Optic neuropathy in iron overload and iron chelation therapy
Authors: Samyuktha Melachuri, Chelsey Chaehee Lim, Jacob Winters
Journal: American Journal of Hematology (2022)

States of systemic iron overaload, such as hereditary hemosiderosis and iron overload secondary to transfusion dependence, are known to be associated with optic neuropathy.1-3 Similarly, several studies have shown the treatment of such states with chelation therapy, particularly deferoxamine, to be associated with optic neuropathy.4-8 We report a case of optic neuropathy in a patient with hereditary xerocytosis (HX), an autosomal dominant hemolytic anemia that requires frequent and life-saving blood transfusions, which resulted in iron overload treated with chelation therapy. A 28-year-old female with history of HX with transfusion dependence on chronic chelation therapy presented with acute, painless, unilateral, and sectoral vision loss during her hospitalization for an episode of symptomatic anemia. At age 6, the patient was given a presumed diagnosis of transfusion-dependent congenital idiopathic hemolytic anemia and iron overload, which required leukoreduced packed red blood cell exchange transfusions every 3–4 weeks with an estimated 264 lifetime transfusions with corresponding ferritin elevation (Figure 1). Despite trialing multiple chelating agents such as deferasirox, deferoxamine, and deferiprone, she developed significant multisystemic hemosiderosis including heart, liver, kidneys, spleen, pancreas, pituitary, and bone marrow. Because of this, the patient experienced childhood complications including splenectomy, cholecystectomy, hypogonadotropic hypogonadism, pancreatic insufficiency with type III diabetes mellitus, hypoparathyroidism, vitamin D deficiency, nonischemic dilated cardiomyopathy requiring orthotopic cardiac transplant, and portal, superior mesenteric, and deep venous thromboses, which necessitated lifelong anticoagulation. In adulthood, she developed Hashimoto thyroiditis and stage III chronic kidney disease secondary to iron deposition and years of calcineurin inhibitor-induced nephropathy. Her medications included immunosuppression with tacrolimus and mycophenolate, apixaban, insulin, nadolol, a serotonin-norepinephrine reuptake inhibitor, and a weekly darbepoetin injection. Notably, our patient had a local drug allergy to deferoxamine and was thus prescribed 1000 mg of home deferiprone. Family history was remarkable for uncharacterized myeloproliferative disease with chronic leukocytosis and thrombocytosis in maternal family. The patient underwent genetic workup, with initial studies indicating heterozygosity in the HFE gene. However, the identified genetic variant was p.H63D; without the p.C292Y variant, a known culprit of hereditary hemochromatosis, this finding was insufficient to explain her disease process.9 Thus, further work-up revealed two variants of unknown significance of the ANK1 gene, which is associated with hereditary spherocytosis with variable degrees of hemolytic anemia, splenomegaly, and cholelithiasis.9 This, along with identification of a pathogenic variant of the PIEZO1 gene, ultimately led to a diagnosis of HX. On day 4 of hospitalization for symptomatic anemia, she reported acute, painless, sectoral visual field defect in her left eye, and the ophthalmology service was consulted. Corrected visual acuity was 20/25 in both eyes. Intraocular pressures were 9 mmHg in both eyes. Pupillary exam yielded a 3+ relative afferent pupillary defect in the left eye. Her extraocular movements were full and Ishihara color testing was 11/11 bilaterally. Slit-lamp examination revealed bilateral scleral icterus. Fundus examination revealed 360° elevation and blurring of disc margins with inferior pallor in the left eye and an estimated cup to disk ratio of 0.1 bilaterally. Fundus photos showed a crowded right optic disk and a swollen left optic nerve (Figure 2). Formal visual field testing (Humphrey visual field) showed a corresponding inferior altitudinal defect in her left visual field (Figure 3). Optical coherence tomography (OCT) yielded a supranormal retinal nerve fiber layer of 191 μm in the left eye and confirmed a small cup-to-disk ratio (0.06) bilaterally. She underwent a comprehensive workup to rule out other causes of vision loss, including infectious, autoimmune, infiltrative, and compressive etiologies. These included chest X-ray unrevealing for sarcoidosis, antinuclear antibodies, anti-Ro, anti-La, anti-PR3, anti-MPO, anti-MOG, anti-NMO, and Angiotensin-converting enzyme. Infectious workup was also negative including QuantiFERON TB, syphilis IgG/IgM, rapid plasma reagin (RPR), cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus (HSV), Varicella-zoster virus (VZV), cerebrospinal fluid (CSF) serologies for HSV, Bartonella, Lyme, and toxoplasmosis, and CSF culture. No notable brain imaging finding concerning for angio-invasive mucormycosis was identified. Given these findings, a diagnosis of nonarteritic anterior ischemic optic neuropathy (NAION) secondary to optic nerve hemosiderosis was made. Magnetic resonance imaging (MRI) of the brain and orbit with and without gadolinium contrast showed hemosiderin deposition scattered throughout the brain parenchyma, particularly within the choroid plexus as well as bilateral optic nerve atrophy, worse on left than right (Figure 4). Iron overload and its treatment modality of chelation therapy are associated with optic neuropathy.10 This is perhaps due to iron's potential to cause oxidative damage and link to inflammation.11 During inflammation, hepcidin, an iron regulatory hormone, is upregulated, increasing iron storage. These changes include pigment deposition in ocular structures, anterior ischemic optic neuropathy, age-related macular degeneration, and retinal atrophy.10 Excessive iron in the retinal pigment epithelium (RPE) and photoreceptors contributes to RPE destruction.12 There is increasing evidence that oxidative damage contributes to four major diseases of the optic nerve: optic neuritis, ischemic optic neuropathy, traumatic optic neuropathy, and glaucoma.10-13 Normalization of serum ferritin levels via serial phlebotomy has been shown to halt progression of retinopathy and reduce ocular pigmentation.14-16 However, this is a complicated proposition in patients with anemia such as ours. Deferoxamine has been utilized for transfusion-related iron overload since 1968; however, recent case reports and series have shown an association with toxic retinopathies including pigmentary retinopathy, bull's eye maculopathy, and vitelliform maculopathy.3, 7 Deferiprone and deferasirox, more recently developed chelators, have shown more facile forms of administration (oral versus continuous intravenous infusion) and longer half-lives than that of deferoxamine. The available literature shows no adverse ocular events associated with deferiprone.7, 8 Furthermore, our patient was immunosuppressed with tacrolimus, which has been rarely associated with optic neuropathy.17 Although reported patterns of optic neuropathy in tacrolimus use (i.e., bilateral visual field deficits not respecting the horizontal meridian) are not entirely consistent with our case, its presence may have served as a predisposing factor. We report a case of optic neuropathy in a patient with HX on deferiprone chelation therapy. While to our knowledge, this is the first patient reported to have ocular manifestations on deferiprone, there is no definite evidence in our case to suggest a causal relationship between deferiprone and our patient's optic neuropathy. In fact, the patient's ultimate development of optic neuropathy may be related to the decreased mortality afforded by newer chelation therapy. Our study highlights the importance of ophthalmologic monitoring (such as OCT) in transfusion-dependent patients on chelation therapy.6 No data available.