Ocular findings in children with acute leukemia at a tertiary care center in South America.

PURPOSE: The purpose of this study was to evaluate ophthalmological findings in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) in a Latin American population.
MATERIALS AND METHODS: This was a single-center, retrospective study. The observational analysis was conducted in AML and ALL patients seen as a routine examination at the department of ophthalmology of tertiary care center in Argentina between March 1, 2017, and February 28, 2018.
RESULTS: Overall, 137 patients with acute leukemia were included. The mean age was 7.9 ± 5.2 years (0-18), and 55% were male (n = 75) and 45% female (n = 45). At least one-fifth (n = 31) of the patients presented some type of ocular manifestation (23%). The most frequently observed manifestation was retinal hemorrhages (n = 14), followed by papilledema (n = 9) and ocular surface involvement (n = 5). The eye involvement was more frequently identified in the AML group (24%), compared to the ALL group (22%), especially papilledema with central nervous system compromise ALL (5%) and AML (11%), P < 0.01. The presence of hemorrhages was similar in both groups. In patients with retinal hemorrhage (n = 14), the mean hematological findings were hemoglobin 7.4 ± 0.4 g/dL (6.5-8.0), erythrocytes 2.5M ± 0.3/mm3 (confidence interval [CI], 2.0-3.1), and platelets 76,000 ± 32,000/mm3 (CI, 8000-384,000). Patients without retinal findings (n = 123), the mean hematological findings were hemoglobin 9.1 ± 0.6 g/dL (8.0-10.2), erythrocytes 3.2M ± 0.6/mm3 (CI, 2.5-3.5), and platelets 92,000 ± 44,000/mm3 (CI, 42.000-390.000). Multivariable analysis found that hemoglobin levels were the most reliable predictive factor for retinal findings. It was observed that the risk diminishes in patients with levels higher than 8.5 g/dL, and that it increased in patients with levels ranging between 6.5 and 7.5 g/dL at least twice (P < 0.01).
CONCLUSIONS: Our results show that ocular involvement occurs in a high percentage of patients with leukemia with a clear clinical, humoral, and sometimes prognostic correlation, suggesting routine ophthalmologic evaluation in these patients. Copyright:

Introduction

Leukemia is a group of diseases that start in the bone marrow and produce large numbers of abnormal blood cells that enter the bloodstream, sometimes leading to systemic infiltration of immature neoplastic lymphocytes in distant organs and tissues. Ocular involvement in leukemia is a well-known phenomenon in which any ocular tissue may be compromised.[12]

In leukemia, ocular involvement may precede the diagnosis or develop during the course of the disease. The ophthalmologic symptoms may be the result of primary involvement due to infiltration of ocular tissues or secondary to hematological changes produced by the disease.[34]

In primary leukemic infiltration, three different patterns are recognized: uveal infiltration of the anterior segment; infiltration of the orbit, including chloromas, orbital hemorrhages, and proptosis; and a neuro-ophthalmologic pattern, characterized by central nervous system (CNS) involvement, including optic nerve infiltration, cranial nerve paralysis, and papilledema.[156789]

Secondary findings, such as vitreoretinal hemorrhages, glaucoma, infections, and alterations of the ocular surface, may be due to hematological abnormalities resulting from the presence of anemia, thrombocytopenia, or hyperviscosity as well as adverse effects of treatments with corticosteroids, chemotherapy, bone marrow transplantation, and radiotherapy; and finally, to immunosuppression caused by the sum of several of the factors previously mentioned.[1234567]

In both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), the presence of specific orbital and eye lesions has a high statistically significant correlation with disease relapse or CNS involvement, resulting in a lower survival rate.[456] In patients with leukemia, the finding of leukemic infiltrates, among other signs, warrants a systemic and neurological re-evaluation. The above data suggest that an ophthalmological evaluation should be performed in all patients with leukemia.[45678] This study in our knowledge is the first one offering findings that are not previously published from a large Latin American pediatric sample.

Materials and Methods

A single-center, retrospective, observational analysis was conducted including all patients with AML and ALL seen at the Department of Ophthalmology of J. P. Garrahan National Pediatric Hospital between March 1, 2017, and February 28, 2018.

The patients underwent complete ophthalmological examination that is a routine practice pattern to obtain a baseline eye examination for children with leukemia in our institution, including evaluation of visual acuity and eye movement, biomicroscopy (slit lamp), and fundoscopy (indirect binocular ophthalmoscope). These examinations are performed at diagnosis, relapse, or relapse suspect. Imaging studies were also performed. Imaging studies including fundus photography, fluorescein angiography, were also included when available.

Variables such as age, sex, diagnosis, presence or absence of ophthalmologic findings, type of ophthalmologic findings, considering retinal lesions, papilledema, cataracts, orbital infiltration, proptosis, and involvement of the eye surface, as well as hematologic findings were evaluated in the analysis. All continuous variables were expressed as mean with standard deviation or median with interquartile range, and categorical variables were presented as proportions. Categorical variables were compared using the Chi-square or the Fisher exact test. All data were entered in Microsoft Excel 2015 (Microsoft Corp, Redmond, WA) and were analyzed using Stata Statistical Software: Release 15. College Station, TX: Stata Corp LLC. All P ≤ 0.05 were considered statistically significant.

Results

Overall, 137 patients with acute leukemia underwent ophthalmological examination between March 2017 and February 2018. The mean age was 7.9 ± 3.2 years (0–18), and 55% were male (n = 75) and 45% female (n = 45). At least one-fifth (n = 31) of the patients presented some type of ocular manifestation (23%).

The largest group consisted of 99 patients with a diagnosis of ALL, accounting for 72% of the whole cohort. The remaining group included 38 patients with a diagnosis of AML, accounting for 28% of the patients.

In patients with ALL (n = 99), the following ophthalmological manifestations were found: intraretinal and preretinal hemorrhages (n = 10) [Figure 1], papilledema (n = 5), ocular surface involvement (corneal ulcers and conjunctivitis) (n = 5), retinochoroideal infiltration (n = 1), and chloroma with proptosis (n = 1).

Figure 1

Fundus photograph of a patient with acute lymphoid leukemia, superficial (white arrow) and deep hemorrhages, and a subhyaloid bleed involving the macula (black arrow)

Meanwhile, in the AML group (n = 38), the following ophthalmological manifestations were found: intraretinal and preretinal hemorrhages (n = 4), papilledema (n = 4) [Figure 2a and b], and proptosis (n = 1).

Figure 2

(a) Fundus photograph of a patient with acute myeloid leukemia, showing multiple retinal hemorrhages (white arrow) and optic nerve infiltration (black arrow). (b) Fundus photograph of a patient with acute myeloid leukemia, showing papilledema

The most frequently observed manifestation was retinal hemorrhages (n = 14), followed by papilledema (n = 9) and ocular surface involvement (n = 5). Out of the full cohort, 31 patients (23%) had positive ophthalmologic findings, were more frequently identified in the AML group (24%), compared to the ALL group (22%), especially papilledema with CNS compromise ALL (5%) and AML (11%), P < 0.01. The presence of hemorrhages was similar in both groups. The patient characteristics are summarized in Table 1.

Table 1

Comparison of ophthalmic manifestations among the different types of leukemia

	ALL	AML	Total
Total number of patients included in our study	99	38	137
Ocular involvement	22 (22)	9 (24)	31 (23)
Leukemic retinal/choroides infiltrates	1 (1)	0	1 (<1)
Optic nerve infiltration/disc edema	5 (5)	4 (11)	9 (7)
Subconjunctival hemorrhages/ecchymosis	5 (5)	0	5 (4)
Periorbital edema, mechanical ptosis	1 (1)	1 (3)	2 (2)
Dot/blot/splinter/subhyaloid hemorrhages	10 (10)	4 (10)	14 (10)

Data are n (%) unless otherwise indicated. ALL: Acute lymphoid leukemia, AML: Acute myeloid leukemia

In patients with retinal hemorrhage (n = 14), mean hematological findings were hemoglobin 7.4 ± 0.4 g/dL (6.5–8.0), erythrocytes 2.5M ± 0.3/mm3 (confidence interval [CI], 2.0–3.1), and platelets 76,000 ± 32,000/mm3 (CI, 8000–384,000). Patients without retinal findings (n = 123), mean hematological findings were hemoglobin 9.1 ± 0.6 g/dL (8.0–10.2), erythrocytes 3.2M ± 0.6/mm3 (CI, 2.5–3.5), and platelets 92,000 ± 44,000/mm3 (CI, 42.000–390.000).

Discussion

A large sample of pediatric patients with ALL and AML were studied. In the majority of those who had ocular involvement, the manifestations were secondary to changes in hematological levels. Of all the patients with leukemia, 23% (n = 31) presented ocular findings. These figures are comparable with 35.4% reported in Malaysia and 39% reported in the United States.[910]

In a study of 288 patients with leukemia, Reddy et al. found that 49.1% of the adults and only 16.5% of the children had some type of ocular involvement. Guyer et al. studied ocular findings only in patients with acute leukemia and found a similar difference of 73.9% versus 15% in adults and children, respectively.[1011] Given that our series report similar percentages to those observed in other pediatric studies, age might be an important factor in the frequency of ocular manifestations in acute leukemia.

Russo et al. studied a series of 180 children with acute leukemia associated with ophthalmologic findings and found that these manifestations were more frequent in patients with AML. In our study, we observed differences in the rate of ocular involvement, especially papilledema with CNS compromise ALL (5%) and AML (10%), P < 0.01.[12131415]

Similar to our study, many reports have shown that the most common ocular signs are findings on fundoscopy, mainly in the retina, of which retinal hemorrhage is the most common.[681416] The majority of retinal hemorrhages are related to bleeding diathesis secondary to leukemia. Sharma et al. stated that rheological changes are the main predisposing and causative factor of the ophthalmologic signs and are mainly found in the posterior segment. They reported that at least 69% of the patients will have retinal manifestations at some point in the course of their disease.[16171819]

Multivariable analysis found that hemoglobin levels were the most reliable predictive factor for retinal findings. It was observed that the risk diminishes in patients with levels higher than 8.5 g/dL, and that it increased in patients with levels ranging between 6.5 and 7.5 g/dL at least twice (P < 0.01). Abu el-Asrar et al. described that low hemoglobin levels are associated with retinal hemorrhages and soft exudates in patients with ALL.[202122]

Acute leukemias present frequently at a young age, and there is a high percentage of ocular involvement and visual morbidity, as seen from our study. Soman et al. described that children had significantly lower Hb levels and platelet counts than their adult counterparts did, partly explaining the greater numbers of children with hemorrhage.[23] Pediatric ophthalmologists should be especially aware of hemorrhagic diathesis status given that subsequent vitreal or subhyaloid bleeding could pose a risk of amblyopia.

Involvement of the optic nerve is usually associated to the increased intracranial pressure seen in CNS compromise, as well as direct infiltration by blast cells. Therefore, in patients with optic nerve alterations, the CNS is likely affected and treatment should be indicated according to the diagnosis and stage of the disease.[38] In AML, a tumor type called granulocytic sarcoma or chloroma due to the greenish color of its surface may occur. Chloromas may even appear before the appearance of blasts in peripheral blood.[24] In general, it is not necessary to take a biopsy of the lesion, except when a relapse is suspected, and ocular features are the only disease manifestations at that moment.

The treatment of choice of ocular infiltration is systemic chemotherapy for the specific cell lineage. This is usually indicated by the pediatric oncologist, intercalated with regular ophthalmologic consultations to monitor local response.

Conclusions

Our study shows the high prevalence of ophthalmic findings in children with acute leukemia in a tertiary hospital in South America in a Latin American children group. As many as one in five children with leukemia showed ocular manifestations of the disease.

Retinal hemorrhages were the most commonly found ophthalmologic manifestation and were associated with anemia and/or thrombocytopenia. Limitations to our study are bound to the retrospective nature of the data collection. Strengths include the number of patients and the novel ethnicity sample.

The high rate of ocular manifestations in patients with leukemia shows the importance of regular ophthalmological evaluations in these patients. It is possible, with an ocular exam, to aid in establishing a prompt diagnosis in case of relapse. We suggest at least one examination at diagnosis, relapse, or relapse suspect.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.