Letter to the Editor: Eye as a window to disease burden in pediatric acute leukemia

Abstract

Ocular involvement in pediatric acute leukemia is an increasingly recognized, clinically relevant manifestation, but prevalence and patterns vary. It may arise from direct leukemic infiltration or secondary hematologic abnormalities. Recent observational studies, including Eastern India cohorts, underscore systematic ophthalmic evaluation at diagnosis. In a cohort of 47 children by Parija et al published in the World Journal of Experimental Medicine, ocular findings were present in 40.4% at presentation; most were asymptomatic and retinal hemorrhages predominated. Other series report similar patterns, with retinal hemorrhages common and prevalence roughly 40%-45%, while pooled meta-analytic estimates suggest an overall prevalence near 20%, differences likely reflect ethnicity, healthcare access, diagnostic protocols, study design, and sample size. Hematologic factors such as anemia and thrombocytopenia favor hemorrhagic lesions, whereas marked leukocytosis and high blast counts associate with infiltrative involvement of the retina, optic nerve, or orbit. Although some studies link ocular involvement to higher disease burden and worse outcomes, evidence is inconsistent because of methodological limitations and short follow-up. These findings support routine baseline ophthalmic screening, even in asymptomatic children, to detect vision-threatening lesions and clearly inform risk assessment. Larger prospective studies with standardized ocular and hematologic correlations are needed to define prognostic significance and optimize screening.

Key Words: Acute paediatric leukaemia; Ocular involvement; Leukemic retinopathy; Intraretinal hemorrhages; Disease burden; Ophthalmology

Core Tip: Ocular manifestations in pediatric acute leukemia are common but often underrecognized, despite reflecting underlying systemic disease burden. Retinal and optic nerve abnormalities may result from hematologic disturbances or direct leukemic infiltration and frequently occur without visual symptoms. Advances in retinal imaging have enhanced detection of overt and subclinical changes, supporting early ophthalmic assessment. This letter highlights the eye as a non-invasive indicator of disease severity and emphasizes the need for standardized screening and prospective research to improve multidisciplinary care.

TO THE EDITOR

In the recent issue of World Journal of Experimental Medicine, Parija et al[1] explored the spectrum of ocular manifestations in pediatric acute leukemia using a structured, hospital-based observational approach. By integrating confirmed hematological diagnosis with comprehensive ophthalmic evaluation prior to chemotherapy, the study captured disease-related ocular changes without therapeutic confounding. It highlights the prevalence and patterns of ocular involvement and their association with clinical and hematological parameters. The study underscores the importance of routine ophthalmic screening in children with acute leukemia, demonstrating how early ocular assessment can aid in timely detection of vision-threatening complications and support holistic disease management.

STUDY DESIGN AND ANALYTICS

Parija et al[1] conducted a hospital-based, descriptive cross-sectional study enrolling children (< 15 years) with acute leukemia receiving chemotherapy between July 2016 and December 2019. Diagnosis was established using peripheral smear, bone-marrow aspiration, and multicolor flow-cytometric immunophenotyping, while patients with ocular-mimicking conditions or significant comorbidities were excluded. All participants underwent a standardized ophthalmic evaluation prior to chemotherapy, and demographic, clinical, hematological, and treatment-related data were systematically recorded. Data were analysed using SPSS v16, with continuous variables expressed as means or medians and categorical variables as frequencies and percentages, with P < 0.05 considered statistically significant. A key strength of this methodology is the uniform pre-therapeutic ophthalmic assessment, which reduces treatment-related bias and enhances internal validity.

SPECTRUM AND MECHANISM

Posterior-segment abnormalities - most commonly retinal hemorrhages, Roth spots and cotton-wool exudates - dominate the ocular spectrum at presentation in pediatric acute leukemia, with vitreous hemorrhage and dilated tortuous veins reported less frequently[2]. Direct leukemic infiltration may involve the optic nerve, choroid, orbit or uveal tissues and, although rarer, presents an urgent threat to vision and can signal central nervous system relapse[3]. Indirect mechanisms are mainly related to blood abnormalities. Severe anemia, low platelet counts, clotting disturbances, and increased blood viscosity can impair retinal blood flow, making the retina more vulnerable to hemorrhages and ischemic damage to the nerve fiber layer[4,5]. Certain myeloid phenotypes (acute myeloid leukemia) appear to show higher rates of ophthalmic involvement than lymphoid disease in contemporary cohorts, suggesting biologic heterogeneity in ocular tropism[4]. Advances in multimodal imaging and machine-learning analysis are improving detection and etiologic classification of pediatric retinal lesions, facilitating distinction between leukemic and non-leukemic causes[6]. These pathogenic mechanisms provide a pathophysiological basis for the spectrum of retinal and optic nerve findings observed at initial diagnosis and help explain their association with systemic disease severity.

DIAGNOSTIC AND TECHNOLOGICAL ADVANCES

Recent diagnostic and imaging advances have expanded detection of ocular involvement in acute leukemia beyond conventional fundoscopy. Optical coherence tomographic angiography (OCTA) allows high-resolution, non-invasive visualization of retinal microvascular changes, revealing subclinical impairments even in remission and offering insights into leukemic microangiopathy that precede ophthalmoscopic signs[7,2]. Multimodal imaging, including spectral-domain optical coherence tomography and wide-field fundus photography, enhances characterization of retinal and choroidal lesions. Contemporary studies also highlight emerging roles for machine learning and automated image analysis in quantifying and classifying subtle retinal abnormalities, potentially improving early detection and monitoring of ocular disease burden in pediatric leukemia[8,9].

CLINICAL IMPLICATIONS

Ocular findings in pediatric acute leukemia have substantive clinical implications beyond visual symptoms, often reflecting systemic disease severity and hematologic derangements. Retinal hemorrhages, roth spots, and optic disc changes correlate with anemia and thrombocytopenia, guiding clinicians to investigate underlying hematologic instability[4]. This relationship underscores how ocular manifestations integrate etiologic factors with clinical expression and prognostic assessment. Systematic ophthalmic screening at diagnosis improves detection of asymptomatic involvement, enabling earlier multidisciplinary management and tailored supportive care. Meta-analyses demonstrate that up to one-fifth of children with newly diagnosed leukemia have ocular involvement, with a meaningful subset at risk of vision-threatening complications[5]. Retinal hemorrhages are frequently reported as the predominant ocular manifestation, and cohort studies have documented ocular involvement in approximately 40%-45% of patients, while pooled meta-analytic estimates suggest an overall prevalence of around 20% with substantial inter-study heterogeneity possibly due to differences in ethnicity, healthcare infrastructure, diagnostic protocols, and study design[2,4,5,10]. Early recognition may prompt urgent hematologic evaluation, influence monitoring frequency, and reduce long-term visual and systemic morbidity.

RESEARCH GAPS AND PRIORITIES

Despite growing recognition of ocular involvement in pediatric acute leukemia, several critical research gaps persist. There is a need for prospective, multicentre pediatric studies using standardized ophthalmic assessment protocols to improve comparability and clinical translation[10]. The prognostic relevance of subclinical retinal microvascular alterations detected by advanced imaging modalities such as OCTA remains insufficiently defined and warrants longitudinal evaluation alongside hematologic and molecular parameters[7]. In addition, artificial intelligence-based retinal image analysis requires rigorous external validation and feasibility testing, particularly in resource-limited settings. Future research should prioritize integrated ocular-systemic biomarker studies and assess whether routine baseline ophthalmic screening meaningfully influences clinical decision-making and long-term outcomes.

CONCLUSION

Ocular manifestations in pediatric acute leukemia provide valuable, non-invasive insight into systemic disease burden and hematologic instability. Evidence from recent studies indicates that many ocular findings are asymptomatic yet correlate with anemia, thrombocytopenia, leukemic infiltration, and, in some cases, central nervous system involvement. However, the prognostic significance of these manifestations remains incompletely defined, with existing data limited by heterogeneous study designs, small sample sizes, and variable follow-up durations. The interrelationship between systemic hematologic abnormalities, ocular changes, and emerging diagnostic approaches is summarized schematically (Figure 1). Advances in retinal imaging have enhanced the detection of both overt and subclinical abnormalities, strengthening the role of the eye as a potential surrogate marker of disease activity. Incorporating routine baseline ophthalmic evaluation into pediatric leukemia care pathways may improve early risk recognition, support multidisciplinary decision-making, and reduce the risk of irreversible visual morbidity. Further large-scale, prospective studies with standardized assessment protocols are warranted.

Figure 1 Conceptual overview illustrating how systemic hematologic abnormalities and leukemic infiltration in pediatric acute leukemia manifest as ocular findings, and how retinal imaging modalities support early detection, risk recognition, and multidisciplinary clinical management. OCT: Optical coherence tomography; SD-OCT: Spectral-domain optical coherence tomography; AI: Artificial intelligence; CNS: Central nervous system. Created in BioRender.