Magnetic Resonance Imaging in the Evaluation of Leul
Abstract: Leukocoria is an important clinical sign in ophthalmology. Conditions producing this white pupillary reflex must be differentiated from retinoblastoma to insure appropriate and timely treatment. Auxiliary diagnostic testing has been helpful in securing a clinical diagnosis. A new diagnostic modality, magnetic resonance imaging, provides similar morphologic information with the additional potential for biochemical characterization. A series consisting of 14 patients presenting with leukocoria as a result of retinoblastoma and simulating conditions was examined. The magnetic resonance imaging findings are discussed. [Key words: computed tomography, Coats' disease, intraocular hemorrhage, leukocoria, magnetic resonance imaging, retinoblastoma, toxocara endophthalmitis.] Ophthalmology 92:1143-1152, 1985
Leukocoria, a white pupillary reflex, is an important clinical sign, since it is the most common presenting sign of the pediatric ocular malignancy, retinoblastoma. Leukocoria is caused by the reflection of light from a light colored intraocular background. This is classically a white or light colored intraocular mass, membrane, or retinal detachment. Numerous simulating conditions (Coats' disease, persistent hyperplastic primary vitreous, toxocariasis, intraocular hemorrhage, and endophthalmitis) need to be differentiated from retinoblastoma. This is critical to insure prompt recognition and treatment of all conditions. The majority of cases can be diagnosed through careful clinical examination and correlation with the history. However, in approximately From the Departments of Ophthalmology and Radiology,* Cornell University Medical College, The New York Hospital, Memorial SloanKettering Cancer Center, Division of Ophthalmology-Department of Surgery, New York, New York. Presented at the Eighty-ninth Annual Meeting of the American Academy of Ophthalmology, Atlanta, Georgia, November 11-15, 1984. Supported in part by House of St. Giles the Cripple, Brooklyn, and G. Harold and Leila Y. Mathers Charitable Foundation, White Plains, New York. Reprint requests to Barrett G. Haik, MD, 515 East 71st Street, New York, NY 10021.
20% of cases where the diagnosis can not be established through standard clinical techniques, ancillary diagnostic testing has proven valuable. Through imaging techniques such as computed tomography and ultrasonography, diagnostic images can be obtained in many instances. However, both typical and atypical cases can present similarly on these techniques. Thus, newer imaging technology may play a role in distinguishing or characterizing lesions presenting diagnostic difficulty. Magnetic resonance imaging (MRI) may be valuable in defining the topography of the intraocular abnormality as well as detecting extraocular extension and in establishing biochemical characteristics of the intraocular abnormalities. Magnetic resonance imaging (MRI) is a new diagnostic imaging modality that generates high resolution medical images of any portion of the human body. Its remarkable advantage is the ability to produce such images in any orientation without the use of ionizing radiation. Additionally, it has the ability to provide information on the biochemical nature of the imaged tissues. 1•2 The physical basis of magnetic resonance imaging is the interaction of the nuclei of selectively stimulated atoms, mainly protons, within the body with an external static magnetic field and an applied radio frequency stimulus. 1143
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Fig 1. Axial nuclear magnetic resonance (NMR) spin echo (SE) images performed through the globe and orbit. All images have a slice thickness of0.75 em and an inplane (pixel) resolution of 1.0 X 1.0 mm. A, TR 500 ms; TE 30 ms: the vitreous and sclera are both low intensity, thus the sclera is not seen as a distinct structure. B-D, TR 2000 ms (B); TE 30 ms (C), 60 ms (D) and 90 ms, respectively, as the TE increases (progressive "T2 weighting"). Auid compartments such as the vitreous and cerebro-spinal fluid increase in intensity, while soft tissue structures such as the lens, the orbital fat and extraocular muscles, and the brain decrease in intensity.
By observing the response of tissues and their differences as a result of four MRI parameters (proton density, T1, T2, and flow) noninvasive tissue characterization can be achieved. These parameters are: 1. Proton density: concentration of nuclei, such as hydrogen, carbon, sodium, fluorine, phosphorous, or any other element with an odd number of charged particles. 2. Spin lattice relaxation time (T-1 ): related to the particular environment (eg. viscosity, temperature, concentration, and physical state of the nuclei being examined). 3. Spin-spin relaxation time (T-2): depends on local interactions of nuclei with one another. 4. Motion: volume flow related to the change in signal intensity due to the movement of nuclei through the resonance region and pulse timing of the radiofrequency stimuli and receiver system. By varying these parameters, one may produce images that are predominantly influenced by the T 1 or T2 components of the tissues. These "weighted" images will highlight specific tissue characteristics, since brightness or intensity of the image is an index of the T 1 or T2 of a specific tissue. The brighter structures on a T 1 "weighted" sequence have a short Tl. Conversely, the brighter structures on a T2 "weighted" image have a 1144
long T2. The characteristic T 1 and T2 response of ocular structures allows us to separate them on these sequences. Inversion recovery is a method of producing a purely T 1 "weighted" image which will accentuate certain normal structures such as fat and vitreous or abnormal conditions such as hemorrhage, and thus has potential clinical utility. However, a minimum of nine additional minutes per plane is required to produce these images, which is beyond the practical limits of fixation in almost all patients. It therefore, significantly lengthens the examination period, and is only obtainable in sedated patients. These parameters of the imaged tissues will also help to better characterize abnormal tissues and may well produce tissue signatures resulting in a noninvasive biopsy or histochemical image. This image can be combined with information obtained from computed tomography (CT) and ultrasonography to provide additional characterization. For example, CT would establish parameters related to atomic number and contrast enhancement, while ultrasonography would give parameters related to relative amplitude attenuation or absorption coefficients and the velocity of sound in specific tissues. Magnetic resonance imaging is well suited for the examination of the eye and orbit, since structures of different tissue composition are present. The difference in the amount of protons of these tissues affords excellent inherent contrast for MRI imaging. 3•4
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Fig 2. A, axial CT scan performed with contrast demonstrating a spherical high density mass in the left globe. Densities corresponding to calcium on the Hounsfield scale were noted. A crescentic area of vitreous is noted temporally. B, T1 "weighted" (30/500) image demonstrates a slightly brighter image when compared to the right globe. However, no anatomic detail is obtained on .the sequence. C, T2 "weighted" (90/2000) image demonstrating the calicifed tumor mass as a lower intensity area contrasted by the bright crescent of residual vitreous.
Figure 1 demonstrates the appearance of various ocular and orbital tissues at different imaging sequences. The globe presents a contrasting structure as the anterior border of the orbital structures. The lens, consisting of 65% water and 35% protein, will yield relatively intermediate signal strengths at short TRs and TEs (T 1, 7 50850 ms; T2, 40-50 ms) (Fig lA), and a lower signal with respect to vitreous at longer sequences (Fig lB-D). The vitreous, which is composed almost entirely of water, will have a relatively long Tl of 1200 to 1400 ms and T2 of 85 to 95 ms, and therefore will have a low signal intensity (Fig. 1A). A significant change in signal intensity does not occur until the application of longer TRs and TEs, eg. a TR greater than 1 second and TE greater than or equal to 90 ms (Fig 1B-D). The sclera is also better visualized on the longer sequences because it is bordered and thus contrasted by the higher signal strengths of vitreous and orbital fat (Fig 1B-D). The low signal of the sclera is probably due to its very long T 1 and very short T2, as well as a low proton density. Fat, having a very short T1 of250 to 350 milliseconds and an intermediate T2 of 40 to 50 ms with respect to the other orbital structures, will yield the strongest signal intensity on almost all spin-echo sequences (Fig lA-C). The intermediate T2 is demonstrated by a slight decrease
in intensity as the echo delay (TE) increases (Fig 10). The strong signal intensity as a result of the very short T 1 of fat makes the reduction caused by an intermediate T2 insignificant. The lack of signal from nonmobile protons present in bone or calcification limits the usefulness of MRI in delineating bony abnormalities and fractures. The inability to image calcification on MRI can accentuate its application in the evaluation of leukocoria, since we are differentiating presumably calcified lesions such as retinoblastoma from simulating lesions with no calcification.
MATERIALS AND METHODS Fourteen patients presenting with leukocoria were studied. Each of these patients had already undergone extensive clinical, ultrasonographic, and radiographic evaluation and a presumptive clinical diagnosis had been established. Magnetic resonance imaging was performed to verify the ability of the technique, to detect and portray the structural abnormalities with the same reliability as other diagnostic techniques, but also to investigate additional biochemical parameters of the diseased tissues. All examinations were performed on a Technicare 0.5 Tesla super conducting magnet at a slice thickness 1145
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Fig 3. A, axial CT scan performed with contrast demonstrating a dense homogeneous calcific area within a large retinoblastoma tumor mass in the left globe. The homogeneous appearance of the calicific area is related to averaging techniques and spatial resolution. B, T2 "weighted" (90/ 2000) image demonstrating more heterogeneous tumor mass, This is a result of the lower T2 levels of calcium within the tumor and the ability of MRI to depict this area with greater contrast.
RESULTS Of the 14 patients in this study, 6 presented with retinoblastoma; 4 presented with advanced Coats' disease; 3 with toxocara endophthalmitis and 1 with organized subretinal hemorrhage. The sequence-specific morphologic characteristics are discussed for each disease entity. T 1 and T2 measurements can not be determined in a quantitative fashion due to system limitations, however these can be determined by relative intensity comparison · with the intensity value of known structures. RETINOBLASTOMA Fig 4. T2 "weighted" (90/2000) image of a child with retinoblastoma and an associated exudative retinal detachment. The areas of subretinal exudate appear extremely bright as contrasted against lower intensity of tumor on this sequence.
of 7.5 mm and an interslice thickness of 7.5 mm in the axial plane. When deemed necessary, additional sagittal or coronal images were performed. Magnetic resonance imaging sequences used were spin-echo at a TE of 30 ms and TR of 500 ms; and a TE of 90 ms and a TR of 2000 ms. Selected images were performed at a TR of 1000 ms. Inversion recovery sequences were performed at a TI (time inversion) of 450 ms and a TR of 1500 ms. All pediatric patients were sedated with Demerol 2 mg/kg, Phenergan 1 mg/kg, and Thorazine 1 mg/kg via intramuscular injection to minimize head and ocular movement, and positioned in a supine position for all projections.
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On T1 "weighted" images, the tumor mass (previously localized on CT, Fig 2A) was of relatively low intensity and, depending upon degree of calcification, was indistinguishable from surrounding vitreous (Fig. 2B). On T2 "weighted" images, the mass was demonstrated in all cases, appearing to be of very low intensity in comparison to vitreous, which is bright on T2 "weighted" sequences (Fig 2C). The calcified masses were internally heterogenous, since areas of calcium are even lower in intensity than the soft tissue components (Fig 3). Another secondary characteristic of retinoblastoma is an associated hemorrhagic or exudative retinal detachment which is commonly present in these children and is represented as a localized subretinal area of higher signal intensity with respect to vitreous on both T 1 and T2 "weighted" sequences (Fig 4). These areas of retinal detachment were not clearly seen on CT examination. COATS' DISEASE
Four patients with advanced Coats' disease were examined. Each patient had a total retinal detachment
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Fig 5. A, axial CT scan performed with contrast demonstrating diffuse increase in subretinal densities in this patient With advanced Coats' disease and a total retinal detachment. B, Tl "weighted" (30/500) demonstrating a moderate increase in the intensity of the subretinal space. C, T2 "weighted" (90/2000) image demonstrating a dramatic increase in intensity of the subretinal material. ·
with subretinal exudation (Figs SA, 6A). On MRI, this detachment was demonstrated on both T 1 and T2 "weighted" sequences. The subretinal fluid/exudate appeared internally homogeneous and was of moderate intensity on T1 "weighted" sequences (Figs 5B, 6B). The T2 "weighted" sequences demonstrated. a much higher intensity in the subretinal areas (Figs 5C, 6C). One patient had progressed to phthisis bulbi by the time of study. Due to the disorganization and atrophy of the ocular structures, an image differing from that described above was seen. TOXOCARA ENDOPHTHALMITIS
Three patients with toxocara endophthalmitis who presented with leukocoria secondary to retinal detachment were examined. In each of these patients, a generalized scleral thickening was seen. When seen contrasted by the vitreous, this resulted in a pseudo-microophthalmia (Fig 7A). On T1 "weighted" sequences, the subretinal material was of moderate intensity in comparison to the vitreous cavity, but was very high on T2 ·~weighted" sequences (Fig 7B). The vitreous is also involved in this inflammatory process and is brighter
on T2 sequences than normal (Fig 8A-C). While the subretinal exudate is homogeneous on all spin-echo sequences, inversion recovery techniques permit visualization of an isolated area of hyperintensity corresponding to the presumed granuloma (Fig 80). ORGANIZED SUBRETINAL QEMORRHAGE
One patient with retinal detachment and organized subretinal hemorrhage bilaterally was examined. The retina was well delineated by the contrast between the vitreous cavity and the subretinal space. The subretinal hemorrhage was internally homogeneous in composition and of extremely high intensity on both T 1 and T2 "weighted" images (Fig 9). Associated vitreous hemorrhage in one eye showed an increase in intensity on T2 sequences (Fig 9B). COMPARATIVE ANALYSIS
Obviously, analysis of the images produced by MRI is difficult, since it is based on relative tissue intensities that are not easily quantified. Therefore, we have attempted to present our results in a simplified graphical
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Fig 6. A, axial CT scan performed with contrast demonstrating retinal detachment and diffuse increase in subretinal density in the right eye of this patient with advanced Coats' disease. B, T1 "weighted" (30/ 500) image plane, angled slightly more inferiorly than shown in A, demonstrating moderate increase in intensity of subretinal fluid. C, T2 "weighted" (90/2000), again demonstrating the pronounced increase in intensity.
Fig 7. A, Tl "weighted" (30/1500) image of a patient with a total retinal detachment in the right eye secondary to toxocara canis infection. An apparent microophthalmia is produced by highlighting of the thickened sclera circumferentially. The subretinal exudate is seen as areas of moderate hyperintensity. B, T2 "weighted" (90/2000) image demonstrating increased intensity in both the subretinal space and remaining vitreous. The hypointense sclera provides a contrasting boundary to intraocular pathology.
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Fig 8. Toxocariasis. A, Contrast enhanced axial computed tomography demonstrates the thickened sclera, as well as the extent of the retinal detachment. No obvious vitreous pathology is demonstrated. B, T I "weighted" (30/500) image is similar to the CT scan in its ability to demonstrate the sclera and subretinal exudation. C, T2 "weighted" (90/2000) image showing marked increase in intensity of the subretinal fluid and associated hyperintensity of the vitreous cavity. D, inversion recovery image (Tl 450) performed to isolate the site of larval granuloma temporally which has a shorter Tl than the adjacent inflamed sclera.
Fig 9. A, T1 "weighted" (30/500) image of a patient with bilateral retinal detachments. The right eye demonstrates high intensity signals corresponding to the ophthalmoscopically visible subretinal hemorrhage. The left eye presented with a vitreous hemorrhage (seen as moderately intense echoes on this sequence) and an ultrasonically defined retinal detachment with subretinal hemorrhage or exudate which was similar in intensity to that seen in the right eye. B, T2 "weighted" (90/2000) image demonstrates persistently high intensity to the subretinal material bilaterally. The brightness of the vitreous hemorrhage in the left eye was accentuated on this sequence.
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Fig 10. Chart comparing Tl "weighted" responses of conditions producing leukocoria.
Fig ll. Chart comparing T2 "weighted" responses of conditions producing leukocoria.
manner to compare our observations of both normal and pathological states. On the graph for T1 "weighted" sequences (Fig 10) values for normal lens, vitreous, fat, extraocular muscle, and bone are presented for baseline reference. Retinoblastoma, Coats' disease, and toxocara endophthalmitis all appear more intense than normal vitreous, although lower in intensity than lens. Only subretinal hemorrhage produces an extremely bright image on these T 1 "weighted" sequences. On the graph for T2 "weighted" sequences (Fig 11) values are again presented for the normal ocular and orbital structures. The most notable difference is the increase in the brightness of the vitreous on these longer TR and TE sequences. On these sequences, retinoblastoma will now be contrasted due to its short T2, and thus appear less intense than the brighter vitreous. Hemorrhage, exudation, and inflammatory subretinal material seen in the other conditions appear brighter than vitreous and retinoblastoma.
fying retinoblastoma, ultrasonography is not diagnostic. Computed tomography yields excellent morphologic data. Characteristics related to vascular enhancement and atomic number can be determined. Additionally, gross extension into the optic nerve and the extrascleral space can be identified. Unfortunately, computed tomography is relatively limited by its use of ionizing irradiation, a particular consideration in a pediatric patient population. Contrast enhancement is often needed to fully characterize abnormalities, exposing patients to the risk of anaphylactic or idiosyncratic reactions. Computed tomography has not been capable of distinguishing poorly calcified retinoblastoma from simulating infiltrating lesions of the eye. Even in our limited series of 14 patients, MRI has demonstrated its ability to delineate ocular abnormalities and has proven to be valuable in the evaluation of patients presenting with leukocoria. As the patient population and data base increases, more information will be available for analysis, but some valuable clinical correlations and characteristic MRI findings have been noted.
DISCUSSION Ultrasonography and computed tomography are both excellent in delineating certain aspects of ocular pathology, but each has its limitations. Ultrasonography has good resolution, is easily used, and basically is an extension of the clinical examination. Its use is limited in certain situations, such as dense intraocular calcification, since calcification causes absorption of sound and will not permit accurate evaluation of the posterior portions of the globe and optic nerve. This, therefore, limits the value of ultrasonography in determining extraocular extension and optic nerve enlargement. In several conditions with diffuse vitreous infiltration which include vitreous hemorrhage, vitritis, and poorly calci1150
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In all patients, a discrete intraocular mass was identified. In selected patients, the T 1 "weighted" sequence demonstrated the mass. However, in other cases, the T 1 "weighted" images did not show an appreciable difference in the intensity of the mass and surrounding vitreous. The mass was more apparent on T2 "weighted" sequences and areas of calcification were accentuated on T2 sequences. As has been demonstrated by other diagnostic techniques, the ability to portray and delineate retinoblastoma is directly related to the amount of distribution of calcium in this tumor and to the degree of contrast
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enhancement. Magnetic resonance imaging may be able to overcome diagnostic dependence on these tissue parameters by providing us with characteristic soft tissue images. Secondary findings in patients with retinoblastoma include associated hemorrhage and exudate. Since these materials have markedly different T2 characteristics, they should be easily identified and differentiated from the main tumor mass on MRI. Thus MRI has potential utility in evaluating patients prior to treatment and in monitoring their response to therapy. In these patients, recurrence of active tumor can often be confused clinically with post-treatment hemorrhage and exudation and the ability of MRI to identify hemorrhage and exudate versus tumor can direct appropriate treatment. COATS' DISEASE
Total retinal detachment with subretinal exudate is characteristic of advanced Coats' disease, but similar to CT imaging the retina itself is beyond the limits of spatial resolution of MRI, and the detachment is only visualized as the boundary between fluids of different composition and density. Depending on the degree of contracture and organization of the detachment, it can be seen as a V-shaped configuration in the vitreous cavity, as noted on two of the patients examined. It may also be drawn forward to the lens, so that the vitreous cavity is ablated and the subretinal space is all that is seen, as was the case in the remaining two patients. The exudative subretinal material, composed of cholesterol, free fatty acids, and protein, is oflower intensity on T 1 "weighted" sequences than would have been expected due to its biochemical similarity to fat. This may be explained by the large size of the cholesterol crystals and that they may be in complexes with surrounding protein molecules. The contrast between the subretinal exudate in Coats' disease and the vitreous cavity is accentuated on the T2 "weighted" sequences, and the subretinal material is seen as a brighter area, homogeneous in nature. No areas of low intensity, suggestive of calcification were seen in these patients, which provided a point of differentiation from retinoblastoma. One patient examined had advanced to phthisis bulbi, and presented with a dense cataract, total organized retinal detachment, and calcification of the intraocular structures. This condition produced images which differed drastically from the images seen in other cases of Coats' disease, but reflects the typical dysplastic changes of a phthisical eye. TOXOCARA ENDOPHTHALMITIS
In toxocara endophthalmitis, the most distinctive morphologic sign is the scleral enhancement and thickening which gives the impression of decreased vitreous volume and apparent microophthalmia. This results from diffuse inflammatory infiltration of the sclera. The retina was detached in these patients. The proteinaceous subretinal exudate produced by this inflammatory re-
spouse to larval infiltration is of moderate intensity levels on T 1 "weighted" sequences, but yielded the highest intensity T2 •;weighted" levels in our series. The vitreous is brighter than normal on T2 "weighted" sequences, due to released protein-laden exudate into the vitreous. In addition, on an inversion recovery sequence the presumed site of the larval granuloma could be identified by its shorter T 1 than surrounding inflammatory tissue. ORGANIZED SUBRETINAL HEMORRHAGE
In the one patient with bilateral retinal detachment and organized subretinal hemorrhages, the contours of the detachment were well outlined by the contrast between the vitreous cavity and the subretinal hemorrhage. Our knowledge of the MRI characteristics of hemorrhage is extrapolated from experience gained in the evaluation of subdural or subarachoid hemorrhage and supports our findings in this one case. Extremely fresh hemorrhage is not well seen on MRI since there is little free hemoglobin and it is similar in density, composition and thus MRI intensity to vitreous. When hemoglobin is released in the breakdown of hemorrhagic products, the paramagnetic properties of hemoglobin enhance the MR image. In this patient, the retinal detachments and subretinal hemorrhages had been long-standing and there was excellent portrayal of the hemorrhage. The hemorrhage was generally internally homogenous on both T 1 and T2 sequences. However, mild variations were noted as would be expected due to varying foci of hemorrhagic organization and degeneration. We found hemorrhage to demonstrate the highest T 1 levels seen with any of the pathologic entities examined, making it clearly distinguishable from our cases of retinoblastoma. The T2 "weighted" sequences also showed extremely high intensity signals, exceeded only by those produced by the protein laden inflammatory exudates of toxocariasis. The vitreous hemorrhage, seen in one eye, demonstrated an increase in intensity on T2 "weighted" sequences. In summary, auxiliary diagnostic testing such as ultrasonography and computed tomography has been highly reliable in the differentiation of pathological intraocular conditions responsible for leukocoria. However, MRI offers a new modality for the evaluation and diagnosis of these patients. Magnetic resonance imaging has the ability to demonstrate a spectrum of primary retinal and vitreal abnormalities with morphologic specificity. It accomplishes this without radiation or contrast agents and may indeed give more detail regarding the heterogenicity of the mass and the biochemical processes in the atypical presentations of leukocoria producing conditions. Disadvantages of MRI include the initial cost of hardware and site preparation and continuing costs of maintenance. Acquisition of the images is performed at a relatively low speed as compared to radiologic or ultrasound methods, thus extremely ill or recently trau1151
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matized patients who move involuntarily during image acquisition periods are better evaluated with CT where images can be obtained in several seconds. Even in cooperative patients, the interval required for image acquisition may exceed the span affixation and minimal ocular movement will detract from image quality. Therefore, sedation for small children and fixation monitors in adults are required. The potential risks of MRI fall into two categories: a static magnetic field of that can induce movement in intraocular, intracranial, intraorbital prostheses, or foreign bodies; and a rapidly changing magnetic field which can heat prosthetic devices or cause erratic pacemaker function. Additionally, the long term effects of exposure are unknown in humans, particularly effects on early development. While presently not generally available, there are several promising developments expected to have a significant impact on the clinical use of magnetic resonance imaging. These are the potential for spectroscopy, the use of paramagnetic contrast agents, and the introduction of surface coil receivers. Spectroscopy permits determination of the molecular composition of tissues and may allow clear cut distinction of materials such as cholesterol. Paramagnetic contrast agents can be selectively absorbed by tissues and enhance their imaging signal. While these two techniques do not appear to be practical at the present time in the evaluation of leukocoria, high resolution surface coil techniques 5 are being developed that will permit not only the detection of small abnormalities intraocularly and intraorbitally, but also will permit the clinician to assess minute changes
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in the biochemical structure of organs and tissue structures, such as the lens and vitreous. In conclusion, the present magnetic resonance imaging systems can produce high quality images of the intraocular pathology in patients with leukocoria. While the inherent spatial resolution capabilities are not equal to that of computed tomography and ultrasonography, the contrast resolution demonstrates morphology as well as these other diagnostic techniques. The introduction of surface coil receivers 5 and more powerful magnets will improve both spatial and contrast resolution and improve diagnostic accuracy by providing more information on both the structure and etiology of intraocular abnormalities.
ACKNOWLEDGMENTS The authors thank Lorraine M. Gattuso and Kenneth E. Fong for assistance in the preparation of this manuscript.
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