Iohexol vs. metrizamide in studies of glucose metabolism. A survey.

Nonionic contrast media represent a significant advance for myelography due to their substantially lower neurotoxicity. Some side effects have been noted with metrizamide, however. Origins of adverse effects have not been clearly defined. Studies reviewed here investigated the effects of two nonionic contrast media, metrizamide and iohexol, on glucose metabolism in neural tissue cells in vitro using rat hippocampal tissue slices. Isotonic metrizamide produced metabolic disturbances that may partially explain some clinical adverse effects. It was hypothesized that iohexol, which, unlike metrizamide, does not contain a 2-deoxy-D-glucose component, would not have this effect. A series of in vitro experiments compared the two media. Results showed no evidence that iohexol caused metabolic disturbances, but in vitro there was a depressive effect on metabolism from hypertonicity. In vivo water will rapidly diffuse toward hypertonic areas, thus neutralizing the osmotic effect. The lesser metabolic effect suggests that iohexol would be safer than metrizamide for subarachnoid examinations.

Effects of radiopaque contrast media on calcium uptake and phosphatidylinositol metabolism in rat brain synaptosomes.

Radiographic contrast media (RCM) used in the subarachnoid space are associated with occasional adverse reactions. This study examines the possibility that RCM reactions are caused by interactions with the plasma membrane phosphatidylinositol (PI) second messenger system. Isolated nerve endings, known as synaptosomes, were produced from rat brain homogenates. The synaptosomes were then incubated with RCM to determine if 32Pi labeling of the PIs or the uptake of 45Ca were influenced in a manner consistent with known mechanisms. The RCM metrizamide, iopamidol, iodixanol, and iotrol (but not iohexol) increased the 32Pi labeling. Hyperosmolality produced large increases in phosphatidylinositol-4-phosphate (PIP) and phosphatidylinositol-4, 5,-bisphosphate (PIP2) labeling. In the non-depolarized state iodixanol, but not metrizamide or iohexol, caused a time-dependent increase in 45Ca uptake. Iodixanol, iohexol, and metrizamide also augmented the veratrine-stimulated uptake of calcium, but none of the RCM affected the uptake of Ca resulting from potassium depolarization. The increased 32Pi labeling of the PIs caused by RCM is not directly related to Ca uptake, because the direction of change is wrong. RCM perturbations of the plasma membrane may cause an inhibition of other membrane components and systems. Hyperosmolality also may cause inhibition of membrane components. It is not known if these effects are important in clinically observed RCM toxicity.

The effects of gadolinium-DTPA and -DOTA on neural tissue metabolism.

Gadolinium DTPA and DOTA are being used extensively for imaging blood-brain barrier lesions. This study was performed to determine clinically relevant blood, cerebrospinal fluid (CSF), and neural tissue concentrations of these agents, and to determine if they alter neural tissue glucose metabolism. Bolus injections of 0.2 mmol Gd-DTPA/kg were made in rabbits, and blood, CSF, and neural tissue Gd concentrations were measured using atomic emission. Rat hippocampus slices were incubated for 6 hours in solutions of Gd-DTPA and Gd-DOTA, and effects on the production of carbon-14-labeled CO2 from glucose determined. Plasma concentrations reached a peak of 2.46 mmol at 1 minute postinjection, and dropped to 50% of peak in 6 minutes. The highest CSF concentration observed was approximately 0.1 mmol, and the mean lumbar cord concentration was approximately 8.5 mumol/g. Gd-DTPA and Gd-DOTA concentrations greater than 1.0 mmol caused significant increases in CO2 production. In areas of blood-brain barrier lesions, Gd-DTPA and Gd-DOTA may cause changes in tissue metabolism; however, in other areas it is much less likely.

Iopamidol and neural tissue metabolism. A comparative in vitro study.

Metrizamide was the first water-soluble contrast medium with a neurotoxicity low enough to allow it to be used routinely in the entire subarachnoid space. However, neurologic complications are still observed in some patients following the use of metrizamide. The cause of this toxicity has not been established, but existing evidence suggests an interference with glucose metabolism. In previous studies, a depression in CO2 production in neural tissue slices was demonstrated when isotonic metrizamide was added but not isotonic iohexol. In addition to iohexol, there is another new, nonionic, monomeric, water-soluble CM, iopamidol, soon to be released for clinical use in the United States. Iopamidol, like iohexol, has shown fewer adverse reactions and seems to be safer for myelography than metrizamide. Direct comparative studies of iopamidol and iohexol are sparse and the cause of their toxicity is not yet understood. This study was performed to determine the effect of iopamidol on neural tissue glucose metabolism as compared with the effects of iohexol and metrizamide. Metrizamide decreased CO2 production in neural tissue slices by 23%. Iopamidol and iohexol did not produce significant depression. Moreover, this model could not demonstrate any significant difference between iopamidol and iohexol in direct comparisons. The new monomeric contrast media, iopamidol and iohexol, thus do not appear to interfere with glucose metabolism. Adverse reactions to these new media are most likely caused by other mechanisms.

Further support for the glucose hypothesis of metrizamide toxicity. The effect of metrizamide and glucose analogue-free contrast media on hexokinase.

Metrizamide neurotoxicity has been hypothesized to be caused by an inhibitory effect of the drug on glucose metabolism. Metrizamide contains a glucose side chain, and glucose analogues including metrizamide have been shown to be inhibitors of hexokinase, an enzyme that is central to cerebral glucose metabolism. We studied the effect of the nonionic contrast agents iohexol, iotrol, and iopamidol, and the ionic contrast meglumine diatrizoate, on hexokinase in vitro. Although metrizamide reproducibly caused competitive inhibition of the reaction, the nonglucose contrast agents had no significant effect on the enzyme. These results add further support for the glucose hypothesis of metrizamide neurotoxicity.

The effect of iohexol on glucose metabolism compared with metrizamide.

In a previous in vitro study we demonstrated reduced CO2 production in rat hippocampal tissue when metrizamide was added. This metabolic depression is believed to be a result of the 2-deoxy-D-glucose (2-DG) portion of the metrizamide molecule since 2-DG is a known competitive inhibitor of glucose metabolism. This competitive inhibition probably occurs at the cell membrane since it has never been shown that metrizamide penetrates neural cells. Further the inhibition is most likely related to competition for the membrane glucose carrier. A new nonionic contrast medium, iohexol, does not contain a 2-DG component and if the hypothesis for the metabolic inhibition is valid we should not expect metabolic inhibition with iohexol. This hypothesis was tested using the rat hippocampus model previously used for metrizamide. We compared iohexol with metrizamide in isotonic concentrations and also examined the effect of hypertonicity. These experiments did not demonstrate inhibition of CO2 production with iohexol at near physiologic osmolalities, however, there was a marked depressive effect with increasing osmolality. This effect from hypertonicity is, however, probably of less importance in vivo where water will rapidly diffuse toward the hypertonic areas. The apparent lack of interference of the iohexol molecule on glucose metabolism should therefore make iohexol a more suitable contrast medium, for subarachnoid investigations than metrizamide.

Penetration of subarachnoid contrast medium into rabbit spinal cord. Comparison between metrizamide and iohexol.

The penetration into rabbit spinal cord of two nonionic contrast media, iohexol and metrizamide, and a reference tracer, technetium DTPA, were compared. The spinal subarachnoid space was perfused for 4 hours with a CSF solution to which technetium DTPA and either iohexol or metrizamide had been added. The contrast media and technetium DTPA concentrations reached a plateau level in CSF outflow within 80 minutes. The contrast media concentrations in CSF were higher than the technetium DTPA (P less than .001). In the cord tissue, technetium DTPA reached higher concentrations than the contrast media (P less than .001), and iohexol reached higher concentrations relative to technetium DTPA than metrizamide (P less than .001). The mean contrast media distribution volumes in the thoracic cord were 13% (iohexol) and 12% (metrizamide). The smaller distribution volume observed for metrizamide could be related to the larger effective size of "associated" metrizamide molecules or an interference with diffusion perhaps related to binding to glucose carriers.

In vitro models for testing the metabolic effects of myelographic contrast media.

Water-soluble nonionic x-ray contrast media have greatly improved the quality and safety of myelography. Toxic side effects are still observed however. The side effects are generally worse with the first nonionic agent, metrizamide, which has a glucoselike side group. Two in vitro models were developed to examine the effects of contrast media on glucose metabolism. Using rat hippocampus slices, the authors observed significant depression of carbon dioxide production by metrizamide and by deoxyglucose, a known metabolic inhibitor. Iohexol and iopamidol did not cause significant depressions. In rat brain synaptosomes the authors did not observe a depression of the uptake of deoxyglucose 14C by any media tested. These studies indicate that metrizamide can create metabolic depression but that it does not compete with glucose for the membrane glucose carrier.

Effects of contrast media on neural tissue glucose uptake in vitro.

The authors previously showed that metrizamide causes an inhibition in CO2 production in rat neural tissue. The purposes of this work were to test if this inhibition was the result of a competitive inhibition of metrizamide with the D-glucose transport system and to test the effect of other contrast media. Deoxyglucose was used as a marker for glucose. The first cellular system using rat hippocampus slices was designed to examine the effect of 15 mM and 80 mM metrizamide on deoxyglucose uptake. The second cell-free system, using isolated rat brain synaptosomes, was designed to evaluate more accurately the mechanism and kinetics of metrizamide's inhibitory effect on the uptake of deoxyglucose and to compare metrizamide to other nonionic contrast media (iohexol, iopamidol, iotrol, and iodixanol). These experiments demonstrate that there is inhibition of D-glucose uptake only in hippocampus slices and that the inhibition is dependent on the concentration of metrizamide. This does not, however, appear to be a competitive inhibitory effect on the carrier such as that between D-glucose and 2-deoxy-D-glucose. In synaptosomes, none of the contrast media had a significant effect on the uptake of 2-deoxyglucose.

Angiographic and pathologic correlates in carotid artery disease.

Eighty-four consecutive intact atheromata from the carotid bifurcation were examined macroscopically and by standard microscopic techniques. Preoperative angiograms of these cases were reviewed by a single radiologist with special attention to detecting the presence of ulceration. Pathologic and angiographic findings were compared and correlated with the patient's clinical presentation. Macroscopic findings of ulceration were present in 43 cases (51%). Thirty-four specimens contained intramural hemorrhage and 27 showed evidence of mural thrombus. Mural thrombus was significantly associated with evidence of ulceration (p less than 0.01). Intramural hemorrhage was commonly associated with ulceration (25/34) but was also seen in nonulcerated plaques (p greater than 0.05). Angiographic diagnosis of ulceration was made in 54 cases (64%). While angiography identified 78% of macroscopic ulcers (34/43; p = 0.05), seven typical ulcerations were missed angiographically and there were 18 angiographic false positive results (18/54:33%). Macroscopic ulcerations were most common in patients with symptoms of hemispheric ischemia (p less than 0.1). The angiographic diagnosis of ulceration did not correlate with the patient's clinical presentation (i.e., hemispheric ischemia, nonhemispheric ischemia, or asymptomatic stenosis). These results support the thesis that macroscopic ulceration is an important cause of hemispheric ischemia. Angiography does not reliably predict the presence of macroscopic ulceration and this limitation should be kept in mind when patients with hemispheric symptoms are evaluated. Such patients should not be denied consideration for endarterectomy simply because the angiogram fails to demonstrate ulceration.

Iotrol, iodixanol, and 2-deoxy-D-glucose effects on neural tissue CO2 production.

In vivo and in vitro experiments have demonstrated that the myelographic agent metrizamide decreases neural tissue glucose metabolism whereas iohexol and iopamidol do not. This study compares the changes in slices of rat hippocampus CO2 production caused by the nonionic dimers iotrol and iodixanol with the effects of metrizamide and 2-deoxy-D-glucose. After 6-hr incubations, 70-mmol/l concentrations of iotrol and iodixanol increased CO2 production by 11 +/- 20% and 31 +/- 35%, respectively, as compared with the artificial CSF control medium. Metrizamide at 70 mmol/l and 2-deoxy-D-glucose at 35 mmol/l decreased CO2 production by 32 +/- 13% and 96 +/- 1%, respectively. The increases in CO2 production with iotrol and iodixanol appear to indicate that these molecules have some effect on cell metabolism. The mechanism for the increase in CO2 production could involve an effect on the glucose metabolic pathway or could be indirect via a mechanism that increases cell energy utilization. These in vitro effects have not been verified with in vivo experiments.

MR of the cauda equina.

To define the anatomy of the cauda equina nerve roots by MR imaging, the lower spine of 14 normal volunteers was imaged using a high-field surface-coil technique. A total of 56 sagittal and 56 axial MR sections (eight selected slices from each case) were correlated with undistorted anatomic sections from cadaver spine specimens, and the visualization of the nerve roots was assessed. In addition, MR images of three patients with infiltrating or seeding tumors affecting the cauda equina were analyzed. Seventy-eight percent of the MR sections from normal cases clearly showed the anatomy of the cauda equina nerve roots. The nerve roots were fairly shown in 17% of the sections; and false findings (presumably caused by CSF pulsation) were observed in the remaining 5%. Coronal imaging provided excellent anatomic views of the nerve roots within the intervertebral foramina. Morphologic alterations in the pathologic cases were correctly shown when both T1- and T2-weighted imaging were used. In conclusion, MR proved efficient in viewing the cauda equina region.

PCR diagnosis of primary herpesvirus type I in poliomyelitis-like paralysis and respiratory tract disease.

Successful and rapid recovery of HSV-1 DNA from the cerebrospinal fluid after amplification by polymerase chain reaction was obtained in a 7-year-old boy with subtotal and permanent upper extremity paralysis with rapid onset and magnetic resonance imaging evidence of cervical cord involvement. Early administration of intravenous acyclovir probably limited neuronal loss. The clinical course and outcome of this disorder best conformed with what has been described as poliomyelitis-like paralysis associated with respiratory tract infection (Hopkins syndrome).

Preoperative treatment of squamous cell carcinoma of the lung with mitomycin-C in the bronchial artery.

Five patients with clinically inoperable bronchial squamous cell carcinoma were treated with infusions of 10 mg Mitomycin-C in the bronchial artery feeding the tumour, in an attempt to make inoperable bronchogenic carcinoma resectable. One patient had only one treatment while the other four had the infusion repeated three times with an interval of two weeks between treatments. In all cases there was a marked regression of the tumour. Four patients had the tumour resected 1-2 weeks following the last treatment and two of these are still alive 2 1/2 and 4 years later. The other two patients died 14 and 22 months following the initiation of the treatment. The fifth patient developed serious adverse effects to the drug that only slowly subsided. He died 5 1/2 months following the initiation of the treatment and his tumour was not resected. This limited study demonstrates the possibility of making certain inoperable patients with bronchogenic carcinoma operable, but it also stresses the problems of a correct preoperative staging.

MRI staging using gadodiamide for soft-tissue tumors of the head and neck region. Results from a phase II trial and a 5-year clinical follow-up.

In order to document the safety, tolerability and efficacy of gadodiamide outside CNS, an open, non-drug comparative study was performed in patients with tumors of the head and neck region. Fifty adult patients were included and 48 patients received the contrast medium. The examinations were performed on a 1.5 T imager using transverse, non-enhanced T1- and PD-/T2-weighted conventional spin-echo sequences, followed by a contrast-enhanced transverse T1-weighted sequence. Post-contrast images provided more diagnostic information compared to unenhanced images in 33 of 48 patients (69%). This information was of significant help in four and of moderate help in 14 cases. Post-contrast images compared to non-enhanced T1-weighted showed improvement in lesion delineation for 29 of the 43 patients where a lesion was observed. Only in two patients was the diagnostic information lower post-contrast. A comparison between all pre-contrast images versus contrast medium enhanced showed post-contrast images to give more diagnostic information in 14 and less in nine patients. No patient experienced discomfort in relation to gadodiamide injection. Only one adverse event occurred which was described as thirst, being of moderate intensity. The 5-year clinical outcome was analyzed and compared with the pre-operative staging. The case-books of all patients were reviewed and in 44 patients all information could be found. Of those, 18 were still alive, one with active disease (AAD) and 17 with no evidence of disease (NED). Two of those four patients, where information was incomplete, showed NED and two had died. This trial showed that contrast-enhancement using gadodiamide for evaluation of soft tissue tumors in the head and neck region was safe and provided statistically significant more diagnostic information compared with unenhanced images. MRI, when compared with palpation/inspection, changed tumor staging in approximately 30% of all cases.

Postoperative radiographic appearance of intracranial hemostatic gelatin sponge.

Hemostatic gelatin sponges were placed in hemispheric defects created in four dogs which were then periodically scanned by computed tomography to determine the postoperative appearance of the sponges. The hemostatic sponges appeared as low attenuation regions for 7-10 days. The attenuation value of these Gelfoam cavities was intermediate between fat and air. Subsequently, clinical cases were selected in which the location of gelatin sponges were known to demonstrate the appearance of the material in patients. In addition to enhancing the accuracy of computed tomographic interpretation, we have found that the gelatin sponge can be useful as a transient computed tomography marker for localization of surgical activity.

Parietal osteomyelitis and epidural abscess: a delayed complication of fetal monitoring.

Infected cephalohematomas are extremely rare. In this report an infant of 14 weeks developed an infected cephalohematoma, osteomyelitis of the parietal bone and an epidural abscess after fetal monitoring with scalp electrodes. Streptococcus pneumoniae was isolated from the purulent aspirate.