverse effects. Although no serious complications occurred in the present series, the various symptoms reported by the patients, the transient EEG changes (25), and the increased white cell count in the cerebrospinal fluid seen . in some of the patients (33) indicate that metrizamide in some way affects the nervous system. However, we consider these drawbacks to be outweighed by the remarkable reduction of the convulsant effect, since this effect has been responsible for serious complications with meglumine iothalamate and meglumine iocarmate . (11, 20). We have also had some experience with the use of metrizamide for thoracic and cervical myelography, a promising experience in regard to both toxicity and radiologic properties. We have never seen convulsions in any of our patients. Greitz (17) recently reported one case of grand mal fits occurring after cervical myelography with metrizamide. Due to technical difficulties during the examination the contrast medium was in contact with the cervical cord for an unusually long period of time. Furthermore, the.patient was treated with a neuroleptic drug which by itself may precipitate grand mal attacks (16). Therefore, we do not consider this report to contraindicate the use of metrizamide for the higher levels of the subarachnoid space. The possibility of late sequelae after radiculography with water-soluble contrast media must be seriously considered, since recent reports indicate that adhesive arachnoiditis may occur. Radiologic changes indicating
LUMBAR RADICULOGRAPHY WITH METRIZAMIDE
Vol. 115
adhesive arachnoiditis are described after administration of methiodal sodium, meglumine iothalamate, and meglumine iocarmate (3, 7, 22, 23, 30). No such changes were seen in 16 patients in the present series who were reexamined. Further information is needed about this problem, but so far it seems that metrizamide is superior to other water-soluble contrast media in this respect. In conclusion, metrizamide is a safe medium for lumbar radiculography, even when the conus of the spinal cord is included in the examination. It is superior to other water-soluble contrast media in present use for examination of the subarachnoid space, mainly because of the marked reduction of the spasmogenic effects. Neuroradiological Department Ullev~1 Hospital Oslo 1, Norway
REFERENCES 1. Ahlgren P: Oimer-X: a new contrast medium for lumbar myelography without spinal anaesthesia. Acta Radiol [Oiag] [9th Symp Neuroradiol 1970113:753-761, 1972 2. Ahlgren P: Long-term side effects after myelography with water-soluble contrast media: Conturex, Conray Meglumin 282 and Dimer-X. Neuroradiology 6:206-211, Dec 1973 3. Ahlgren P: Lumbale Myelographie mit Conray Meglumin 282. Fortschr Geb Rontgenstr Nuklearmed 111:270-276, Aug 1969 4. Ahlgren P, Praestholm J: Komplikationer ved myelografi med methiodalum. Nord Med 82:1600-1604, 18 Dec 1969 5. Alman T: Contrast agent design: some aspects on the synthesis of water-soluble contrast agents of low osmolality. J Theor Bioi 24:216-226, Aug 1969 6. Amundsen P, Helsingen P, Kristiansen K: Evaluation of lumbar radiculography ('myelography') with water-soluble media. Acta radiol [Diag] 1:659-665, 1963 7. Autio E, Suolanen J, Norrback S, et al: Adhesive arachnoiditis after lumbar myelography with meglumine iothalamate (Conray). Acta radioI [Diag] 12:17-24, Jan 1972 8. Baumgartner J, Braun JP, Caron J, et al: Radiculographie au Oimer X. Premiers resultats apres 630 examens. J Radiol Electrol Med NucI51:557-559, Oct 1970 9. Bettinger B, Sondheimer FK: Post-myelogram headaches: some of the things you've always wanted to know but were afraid to ask. X Symp Neuroradiol, Punta del Este, Uruguay, 10-16 Mar 1974 10. Bjork L: The osmotic effects of Urografin 76 per cent and Isopaque 60 per cent in angiocardiography. Am J Roentgenol 98: 922-926, Dec 1966 11. Boisen E, Lindholmer E: Alvorlige myelografi-komplikationer med jodtalaminmeglumin: en opg¢relse over 324 lumbale myelografier, samt beskrlvelse af 2 tilfaelde af svaere kramper i underekstremiteterne. Nord Med 85:520-524, 29 Apr 1971 12. Brocker RJ: Technique to avoid spinal-tap headache. JAMA 168:261-263, 20 Sep 1958
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Neuroradiology
13. Campbell RL, Campbell JA, Heimburger RF, et al: Ventriculography and myelography with absorbable radiopaque medium. Radiology 82:286-289, Feb 1964 14. Oi Chiro G, Fisher RL: Contrast radiography of the spinal cord. Arch NeuroI11:125-143, Aug 1964 15. Gonsette RE: Metrizamide as contrast medium for myelography and ventriculography. Preliminary clinical experiences. Acta Radiol [Oiag] [Suppl] 355:346-358, 1973 16. Goodman LS, Gilman A, ed: The Pharmacological Basis of Therapeutics. New York, Macmillan, 3d ed, 1965 17. Greitz T: Personal communication, 1973 18. Hilal SK: Hemodynamic changes associated with the intraarterial injection of contrast media: new toxicity tests and a new experimental contrast medium. Radiology 86:615-633, Apr 1966 19. Hindmarsh T: Methiodal sodium and metrizamide in lumbar myelography. Acta Radial [Oiag] [Suppl] 335:359-366, 1973 20. Irstam L: Side effects of water-soluble contrast media in lumbar myelography. Acta Radiol [Oiag] 14:647-656, Nov 1973 21. Irstam L, Lormerholm T, Sundstrom R, et al: Lumbal myelografi med Conray-Meglumin 282. Uikartidningen 67:3185-3190, 8 Jul 1970 22. Irstam L, Rosencrantz M: Water-soluble contrast media and adhesive arachnoiditis. I. Reinvestigation of nonoperated cases. Acta Radiol [Oiag] 14:497-506, Sep 1973 23. Irstam L, Rosencrantz M: Water-soluble contrast media and adhesive arachnoiditis. II. Reinvestigation of operated cases. Acta Radiol [Oiag] 15:1-15, Jan 1974 24: Kaada B: Transient EEG abnormalities following lumbar myelography with metrizamide. Acta Radiol [Diag] [Suppl] 335: 380-386, 1973 25. Kolstad P, Solem GH: Myelografi med vannopplesellq kentrastmiddel: en analyse av 427 myelografier. Nord Med 61:306-309, 19 Feb 1959 26. Lange J, (ZIdegaard H: Abrodil myelography in herniated disk in the lumbar region. Radiology 57:186-192, Aug 1951 27. Lindblom K: Lumbar myelography by abrodil. Acta Radiol 27:1-7, Jan 1946 28. Metrizamide, a non-ionic water-soluble contrast medium. Experimental and preliminary clinical investigations. Acta Radial [Oiag] Supp1335, 1973 29. Praestholm J, Lester J: Water-soluble contrast lumbar myelography with meglumine lothalarnate (Conray). Br J Radiol 43: 303-308, May 1970 30. RAdberg C, Wennberg E: Late sequelae following lumbar myelography with water-soluble contrast media. Acta Radiol [Oiag] 14:507-512, Sep 1973 31. Skalpe 10: Lumbar myelography with Conray Meglumin 282: report of 100 investigations with special reference to the adverse effects. Acta Neurol Scand 47:569-578, 1971 32. Skalpe 10, Talle K: Lumbar radiculography with meglumine iocarmate (Dimer-X): a clinical report with special reference to the adverse effects. J Oslo City Hasp 23:121-127, Aug 1973 33. Skalpe 10, Torbergsen T, Amundsen P, et ai: Lumbar myelography with metrizamide. Acta Radiol [Diag] [Suppl] 335: 367-379, 1973 34. Svare A, Talle K: Lumbar myelography with metrizamide; an evaluation of 15 cases. Acta Radiol [Diag] [Suppl] 335:387390, 1973 35. Tourtellolte WW, Haerer AF, Heller GL, et al: Post-lumbar puncture headaches. Springfield, III., Thomas, 1964
Neuroradiology
Lumbar Radiculography with Metrizamide A Nonionic Water-Soluble Contrast Medium 1 Ingar O. Skalpe, M.D., and Per Amundsen, M.D. Six hundred lumbar radiculographies were performed with metrizamide in 581 patients. Excellent radiographs were obtained in almost all cases. The adverse effects were minor and no serious complications occurred. The authors consider metrizamide superior to other water-soluble contrast media in present use from both toxicological and radiological points of view. INDEX TERMS:
Contrast Media, comparative studies. Metrizamide • Myelography, con-
trast media Radiology 115:91-95, Apri/1975
•
•
f~\HOH
controversial subjects in neuroradiology concerns the use of contrast media in the subarachnoid space. Thus, in Scandinavia and other European countries the water-soluble contrast medium methiodal sodium was until recently considered "the medium of choice" for examination of the lumbar subarachnoid space. This medium is not used in the United States and other English-speaking countries, where the oily medium Pantopaque (ethyl iodophenylundecylate) is preferred. An illustrative example of the difference in opinions is the fact that the Swedish health authorities have forbidden the use of the last-named. The drawbacks of both methiodal sodium and ethyl iodophenylundecylate are obvious. The local irritative properties of methiodal sodium make spinal anesthesia necessary. Therefore, this medium can be used only below the conus of the spinal cord. Both acute and long-term complications are reported with this medium (3,4, 22, 23, 24, 27, 30). With a proper technique, however, the complication rate is low and the diagnostic accuracy is satisfactory (6). The most important indication for lumbar radiculography is suspected disk herniation. There· is general agreement that this diagnosis is made with higher accuracy with a water-soluble medium than with ethyl iodophenylundecylate because the former medium gives better filling of the root sleeves. Another disadvantage with Pantopaque is that it is slowly resorbed from the subarachnoid space. Although most radiologists try to withdraw it at the end of the examination, a complete withdrawal is seldom achieved, and the small residual amount might therefore exert an irritative effect through the years. Reports on severe complications claimed to be due to arachnoiditis caused by ethyl iodophenylundecylate have appeared, as summarized by Di Chiro and Fisher (14). However, many radiologists consider these obvious drawbacks to be outweighed by its advantages. NE OF THE MOST
O
H~ ~H
CO
CH3CO~O~COCH3 CYH 3 I
Fig. 1.
Structural formula for metrizamide.
It has a low acute toxicity and can be used for examination of the entire spinal subarachnoid space. The introduction of meglumine iothalamate (Conray Meglumin) and later its dimer, meglumine iocarmate (Dlmer-X), seemed to change the situation in favor of water-soluble contrast agents (1,2,8, 13,29). A major disadvantage of methiodal sodium was eliminated, since both media could be used without spinal anesthesia. It soon appeared, however, that these media were not ideal for subarachnoid use. Most authors reported clonic convulsions in the lower extremities after lumbar radiculography with meglumine iothalamate and meglumine iocarmate (1,2,21,29,31,32). Due to this spasmogenic effect the media should be used only below the conus of the spinal cord. Recent reports on adhesive arachnoiditis occurring as a long-term effect after use of these media have also precluded their general acceptance (3, 7, 22, 23, 30). With adequate doses and a proper technique, however, many authors claim that both meglumine iothalamate and meglumine iocarmate are safe media for lumbar radiculography. A new principle for the synthesis of water-soluble contrast agents was suggested by Almen in 1969 (5).
1 From the Department of Neuroradiology, Ulleval Hospital, Oslo, Norway. Accepted for publication in October 1974. Additional articles on the use of metrizamide will be found on pages 59 and 237 of this issue.
91
ah
92
INGAR
O.
April 1975
SKALPE AND PER AMUNDSEN
Table I:
Age and Sex Distributions in 600 Lumbar Radiculographies with Metrizamide Women
Age (yr.) 10-19 20-29 30...:39 40-49 50-59 60-69 70-
TH XII
Totals
Men
Total
4
5
9
18 21 63 68 20
52 76 121
70 97 184 169 65
101 45
2
4
6
196
404
600
Table II: Dose (ml) and Concentration (mg Iodine i'er ml) of Metrizamide in 600 Lumbar Radiculographies Dose --... Concentration --...
~~10~
~-15~
119
170
170
200
153* 270
26 87
17 41
113
58
Women Men
1 5
Total
6
---
423
* One patient received 10 ml/200 mg iodine per ml. Table III:
Adverse Effects After Lumbar Radiculography with Metrizamide Dizziness
Pain Numbness
Headache
Nausea
Women Men
78 (40%) 109 (27%)
33 (17%) 44 (11%)
35 (18%) 37 (9%)
37 (19%) 70 (17%)
Total
187 (31%)
77 (13%)
72 (12%)
107 (18%)
-----
Fig. 2. Lumbar radiculography with 10 ml metrizamide (170 mg iodine per ml). Lateral position, horizontal beam direction. A. Good filling of the root sleeves on the right side. B. No filling of the root sleeve of the fifth lumbar root on the left side (arrowhead). Minor indentation in the contrast column at the same level. Findings indicate disk herniation. C. Contrast material is transported to the subarachnoid space in the conus region by lowering the head end of the table.
an extremely low toxicity and a remarkably low irritative effect on the central nervous system when introduced into the subarachnoid spaces in experimental animals (28).2 The pilot clinical studies with metrizamide were carried out in four medical centers working in close contact. The results of these preliminary clinical studies indicated that it was the best of the hitherto known watersoluble contrast media used in the subarachnoid space (15, 19, 33, 34). In this communication, we present our experience with this new water-soluble medium in 600 consecutive lumbar radiculographies. Special attention was paid to its possible adverse effects, since this is one of the main problems with the use of positive contrast media in the subarachnoid spaces. MATERIAL
He advocated the use of nonionic compounds in order to decrease the osmolarity of water-soluble contrast agents, since the hypertonicity was responsible for some of the adverse effects of these media (10, 18). Based upon Alrnen's proposal, a series of nonionic compounds were synthesized in the research laboratories of Nyegaard & Co., Oslo, Norway. One of these substances, metrizamide (Fig. 1), was found to be promising in preliminary studies. It was therefore chosen for further studies. More than three years intensive laboratory studies with a view to pharmacology, toxicology, and physiology preceded its use in humans. On the basis of these studies metrizamide was found to have
Six hundred lumbar radicufographies were carried out in 581 patients from June 1972 through February 1974. The patients were referred with a clinical diagnosis of lumbar disk herniation. From June 1972 to September 1973 women of fertile age were excluded, but later there was no selection. The sex distribution is given in TABLE I. METHODS
The first 100 examinations were performed by an ex2 It should be pointed out that the Food and Drug Administration of the United States has not yet accepted metrizamide.
LUMBAR RADICULOGRAPHY WITH METRIZAMIDE
Vol. 115
perienced neuroradiologist; the last 500 were carried out as routine procedures mainly by residents with varying experience in neuroradiology. No premedication was given. The spinal puncture was performed with a 22gauge needle with the patient on his side. The dose and concentration of contrast medium are shown in TABLE II. The position of the contrast medium was checked by television screening. In 134 patients the agent was allowed to pass above the tenth thoracic vertebra in order to include the conus region in the examination. In the others the contrast medium was not allowed to pass above this level. Usually the upper limit was at T 12L 1 . The radiologic technique was otherwise approximately the same as had been used with methiodal sodium (6, 27). Most of the patients were examined in the lateral position with horizontal beam direction, but in some radiographs were also obtained in prone or supine position with a vertical beam direction. After the examination the patients were kept supine in bed with the upper end elevated 10° for 24 hours. Sixty-five were placed in the prone position for one hour, whereafter they were placed in the supine position with the bed horizontal. In the first series of 100 patients a: complete neurologic examination was carried out by the same neurologist before the radiculography and 24 hours later. A series of other procedures, including electroencephalography and cerebrospinal fluid examinations were also performed, and the results recorded before and after radiculography in this part of the study (33). In the last 500 patients a questionnaire regarding the adverse effects expected to follow the radiculography was sent to the referring department. The physician in charge of the patient was asked to answer the questions and return the questionnaire when the patient was discharged or operated upon. RESULTS Radiologic Findings: Excellent films with good filling of the root sleeves to the level of T 12 L 1 were obtained in almost all cases (Fig. 2). Opacification of the subarachnoid space in the conus region was easy to achieve with a horizontal beam direction and the patient on his side (Fig. 2,q. Demonstration of the conus itself could be obtained with a vert ical beam direction and the patient either supine or prone (Fig. 3). However, this was technically difficult in some cases because the contrast medium was diluted with cerebrospinal fluid when it was transported up into the conus region. Adverse Effects (TABLE III): The frequency of headache, nausea, and dizziness was higher in women than in men. The headache was moderate to minor in most patients, usually lasting a few hours, but in a few it lasted for several days. This headache usually appeared in the erect position and vanished when the patient lay down. The frequency of headache was the same (31 % ) in the patients in whom the contrast medium was al-
93
Neuroradiology
Fig. 3. Opacificat ion of the conus region with delineation of the conus (arrowheads) and the cauda equlna. Subtraction technique.
lowed to rise above T 10 and in those in whom it had been kept below this level during the examination. Increase in dose and iodine concentration did not affect the frequency of headache in the men in the present series, while the women had a significantly higher frequency (p < 0.05) after 15 ml with a concentration of 200 mg iodine/ml than after 10 ml metrizamide with a concentration of 170 mg iodine/ml (59 and 32%, respectively). The frequency of headache was 63 % in the patients placed in the horizontal position shortly after radiculography. Nausea and dizziness represented minor complaints in most of the patients , but a few, vomited repeatedly for several hours. The most frequent other complaint was pain in the buttocks and thighs of another character than the usual sciatic pain, often associated with a feeling of stiffness or numbness in the leg muscles. A few patients complained of transitory micturition disturbances in the evening on the day of radiculography. This was probably due to the fact that they were
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asked to urinate while lying in their beds. The next day when they were allowed to go to the toilet, no difficulties with the urination occurred. A slight-to-moderate increase in the white cell count occurred in 21 of 29 patients in whom a repeat spinal puncture was performed six to 48 hours after the radlculoqraphy (33). Three patients with increased white cell count in the cerebrospinal fluid were reexamined two weeks to four months later, and the counts were normal in all three. Transitory changes in the EEG recordings occurred in 13 of 79 patients examined 24 hours after the radiculography (24). Nineteen of the patients in the present series were examined twice, three because the first contrast medium injection was made subdurally. In the other 16 the root sleeves could be studied at both examinations. The interval between the examinations was less than two months in six patients and more than two months in 10. No changes indicating adhesive arachnoiditis were found. DISCUSSION
Metrizamide gave the same excellent quality of radiographs as did meglumine iothalamate and meglumine iocarmate. A major advantage of metrizamide compared with these media, however, was the marked reduction of spasmogenic effects. Thus, in spite of the high doses and high iodine concentrations used in many patients in the present series, and in spite of the fact that the conus region was included in the examination in many patients, no convulsions were seen. The introduction of meglumine iothalamate and later meglumine iocarmate for lumbar radiculography increased the interest in possible adverse effects following such examinations. It has been shown that after administration of both these media approximately one third of the patients complain of headache and many complain of nausea and dizziness (31, 32). However, it should be noted that a similar frequency of headache is reported after diagnostic lumbar puncture (35). The same tendency of higher frequency of headache in women than in men which was found after radiculography with meglumine iothalarnate (31), meglumine iocarmate (32), and metrizamide is also found after diagnostic lumbar puncture (35). In many patients in the present series the headache had the same character as a postlumbar puncture headache, that is, it was present only when the patient was in the erect position and vanished when he lay down. The increased frequency of headache seen after increasing the dose and iodine concentration in the women in the present series, however, indicates that the contrast medium is also responsible for the headache in some patients. The same conclusion may be drawn from the fact that the frequency of headache seems to increase when the patients lie prone for one hour after the radiculography and then are placed su-
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pine with the bed horizontal. This procedure was expected to reduce the leakage of cerebrospinal fluid and thus probably reduce the frequency of headache (12). The same observation was recently made by Bettinger and Sondheimer (9) who found that headache was twice as common after ethyl iodophenylundecylate myelography in patients who remained prone as in patients who maintained a supine position following the examination. It should also be noted that these authors reported an overall incidence of headache following ethyl iodophenylundecylate myelography of 27 per cent, approximately the same frequency as is reported with water-soluble contrast media. Evaluation of increase in the patients' usual sciatic pain was difficult on the basis of the questionnaires. Probably such increase was in most cases due to the withdrawal of analgesics prior to radiculography and unusual movements during the examination. However, many patients complained of pain of another character than their sciatic pain, usually located in the buttocks and thighs. This pain was often associated with a feeling of stiffness or numbness in the leg muscles. These symptoms are most probably due to irritative effects of the contrast medium. In most of the cases the adverse effects described above might be reduced by suitable drugs. In the present series the use of drugs was restricted, since we wanted a complete registration of the adverse effects. Although no serious complications occurred in the present series, the various symptoms reported by the patients, the transient EEG changes (25), and the increased white cell count in the cerebrospinal fluid seen . in some of the patients (33) indicate that metrizamide in some way affects the nervous system. However, we consider these drawbacks to be outweighed by the remarkable reduction of the convulsant effect, since this effect has been responsible for serious complications with meglumine iothalamate and meglumine iocarmate . (11, 20). We have also had some experience with the use of metrizamide for thoracic and cervical myelography, a promising experience in regard to both toxicity and radiologic properties. We have never seen convulsions in any of our patients. Greitz (17) recently reported one case of grand mal fits occurring after cervical myelography with metrizamide. Due to technical difficulties during the examination the contrast medium was in contact with the cervical cord for an unusually long period of time. Furthermore, the.patient was treated with a neuroleptic drug which by itself may precipitate grand mal attacks (16). Therefore, we do not consider this report to contraindicate the use of metrizamide for the higher levels of the subarachnoid space. The possibility of late sequelae after radiculography with water-soluble contrast media must be seriously considered, since recent reports indicate that adhesive arachnoiditis may occur. Radiologic changes indicating
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adhesive arachnoiditis are described after administration of methiodal sodium, meglumine iothalamate, and meglumine iocarmate (3, 7, 22, 23, 30). No such changes were seen in 16 patients in the present series who were reexamined. Further information is needed about this problem, but so far it seems that metrizamide is superior to other water-soluble contrast media in this respect. In conclusion, metrizamide is a safe medium for lumbar radiculography, even when the conus of the spinal cord is included in the examination. It is superior to other water-soluble contrast media in present use for examination of the subarachnoid space, mainly because of the marked reduction of the spasmogenic effects. Neuroradiological Department Ullev~1 Hospital Oslo 1, Norway
REFERENCES 1. Ahlgren P: Oimer-X: a new contrast medium for lumbar myelography without spinal anaesthesia. Acta Radiol [Oiag] [9th Symp Neuroradiol 1970113:753-761, 1972 2. Ahlgren P: Long-term side effects after myelography with water-soluble contrast media: Conturex, Conray Meglumin 282 and Dimer-X. Neuroradiology 6:206-211, Dec 1973 3. Ahlgren P: Lumbale Myelographie mit Conray Meglumin 282. Fortschr Geb Rontgenstr Nuklearmed 111:270-276, Aug 1969 4. Ahlgren P, Praestholm J: Komplikationer ved myelografi med methiodalum. Nord Med 82:1600-1604, 18 Dec 1969 5. Alman T: Contrast agent design: some aspects on the synthesis of water-soluble contrast agents of low osmolality. J Theor Bioi 24:216-226, Aug 1969 6. Amundsen P, Helsingen P, Kristiansen K: Evaluation of lumbar radiculography ('myelography') with water-soluble media. Acta radiol [Diag] 1:659-665, 1963 7. Autio E, Suolanen J, Norrback S, et al: Adhesive arachnoiditis after lumbar myelography with meglumine iothalamate (Conray). Acta radioI [Diag] 12:17-24, Jan 1972 8. Baumgartner J, Braun JP, Caron J, et al: Radiculographie au Oimer X. Premiers resultats apres 630 examens. J Radiol Electrol Med NucI51:557-559, Oct 1970 9. Bettinger B, Sondheimer FK: Post-myelogram headaches: some of the things you've always wanted to know but were afraid to ask. X Symp Neuroradiol, Punta del Este, Uruguay, 10-16 Mar 1974 10. Bjork L: The osmotic effects of Urografin 76 per cent and Isopaque 60 per cent in angiocardiography. Am J Roentgenol 98: 922-926, Dec 1966 11. Boisen E, Lindholmer E: Alvorlige myelografi-komplikationer med jodtalaminmeglumin: en opg¢relse over 324 lumbale myelografier, samt beskrlvelse af 2 tilfaelde af svaere kramper i underekstremiteterne. Nord Med 85:520-524, 29 Apr 1971 12. Brocker RJ: Technique to avoid spinal-tap headache. JAMA 168:261-263, 20 Sep 1958
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13. Campbell RL, Campbell JA, Heimburger RF, et al: Ventriculography and myelography with absorbable radiopaque medium. Radiology 82:286-289, Feb 1964 14. Oi Chiro G, Fisher RL: Contrast radiography of the spinal cord. Arch NeuroI11:125-143, Aug 1964 15. Gonsette RE: Metrizamide as contrast medium for myelography and ventriculography. Preliminary clinical experiences. Acta Radiol [Oiag] [Suppl] 355:346-358, 1973 16. Goodman LS, Gilman A, ed: The Pharmacological Basis of Therapeutics. New York, Macmillan, 3d ed, 1965 17. Greitz T: Personal communication, 1973 18. Hilal SK: Hemodynamic changes associated with the intraarterial injection of contrast media: new toxicity tests and a new experimental contrast medium. Radiology 86:615-633, Apr 1966 19. Hindmarsh T: Methiodal sodium and metrizamide in lumbar myelography. Acta Radial [Oiag] [Suppl] 335:359-366, 1973 20. Irstam L: Side effects of water-soluble contrast media in lumbar myelography. Acta Radiol [Oiag] 14:647-656, Nov 1973 21. Irstam L, Lormerholm T, Sundstrom R, et al: Lumbal myelografi med Conray-Meglumin 282. Uikartidningen 67:3185-3190, 8 Jul 1970 22. Irstam L, Rosencrantz M: Water-soluble contrast media and adhesive arachnoiditis. I. Reinvestigation of nonoperated cases. Acta Radiol [Oiag] 14:497-506, Sep 1973 23. Irstam L, Rosencrantz M: Water-soluble contrast media and adhesive arachnoiditis. II. Reinvestigation of operated cases. Acta Radiol [Oiag] 15:1-15, Jan 1974 24: Kaada B: Transient EEG abnormalities following lumbar myelography with metrizamide. Acta Radiol [Diag] [Suppl] 335: 380-386, 1973 25. Kolstad P, Solem GH: Myelografi med vannopplesellq kentrastmiddel: en analyse av 427 myelografier. Nord Med 61:306-309, 19 Feb 1959 26. Lange J, (ZIdegaard H: Abrodil myelography in herniated disk in the lumbar region. Radiology 57:186-192, Aug 1951 27. Lindblom K: Lumbar myelography by abrodil. Acta Radiol 27:1-7, Jan 1946 28. Metrizamide, a non-ionic water-soluble contrast medium. Experimental and preliminary clinical investigations. Acta Radial [Oiag] Supp1335, 1973 29. Praestholm J, Lester J: Water-soluble contrast lumbar myelography with meglumine lothalarnate (Conray). Br J Radiol 43: 303-308, May 1970 30. RAdberg C, Wennberg E: Late sequelae following lumbar myelography with water-soluble contrast media. Acta Radiol [Oiag] 14:507-512, Sep 1973 31. Skalpe 10: Lumbar myelography with Conray Meglumin 282: report of 100 investigations with special reference to the adverse effects. Acta Neurol Scand 47:569-578, 1971 32. Skalpe 10, Talle K: Lumbar radiculography with meglumine iocarmate (Dimer-X): a clinical report with special reference to the adverse effects. J Oslo City Hasp 23:121-127, Aug 1973 33. Skalpe 10, Torbergsen T, Amundsen P, et ai: Lumbar myelography with metrizamide. Acta Radiol [Diag] [Suppl] 335: 367-379, 1973 34. Svare A, Talle K: Lumbar myelography with metrizamide; an evaluation of 15 cases. Acta Radiol [Diag] [Suppl] 335:387390, 1973 35. Tourtellolte WW, Haerer AF, Heller GL, et al: Post-lumbar puncture headaches. Springfield, III., Thomas, 1964
