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Ependymitis and arachnoiditis induced by intraventricular contrast media
Ependymitis and Arachnoiditis Induced by Intraventricular Contrast Media Manuel Dujovny, M.D., Nir Kossovsky, B.A.,* Pedro J. Barrionuevo, M.D.,t Debra Nelson, B.S.,$ and Ranjit K. Laha, M.D. §
used Lipiodol (iodized oil) in 1928 [6]. Although accurate imaging of the lateral and third ventricular chambers could be obtained at low risk when intracranial pressure was not elevated, pathological studies of the spinal cord by Bucy and Spiegel [9] and other investigators [27, 37, 44, 56] demonstrated that Lipiodol was not innocuous and frequently caused the formation of granulomas and cysts. Similar problems were subsequently noted with iophendylate (Pantopaque), but no other radiographically suitable substance was available in North America [2, 38, 41, 43, 55, 57]. While these lipid-soluble contrast media were being developed, several water-soluble agents were also being used clinically. However, the high toxicity of the early water-soluble solutions (Kontrast-U and Abrodil [sodium methiodol]) made them unacceptable for ventriculography, and their restricted use only in the lumbosacral subarachnoid space resulted in irreversible lesions of the conus It seems unlikely that any solution of radiographic value will be medullaris and cauda equina [4, 36, 37, 41]. found which is sufficiently harmless to justify its injection into the During the past 15 years, safer low-sodium, lowcentral nervous system. osmolality contrast agents have been introduced, such as meglumine iothalamate (Conray), meglumine iocarmate Walter E. Dandy (Dimer-X), and especially metrizamide (Amipaque) [3, Walter E. Dandy's introduction of air ventriculography in 10, 20, 21, 23, 26, 61]. Despite computed tomography 1918 [13] and pneumoencephalography in 1919 [14] rep- (CT), angiography, and pneumoencephalography, the resented the first uses of a contrast medium to enhance growing radiodiagnostic role of safe and effective innoninvasive x-ray images for preoperative diagnosis. Iodine trathecal agents has made these agents useful for CT inventriculography was initially developed by Sicard and trathecal enhancement and stereotactic surgery, as well as Forestier in 1922 [52] and was modified by Balado who for imaging of the optic nerve sheath [15, 17, 24, 39, 40, 49, 62]. We evaluated the relative toxicities of several ventriculographic contrast media through light and scanning *Division of BiologicalSciencesand Pritzker School of Medicine, Uni- electron microscopy studies of the morphology of the basal versityof Chicago, Chicago, IL 60637. cisterns, arachnoid, and ventricular walls. tUniversidad Nacional de Cordoba, Cordoba, R. Argentina5000. SDepartmentof NeurologicalSurgery,Universityof PittsburghSchoolof Medicine, Pittsburgh, PA 15213. Method §W.C.A. Hospital,Jamestown,NY 14701. Thirty-six dogs weighing between 18 and 22 kg were diFromthe Departmentof NeurologicalSurgery,HenryFordHospital, De- vided into one control and five experimental groups of 6 troit, MI. animals each. The animals were anesthetized by intraveAddress reprint requests to Dr. Manuel Dujovny, Department of NeurologicalSurgery,HenryFordHospital, 2799 West Grand Blvd., De- nous sodium pentobarbital (25 milligrams per kilogram of body weight) and intubated. Controlled respiration was troit, MI 48202. Key words: arachnoid;cerebrospinalfluid;scanningelectron microscopy; maintained with a Harvard respirator, and blood gases were ventriculography;contrast media; intrathecalenhancement. checked frequently to maintain the pH, pO2, and pCO2 Thirty-six dogs were subdivided into five experimental groups and one control group for assessing reactions to contrast media during ventriculography. The five contrast agents were air, iophendylate, meglumine iothalamate, meglumine iocarmate, and metrizamide. Electroencephalographic patterns observed for the experimental animals deviated from the norm; this shift corresponded variably with the arrival of the contrast media in the basal cisterns. Scanning electron microscopy examination of the cisterns revealed significant free-cell proliferation and incipient granulomas in all groups of animals, except those injected with air. DujovnyM, KossovskyN, BarrionuevoPJ, Nelson D, LahaRK: Ependymitisand arachnoiditisinduced by intraventricularcontrastmedia. SurgNeurol 18:216-224, 1982
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0090-3019/82/090216-09501.25 O 1982 by Little, Brown and Company (Inc.)
Dujovny et al: Ependymitis and Arachnoiditis
within physiological limits. Ringer's lactate solution was infused via the saphenous vein for fluid replacement• Femoral arterial blood pressure was measured with a Statham transducer; cenl:ral venous pressure, intracranial pressure, electrocardiogram, and electroencephalogram (EEG) were recorded on a Grass polygraph. An 8 mm-diameter burr hole was drilled into the right parietal region about 1 cra from the midsagittal plane, and cannulation of the right lateral ventricle with a 22-gauge needle was performed on all animals. In the control group, only the cannulation was performed. The experimental animals were given a 1.5 ml intraventricular injection of either air, iophendylate (Pantopaque), 384.3 mg/ml; meglumine iothalamate (Conray), 280 mg/ml of iodine; meglumine iocarmate (Dimer-X), 280 mg/ml; or metrizamide (Amipaque), 170 mg/ml of iodine• Electrocardiogram, elcvtroencephalogram, blood pressure, central venous pressure, and intracranial pressure were continuously monitored for the duration of the intraventricular injection and for 2 hours afterwards. The correct placement of the contrasl medium was confirmed with anteroposterior and lateral x-ray films of the skull taken immediately after the intraventricular injection. Plain films were also taken 1 and 2 hours after injection, and a final set of films was taken 120 &tys later• The animals were then anesthetized, killed, and peffused with physiologically normal saline solution followed by 2% buffered glutaraldehyde (pH, 7.2). After the cranial vault of each animal was removed, the dura mater was exposed and opened. The brain was carefully removed while the cranial nerves and vessels were severed at the base of the skull under the Zeiss OPMI operating microscope. The arachnoid membrane was then excised en bloc from the following regions: olfactory cistern, chiasmatic cistern, interpeduncular cistern, w:ntricular walls, aqueduct of Sylvius, fourth ventricle, and cisterna magna. The choroid plexus was also removed.
The specimens were fixed in phosphate-buffered 2% glutaraldehyde (pH, 7.2) for 1 week and then dehydrated by a 30-minute serial passage through 30, 50, 70, and 90% solutions of methanol. In preparation for scanning electron microscopy, the specimens first underwent critical point drying with carbon dioxide• They were then individually mounted with silver paint adhesive on aluminum stubs 1 cm in diameter• Finally, the specimens were coated with a 10 to 40 nm-thick layer of palladium gold in a PolaronSputter Coater vacuum chamber (Polaron Instrument Corp., Line Lexington, PA). We examined the inner surfaces of the arachnoid, ventricular wall, and choroid plexus with a scanning electron microscope (American Metals Research Corp., Burlington, MA) at magnifications of from ×30 to ×40,000. Each inner arachnoid specimen was divided into eight regions along perpendicular axes and photographed. All 3 × 5 inch (7.5 x 12.5 cm) photomicrographs were enlarged to 5 × 7 inch (12.5 × 17.5 cm) prints and then integrated to form scanning electron microscope montages. Numerous stereoscope photographic pairs were made at a parallax difference of 7 degrees. The three-dimensional images from the stereoscope and the large surface views of the montages permitted us to assess the details more clearly. We also made corresponding specimens for light microscopy. In addition, selected scanning electron microscope specimens were later rehydrated in order to further correlate the scanning electron microscopical and conventional findings
[35]. Results
While all five contrast media produced very satisfactory radiographic images, toxicity differences in the central nervous system (CNS) among the media were substantial (Table). The control animals demonstrated no physiological or physical abnormalities during or after the experiments, and none of the animals in the six groups exhibited
Summary of Clinical and Physiological Changes following Ventriculography Electroencephalographic Findings (No. of Animals) Experimental Group a
Concentration
Control Air lophendylate Meglumine iothalamate Meglumine iocarmate Metrizamide
None None 384.3 mg/ml 280 mg I/ml 280 mg/ml 170 mg I/ml
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aSix animals per group• EEG = electroencephalogram;mg I/ml = milligramsof iodine per milliliter.
Slow Waves
Epileptogenic Activity
5
1
6
,
,
Clinical Seizures (No. of Animals)
•
•
,
•
6
4
•
,
,
6
4
•
•
•
6
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abnormal blood pressure, cerebral venous pressure, or cardiac signs. AIR VENTRICULOGRAPHYGROUP. Five of the 6 animals into which air was injected developed slow, low-voltage EEG waves 2 to 10 minutes after injection. The sixth animal developed sharp, rapid waves, indicative of epileptogenic activity, but by 2 hours the EEG patterns in all 6 animals had returned to normal. I O P H E N D Y L A T E V E N T R I C U L O G R A P H Y G R O U P . These animals, conversely, showed only a mild decrease of EEG voltage that began immediately after the injection and lasted for 30 minutes before returning to normal. W A T E R - S O L U B L E V E N T R I C U L O G R A P H Y G R O U P S . Prolonged high-voltage, spiked activity began 5 minutes after the injection of meglumine iothalamate, 5 to 10 minutes after meglumine iocarmate, and 20 minutes after the injection of metrizamide in all 18 animals in the three groups. The sharp waves and rapid rhythm became more frequent at 4 to 50 minutes and persisted for 2 to 3 days. At 120 days, before the animals were killed, no EEG abnormalities were present.
Fig. 1. Scanning electron micrograph of a specimen from the subarachnoid membrane in a control animal. ( A) Fenestrated sheet (F), network fibers (N), macrophages (m), and other free cells (g). (×900.) (B) Higher magnification of an embossed sheet with a macrophage (m) and an erythrocyte (r). ( × 1800.)
Although no clinical seizures were observed in the metrizamide group, EEG epileptogenic patterns briefly preceded the development of convulsions in 4 of the animals injected with meglumine iothalamate and in 4 injected with meglumine iocarmate. Myoclonus of the eyelids, both ipsilateral and contralateral to the burr hole and limited principally to the facial area during the first 5 minutes, was then followed by a generalized epileptic seizure. At 2 hours, after the animals had received 5 mg Valium (diazepam) intravenously in addition to normal anesthesia, clinical seizures and epileptogenic activity disappeared. The seizures did not recur even after the animals awoke.
Anatomopathological Studies No macroscopic pathological changes, such as dilation, deformation, or general and focalized atrophy, were noted in any of the animal brains. Light microscopy revealed characteristic meningeal inflammation, arachnoiditis, micro-
Dujovny et ah Ependymitis and Arachnoiditis
Fig. 2. Following an injection of Pantopaque ( iophendylate), a large fibrous mass and investing film with numerous adherent erythrocytes, neutrophils, and macrophages is formed. (x900.)
abscesses, and necrosis. These responses were most acute in the specimens previously injected with iophendylate, less so in the meglumine iothalamate and iocarmate groups, and least in the metrizamide group. Subsequent scanning electron microscopical studies of control animals revealed no changes in the base sheet and fiber structures, the number of macrophages, or the number of other free cells investing the subarachnoid space (]Fig. 1). The inner arachnoid surface foundation in the control animals comprised both a fenestrated sheet and an embossed sheet to which remaining fibers and microfibers were anchored. The radiciforra fibers consisted of a plexus of trabeculae from which rootlike extensions projected multidirectionally that blended into the surface of the underlying tissues and arteries situated at the periphery. The network fibers were also trabeculated but were smooth and radiated from a central body to form fenestrations as large as 100 ~ in diameter. The anchoring fibers were short and consisted of single strands that neither branched nor formed
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networks. The straight, plexiform, and network microfibers had a diameter of only 0.125/* and adhered to the surfaces of the larger trabeculae, coursed over arteries, or bridged the gaps between the trabeculae. Free cells were seen adhering to the arachnoid-pia complex, ventricular walls, and choroid plexus. The most frequently encountered cells were macrophages, which were 4 to 7/* in diameter. They appeared spherical and had either ruffled or blebbed surface forms. A second cell type, spherical lymphocytes, ranged from 6 to 11/, in diameter. These cells exhibited extremely smooth surfaces with thick basal microvilli that were larger than those of the blebbed macrophages. Similar results were observed in the air-injected groups. Iophendylate-injected animal specimens revealed an extensive organic film investing the base arachnoid sheets (Fig. 2) and their fenestrations, thereby obscuring the details of the underlying fibers. Foreign particles were attached to the fibers and the ventricular cilia. Numerous free cells, principally macrophages but occasionally lymphoblasts or erythrocytes, were also adhering to the arachnoid sheets, fibers, and ventricle walls. The x-ray energy dispersive analysis of the investing film revealed no traces of residual iodine, although frequent calcium deposits were
220 SurgicalNeurology Vol 18 No 3 September 1982
present and were enmeshed with foreign-body macrophages. The meglumine iothalamate specimens showed film on many portions of the base sheet, but its magnitude was less extensive than the film seen with the iophendylate specimens (Fig. 3). Interestingly, the aggregates of macrophages, lymphocytes, and foreign bodies were present in larger-sized clumps than on the iophendylate specimens, but the overall frequency of these aggregates was much lower. Meglumine iocarmate specimens exhibited no investing layer, but there were free-cell aggregates similar to those seen in the meglumine iothalamate-injected specimens (Fig. 4). Metrizamide produced the mildest free-cell response, with no film present and only occasional cell aggregates (Fig. 5). Discussion Since Dandy [13, 14] introduced ventriculography in 1918, air has been the most widely used contrast medium. To date, gases seem to be the safest contrast media because they are both diffusible and are rapidly eliminated from the central nervous system. Unfortunately, because radiographic images of certain midline structures are sometimes difficult to delineate [3, 10] without tomography, it is frequently necessary to vary the patient's position during
Fig. 3. Granulomatouslike (g) deposits of cells and debris produced by meglumine iothalamate, seen here in a film investing a network fiber (N). (r = erythrocyte.) (×3,600.)
fractional ventriculography. The increased intracranial pressure and pain following injection of the gas further exacerbates the problems associated with gas ventriculography. Since negative-contrast media (gas) were not able to reproduce satisfactory ventriculograms, particularly since most operating rooms had only conventional x-ray equipment, neurosurgeons began to use iodinated positivecontrast media. High-quality roentgenographic images were produced more readily, but pharmacological problems arose because of the toxic effects of the media on the central nervous system [1, 12, 18, 23, 29, 33, 38, 42, 50, 55, 57,
58]. The newest products, meglumine salts and a nonpolar compound metrizamide, have a lower toxicity, and their development can be credited to the theoretical work by Almen [1]. Based on physiochemical laws, he reasoned that a monomer of a nonelectrolytic contrast agent would have a lower osmolarity. He realized, further, that by keeping the
Dujovny et al: Ependymitis and Arachnoiditis
Fig. 4. Animals injected with meglumine iocarmate underwent freecell proliferation but no film deposit. Racliciform fiber (R), macrophage (m), erythrocyte (r), foreign debris (g), lymphocyte (1), microfiber (M). ( × 1,100.) axial ratio of the contras: molecule as close to one as possible, the fluid would have a low viscosity. Nonetheless, potential and real complications can compromise the usefulness of the media. For example, metrizamide readily penetrates the brain substance, and mental disorders such as organic psychoses and visual hallucinations have been reported sporadically [1,5]. The ready penetration of the drug has been explained recently by the finding that the cerebrospinal fluid and extracellular fluid spaces of the brain are the same compartment [59]. The most common problem following the injection of water-soluble contrast media has been the development of severe epileptogenic EEG patterns and epileptic seizures [2, 5, 19, 28, 29, 48, 50, 51, 53, 54, 60, 61]. Nau [47], for example, described a series of 36 patients who underwent ventriculography with either Dimer-X or Amipaque. Before the ventriculographic procedure, the main frequency of the EEG was in the alpha range (from 8 to 10 cps) in all patients except 3, who had intracranial tumors and EEGs in the theta range. No substantial change in the main fre-
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quency of the EEG was found after the procedure. However, focal frequency irregularities were seen in 4 patients afterwards and in a fifth during hyperventilation. General irregularities were seen in 4. Paroxysmal dysrhythmic discharges were seen in 3, and seizure potentials with sharp and slow waves or spikes, or both, were seen in 5. Eight patients had generalized convulsions: 3 after Dimer-X ventriculography, 3 after Dimer-X lumbar myelography, 1 after a suboccipital injection of Dimer-X, and 1 after cervical myelography using Amipaque. We observed the same complication of epileptogenic activity in four of the experimental groups in our study. Grepe and Widen [22] reported epileptogenic activity when either meglumine or metrizamide came in contact with the cerebral cortex, but they believed that the activity observed with metrizamide was probably due to the lowered seizure threshold produced by a neuroleptic anesthesia. We therefore did not anesthetize our animals with phenothiazine drugs. Although we consider that the EEG change in the 1 animal in the air-injected group can be attributed to an "EEG activation" phenomenon suggested by Gonsette [20, 21], the epileptogenic activity observed in all 18 animals of the meglumine iothalamate, meglumine iocarmate, and metrizamide groups was not the result of a pharmacological interaction.
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Investigators have previously reported that increased Fig. 5. Specimen recovered from a memzamide-injected animal shows evoked corticospinal-mediated convulsions constitute the a minimal amount of debris or cellular response. (A) Anchoring fiber most serious, immediate complication following the use of a (A) on a venule (V). (N = network fiber.) (x450.) (B) Debris (g) a macrophage (m) on a fenestrated sheet. (M = microfiber.) meglumine compound in the subarachnoid space [53]. This and (xl,800. appears to be a neurotoxic phenomenon that resists the usual anticonvulsant medications and requires sophisticated personnel and emergency procedures if death is to be prevented [28]. Our study also showed that the epileptogenic granulation tissue that contained multinucleated giant activity and clinical convulsions were much more severe in cells. the meglumine-iothalamate and meglumine-iocarmate Other histopathological studies of reactions of the cengroups. Hilal and associates [28] have proposed that the tral nervous system after injections of contrast media have convulsive activity is directly related to the neurotoxic been principally confined to the spine [33, 34]. Both properties of the molecular structure of the contrast Bergeron et al [8] and Howland et al [30] have reported medium. meningeal inflammation, arachnoiditis, microabscesses, Clinically, both constrictive arachnoiditis and obstruc- and necrosis after suboccipital iophendylate injections. tive hydrocephalus have been seen after Pantopaque Smith et al [55] believe that these lesions are identical to myelography [7, 32]. Barsoum and Cannillo [7] reported 2 chronic adhesive arachnoiditis. Jakobsen [31] reported patients with thoracic constrictive arachnoiditis that re- meningeal fibrous scarring, nerve root fibrosis, and myelin quired surgical intervention to relieve pain. The pathologi- sheath degeneration after intrathecal ventriculography on cal findings were fibrotic thickenings of the dura mater. 50 rats injected with iophendylate. The use of excessively Jensen and co-workers [32] reported a case of the delayed large volumes and concentrations of metrizamide studied by development of obstructive hydrocephalus with death en- Haughton and associates [25] may also involve the risk of suing 68 days after a lumbar injection of 9 ml of Pan- arachnoiditis. Clark and colleagues [11] reported that 4 of topaque. At postmortem examination it was found that the 13 dogs died suddenly 4 to 7 months after iophendylate foramina of Luschka and Magendie were occluded by ventriculography.
Dujovny et al: Ependymitis and Arachnoiditis
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3. Andreussi L, Clarisse J, Jomin M, Passeri A: Ventriculographywith water-soluble contrast in the diagnosis of posterior fossa tumors (107 cases). Neuroradiology8:25-38, 1974 4. Autro E, Suolanen J, Norrback S, Slastic P: Adhesive arachnoiditis after lumbar myelography with meglumine iothalamate (Conray}. Acta Radiol (Stockh) 12:17-24, 1972 5. Bagehi AK: Convulsions, subarachnoid haemorthage and death following myelographywith meglumine iothalamate 280. Surg Neurol 5:285-286, 1976 6. Balado M: Radiografia del tercer ventriculo, mediante la injeccion, intraventricular de Lipiodol. Arch Argent Neurol 2:69-79, 1928 7. BarsoumAH, Cannillo KL: Thoracic constrictive arachnoiditis after Pantopaque myelography: Report of two cases. Neurosurgery 16:314-316, 1980 8. Bergeron RT, Rumbaugh CL, Fang H, Cravioto H: Experimental Pantopaque arachnoiditis in the monkey. Radiology99:95-101,1971 9. BucyPC, Spiegel IJ: An unusual complicationof the intraspinal use of iodized oil. JAMA 122:367-369, 1943 10. Campbell RL, Campbell JA, Heinburger RF, Kalseck JE, Mealey J: Ventriculography and myelography with absorbable radiopaque medium. Radiology82:286-289, 1964 11. Clark RG, Milhorat TH, Stanley WC, DiChiro G: Experimental Pantopaque ventriculography. J Neurosurg 34:387-395, 1971 12. Cristi G, ScialfaT, DiPierro G, Tassoni A: Visual loss: a rare complication followingoil myelography.Neuroradiology 7:287-290, 1974 13. Dandy WE: Venticulographyfollowing the injection of air into the cerebral ventricles. Ann Surg 68:5-11, 1918 14. Dandy WE: Roentgenographyof brain after the injection of air into the spinal canal. Ann Surg 70:397-403, 1919 15. DiChiro G, Fisher RL: Contrast radiographyof the spinal cord. Arch Neurol 11:125-143, 1964 16. Drayer BP, Rosenbaum AE: Metrizamide brain penetrance. Acta Radiol [Diagn] (Stockh) 355(suppl):218-293, 1977 17. Drayer BP, Rosenbaum AE: Studies of third circulation. Amipaque CT cistemography and ventriculography. J Neurosurg 48:946-956, 1978 18. Erickson TC, van Baaren HJ: Late meningeal reaction to ethyl iodophenylundecylateused in myelography:report of a case that terminated fatally. JAMA 153:636-639, 1953 19. Gjerris A, Praestholm J, Klinken L: Comparison of metrizamide and iodophenydylate for cerebral ventriculography. Neuroradiology 15:79-84, 1978 20. Gonsette RE: An experimental and clinical assessment of watersoluble contrast medium in neuroradiology: A new medium-Dimer-X. Clin Radiol 22:44-56, 1971 21. Gonsette RE: Metrizamide as contrast medium for myelographyand ventriculography. Acta Radiol [Diagn] (Stockh) 334(suppl):346-358, 1973 22. Grepe A, Widen L: Effects of cistemal application of metrizamide. An experimental investigation in dogs in N20 analgesia and without halothane. Acta Radiol [Diagn] (Stockh) 334(suppl):l19-124, 1973 23. Hansen EB, Fahren Krug A, Praestholm J: Late meningeal effects of myelographic contrast media with special reference to metrizamide. Br J Radiol 51:321-327, 1978 24. Haughton VM, DavisJP, EldevikOP, Gager WE: Optic nerve sheath imaging with metrizamide. Invest Radiol 13:544-546, 1978 25. Haughton VM, Ho KC, Larson SJ, Unger GF, Correa Paz F: Experimental production of arachnoiditis with water-soluble myelogmphic media. Radiology 123:681-685, 1977 We wish to thank Gertrude Voheringer and George McManus for their 26. Heimburger RF, Kalsbeck JE, Campbell RL, Mealey J: Positive contrast cerebral ventriculography using water-soluble media. J Neurol technical assistance and Beth Bran&gee and Patricia Cornett for their Neurosurg Psychiatry 29:281-290, 1966 editorial assistance. Also, thanks to Cindy Skrzyniarzfor her assistance in 27. Hempel KJ, Zeitler E: Histologischeverandemngen bei myelographie the preparation of the manuscript. mit positiven kontrastrniheln. Radiologe 5:508-512, 1965 28. Hilal SK, Danth GW, Hess KH, Gilman S: Development and evaluation of a new water-soluble iodinate myelographiccontrast medium with markedly reduced convulsive effects. Radiology 126:417-427, References 1978 1. Almen T: Contrast agent design. J Theor Biol 24:216-226, 1969 2. Allen WEA, D'Angelo CM: Pulmonary oil embolization following 29. Hindmarsh T, Grepe A, Widen L: Metrizamide-phenothiazine interaction. Report of a case with seizures followingmyelography.Acta Pantopaque ventriculography in a patient with a ventriculovenous Radiol [Diagn] (Stockh) 16:129-133, 1975 shunt. Case report. J Neurosurg 35:623-627, 1971
Our study has also shown that the currently used contrast media are variably toxic to the central nervous system. We believe that the deposition of the filmlike layer on the arachnoid inner face and the subsequent filling of the sheet fenestrations account in part for this toxicity. Although neither meglumine iocarmate nor metrizamide produced a film layer, injections of all four contrast media, except air, resulted in substantial proliferation of free cells (e.g., macrophages and lymphocytes) and aggregations of free cells and foreign bodies in our preparations. Similar aggregations of free cells in response to intrathecal BCG (bacille Calmette Gu~rin) injections have been reported [45, 46]. The occasional calcium patches detected by x-ray energy dispersive analysis in conjunction with these aggregates of free cells and foreign bodies suggests the existence of incipient granulomas. It has been reported that 1 to 7 months after iophendylate ventriculography, the brains of experimental dogs exhibit extensive granulomatous lesions that erode through the ventricular wall deep into the interior of the brain [10]. Our studies with light microscopy correspond with observations previously reported in the literature [8, 11, 15, 23, 25, 27, 30, 34, 44, 51]. Iophendylate produced the most serious response of proliferating inflammatory infiltrates, perivascular inflammation, and microscopic hemorrhages [11, 21]. Since ventriculographic media come in contact first with the ventricular walls and inner surfaces of the arachnoid, it seemed that a study of the surfaces of these structures was warranted. N o t only is scanning electron microscopy ideally suited for this purpose, but it can also scan intact specimens that can be later rehydrated and prepared for conventional microscopy [35]. The toxicities of the positive contrast media are very important factors that mu:~t be seriously considered in the selection of a contrast agent. Future work should be directed toward the development of a truly innocuous medium that would have: the following properties: satisfactory roentgen-ray absorp:ion, miscibility and isoosmolarity with cerebrospinal fluid :For uniform distribution, low dose and low viscosity for rapid cannula injections, complete and rapid reabsorbabilit¥, nonepileptogenicity, and nontoxicity, as well as being: pharmacologically inert.
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30. Howland WJ, Currey JL, Butler AK: Pantopaque arachnoiditis. Experimental study of blood as potentiating agent. Radiology 80:489491, 1963 31. Jakobsen JK: On the side effects of contrast media for myelography. Acta Pathol Microbiol Scand [A] 81:323-326, 1973 32. Jensen F, Reske-Nielsen E, Ratjen E: Obstructive hydrocephalus following Pantopaque myelography. Neuroradiology 18:139-144, 1979 33. Jensen TS, Hein O: Intraspinal arachnoiditis and hydrocephalus after lumbar myelography using methylglucamine isocarmate. J Neurol Neurosurg Psychiatry 41:108-112, 1978 34. Kun M, Alwasiak J, Gronska J: Morphological changes in the CNS after Dimer-X ventriculography. Neuroradiology 15:99-106, 1978 35. Leffingwell HA: Fossil palynomorphs, in Hayat MA (ed): Principles and Techniques of Scanning Electron Microscopy. New York: Van Nostrand Reinhold, 1974, Vol 2, pp 150-162 36. Liliequist B, Lundstrom B: Lumbar myelography and arachnoiditis. Neuroradiology 7:91-94, 1974 37. Lindblom K: Complications of myelography by Abrodil. Acta Radiol (Stockh) 28:69-73, 1947 38. Luce JC, Leith W, Burrage WS: Pantopaque meningitis due to hypersensibility. Radiology 57:878-881, 1951 39. Manelfe CL, Guiraud B, Espagno J, Roscol A: Cistemographic computerisee au Metrizamide. Rev Neurol (Paris) 134:471-484, 1978 40. Marc JA, Kahn A, Pillari G, Rosenthal A, Baron MG: Positive contrast ventriculography combined with computed tomography: technique and applications. J Comput Assist Tomogr 4:608-613, 1980 41. Marcovich AW, Walker AE, Jessico CM: Immediate and late effects of intrathecal injection of iodized oil. JAMA 116:2247-2254, 1941 42. Mason MS, Raaf J: Complications of Pantopaque myelography. Case report and review. J Neurosurg 19:302-311, 1962 43. Maupin RA, Baker HL, Kerr IWI: Emulsified Pantopaque. Its possible application for myelography. Radiology 86:509-514, 1966 44. McLaurin RL, Bailey OT, Schurr PH, Ingraham FD: Myelomalacia and multiple cavitations of spinal cord secondary to adhesive arachnoiditis. Arch Pathol 57:138-146, 1954 45. Merchant RE: Scanning electron microscopy of spinal nerve exits of normal and BCG-infected dogs, in Becker RP, Johare O (eds): Scanning Electron Microscopy. Chicago: SEM, Inc, 1979, Vol Ill, pp 341-346 46. Merchant RE, Kelleher JJ, Low FN: Scanning electron microscopy of the subarachnoid free cells challenged in the primary and secondary immune response. J Submicr Cytol 11:293-312, 1979
47. Nau HE: Electroencephalography (EEG) after introduction of water-soluble contrast media into cerebrospinal fluid (CSF). Acta Neurochir (Wien) 57:75-82, 1981 48. Ofterdal SI, Sawhney BB: Effect of water-soluble contrast media on cortically evoked potentials in the cat. Acta Radiol [Diagn] (Stockh) 335(suppl):84--92, 1973 49. Partain LC, Scatliff JH, Staab EV, Wu HP: Quantitative multiregional CSF kinetics using serial metrizamide enhanced computed tomography. J Comput Assist Tomogr 2:467-470, 1978 50. PicazaJA, Hunter SE, Lee L: Seizures associated with the use of meglumine iothalamate 60% in ventriculography. J Neurosurg 36:476480, 1972 51. Praestholm J: Experimental evaluation of water-soluble contrast media for myelography. Neuroradiology 13:25-35, 1977 52. Sicard JA, Forestier J: Roentgenologic exploration of the central nervous system with iodized oil (Lipiodol). Arch Neurol Psychiatry 16:420-434, 1926 53. Skalpe IO: Myelography with metrizamide meglumine iothalamate and meglumine iocarmate. Acta Radiol [Diagn] (Stockh) 335(suppl): 57-66, 1973 54. Skalpe IO, Amunclesen P: Clinical remits with metrizamide ventriculography. J Neurosurg 43:432-436, 1975 55. Smith RA, Collier HI, Underwood FO: Cerebral vasospasm following myelography. Surg Neurol 1:87-93, 1973 56. Tabados K: Unusual complications of iophendylate injection myelography. Arch Neurol 29:435-436, 1973 57. Vinas FJ, Barrionuevo PJ, Dujovny M: Ventriculography by direct catheterization of third ventricles using a water-soluble substance. Am J Roentgenol 101:141-146, 1967 58. Ward W, Mathenson M, Gonski A: Three cases of granulomatous arachnoiditis after myelography. Med J Aust 2:333-335, 1976 59. Winkler SS, Sackett JF: Explanation of metrizamide brain penetration: a review. J Comput Assist Tomogr 4:191-193, 1980 60. Wylie IG, Afshan F, Koeze TH: Remits of the use of a new watersoluble contrast medium (metrizamide) in the posterior fossa of the baboon. Br J Radiol 48:1007-1012, 1975 61. Yonekawa Y, Nishikawa M, Egli M, Klaibes R: A clinical and experimental study of meglumine iocarmate in the subarachnoid space. Surg Neurol 5:167-170, 1976 62. Zito JL, Davis KR: The role of computed metrizamide myelography in evaluation of extradural extension from vertebral chordoma. J Ca)mput Assist Tomogr 4:38-42, 1980
Notice: Help for Poland Surgical Neurology has just received a letter from Profes- They would appreciate any financial help that the readers of sor Jerzy Wronski, a neurosurgeon connected with the SurgicalNeurology can give them to cover the cost of books Academy of Medicine of Wroclaw, Poland. (Wroclaw is the present name of the city of Breslau, where I once worked with Professor Otfrid Foerster.) Professor Wronski tells us of their difficulty in obtaining books and journals.
and journals. Such donations would be of great help to our neurosurgical conferees in Poland.
Paul C. Bucy, M.D., Editor
used Lipiodol (iodized oil) in 1928 [6]. Although accurate imaging of the lateral and third ventricular chambers could be obtained at low risk when intracranial pressure was not elevated, pathological studies of the spinal cord by Bucy and Spiegel [9] and other investigators [27, 37, 44, 56] demonstrated that Lipiodol was not innocuous and frequently caused the formation of granulomas and cysts. Similar problems were subsequently noted with iophendylate (Pantopaque), but no other radiographically suitable substance was available in North America [2, 38, 41, 43, 55, 57]. While these lipid-soluble contrast media were being developed, several water-soluble agents were also being used clinically. However, the high toxicity of the early water-soluble solutions (Kontrast-U and Abrodil [sodium methiodol]) made them unacceptable for ventriculography, and their restricted use only in the lumbosacral subarachnoid space resulted in irreversible lesions of the conus It seems unlikely that any solution of radiographic value will be medullaris and cauda equina [4, 36, 37, 41]. found which is sufficiently harmless to justify its injection into the During the past 15 years, safer low-sodium, lowcentral nervous system. osmolality contrast agents have been introduced, such as meglumine iothalamate (Conray), meglumine iocarmate Walter E. Dandy (Dimer-X), and especially metrizamide (Amipaque) [3, Walter E. Dandy's introduction of air ventriculography in 10, 20, 21, 23, 26, 61]. Despite computed tomography 1918 [13] and pneumoencephalography in 1919 [14] rep- (CT), angiography, and pneumoencephalography, the resented the first uses of a contrast medium to enhance growing radiodiagnostic role of safe and effective innoninvasive x-ray images for preoperative diagnosis. Iodine trathecal agents has made these agents useful for CT inventriculography was initially developed by Sicard and trathecal enhancement and stereotactic surgery, as well as Forestier in 1922 [52] and was modified by Balado who for imaging of the optic nerve sheath [15, 17, 24, 39, 40, 49, 62]. We evaluated the relative toxicities of several ventriculographic contrast media through light and scanning *Division of BiologicalSciencesand Pritzker School of Medicine, Uni- electron microscopy studies of the morphology of the basal versityof Chicago, Chicago, IL 60637. cisterns, arachnoid, and ventricular walls. tUniversidad Nacional de Cordoba, Cordoba, R. Argentina5000. SDepartmentof NeurologicalSurgery,Universityof PittsburghSchoolof Medicine, Pittsburgh, PA 15213. Method §W.C.A. Hospital,Jamestown,NY 14701. Thirty-six dogs weighing between 18 and 22 kg were diFromthe Departmentof NeurologicalSurgery,HenryFordHospital, De- vided into one control and five experimental groups of 6 troit, MI. animals each. The animals were anesthetized by intraveAddress reprint requests to Dr. Manuel Dujovny, Department of NeurologicalSurgery,HenryFordHospital, 2799 West Grand Blvd., De- nous sodium pentobarbital (25 milligrams per kilogram of body weight) and intubated. Controlled respiration was troit, MI 48202. Key words: arachnoid;cerebrospinalfluid;scanningelectron microscopy; maintained with a Harvard respirator, and blood gases were ventriculography;contrast media; intrathecalenhancement. checked frequently to maintain the pH, pO2, and pCO2 Thirty-six dogs were subdivided into five experimental groups and one control group for assessing reactions to contrast media during ventriculography. The five contrast agents were air, iophendylate, meglumine iothalamate, meglumine iocarmate, and metrizamide. Electroencephalographic patterns observed for the experimental animals deviated from the norm; this shift corresponded variably with the arrival of the contrast media in the basal cisterns. Scanning electron microscopy examination of the cisterns revealed significant free-cell proliferation and incipient granulomas in all groups of animals, except those injected with air. DujovnyM, KossovskyN, BarrionuevoPJ, Nelson D, LahaRK: Ependymitisand arachnoiditisinduced by intraventricularcontrastmedia. SurgNeurol 18:216-224, 1982
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0090-3019/82/090216-09501.25 O 1982 by Little, Brown and Company (Inc.)
Dujovny et al: Ependymitis and Arachnoiditis
within physiological limits. Ringer's lactate solution was infused via the saphenous vein for fluid replacement• Femoral arterial blood pressure was measured with a Statham transducer; cenl:ral venous pressure, intracranial pressure, electrocardiogram, and electroencephalogram (EEG) were recorded on a Grass polygraph. An 8 mm-diameter burr hole was drilled into the right parietal region about 1 cra from the midsagittal plane, and cannulation of the right lateral ventricle with a 22-gauge needle was performed on all animals. In the control group, only the cannulation was performed. The experimental animals were given a 1.5 ml intraventricular injection of either air, iophendylate (Pantopaque), 384.3 mg/ml; meglumine iothalamate (Conray), 280 mg/ml of iodine; meglumine iocarmate (Dimer-X), 280 mg/ml; or metrizamide (Amipaque), 170 mg/ml of iodine• Electrocardiogram, elcvtroencephalogram, blood pressure, central venous pressure, and intracranial pressure were continuously monitored for the duration of the intraventricular injection and for 2 hours afterwards. The correct placement of the contrasl medium was confirmed with anteroposterior and lateral x-ray films of the skull taken immediately after the intraventricular injection. Plain films were also taken 1 and 2 hours after injection, and a final set of films was taken 120 &tys later• The animals were then anesthetized, killed, and peffused with physiologically normal saline solution followed by 2% buffered glutaraldehyde (pH, 7.2). After the cranial vault of each animal was removed, the dura mater was exposed and opened. The brain was carefully removed while the cranial nerves and vessels were severed at the base of the skull under the Zeiss OPMI operating microscope. The arachnoid membrane was then excised en bloc from the following regions: olfactory cistern, chiasmatic cistern, interpeduncular cistern, w:ntricular walls, aqueduct of Sylvius, fourth ventricle, and cisterna magna. The choroid plexus was also removed.
The specimens were fixed in phosphate-buffered 2% glutaraldehyde (pH, 7.2) for 1 week and then dehydrated by a 30-minute serial passage through 30, 50, 70, and 90% solutions of methanol. In preparation for scanning electron microscopy, the specimens first underwent critical point drying with carbon dioxide• They were then individually mounted with silver paint adhesive on aluminum stubs 1 cm in diameter• Finally, the specimens were coated with a 10 to 40 nm-thick layer of palladium gold in a PolaronSputter Coater vacuum chamber (Polaron Instrument Corp., Line Lexington, PA). We examined the inner surfaces of the arachnoid, ventricular wall, and choroid plexus with a scanning electron microscope (American Metals Research Corp., Burlington, MA) at magnifications of from ×30 to ×40,000. Each inner arachnoid specimen was divided into eight regions along perpendicular axes and photographed. All 3 × 5 inch (7.5 x 12.5 cm) photomicrographs were enlarged to 5 × 7 inch (12.5 × 17.5 cm) prints and then integrated to form scanning electron microscope montages. Numerous stereoscope photographic pairs were made at a parallax difference of 7 degrees. The three-dimensional images from the stereoscope and the large surface views of the montages permitted us to assess the details more clearly. We also made corresponding specimens for light microscopy. In addition, selected scanning electron microscope specimens were later rehydrated in order to further correlate the scanning electron microscopical and conventional findings
[35]. Results
While all five contrast media produced very satisfactory radiographic images, toxicity differences in the central nervous system (CNS) among the media were substantial (Table). The control animals demonstrated no physiological or physical abnormalities during or after the experiments, and none of the animals in the six groups exhibited
Summary of Clinical and Physiological Changes following Ventriculography Electroencephalographic Findings (No. of Animals) Experimental Group a
Concentration
Control Air lophendylate Meglumine iothalamate Meglumine iocarmate Metrizamide
None None 384.3 mg/ml 280 mg I/ml 280 mg/ml 170 mg I/ml
217
aSix animals per group• EEG = electroencephalogram;mg I/ml = milligramsof iodine per milliliter.
Slow Waves
Epileptogenic Activity
5
1
6
,
,
Clinical Seizures (No. of Animals)
•
•
,
•
6
4
•
,
,
6
4
•
•
•
6
218 Surgical Neurology Vol 18 No 3 September 1982
abnormal blood pressure, cerebral venous pressure, or cardiac signs. AIR VENTRICULOGRAPHYGROUP. Five of the 6 animals into which air was injected developed slow, low-voltage EEG waves 2 to 10 minutes after injection. The sixth animal developed sharp, rapid waves, indicative of epileptogenic activity, but by 2 hours the EEG patterns in all 6 animals had returned to normal. I O P H E N D Y L A T E V E N T R I C U L O G R A P H Y G R O U P . These animals, conversely, showed only a mild decrease of EEG voltage that began immediately after the injection and lasted for 30 minutes before returning to normal. W A T E R - S O L U B L E V E N T R I C U L O G R A P H Y G R O U P S . Prolonged high-voltage, spiked activity began 5 minutes after the injection of meglumine iothalamate, 5 to 10 minutes after meglumine iocarmate, and 20 minutes after the injection of metrizamide in all 18 animals in the three groups. The sharp waves and rapid rhythm became more frequent at 4 to 50 minutes and persisted for 2 to 3 days. At 120 days, before the animals were killed, no EEG abnormalities were present.
Fig. 1. Scanning electron micrograph of a specimen from the subarachnoid membrane in a control animal. ( A) Fenestrated sheet (F), network fibers (N), macrophages (m), and other free cells (g). (×900.) (B) Higher magnification of an embossed sheet with a macrophage (m) and an erythrocyte (r). ( × 1800.)
Although no clinical seizures were observed in the metrizamide group, EEG epileptogenic patterns briefly preceded the development of convulsions in 4 of the animals injected with meglumine iothalamate and in 4 injected with meglumine iocarmate. Myoclonus of the eyelids, both ipsilateral and contralateral to the burr hole and limited principally to the facial area during the first 5 minutes, was then followed by a generalized epileptic seizure. At 2 hours, after the animals had received 5 mg Valium (diazepam) intravenously in addition to normal anesthesia, clinical seizures and epileptogenic activity disappeared. The seizures did not recur even after the animals awoke.
Anatomopathological Studies No macroscopic pathological changes, such as dilation, deformation, or general and focalized atrophy, were noted in any of the animal brains. Light microscopy revealed characteristic meningeal inflammation, arachnoiditis, micro-
Dujovny et ah Ependymitis and Arachnoiditis
Fig. 2. Following an injection of Pantopaque ( iophendylate), a large fibrous mass and investing film with numerous adherent erythrocytes, neutrophils, and macrophages is formed. (x900.)
abscesses, and necrosis. These responses were most acute in the specimens previously injected with iophendylate, less so in the meglumine iothalamate and iocarmate groups, and least in the metrizamide group. Subsequent scanning electron microscopical studies of control animals revealed no changes in the base sheet and fiber structures, the number of macrophages, or the number of other free cells investing the subarachnoid space (]Fig. 1). The inner arachnoid surface foundation in the control animals comprised both a fenestrated sheet and an embossed sheet to which remaining fibers and microfibers were anchored. The radiciforra fibers consisted of a plexus of trabeculae from which rootlike extensions projected multidirectionally that blended into the surface of the underlying tissues and arteries situated at the periphery. The network fibers were also trabeculated but were smooth and radiated from a central body to form fenestrations as large as 100 ~ in diameter. The anchoring fibers were short and consisted of single strands that neither branched nor formed
219
networks. The straight, plexiform, and network microfibers had a diameter of only 0.125/* and adhered to the surfaces of the larger trabeculae, coursed over arteries, or bridged the gaps between the trabeculae. Free cells were seen adhering to the arachnoid-pia complex, ventricular walls, and choroid plexus. The most frequently encountered cells were macrophages, which were 4 to 7/* in diameter. They appeared spherical and had either ruffled or blebbed surface forms. A second cell type, spherical lymphocytes, ranged from 6 to 11/, in diameter. These cells exhibited extremely smooth surfaces with thick basal microvilli that were larger than those of the blebbed macrophages. Similar results were observed in the air-injected groups. Iophendylate-injected animal specimens revealed an extensive organic film investing the base arachnoid sheets (Fig. 2) and their fenestrations, thereby obscuring the details of the underlying fibers. Foreign particles were attached to the fibers and the ventricular cilia. Numerous free cells, principally macrophages but occasionally lymphoblasts or erythrocytes, were also adhering to the arachnoid sheets, fibers, and ventricle walls. The x-ray energy dispersive analysis of the investing film revealed no traces of residual iodine, although frequent calcium deposits were
220 SurgicalNeurology Vol 18 No 3 September 1982
present and were enmeshed with foreign-body macrophages. The meglumine iothalamate specimens showed film on many portions of the base sheet, but its magnitude was less extensive than the film seen with the iophendylate specimens (Fig. 3). Interestingly, the aggregates of macrophages, lymphocytes, and foreign bodies were present in larger-sized clumps than on the iophendylate specimens, but the overall frequency of these aggregates was much lower. Meglumine iocarmate specimens exhibited no investing layer, but there were free-cell aggregates similar to those seen in the meglumine iothalamate-injected specimens (Fig. 4). Metrizamide produced the mildest free-cell response, with no film present and only occasional cell aggregates (Fig. 5). Discussion Since Dandy [13, 14] introduced ventriculography in 1918, air has been the most widely used contrast medium. To date, gases seem to be the safest contrast media because they are both diffusible and are rapidly eliminated from the central nervous system. Unfortunately, because radiographic images of certain midline structures are sometimes difficult to delineate [3, 10] without tomography, it is frequently necessary to vary the patient's position during
Fig. 3. Granulomatouslike (g) deposits of cells and debris produced by meglumine iothalamate, seen here in a film investing a network fiber (N). (r = erythrocyte.) (×3,600.)
fractional ventriculography. The increased intracranial pressure and pain following injection of the gas further exacerbates the problems associated with gas ventriculography. Since negative-contrast media (gas) were not able to reproduce satisfactory ventriculograms, particularly since most operating rooms had only conventional x-ray equipment, neurosurgeons began to use iodinated positivecontrast media. High-quality roentgenographic images were produced more readily, but pharmacological problems arose because of the toxic effects of the media on the central nervous system [1, 12, 18, 23, 29, 33, 38, 42, 50, 55, 57,
58]. The newest products, meglumine salts and a nonpolar compound metrizamide, have a lower toxicity, and their development can be credited to the theoretical work by Almen [1]. Based on physiochemical laws, he reasoned that a monomer of a nonelectrolytic contrast agent would have a lower osmolarity. He realized, further, that by keeping the
Dujovny et al: Ependymitis and Arachnoiditis
Fig. 4. Animals injected with meglumine iocarmate underwent freecell proliferation but no film deposit. Racliciform fiber (R), macrophage (m), erythrocyte (r), foreign debris (g), lymphocyte (1), microfiber (M). ( × 1,100.) axial ratio of the contras: molecule as close to one as possible, the fluid would have a low viscosity. Nonetheless, potential and real complications can compromise the usefulness of the media. For example, metrizamide readily penetrates the brain substance, and mental disorders such as organic psychoses and visual hallucinations have been reported sporadically [1,5]. The ready penetration of the drug has been explained recently by the finding that the cerebrospinal fluid and extracellular fluid spaces of the brain are the same compartment [59]. The most common problem following the injection of water-soluble contrast media has been the development of severe epileptogenic EEG patterns and epileptic seizures [2, 5, 19, 28, 29, 48, 50, 51, 53, 54, 60, 61]. Nau [47], for example, described a series of 36 patients who underwent ventriculography with either Dimer-X or Amipaque. Before the ventriculographic procedure, the main frequency of the EEG was in the alpha range (from 8 to 10 cps) in all patients except 3, who had intracranial tumors and EEGs in the theta range. No substantial change in the main fre-
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quency of the EEG was found after the procedure. However, focal frequency irregularities were seen in 4 patients afterwards and in a fifth during hyperventilation. General irregularities were seen in 4. Paroxysmal dysrhythmic discharges were seen in 3, and seizure potentials with sharp and slow waves or spikes, or both, were seen in 5. Eight patients had generalized convulsions: 3 after Dimer-X ventriculography, 3 after Dimer-X lumbar myelography, 1 after a suboccipital injection of Dimer-X, and 1 after cervical myelography using Amipaque. We observed the same complication of epileptogenic activity in four of the experimental groups in our study. Grepe and Widen [22] reported epileptogenic activity when either meglumine or metrizamide came in contact with the cerebral cortex, but they believed that the activity observed with metrizamide was probably due to the lowered seizure threshold produced by a neuroleptic anesthesia. We therefore did not anesthetize our animals with phenothiazine drugs. Although we consider that the EEG change in the 1 animal in the air-injected group can be attributed to an "EEG activation" phenomenon suggested by Gonsette [20, 21], the epileptogenic activity observed in all 18 animals of the meglumine iothalamate, meglumine iocarmate, and metrizamide groups was not the result of a pharmacological interaction.
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Investigators have previously reported that increased Fig. 5. Specimen recovered from a memzamide-injected animal shows evoked corticospinal-mediated convulsions constitute the a minimal amount of debris or cellular response. (A) Anchoring fiber most serious, immediate complication following the use of a (A) on a venule (V). (N = network fiber.) (x450.) (B) Debris (g) a macrophage (m) on a fenestrated sheet. (M = microfiber.) meglumine compound in the subarachnoid space [53]. This and (xl,800. appears to be a neurotoxic phenomenon that resists the usual anticonvulsant medications and requires sophisticated personnel and emergency procedures if death is to be prevented [28]. Our study also showed that the epileptogenic granulation tissue that contained multinucleated giant activity and clinical convulsions were much more severe in cells. the meglumine-iothalamate and meglumine-iocarmate Other histopathological studies of reactions of the cengroups. Hilal and associates [28] have proposed that the tral nervous system after injections of contrast media have convulsive activity is directly related to the neurotoxic been principally confined to the spine [33, 34]. Both properties of the molecular structure of the contrast Bergeron et al [8] and Howland et al [30] have reported medium. meningeal inflammation, arachnoiditis, microabscesses, Clinically, both constrictive arachnoiditis and obstruc- and necrosis after suboccipital iophendylate injections. tive hydrocephalus have been seen after Pantopaque Smith et al [55] believe that these lesions are identical to myelography [7, 32]. Barsoum and Cannillo [7] reported 2 chronic adhesive arachnoiditis. Jakobsen [31] reported patients with thoracic constrictive arachnoiditis that re- meningeal fibrous scarring, nerve root fibrosis, and myelin quired surgical intervention to relieve pain. The pathologi- sheath degeneration after intrathecal ventriculography on cal findings were fibrotic thickenings of the dura mater. 50 rats injected with iophendylate. The use of excessively Jensen and co-workers [32] reported a case of the delayed large volumes and concentrations of metrizamide studied by development of obstructive hydrocephalus with death en- Haughton and associates [25] may also involve the risk of suing 68 days after a lumbar injection of 9 ml of Pan- arachnoiditis. Clark and colleagues [11] reported that 4 of topaque. At postmortem examination it was found that the 13 dogs died suddenly 4 to 7 months after iophendylate foramina of Luschka and Magendie were occluded by ventriculography.
Dujovny et al: Ependymitis and Arachnoiditis
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3. Andreussi L, Clarisse J, Jomin M, Passeri A: Ventriculographywith water-soluble contrast in the diagnosis of posterior fossa tumors (107 cases). Neuroradiology8:25-38, 1974 4. Autro E, Suolanen J, Norrback S, Slastic P: Adhesive arachnoiditis after lumbar myelography with meglumine iothalamate (Conray}. Acta Radiol (Stockh) 12:17-24, 1972 5. Bagehi AK: Convulsions, subarachnoid haemorthage and death following myelographywith meglumine iothalamate 280. Surg Neurol 5:285-286, 1976 6. Balado M: Radiografia del tercer ventriculo, mediante la injeccion, intraventricular de Lipiodol. Arch Argent Neurol 2:69-79, 1928 7. BarsoumAH, Cannillo KL: Thoracic constrictive arachnoiditis after Pantopaque myelography: Report of two cases. Neurosurgery 16:314-316, 1980 8. Bergeron RT, Rumbaugh CL, Fang H, Cravioto H: Experimental Pantopaque arachnoiditis in the monkey. Radiology99:95-101,1971 9. BucyPC, Spiegel IJ: An unusual complicationof the intraspinal use of iodized oil. JAMA 122:367-369, 1943 10. Campbell RL, Campbell JA, Heinburger RF, Kalseck JE, Mealey J: Ventriculography and myelography with absorbable radiopaque medium. Radiology82:286-289, 1964 11. Clark RG, Milhorat TH, Stanley WC, DiChiro G: Experimental Pantopaque ventriculography. J Neurosurg 34:387-395, 1971 12. Cristi G, ScialfaT, DiPierro G, Tassoni A: Visual loss: a rare complication followingoil myelography.Neuroradiology 7:287-290, 1974 13. Dandy WE: Venticulographyfollowing the injection of air into the cerebral ventricles. Ann Surg 68:5-11, 1918 14. Dandy WE: Roentgenographyof brain after the injection of air into the spinal canal. Ann Surg 70:397-403, 1919 15. DiChiro G, Fisher RL: Contrast radiographyof the spinal cord. Arch Neurol 11:125-143, 1964 16. Drayer BP, Rosenbaum AE: Metrizamide brain penetrance. Acta Radiol [Diagn] (Stockh) 355(suppl):218-293, 1977 17. Drayer BP, Rosenbaum AE: Studies of third circulation. Amipaque CT cistemography and ventriculography. J Neurosurg 48:946-956, 1978 18. Erickson TC, van Baaren HJ: Late meningeal reaction to ethyl iodophenylundecylateused in myelography:report of a case that terminated fatally. JAMA 153:636-639, 1953 19. Gjerris A, Praestholm J, Klinken L: Comparison of metrizamide and iodophenydylate for cerebral ventriculography. Neuroradiology 15:79-84, 1978 20. Gonsette RE: An experimental and clinical assessment of watersoluble contrast medium in neuroradiology: A new medium-Dimer-X. Clin Radiol 22:44-56, 1971 21. Gonsette RE: Metrizamide as contrast medium for myelographyand ventriculography. Acta Radiol [Diagn] (Stockh) 334(suppl):346-358, 1973 22. Grepe A, Widen L: Effects of cistemal application of metrizamide. An experimental investigation in dogs in N20 analgesia and without halothane. Acta Radiol [Diagn] (Stockh) 334(suppl):l19-124, 1973 23. Hansen EB, Fahren Krug A, Praestholm J: Late meningeal effects of myelographic contrast media with special reference to metrizamide. Br J Radiol 51:321-327, 1978 24. Haughton VM, DavisJP, EldevikOP, Gager WE: Optic nerve sheath imaging with metrizamide. Invest Radiol 13:544-546, 1978 25. Haughton VM, Ho KC, Larson SJ, Unger GF, Correa Paz F: Experimental production of arachnoiditis with water-soluble myelogmphic media. Radiology 123:681-685, 1977 We wish to thank Gertrude Voheringer and George McManus for their 26. Heimburger RF, Kalsbeck JE, Campbell RL, Mealey J: Positive contrast cerebral ventriculography using water-soluble media. J Neurol technical assistance and Beth Bran&gee and Patricia Cornett for their Neurosurg Psychiatry 29:281-290, 1966 editorial assistance. Also, thanks to Cindy Skrzyniarzfor her assistance in 27. Hempel KJ, Zeitler E: Histologischeverandemngen bei myelographie the preparation of the manuscript. mit positiven kontrastrniheln. Radiologe 5:508-512, 1965 28. Hilal SK, Danth GW, Hess KH, Gilman S: Development and evaluation of a new water-soluble iodinate myelographiccontrast medium with markedly reduced convulsive effects. Radiology 126:417-427, References 1978 1. Almen T: Contrast agent design. J Theor Biol 24:216-226, 1969 2. Allen WEA, D'Angelo CM: Pulmonary oil embolization following 29. Hindmarsh T, Grepe A, Widen L: Metrizamide-phenothiazine interaction. Report of a case with seizures followingmyelography.Acta Pantopaque ventriculography in a patient with a ventriculovenous Radiol [Diagn] (Stockh) 16:129-133, 1975 shunt. Case report. J Neurosurg 35:623-627, 1971
Our study has also shown that the currently used contrast media are variably toxic to the central nervous system. We believe that the deposition of the filmlike layer on the arachnoid inner face and the subsequent filling of the sheet fenestrations account in part for this toxicity. Although neither meglumine iocarmate nor metrizamide produced a film layer, injections of all four contrast media, except air, resulted in substantial proliferation of free cells (e.g., macrophages and lymphocytes) and aggregations of free cells and foreign bodies in our preparations. Similar aggregations of free cells in response to intrathecal BCG (bacille Calmette Gu~rin) injections have been reported [45, 46]. The occasional calcium patches detected by x-ray energy dispersive analysis in conjunction with these aggregates of free cells and foreign bodies suggests the existence of incipient granulomas. It has been reported that 1 to 7 months after iophendylate ventriculography, the brains of experimental dogs exhibit extensive granulomatous lesions that erode through the ventricular wall deep into the interior of the brain [10]. Our studies with light microscopy correspond with observations previously reported in the literature [8, 11, 15, 23, 25, 27, 30, 34, 44, 51]. Iophendylate produced the most serious response of proliferating inflammatory infiltrates, perivascular inflammation, and microscopic hemorrhages [11, 21]. Since ventriculographic media come in contact first with the ventricular walls and inner surfaces of the arachnoid, it seemed that a study of the surfaces of these structures was warranted. N o t only is scanning electron microscopy ideally suited for this purpose, but it can also scan intact specimens that can be later rehydrated and prepared for conventional microscopy [35]. The toxicities of the positive contrast media are very important factors that mu:~t be seriously considered in the selection of a contrast agent. Future work should be directed toward the development of a truly innocuous medium that would have: the following properties: satisfactory roentgen-ray absorp:ion, miscibility and isoosmolarity with cerebrospinal fluid :For uniform distribution, low dose and low viscosity for rapid cannula injections, complete and rapid reabsorbabilit¥, nonepileptogenicity, and nontoxicity, as well as being: pharmacologically inert.
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30. Howland WJ, Currey JL, Butler AK: Pantopaque arachnoiditis. Experimental study of blood as potentiating agent. Radiology 80:489491, 1963 31. Jakobsen JK: On the side effects of contrast media for myelography. Acta Pathol Microbiol Scand [A] 81:323-326, 1973 32. Jensen F, Reske-Nielsen E, Ratjen E: Obstructive hydrocephalus following Pantopaque myelography. Neuroradiology 18:139-144, 1979 33. Jensen TS, Hein O: Intraspinal arachnoiditis and hydrocephalus after lumbar myelography using methylglucamine isocarmate. J Neurol Neurosurg Psychiatry 41:108-112, 1978 34. Kun M, Alwasiak J, Gronska J: Morphological changes in the CNS after Dimer-X ventriculography. Neuroradiology 15:99-106, 1978 35. Leffingwell HA: Fossil palynomorphs, in Hayat MA (ed): Principles and Techniques of Scanning Electron Microscopy. New York: Van Nostrand Reinhold, 1974, Vol 2, pp 150-162 36. Liliequist B, Lundstrom B: Lumbar myelography and arachnoiditis. Neuroradiology 7:91-94, 1974 37. Lindblom K: Complications of myelography by Abrodil. Acta Radiol (Stockh) 28:69-73, 1947 38. Luce JC, Leith W, Burrage WS: Pantopaque meningitis due to hypersensibility. Radiology 57:878-881, 1951 39. Manelfe CL, Guiraud B, Espagno J, Roscol A: Cistemographic computerisee au Metrizamide. Rev Neurol (Paris) 134:471-484, 1978 40. Marc JA, Kahn A, Pillari G, Rosenthal A, Baron MG: Positive contrast ventriculography combined with computed tomography: technique and applications. J Comput Assist Tomogr 4:608-613, 1980 41. Marcovich AW, Walker AE, Jessico CM: Immediate and late effects of intrathecal injection of iodized oil. JAMA 116:2247-2254, 1941 42. Mason MS, Raaf J: Complications of Pantopaque myelography. Case report and review. J Neurosurg 19:302-311, 1962 43. Maupin RA, Baker HL, Kerr IWI: Emulsified Pantopaque. Its possible application for myelography. Radiology 86:509-514, 1966 44. McLaurin RL, Bailey OT, Schurr PH, Ingraham FD: Myelomalacia and multiple cavitations of spinal cord secondary to adhesive arachnoiditis. Arch Pathol 57:138-146, 1954 45. Merchant RE: Scanning electron microscopy of spinal nerve exits of normal and BCG-infected dogs, in Becker RP, Johare O (eds): Scanning Electron Microscopy. Chicago: SEM, Inc, 1979, Vol Ill, pp 341-346 46. Merchant RE, Kelleher JJ, Low FN: Scanning electron microscopy of the subarachnoid free cells challenged in the primary and secondary immune response. J Submicr Cytol 11:293-312, 1979
47. Nau HE: Electroencephalography (EEG) after introduction of water-soluble contrast media into cerebrospinal fluid (CSF). Acta Neurochir (Wien) 57:75-82, 1981 48. Ofterdal SI, Sawhney BB: Effect of water-soluble contrast media on cortically evoked potentials in the cat. Acta Radiol [Diagn] (Stockh) 335(suppl):84--92, 1973 49. Partain LC, Scatliff JH, Staab EV, Wu HP: Quantitative multiregional CSF kinetics using serial metrizamide enhanced computed tomography. J Comput Assist Tomogr 2:467-470, 1978 50. PicazaJA, Hunter SE, Lee L: Seizures associated with the use of meglumine iothalamate 60% in ventriculography. J Neurosurg 36:476480, 1972 51. Praestholm J: Experimental evaluation of water-soluble contrast media for myelography. Neuroradiology 13:25-35, 1977 52. Sicard JA, Forestier J: Roentgenologic exploration of the central nervous system with iodized oil (Lipiodol). Arch Neurol Psychiatry 16:420-434, 1926 53. Skalpe IO: Myelography with metrizamide meglumine iothalamate and meglumine iocarmate. Acta Radiol [Diagn] (Stockh) 335(suppl): 57-66, 1973 54. Skalpe IO, Amunclesen P: Clinical remits with metrizamide ventriculography. J Neurosurg 43:432-436, 1975 55. Smith RA, Collier HI, Underwood FO: Cerebral vasospasm following myelography. Surg Neurol 1:87-93, 1973 56. Tabados K: Unusual complications of iophendylate injection myelography. Arch Neurol 29:435-436, 1973 57. Vinas FJ, Barrionuevo PJ, Dujovny M: Ventriculography by direct catheterization of third ventricles using a water-soluble substance. Am J Roentgenol 101:141-146, 1967 58. Ward W, Mathenson M, Gonski A: Three cases of granulomatous arachnoiditis after myelography. Med J Aust 2:333-335, 1976 59. Winkler SS, Sackett JF: Explanation of metrizamide brain penetration: a review. J Comput Assist Tomogr 4:191-193, 1980 60. Wylie IG, Afshan F, Koeze TH: Remits of the use of a new watersoluble contrast medium (metrizamide) in the posterior fossa of the baboon. Br J Radiol 48:1007-1012, 1975 61. Yonekawa Y, Nishikawa M, Egli M, Klaibes R: A clinical and experimental study of meglumine iocarmate in the subarachnoid space. Surg Neurol 5:167-170, 1976 62. Zito JL, Davis KR: The role of computed metrizamide myelography in evaluation of extradural extension from vertebral chordoma. J Ca)mput Assist Tomogr 4:38-42, 1980
Notice: Help for Poland Surgical Neurology has just received a letter from Profes- They would appreciate any financial help that the readers of sor Jerzy Wronski, a neurosurgeon connected with the SurgicalNeurology can give them to cover the cost of books Academy of Medicine of Wroclaw, Poland. (Wroclaw is the present name of the city of Breslau, where I once worked with Professor Otfrid Foerster.) Professor Wronski tells us of their difficulty in obtaining books and journals.
and journals. Such donations would be of great help to our neurosurgical conferees in Poland.
Paul C. Bucy, M.D., Editor