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The Official Scientific Journal of Delhi Ophthalmological Society
Ophthalmic Manifestations In Patients of Acute Leukaemia Presenting to A Tertiary Care Centre In Western Rajasthan
Shilpi Kochar, Yamini Singhal, Jaishree Murli Manohar, Kalpana Jain
Department of Ophthalmology, Sardar Patel Medical College, Bikaner, Rajasthan, India
Corresponding Author:
Shilpi Kochar 
MS
Assistant Professor
Department of Ophthalmology
S.P. Medical College, Bikaner, India
Email id: drshilpijain38@yahoo.com
Published Online: 30-APR-2018
DOI: http://dx.doi.org/10.7869/djo.350
Abstract
Purpose:- To determine the prevalence and pattern of ophthalmic manifestations in patients of Acute Myeloid Leukemia (AML) and Acute Lymphoid Leukemia (ALL) presenting to a tertiary care centre in Western Rajasthan. 

Materials and Methods:- This cross-sectional non-interventional study was conducted from April 2015 to March 2016 to study the spectrum of ophthalmic manifestations in 110 acute leukaemia patients. Patient’s demographic data, medical and treatment history, anterior and posterior segment examination with haematological and radiological investigations were recorded.

Results:- The study subjects (n = 110: 57 males and 53 females) comprised 64 ALL and 46 AML patients whose age ranged from 22 months to 58 years. There were 44 adults and 66 children. Leukemic ophthalmopathy was present in 61 (55.45%) subjects. Ocular changes were present in 30/44 (68.18%) adults and 31/66 (46.97%) children (P<0.04). Thirty four males (34/57, 59.65%) and 27/53 (50.94%) females had ocular manifestations (P<0.46). The leading posterior segment ophthalmic manifestation was superficial haemorrhage and the anterior segment manifestation was sub-conjunctival hemorrhage. Primary or direct leukemic infiltration was seen in 11 (10%) subjects while secondary or indirect involvement was seen in 60 (54.54%) subjects. Leukemic ophthalmopathy was more prevalent in Acute Myeloid Leukaemia in comparison to Acute Lymphoid Leukaemia, frequently affected the ocular posterior segment and often resulted from secondary hematologic complications (P <0.001). 

Conclusion:- Leukemic ophthalmic lesions were found in 61/110 (55.45%) patients. Ocular involvement is more often seen in Acute Myeloid Leukemia. Early diagnosis and regular ophthalmic examinations are recommended to optimize diagnosis, prognostic and treatment outcomes of Acute Leukaemia patients.
Keywords : Leukemia, retinal haemorrhage
Introduction

Leukaemias are malignant neoplasms of the haematopoietic stem cells, characterized by diffuse replacement of the bone marrow by neoplastic cells and widespread infiltration of organs, tissues and peripheral blood by immature leucocytes.1 The resultant displacement of normal hematopoietic stem cells from the bone marrow leads to secondary hematologic complications such as erythropenia, thrombocytopenia and leukostasis. Although there is peripheral leucocytosis, the circulating leucocytes are immature and dysfunctional. These secondary hematologic alterations are responsible for tissue ischemia, bleeding diathesis, immune-suppression, and hyperviscosity state which are the cardinal pathologic features of leukemia.2

With evolving diagnostic and therapeutic advances, the survival of patients with acute leukaemia has considerably improved. This has led to an increase in the variability of ocular presentations in the form of side effects of the treatment and the ways leukaemic relapses are being first identified as an ocular presentation. Leukaemia may involve any ocular tissues either by direct infiltration, haemorrhage, ischaemia, or toxicity due to various chemotherapeutic agents. Ocular involvement may also be seen in graft-versus host reaction in patients undergoing allogeneic bone marrow transplantation, or simply as increased susceptibility to infections as a result of immunosuppression that these patients undergo. 

Ophthalmic involvement can be classified into two major categories: 
1. Primary or Direct leukaemic infiltration 
2. Secondary or Indirect involvement. 

The Direct leukaemic infiltration can show three patterns: anterior segment uveal infiltration, orbital infiltration, (Figure 1) and neuro-ophthalmic signs of central nervous system leukaemia that include optic nerve infiltration, cranial nerve palsies, and papilloedema. The Secondary changes are the result of haematological abnormalities of leukaemia such as anaemia, thrombocytopenia,


hyperviscosity, and immunosuppression. These can manifest as retinal or vitreous haemorrhage, infections, and as vascular occlusions.3 In some cases the ocular involvement may be asymptomatic. In one prospective study, there was a high prevalence of asymptomatic ocular lesions in childhood acute leukaemia.4 In the era before effective anti leukaemic therapy, retinopathy was believed to be of no prognostic significance in acute leukaemia.5,6 However, recent reports have demonstrated that the presence of ocular involvement is associated with poor prognosis in acute childhood leukaemias.6 Therefore, it is important to consider an ophthalmic evaluation at the time of diagnosis of acute leukaemia in adults and children. Recognition of the varied ocular presentations is also important in assessing the course and prognosis of leukaemia. We have presented a systematic approach by conducting detailed ophthalmological examination of every part of the eye and outlining how leukaemia has been shown to affect it.

Materials and Methods

This cross-sectional non-interventional study was conducted from April 2015 to March 2016 in Department of Ophthalmology, S.P. Medical College, Bikaner in conjunction with Acharya Tulsi Regional Cancer Centre. One hundred and ten subjects diagnosed with Acute leukemia at Acharya Tulsi Regional Cancer Centre, Bikaner were enrolled in this study. The diagnosis of leukemia was based on history, clinical features, examination of blood film and bone marrow aspiration. Patients with diabetes, hypertension, primary ocular diseases, dense cataractous changes and other media opacities were excluded from the study. Subjects not giving an informed consent, unwilling for a complete eye examination or were too sick to be examined were also excluded. All patients underwent detailed examination of anterior and posterior segment which included Snellen’s best corrected visual acuity, slit lamp examination, intraocular pressure measurement by Applanation tonometry, posterior segment examination under pharmacological mydriasis using direct, indirect ophthalmoscopy and slit lamp biomicroscopy using Volk 78D lens. Fundus photography documentation was done in cases with positive finding. A proforma was devised to include patient’s demographic data, brief medical and treatment history, anterior and posterior segment examination and detailed haematological and radiological investigations.

Results

The study subjects comprised 57 males and 53 females whose age ranged from 22 months to 58 years. There were 44 adults and 66 children. Out of total 110 diagnosed cases of leukemia enrolled in the study, 64 subjects (58.18%) had Acute Lymphoblastic Leukaemia and 46 patients (41.82%) (Graph1) were of Acute Myeloblastic Leukaemia. Ocular lesions were found in 61 subjects (55.45%). Twenty nine subjects (63.04%) of the Acute Myeloid Leukemia (n=46) and 32 (50.0%) (Graph 2) of acute lymphoid leukemias (n=64) had ophthalmic manifestations of leukemia (p<0.004). Primary or direct leukemic infiltration was seen in 11 (10%) patients. Of the 11 patients with direct leukaemic manifestations, 8 (72.73%) had AML and 3 (27.27%) had ALL. Secondary or indirect involvement due to anemia, thrombocytopenia, hyperviscosity, and immunosuppression were seen in 60 (54.54%) patients. Of these 60 patients, 28 were AML (46.67%) and 32 (53.33%) were ALL. (p<0.001) Of the 44 adult leukemic patients, 30 (68.18%) had leukemia related ocular changes while 31 (46.97%) of 66 children with leukemia had leukemic ophthalmopathy. Thirty four (59.65%) males and 27 (50.94%) females had ophthalmic manifestations of leukemia (Graph 3). Ninety four (85.45%) subjects were undergoing chemotherapy while 16 (14.55%) subjects were not undergoing any form of treatment prior to ophthalmic evaluation. Of these subjects, 54/94 (57.45%) who had chemotherapy had changes while 7/16 (43.75%) of those who did not have chemotherapy had changes. Eight patients out of 110 (7.27%) had ophthalmic manifestation on presentation. Leukemic ophthalmic involvement was symptomatic in 38 (62.29%) and asymptomatic in 23 (37.71%) of subjects.








Discussion

Knowledge of ocular involvement in leukemia is important because the eye is the only site where the leukemic involvement of nerves and blood vessels can be directly observed. Ophthalmic involvement in leukaemia can precede the diagnosis of leukaemia or can occur during course of the disease or secondary to treatment.7 The reported prevalence of ocular involvement in leukaemia ranges from 9% to as high as 90%.8,9 This divergent variation in results may imply the transient nature of leukemic ocular findings, which may be waxing and waning with time and treatment. It may also be due to the varied study designs and study centres. It is estimated that up to 69% of all patients with leukaemia show fundus changes at some point in the course of their disease.10

The 55.45% prevalence of leukemic ophthalmopathy documented in the present study is comparable to 69.0% reported by Alemayehu et al,10 but differed markedly from 35.4% reported by Reddy et al,11 and 39.0% in a series by Schachat et al.12 The observed disparity could be attributed to the difference in case mix between the present study and those of Reddy et al, and Schachat et al. In the present study, the spectrum of leukemic ophthalmopathy showed a preponderance of posterior segment over anterior segment manifestations. These resulted predominantly from secondary hematologic complications caused either by the leukemia itself or its treatment rather than primary leukemic ocular infiltration.8,12 Superficial and deep retinal hemorrhages were the leading posterior segment lesions while sub-conjunctival hemorrhage (Figure 2) was the commonest anterior segment sign observed in this study [Table 1]. These findings corroborated with the spectrum of leukemic ocular involvement reported in America,2,12 Asia,11 and Africa10 but differed from the high rate of primary neoplastic leukemic ocular infiltration in an autopsy series reported in America.9






Subjects with AML (63.04%) had higher incidence of ocular manifestation than ALL patients (50%). This was similar to studies by Reddy et al11 and Omoti et al13 (Figure 3 & 4).





There were 44 adults and 66 children who were examined. Among the adults, 30/44 (68.18%) had ocular changes while 31/66 (46.97%) of children had changes. Reddy et al 11 in a study of 288 cases of leukemia found that 49.1% of adults had ocular involvement as compared to only 16.5% of children. Guyer et al 14 studied retinal changes in acute leukemias only and found 73.9% of adults had changes versus only 15.9% of children. Thirty four (59.65%) males and 27 (50.94%) females had ophthalmic manifestations of leukemia however; there were no statistically significant gender based differences in the presence of leukemic ophthalmopathy. The important drawback of present study similar to previous other ante-mortem studies2,4,10,12 which documented only the clinically evident leukemia-related ocular lesions thus probably bypassing the occult manifestations. It is sometimes difficult for the physician to appreciate the ocular manifestations of leukemia because most subjects remain asymptomatic. This definitely has implications for ophthalmologists involved in the care of leukemic patients that mandatory and periodic eye checkups at least every 6 months are a must despite the apparent noninvolvement of the eye. 

There were a few limitations of this study. This study was one time analysis and patients were not under continuous follow up therefore details of response to therapy could not be documented. Second, ultrasonography of the eye, computed tomography scan, or magnetic resonance imaging scan was not done routinely in all subjects to look for choroidal involvement of leukemia.

Conclusion 

Leukaemic ophthalmic lesions were found in 55.45% of patients. Ocular involvement is more common in AML than in ALL. Secondary involvement of the retina is the most common ocular manifestation in leukemia. The ophthalmic manifestations of leukemia tended to involve more of the posterior than the anterior segment structures of the eye, and resulted more from secondary hematologic complications rather than primary leukemic infiltration. It is sometimes difficult for the physician to fully appreciate how frequently leukaemia involves the eye, probably because many patients remain asymptomatic in the earlier stages of ocular involvement. Numerous intra-ocular and extra-ocular changes may be rare, but can still be of prognostic significance. All leukaemia patients should have an ophthalmic assessment at diagnosis and periodically at least every 6 months as it could be a critical part of their follow-up and will guide the choice of therapeutic regimen. We suggest that full collaboration among physicians, oncologists, and ophthalmologists is needed, with prompt ophthalmic assessment of patients suspected to have eye manifestations.

References
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Shilpi Kochar, Yamini Singhal, Jaishree Murli Manohar, Kalpana JainOphthalmic Manifestations In Patients of Acute Leukaemia Presenting to A Tertiary Care Centre In Western Rajasthan.DJO 2018;28:20-24
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Shilpi Kochar, Yamini Singhal, Jaishree Murli Manohar, Kalpana JainOphthalmic Manifestations In Patients of Acute Leukaemia Presenting to A Tertiary Care Centre In Western Rajasthan.DJO [serial online] 2018[cited 2018 Sep 24];28:20-24. Available from: http://www.djo.org.in/articles/28/4/Ophthalmic-Manifestations-In-Patients-of-Acute-Leukaemia.html
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