Fig. 18.2 Retinal image taken with a wide-angle camera

There is good evidence to suggest that this device can be operated by a non-ophthalmologist, acquiring digital images that enable accurate diagnosis. Scott et al. [17] carried out a prospective study to evaluate the intra-physician agreement between ophthalmoscopic examination and image-based telemedical interpretation for retinopathy of prematurity (ROP) diagnosis, when performed by the same expert physician grader. Sixty-seven consecutive premature infants who underwent ROP examination at a tertiary hospital whose parents consented for participation were recruited in this study. Infants underwent standard dilated ophthalmoscopy by one of two paediatric ophthalmologists, and this was followed by retinal imaging with a wide-angle fundus camera by a trained neonatal nurse. Study examinations were performed at 31–33 weeks corrected age (CA) and/or 35–37 weeks CA. Images were then uploaded to a web-based telemedicine system. After a 4- to 12-month period, telemedical interpretations were performed in which each physician graded images from infants upon whom he had initially performed ophthalmoscopic examinations. Diagnoses were classified into four categories: no ROP, mild ROP, type 2 pre-thresh- old ROP, and treatment-requiring ROP. Absolute intra-physician agreement and kappa statistic between ophthalmoscopic examination and telemedical interpretation were calculated by each eye. The investigators found that intra-physician

agreement between ophthalmoscopic examination and telemedical interpretation was 86.3%. The kappa statistic for intra-physician agreement between examinations ranged from 0.657 (substantial agreement) for diagnosis of treatmentrequiring ROP to 0.854 (near-perfect agreement) for diagnosis of mild or worse ROP. Among 206 eye examinations (103 infant examinations), there were 28 (13.6%) intra-physician discrepancies in diagnosis, 8 of which resulted from uncertainty about presence of zone 1 disease and 4 from uncertainty about presence of plus disease. The investigators concluded that intra-physician agreement between ophthalmoscopic examination and telemedical interpretation for ROP was very high. Neither examination method of assessment appeared to have a tendency to overor underdiagnose ROP.

18.4Effect of Different Examination Techniques on Stress

Do examination techniques for ROP screening of babies have an impact on pain and stress? Muherjee et al. [11] carried out a study on a larger cohort of preterm infants and compared the impact of ROP screening examination between a digital retinal camera and conventional binocular indirect ophthalmoscope (BIO) using cardiorespiratory indices as a measure of distress. The investigators did not use the PIPP score. Eightysix preterm infants with a birth weight of £1,500 g or gestational age of £32 weeks and undergoing ROP screening were included. Heart rate (HR), oxygen saturation, respiratory rate (RR), and mean blood pressure (BP) were recorded before, during, and 1 h after examination. The increase in HR and RR was significantly higher in the indirect ophthalmoscope group than in the digital camera group. There was a significant increase in HR and mean BP during examination in both groups. The investigators concluded that screening for ROP with a digital retinal camera was associated with a significantly lower stressrelated response than with a conventional indirect ophthalmoscope.

18.5Future of Retinal Imaging in Babies

Non-contact retinal camera could make the eye examination less stressful for babies. It would more likely be tolerated by these fragile infants. The studies which have used such device are limited. Devices such as Nidek NM-200D (Nidek, Inc., Aichi, Japan) and OIS EyeScan (OISI, USA) could be potentially be used for ROP assessment. Currently, there are no studies comparing this device with contact cameras (such as RetCam) or indirect examination. The limitation of the currently available non-contact camera is that it has a narrower angle for viewing the retina as accurate assessment of ROP involves the peripheries of the retina. A few studies have been done using non-contact cameras for the purpose of measuring retinal vessel diameters with good accuracy [18, 19]. The limitation with these devices could be overcome by using lens to increase the angle of view.

References

1. Vohr BR, Allen M (2005) Extreme prematurity – the continuing dilemma. N Engl J Med 352:71–72

2. Steinkuller PG, Du L, Gilbert C, Foster A, Collins ML, Coats DK (1999) Childhood blindness. J AAPOS 3:26–32

3. Beck S, Wojdyla D, Say L et al (2010) The worldwide incidence of preterm birth: a systematic review of maternal mortality and morbidity. Bull World Health Organ 88:31–38

4. Leversen KT, Sommerfelt K, Ronnestad A et al (2010) Predicting neurosensory disabilities at two years of age in a national cohort of extremely premature infants. Early Hum Dev 86:581–586

5. Chen Y, Li XX, Yin H et al (2008) Risk factors for retinopathy of prematurity in six neonatal intensive care units in Beijing, China. Br J Ophthalmol 92:326–330

6. Di Fiore JM, Bloom JN, Orge F et al (2010) A higher incidence of intermittent hypoxemic episodes is associated with severe retinopathy of prematurity. J Pediatr 157:69–73

7. Rahi JS, Cable N (2003) Severe visual impairment and blindness in children in the UK. Lancet 362: 1359–1365

8. Section on O, American Academy of P, American Academy of O, American Association for Pediatric Ophthalmology and S (2006) Screening examination of premature infants for retinopathy of prematurity. Pediatrics 117:572–576

9. Laws DE, Morton C, Weindling M, Clark D (1996) Systemic effects of screening for retinopathy of prematurity. Br J Ophthalmol 80:425–428

10. Grabska J, Walden P, Lerer T et al (2005) Can oral sucrose reduce the pain and distress associated with screening for retinopathy of prematurity? J Perinatol 25:33–35

11.Mukherjee AN, Watts P, Al-Madfai H, Manoj B, Roberts D (2006) Impact of retinopathy of prematurity screening examination on cardiorespiratory indices: a comparison of indirect ophthalmoscopy and retcam imaging. Ophthalmology 113:1547–1552

12.Dhaliwal CA, Wright E, McIntosh N, Dhaliwal K, Fleck BW (2010) Pain in neonates during screening for retinopathy of prematurity using binocular indirect ophthalmoscopy and wide-field digital retinal imaging: a randomised comparison. Arch Dis Child Fetal Neonatal Ed 95:F146–F148

13.American Academy of P, Committee on Fetus and Newborn and Section on S, Section on Anesthesiology

and Pain M, Canadian Paediatric S, Fetus and Newborn C (2006) Prevention and management of pain in the neonate: an update. Pediatrics 118:2231–2241

14. Stevens B, Johnston C, Taddio A, Gibbins S, Yamada J (2010) The premature infant pain profile: evaluation 13 years after development. Clin J Pain 26:813–830

15. Stevens B, Johnston C, Petryshen P, Taddio A (1996) Premature infant pain profile: development and initial validation. Clin J Pain 12:13–22

16. Ballantyne M, Stevens B, McAllister M, Dionne K, Jack A (1999) Validation of the premature infant pain profile in the clinical setting. Clin J Pain 15:297–303 17. Scott KE, Kim DY, Wang L et al (2008) Telemedical diagnosis of retinopathy of prematurity intraphysician agreement between ophthalmoscopic examination and image-based interpretation. Ophthalmology

115:1222–1228.e3

18.Johnson KS, Mills MD, Karp KA, Grunwald JE (2007) Semiautomated analysis of retinal vessel diam-

eter in retinopathy of prematurity patients with and without plus disease. Am J Ophthalmol 143:723–725 19. Grunwald L, Mills MD, Johnson KS et al (2009) The rate of retinal vessel dilation in severe retinopathy of prematurity requiring treatment. Am J Ophthalmol

147:1086–1091, 1091.e1–2

19.1Introduction

Retinoblastoma is a malignant pediatric eye tumor that is highly curable if the disease remains intraocular; its cure rate and sight preservation rate exceeds 90% in developed countries in part because of early diagnosis and access to adequate treatment. Retinoblastoma accounts for approximately 3% of all pediatric malignancies, and approximately two-thirds of patients present with unilateral disease, while one-third have bilateral involvement. Patients with unilateral disease are usually treated with enucleation, while few also receive adjuvant chemotherapy or radiation therapy. Management of bilateral patients is much more challenging since eye salvage and vision preservation must also be considered. The management of these cases includes chemotherapy and careful, intensive use of focal treatments. Such a regimen therefore requires the cooperation of a highly specialized, multidisciplinary team.

B.G. Haik, M.D., FACS Department of Ophthalmology,

College of Medicine, UT Health Science Center, UT Hamilton Eye Institute, 930 Madison Avenue, Suite #200, Memphis, TN 38103, USA

Division of Ophthalmology, Department of Surgery, St. Jude Children’s Research Hospital

e-mail: bhaik@uthsc.edu

In developing countries, however, cure rates are estimated to be between 30% and 50% and loss of sight of the affected eye is about 90%, primarily because of: (1) delays in diagnosis, resulting in advanced intraocular and extraocular disease (in Central America, approximately 50–60% of patients present with extraocular disease, compared with less than 5% in the United States or Europe) and (2) deficiencies in treatment, as defined by the lack of specialized care and centers of excellence, suboptimal training in ocular oncology, and deficiencies in technology for diagnosing, monitoring, and treating retinoblastoma.

Early diagnosis, which is paramount to improving survival and preservation of vision in children with retinoblastoma, requires that parents and primary care providers recognize leukocoria (white pupil), the most common initial sign of retinoblastoma, and promptly refer the child to an ophthalmologist trained to treat the tumor. In a recent review of the Central American experience, 161 children were diagnosed with retinoblastoma between 1998 and 2001. More than 50% were older than 3 years of age and more than 20% were older than 4 years of age, which indicate a significant delay in diagnosis or in the referral to a pediatric cancer center. Sixty percent of patients had extraocular disease at the time of presentation (involvement of the orbit, brain, or with distant metastases to the bones or bone marrow). In the United States, by comparison, less than 10% of patients have extraocular disease. Furthermore, anecdotal evidence has suggested

that retinoblastoma is more common in developing countries with higher indigenous populations. For example, in many of our partner sites, retinoblastoma is one of the most common solid tumors diagnosed in children.

Although retinoblastoma is a rare cancer, research into its causes and treatment is important for all cancer patients. Retinoblastoma was the first cancer in humans that was found to be a hereditary disease. A landmark hypothesis by Knudson predicted two genetic “hits” are key to the development of retinoblastoma, laying the groundwork for understanding the difference between patients with a germinal mutation versus those with spontaneous disease. The identification of the mutation that causes retinoblastoma led to the discovery of RB1, the first human tumor suppressor gene. Additionally, the RB pathway is directly connected to another major tumor suppressor pathway called the p53 pathway. It is now well established that most human cancers have acquired mutations that inactivate both the RB and p53 pathways. The discovery that increased expression of a key regulator of the p53 pathway called MDMX provided novel opportunities for targeted therapy retinoblastoma. With the recently developed animal models of retinoblastoma and comprehensive preclinical testing, there are now unprecedented opportunities to accelerate translational research for this devastating childhood cancer.

Since 2003, hundreds of professionals at the Hamilton Eye Institute at the University of Tennessee Health Science Center (UTHSC) and St. Jude Children’s Research Hospital (SJCRH) in Memphis, Tennessee – including ophthalmologists, pediatric oncologists, technicians, researchers, photographers, writers, and other staff – have been reaching out to underserved areas of the world in the fight against pediatric eye cancers. The St. Jude International Outreach Program is constantly looking for new, innovative ways to continue its mission of improving the survival rates of children with catastrophic illness worldwide through the transfer and implementation of knowledge, technology, and organizational skills. This mission is accomplished through international partnerships via a strategy of mentoring

and consultation of clinical services, education, and research, the combination of which creates local and regional capacity for long-term, sustainable health systems.

Working together with ORBIS® International, we have developed centers of excellence in Guatemala, Honduras, Panama (Fig. 19.1), and Jordan, where we have been able to aid physicians by providing the technology and training they need to better diagnose and treat retinoblastoma and other ophthalmic diseases. Part of this technology includes telecommunications tools enabling physicians at those sites to engage in weekly consults with ophthalmologists and oncologists at SJCRH and UTHSC to discuss diagnoses, treatments, and collaborative research.

Improved therapy has dramatically increased survival rates for children with cancer over the past three decades, but worldwide, fewer than 30% of children with cancer have access to modern treatment. International Outreach transfers the progress achieved in the treatment of childhood cancer in developed countries to those with limited resources.

19.2History of the Program

The St. Jude International Outreach Program was formally established in 1998 with El Salvador as the first partner site. The program has since expanded to partner with 20 pediatric cancer treatment centers in 15 countries around the globe – Brazil, Chile, China, Costa Rica, Ecuador, El Salvador, Guatemala, Honduras, Ireland, Jordan, Lebanon, Mexico, Morocco, the Philippines, and Venezuela. The International Outreach Program was created to develop partnerships with medical institutions and fund-raising organizations in partner countries and recruit other agencies and organizations to support key programs and the education of local personnel. Regionally, advanced telecommunications are used to link programs and professionals who learn from and assist each other. The cost-efficiency of shared resources also promotes local and regional

self-sufficiency, which in turn enhances local capacity to treat children with cancer.

The retinoblastoma outreach project began in June 2003, when Dr. Eugene Helveston visited the UTHSC Department of Ophthalmology and St. Jude Children’s Research Hospital in Memphis. He proposed a childhood eye cancer project to be started in Guatemala, offering the ORBIS® Cyber-Sight web-based telecommunications program as a way to link doctors in Central America with those at UTHSC and SJCRH. When leaders at both organizations expressed their wish to participate, Dr. Helveston then presented the proposed project at an ORBIS® board meeting, where board chairman Al Ueltschi agreed to donate the money to purchase a RetCam® and laser treatment equipment for the pilot project in Guatemala City.

After months of preparations, in January 2004, the International Outreach Program initiated its pilot program in Honduras and Guatemala, aimed at reducing the high rate of mortality and blindness

caused by ophthalmologic diseases. Later the same year, Panama became the third site in our program (Fig. 19.2). Each center was supplied with advanced ophthalmic devices including fundus cameras, diode lasers, and RetCams®, ensuring that experts at St. Jude Children’s Research Hospital and the UTHSC Hamilton Eye Institute in Memphis would be able to provide more detailed input and advice on cases examined by physicians at these sites. Our primary reasons for selecting these countries were: (1) the large number of patients, (2) the presence of an existing committed treatment team and effective local fund-raising foundation, and (3) the central location of these countries, which facilitates expansion to all of Central America. The UTHSC Hamilton Eye Institute, St. Jude Children’s Research Hospital, and ORBIS® partnered in this initiative by capitalizing on complementary expertise and experience to treat eye diseases in Central America. These organizations collaborate to establish a comprehensive ophthalmology

program with a strong telemedicine component. In addition to improving eye care in the region, this program builds health-care infrastructure at program sites; serves as a template for the development of other medical treatment, education, and data management programs; and enhances international goodwill. Our retinoblastoma program is one of the most successful programs at St. Jude’s International Outreach Program.

In November 2005, Dr. Matthew W. Wilson, professor of ophthalmology at the UT Hamilton Eye Institute, volunteered to travel to Guatemala and establish a localized brachytherapy protocol there. Three brachytherapy plaques were made in Memphis and sent with Dr. Wilson, who met with the radiation oncology team, physicist, and Dr. Margarita Barnoya in Guatemala for transfer of skills in the handling and placement of plaques (Fig. 19.3). In December of the same year, Dr. Wilson did the same for our newly developing site at the King Hussein Cancer Center in Amman, Jordan. There, another center of excellence in the retinoblastoma outreach program was established as a result of consults on the ORBIS Cyber-Sight,

leading to the introduction of state-of-the-art treatment modalities in Jordan, such as transpupillary thermotherapy and subconjunctival chemotherapy.

In January of 2006, a landmark event, the world’s first international ophthalmology telehealth symposium held on board an airplane, was held aboard the ORBIS® flying eye hospital, with physicians connecting from the aircraft parked at the FedEx global “SuperHub” to telehealth sites at the UTHSC Hamilton Eye Institute, St. Jude Children’s Research Hospital, and our centers of excellence in Guatemala and Honduras (Fig. 19.4). This important event received a great deal of media attention, demonstrating how effectively this outreach program has brought physicians in underserved nations together with physicians at UTHSC and SJCRH.

In 2009, Dr. Gaston K. Rivera, medical director of the Chile program at the St. Jude International Outreach Program, invited leaders at UT Hamilton Eye Institute on a site visit to Santiago, Chile, to determine what equipment will be needed there (telecommunications