Background
Thalassemia is a severe genetic blood disorder caused by a mutation in the globin gene. Abnormal globin chains lead to the excessive destruction of red blood cells [
1]. The phenotypes of homozygous or genetic heterozygous compound beta-thalassemias include thalassemia major (TM) and thalassemia intermedia (TI). Individuals with thalassemia major usually come to medical attention within the first two years of life. These patients require lifelong RBC transfusions at regular intervals to survive. Thalassemia intermedia includes patients with milder symptoms, who present at an older age and do not require regular transfusions [
2]. More than 42,000 newborns are affected by Beta-thalassemia every year worldwide. Without blood transfusions, Beta-thalassemia major (TM) causes death amongst infected children before the age of 3 years old [
3]. Although transfusions can prevent death and decrease mortality, iron accumulated from transfused red blood cells can lead to organ failure [
4,
5]. Iron chelation treatment, to reduce iron store in the body and improve the long-term survival rate of patients with TM, is considered a mandatory adjuvant therapy.
As a group, the thalassemias are the most common single gene disorder in the world. High prevalence occurs in developing regions as well as in large multiethnic Western cities due to an expanding immigrant population [
6]. The inheritance of β-thalassemias is recessive. The mutations in the β-globin gene and consequent defective β-chain production leads to a devastating cascade: imbalance in α/β- globin chain synthesis, ineffective erythropoiesis, reduced red blood cell survival and subsequent anemia [
7]. Although the disease is confirmed genetically, the phenotype of β-thalassemia is determined based on clinical observation.
Therapeutic measures resulted in a progressive improvement in life expectancy in both developed and developing countries [
8‐
16]. Increased awareness, better education and optimal health care provision efforts, a large body of evidence attained by clinical trials and observational studies conducted in the last 3 decades, allowed for remarkable advances in diagnostic and therapeutic options. Milestones in this effort include the introduction of guidelines for safe processing of blood products, noninvasive techniques for the assessment of iron overload in target organs, oral iron chelators, and prevention/management schemes for specific complications [
17].
Thalassemia major is a multidimensional medical, social, and psychological problem. The course of thalassemia patients depends on the availability of adequate blood transfusion and other therapeutic modalities. The closer and more systematic follow-up of thalassemia patients, along with the significant improvement of available treatments, prolonged life expectancy lead to the gradual broadening of the clinical spectrum of beta thalassemia with new, previously unknown manifestations [
18].
The purpose of the present review is to identify the whole spectrum of ocular complications of thalassemia presented in the literature and provide an extensive review on both functional and structural abnormalities related to chelation therapy. We also underline the need for updated guidelines for screening and follow up of thalassemia patients and the proper utilization of multimodal imaging techniques.
Results
Below we present the findings of case control and case series studies regarding ocular findings in β-thalassemia.
Jafari et al. [
19], in a cross sectional, controlled study, examined 54 thalassemia major patients. All the thalassemic patients were asymptomatic. Ocular findings including dry eye (33.3 %), cataract (10.2 %), retinal pigment epithelium degeneration (16.7 %), color vision deficiency (3.7 %), and visual field defects (33.7 %) were detected in 68.5 % of thalassemic group. The prevalence of ocular abnormalities in the control group of normal individuals was 19.4 %, significantly lower than that in thalassemia patients (
P = 0.000). The was no statistically significant correlation between ocular abnormalities and mean serum ferritin level (
P = 0.627) and mean hemoglobin concentration (
P = 0.143). Finally, the number of blood transfusions was positively correlated with the presence of ocular abnormalities (
P = 0.005).
Barteselli et al. [
20] in a cross-sectional, observational study involving a total of 255 patients with β-thalassemia major (TM: 153 patients) and β-thalassemia intermedia (TI: 102 patients) report ocular fundus abnormalities characteristic of pseudoxanthoma elasticum (PXE) detected by cSLO in 70 of 255 patients (27.8 %). These included peau d’orange (19.6 %), angioid streaks (12.9 %), pattern dystrophy-like changes (7.5 %), and optic disc drusen (2.0 %). Pseudoxanthoma elasticum-like (PXE-like) changes were more frequent in patients with TI (
P <0.001). Patients with PXE-like fundus changes were older than patients without these fundus changes (
P <0.001). In both patients with TI and TM, age (
P = 0.001) and splenectomy (
P = 0.001) had the strongest association with presence of PXE-like fundus changes in multivariate analyses. A total of 43 of 255 patients (16.9 %) showed increased retinal vascular tortuosity independently of the PXE-like fundus changes, which was associated with aspartate amino transferase (
P = 0.036), hemoglobin (
P = 0.008), and ferritin levels (
P = 0.005). The authors concluded that PXE-like fundus changes are a frequent finding in patients with β-thalassemia. In TI, these changes increase with duration or severity of the disease. This particular ocular phenotype suggests an ocular pathology similar to PXE. Retinal vascular tortuosity may be an additional disease manifestation independent of the PXE-like syndrome. Patients with long-standing disease requiring iron-chelating treatment and those with a history of splenectomy need regular ophthalmic checkups because they are at risk of developing PXE-like fundus changes and potentially of subsequent choroidal neovascularization.
In a controlled study conducted by Nowroozzadeh et al. [
21] in 47 patients (94 eyes) to investigate the effect of altered bony orbit in beta thalassemia major on ocular biometry found that shorter axial length, thicker lens, steeper corneal curvature and more against-the-rule pattern were common findings in patients with thalassemia major.
In a prospective (1 year follow-up) observational study by Taneja et al. [
22], 45 beta-thalassemia major children under regular transfusion therapy aged between six months and 21 years,assigned in groups according to the thalassemia treatment regimes they followed at the time of presentation. Group A received only blood transfusions (six patients), Group B blood transfusions with subcutaneous desferrioxamine (six patients), Group C blood transfusions with desferrioxamine and oral deferriprone (13 patients) and Group D blood transfusions with deferriprone (20 patients). Ocular involvement was detected in 26/45 patients. Also, 18/45 patients had lenticular opacities. None of these opacities was located in the visual axis and therefore none of them interfered with vision. Lens opacities correlated significantly with higher average serum iron levels, ferritin levels and number of blood transfusions received (
P <0.001). Unaided visual acuity was found normal in 30/45 patients. Retinal Pigment Epithelium (RPE) degeneration was found in 15/45 patients and RPE mottling was seen in 4/45 patients, both more common with increasing age. Statistical significance was found between RPE degeneration or RPE mottling and higher average serum iron levels, serum ferritin levels and number of blood transfusions received but not the iron-chelating agent used. The same was true for venous tortuosity. The authors admit that the study cannot provide conclusive evident regarding the cardinal question: Are ocular changes a result of the disease per se or they emerge due to therapy with iron-chelating agents.
In a cross-sectional study, Jethani et al. [
23] studied 112 children with beta-thalassemia (224 eyes), aged 4–15 years, of whom 95 children (190 eyes, 84.8 %) not on desferrioxamine therapy (case group) and 17 children (34 eyes, 15.2 %) on desferrioxamine (control group). They found that conjunctival blanching and isolated cataractous changes in the lens were the most common anterior segment findings in the untreated children (case group). Both conditions coexisted in 12 eyes. In the control group, although no lens opacities had been detected, 4/17 children had tessellated fundus. This suggests that serum ferritin levels and iron load may not be the direct cause for the beta thalassemia ocular manifestations. According to authors, this study excludes desferrioxamine of any causal role in ocular surface disease in thalassemia patients. Rather, it is thalassemia itself the most probable cause of these disorders.
Gartaganis et al. [
24] in a controlled study of 52 beta-thalassemia patients (104 eyes) examined tear function parameters and conjuctival changes and reported that in ocular surface disorder of beta-thalassemia patients goblet cell loss and conjunctival squamous metaplasia was a constant finding.
Jiang et al. [
25] undertook an electroretinographic (ERG) controlled study on 11 patients with beta-thalassemia major to test the hypothesis that scotopic retinal function is altered in transfused thalassemia patients on chronic Deferoxamine (DFO). The authors came to the conclusion that the gradual accumulation of iron, rather than DFO toxicity underlies the scotopic dysfunction detected in older thalassemia patients, some of whom may have had extended periods of transfusion without the protection of chelation. Thus, monitoring of retinal function is recommended in such patients.
In a prospective non-controlled cohort study conducted by Dennerlein et al. [
26] to evaluate the presence of ocular side effects related to Desferrioxamine (DFO) treatment, examined 17 patients on DFO treatment: lens opacities were found in 41 % (7/17), changes in the retinal pigment epithelium in 35 % (6/17), tortuosity of retinal vessels in 24 % (4/17), dilation and sheathing of the retinal vessels in 18 % (3/17), defects in color vision in 29 % (5/17), and abnormal dark adaptation in 18 % (3/17) of the patients. The authors concluded that the ocular toxicity of DFO is dose-dependent. Major side effects including depression of the visual acuity are partially reversible by discontinuing the therapy. Under this light, regular ophthalmic evaluation becomes a necessity. Sorcinelli et al. [
27] in a case series of 53 patients with Cooley’s disease in treatment with transfusions and desferrioxamine in subcutaneous infusion, report fundus mottling appearance like “leopard skin” (15 %) as the most frequent ocular change. Additional findings were lens opacity (11 %), drusen (7 %), retinal venous tortuosity (5 %), without impairment of visual acuity. According to the authors, the pathogenic factors of the ocular change are related to abnormality of iron metabolism and these results suggest that the involvement of desferrioxamine to remove iron from the eyeball is relatively small.
Gartaganis et al. [
28] examined 29 patients with homozygous beta thalassemia and found that 12/29 patients had one or more ocular abnormalities. 5/29 patients with degeneration of the retinal pigment epithelium, 1/29 with lens opacities, 2/29 with lens opacities and degeneration of the retinal pigment epithelium, 1/29 with vascular abnormalities and degeneration of the retinal pigment epithelium, 1/29 with angioid streaks, lens opacities, and degeneration of the retinal pigment epithelium, and 2/29 with angioid streaks and degeneration of the retinal pigment epithelium. These abnormalities were not restricted in the thalassemia major group, as patients with thalassemia intermedia presented with the same findings. As expected, the frequency of these ocular abnormalities increased with age. There was no correlation between the abnormalities observed and the serum ferritin level, the mean hematocrit value, and the dose of desferrioxamine, given to the patients.
De Virgiliis et al. [
29] studied 15 children, (9 to 16 years old), with transfusion dependent thalassemia major and moderate iron overload (serum ferritin concentrations between 1100 and 2000 μg/l). They were treated with a combination of daily subcutaneous infusion and monthly intravenous administration of very large doses od desferrioxamine (according to a previously published scheme), a result of inadequate compliance with the usual daily infusion scheme. This study provided evidence that high doses of intravenous desferrioxamine infused over a short period may lead to a reversible minor toxic effect on the retina, characterized by reduced amplitude on adapted electroretinography and defective dark adaptation. The severity of toxicity on retina and optic nerve with symptoms as night blindness, field defects, visual loss, loss of color vision, and delayed visual evoked potential was correlated to intravenous or subcutaneous infusion of similar large doses of desferrioxamine for a prolonged period. Longitudinal studies in some of these patients revealed a trend towards the evolution of pigmentary degeneration of the retina indicating toxicity at the level of retinal pigment epithelium. The depletion of substances such as iron, zinc, and copper may be related to these findings.
Gelmi et al. [
30] conducted an electroretinographic and visual-evoked potential (VEP) study in 31 thalassemic patients who had never received high doses of DFO. The abnormalities found were very similar to those reported in early siderosis bulbi and included a b1-wave of significantly higher amplitude at 1 min and at the alpha point. Also, VEPs showed a N1-P1 amplitude significantly greater than in controls. According to the authors, these findings, which were more marked in older patients, point to an important causative role of iron in their genesis.
In a small case series, Davies et al. [
31] followed up four beta thalassemia major patients on intravenous DFO therapy at higher doses than previously reported. Two of them developed retinal abnormalities with symptoms as night blindness and field defects. Both showed improvement on discontinuation of the drug. One of the two affected patients died in the course of the study from heart failure, and Rahi et al. [
32] were able to obtain and examine an eye. They reported a complete set of histochemical, light microscopic, scanning and transmission electron microscopic findings. It was the first report that documented light and electron microscopical changes in the retinal pigment epithelium (RPE) following treatment with high dose desferrioxamine for systemic iron overload. The changes described include loss of microvilli from the apical surface, patchy depigmentation, vacuolation of the cytoplasm, disorganization of the plasma membrane, swelling and calcification of mitochondria. In addition, Bruch’s membrane overlying degenerated RPE cells appeared abnormally thickened owing to the accumulation of large amounts of mature elastic fibres, pre-elastic oxytalan, and long spacing collagen.
Haimovici et al. [
33] in a well characterized case series studied 16 patients with desferrioxamine-induced retinal toxicity, described some early and unusual features. The authors assessed the role of diagnostic tests in the diagnosis and management of patients with the disorder and confirmed previously reported findings in patients with established disease, including pigmentary changes in the macula and/or the peripheral fundus, reduced amplitudes in the electroretinography (ERG), and reduced electrooculographic (EOG) light-peak to dark-trough ratios. Peripapillary, papillomacular, and paramacular patterns of retinal pigment epithelial (RPE) degeneration were each observed in one patient. Diffuse RPE or outer retinal fluorescence by fluorescein angiography was a marker for active retinopathy (both at the onset of disease and during recurrence) and preceded the development of RPE pigment mottling. The authors concluded that unusual patterns of desferrioxamine retinopathy may occur in addition to the foveomacular and/or peripheral patterns previously described. Fluorescein angiography is particularly useful for determining whether there is ongoing retinal/RPE injury. ERG and EOG testing may indicate early onset or extended widespread injury, more severe than suggested by funduscopy. Patients who do not discontinue desferrioxamine after the development of retinopathy risk further retinal/RPE injury and visual deterioration
Taher et al. [
34] in a cross-sectional study of 84 randomly selected thalassemia patients reported that visual acuity (VA) was affected in 13 patients and changes in the retinal pigment epithelium were detected in 21 of them. Decreased visual acuity was significantly associated with the type of thalassemia (
P <0.05) and a history of splenectomy (
P = 0.05). Increased retinal vascular tortuosity was present in 14 patients. Changes regarding the retinal pigment epithelium, were significantly correlated to the type of iron chelation: patients on Deferriprone were more likely to have RPE degenerations as compared to patients on Desferrioxamine.
Viola et al. [
35] described macular lesions in 40 eyes of 20 beta thalassemia patients with desferrioxamine (DFO) retinopathy (minimum duration of DFO treatment 10 years), and documented their course using multimodal imaging in a retrospective chart. Imaging included fundus photography, near-infrared reflectance and fundus autofluorescence on confocal laser scanning ophthalmoscope (cSLO),and spectral domain optical coherence tomography. Ten patients (50 %) showed a variety of pattern dystrophy-like fundus changes, including butterfly shaped-like (
n = 3), fundus flavimaculatus-like (
n = 3), fundus pulverulentus-like (
n = 3), and vitelliform-like (
n = 1) changes. Ten patients (50 %) presented with negligible changes in the macula; these patients were significantly younger than patients presenting other patterns (
P = 0.023). Confocal laser scanning ophthalmoscope and spectral domain optical coherence tomography revealed a wide diversity in these abnormalities. They also seemed to be more widespread than suggested by slit lamp biomicroscopy alone. Abnormal fundus autofluorescence and/or near-infrared reflectance are produced by the accumulation of material within the outer retina or in the Bruch membrane-retinal pigment epithelium (RPE) complex. Follow-up examinations during a 40-month period revealed progressive development of RPE atrophy in areas of pattern dystrophy-like changes. This could be attributed to the fact that DFO retinopathy included a variety of pattern dystrophy-like changes or minimal changes affecting the RPE-Bruch membrane-photoreceptor complex. Multimodal imaging revealed the broad spectrum and real incidence of fundus changes in beta thalassemia patients, also confirming the evidence of previous histologic description of DFO retinopathy, suggesting that photoreceptor outer-derived retinoids, various fluorophores, and RPE displacement or clumping are involved in DFO retinopathy. These changes finally induce the RPE atrophy in most cases of pattern dystrophy-like changes.
Viola et al. [
36] conducted a prospective, cross-sectional, case-control study on 197 consecutive patients with β-thalassemia major or intermedia with at least 10 years of treatment with DFO (79 thalassemic patients without a history of chelation therapy were included as a control group) observed abnormal Fundus Autofluorescence (FAF) not related to other diseases in 18 of the 197 patients (9 %) and was classified into 4 phenotypic patterns: minimal change, focal, patchy, and speckled. The abnormal increased or decreased FAF was bilateral in all the cases, and only in some cases did it correspond to funduscopically visible alterations. There were no FAF abnormalities in the control group. During the follow-up, progressive FAF changes related to retinal pigment epithelium (RPE) damage occurred in the patchy pattern, associated with decreasing Best Corrected Visual Acuity (BCVA). Patients with speckled and focal patterns showed limited or no changes in FAF during the follow-up. No changes in FAF were found in patients with a minimal change pattern. No treated patient with a normal baseline examination demonstrated FAF changes. Patients with patterns other than the minimal change showed significant BCVA deterioration (
P <0.001). The authors concluded that various phenotypic patterns of abnormal FAF can be identified with cSLO imaging. Fundus autofluorescence is a helpful, fast, and noninvasive tool that allows close monitoring of the macula in patients at risk of DFO retinopathy. It may be useful in the decision to discontinue or switch the therapy in cases of particular high risk for disease progression. The progressive changes at the level of the RPE may play an important role in the evolution of visual loss during long-term treatment with DFO.
Aksoy et al. [
37] report mean peripapillary Retinal Nerve Fiber Layer significantly thinner in all four quadrants in the thalassemia major group (47 patients) versus iron deficiency anemia (IDA), group (IDA: 22 patients) and healthy controls (35 individuals) (
p <0.01), and in only the inferior quadrant in the IDA group (
p <0.05). They also documented a positive correlation between average RNLF thickness and mean hemoglobin concentration (
r = 0.488;
p <0.001) and a negative correlation with the mean ferritin level (
r = −0.544;
p <0.001). Finally, no correlation was found between average RNLF thickness and the mean number of transfusions or the mean visual acuity of these patients (
p >0.05).
Incorvaia et al. [
38] conducted a retrospective matched controlled study to investigate retinal venous tortuosity (RVT) and possible associations with other disease parameters in 36 patients with beta-thalassemia and found significantly greater mean venous length in the thalassaemic group which was significantly associated to patient’s age. The authors concluded that patients with beta-thalassemia major have increased RVT, as compared to normal subjects. Given that in this selected population, patient’s age, (closely related to anemia duration) is the only variable responsible for the RVT increment. This clinical sign may suggest a long-standing duration of anemia. Aksoy et al. [
39] in an age/sex matched controlled cross-sectional study investigated ophthalmic findings in 43 children with thalassemia major and found that In TM, Schirmer test scores are less than normal, while corneal thickness, axial length, and tear break-up time (BUT) are close to controls.
Several case reports on β-thalassemia have been retrieved in our bibliography search. These reports include: high-dose intravenous Desferrioxamine-related ocular toxicity [
40] which partially recovered following cessation of DFO, macular vitelliform lesion in desferrioxamine-related retinopathy [
41], loss of vision associated with angioid streaks in beta-thalassemia intermedia [
42], rapidly progressing bilateral cataracts in a patient with beta thalassemia and pellagra [
43] and Takayasu’s arteritis presenting with temporary loss of vision in a 23-year-old woman with beta thalassemia trait [
44].