NEUROIMAGING CONTRAST AGENTS IN NEURO-OPHTHALMOLOGY

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1 NEUROIMAGING CONTRAST AGENTS IN NEURO-OPHTHALMOLOGY Andrew G. Lee, MD Iowa City, Iowa INTRODUCTION Neuroimaging studies including magnetic resonance (MR) imaging, computed tomography (CT) scans, and cerebral angiography are among the most commonly performed tests for the neuro-ophthalmologist. Contrast material is routinely used in these studies to improve diagnostic accuracy. This monograph reviews the basics of radiologic contrast material in neuroimaging and the potential side effects and complications associated with their use (1-15) TYPES OF CONTRAST AGENTS There are two major types of contrast material in neuroimaging, 1) ionic and nonionic iodinated contrast for CT and cerebral angiography and 2) gadolinium for MR scanning. The ideal contrast material would highlight important structures (a process known as radiographic contrast). Contrast agents should be inexpensive, water-soluble, stable (chemical and heat), iso-osmolar to serum, low viscosity, rapidly excreted, safe, biologically inert, non-toxic and well tolerated agent. Contrast material properties that affect safety and utility include density (mass per unit volume), viscosity (resistance to flow), osmolality (number of particles in solution), and chemical composition. Iodinated contrast agents are used in x-ray based neuroimaging (e.g. computed tomography, myelography, and cerebral angiography) because they attenuate (radioopaque) x-rays (due to the iodine molecules). Gadolinium on the other hand is a paramagnetic agent that influences local magnetic field in MR imaging and is the contrast agent for MR scanning. Very high concentrations of gadolinium paradoxically produce signal voids while routine concentrations create high signal on T1 weighted MR scans. HISTORY AND BASICS OF IODINATED CONTRAST MATERIAL Moniz in 1927 performed the first injection of contrast material (strontium bromide) into a carotid artery. Later, he changed to sodium iodide because of the higher atomic number and the photoelectric effect of iodide. However, organic iodine is toxic and, therefore, a low toxicity carrier is required. Sodium iodide was replaced eventually by mono-, di- and tri-iodinated agents. Tri-iodo-benzoic acid was made more soluble by salinification with sodium, meglumine, calcium, and magnesium (ionic contrast agents). These ionic contrast agents (used in the 1970s) dissociate in solution to form an anion and a cation (but only the anion carries the radio-opaque iodine atom). In order to decrease osmolality, the non-ionic contrast agents were developed in the mid-1980s. They do not dissociate in solution. The most common non-ionic agents are iohexol, iopamidol, and ioversol. Although the non-ionic agents are less toxic than the ionic agents, one ionic agent, Hexabrix has fewer side effects, less osmolality, and has a safety profile similar to non-ionic agents. (1) IODINATED CONTRAST AGENTS Iodine is radio-opaque (attenuates x-rays) and the density of iodinated contrast is a linear function of iodine content. Iodinated contrast agents are used in angiography, myelography, and CT scanning. These iodinated agents do not influence proton resonance and therefore are not suitable contrast agents for MR scans. Because iodine in its simple organic form is toxic, watersoluble and low-toxicity carriers are necessary. Iodinated contrast agents are divided into four groups: 1) ionic monomer, 2) ionic dimer, 3) non-ionic monomer, and 4) non-ionic dimer. Ionic monomer contrast agents are soluble and stable in water, have low lipid solubility, and are eliminated by renal glomerular filtration. The ionic dimer agents also have a high water and low lipid solubility. The non-ionic contrast agents do not dissociate in solution like the ionic salts. Thus the number of particles in solution per atom of iodine is about half of the ionic contrast agents. An osmotic pressure gradient is created when there is a difference between the osmolality of the contrast media and body fluids. Adverse reactions to iodinated contrast material occur due to chemotoxic reactions, to the hyperosmolality of the contrast material, or to inherent neurotoxicity of the agent itself. In addition, idiosyncratic adverse reactions may occur and these are similar to allergic or anaphylactic reactions to other noncontrast agents. The chemotoxic effects may affect any organ system. A rapid injection of a markedly hyperosmolar agent results in a sudden shift of intracellular fluid to the extracellular space across semi-permeable cell membranes. Osmolality is a measure of the number of molecules per liter of solution. Ionic agents have osmolality in the 5-10 times serum range. They are rapidly diluted by extracellular fluid to maintain a physiologic plasma osmolality. Over half of the hyperosmolality of ionic contrast material results from the cations (typically sodium or meglumine) in solution. The non-ionic dimers have the lowest osmolality and the ionic monomers have the highest osmolality. The high osmotic nature of ionic contrast may exert its effects by altering extracellular fluid composition (osmotic pressure gradient), membrane potentials, or by binding calcium. These effects may result in vasodilation, fluid shifts, red blood cell damage, myocardial depression or arrhythmia (calcium-binding effects may alter electrical conduction), renal toxicity (acute tubular necrosis and renal failure), and bronchospasm. Some agents cause a vagal response with secondary bradycardia and hypotension possibly due to effects on the brainstem cardiac center. Contrast agents may interfere with coagulation and clotting factors but in standard doses this is not usually significant. Ionic agents inhibit coagulation more than non-ionic agents do. Extravasation of contrast into subcutaneous tissues at the injection site is usually mild but may result in tissue necrosis in ionic contrast material. The common adverse effects and reactions to 121

2 iodinated contrast are listed in Table 2. Table 3 compares ionic and non-ionic contrast agents. Table 4 summarizes the relatively low mortality rates for high and low osmolality contrast agents for the years (8). TABLE 2: ADVERSE EFFECTS OF INTRAVENOUS IODINATED CONTRAST AGENTS Mild reactions Severe adverse reactions Nausea and vomiting Wheezing Headache Dyspnea Dizziness Laryngospasm Feeling of warmth Status asthmaticus Metallic taste in the mouth Subglottic edema Tingling in the lips, mouth, & tongue Angioneurotic edema Faintness Pulmonary edema Flushing Anaphylactic shock Anxiety Cardiovascular collapse Tremor Death Chills Fever Urticaria Generalized pruritis Sneezing Rhinitis Nasal Stuffiness Coughing Lacrimation TABLE 3: IONIC CONTRAST AGENTS VERSUS NON-IONIC CONTRAST AGENTS IONIC NON-IONIC Low cost Anticoagulation properties (useful in angiographic procedures) Low viscosity More adverse reactions Higher osmolality Burning sensation, nausea and vomiting upon injection Higher cost No anticoagulation properties Higher viscosity Fewer mild to moderate adverse reactions via intravenous route Lower osmolality No discomfort on injection TABLE 4: MORTALITY RATES ACCORDING TO TYPE OF CONTRAST MEDIA USED Years HOCM Deaths LOCM Deaths Mortality rate 108 of 25 M exams = ( ) 144 of 50 M exams =( ) HOCM = high osmolality contrast media LOCM = low osmolality contrast media M = million 122

3 NEUROTOXICITY OF IODINATED CONTRAST MEDIA Neurologic side effects following cerebral angiography include seizures, cortical blindness, paresis and encephalopathy. Seizures may be due to emboli, vascular spasm, contrast material crossing the bloodbrain barrier, pre-existing pathology, or osmotic breakdown. Significant complications occur in up to 0.2% of angiograms. Some patients with cerebral neoplasms might suffer a seizure after the administration of intravenous ionic contrast medium. Of these contrast agents, sodium salts are more neurotoxic. Transient cortical blindness may follow cerebral angiography if the temperature of the contrast material or flush solutions is greater than 98.6/F. Jackson et al. reported six cases of severe retrograde amnesia and one case of cortical blindness during selective vertebral artery injection angiography with non-ionic contrast (15). Analysis of the contrast batch detected no abnormalities but investigation of the angiography suite indicated a faulty contrast warming cabinet. The contrast material was injected above body temperature. The warming cabinet was removed and the complication did not recur. The authors postulate that ischemia caused by vertebral artery spasm was responsible for the findings (15). Spinal cord complications after angiography may be due to direct toxicity, ischemia, or both. Indirect neurotoxic effects on the brainstem may cause secondary respiratory or cardiac dysfunction. Severe life threatening reactions including death (mostly cardiac arrest) have occurred. Most of the deaths occurred within 5 to 10 minutes of injection and at a frequency of 6.6 per 1 million to 1 in 10,000 for iodinated contrast agents. Contrast myelography-related adverse reactions have been reported with iophendylate, an iodinated ethyl ester (Pantopaque). These reactions included headache, chronic meningeal reaction, cranial neuropathy, and seizures. Myelography should never be performed with ionic iodinated contrast material. Deaths and severe impairment have resulted in cases in which this agent was inadvertently used. The first water-soluble contrast nonionic agent metrizamide (Amipaque) caused headache, nausea, vomiting, seizures, mental disturbances, cortical blindness, and aphasia. The mechanism of metrizamide toxicity is thought to be due to glucose transport inhibition of intracellular membrane carriers. ARE THERE ANY DIFFERENCES BETWEEN THE USE OF CONTRAST IN CHILDREN VERSUS ADULTS? The effects of contrast in children are similar to adults. The major difference relates to weight and age appropriate dosing. Non-ionic material is preferred however for younger children because of lower osmolality and fluid shifts. In general, children tend to have fewer adverse reactions (mild to severe) to all contrast agents (ionic and non-ionic) when compared with adults. (1) Eldevik and Brunberg reported 125 cases of Gd contrast MR in children less than 2 years of age. These authors concluded that the indiscriminate use of Gd in MR imaging in children less than 2 years of age was not warranted but that there were no serious side effects due to Gd in this population (11). DOES THE ROUTE OF ADMINISTRATION OF CONTRAST CHANGE TOXICITY? The route of administration of iodinated contrast affects clinical toxicity. Intra-arterial injections may produce osmolar effects including shrinkage and increased red blood cell clumping, damage to vascular endothelium, and transient or permanent brain ischemia. Myelography employs iodinated contrast agents. Iodinated ethyl esters (Pantopaque) rarely resulted in adverse reactions such as headache, chronic arachnoiditis and meningeal reaction, cranial nerve palsies and seizures. Pantopaque had to be directly withdrawn following the myelography procedures in which it was used. The first non-ionic water-soluble contrast agent metrizamide was developed for myelography. Metrizamide was less likely to produce arachnoiditis but still was associated with side effects such as headache, nausea and vomiting, seizures, mental disturbances, electroencephalographic abnormalities, cortical blindness, and aphasia. Currently, the non-ionic agents produce fewer adverse effects and are used for myelography. The ionic agents including Hexabrix are never used for myelography due to their severe toxicity. (1) Idiosyncratic reactions mimic anaphylactic reactions (i.e. tachycardia, bronchospasm, and hypotension). These reactions are variable and ranging from mild hives, to moderate to severe bronchospasm, or sudden death. Histamine release, complement cascade activation and the release of other activators (e.g. prostaglandins) are the presumed mechanisms. Patients with asthma, drug or food allergies, previous contrast reactions, have a 5 to 10 fold increased risk of an idiosyncratic contrast reaction. Prophylactic, pre-procedure, oral corticosteroid steroid administration and antihistamine treatment and the use of a non-ionic contrast may reduce the risk of severe adverse reaction in these patients at risk. Iodinated contrast material is nephrotoxic. Intravascular contrast causes initial mild vasodilation followed by more prolonged vasoconstriction leading to renal ischemia breakdown of renal basement membrane junction, renal tubular epithelial toxicity and further exposure of the kidney to contrast toxicity. Risk factors for renal toxicity include renal insufficiency, diabetes mellitus, and congestive heart failure. The risk of nephrotoxicity is between 2 and 16%. There is no clinical difference in renal toxicity between ionic and non-ionic contrast material. Moderate doses of contrast are probably safe at creatinine levels of 1.5 mg/dl or less. Hydration before and after the procedure may minimize the nephrotoxicity. This is especially important for patients at special risk such as multiple myeloma patients or sickle cell disease. Iodinated contrast may precipitate a hypertensive crisis in patients with pheochromocytoma. The overall risk of adverse reaction to contrast material is 5-10% and most of these reactions are minor (e.g., sneezing, coughing, rhinitis, conjunctival edema, urticaria, pruritus, vomiting, lightheadedness). Severe reactions occur in 1 in 500 injections of ionic contrast and the death rate ranges from 1 in 40,000 to 1 in 100,000. The rate of adverse reaction with non-ionic contrast is much lower (in both animal models and 123

4 human series) at one sixth that of ionic agents and the rate of severe reaction with non-ionic contrast is 1 in Overall the percentage of adverse reactions for ionic agents is 12.66% and for non-ionic agents is 3.13%. Newer non-ionic contrast and low osmolar materials are not salts. These agents are soluble in water because of large hydrophilic hydroxyl side chains attached to fully substituted benzene rings containing three iodine molecules. In addition, the use of non-ionic contrast does not reduce the quality of the imaging. Unfortunately these agents are not universally used because the cost of non-ionic contrast is up to 10 to 25 times higher than ionic contrast material. Nevertheless, non-ionic contrast should be considered in high-risk patients (e.g., asthma, allergies, cardiac disease, pulmonary hypertension, and previous contrast reaction). Some authors have advocated that cost may no longer be a barrier to the conversion to lower risk non-ionic contrast (13). HISTORY AND BASICS OF GADOLINIUM Gadolin, a Finnish scientist discovered the lanthanide rare earth series in Soluble paramagnetic species include transitional metal complexes and the lanthanide (rare earth) complexes. The lanthanide metals are paramagnetic because of unpaired electrons and Gd is the most clinically relevant ion in this group. The free gadolinium (Gd) has no known function in the mammalian system and it is present only in trace amounts in nature. Gd contrast indirectly increases contrast enhancement by affecting T1 and T2 relaxation through alteration of the local magnetic field in MR imaging. Because these metal cations are toxic, the metal ion is chelated with a metal complex or ligand. Gd has a similar molecular weight and biodistribution to iodinated contrast media. In MR imaging, a good contrast agent has unpaired electrons in its outer orbited shell and its magnetic spins must be able to influence surrounding molecules. Gd has seven unpaired electrons, demonstrates the largest paramagnetic moment, and is thus an excellent MR contrast agent. Gd however is toxic in its ion form and requires a chelating agent to prevent it from dissociating in vivo. The Gd ion is the cation and the chelating agent is the anionic organic ligand, usually diethylenetriaminepenta-acetic acid (DTPA). The Gd- DTPA complex is coupled to dimeguline to increase solubility. Magnevist (formerly Gd-DTPA, now known as gadopentate dimeglumine) was the first MR contrast agent. It may cause transient rise in serum iron, bilirubin, mild headache, nausea (3-4%), and hypotension. There are only seven reported cases in the literature of severe anaphylactoid reactions to Gd-DTPA. Thus, Gd-DTPA (Magnevist) is a very safe ionic contrast. Like the development of non-ionic iodinated contrast material other non-ionic Gd agents are available including gadoteridol (Prohance) and gadodiamide (Omniscan). The side effects and adverse reactions to Gd are uncommon but occur in 1%-4% of cases. Omniscan and Prohance have not demonstrated any changes in serum iron or bilirubin. Severe anaphylactoid reactions are rare with Gd-DTPA (Lufkin). These agents may cause nausea and taste disturbances however. Table 5 lists the common side effects of Gd. Double and triple doses (e.g. multiple MR scans on the same day) of Prohance may be given without an increased incidence of side effects. The T1 shortening effects of Gd result in contrast enhancement and unlike iodinated contrast, increasing the concentration of Gd eventually leads to signal voids due to T2 shortening effects. All three Gd agents (Magnevist, Prohance, Omniscan) are safe in children (and are approved for children > 2 years old). They are safe and effective. They are eliminated by the kidneys by glomerular filtration and have an elimination half-life of 1.5 to 2 hours. Within 24 hours, 95% of all the Gd is eliminated by urinary excretion. Gd has fewer renal side effects than iodinated contrast material and thus enhanced MR is the procedure of choice for patients in renal failure. The volume of the injected dose of Gd is significantly less than with iodinated contrast materials and thus the osmotic load is less. There is less than a 5% change in total plasma osmolality after a routine dose of Gd. (2) Kashanian, et al. found that for routine peripheral venous injection that there were no clinically significant changes or adverse reactions with Gd dimeglumine. (3) TABLE 5: COMMON ADVERSE REACTIONS TO GADOLINIUM Headaches Dizziness Nausea Taste perversion Anxiety Warmth Arthralgia Dyspnea Rhinitis Cough Tinnitus Malaise Urticaria Paresthesia Seizure Tremor Hypotension IS GADOLINIUM NEUROTOXIC? Gd is normally confined to the extracellular space outside the central nervous system. Gd contrast enhancement occurs at areas of blood-brain barrier breakdown or in structures lacking a blood-brain barrier. In experimental models, local concentration of Gd chelates can reach levels that affect metabolic activity. The clinical significance in humans however of these 124

5 experimental findings remains unknown. Thus, there is little evidence that Gd is neurotoxic. WHAT IS THE UTILITY OF MAGNETIC RESONANCE CONTRAST? Several studies using different evaluative methods have shown that enhancement is effective and useful in clinical neuroimaging. Wolf et al. reviewed 330 scans and demonstrated an increase in diagnostic merit from 83.9% to 88.7% with enhanced scans. (4) Elster et al reported that contrast administration was helpful in 57% of cases based upon blind interpretation of unenhanced scans and open interpretation of unenhanced and enhanced images. (5) Kucharcyzk et al concluded that enhancement was valuable in 75% cases of unblinded brain MR imaging in Canada. (6) We believe that the routine use of Gd is safe and that the benefits of increased diagnostic sensitivity and accuracy outweigh the minor and uncommon side effects. However, Gd is relatively expensive. $ 150 per MR scan (personal communication, The Methodist Hospital Radiology Department, Houston, Texas). CONTRAST AGENTS IN PREGNANCY All pharmaceuticals are assigned to one of the following pregnancy categories: A, B, C, or D. Category A drugs have been used by a large number of pregnant women and women of child-bearing age without any form of definite disturbance in the reproductive process noted to date. Category B agents have been used only by a limited number of pregnant women but without any definite disturbance in the reproductive process (e.g., malformations, direct or indirect harm to the fetus). Category C drugs have pharmaceutical effects that cause or must be suspected of causing disturbances in the reproduction process and that may involve risk to the fetus without being directly teratogenic. Category D drugs have caused an increased incidence of fetal malformations or other permanent damage in man or on the basis of reproduction-toxicology studies must be References 1. Byrd SE, Darling CF, Allen E. Contrast agents in neuroimaging. Neuroimaging Clin N Am 4:9-26, Carr JJ. Magnetic resonance contrast agents for neuroimaging. Neuroimaging Clin N Am 4:43-54, Kashanian FK, Goldstein HA, Blumetti RF, et al. Rapid bolus injection of gadopentate dimeglumine: absence of side effects in normal volunteers. AJNR 11:- 853, Wolf GL, Walsh SJ, McNeil BJ. Utility of magnetic resonance contrast agents in routine cranial imaging. Neuroimaging Clin N Am 4:55-62, Elster AD, Moody DM, Ball MR, et al. Is Gd-DTPA required for routine cranial MR imaging? Radiology 173: , Kucharcyzk W, Lee DN, McClarty B, et al. Routine contrast enhancement for cranial magnetic resonance imaging. An analysis of its diagnostic value in adults. Can Assoc Radiol J 42: , Wolf GL. Safety of ionic and nonionic contrast media. Radiology 206:560, Spring DB, Barkan HE, Bettmann MA. Safety of ionic and nonionic contrast media. suspected of doing so. Gadolinium is a category C agent. Gd crosses the placenta and theoretically could result in fetal toxicity. Gd also has some mutagenic potential in vivo in the mouse. Studies reported by manufacturers indicated no congenital anomalies in rats given 2.5 human dose or in rabbits given 7.5 and 12.5 human doses of Gd. A single report of inadvertent administration of Gd to a mother carrying a 9-day old preimplantation blastocyst did not result in spontaneous abortion or fetal malformation (9). Non-ionic contrast agents are category B. Although it has not been established that serious adverse reactions occur in nursing infants with contrast material it is recommended that nursing be temporarily discontinued following the administration of contrast. Rofsky et al. found no adverse effects on fetal mouse development after Gd (12). In addition, there is no convincing evidence from animal studies that MR imaging and the associated electromagnetic exposure carries any risk of reduction in litter size, development of malformations, cytogenetic effects, or carcinogenesis (12). This is in contrast to the known teratogenic effects of exposure to ionizing radiation. SUMMARY Clinicians should be aware of the potential side effects and complications related to contrast agents used in neuroimaging. Gd is generally safe with minimal side effects and Gd is recommended for routine diagnostic use. Iodinated contrast material in CT scanning my cause more significant side effects. Patients with multiple myeloma or other renal conditions, especially if the prestudy creatinine is greater than 1.5 mg/dl should be given contrast with caution. Newer non-ionic iodinated contrast agents are better tolerated, but are more expensive than ionic contrast agents. Neuro-ophthalmic complications including cortical blindness may occur after contrast angiography or myelography. Radiology 206:561, Barkof F, Heijboer RJJ, Algra PR. Inadvertent IV administration of gadopentate demeglumine during early pregnancy. AJR 158:1171, Lufkin RB. Severe anaphylactoid reaction to Gd-DTPA. Radiology 176:879, Eldevik OP, Brunberg JA. Gadopentetate dimeglumine-enhanced MR of the brain: Clinical utility and safety in patients younger than two years of age. AJNR 15: , Rofsky NM, Pizzarello DJ, Weinreb JC, et al. Effect on fetal mouse development of exposure to MR imaging and gadopentetate dimeglumine. JMRI 4:805-7, Williams TE, Adam EJ. Intravascular contrast media: can we justify the continued use of ionic contrast agents. Clin Radiol 52:59-61, Almen T. The etiology of contrast medium reactions. Invest Radiol 29:237-S45, Jackson A, Stewart G, Wood A, Gillespie JE. Transient global amnesia and cortical blindness after vertebral angiography: further evidence for the role of arterial spasm. AJNR 16:955-9,