Demographic profi le & correlation between retinal exudates and hematological parameters in leukemic patients

Results: Among 50 leukemic patients’, the fundal lesion was detected in 32 patients (64%), retinal exudates are rare. Only 3 patients (6%) had exudates while others (29 patients, 58%) have retinal hemorrhages. Exudates did not show any statistically signifi cant relationship with types of leukemia (p value = 0.53). There was no statistically signifi cant association between fundal exudates and high white cell count (p = 0.56) or low hemoglobin level (p = 0.11) or low platelet level (p = 0.11).


Introduction
Leukemia is a malignant proliferative disorder of leukopoitic bone marrow stem cells characterized by overcrowding of the bone marrow by immature neoplastic leukocytes and widespread in iltration of organs, tissues and peripheral blood by immature leukocytes [1]. The resultant displacement of normal haemopoitic stem cells from the bone marrow leads to secondary hematologic complications such as erythropenia, thrombocytopenia and leukostasis. Although there is peripheral leukocytosis, the circulating leukocytes are immature and dysfunctional. The secondary hematologic alterations are responsible for tissue ischemia, bleeding diathesis, immunosuppression, and hyperviscosity state which are the cardinal pathological features of leukaemia [2].
Based on cell types, differentiation, morphology, cytogenetic characteristics and immunophenotyping, leukemia is classi ied into acute and chronic subgroups. Each subgroup further sub-divided into myeloblastic and lymphoblastic variants such as acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), chronic lymphocytic leukemia (CLL) and chronic myelocytic leukemia (CML) [1][2][3]. In a study, reports of patients with acute lymphoblastic leukemia presenting with visual symptoms as the initial sign of the disease are rare. However, the ocular changes in acute lymphoblastic leukemia (ALL) are common. It has been reported to occur in up to 90% of patients with this disease. It was observed in 48 of the 50 patients in a study [4]. Leukemic relapses are often diagnosed after the ocular presentation. The ocular involvement has been associated with higher frequency of bone marrow relapses and central nervous system compromise weeks or months later, which means a poor prognosis and low survival rate.
A lot of lesions are asymptomatic and patients are diagnosed during routine examination by ophthalmologist [5]. Therefore it is important to consider fundoscopic evaluation at the time of diagnosis of leukemia. Ophthalmic involvement in acute lymphoblastic leukemia can be classi ied into two major categories: primary or direct leukemic in iltration of the ocular structures and secondary or indirect involvement. These secondary changes may be the result of hematological abnormalities such as anemia, thrombocytopenia, leucopenia, and hyperviscosity. Likewise, opportunistic infections due to immunosuppression particularly viral, protozoal and fungal infections and the leukemia treatment itself may secondarily involve the ocular system [6]. Previous studies revealed optic disc edema, dilated and tortuous retinal vessels, retinal blot and lame shaped hemorrhages, Roth's spot, perivascular sheathing and exudates during fundoscopic examination of leukemic patients [7].

Materials and methods
This descriptive, cross-sectional study was carried out in Medicine and Oncology departments of Bangladesh Medical College Hospital from May, 2020 to October 2020. Total 50 known cases of leukemia were selected. The diagnosis was made by bone marrow study in case of acute leukemia's and chronic myeloid leukemia and by peripheral blood ilm with immunophenotyping in case of chronic lymphocytic leukemia. Fundoscopic indings and hematological parameters of these diagnosed cases were collected in this study. Fundoscopic examination was reviewed by an ophthalmologist. Collected data was analyzed statistically by using SPSS-17 (Chicago, Illinois).
Diagnosis of acute leukemia will be based on bone marrow evidence and chronic leukemia on Complete Blood count (CBC) and peripheral blood ilm (PBF) and immunophenotyping in case of CLL.

Results
This descriptive cross sectional study on 50 Leukemic patients was carried out in the in-patients departments of medicine and oncology of Bangladesh Medical College and Hospital (BMCH), Dhaka from May, 2020 to October, 2020 to ind out the demographic pro ile and correlation between fundoscopic indings and hematological parameters of leukemia patients in the tertiary level hospital in Bangladesh. Figure 1 and table 1 showing the age distribution of 50 leukemic patients. It was obvious that more than 60 years persons were affected more (total 16, 32%) than that of any age group followed by age between 21-30 years (total 14, 28%), between 41-50 years (total 9, 18%), between 31-40 years (total 6, 12%), between 51-60 years (total 3, 6%). Age less than 20 years were the least affected (total 2, 4%). Figure 2 showing females were affected more (total 26, 52%) than males (total 24, 48%). Figure 3 showing among the 50 patients, the fundal lesion was detected in 32 patients (64%). Figure 4 showing among 32(64%) patients with fundoscopic abnormalities, only 3 patients (9%) had exudates while others (29, 91%) have retinal hemorrhages. Exudates did not show any statistically signi icant relationship with types of leukemia (p value=0.53) Figure 5. Table 2 shows 3 out of 32 patients with anemia (hemoglobin less than 10 gram/dl) have retinal exudates and 18 out of 18 patients without anemia have no exudates.   There were no statistically signi icant correlation between anemia and retinal exudates (p value > 0.05). Table 3 shows 28 out of 29 patients without high leukocyte count (white blood cell count more than 100000/cmm) have no exudates and only 2 out of 21 patients with high leukocyte count have exudates. P value was > 0.05 which was not statistically signi icant. Table 4 shows 35 out of 36 patients with thrombocytopenia (platelet count less than 150000/cmm) have no retinal exudates and 2 out of 14 patients without thrombocytopenia have exudates. Statistically signi icant relation was not found between thrombocytopenia and retinal exudates (p value > 0.05).

Discussion
Leukemic retinopathy is the term most used to denote fundus manifestations of anaemia, thrombocytopenia and increased blood viscosity seen in patients with leukemia. 9 In the present study, higher prevalence (64%) of leukemic retinopathy was noted than the prevalence of 42%, 43% and 49% reported by Guyer, et al. [9], Abu, el-Asrar, et al. [13] and SC Reddy and N Jackson [16] respectively. Intra retinal hemorrhages were seen more often than above three studies. This very high percentage of fundoscopic abnormalities may due to majority of patients with acute leukaemia and cooccurrence of thrombocytopenia and anemia in the majority of patients.
In the present study, 28 out of 36 patients with thrombocytopenia have retinal hemorrhages and 13 out of 14 patients without thrombocytopenia have no hemorrhages. Statistically signi icant relation was found between thrombocytopenia and retinal hemorrhages (p value < 0.05). This inding is consistent with the study inding of "A Prospective Ophthalmic Evaluation of Patients with Acute Myeloid Leukemia: Correlation of Ocular and Hematologic indings" done by Karesh, et al. [3] and Retinopathy in acute leukemia at initial diagnosis: correlation of the fundal lesions and hematological parameters" done by Reddy, Jackson [16]. In contrast another study was done by Abu el-Asar, et al. inds no relation between thrombocytopenia and retinal haemorrhage [13].
In this study, 21 out of 32 patients with anemia have      [14,16]. This inding may be due to small sample size in this study.
Shivaprasad C and Srinivasan R, studied, 120 eyes of 60 consecutive patients with leukemia and lymphoma who presented to the hematology clinic of Jawaharlal Nehru Institute of Postgraduate Medical Education and Research were included in this study. Of the 60 patients examined which included 32 males and 28 females, 36 of them had chronic leukemia, 18 had acute leukemia and 6 patients had lymphomas. Ocular manifestations were present in 42.85% (25 patients). The most common ocular manifestation was conjunctival pallor in 30.95% (18 patients). Retinal changes were seen in 26.19% (16 patients) which included optic disc pallor and retinal vascular changes with hemorrhages and soft exudates. The retinal changes were bilateral and asymmetrical. Patients with optic disc pallor had hemoglobin ranging from 2.0-6 gram%. Of the total 8 patients presenting with retinal hemorrhages and soft exudates, six of them were acute leukemias, one chronic leukemia, another being Non-Hodgkins lymphoma. All of them had reduced platelet count counts ranging from10000 to 59000. The patient with platelet count of 10000 had more retinal hemorrhages which had also involved the macular area. Visual acuity was decreased in 7.1% due to hemorrhage at macula. Correlation between total white cell count, anemia and retinal hemorrhages or cotton wool spots was not observed in their study. No signi icant association was found between gender and the presence of retinal lesions. Retinal vascular changes with hemorrhages correlated with platelet counts and are commoner in acute leukemias [15].
Hemorrhages of the retina are the most striking feature of leukemia. They tend to occur most commonly at the posterior pole, may be at any level of the retina and may extend into the subretinal or vitreous spaces. Retinal hemorrhages have been described as dot and blot, or lame-shaped or classically as white-centered hemorrhages. It has been proposed that this white center represent platelet ibrin aggregates.or an accumulation of leukemic cells.
In this study, 19 out of 29 patients without high leukocyte count have hemorrhages and 11 out of 21 patients with high leukocyte count have no hemorrhages. P value was > 0.05 which was not statistically signi icant. Similarly, Holt and Gordon-Smith and Mahneke and Videbaek, describe that the white blood cell count was not related to the occurrence of White Centered Hemorrhage (WCH) [20]. Guyer, et al. found a non-signi icant trend of leukocytosis in patients with WCH [10]. In contrast this study inding is not consistent with the observation of Gibson 1938 and Abu el-Asrar, et al. [13].
This prospective, observational case series surveyed adult leukemia patients presenting at Tertiary Hospital population of adult Nigerian Africans departments of Hematology/Immunology and Ophthalmology from July 2003 to August 2008. The demographic pro ile, clinical data from for each individual in the cohort were statistically collated and analyzed. A p < 0.05 was considered as statistically signi icant. There were 72 participants (45 males and 27 females), aged 32.7 ± 9.8 years (range, 18 years to 72 years). Leukemic ophthalmopathy was present in 77.8% of subjects. The leading ophthalmic manifestations of leukemia were retinal vascular abnormalities in 50.0% of subjects, conjunctival pallor in 27.8% of subjects, sub-conjunctival hemorrhage in 19.4% of subjects and retinal hemorrhage in 16.7% of subjects. Ocular co-morbidity was present in 47.2% of subjects. Vision loss occurred in 37.5% of subjects, of which 32.1% was leukemia related, and the remaining due to ocular co-morbidity. Leukemic ophthalmopathy was more prevalent in chronic leukemia (p < 0.05), frequently affected the ocular posterior segment (p < 0.05), and often resulted from secondary hematologic complications (p < 0.05). There was no gender difference in the prevalence of leukemia (p = 0.0822) or leukemic ophthalmopathy (p = 0.6624). The prevalence of leukemic ophthalmopathy in Enugu is high. It is often associated with signi icant ocular co-morbidity and vision loss. These have implications for clinicians involved in leukemia management. Early diagnosis and regular ophthalmic examinations are recommended to optimize treatment outcomes. 17 A prospective study of ocular disorders in adult patients with leukemia at the University of Benin Teaching Hospital, Benin City, Nigeria, between July 2004 and June 2008 was conducted. The patients were interviewed and examined by the authors and the ocular indings were recorded. The means, standard deviation, and the Kruskal-Wallis non parametric test was performed. Forty-seven patients with leukemia were seen. Nineteen patients (40.4%) had CLL, 14(29.8%) had CML, 9(19.1%) had AML and 5(10.6%) had ALL. Seven patients (14.9%) had ocular disorders due to leukemia. The ocular disorders due to the leukemia were proptosis in two patients (4.3%), retinopathy in one patient (2.1%), conjunctival in iltration in one patient (2.1%), periorbital edema in one patient (2.1%), retinal detachment in one patient (2.1%), and subconjunctival hemorrhage in one patient (2.1%). There was no signi icant difference in rate of the ocular disorders in the various types of leukemia (Kruskal-Wallis KW = 4.019; corrected for ties. P = 0.2595). One patient (2.1%) was blind from bilateral exudative retinal detachment while 1 patient (2.1%) had monocular blindness from mature cataract. Ophthalmic disorders that are potentially blinding occur in leukemia. Ophthalmic evaluation is needed in these patients for early identi ication and treatment of blinding conditions [18]. https://doi.org/10.29328/journal.jhcr.1001017 Chronic myeloid leukemia (CML) is a well-studied entity and advances made in diagnosis and treatment has improved the disease outcome. Patients with ophthalmic manifestation of CML have been reported to have lower 5-year survival rates. Hence, recognizing the early fundus changes may improve outcome by allowing earlier diagnosis and treatment. They report a case of a previously healthy 30-year-old Myanmarese male, who presented with a minor visual disturbance, complaining of seeing a 'black dot' in his left visual ield for the past 1 week. Fundoscopic examination revealed bilateral retinal blot hemorrhages, white-centered hemorrhage, and preretinal hemorrhage over the left fovea. The full blood count and peripheral blood ilm were abnormal, and bone marrow biopsy con irmed the diagnosis of CML. Cytoreduction therapy was promptly commenced and his symptoms resolved, with improvement in visual acuity. No complications were recorded at 1-year follow-up [21].
The autopsy study by Leonardy, et al. [22] showed a highly signi icant correlation between ocular leukaemic cell in iltration and white blood cell counts; in a number of cases, leukaemic cells were seen migrating in choroidal vessels or in iltrating perivascularly. It is probable that this mechanism may explain the role of a white blood cell count in the pathogenesis of retinal hemorrages in these patients.
In this study, 35 out of 36 patients with thrombocytopenia have no retinal exudates and 2 out of 14 patients without thrombocytopenia have exudates. Statistically signi icant relation was not found between thrombocytopenia and retinal exudates (p value > 0.05).
Similar to the observation of Guyer, et al. [10]. I didn't ind any signi icant association between the presence of cottonwool spots and hemoglobin level. However, Abu el-Asrar, et al. [16]. reported that ALL patients with cotton-wool spots had signi icantly lower hemoglobin levels than patients without such lesions. This study showed no statistically signi icant correlation between Hemoglobin levels with exudates.
It is observed that the mean white cell counts in patients with cotton wool spot (CWS) in AML and ALL groups was higher than in those without CWS, but this was not statistically signi icant. Abu el-Asrar, et al.
[16] found a signi icantly lower leukocyte count in patients with AML with CWS, and higher leukocyte count in patients with ALL with CWS, while Guyer, et al. [10]. In the present study, there is no statistically signi icant association between leukocytosis and the presence of CWS.
Cotton-wool spot are often present in patients with leukemia. They are caused by occlusion of precapillary arterioles resulting in retinal ischaemia 23 . This focal ischaemia leads to a blockage of exoplasmic low within the nerve ibre layer of the retina, with the subsequent deposition of intraaxonal organelles. The reason for this occlusion in leukemia is poorly understood. They may be related to ischaemia secondary to anemia, direct occlusion by leukemic cells and occlusion by platelet ibrin aggregates or sludging resulting from hyperviscosity [24,25].
Reddy and Jackson study reported, a total of 127 patients with acute leukemia were examined for retinal changes, of whom 78 (61%) were male and 49 (39%) were female; 83 (65%) had myeloid leukemia and 44 (35%) had lymphoid leukemia. The mean age of the patients was 34.6 years (range 13-77 years) [16].

Conclusion
This study has identi ied retinal exudates among patients with leukemia patients. Retinal exudates were rare (6%) in our study group. However a high percentage of patients (64%) with leukemia had fundal lesions. Recognition of retinopathy is important to improve care of leukemia patients because it has impact on the prognosis and overall management of these patients. Therefore an adequate attention should be paid to fundoscopic evaluation while treating leukemic patients.

Limitation of study
The present study did not represent the actual scenario of leukemic retinopathy in Bangladesh because the study was conducted in one tertiary level hospital (Bangladesh Medical College and Hospital (BMCH) in Dhaka city only. Sample size and duration of the study was short. Treatment outcomes were also not assessed because of lack of follow up.
Ethical clearance: Appropriately taken.