Discussion and conclusions
Beta-thalassemia is an autosomal recessive hemoglobinopathy resulting in anemia due to defective beta-chain globin production leading to impaired production of Hb A. Beta-thalassemia major (β-TM) is associated with diminished b-globin production, while beta-thalassemia intermedia (β-TI) is characterized by some degree of b-globin chain production. Patients with β-TI, however, may also need regular blood transfusions. Sickle beta thalassemia is a particular form of sickle cell disease in which an allele for S hemoglobulin and an allele for β-TM coexist. These patients may also require chronic blood transfusions depending on the severity of their anemia [
5].
A number of ocular abnormalities have been described in patients with β-TM some of which are attributable to the natural course of the disease and the impact of the anemia on ocular tissues, while others are associated with the chronic chelation treatment [
6‐
9]. More precisely, retinal changes present in β-TM are divided in two categories: pseudoxanthoma elasticum (PXE)-like changes that include angioid streaks, peau d’orange like fundus and optic nerve head drusen [
10] and non-PXE-like changes such as increased venous tortuosity [
11]. Furthermore, in a study of 255 patients with β-TM or β-TI, Barteselli et al. found a 7.5% incidence of pattern dystrophy-like changes [
11].
Concerning sickle thalassemia, Aesopos et al. reported a 10% incidence of angioid streaks in a group of 58 cases [
12]. Fanny et al., studied 18 patients suffering from sickle beta thalassemia and found that 13 of the patients had sickle cell retinopathy with 3 of them having proliferative disease. It appears that retinopathy in sickle thalassemia shares similar characteristics with sickle cell retinopathy [
13].
Due to chronic repeated blood transfusions, these patients tend to accumulate iron in various organs such as liver, spleen, myocardium and eyes [
14]. In order to prevent iron overload and possible iron-induced toxicity, chelating agents responsible for binding and excreting iron excess are administered. [
1] Deferoxamine is a widely used iron-chelator available for both intravenous and subcutaneous administration. Deferoxamine related ocular toxicity involves a wide spectrum of ocular abnormalities such as nyctalopia, colour perception anomalies, visual field disturbances, cataract formation, optic neuropathy and pigmentary retinopathy [
3]. Deferiprone, which is an alternative or adjunctive regimen to DFO, is orally administered and can cross the blood-retina barrier. While degeneration of the RPE has been reported to occur under deferiprone [
6,
7], newer studies have demonstrated that it can be a retinal protective iron chelator [
15‐
17]. Finally, deferasirox is a newer oral efficient iron chelator without documented retinal penetration, while cases of reversible toxicity have also been reported. [
18,
19]
The standard dose of DFO for chronic transfusional hemosiderosis in patients undergoing chronically repeated blood transfusions is 25–50 mg/kg/day, while a dose of 100 mg/kg/day or more is probable of toxicity [
20]. It has been proposed that a daily dose of 50 mg/kg is the upper safe limit for ocular toxicity [
21]. Moreover, DFO administered intravenously has been found to carry a higher risk of toxicity than the subcutaneous or intramuscular route [
22].
Manifestations of DFO-induced retinal toxicity include RPE changes either at the posterior pole or at the periphery of the retina. Fundus autofluorescence examination in 197 patients with β-TM under DFO treatment, showed a 9% incidence of retinal abnormalities, which were classified, based on their severity, as minimal, focal, patchy and speckled [
23]. Out of those, eyes with the patchy pattern showed further RPE damage as demonstrated with FAF, whereas patients with the focal and speckled patterns showed little or no change on follow up examinations with FAF. Visual acuity deteriorated in all eyes except from those with minimal FAF changes [
23]. Pattern dystrophy-like lesions have also been described in patients undergoing prolonged DFO treatment (Table
1). Reviewing the cases in Table
1 we found 4 published cases of vitelliform maculopathy and 3 cases of butterfly shaped macular lesions associated with DFO in literature [
24‐
26].
Table 1
Published pattern dystrophy cases associated with chelation therapy
| Case report 1 Case | SQ N/A | ERG normal | Vitelliform Macular Lesion | Splenectomy Mild hearing impairment | N/A regarding chelation therapy Brinzolamide 0.1% Initiation | Improvement of vitelliform lesion in one eye with Brinzolamide 0.1% drops |
| Case series 2 Patients | PT1 1 g/2xdaily/SQ for 11 months, PT2 IV 2680 mg/5x weekly for 3 years | PT1 ERG, EOG normal PT2 ERG reduction in cone mediated responses EOG normal | Vitelliform Macular Lesion | Myelodysplasia | PT1 initially DFO dose reduced to 500 mg/day SQ, at 4 months increased to 1 g/d, discontinued at 1 year PT2 DFO discontinuation | PT1 Vision deteriorated, vitelliform lesion increased and atrophy developed at 2 years follow up, inspite of DFO dose modification and final discontinuation PT2 Vision deteriorated at 1 year follow up Lesion anatomically unchanged in one eye, resolution of vitelliform lesion in the fellow eye |
| Retrospective 10/20 Chart Review Study 20/290 | SQ Range 1.5–4.5 mg/kg Mean 32.7 ± 8.7 years Range 20–52 years | N/A | Butterfly shaped macular lesion [ 3] Vitelliform macular lesion [ 1] Fundus flavimaculatus-like [ 3] Fundus pulvirulentus-like [ 3] | Beta-thalassemia | Vitelliform PT switched to deferasirox 1 butterfly PT switched to deferasirox, 2 unchanged | Mean duration of follow up 19.7 ± 8.8 months (range 10–45 months). 6 patients (one with Butterfly shaped and one with Vitelliform-like macular lesion) switched to deferasirox 14 patients remained on the same chelation regimen All Butterfly shaped and Vitelliform cases progressed to RPE atrophy during follow up |
| Case report 1 Case | N/A 16 g/week for 5 years | ERG diffuse rod dysfunction in one eye diffuse dysfunction in EOG in both eyes | Vitelliform Macular Lesion | Myelodysplasia Adult onset hearing loss | DFO discontinuation Switch to deferasirox Brinzolamide 0.1% Initiation | Lesion reduced in size 2 months after DFO discontinuation then increased on deferasirox Vision remained stable PT lost on follow up |
The exact mechanism of DFO toxicity, although thoroughly studied, remains unclear. Rahi et al. noticed thickening of Bruch’s membrane and depigmentation and degeneration of the RPE cells in microscopic examination of eyes with DFO retinopathy [
27]. Pathophysiology of retinal damage in patients chronically treated with DFO is supposed to occur due to disruption of iron homeostasis in the retina [
28] as well as chelation of other metals vital for proper retinal function such as copper, cobalt, zinc and nickel. [
29,
30] In addition, DFO has been found to exhibit a direct p38 mediated toxic effect to RPE cells in in vitro studies [
31]. In respect to pattern dystrophies in patients receiving DFO, histologic studies are required to elucidate the pathogenetic process of fluorophore buildup between RPE and outer photoreceptor segments that lead to the development of such lesions.
Electrophysiology testing has been proposed as a means for monitoring retinal function in cases of suspected DFO toxicity. Electroretinogram and electrooculogram (EOG) are usually confirmatory of DFO retinopathy and appear to be more sensitive in detecting early retinal damage than fundoscopy alone [
3]. A recent study suggests that ffERG and multi-focal ERG are more sensitive in early damage detection than visual evoked potential, FAF imaging and OCT scans in patients under chelation therapy [
32]. For instance, there are reports of bilateral reductions in response densities at the central retina corresponding to RPE changes related to DFO toxicity [
3,
33,
34]. Repeated examinations with multifocal ERG have also been used for the follow up of patients with DFO related maculopathy in order to record functional changes. However, due to lack of specificity of these tests for DFO toxicity, various different results have been presented in literature [
33]. Regarding pattern dystrophies, various contradicting electrophysiology findings have been reported in literature (Table
1). More specifically, ERG results range from normal [
3,
26] to impaired cone [
25] or rod responses [
35]. Diffuse dysfunction in EOG has also been reported in one vitelliform case [
35]. In our cases, patients had normal cone and rod responses in the full field ERG.
Cessation of DFO treatment has been reported to reverse early DFO toxicity related changes [
36]. Kertes et al. however, reported progressive deterioration in mfERG during the first 4 months after discontinuation of DFO, which did not stabilize until 8 months later [
37]. Regarding macular pattern-like dystrophies, limited information exists in literature on the possible effect of DFO cessation or DFO dose modification (Table
1). Viola et al. reported switch of chelation treatment, from DFO to deferasirox, in a patient with a vitelliform-like lesion as well as one patient with butterfly shaped macular changes while chelation therapy remained unchanged on two patients with butterfly shaped-like macular changes [
24]. Interestingly, progressive RPE atrophy was demonstrated during follow-up in all of the above four patients, although resolution of the hyperreflective material had initially been observed in the patient with the vitelliform-like lesion [
24]. In the cases reported by Gonzales visual deterioration occurred despite DFO discontinuation [
25]. Finally, administration of brinzolamide 0.1% in a patient with vitelliform maculopathy related to DFO resulted in reduction of the macular lesion [
38]. In a recent case report of a pseudovitelliform maculopathy related to DFO, further deterioration occurred after changing the chelator from DFO to deferasirox [
35].
In this report, we present two cases of relatively rare pattern dystrophy like macular changes in patients treated with DFO for a prolonged period of time. Multimodal imaging utilization in our patients allowed a better evaluation and possibly earlier detection of the DFO-related changes. The correlation between DFO and the retinal changes presented in our patients is enhanced by the absence of any family history of macular pathology, the chronic treatment with DFO and the symmetric and bilateral appearance of macular changes. The age of presentation of visual disturbances in both patients is the 5th and 6th decade of life respectively, which also favors the diagnosis of an adult onset macular dystrophy. However, exclusion of possible genetic defects would further support the conclusion of an acquired pattern dystrophy of the macula induced by desferrioxamine. Adjustment of chelation treatment could have been a more proactive approach. However, in our cases, haematologist consultation suggested that patients should remain on the prescribed chelation therapy and be closely followed-up every three months. No sign of deterioration was observed over a period of 2 and 4 years respectively. Screening is therefore important for early detection, prompt diagnosis and follow up of possible drug-related toxicity in this particular group of patients.