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Is There a Role for High-Frequency Ultrasonography in ClinicalStaging of Retinopathy of Prematurity?

Danny H.-Kauffmann Jokl, MD, Ronald H. Silverman, PhD, Sheri L. Nemerofsky, MD, StevenA. Kane, MD, PhD, Michael F. Chiang, MD, Robert Lopez, MD, and Grace Lee, MDDepartment of Ophthalmology

Department of Pediatrics, Columbia University, College of Physicians and Surgeons, New York,New York.

Department of Ophthalmology, Weill Medical College of Cornell University, New York, New York.

AbstractPurpose— To compare 20-MHz ultrasonography with ophthalmoscopy in the staging ofretinopathy of prematurity (ROP).

Methods— We used a handheld 20-MHz ultrasound system to examine 38 eyes of 19 neonates whohad an indirect ophthalmoscopic examination (diagnosis masked) within 48 hours prior toultrasonography. Determination of ROP by indirect ophthalmoscopy was compared withindependent identification of ultrasonic features indicative of ROP stages.

Results— In masked cases, ultrasonography correctly identified 13 of 18 (72.2% sensitivity) eyeswith zone 2, stage 2 ROP or worse and 19 of 20 (95.0% specificity) normal eyes (zone 2, stage 1ROP or better) (chi-square, 18.4; P < .001).

Conclusion— In the neonatal nursery, a 20-MHz handheld ultrasound system may be an effectivescreening tool to initially identify ROP for further ophthalmoscopic evaluation and management.

IntroductionCurrently, the clinical detection of retinopathy of prematurity (ROP) is limited to indirectophthalmoscopy, a technique that requires a skilled and experienced examiner and has thepossibility of significant morbidity.1–3 More recent techniques using digital photography andtelemedicine4 and confocal scanning laser ophthalmoscopy5 have complemented indirectophthalmoscopy techniques and have warranted a fresh look at methods for screening ROP.6,7

We recently reported use of 10-MHz B-scan ultrasonography for the detection of ROP stagesand demonstrated that findings on ultrasonography were in agreement with those on clinicalophthalmoscopy to a high level of statistical confidence.8

We herein report our findings regarding the comparison of clinical ophthalmoscopy with B-scan ultrasonography using a 20-MHz probe that offers a higher resolution than previouslyavailable.

Address reprint requests to Danny H.-Kauffmann Jokl, MD, 1 Stone Place, Bronxville, NY 10708..Dr. Jokl is also from the Department of Ophthalmology, New York Medical College, New York, New York.The authors thank John Flynn, MD, for his helpful suggestions.Supported in part by the National Institutes of Health (grant EB00238), Research to Prevent Blindness, and Quantel Medical, Inc.

NIH Public AccessAuthor ManuscriptJ Pediatr Ophthalmol Strabismus. Author manuscript; available in PMC 2006 October 20.

Published in final edited form as:J Pediatr Ophthalmol Strabismus. 2006 ; 43(1): 31–35.

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MethodsThis study adhered to the tenets of the Declaration of Helsinki and was approved by theinstitutional review boards of the Columbia Presbyterian Medical Center, the Weill MedicalCollege of Cornell University, and New York Medical College. In each case, informed consentwas obtained from a parent.

We examined 19 neonates (38 eyes) with the diagnosis masked. Clinical diagnosis wasestablished by ophthalmoscopic examination. Three of the authors (SAK, RL, MFC) performedscreening dilated ophthalmoscopic evaluations using 0.5% cyclopentolate for pupillarymydriasis administered 1 hour prior to the examination. A lid speculum was used for retinalviewing. Indirect ophthalmoscopy with scleral depression was performed using a 25-D lens.Clinical diagnoses were made using the international classification.9

Ultrasound examination was performed crib side by one of the authors (RHS) in the neonatalfacility at Children’s Hospital, Columbia Presbyterian Medical Center, within 48 hours ofclinical examination. The ultrasound examination was performed without general, local, ortopical anesthesia, and without use of a lid speculum or pupil dilation. We used a Cinescan(Quantel Medical, Inc., Bozeman, MT) equipped with a 20-MHz mechanical B-scan sectorprobe configured for retinal imaging.

The probe was offset from the eye by placing it in a thin latex sheath filled with sterile normalsaline (Fig. 1). After one or two drops of methylcellulose were placed on the eyelid, the sheathwas placed in contact with the lid. Initially the transducer range was adjusted so as to place thefocal zone in the region of the posterior pole, allowing evaluation of this region for zone 1ROP. Zone 1 was defined ultrasonically as encompassing the posterior segment approximatelywithin a radius twice the distance from the optic nerve to the fovea. In order to visualize zone2, the probe within the water-filled sheath was oriented obliquely to the optic axis, both nasallyand temporally. The position of the probe within the sheath was adjusted to place the focalzone near the retina to obtain the best resolution and sensitivity.

The real-time ultrasound examination was stored on digital videotape, thus allowingvisualization and evaluation of the elliptical zone 2 even in the presence of eye movements.Each eye could be evaluated ultrasonically in approximately 3 minutes. Recorded ultrasounddata were carefully reviewed for the presence of diagnostically significant pathology andgraded accordingly. The review of the video images took no longer than 5 minutes per eye.The review took place without the ultrasound examiner being informed of the clinical stagedetermined during the prior indirect ophthalmoscopic examination by the retinologist.

Presence of the following ultrasonic features was considered significant: an acoustic reflex atthe periphery of the posterior pole suggestive of zone 1 ROP; an acoustic reflex suggestive ofa ridge in the region between the ciliary body and the equator (ultrasound zone 2, stage 2);elevation or layer separation in this anterior retinal ridge region (ultrasound zone 2, stage 3);retinal detachment (ultrasound zone 2, stage 4); and a closed-cone retinal detachment(ultrasound stage 5).

Ultrasound-derived classifications were crosstabulated against clinical classifications by amasked observer (GL). Sensitivity and specificity were determined along with statisticalsignificance using the chi-square statistic.

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J Pediatr Ophthalmol Strabismus. Author manuscript; available in PMC 2006 October 20.

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ResultsFigures 2 and 3 provide examples of the appearance of zone 2 in a normal eye and in an eyewith ROP, respectively. Figure 4 shows a series of images demonstrating progression of zone1 ROP.

The table provides a classification of eyes by stage of ROP as determined by clinicalophthalmoscopy and by independent ultrasonography.

Stages determined by ultrasonography were in agreement with stages determined byophthalmoscopy in 32 of 38 eyes, including 19 of 20 clinically negative cases (95.0%specificity) and 13 of 18 clinically positive cases (72.2% sensitivity). This distribution wasstatistically significant (chi-square, 18.4; P < .001). Among the six cases in whichultrasonography was not in agreement with clinical ophthalmoscopy, one case wasoverdiagnosed (ie, a ridge was thought to be present in an eye vascularized within zone 3). Infive cases, ultrasound findings were negative in the presence of zone 2, stage 2 (3 cases) andzone 2, stage 3 (2 cases).

DiscussionRecent reports have emphasized the need for more effective screening for ROP,1–14 citing thestress induced by the indirect ophthalmoscopy examination, specifically the cardiovascularand respiratory depression and pain induced by scleral depression, speculum placement, anduse of mydriatic drops.3,13,15 Confocal scanning laser ophthalmoscopy has been used in anattempt to alleviate this morbidity without the need for mydriasis. The longer wavelength oflight employed with this technique may be of use in imaging the autofluorescence offluorophores from the retina, but, to date, scanning laser ophthalmoscopy provides only scantinformation regarding disc contour and none regarding the retinal periphery, where thedetection of ROP is paramount.5

Telemedicine employing digital photography has been used to support screening for ROP.4,16–18 In 23 eyes, a sensitivity of 100% and a specificity of 96% were obtained in “referral-warranted” ROP, defined as zone 1 in the presence of plus disease and zone 2, stage 3.4 Thiscompares well with the gold standard for the clinical identification of the stages of ROP, namelyindirect ophthalmoscopy. Despite these encouraging findings, screening for ROP using currentdigital photographic techniques is cumbersome and requires pupillary dilatation and use of alid speculum,4,16 both known causes of significant morbidity.1,2

B-scan ultrasonography provides the potential for imaging and detecting the clinical stages ofROP, avoiding the morbidity associated with both clinical ophthalmoscopy and digitalphotography.8 Although it does not provide the superb resolution of ultrasoundbiomicroscopy19 (which requires the use of a water bath or scleral shell), this techniquecombines simplicity and accuracy in determining the clinical stages of ROP. The use of a latexsheath provides a gentle, aseptic technique and, similar to immersion ultrasonography,improved visualization of anterior structures without the systemic cardiovascular, respiratory,and pain manifestations that occur with techniques requiring pupillary mydriasis. 1,2

We report the use of contact B-scan ultrasonography with a 20-MHz probe, which offers aspecificity of 95% and a sensitivity of 72%, for detection of all stages of ROP. When ultrasoundresolution is further refined, we think that the sensitivity will improve. Higher ultrasoundrefresh rates (ie, the number of scans per second) will also improve our ability to detectpathology in neonates, in whom eye movement is often present. The speed and simplicity ofultrasonography allows for the screening of all at-risk neonates, thus permitting examinationof infants who might not have been screened because of the logistic demands created by the

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current, burdensome method of indirect ophthalmoscopy at a gestational age of 32 weeks orolder or a weight of 1,500 g or greater.6,7,10,14 Whereas the clinical ophthalmologicexamination remains the gold standard for the diagnosis of all stages of ROP, these findingssuggest that there may be a role for high-resolution B-scan ultrasonography as an effective firststep, free of morbidity, in the screening of neonates. Cases of suspected ROP detected byultrasound could then be referred to retinologists for verification and management.

In the case of posterior zone 2 or zone 1 disease with flat retinal neovascularization (Fig. 4),our observations of a tangential membrane presumably at the margins of surface retinalneovascularization suggest the intriguing possibility that ultrasonography may provide a meansfor monitoring this atypical form of ROP. This has therapeutic implications in that the patientdepicted in Figure 4 underwent follow-up with ultrasonography and ultimately developed atractional retinal detachment that required vitrectomy.

However, ultrasonography alone cannot determine the presence or absence of either thresholddisease or plus disease, both essential to the timing of initiation of laser treatment to theretina20; this must await future technology. Digital photographic analysis of retinal vesseltortuosity and its correlation with plus disease, as has recently been described,21 is a first stepin this direction.

We suggest the usefulness of 20-MHz B-scan ultrasonography as an initial screening techniqueto detect the early presence of ROP, obviating the need to use indirect ophthalmoscopy, withits attendant morbidity, as the sole initial modality to identify ROP. Evaluation by retinologistsusing conventional indirect ophthalmoscopy along with documentation of the ROP and thepresence or absence of threshold disease, plus disease, or both by digital photographic methodsor other technologies may then be employed.

References1. Laws DE, Morton C, Weindling M, Clark D. Systemic effects of screening for retinopathy of

prematurity. Br J Ophthalmol 1996;80:425–428. [PubMed: 8695564]2. Epley KD, Tychsen L, Lueder GT. The effect of an eyelid speculum on intraocular pressure

measurement in children. Am J Ophthalmol 2002;134:926–927. [PubMed: 12470773]3. Slevin M, Murphy JF, Daly L, O’Keefe M. Retinopathy of prematurity screening, stress related

responses, the role of nesting. Am J Ophthalmol 1997;81:762–764.4. Ells AL, Holmes JM, Astle WF, et al. Telemedicine approach to screening for severe retinopathy of

prematurity: a pilot study. Ophthalmology 2003;110:2113–2117. [PubMed: 14597517]5. Kelly JP, Weiss AH, Zhou Q, et al. Imaging a child’s fundus without dilation using a handheld confocal

scanning laser ophthalmoscope. Arch Ophthalmol 2003;121:391–396. [PubMed: 12617711]6. Brennan R, Gnanaraj L, Cottrell DG. Retinopathy of prematurity: I. Screening for threshold disease.

Eye 2003;17:183–188. [PubMed: 12640404]7. Fielder AR. Time for a fresh look at ROP screening. Eye 2003;17:117–118. [PubMed: 12640393]8. Jokl DH-K, Silverman RH, Springer AD, et al. Ultrasonic evaluation of retinopathy of prematurity. J

Pediatr Ophthalmol Strabismus 2004;41:345–350. [PubMed: 15609519]9. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for

retinopathy of prematurity: ophthalmological outcomes at 10 years. Arch Ophthalmol 2001;119:1110–1118. [PubMed: 11483076]

10. Larsson E, Holmstrom G. Screening for retinopathy of prematurity: evaluation and modification ofguidelines. Br J Ophthalmol 2002;86:1399–1402. [PubMed: 12446374]

11. Donahue SP. Retinopathy of prematurity. Br J Ophthalmol 2002;86:1071. [PubMed: 12234878]12. Holmstrom G. Ophthalmic screening and follow-up of prematurely born infants. Comprehensive

Ophthalmology Update 2002;3:229–236.

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13. Kumar H, Nainiwal S, Singha U, et al. Stress induced by screening for retinopathy of prematurity. JPediatr Ophthalmol Strabismus 2002;39:349–350. [PubMed: 12458847]

14. Saunders RA, Hutchinson AK. The future of screening for retinopathy of prematurity. J AAPOS2002;6:61–63. [PubMed: 11997799]

15. Rush R, Rush S, Nicolau J, et al. Systemic manifestations in response to mydriasis and physicalexamination during screening for retinopathy of prematurity. Retina 2004;24:242–245. [PubMed:15097885]

16. Hussein MAW, Coats DK, Paysse EA. Use of the RetCam 120 for fundus evaluation in uncooperativechildren. Am J Ophthalmol 2004;137:354–355. [PubMed: 14962432]

17. Roth DB, Morales D, Feuer WJ, et al. Screening for retinopathy of prematurity employing the RetCam120: sensitivity and specificity. Arch Ophthalmol 2001;119:268–272. [PubMed: 11176990]

18. Schwartz SD, Harrison SA, Ferrone PJ, Trese MT. Telemedical evaluation and management ofretinopathy of prematurity using a fiberoptic digital fundus camera. Ophthalmology 2000;107:25–28. [PubMed: 10647714]

19. Brent MH, Pavlin CJ, Kelly EN. Ultrasound biomicroscopy in the screening of retinopathy ofprematurity. Am J Ophthalmol 2002;133:284–285. [PubMed: 11812444]

20. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy forretinopathy of prematurity. One-year outcome: structure and function. Arch Ophthalmol1990;108:1408–1416. [PubMed: 2222274]

21. Swanson C, Cocker KD, Parker KH, et al. Semiautomated computer analysis of vessel growth inpreterm infants without and with ROP. Br J Ophthalmol 2003;87:1474–1477. [PubMed: 14660456]

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Figure 1.Crib-side examination for retinopathy of prematurity.

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Figure 2.Appearance of the normal anterior segment. L = lens posterior; CB = ciliary body; and C =cornea.

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Figure 3.Ridges (arrows) in zone 2, stage 2 retinopathy of prematurity typically appear as shallowelevations, often hyperreflective, seen in the region anterior to the equator. Examples in twoeyes are shown above.

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Figure 4.Progression of zone 1, stage 2 retinopathy of prematurity (ROP) during a 5-week period, andaccompanying diagrammatic interpretations. (a) Zone 1 ROP with a posterior tangentialmembrane (long arrow). The posterior lens is indicated by a short arrow. (b) Additional anteriorcyclitic membrane (arrow) 4 weeks later. Diffuse vitreous hemorrhage is present and retinaltraction is suggested, as indicated in the diagram. (c) At 5 weeks, further hemorrhagicorganization of membranes can be seen. A funnelshaped total retinal detachment created bycentripetal traction by both the posterior zone 1 tangential membrane and the anterior cycliticmembrane (arrow) is evident. Vitreous hemorrhage is present on both membranes, as issubretinal hemorrhage, indicated by the gray area in the adjacent diagram. These findings werecorroborated by subsequent vitrectomy.

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TableClassification of the Neonates by Zone and Stage of Retinopathy of Prematurity and Corresponding IndependentUltrasound Diagnoses

Ophthalmoscopy Findings (N= 38)

Ultrasonography andOphthalmoscopy in Agreement

(N = 32)

Ultrasonography andOphthalmoscopy Not in

Agreement (N = 6)

No ROP 20 19 1Zone 2, stage 2 ROP 8 5 3*Zone 2, stage 3 ROP 10 8 2*

ROP = retinopathy of prematurity.

*Ultrasound findings were negative.


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