Retinoblastoma in Asia: Clinical Presentation and Treatment Outcomes in 2112 Patients from 33 Countries.

PURPOSE: To describe the clinical presentation and treatment outcomes of children who received a diagnosis of retinoblastoma in 2017 throughout Asia. DESIGN: Multinational, prospective study including treatment-naïve patients in Asia who received a diagnosis of retinoblastoma in 2017 and were followed up thereafter. PARTICIPANTS: A total of 2112 patients (2797 eyes) from 96 retinoblastoma treatment centers in 33 Asian countries. INTERVENTIONS: Chemotherapy, radiotherapy, enucleation, and orbital exenteration. MAIN OUTCOME MEASURES: Enucleation and death. RESULTS: Within the cohort, 1021 patients (48%) were from South Asia (SA), 503 patients (24%) were from East Asia (EA), 310 patients (15%) were from Southeast Asia (SEA), 218 patients (10%) were from West Asia (WA), and 60 patients (3%) were from Central Asia (CA). Mean age at presentation was 27 months (median, 23 months; range, < 1-261 months). The cohort included 1195 male patients (57%) and 917 female patients (43%). The most common presenting symptoms were leukocoria (72%) and strabismus (13%). Using the American Joint Committee on Cancer Staging Manual, Eighth Edition, classification, tumors were staged as cT1 (n = 441 [16%]), cT2 (n = 951 [34%]), cT3 (n = 1136 [41%]), cT4 (n = 267 [10%]), N1 (n = 48 [2%]), and M1 (n = 129 [6%]) at presentation. Retinoblastoma was treated with intravenous chemotherapy in 1450 eyes (52%) and 857 eyes (31%) underwent primary enucleation. Three-year Kaplan-Meier estimates for enucleation and death were 33% and 13% for CA, 18% and 4% for EA, 27% and 15% for SA, 32% and 22% for SEA, and 20% and 11% for WA (P < 0.0001 and P < 0.0001), respectively. CONCLUSIONS: At the conclusion of this study, significant heterogeneity was found in treatment outcomes of retinoblastoma among the regions of Asia. East Asia displayed better outcomes with higher rates of globe and life salvage, whereas Southeast Asia showed poorer outcomes compared with the rest of Asia. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Incidence and clinical characteristic of ocular surface manifestation: an evaluation of conjunctival swab results in Corona Virus 2019 (COVID-19) patients in Jakarta, Indonesia.

OBJECTIVES: This study aimed to investigate the spectrum of ocular characteristics and viral presence in the conjunctival swab of patients with COVID-19. METHODS: In this cross-sectional study, fifty-three patients were recruited from two COVID-19 referral hospitals in Jakarta (Cipto Mangunkusumo Hospital and Persahabatan Hospital) from July 2020 to March 2021. The inclusion criteria were patients who were suspected of or confirmed cases of COVID-19 with or without ocular symptoms. Demographic data, history of COVID-19 exposure, underlying medical condition, systemic symptoms, ocular symptoms, supporting laboratory results, reverse-transcriptase polymerase chain reaction (RT-PCR) of naso-oropharyngeal (NOP) swab and conjunctival swab were collected. RESULTS: Fifty-three patients who were suspected, probable or confirmed cases of Covid-19 were included. Forty-six out of 53 patients (86.79%) tested positive for either Covid-19 antibody rapid test or naso-oropharyngeal (NOP) swab. Forty-two patients tested positive for NOP swab. Fourteen out of 42 patients (33.33%) experienced symptoms of ocular infection including red eye, epiphora, itchy eyes, and eye discharge. None of these patients were tested positive for conjunctival swab. Two out of 42 patients (4.76%), who were tested positive for conjunctival swab, did not experience any ocular symptoms. CONCLUSIONS: Establishing the relationship between Covid-19 infection, ocular symptoms, and presence of SARS-CoV-2 virus on the ocular surface proves to be challenging. In Covid-19 patients, ocular symptoms did not warrant a positive conjunctival swab result. On the contrary, a patient without ocular symptoms can also have detectable presence of SARS-CoV-2 virus on the ocular surface.

PATTERN DYSTROPHY-LIKE CHANGES ASSOCIATED WITH A VERY HIGH SERUM FERRITIN LEVEL IN ß-THALASSEMIA MAJOR.

PURPOSE: To report a rare case of pattern dystrophy-like retinal changes in a young ß-thalassemia major patient with a very high serum ferritin level. METHODS: Observational case report of a ß-thalassemia major patient with bilateral pattern dystrophy-like retinal changes. RESULTS: An 18-year-old man experienced blurring of vision in both eyes. Patient had a very high serum ferritin level and had a history of using various iron-chelating drugs. Funduscopy revealed bilateral widespread retinal pigment epithelium changes with macular involvement, which resembled pattern dystrophy-like changes. Fundus autofluorescence imaging showed extensive area of decreased autofluorescence signal interspersed with increased autofluorescence signals, whereas optical coherence tomography demonstrated macular retinal pigment epithelium thinning and interdigitation zone disruption corresponding to retinal pigment epithelium damage and atrophy. CONCLUSION: Pattern dystrophy-like changes should be considered as a possible manifestation of retinal changes in patients with ß-thalassemia major. Iron overload, which is indicated by a very high serum ferritin level, might have a role in the formation of this rare retinal manifestation in ß-thalassemia major.

Retinal abnormalities in universal eye screening of healthy, full-term newborn infants in Jakarta. The incidence and its risk factors: a pilot study.

AIM: To screen for ocular abnormalities in healthy full-term newborn infants using wide-field digital imaging and to analyze factors associated with the findings. METHODS: A total of 1208 full-term newborn infants at a tertiary eye hospital (Cipto Mangunkusumo National Referral Hospital) and a district hospital in Jakarta (Koja Hospital) were enrolled to the study. All eligible newborns underwent fundus examination within 48 h after birth using the RetCam shuttle (Natus Medical Incorporated, USA). Retinal findings were documented and analyzed according to obstetric and neonatal risk factors. RESULTS: Of the 1208 newborn infants enrolled, ocular abnormalities were found in 150 infants (12.4%). Retinal hemorrhage (RH) was the most common finding (88%) in which 2.67% involved the macula, followed by chorioretinitis (4.67%). Univariate analysis showed caesarean section (C-section) (OR 0.27, 95% CI 0.18-0.41, p < 0.001) was a protective factor against RH, while prolonged labor increased the risk of developing RH (OR 1.84, 95% CI 1.24-2.72, p = 0.002). Further multivariate analysis showed similar protective association between C-section and risk of RH (OR 0.29, 95% CI 0.19-0.44, p < 0.001), while other risk factors were not. CONCLUSIONS: Our study showed that universal eye screening in healthy neonates is beneficial in the early diagnosis, monitoring and treatment of ocular abnormalities such as retinal hemorrhage, chorioretinitis and retinoblastoma. Retinal hemorrhage is the most common ocular abnormality and is associated with the delivery method and the duration of labor. Universal eye screening is visual-saving and life-saving for neonates with chorioretinitis, retinoblastoma as well as other abnormalities and should be mandatory in newborn screening.

Novel retinal findings in ß-thalassemia major: older age and higher ferritin level as the risk factors.

PURPOSE: To investigate retinal changes in ß-thalassemia major patients and identify their association with systemic risk factors. METHODS: In this prospective study, 120 ß-thalassemia major patients received complete ophthalmic examinations (best-corrected visual acuity, contrast sensitivity, color vision, and indirect ophthalmoscopy) and retinal imaging using color fundus photography and fundus autofluorescence imaging. Patients were grouped according to the presence of thalassemia-related retinal changes. The association between systemic risk factors (age, type and duration of iron chelator use, history of splenectomy, hemoglobin level, and ferritin level) and thalassemia-related retinal changes was investigated using logistic regression analysis. RESULTS: Thalassemia-related retinal changes were identified in 36.7% of patients. Several distinct retinal changes were observed, including retinal refractile bodies in 10% of patients and retinal hemorrhage in 5.8% of patients. Fundus autofluorescence imaging showed abnormal patterns in 36.3% of patients with thalassemia-related retinal changes and 18.4% of patients without thalassemia-related retinal changes. Age (odds ratio [OR] = 1.10, 95% confidence interval [CI] 1.03-1.18) and ferritin level (OR 1.16, 95% CI 1.01-1.33) were associated with thalassemia-related retinal changes. CONCLUSION: Novel retinal changes were observed in ß-thalassemia major patients. This study identified older age and higher ferritin level as risk factors for thalassemia-related retinal changes.

How to prevent ROP in preterm infants in Indonesia?

BACKGROUND AND AIMS: Retinopathy of prematurity (ROP) is a severe disease in preterm infants. It is seen more frequently in Low-Middle Income Countries (LMIC) like Indonesia compared to High-Income Countries (HIC). Risk factors for ROP development are -extreme- preterm birth, use of oxygen, neonatal infections, respiratory problems, inadequate nutrition, and blood and exchange transfusions. In this paper, we give an overview of steps that can be taken in LMIC to prevent ROP and provide guidelines for screening and treating ROP. METHODS: Based on the literature search and data obtained by us in Indonesia's studies, we propose guidelines for the prevention, screening, and treatment of ROP in preterm infants in LMIC. RESULTS: Prevention of ROP starts before birth with preventing preterm labor, transferring a mother who might deliver <32 weeks to a perinatal center and giving corticosteroids to mothers that might deliver <34 weeks. Newborn resuscitation must be done using room air or, in the case of very preterm infants (<29-32 weeks) by using 30% oxygen. Respiratory problems must be prevented by starting continuous positive airway pressure (CPAP) in all preterm infants <32 weeks and in case of respiratory problems in more mature infants. If needed, the surfactant should be given in a minimally invasive manner, as ROP's lower incidence was found using this technique. The use of oxygen must be strictly regulated with a saturation monitor of 91-95%. Infections must be prevented as much as possible. Both oral and parenteral nutrition should be started in all preterm infants on day one of life with preferably mothers' milk. Blood transfusions can be prevented by reducing the amount of blood needed for laboratory analysis. DISCUSSION: Preterm babies should be born in facilities able to care for them optimally. The use of oxygen must be strictly regulated. ROP screening is mandatory in infants born <34 weeks, and infants who received supplemental oxygen for a prolonged period. In case of progression of ROP, immediate mandatory treatment is required. CONCLUSION: Concerted action is needed to reduce the incidence of ROP in LMIC. "STOP - R1O2P3" is an acronym that can help implement standard practices in all neonatal intensive care units in LMIC to prevent development and progression.

Norrie disease gene polymorphism in Indonesian infants with retinopathy of prematurity.

OBJECTIVE: Retinopathy of prematurity (ROP) is a major cause of blindness in newborn infants, which also occurs in low-income and middle-income countries. Why ROP progresses in some infants while it regresses in others is still presently unknown. Studies suggest that genetic factors might be involved. Mutations in the Norrie disease (ND) gene are suspected to be related to advanced ROP development. Indonesia is a country with relatively high incidence of ROP, yet the role of these genetic factors in the pathogenesis of ROP cases is still unknown. The study aimed to investigate the presence of mutations in ND on the X chromosome in infants with both non-advanced and advanced ROP in Indonesia. METHODS AND ANALYSIS: This is a case-control study of polymorphisms in six variants within the ND gene in exon 3, C597A, L108P, R121W, A105T, V60E and C110G, in preterm newborn infants in four major hospitals in Greater Jakarta, Indonesia. RESULTS: We included 162 preterm newborn infants. ROP was diagnosed in 83 infants, and 79 infants served as controls. Among those with ROP, 57 infants had type 2, while others had type 1. We did not find any gene polymorphisms in any of the infants with ROP nor in the control group. CONCLUSION: We conclude that it is very unlikely that the six polymorphisms in exon 3 of the ND gene studied in this paper are involved in the development or progression of ROP in preterm infants in our population sample in Indonesia.

Post-Ocular Trauma Corneal Staphyloma in a Child Living in an Underdeveloped Region of Eastern Indonesia.

Ocular trauma occurring in children often leads to visual impairment or blindness when it is not properly managed. This often occurs in underdeveloped regions with difficult access to professional care at local health facilities. We report a case of post-trauma corneal staphyloma in an underdeveloped region of eastern Indonesia to illustrate the importance of proper management of ocular trauma in areas lacking such expertise and where patients have difficulty accessing even basic health care. During a community health outreach in Southwest Sumba, eastern Indonesia in May 2017, a 7-year-old boy presented with white protrusion of the left eye of 3 years' duration following an event of sharp trauma. The patient lived in an inaccessible and impoverished area. Upon contemporary examination, visual acuity of the left eye was 1/300 while that of the right eye was 6/6. Anterior examination revealed corneal staphyloma of the left eye, and its posterior segment could not be evaluated. The patient was transported to an eye care center in Jakarta, receiving a stock prosthesis implant while awaiting a corneal evisceration procedure with dermofat graft. Ocular trauma is one of the most common causes of visual impairment in children. This case illustrates the consequences of inadequate post-trauma management and the importance of prevention of infection.

The Efficacy of 1% Chloramphenicol Eye Ointment Versus 2.5% Povidone-Iodine Ophthalmic Solution in Reducing Bacterial Colony in Newborn Conjunctivae.

PURPOSE: This study aimed to evaluate bacterial pattern and reduction of bacterial colonies in neonatal conjunctivae after prophylaxis 1% chloramphenicol eye ointment and 2.5% povidone-iodine ophthalmic solution. DESIGN: A double-blind randomized controlled trial was conducted. METHODS: Swabs were taken from the inferior fornix conjunctiva of the right eyes of 60 newborns 1 hour after birth. Either the 2.5% povidone-iodine ophthalmic solution or the 1% chloramphenicol eye ointment was randomly applied to the conjunctivae. Conjunctival swabs were taken 2 hours after prophylaxis treatment. Specimens were delivered to the Microbiology Laboratory to determine the number of bacterial colonies and to evaluate bacterial pattern. RESULTS: Sixty eye specimens were included in the study. Bacterial growth was shown in 44 eye specimens, whereas it was not found in the remaining 16 eye specimens. The bacteria found in neonatal conjunctivae was gram-positive coccus (61%), followed by gram-positive bacillus (36%) and gram-negative bacillus (2%). Both agents significantly reduced the bacterial colony-forming unit (P = 0.00); however, the effect was not significantly different as shown by statistics between both groups (P = 0.748), indicating that the 2.5% povidone-iodine ophthalmic solution had a similar effect to the 1% chloramphenicol eye ointment. No adverse effect such as toxic conjunctivitis or corneal haziness was found in both groups. CONCLUSIONS: The 2.5% povidone-iodine ophthalmic solution has been proven as effective as the 1% chloramphenicol eye ointment and induces no toxic reaction. Because it is less expensive than the other, it could be recommended as a good alternative for ophthalmia neonatorum prophylaxis. Further studies with a larger sample size should be conducted to confirm its cost-effectiveness.

Intravitreal Bevacizumab in Retinopathy of Prematurity: Inject or Not?

This article is aimed to review and summarize the indications, outcomes and safety profiles regarding the use of intravitreal bevacizumab in patients with retinopathy of prematurity (ROP) as reported in previous studies with no intention to compare the efficacy between intravitreal bevacizumab and laser photocoagulation.Literature search was conducted in databases such as PubMed, Cochrane, Ovid, and Ophthalmology Advance using the terms "ROP," "antiangiogenic," "antivascular endothelial growth factor," "intravitreal bevacizumab," and "Avastin."Eight prospective studies of 278 eyes of ROP infants and 15 retrospective studies involving 385 eyes of ROP infants treated with intravitreal bevacizumab were found. Bevacizumab was used as monotherapy, adjunctive therapy, and/or combined therapy.The varied use of intravitreal bevacizumab in treating ROP and he limited number of landmark studies contribute to the difficulties in drawing a strong conclusion in this review. Intravitreal bevacizumab was more commonly injected in: (1) type 1 ROP zone I and/or posterior zone II; (2) aggressive posterior ROP with poor retinal visualization in which laser photocoagulation would be difficult to perform; and (3) stage 4 ROP before vitrectomy. All cases demonstrated regression of neovascular activity during a varied follow-up period (from 1 week to 1 month) after injection. However, recurrence may occur. Follow-up until 80 weeks of postmenstrual age is thus recommended. Acceleration of fibrous traction is the most common ocular adverse effect after injection, whereas the systemic adverse effect remains uncertain. Landmark studies of the efficacy of intravitreal bevacizumab injection in treating ROP are warranted.

SIOP-PODC recommendations for graduated-intensity treatment of retinoblastoma in developing countries.

Retinoblastoma remains incurable in many regions of the world. The major obstacles to cure are delayed diagnosis, poor treatment compliance, and lack of evidence-based recommendations for clinical management. Although enucleation is curative for intraocular disease, in developing countries retinoblastoma is often diagnosed after the disease has disseminated beyond the eye. A SIOP-PODC committee generated guidelines for the clinical management of retinoblastoma in developing countries and developed a classification system based on the resources available in those settings. Recommendations are provided for staging and treatment of unilateral and bilateral retinoblastoma and counseling of families for whom compliance is an issue.

Strategies to manage retinoblastoma in developing countries.

Survival of retinoblastoma is >90% in developed countries but there are significant differences with developing countries in stage at presentation, available treatment options, family compliance, and survival. In low-income countries (LICs), children present with advanced disease, and the reasons are socioeconomic and cultural. In middle-income countries (MICs), survival rates are better (>70%), but there is a high prevalence of microscopically disseminated extraocular disease. Programs for eye preservation have been developed, but toxicity-related mortality is higher. Although effective treatment of microscopically extraocular disease improved the outcome, worldwide survival will be increased only by earlier diagnosis and better treatment adherence.

The apoptotic paradox in retinoblastoma.

The purpose of this study was to investigate the clinicopathological features and the expression of proteins involved in cell proliferation and the different pathways of apoptosis in retinoblastoma. Nineteen retinoblastoma patients were included, and mitotic index (MI) and apoptotic index (AI) were assessed. The expression of MIB-1, p53, caspase-3, Bcl-2, and Fas protein was assessed by immunohistochemistry. Mann-Whitney U test and Fisher's exact test were used for statistical comparison. High MI (mean 16.84, range 0-66) and high MIB-1 expression (mean 57.89, range 0-90) were found. The MI was significantly related to MIB-1 expression (P= 0.01). The tumors showed a high apoptotic index (mean 40.26, range 1-110), and the AI was associated with the mitotic index (P= 0.02). The caspase-3 expression was positively related to the AI (P= 0.03), although a small number of tumors with no significant or very low caspase-3 staining showed a high number of apoptotic cells, suggestive of a caspase-3-independent apoptosis pathway. Bcl-2 expression was not significantly related to AI (P= 0.07). No striking relationship was found in expression patterns of p53, Bcl-2, caspase-3, and Fas. In conclusion, we found that (1) cell proliferation and apoptosis are linked in retinoblastoma; (2) activation of effector caspase-3 induces apoptosis in retinoblastoma, but Bcl-2 overexpression does not prevent apoptosis in many tumors; (3) there is a p53-independent pathway in approximately one-quarter of cases; (4) the findings suggesting a caspase-3-independent pathway might lead to apoptosis in retinoblastoma; and, finally, we found no consistent pattern of expression of apoptotic and antiapoptotic molecules, suggesting that in retinoblastoma there is no preference for any single pathway of apoptosis. Confirmation of the results in a large set of tumors would be useful.

The effect of therapy refusal against medical advice in retinoblastoma patients in a setting where treatment delays are common.

BACKGROUND: Patients who refuse therapy against medical advice may be at risk of adverse health outcomes. We analyzed the impact of therapy refusal and its effect on the survival of retinoblastoma patients. PATIENTS AND METHODS: 165 consecutive untreated retinoblastoma patients admitted to the CM-Hospital, between 1993-2000 were evaluated retrospectively. Survival outcomes and its association with delays and tumor staging were analyzed using Kaplan-Meier and Cox-Regression. RESULTS: Of the 165 cases, 78 cases (47,3%) were assigned to the "No-Refusal-Group"; 52 cases (31,5%) to "Temporary-Refusal-Group," 30 cases (18,2%) to "Definite-Refusal-Group." Survival rates of patients who temporarily refused were significantly lower than those who did not refuse the therapy (p < 0.05). Progression of tumor stage was highly associated with temporary-refusal (p < 0.0005). In the Cox-Regression model, clinical staging of tumor was highly associated, whereas admission delay and treatment delay were slightly associated with the overall survival (p < 0.05, adjusted-hazard-ratio 6.321, 1.031,1.025, respectively). The clinical staging is the strongest variable associated with patient survival outcome. Delay >or= 6 months between first sign and admission is highly associated with tumor progression (p < 0.0005). CONCLUSIONS: First, the high level of therapy refusal in a developing country like Indonesia has an adverse effect on the survival outcome of retinoblastoma patients. Second, the change of the tumor stage from intraocular to extraocular is the most adverse predictive factor for survival. Third, the advanced stage of the tumor is caused by long delay to admission. In a developing country the parents of many young patients refuse to accept the recommended therapy and therefore the tumor may reach a critical stage for the prognosis.

World disparities in risk definition and management of retinoblastoma: a report from the International Retinoblastoma Staging Working Group.

Following from the publication of the International Retinoblastoma Staging System, an open internet discussion group was created at the www.cure4kids.org resource. The results of a survey distributed among participants are discussed. Although most patients with retinoblastoma were treated under prospective protocols, there was a wide variation in the definition of risk criteria and in the criteria for giving adjuvant chemotherapy following enucleation. Definition of high-risk histological features and the criteria for use of adjuvant therapy will be standardized in future studies. Internet meetings are a valuable mechanism for enabling participation from under-resourced countries in the development of cooperative studies.

Analysis of three genes in Leber congenital amaurosis in Indonesian patients.

PURPOSE: To assess the frequency, the pattern of disease causing mutations, and phenotypic variations in patients with Leber congenital amaurosis (LCA) from Indonesia. PATIENTS AND METHODS: Twenty-one unrelated index cases with a clinical diagnosis of LCA were screened for mutations in the coding sequence of RetGC1, RPE65 and AIPL1 gene with single strand conformation polymorphism analysis followed by direct sequencing and restriction enzyme digestion. RESULTS: Four novel disease causing mutations were identified: Three in the RPE65 gene (106del9bp, G32V and Y435C) in two of 21 index cases and one in the AIPL1 (K14E). Two of them were homozygous and one was compound-heterozygous. No disease causing mutation was identified in RetGC1. CONCLUSIONS: The four novel disease causing mutations identified in this study confirmed the diagnosis of LCA which has not been recognized before in Indonesia. The frequency of RPE65 mutations was 9.5%; and of AIPL1 mutations 4.8%. This was in general accordance with previous studies reported from other countries. Unlike in those studies, no disease causing RetGC1 mutations could be identified in our patients. Phenotypically, the RPE65 and AIPL1 mutations identified in this study caused nearly total blindness by the second decade of life, but had a different onset of symptoms. The patients with the RPE65 mutations retained some useful visual function until the end of the first decade, which progressed to total blindness during the second decade of life, whereas the (homozygous) AIPL1 mutation was associated with nearly total blindness from infancy on. Therefore, RPE65 mutations have to be considered to cause early onset severe retinal degeneration (EOSRD), and AIPL1 mutations a form of LCA.