Retinal iron homeostasis: The cellular roles of ceruloplasmin and hephaestin

Ceruloplasmin and hephaestin are proteins that convert ferrous (Fe 2+) to ferric (Fe3+) iron, thereby facilitating cellular iron export. Although it is known that ceruloplasmin and hephaestin are important for normal retinal iron transport, their roles in the individual retinal cell types, and in the directionality of retinal iron flow, are unclear. As dysregulation of retinal iron transport contributes to retinal diseases such as the rare genetic disease aceruloplasminemia and the more common disease age-related macular degeneration, it is important to study and better understand retinal iron transport. To investigate the roles of ceruloplasmin and hephaestin in retinal cells we used post-mortem human eyes, systemic and conditional knockout mice, primary cultured cells and immortalized retinal cell lines. We found that in humans, ceruloplasmin plays an important role in retinal pigment epithelial (RPE) cells and in the neural retina, as loss of ceruloplasmin resulted in iron accumulation in the neural retina and very high iron accumulation in the RPE cells along with RPE pathology and melanosome degradation. Using mouse models we observed that loss of both ceruloplasmin and hephaestin results in RPE cell iron accumulation, although not to the degree expected. Additionally, loss of ceruloplasmin and hephaestin from both RPE and photoreceptors results in retinal iron redistribution. Both ferroxidases participate in iron export from Muller cells, and both are more important for iron export from the retina than for iron import into the retina. Our results have demonstrated that ceruloplasmin and hephaestin are important in several retinal cell types, and have changed the way that we think about retinal iron transport and its accumulation in RPE cells

Retinal iron homeostasis: The cellular roles of ceruloplasmin and hephaestin

Ceruloplasmin and hephaestin are proteins that convert ferrous (Fe 2+) to ferric (Fe3+) iron, thereby facilitating cellular iron export. Although it is known that ceruloplasmin and hephaestin are important for normal retinal iron transport, their roles in the individual retinal cell types, and in the directionality of retinal iron flow, are unclear. As dysregulation of retinal iron transport contributes to retinal diseases such as the rare genetic disease aceruloplasminemia and the more common disease age-related macular degeneration, it is important to study and better understand retinal iron transport. To investigate the roles of ceruloplasmin and hephaestin in retinal cells we used post-mortem human eyes, systemic and conditional knockout mice, primary cultured cells and immortalized retinal cell lines. We found that in humans, ceruloplasmin plays an important role in retinal pigment epithelial (RPE) cells and in the neural retina, as loss of ceruloplasmin resulted in iron accumulation in the neural retina and very high iron accumulation in the RPE cells along with RPE pathology and melanosome degradation. Using mouse models we observed that loss of both ceruloplasmin and hephaestin results in RPE cell iron accumulation, although not to the degree expected. Additionally, loss of ceruloplasmin and hephaestin from both RPE and photoreceptors results in retinal iron redistribution. Both ferroxidases participate in iron export from Muller cells, and both are more important for iron export from the retina than for iron import into the retina. Our results have demonstrated that ceruloplasmin and hephaestin are important in several retinal cell types, and have changed the way that we think about retinal iron transport and its accumulation in RPE cells

Sometimes a Biopsy is Best

A 30 -year-old pregnant woman without significant medical or ocular history presented with decreased right eye vision. In her 2nd trimester, she was diagnosed with Lyme disease with a bulls-eye rash and positive Lyme antibodies; she was treated with two weeks of amoxicillin. At 33 weeks pregnant she developed a right periorbital headache and decreased brightness with the right eye. The eye was sore but she had no pain with eye movements. Six days later an outside eye provider documented right optic nerve edema with 20/400 vision. An MRI/MRV without contrast at an outside ER reportedly showed right optic neuritis. She received 5 days of IV methylprednisolone (1000mg/day). She reported brighter colors but no objective improvement in vision. Lyme IgM was negative and IgG was positive but no other imaging or serologic workup was performed. Over the next 3 weeks, her vision worsened to no light perception (NLP). At 40 weeks pregnant she presented to our institution with NLP vision in the right eye with an rAPD. The left eye vision and exam was normal. The right eye fundus exam showed mild disc edema with temporal pallor and optociliary shunt vessels. She was admitted and a healthy baby was delivered. A contrast enhanced MRI brain/orbits showed diffuse enhancement, STIR hyperintensity, and restricted diffusion of an enlarged right optic nerve; this was favored to represent right optic neuritis. AQP4-IgG and MOG-IgG were checked twice and negative; lumbar puncture CSF studies were normal. She was treated with IV methylprednisolone (1000mg/day for 5 days), plasmapheresis every other day for 5 sessions, and rituximab weekly for 5 infusions. Her vision briefly improved to light perception but then returned to NLP. A repeat MRI showed stable diffuse enhancement and enlargement of the right optic nerve. A biopsy of the optic nerve was performed

Sometimes a Biopsy is Best

A 30 -year-old pregnant woman without significant medical or ocular history presented with decreased right eye vision. In her 2nd trimester, she was diagnosed with Lyme disease with a bulls-eye rash and positive Lyme antibodies; she was treated with two weeks of amoxicillin. At 33 weeks pregnant she developed a right periorbital headache and decreased brightness with the right eye. The eye was sore but she had no pain with eye movements. Six days later an outside eye provider documented right optic nerve edema with 20/400 vision. An MRI/MRV without contrast at an outside ER reportedly showed right optic neuritis. She received 5 days of IV methylprednisolone (1000mg/day). She reported brighter colors but no objective improvement in vision. Lyme IgM was negative and IgG was positive but no other imaging or serologic workup was performed. Over the next 3 weeks, her vision worsened to no light perception (NLP). At 40 weeks pregnant she presented to our institution with NLP vision in the right eye with an rAPD. The left eye vision and exam was normal. The right eye fundus exam showed mild disc edema with temporal pallor and optociliary shunt vessels. She was admitted and a healthy baby was delivered. A contrast enhanced MRI brain/orbits showed diffuse enhancement, STIR hyperintensity, and restricted diffusion of an enlarged right optic nerve; this was favored to represent right optic neuritis. AQP4-IgG and MOG-IgG were checked twice and negative; lumbar puncture CSF studies were normal. She was treated with IV methylprednisolone (1000mg/day for 5 days), plasmapheresis every other day for 5 sessions, and rituximab weekly for 5 infusions. Her vision briefly improved to light perception but then returned to NLP. A repeat MRI showed stable diffuse enhancement and enlargement of the right optic nerve. A biopsy of the optic nerve was performed

Sometimes a Biopsy is Best

A 30 -year-old pregnant woman without significant medical or ocular history presented with decreased right eye vision. In her 2nd trimester, she was diagnosed with Lyme disease with a bulls-eye rash and positive Lyme antibodies; she was treated with two weeks of amoxicillin. At 33 weeks pregnant she developed a right periorbital headache and decreased brightness with the right eye. The eye was sore but she had no pain with eye movements. Six days later an outside eye provider documented right optic nerve edema with 20/400 vision. An MRI/MRV without contrast at an outside ER reportedly showed right optic neuritis. She received 5 days of IV methylprednisolone (1000mg/day). She reported brighter colors but no objective improvement in vision. Lyme IgM was negative and IgG was positive but no other imaging or serologic workup was performed. Over the next 3 weeks, her vision worsened to no light perception (NLP). At 40 weeks pregnant she presented to our institution with NLP vision in the right eye with an rAPD. The left eye vision and exam was normal. The right eye fundus exam showed mild disc edema with temporal pallor and optociliary shunt vessels. She was admitted and a healthy baby was delivered. A contrast enhanced MRI brain/orbits showed diffuse enhancement, STIR hyperintensity, and restricted diffusion of an enlarged right optic nerve; this was favored to represent right optic neuritis. AQP4-IgG and MOG-IgG were checked twice and negative; lumbar puncture CSF studies were normal. She was treated with IV methylprednisolone (1000mg/day for 5 days), plasmapheresis every other day for 5 sessions, and rituximab weekly for 5 infusions. Her vision briefly improved to light perception but then returned to NLP. A repeat MRI showed stable diffuse enhancement and enlargement of the right optic nerve. A biopsy of the optic nerve was performed

Hemorrhagic choroidal melanoma

Purpose To demonstrate the clinical pathologic correlation in a hemorrhagic choroidal melanoma. Observations A 52 year old patient presented with a large choroidal mass associated with vitreous and retinal hemorrhage. The eye was enucleated and histopathology demonstrated epithelioid-type MART1 positive tumor cells consistent with choroidal melanoma. The tumor had broken through Bruch's membrane, which led to localized vascular compression with bleeding into the subretinal space, retina and vitreous. Conclusions and importance Choroidal melanoma rarely presents with hemorrhage. Tumor rupture through Bruch's membrane may result in a tourniquet effect on the tumor vasculature leading to massive hemorrhage, as in this case. A high level of clinical suspicion is required to make the diagnosis

Posterior Ischemic Optic Neuropathy in the Setting of Cocaine-Induced Orbital Inflammation

Severe cocaine-induced midline destructive lesions (CIMDL) can cause orbital cellulitis and optic neuropathy. We present the first case of acute, painless vision loss in the setting of CIMDL with neuroimaging suggestive of posterior ischemic optic neuropathy (PION)