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Ultrasound Biomicroscopy
Ultrasound Biomicroscopy Charles J. Pavlin, MD, FRCSa,b,*, E. Rand Simpson, MD, FRCSb, F. Stuart Foster, PhDc KEYWORDS Ultrasound Ultrasound biomicroscopy High frequency ultrasound Ocular tumors Imaging
summarizes the theoretic basis for this technology and illustrates the clinical application of this tool in clinical ophthalmology and ophthalmic research.
THEORETIC CONSIDERATIONS AND DEVELOPMENT OF THE ULTRASOUND BIOMICROSCOPE Mechanical waves and vibrations occur over a wide range of frequencies called the acoustic spectrum. This spectrum extends from the audible range (10 to 20,000 Hz), with which we are all familiar, to the range of phonons (>1012 (10 to the 12th power) Hz) which comprise the vibrational states of matter. This article considers the development and application of ultrasound imaging systems that use very high frequency ultrasound in the range of 20 to 100 MHz, which provides subsurface detail with resolution approaching that of optical microscopy.
Resolution The limits in current clinical imaging have been set as a result of the need to provide the maximum resolution consistent with the need for the ultrasound beam to penetrate the globe of the eye and orbit. In an ultrasound imaging system, the lateral resolution can be related via diffraction theory to the full width of the ultrasound beam at half
a Ophthalmology Department, Mt Sinai Hospital, Suite 410, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada b Department of Ocular Oncology, Princess Margaret Hospital, Toronto, Ontario M5G 2M9, Canada c Department of Medical Biophysics, University of Toronto, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario M5G 2M9, Canada * Corresponding author. Mt Sinai Hospital, Ophthalmology, Suite 410, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada. E-mail address: [email protected] (C.J. Pavlin).
Ultrasound Clin 3 (2008) 185–194 doi:10.1016/j.cult.2008.04.001 1556-858X/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.
ultrasound.theclinics.com
Ultrasound is an indispensable tool in medical imaging and has an important role in ophthalmologic diagnoses. Conventional B-scan examinations produce two-dimensional cross-sectional views of the eye and orbit. This method of imaging is the most important examination technique for intraocular lesions, particularly in the presence of anterior segment opacities; however, there are limitations to conventional ultrasound. In our attempts to gain a greater understanding of the mechanisms of ocular disease, we have a never ending need for higher resolution. In the same way that optical microscopy has allowed improved understanding of basic processes, improved imaging resolution allows us to see and understand disease mechanisms that were not previously apparent. The use of high frequencies in the 20 to 100 MHz range for ocular imaging has greatly improved the resolution of ocular ultrasound. The basic physics and techniques of using higher frequency ultrasound to image living structures were developed in the laboratories of Stuart Foster at the University of Toronto. The authors subsequently applied these techniques to ocular imaging and named this process ultrasound biomicroscopy1–5, that is, the imaging of living structures at microscopic resolution. A broad clinical experience in normal patients and ocular disease has been gained over the years since its development. This article
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Pavlin et al maximum amplitude (FWHM) and is given by the equation: FWHM 5 cf=ðy lÞ 5 l ðf - numberÞ where c is the speed of sound, f is the focal length of the transducer, u is the frequency of ultrasound, d is the diameter of the focused transducer, l is the wave length, and f-number is the ratio of the focal length to the diameter of the transducer. It is evident from the equation that high resolution can simply be achieved by selecting the appropriate frequency. For example, if one desires 60 mm resolution, an operating frequency of 60 MHz and an f-number of 2 could be chosen. This resolution is approximately ten times that obtained using conventional clinical instrumentation. The penalty to be paid for this increase in resolution is loss of penetration. All human tissues exhibit ultrasound attenuation coefficients that increase with frequency. If we assume an attenuation coefficient of 0.5 dB/mm MHz, which is consistent with typical soft tissues, the maximum penetration that could be achieved for a 10 MHz system is approximately 50 mm for an 80 dB dynamic range. For a 60 MHz system, penetration is only 5 mm, which reinforces the need to optimize transducer sensitivity and performance in systems development of ultrasound biomicroscopy.
CLINICAL USE OF ULTRASOUND BIOMICROSCOPY Technique The technique of eye examination using ultrasound biomicroscopy is similar to conventional B-scan examination of the anterior segment. A fluid immersion technique is required to provide an adequate standoff from the structures being examined. This standoff is necessary to avoid distortion of the image close to the transducer and to prevent contact of the transducer and the eye. The authors have designed a series of eye cups that hold the eyelids open and allow more rapid patient preparation. These eye cups resemble those used in conventional ultrasound biometry, with a lip that slides under the eyelids and holds the cup in place. They differ from biometry eye cups in being shallower and having a distinct flair, which allows a good view of precisely where the scanning head is being placed. Fig. 1 shows an examination being performed with one of these eye cups. One percent methyl cellulose is an excellent coupling medium with sufficient viscosity to prevent fluid loss during examination. Saline can also be used. Some ultrasound biomicroscope designs have a longer focal length necessitating a deeper cup. Air bubbles must be carefully avoided in the fluid and on the concave surface of the transducer. Unlike in conventional 10 MHz B-scanning, high-frequency transducers are frequently not covered by a membrane. Because the transducer
Transducers The development of high-frequency transducers has been central to the progress achieved in ultrasound biomicroscopy. The piezoelectric polymer polyvinylidene difluoride and co-polymer polyvinylidene difluoride/trifluoroethylene have been used for external imaging applications such as the eye. Such transducers produce short, wide bandwidth pulses with good sensitivity. The highest resolution, defined as FWHM in the previous equation, is only achieved at the focus. The depth of field (DOF), which is defined as the range of depth over which the beam remains well focused, must also be considered. In general, the DOF increases with the square of the f-number. An f-number ranging from 2 to 4 represents a good compromise between DOF and resolution. Typical ultrasound biomicroscopy transducers have an f-number of 2.0 to 3.0. From the previous discussion, it is clear that the choice of transducer parameters will have a significant impact on image quality; therefore, it is necessary to optimize transducer characteristics for each application to obtain the best compromise for resolution, contrast, and DOF.
Fig. 1. An ultrasound biomicroscopic examination performed using a small eye cup.
Ultrasound Biomicroscopy is moving, contact with the eye and resulting corneal abrasion must be carefully avoided. The presence of an articulated arm is helpful in improving control of the scanning head. Careful attention must be paid to the screen image to prevent the scanning head from getting too close to the eye. In the authors’ practice, contact with the eye has been an extremely rare occurrence. Various designs have also incorporated a fluid-filled membrane over the transducer with moderate attenuation of the signal. Any part of the eye that can be approached directly over the surface can be examined. The cornea and anterior segment structures are easily examined in any meridian. The conjunctiva, underlying sclera, and peripheral retina can be examined by rotating the eye as far as possible away from the region being examined. This positioning allows examination past the muscle insertions with a somewhat greater range temporally because of anatomic considerations. Any adnexal structures that can have their surfaces exposed can be examined. Skin penetration is not as good as that through conjunctiva because of attenuation by keratinized epithelium. Examination of structures such as the posterior pole of the eye is not possible at the present time.
Measuring Ocular Structures Ultrasound biomicroscopy expands the ability to accurately measure ocular structures. The improved measurement accuracy of ultrasound biomicroscopy has an axial resolution five to ten times that of conventional 10 MHz ultrasound. The authors perform measurements on the screen during examination using electronic calipers. Stored images can be transferred to a computer via an image capture board and measured using imaging software. Measuring a structure accurately with ultrasound requires knowledge of the speed of sound in the structure being examined. Little is known of the true speed of sound in the structures that are capable of being measured, particularly at these frequencies. The authors have used a speed of sound of 1540 m/s to make the majority of measurements. This speed is used in conventional ultrasound scanning to measure distances in most tissue. A speed of 1640 m/s is generally used for the cornea and has been used for sclera as well, which is similar in structure. Conventional ultrasound is capable of measuring relatively large distances such as anterior chamber depth. Ultrasound biomicroscopy increases the measurement accuracy of such structures because the shorter wavelength allows
a finer positioning of end points, and the exact measurement position can be defined more precisely.6,7 Ocular structures such as the ciliary body, sclera, and iris cannot be measured by other techniques because of inadequate resolution and the inability to differentiate these structures from adjacent tissue. Ultrasound biomicroscopy allows clarification of tissue borders and accurate measurement.
Normal Ocular Structures Anterior chamber Anterior chamber depth is easily measured using ultrasound biomicroscopy (Fig. 2). Measuring the axial distance from the internal corneal surface to the lens surface is facilitated by the ease of distinguishing the iris from the lens surface. This differentiation can be difficult in eyes with small pupils using conventional ultrasound. Measurement of anterior chamber depth is not confined to the axial position but can be taken from any point on the endothelial surface to either the iris or lens surface, providing an improved ability to define the profile of the entire anterior chamber. The cornea All corneal layers can be differentiated in a cross section (Fig. 3). The first highly reflective line is the surface of the corneal epithelium. The epithelium can be differentiated from Bowman’s membrane, which forms a highly reflective line just below this. The distance between these two lines is the epithelial thickness. The corneal stroma reveals a low internal reflectivity that is lower than that found in the more irregular collagen distribution of the sclera. This difference allows definition of the corneoscleral junction.
Fig. 2. Ultrasound biomicroscopic view of anterior chamber. Arrows, anterior chamber depth measurement; I, iris.
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Pavlin et al The iris The iris normally shows variations in thickness. Histologic studies show that it is generally thinnest at the iris root and thickest near the pupillary margin. In addition, there are variations in thickness depending on the presence of crypts and the state of dilation or constriction of the pupil. The iris epithelium forms a constant highly reflective layer on the posterior iris surface. This highly reflective line defines the posterior iris border and can be useful when one is differentiating intra-iris lesions from lesions behind the iris.
Fig. 3. Ultrasound biomicroscopy of the cornea showing corneal layers.
The endothelium cannot be differentiated from Descemet’s membrane, but, together, they form a single highly reflective line at the posterior corneal margin. Greater definition of corneal structure can be achieved with higher frequency transducers. Anterior chamber angle region The corneoscleral junction and scleral spur can be distinguished consistently with ultrasound biomicroscopy (Fig. 4). These structures are important in maintaining orientation in the angle region. The scleral spur in a particularly useful landmark presenting a constant reference point for measurement in the angle region.
The ciliary body The ciliary body is well defined by ultrasound biomicroscopy. The ciliary processes can be variable in configuration and length. The appearance of the ciliary body will vary depending on whether one is passing through a process or a valley between processes. During the examination, one can produce either of these views as desired. The zonule The anterior zonule and lens surface can be consistently visualized in all eyes (see Fig. 4). The zonule inserts smoothly into the surface of the lens but is occasionally more irregular.
ULTRASOUND BIOMICROSCOPY IN OCULAR DISEASE Because ultrasound biomicroscopy is a nonspecific imaging tool, it is suitable for examination of a large range of diseases that fall within the penetration limits of this technique. It is particularly useful in conditions in which structural abnormalities are present, that is, conditions that produce rearrangement of normal anatomy.
Glaucoma
Fig. 4. Ultrasound biomicroscopy of the angle region. The scleral spur (arrow) is used as a stable landmark. The ciliary processes (cp), zonule (Z), lens (L), and iris (I) are clearly imaged. The highly reflective sclera (S) is distinguished from the lower reflective cornea (C). The angle is narrow in this patient with plateau iris syndrome.
Several types of glaucoma are caused by structural abnormalities of the anterior segment of the globe. This observation is particularly true of angle-closure glaucoma and infantile glaucoma. The ability of ultrasound biomicroscopy to image structural abnormalities on a much finer scale than has previously been possible provides a new quantitative tool for research and clinical assessment of glaucomatous disease. Ultrasound biomicroscopy has been helpful in elucidating the mechanisms of angle-closure glaucoma,8–13 pigmentary glaucoma,14–16 malignant glaucoma,17–20 and many other glaucoma entities. The method is also helpful in defining the mechanisms and results of various types of glaucoma surgery (see the article by Rockwood and colleagues, elsewhere in this issue).21,22
Ultrasound Biomicroscopy Corneal and Scleral Disease Ultrasound biomicroscopy can be helpful in patients with opaque corneas before transplantation.23 Anterior segment details such as the depth of the anterior chamber, state of the angle, presence of anterior synechiae, and intraocular lens positioning can be determined preoperatively (see the article by Heur and Jeng, elsewhere in this issue). Intracorneal abnormalities can also be imaged. An arc scanner has recently been developed that uses a transducer path which follows the corneal curvature, allowing imaging of the entire cornea in one sweep.24 This instrumentation has allowed construction of three-dimensional depth maps of corneal thickness, epithelial thickness, and the depth of intracorneal incisions. This instrumentation is helpful in assessing the results and complications of refractive surgery. Ultrasound biomicroscopy is also useful in scleritis,25 allowing differentiation between extrascleral and intrascleral disease and assessment of the degree of scleral thinning (see the article by Ventura and colleagues, elsewhere in this issue).
Intraocular Lens Complications Ultrasound biomicroscopy can easily assess the position of intraocular lens haptics. This information is useful in assessing malpositioned lenses,26 assessing the source of intraocular bleeding, and determining haptic freedom if removal or repositioning is required (see the article by Heur and Jeng, elsewhere in this issue).
Trauma Ultrasound biomicroscopy can image cyclodialysis clefts even when the anterior chamber is shallow and the cyclodialysis cleft is not obvious with gonioscopy (see the article by Heur and Jeng, elsewhere in this issue).27 There is always 360 degrees of supraciliary fluid present in these cases. The region of the cleft is usually obvious from the displacement of the iris root from the scleral spur. Other causes of hypotony in which ultrasound biomicroscopy can provide useful information include occult wound leaks and ciliary body membranes. In other trauma problems, ultrasound biomicroscopy can image the state of the anterior chamber under traumatic opacities28 and detect small foreign bodies that are difficult to image using conventional techniques.29
Fig. 5. Iris tumor. Tumor thickness (arrow) can be measured.
lesions and imaging canalicular conditions.30 Conjunctival tumors can be assessed for underlying scleral integrity and intraocular involvement.
Anterior Segment Tumors Ultrasound biomicroscopy is an important adjunct in the management of anterior segment tumors.31–36 It provides a clear image of even the smallest anterior segment lesions. The ability to measure these lesions accurately adds the dimension of depth to criteria for demonstrating growth. Generally, a radial cross-section image is obtained through the thickest part of the tumor as determined by careful scanning (Figs. 5 and 6). This imaged is stored. The tumor is measured on the B-scan by placing electronic calipers gating the thickest part of the lesion. This method is reproducible and allows accurate serial measurements. The ability to determine the underlying structure of the tumor allows improved classification and the ability to determine ciliary body involvement.
Conjunctival and Adnexal Disease Ultrasound biomicroscopy can provide valuable information in the differential diagnoses of tumors, judging the depth of conjunctival and limbal
Fig. 6. Ciliary body tumor thickness can be measured from the inner sclera (arrow).
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Fig.7. (A) Clinical appearance of a pigmented lesion of the iris. (B) Ultrasound biomicroscopy shows a localized iris nevus (T). (From Pavlin CJ, Foster FS. Ultrasound biomicroscopy of the eye. New York: Springer Verlag; 1994. p. 101; with kind permission of Springer Science and Business Media.)
When observation is elected, lesions may be followed with greater precision. Where surgical intervention is indicated, the information gained is helpful in planning the approach. Iris tumors The presence of a typical morphologic appearance on ultrasound biomicroscopy may be helpful as a diagnostic sign. Several small, minimally elevated lesions involving the peripheral iris and clinically considered nevi have a similar appearance on ultrasound biomicroscopy (Fig. 7). They share the ultrasound biomicroscopic appearance of a small moderately thickened iris lesion not extending past the iris root. There is frequently a hypoechoic layer on the surface of these lesions, possibly indicating that the superficial layer is involved with the closely spaced cells of a surface plaque. It is difficult to be too specific as to histologic diagnosis with ultrasound, even with the added
detail presented by ultrasound biomicroscopy. Resolution is not at the level that can differentiate individual cells. Malignant melanomas of the iris can be variable in their clinical and ultrasonic presentation. Ultrasound biomicroscopy can be helpful in a number of ways. Internal reflectivity varies considerably depending on the degree of vascularity and the patterns of internal cellular structure. Some melanomas show a linear internal pattern, others show a uniform reflectivity, while others show a large degree of internal vascularity. Ciliary body tumors One of the major assets of ultrasound biomicroscopy is the ability to differentiate a peripheral localized iris lesion from a ciliary body tumor that involves the iris (Fig. 8). These lesions can look very similar clinically as can be appreciated in Figs. 7A and 8A. Ciliary body tumors can be easily assessed, although large tumors (>4 mm in depth) cannot be
Fig. 8. (A) Clinical appearance of a pigmented iris tumor. (B) Ultrasound biomicroscopy shows a ciliary body melanoma (T) with iris involvement. (From Pavlin CJ, Foster FS. Ultrasound biomicroscopy of the eye. New York: Springer Verlag; 1994. p. 101; with kind permission of Springer Science and Business Media.)
Ultrasound Biomicroscopy
Fig. 9. (A) Pigmented lesion on the sclera. (B) Ultrasound biomicroscopy shows that this is extrascleral extension (arrow) of choroidal tumor (T). (From Pavlin CJ, Foster FS. Ultrasound biomicroscopy of the eye. New York: Springer Verlag; 1994. p. 135; with kind permission of Springer Science and Business Media.)
Fig.10. (A) Clinical appearance of a tumor involving the cornea. (B) Ultrasound biomicroscopy shows that the tumor (T) is superficial and that Bowman’s membrane is intact over the cornea (C). (From Pavlin CJ, Foster FS. High Resolution Ultrasound. In: Krachmer JH, Mannis MJ, Holland EJ, editors. The Cornea. Mosby-Year book Inc.: St. Louis; 2004; with permission.)
Fig.11. (A) Clinical appearance of a tumor involving the cornea. (B) Ultrasound biomicroscopy shows deep involvement of all corneal layers (T). (From Pavlin CJ, Foster FS. High Resolution Ultrasound. In: Krachmer JH, Mannis MJ, Holland EJ, editors. The Cornea. Mosby-Year book Inc.: St. Louis; 2004; with permission.)
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Pavlin et al tumor. Both of the lesions can be imaged simultaneously with ultrasound biomicroscopy. Frequently, the transscleral connection is imaged.37
Fig. 12. Iridociliary cyst (arrow) under the iris.
completely imaged because of sound attenuation. Small lesions that cannot be detected by conventional ultrasound can be defined by ultrasound biomicroscopy. Larger ciliary body lesions are detectable by conventional ultrasound, but ultrasound biomicroscopy shows improved internal detail of the superficial part of the tumor and frequently allows a more precise localization of the posterior and lateral boundaries. This information is important if iridocyclectomy is considered as a possible treatment. The lateral extension of the tumor can be clearly defined, which can be important in the diagnosis of ring melanoma. These patients frequently present with hyperchromic glaucoma with delayed diagnosis. Ultrasound biomicroscopy is the best method of making the diagnosis in these cases. Extrascleral extension of intraocular tumors In cases of extrascleral extension, the relationship of the tumor to the extrascleral component can be defined (Fig. 9). The extrascleral component generally is located just above the internal ocular
Corneal involvement Tumors that involve the cornea can present difficulty in determining the depth of corneal involvement. Ultrasound biomicroscopy can generally determine the thickness of the tumor and which corneal layers are involved (Figs. 10 and 11).38 This information can have a direct bearing on the type of treatment required. Tumors that are above Bowman’s membrane can generally be surgically removed, leaving the cornea intact. Deeper involvement may require a radiotherapeutic approach to preserve the cornea. Cysts Cysts are clearly imaged by ultrasound biomicroscopy.39,40 The usual clinical presentation of an iridociliary cyst is an elevation of the peripheral iris without iris involvement. The typical ultrasound biomicroscopic appearance of a thin-walled cyst with no internal reflectivity is diagnostic and essentially eliminates any question as to whether a lesion is a cyst or solid tumor (Fig. 12). If the iris is not involved, a cyst would be the most common clinical diagnoses. Occasionally, a ciliary body tumor with an extension under the iris can have this same presentation. Small cysts are also found occasionally as an isolated finding on examination for some other clinical indication or in association with solid lesions of the iris or ciliary body. Peripheral choroidal tumors The anterior aspect of peripherally located choroidal tumors can be imaged by ultrasound biomicroscopy.41 Although it is often impossible to measure these tumors through their greatest thickness, valuable information can be gained
Fig.13. (A) Histology of a choroidal tumor (T) stripping the ciliary body (cb) from the sclera (S), producing a small fluid space (arrow). (B) Ultrasound biomicroscopy image of same tumor showing these features.
Ultrasound Biomicroscopy regarding the anterior extent of the lesion and the involvement of anterior segment structures (Fig. 13). This information is particularly important if radioactive plaque treatment is contemplated, because it provides a guide for placement of the anterior margin of the plaque. This information is also helpful if a surgical approach is taken such as iridocyclectomy. Imaging the internal structure of the anterior aspect of the tumor can also provide helpful differential diagnostic information.
FUTURE DIRECTIONS Ultrasound biomicroscopy provides images in living eyes without affecting the internal relationships of the structures imaged and has proven valuable in clinical practice and research. New methods of using high-frequency ultrasound are in development, including three-dimensional imaging, Doppler42 imaging, and the use of contrast agents. These developments should extend the clinical applications of this technique.
ACKNOWLEDGMENTS The authors are grateful for the contribution of Michael Sherar, Brian Starkoski, and Kasia Harasiewicz in the development of this imaging system.
REFERENCES 1. Pavlin CJ, Sherar MD, Foster FS. Subsurface ultrasound microscopic imaging of the intact eye. Ophthalmology 1990;97:244–50. 2. Pavlin CJ, Harasiewicz K, Sherar MD, et al. Clinical use of ultrasound biomicroscopy. Ophthalmology 1991;98:287–95. 3. Pavlin CJ, Foster FS. Ultrasound biomicroscopy of the eye. New York: Springer Verlag; 1994. 4. Pavlin CJ, Foster FS. Ultrasound biomicroscopy: high-frequency ultrasound imaging of the eye at microscopic resolution. Radiol Clin North Am 1998; 36:1047–58. 5. Pavlin CJ, Foster FS. Ultrasound biomicroscopy of the eye. In: Byrne SF, Green RL, editors. Ultrasound of the eye and orbit. St Louis (MO): Mosby; 2002. p. 223–35. 6. Pavlin CJ, Harasiewicz K, Foster FS. Ultrasound biomicroscopy of anterior segment structures in normal and glaucomatous eyes. Am J Ophthalmol 1992; 113:381–9. 7. Tello C, Liebmann J, Potash SD, et al. Measurement of ultrasound biomicroscopy images: intraobserver and interobserver reliability. Invest Ophthalmol Vis Sci 1994;35:3549–52. 8. Pavlin CJ, Ritch R, Foster FS. Ultrasound biomicroscopy in plateau iris syndrome. Am J Ophthalmol 1992;113:390–5.
9. Pavlin CJ, Foster FS. Plateau iris syndrome: changes in angle opening associated with dark, light, and pilocarpine administration. Am J Ophthalmol 1999; 128:288–91. 10. Woo EK, Pavlin CJ, Slomovic A, et al. Ultrasound biomicroscopic quantitative analysis of light-dark changes associated with pupillary block. Am J Ophthalmol 1999;127:43–7. 11. Pavlin CJ, Harasiewicz K, Foster FS. An ultrasound biomicroscopic dark-room provocative test. Ophthalmic Surg 1995;26:253–5. 12. Mandell MA, Pavlin CJ, Weisbrod DJ, et al. Anterior chamber depth in plateau iris syndrome and pupillary block as measured by ultrasound biomicroscopy. Am J Ophthalmol 2003;136:900–3. 13. Shukla S, Damji KF, Harasymowycz P, et al. Clinical features distinguishing angle closure from pseudoplateau versus plateau iris. Br J Ophthalmol 2008; 92:340–4. 14. Potash SD, Tello C, Liebmann J, et al. Ultrasound biomicroscopy in pigment dispersion syndrome. Ophthalmology 1994;101:332–9. 15. Pavlin CJ, Macken P, Trope GE, et al. Accommodation and iridotomy in the pigment dispersion syndrome. Ophthalmic Surg Lasers 1996;27:113–20. 16. Adam R, Pavlin CJ, Ulanski L. Ultrasound biomicroscopic analysis of iris profile changes with accommodation in pigmentary glaucoma and relationship to age. Am J Ophthalmol 2004;138:652–4. 17. Pavlin CJ, Easterbrook M, Harasiewicz K, et al. An ultrasound biomicroscopic analysis of angleclosure glaucoma secondary to ciliochoroidal effusion in IgA nephropathy. Am J Ophthalmol 1993;116:341–5. 18. Trope GE, Pavlin CJ, Bau A, et al. Malignant glaucoma: clinical and ultrasound biomicroscopic features. Ophthalmology 1994;101:1030–5. 19. Pavlin CJ, Rutnin SS, Devenyi R, et al. Supraciliary effusions and ciliary body thickening after scleral buckling procedures. Ophthalmology 1997;104: 433–8. 20. Liebmann JM, Weinreb RN, Ritch R. Angle-closure glaucoma associated with occult annular ciliary body detachment. Arch Ophthalmol 1998;116: 731–5. 21. Yamamoto T, Sakuma T, Kitazawa Y. An ultrasound biomicroscopic study of filtering blebs after mitomycin C trabeculectomy. Ophthalmology 1995;102: 1770–6. 22. Carrillo MM, Trope GE, Pavlin CJ, et al. Use of ultrasound biomicroscopy to diagnose Ahmed valve obstruction by iris. Can J Ophthalmol 2005;40: 499–501. 23. Milner MS, Liebmann JM, Tello C, et al. Highresolution ultrasound biomicroscopy of the anterior segment in patients with dense corneal scars. Ophthalmic Surg 1994;25:284–7.
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melanomas before and after brachytherapy. Ophthalmic Surg Lasers Imaging 2005;36:129–38. Conway RM, Chew T, Golchet P, et al. Ultrasound biomicroscopy: role in diagnosis and management in 130 consecutive patients evaluated for anterior segment tumours. Br J Ophthalmol 2005;89:950–5. Weisbrod DJ, Pavlin CJ, Emara K, et al. Small ciliary body tumors: ultrasound biomicroscopic assessment and follow-up of 42 patients. Am J Ophthalmol 2006;141:622–8. Vasquez L, Pavlin CJ, McGowan H, et al. Ring melanoma of the ciliary body: clinical and ultrasound biomicroscopic characteristics. Can J Ophthalmol 2008;43:229–33. Noble J, Quazi FA, Lakosha HK, et al. Extrascleral extension in association with cilio-choroidal melanoma: ultrasound biomicroscopy with histopathological correlation. Can J Ophthalmol 2005;40:616–8. Pavlin CJ, Foster FS. Ultrasound biomicroscopy of the cornea. In: Krachmer JH, Mannis MJ, Holland EJ, editors. The cornea. St Louis (MO): Mosby-Year Book; 1996. p. 351–9. Augsburger JJ, Affel LL, Benarosh DA. Ultrasound biomicroscopy of cystic lesions of the iris and ciliary body. Trans Am Ophthalmol Soc 1996;94:259–71. Fine L, Pavlin CJ. Primary iridociliary cysts: a report on 210 cases. Can J Ophthalmol 1999;34:325–9. Maberley DA, Pavlin CJ, McGowan HD, et al. Ultrasound biomicroscopic imaging of the anterior aspect of peripheral choroidal melanomas. Am J Ophthalmol 1997;123:506–14. Pavlin CJ, Christopher DA, Burns PN, et al. Highfrequency Doppler ultrasound examination of blood flow in the anterior segment of the eye. Am J Ophthalmol 1998;126:597–600.
summarizes the theoretic basis for this technology and illustrates the clinical application of this tool in clinical ophthalmology and ophthalmic research.
THEORETIC CONSIDERATIONS AND DEVELOPMENT OF THE ULTRASOUND BIOMICROSCOPE Mechanical waves and vibrations occur over a wide range of frequencies called the acoustic spectrum. This spectrum extends from the audible range (10 to 20,000 Hz), with which we are all familiar, to the range of phonons (>1012 (10 to the 12th power) Hz) which comprise the vibrational states of matter. This article considers the development and application of ultrasound imaging systems that use very high frequency ultrasound in the range of 20 to 100 MHz, which provides subsurface detail with resolution approaching that of optical microscopy.
Resolution The limits in current clinical imaging have been set as a result of the need to provide the maximum resolution consistent with the need for the ultrasound beam to penetrate the globe of the eye and orbit. In an ultrasound imaging system, the lateral resolution can be related via diffraction theory to the full width of the ultrasound beam at half
a Ophthalmology Department, Mt Sinai Hospital, Suite 410, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada b Department of Ocular Oncology, Princess Margaret Hospital, Toronto, Ontario M5G 2M9, Canada c Department of Medical Biophysics, University of Toronto, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario M5G 2M9, Canada * Corresponding author. Mt Sinai Hospital, Ophthalmology, Suite 410, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada. E-mail address: [email protected] (C.J. Pavlin).
Ultrasound Clin 3 (2008) 185–194 doi:10.1016/j.cult.2008.04.001 1556-858X/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved.
ultrasound.theclinics.com
Ultrasound is an indispensable tool in medical imaging and has an important role in ophthalmologic diagnoses. Conventional B-scan examinations produce two-dimensional cross-sectional views of the eye and orbit. This method of imaging is the most important examination technique for intraocular lesions, particularly in the presence of anterior segment opacities; however, there are limitations to conventional ultrasound. In our attempts to gain a greater understanding of the mechanisms of ocular disease, we have a never ending need for higher resolution. In the same way that optical microscopy has allowed improved understanding of basic processes, improved imaging resolution allows us to see and understand disease mechanisms that were not previously apparent. The use of high frequencies in the 20 to 100 MHz range for ocular imaging has greatly improved the resolution of ocular ultrasound. The basic physics and techniques of using higher frequency ultrasound to image living structures were developed in the laboratories of Stuart Foster at the University of Toronto. The authors subsequently applied these techniques to ocular imaging and named this process ultrasound biomicroscopy1–5, that is, the imaging of living structures at microscopic resolution. A broad clinical experience in normal patients and ocular disease has been gained over the years since its development. This article
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Pavlin et al maximum amplitude (FWHM) and is given by the equation: FWHM 5 cf=ðy lÞ 5 l ðf - numberÞ where c is the speed of sound, f is the focal length of the transducer, u is the frequency of ultrasound, d is the diameter of the focused transducer, l is the wave length, and f-number is the ratio of the focal length to the diameter of the transducer. It is evident from the equation that high resolution can simply be achieved by selecting the appropriate frequency. For example, if one desires 60 mm resolution, an operating frequency of 60 MHz and an f-number of 2 could be chosen. This resolution is approximately ten times that obtained using conventional clinical instrumentation. The penalty to be paid for this increase in resolution is loss of penetration. All human tissues exhibit ultrasound attenuation coefficients that increase with frequency. If we assume an attenuation coefficient of 0.5 dB/mm MHz, which is consistent with typical soft tissues, the maximum penetration that could be achieved for a 10 MHz system is approximately 50 mm for an 80 dB dynamic range. For a 60 MHz system, penetration is only 5 mm, which reinforces the need to optimize transducer sensitivity and performance in systems development of ultrasound biomicroscopy.
CLINICAL USE OF ULTRASOUND BIOMICROSCOPY Technique The technique of eye examination using ultrasound biomicroscopy is similar to conventional B-scan examination of the anterior segment. A fluid immersion technique is required to provide an adequate standoff from the structures being examined. This standoff is necessary to avoid distortion of the image close to the transducer and to prevent contact of the transducer and the eye. The authors have designed a series of eye cups that hold the eyelids open and allow more rapid patient preparation. These eye cups resemble those used in conventional ultrasound biometry, with a lip that slides under the eyelids and holds the cup in place. They differ from biometry eye cups in being shallower and having a distinct flair, which allows a good view of precisely where the scanning head is being placed. Fig. 1 shows an examination being performed with one of these eye cups. One percent methyl cellulose is an excellent coupling medium with sufficient viscosity to prevent fluid loss during examination. Saline can also be used. Some ultrasound biomicroscope designs have a longer focal length necessitating a deeper cup. Air bubbles must be carefully avoided in the fluid and on the concave surface of the transducer. Unlike in conventional 10 MHz B-scanning, high-frequency transducers are frequently not covered by a membrane. Because the transducer
Transducers The development of high-frequency transducers has been central to the progress achieved in ultrasound biomicroscopy. The piezoelectric polymer polyvinylidene difluoride and co-polymer polyvinylidene difluoride/trifluoroethylene have been used for external imaging applications such as the eye. Such transducers produce short, wide bandwidth pulses with good sensitivity. The highest resolution, defined as FWHM in the previous equation, is only achieved at the focus. The depth of field (DOF), which is defined as the range of depth over which the beam remains well focused, must also be considered. In general, the DOF increases with the square of the f-number. An f-number ranging from 2 to 4 represents a good compromise between DOF and resolution. Typical ultrasound biomicroscopy transducers have an f-number of 2.0 to 3.0. From the previous discussion, it is clear that the choice of transducer parameters will have a significant impact on image quality; therefore, it is necessary to optimize transducer characteristics for each application to obtain the best compromise for resolution, contrast, and DOF.
Fig. 1. An ultrasound biomicroscopic examination performed using a small eye cup.
Ultrasound Biomicroscopy is moving, contact with the eye and resulting corneal abrasion must be carefully avoided. The presence of an articulated arm is helpful in improving control of the scanning head. Careful attention must be paid to the screen image to prevent the scanning head from getting too close to the eye. In the authors’ practice, contact with the eye has been an extremely rare occurrence. Various designs have also incorporated a fluid-filled membrane over the transducer with moderate attenuation of the signal. Any part of the eye that can be approached directly over the surface can be examined. The cornea and anterior segment structures are easily examined in any meridian. The conjunctiva, underlying sclera, and peripheral retina can be examined by rotating the eye as far as possible away from the region being examined. This positioning allows examination past the muscle insertions with a somewhat greater range temporally because of anatomic considerations. Any adnexal structures that can have their surfaces exposed can be examined. Skin penetration is not as good as that through conjunctiva because of attenuation by keratinized epithelium. Examination of structures such as the posterior pole of the eye is not possible at the present time.
Measuring Ocular Structures Ultrasound biomicroscopy expands the ability to accurately measure ocular structures. The improved measurement accuracy of ultrasound biomicroscopy has an axial resolution five to ten times that of conventional 10 MHz ultrasound. The authors perform measurements on the screen during examination using electronic calipers. Stored images can be transferred to a computer via an image capture board and measured using imaging software. Measuring a structure accurately with ultrasound requires knowledge of the speed of sound in the structure being examined. Little is known of the true speed of sound in the structures that are capable of being measured, particularly at these frequencies. The authors have used a speed of sound of 1540 m/s to make the majority of measurements. This speed is used in conventional ultrasound scanning to measure distances in most tissue. A speed of 1640 m/s is generally used for the cornea and has been used for sclera as well, which is similar in structure. Conventional ultrasound is capable of measuring relatively large distances such as anterior chamber depth. Ultrasound biomicroscopy increases the measurement accuracy of such structures because the shorter wavelength allows
a finer positioning of end points, and the exact measurement position can be defined more precisely.6,7 Ocular structures such as the ciliary body, sclera, and iris cannot be measured by other techniques because of inadequate resolution and the inability to differentiate these structures from adjacent tissue. Ultrasound biomicroscopy allows clarification of tissue borders and accurate measurement.
Normal Ocular Structures Anterior chamber Anterior chamber depth is easily measured using ultrasound biomicroscopy (Fig. 2). Measuring the axial distance from the internal corneal surface to the lens surface is facilitated by the ease of distinguishing the iris from the lens surface. This differentiation can be difficult in eyes with small pupils using conventional ultrasound. Measurement of anterior chamber depth is not confined to the axial position but can be taken from any point on the endothelial surface to either the iris or lens surface, providing an improved ability to define the profile of the entire anterior chamber. The cornea All corneal layers can be differentiated in a cross section (Fig. 3). The first highly reflective line is the surface of the corneal epithelium. The epithelium can be differentiated from Bowman’s membrane, which forms a highly reflective line just below this. The distance between these two lines is the epithelial thickness. The corneal stroma reveals a low internal reflectivity that is lower than that found in the more irregular collagen distribution of the sclera. This difference allows definition of the corneoscleral junction.
Fig. 2. Ultrasound biomicroscopic view of anterior chamber. Arrows, anterior chamber depth measurement; I, iris.
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Pavlin et al The iris The iris normally shows variations in thickness. Histologic studies show that it is generally thinnest at the iris root and thickest near the pupillary margin. In addition, there are variations in thickness depending on the presence of crypts and the state of dilation or constriction of the pupil. The iris epithelium forms a constant highly reflective layer on the posterior iris surface. This highly reflective line defines the posterior iris border and can be useful when one is differentiating intra-iris lesions from lesions behind the iris.
Fig. 3. Ultrasound biomicroscopy of the cornea showing corneal layers.
The endothelium cannot be differentiated from Descemet’s membrane, but, together, they form a single highly reflective line at the posterior corneal margin. Greater definition of corneal structure can be achieved with higher frequency transducers. Anterior chamber angle region The corneoscleral junction and scleral spur can be distinguished consistently with ultrasound biomicroscopy (Fig. 4). These structures are important in maintaining orientation in the angle region. The scleral spur in a particularly useful landmark presenting a constant reference point for measurement in the angle region.
The ciliary body The ciliary body is well defined by ultrasound biomicroscopy. The ciliary processes can be variable in configuration and length. The appearance of the ciliary body will vary depending on whether one is passing through a process or a valley between processes. During the examination, one can produce either of these views as desired. The zonule The anterior zonule and lens surface can be consistently visualized in all eyes (see Fig. 4). The zonule inserts smoothly into the surface of the lens but is occasionally more irregular.
ULTRASOUND BIOMICROSCOPY IN OCULAR DISEASE Because ultrasound biomicroscopy is a nonspecific imaging tool, it is suitable for examination of a large range of diseases that fall within the penetration limits of this technique. It is particularly useful in conditions in which structural abnormalities are present, that is, conditions that produce rearrangement of normal anatomy.
Glaucoma
Fig. 4. Ultrasound biomicroscopy of the angle region. The scleral spur (arrow) is used as a stable landmark. The ciliary processes (cp), zonule (Z), lens (L), and iris (I) are clearly imaged. The highly reflective sclera (S) is distinguished from the lower reflective cornea (C). The angle is narrow in this patient with plateau iris syndrome.
Several types of glaucoma are caused by structural abnormalities of the anterior segment of the globe. This observation is particularly true of angle-closure glaucoma and infantile glaucoma. The ability of ultrasound biomicroscopy to image structural abnormalities on a much finer scale than has previously been possible provides a new quantitative tool for research and clinical assessment of glaucomatous disease. Ultrasound biomicroscopy has been helpful in elucidating the mechanisms of angle-closure glaucoma,8–13 pigmentary glaucoma,14–16 malignant glaucoma,17–20 and many other glaucoma entities. The method is also helpful in defining the mechanisms and results of various types of glaucoma surgery (see the article by Rockwood and colleagues, elsewhere in this issue).21,22
Ultrasound Biomicroscopy Corneal and Scleral Disease Ultrasound biomicroscopy can be helpful in patients with opaque corneas before transplantation.23 Anterior segment details such as the depth of the anterior chamber, state of the angle, presence of anterior synechiae, and intraocular lens positioning can be determined preoperatively (see the article by Heur and Jeng, elsewhere in this issue). Intracorneal abnormalities can also be imaged. An arc scanner has recently been developed that uses a transducer path which follows the corneal curvature, allowing imaging of the entire cornea in one sweep.24 This instrumentation has allowed construction of three-dimensional depth maps of corneal thickness, epithelial thickness, and the depth of intracorneal incisions. This instrumentation is helpful in assessing the results and complications of refractive surgery. Ultrasound biomicroscopy is also useful in scleritis,25 allowing differentiation between extrascleral and intrascleral disease and assessment of the degree of scleral thinning (see the article by Ventura and colleagues, elsewhere in this issue).
Intraocular Lens Complications Ultrasound biomicroscopy can easily assess the position of intraocular lens haptics. This information is useful in assessing malpositioned lenses,26 assessing the source of intraocular bleeding, and determining haptic freedom if removal or repositioning is required (see the article by Heur and Jeng, elsewhere in this issue).
Trauma Ultrasound biomicroscopy can image cyclodialysis clefts even when the anterior chamber is shallow and the cyclodialysis cleft is not obvious with gonioscopy (see the article by Heur and Jeng, elsewhere in this issue).27 There is always 360 degrees of supraciliary fluid present in these cases. The region of the cleft is usually obvious from the displacement of the iris root from the scleral spur. Other causes of hypotony in which ultrasound biomicroscopy can provide useful information include occult wound leaks and ciliary body membranes. In other trauma problems, ultrasound biomicroscopy can image the state of the anterior chamber under traumatic opacities28 and detect small foreign bodies that are difficult to image using conventional techniques.29
Fig. 5. Iris tumor. Tumor thickness (arrow) can be measured.
lesions and imaging canalicular conditions.30 Conjunctival tumors can be assessed for underlying scleral integrity and intraocular involvement.
Anterior Segment Tumors Ultrasound biomicroscopy is an important adjunct in the management of anterior segment tumors.31–36 It provides a clear image of even the smallest anterior segment lesions. The ability to measure these lesions accurately adds the dimension of depth to criteria for demonstrating growth. Generally, a radial cross-section image is obtained through the thickest part of the tumor as determined by careful scanning (Figs. 5 and 6). This imaged is stored. The tumor is measured on the B-scan by placing electronic calipers gating the thickest part of the lesion. This method is reproducible and allows accurate serial measurements. The ability to determine the underlying structure of the tumor allows improved classification and the ability to determine ciliary body involvement.
Conjunctival and Adnexal Disease Ultrasound biomicroscopy can provide valuable information in the differential diagnoses of tumors, judging the depth of conjunctival and limbal
Fig. 6. Ciliary body tumor thickness can be measured from the inner sclera (arrow).
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Fig.7. (A) Clinical appearance of a pigmented lesion of the iris. (B) Ultrasound biomicroscopy shows a localized iris nevus (T). (From Pavlin CJ, Foster FS. Ultrasound biomicroscopy of the eye. New York: Springer Verlag; 1994. p. 101; with kind permission of Springer Science and Business Media.)
When observation is elected, lesions may be followed with greater precision. Where surgical intervention is indicated, the information gained is helpful in planning the approach. Iris tumors The presence of a typical morphologic appearance on ultrasound biomicroscopy may be helpful as a diagnostic sign. Several small, minimally elevated lesions involving the peripheral iris and clinically considered nevi have a similar appearance on ultrasound biomicroscopy (Fig. 7). They share the ultrasound biomicroscopic appearance of a small moderately thickened iris lesion not extending past the iris root. There is frequently a hypoechoic layer on the surface of these lesions, possibly indicating that the superficial layer is involved with the closely spaced cells of a surface plaque. It is difficult to be too specific as to histologic diagnosis with ultrasound, even with the added
detail presented by ultrasound biomicroscopy. Resolution is not at the level that can differentiate individual cells. Malignant melanomas of the iris can be variable in their clinical and ultrasonic presentation. Ultrasound biomicroscopy can be helpful in a number of ways. Internal reflectivity varies considerably depending on the degree of vascularity and the patterns of internal cellular structure. Some melanomas show a linear internal pattern, others show a uniform reflectivity, while others show a large degree of internal vascularity. Ciliary body tumors One of the major assets of ultrasound biomicroscopy is the ability to differentiate a peripheral localized iris lesion from a ciliary body tumor that involves the iris (Fig. 8). These lesions can look very similar clinically as can be appreciated in Figs. 7A and 8A. Ciliary body tumors can be easily assessed, although large tumors (>4 mm in depth) cannot be
Fig. 8. (A) Clinical appearance of a pigmented iris tumor. (B) Ultrasound biomicroscopy shows a ciliary body melanoma (T) with iris involvement. (From Pavlin CJ, Foster FS. Ultrasound biomicroscopy of the eye. New York: Springer Verlag; 1994. p. 101; with kind permission of Springer Science and Business Media.)
Ultrasound Biomicroscopy
Fig. 9. (A) Pigmented lesion on the sclera. (B) Ultrasound biomicroscopy shows that this is extrascleral extension (arrow) of choroidal tumor (T). (From Pavlin CJ, Foster FS. Ultrasound biomicroscopy of the eye. New York: Springer Verlag; 1994. p. 135; with kind permission of Springer Science and Business Media.)
Fig.10. (A) Clinical appearance of a tumor involving the cornea. (B) Ultrasound biomicroscopy shows that the tumor (T) is superficial and that Bowman’s membrane is intact over the cornea (C). (From Pavlin CJ, Foster FS. High Resolution Ultrasound. In: Krachmer JH, Mannis MJ, Holland EJ, editors. The Cornea. Mosby-Year book Inc.: St. Louis; 2004; with permission.)
Fig.11. (A) Clinical appearance of a tumor involving the cornea. (B) Ultrasound biomicroscopy shows deep involvement of all corneal layers (T). (From Pavlin CJ, Foster FS. High Resolution Ultrasound. In: Krachmer JH, Mannis MJ, Holland EJ, editors. The Cornea. Mosby-Year book Inc.: St. Louis; 2004; with permission.)
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Fig. 12. Iridociliary cyst (arrow) under the iris.
completely imaged because of sound attenuation. Small lesions that cannot be detected by conventional ultrasound can be defined by ultrasound biomicroscopy. Larger ciliary body lesions are detectable by conventional ultrasound, but ultrasound biomicroscopy shows improved internal detail of the superficial part of the tumor and frequently allows a more precise localization of the posterior and lateral boundaries. This information is important if iridocyclectomy is considered as a possible treatment. The lateral extension of the tumor can be clearly defined, which can be important in the diagnosis of ring melanoma. These patients frequently present with hyperchromic glaucoma with delayed diagnosis. Ultrasound biomicroscopy is the best method of making the diagnosis in these cases. Extrascleral extension of intraocular tumors In cases of extrascleral extension, the relationship of the tumor to the extrascleral component can be defined (Fig. 9). The extrascleral component generally is located just above the internal ocular
Corneal involvement Tumors that involve the cornea can present difficulty in determining the depth of corneal involvement. Ultrasound biomicroscopy can generally determine the thickness of the tumor and which corneal layers are involved (Figs. 10 and 11).38 This information can have a direct bearing on the type of treatment required. Tumors that are above Bowman’s membrane can generally be surgically removed, leaving the cornea intact. Deeper involvement may require a radiotherapeutic approach to preserve the cornea. Cysts Cysts are clearly imaged by ultrasound biomicroscopy.39,40 The usual clinical presentation of an iridociliary cyst is an elevation of the peripheral iris without iris involvement. The typical ultrasound biomicroscopic appearance of a thin-walled cyst with no internal reflectivity is diagnostic and essentially eliminates any question as to whether a lesion is a cyst or solid tumor (Fig. 12). If the iris is not involved, a cyst would be the most common clinical diagnoses. Occasionally, a ciliary body tumor with an extension under the iris can have this same presentation. Small cysts are also found occasionally as an isolated finding on examination for some other clinical indication or in association with solid lesions of the iris or ciliary body. Peripheral choroidal tumors The anterior aspect of peripherally located choroidal tumors can be imaged by ultrasound biomicroscopy.41 Although it is often impossible to measure these tumors through their greatest thickness, valuable information can be gained
Fig.13. (A) Histology of a choroidal tumor (T) stripping the ciliary body (cb) from the sclera (S), producing a small fluid space (arrow). (B) Ultrasound biomicroscopy image of same tumor showing these features.
Ultrasound Biomicroscopy regarding the anterior extent of the lesion and the involvement of anterior segment structures (Fig. 13). This information is particularly important if radioactive plaque treatment is contemplated, because it provides a guide for placement of the anterior margin of the plaque. This information is also helpful if a surgical approach is taken such as iridocyclectomy. Imaging the internal structure of the anterior aspect of the tumor can also provide helpful differential diagnostic information.
FUTURE DIRECTIONS Ultrasound biomicroscopy provides images in living eyes without affecting the internal relationships of the structures imaged and has proven valuable in clinical practice and research. New methods of using high-frequency ultrasound are in development, including three-dimensional imaging, Doppler42 imaging, and the use of contrast agents. These developments should extend the clinical applications of this technique.
ACKNOWLEDGMENTS The authors are grateful for the contribution of Michael Sherar, Brian Starkoski, and Kasia Harasiewicz in the development of this imaging system.
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