Signal intensity in proton magnetic resonance imaging (MRI) depends on several factors including the local environment of a proton, density of protons in a tissue, and the sequence of radiofrequency (RF) and gradient pulses used to generate the magnetic resonance signal. The local environment of a proton affects relaxation, that is, the rate of return to equilibrium of proton magnetization after perturbation by a RF pulse. At equilibrium, net proton magnetization is in the longitudinal axis. With an applied RF pulse, longitudinal magnetization decreases and there is some magnetization in the transverse plane. The longitudinal and transverse components of proton magnetization then return to equilibrium with different time constants. Longitudinal magnetization recovers at a rate determined by the average T1 relaxation time of the tissue. Tissues with short T1 recover a greater portion of their longitudinal magnetization within a given time period, and tend to have a higher signal intensity than tissues with a longer T1. After an RF pulse, transverse magnetization de-creases because of spin-spin relaxation, or dephasing, and is described by the T2 relaxation time.

In MRI, differences in tissue relaxation can be translated into differences in image contrast. Each tissue has unique T1 and T2 relaxation times that are affected by both the internal biochemical environment as well as the external environment. Internal factors that affect proton relaxation include motion, chemical shift, and blood flow. External factors include external field strength, magnetic field inhomogeneity, and the use of exogenous contrast agents. For example, T1 relaxation time varies with magnetic field strength (Larmor frequency) to a much greater degree than does T2 relaxation time, to such an extent that T2 is often considered to be independent of field strength. ¹

Magnetic resonance contrast material

Magnetic resonance (MR) contrast agents act by enhancing T1 and/or T2 relaxation rates for a given tissue type in a particular environment. Materials can be distinguished based on their inherent magnetic properties. Paramagnetic agents are materials that have no intrinsic magnetic field, but, when placed within an external field, can augment that field by alignment of its dipoles. Examples of paramagnetic materials are copper, iron, and manganese. Superparamagnetic materials are small particles that can act as single magnetic domains. A collection of these particles, when placed within an external magnetic field, enhance that field to a greater degree than do paramagnetic materials.

The affinity of a material for magnetization is termed susceptibility, with the magnitude and vector of the induced magnetic field dependent on the characteristics of the material. Relaxivity is a term used to describe the energy exchange that occurs when excited protons in water molecules return to a state of equilibrium more quickly when within the sphere of influence of paramagnetic materials. ² Selective enhancement may be based on differences in biodistribution and residence times of the contrast agent within a particular tissue. This allows a very small amount of contrast material to affect a large number of protons. Compared to iodinated contrast media doses, MR contrast doses are relatively small.

The most commonly used intravenous (IV) MR contrast media are agents that enhance T1 relaxation times. All have metal ions that contain one or more unpaired electrons. These metal ions are either part of a metal-chelate compound, such as gadolinium diethylenetriamine pentaacetic acid (DTPA) or are contained within a macromolecular ligand. When T1 contrast agents are used, tissue water diffuses into the sphere of influence of the metal ion and the relaxed water is then exchanged with bulk tissue water, resulting in a rapid relaxation of tissue water in the vicinity of the contrast agent. In this way, a very small amount of contrast agent can exert a large influence on tissue longitudinal magnetization.

Other T1 contrast media use manganese as the metal ion, usually chelated with dipyridoxylethylenediamine diacetate bisphosphate (DPDP). This complex is specific for hepatocellular uptake.

Gadolinium DTPA (GdDTPA) is the most commonly used IV T1 contrast agent. GdDTPA is the meglumine salt of diethylenetriamine pentaacetic acid, and acts by enhancing the relaxation rates of protons in its vicinity, having its greatest effect on T1 relaxation time. The usual dosage is 0.1 mmol/kg. GdDTPA is excreted primarily by glomerular filtration, and has a half-life of 90 minutes. Excretion is slower in patients with renal failure, but this does not increase the incidence of adverse side effects as there is no associated nephrotoxicity. The incidence of minor side effects is 1.5% with the most commonly reported effects being headache, symptoms at the injection site, and nausea. Death is rare with a reported incidence of 1 in 2,500,000. ³

T2 contrast agents are iron oxides and other materials that can form tiny particles called nanoparticles measuring 10 ^-9 meters (1 nanometer [nm]). These nanoparticles share electron fields, and produce large magnetic fields in the MR scanner magnet. Superparamagnetic agents have greater magnetic moment than paramagnetic agents, and their biodistribution is affected by particle characteristics including material, crystalline symmetry, core size, and coating.

A particle smaller than 15 nm can act as a single magnetic domain, and can create a large magnetic gradient that produces local field inhomogeneity. Diffusion of water protons through these gradients results in rapid dephasing of spin, and leads to a relative shortening of T2 relaxation times. Surface coatings affect biodistribution, a well-known feature of scintigraphic agents. It is possible to target agents to specific body tissues as a result. Superparamagnetic agents have a powerful effect on the relaxation times of targeted tissues, making it possible to use only small amounts. This is beneficial from a toxicity standpoint. ³

Safety

The inherent toxicity of native metal ions necessitates careful chelation. Gadolinium chelates have been used since the 1980s, and the adverse reaction rate has been reported in the 3% range. ⁴ Most reactions are categorized as minor; however anaphylactoid, severe asthmatic, and even fatal reactions have been reported. ⁴ There is no appreciable difference in the incidence of adverse reactions among the four approved gadolinium agents currently in use (gadopentetate meglumine, gadoteridol, gadodiamide, and gadoterate meglumine). ⁴ The incidence of adverse reactions is somewhat higher with the single manganese chelate (7% to 17%) and the larger ferumoxide particles (15%) than with gadolinium agents. ⁴ In the United States, IV administration of contrast agents is not approved for use in children under 2 years of age; however, off-label use of contrast is common in these children. ⁵ In European countries, approval for use of IV contrast in children under 2 years of age is more common, and there is no reported increase in incidence of adverse reactions in the younger pediatric group. ⁶

Extracellular magnetic agents are excreted in breast milk, and cross the placenta and are excreted by the fetal kidneys. These agents are therefore category C, not proven safe for use in pregnant or lactating women. They can be used in patients with diminished renal function as they are partially dialyzable, however, agents designed for the hepatobiliary and reticuloendothelial systems have an intracellular biodistribution and as such can be considered to be of greater potential harm.

Newer applications of contrast-enhanced MRI in pediatrics

Cardiac and vascular anomalies --Many congenital anomalies of the heart and great vessels require early detection and surgical repair in the neonatal period. Abnormal development of the aortic arch and the great vessels can result in a variety of symptoms related to extrinsic pressure or shunt vascularity. Arch anomalies can also be largely asymptomatic. Obviously, the more symptomatic lesions are detected earlier in infancy. ^7-9

An aberrant right subclavian artery is the most common arch anomaly, occurring when the proximal part of the right fourth embryonic vascular arch is absorbed rather than the distal part. The aberrant right subclavian artery runs posteriorly from the descending thoracic aorta on its path to the right arm, passing behind the esophagus and causing a typical indentation. This anomaly is usually asymptomatic and may be an incidental finding on a barium swallow esophagram. ¹⁰

A right-sided aortic arch occurs when the distal fourth arch is absorbed on the left instead of on the right (figure 1). This may result in mirror image or non-mirror image reversal of the great vessel origins. A right arch can be asymptomatic, but is commonly associated with tetralogy of Fallot and truncus arteriosus.

The more symptomatic anomalies typically result from vascular rings formed around the trachea and esophagus. These are seen with a double aortic arch (figure 2) formed when there is no absorption of any part of the embryonic fourth vascular arch. The right arch causes compression posteriorly on the esophagus as it passes behind to join the left arch. Both left and right arches cause lateral indentation of the trachea and esophagus. The descending aorta is usually left sided, but can be right sided with a retroesophageal left arch. A constricting ring can also be formed with a right-sided aortic arch and a left-sided patent ductus arteriosus or ligamentum arteriosum, causing indentations on the esophagus and trachea similar to those seen with a double arch.

Obstructive aortic anomalies can be divided into diffuse or localized narrowing of the aorta. Diffuse narrowing is usually associated with some degree of arch hypoplasia, formerly known as preductal coarctation, in the region of the aortic isthmus. In severe cases, this may result in complete interruption of the arch and is frequently associated with devastating congenital cardiac defects. ^7-9 A localized juxtaductal or postductal coarctation (figure 3) can be seen as an isolated anomaly, but is also associated with bicuspid aortic valve (85%), aberrant subclavian arteries, ventricular septal defects, patent ductus arteriosus, berry aneurysms of the circle of Willis, and Turner's syndrome. Overall fetal development is usually normal with an isolated juxtaductal coarct because of blood flow through the widely patent ductus arteriosus. As the ductus closes off, the changing blood flow patterns can cause left ventricular failure and symptoms of aortic stenosis. Uncorrected coarcts can cause development of collateral circulation with typical rib notching in later life; in the neonatal period, collaterals have not yet developed.

Surgical repair of congenital vascular anomalies is done as early as possible to prevent strain on the developing cardiovascular system. Presurgical planning is almost as important as the surgery itself. A reliable noninvasive method of mapping is required for optimum pediatric patient care. Studies have shown that 3D gadolinium- enhanced MR angiography (MRA) using the double-dose "FASTCARD" technique is a safe and effective adjunct to traditional arteriography. ^11-12

MRI of the thoracic aorta --Aortic imaging studies provide anatomic information for the surgeon as well as an indication of the functional effects of a vascular lesion on hemodynamics. Current vascular MRI techniques are considered more accurate than echocardiography in the depiction of the aortic arch and the descending thoracic aorta. ¹¹ Compared with conventional catheter aortography, MRA is appealing because it is noninvasive and requires neither iodinated contrast nor ionizing radiation. Sedation is still usually required for children under the age of 5 years, but older children are usually able to remain still for the required image acquisition time. Body coils are generally used for optimum signal-to-noise ratio, but in infants and small children a head coil may provide even better resolution. Electrocardiographic gating can be used to acquire images at a particular point in the cardiac cycle, and respiratory compensation may be applied as needed. ¹²

Three types of MRA are currently in use: black blood, bright blood non-contrast-enhanced, and bright blood contrast-enhanced techniques. The simplest sequence is a T1-weighted spin echo acquisition that produces a static "black blood" image from the flow voids within vessels. Slab thickness in children is usually 3 to 5 mm. Transaxial, sagittal oblique, and coronal oblique planar images provide views equivalent to the standard conventional angiographic positions, allowing ease of interpretation.

The second type of MRA is a gradient refocused echo technique that provides a dynamic "bright blood" image secondary to flow-related enhancement. In these images, the signal intensity is roughly equivalent to the blood flow velocity. MRA can be performed using phase contrast or time-of-flight sequences. Phase contrast techniques are generally not used in the chest secondary to degradation by cardiac and respiratory motion artifact.

Gadolinium contrast-enhanced MRA has been used to better delineate complex anatomy prior to surgery, especially in lesions which disrupt the normal blood flow. Gadolinium-enhanced 3D time-of-flight images are acquired as slabs in the sagittal and coronal planes, and post-processed into 3D volumes. These volumes can then be rotated in space and viewed from multiple angles. Breath hold time-of-flight images provide im-proved signal-to-noise ratio, in-creased resolution, and decreased image acquisition time, but are not always practical in the pediatric population without the use of general anesthesia. ¹²

Musculoskeletal --Musculoskeletal injuries in children can adversely influence future growth and development of normal bone. A "simple" fracture that would be easily treated in an adult may have serious implications in a skeletally immature individual. Careful imaging plays a major role in the accurate assessment of injury and the subsequent treatment plan.

MRI has become a mainstay of pediatric musculoskeletal imaging, with its superior depiction of marrow spaces, joints, soft tissues and its ability to aid in the accurate characterization of tumors. Contrast-enhanced MRI is being used to better evaluate cartilaginous and synovial injury. Physeal injuries, growth plate fractures, and any cause of ischemia to the growth plate have important implications for future growth arrest, and consequently need careful imaging evaluation. These changes can be seen in developmental dysplasia of the hip (DDH), proximal focal femoral dysplasia (PFFD), hemimelias, acute fractures, chronic trauma, and infection. The use of gadolinium contrast has allowed early identification of Legg-Calvé-Perthes disease, infection, and ischemia due to physeal injury. ¹³ Synovial overgrowth, the hallmark of juvenile rheumatoid arthritis (JRA), can be easily delineated using contrast-enhanced MRI techniques. The affinity of gadolinium contrast agents for synovium permits diagnosis of JRA before bony erosions have occurred (figure 4). ^14-16

In a Swiss study by Weishaupt et al, ¹⁷ dynamic MRI of Legg-Calvé Perthes disease in the pediatric hip was found to be as effective as arthrography in the evaluation of the articular surfaces. The MRI must be performed on an open magnet to allow for changes in hip position. Dynamic MRI was noninvasive, did not use ionizing radiation, and, in this study, did not require sedation.

Intravenously administered gadolinium contrast medium concentrates in synovial joint fluid, and the relative enhancement can be increased with moderate exercise. ¹⁷ This arthrogram effect can be utilized in patients who will not tolerate an intra-articular injection. The synovium itself can be seen to enhance following IV administration of gadolinium contrast media. ¹⁸

In a study performed at Children's Hospital in Boston, gadolinium contrast-enhanced MRI was performed following reduction and spica casting of dysplastic hips. ¹⁹ Hip position and physeal vascularity were adequately demonstrated. This technique may aid in predicting response to conservative treatment and the need for surgical intervention in developmental dysplasia of the hip. ^20,21

Conclusions

MRI techniques are attractive for use in the pediatric patient population mainly due to the lack of ionizing radiation. In the United States, most gadolinium contrast agents are approved for IV use in the over
2-year-old age group, but "off-label" applications are frequently utilized in children under 2 years of age. Pediatric approval in European countries has been less stringent with no increase in reported adverse reactions. New techniques utilizing gadolinium contrast are improving diagnosis of congenital vascular anomalies, making surgical planning easier, and obviating the need for invasive angiographic examinations. Applications of contrast-enhanced MR techniques in the musculoskeletal system are improving prognostic predictions in the management of Legg-Calvé-Perthes disease, JRA, and developmental dysplasia of the hip. Continued development of sophisticated imaging sequences will provide faster and better examinations in the pediatric patient population.

Acknowledgements

The author wishes to thank Dr. Glen Tung for his review of this manuscript; Drs. Michael Wallach, Diego Jaramillo, and Ramiro Hernandez for assistance with images; and Nathan Goldshlag for technical support.