Interferon Induced Retinopathy


Article Author:
Kaberi Feroze


Article Editor:
Jim Wang


Editors In Chief:
Jasleen Jhajj
Cliff Caudill


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Frank Smeeks
Kristina Soman-Faulkner
Trevor Nezwek
Radia Jamil
Patrick Le
Sobhan Daneshfar
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
3/18/2019 11:17:11 PM

Introduction

Interferons are glycoproteins which have antiviral, antiproliferative, and immunomodulatory functions. They are used widely for the treatment of many conditions like Hepatitis C, cancers, and immune-mediated disorders like multiple sclerosis. Interferon was discovered by Issacs and Lindenmann in 1957 while studying the phenomenon of virus interference. The FDA approved the use of Interferon alpha-2a and alpha-2b for the treatment of hairy cell leukemia in 1986. As time progressed, the use of interferons (IFN) has expanded to include a broad spectrum of conditions. However, their use is associated with numerous adverse effects like fatigue, influenza-like syndrome, toxicities related to the central nervous system, the gastrointestinal tract, endocrine system, and cardiovascular, renal, and musculoskeletal systems.[1] The first report of ocular toxicity of IFN therapy was made by Ikebe and associates in 1990 in a 39-year-old patient who developed retinal hemorrhages and cotton wool spots after receiving intravenous IFN. 

Etiology

Interferons are a family of proteins which are released by a variety of cells in response to infections caused by viruses. There are several classes of IFN including IFN alpha, beta, and gamma. IFN alpha has been used for management of hairy cell leukemia, malignant melanoma, follicular lymphoma, condylomata acuminata, AIDS-related Kaposi sarcoma, and chronic hepatitis B and C. IFN beta has been used for multiple sclerosis, and IFN gamma has been used for chronic granulomatous disease and malignant osteopetrosis. In ophthalmology, IFN has been used to manage subretinal neovascularisation of age-related macular degeneration, glaucoma filtering surgery, and ocular cicatricial pemphigoid. The ophthalmic complications of IFN are mainly limited to the optic disc and retina, and the characteristic finding is a vascular retinopathy.[2][3]

Epidemiology

The reported incidence of IFN-associated retinopathy ranges from 18% to 86%, according to various studies.[4] Higher incidences are seen in some parts of Japan where values of more than 50% are common. Increased incidences of retinopathy were seen with older age and in patients with systemic conditions like hypertension and diabetes mellitus and are probably related to the dose of IFN as well. IFN retinopathy can occur at any time between four to 28 weeks of initial treatment, and various studies report the average time of presentation at around 20 weeks. Another peculiar phenomenon reported in some studies is that nonresponsiveness to IFN therapy was more prevalent in those developing retinopathy.[5]

Pathophysiology

The exact pathogenesis of the development of IFN retinopathy is not clear. Some authors suggest ischemia as the cause of the vascular changes. Others implicate immune complex deposits in the blood vessel walls which can cause a reduction in retinal capillary perfusion and formation of cotton wool spots. It is also suggested that inflammatory cytokine deposition in the blood vessel wall may be the underlying causative factor for this condition. Some studies have found an association between IFN retinopathy and elevated serum vascular endothelial growth factor (VEGF) levels. Vascular endothelial growth factor is associated with neovascularization, but the correlation between IFN retinopathy and elevated serum vascular endothelial growth factor levels is not clear. Studies were conducted by Abe and associates about the long-term effect of IFN on mice. They discovered that the retinal vascular bed was occluded in mice pretreated with urethane and not in those without pretreatment. They concluded that a diseased retina predisposed to the development of IFN retinopathy.[6]

It has been suggested by different authors that there are certain risk factors which predispose the patient to the development of IFN retinopathy. They include systemic hypertension, diabetes mellitus, the age of the patient, and the dose of interferon. Concomitant administration of drugs like ribavirin may predispose patients to the development of retinopathy. Arterial sclerosis, erythrocyte count, leukocyte count, platelet count, serum glutamic-pyruvic transaminase (SGPT) levels, serum glutamic-oxaloacetic transaminase (SGOT) levels, hemoglobin, triglycerides, and total cholesterol have been examined as risk factors, but so far, the results are inconclusive.

History and Physical

The classical presenting complaint in the typical IFN retinopathy is a defective vision, but many patients may be asymptomatic. Typical ocular findings include cotton wool spots, and retinal hemorrhages in the posterior pole, particularly around the optic disc. [7][8]

Atypical ocular side effects have been seen in some patients. These include central retinal artery occlusion, central retinal vein occlusion, anterior ischemic optic neuropathy, optic disc edema, neovascular glaucoma, vitreous hemorrhage, Vogt-Koyanagi-Harada-like disease, retinal detachment, subconjunctival hemorrhage, optic disc edema, and panophthalmitis.[9] Common to these conditions are severe and permanent visual impairment, which persists despite discontinuation of IFN therapy and instituting appropriate ophthalmological management. Some authors believe that IFN may not be entirely responsible for these complications but could be related to pre-existing ocular pathology in these patients.

Most authors claim that there is no difference in the clinical features of patients receiving different types of IFN.

Evaluation

Any patient complaining of any ocular symptoms while receiving IFN treatment should be examined thoroughly. One should especially be vigilant in older patients, those receiving higher doses of IFN or combination with other medicines, and patients with pre-existing morbidities like hypertension and diabetes mellitus. Visual acuity testing, pupil examination, and dilated fundus examination are mandatory. Fluorescein angiography may reveal areas of capillary dropout, hemorrhages and cotton wool spots may cause blocked fluorescence. Optical coherence tomography may help to diagnose macular edema, especially in subtle cases.[1][10][11]

It is recommended that all patients receiving IFN therapy should have a thorough ophthalmological examination before starting treatment. Any preexisting retinopathy should be ruled out. Monthly monitoring of patients should be done while receiving treatment if there is preexisting retinopathy and every three months in asymptomatic patients unless they complain of defective vision.

Treatment / Management

If a patient presents with an ophthalmological complication while receiving IFN therapy, the general recommendation is to stop IFN treatment. However, some authors suggest discontinuing treatment only in those with severe retinopathy or those with preexisting diseases like diabetes mellitus. A good outcome is seen in many cases after stopping IFN.

Pearls and Other Issues

IFN retinopathy is a relatively new entity, but it requires attention since a large number of patients, especially those suffering from Hepatitis C receive IFN as a part of their treatment. All patients should undergo a comprehensive ocular examination before starting treatment and regular follow up is important, especially in the first six months when most complications arise.

Enhancing Healthcare Team Outcomes

The internist, infectious disease expert, oncologist, and hematologist may administer interferon to their patients for a variety of reasons. However, it is important for these professionals to be aware of interferon-induced retinopathy. A baseline eye exam by an ophthalmology nurse is recommended. If the patient has any change in vision or ocular complaints, a consult with an ophthalmologist is necessary. If a patient presents with an ophthalmological complication while receiving IFN therapy, the general recommendation is to stop IFN treatment. However, some authors suggest discontinuing treatment only in those with severe retinopathy or those with preexisting diseases like diabetes mellitus. A good outcome is seen in many cases after stopping IFN.[12]


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Interferon Induced Retinopathy - Questions

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A 45-year-old male patient, who is a known to have hepatitis C and is receiving interferon alfa, complains of blurred vision. He has no other systemic diseases. Which of the following ophthalmoscopic findings is most likely to be seen in this patient?

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    Contributed by Steve Bhimji, MS, MD, PhD
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A 26-year-old male with hepatitis C who is receiving interferon and ribavirin is brought to the ophthalmologist for a routine ophthalmological check up. He is a known myope using -2.5Dsph spectacles in both eyes. Which of the following are risk factors for the development of interferon retinopathy in this patient?



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A 55-year-old known patient suffering from diabetes mellitus type 2 and hepatitis C is receiving interferons as part of his treatment. For the past three weeks, he has complained of blurring of his vision. Fundus examination reveals scattered cotton wool spots and hemorrhages in the posterior poles of both eyes. What would be the appropriate treatment option for this patient?



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Which of the following is an ocular condition in which interferon therapy is widely used?



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A 55-year-old patient who is on interferon treatment for Hepatitis C presents with complaints of defective vision. Interferon retinopathy is suspected. Which of the following features would most likely support a diagnosis of interferon retinopathy?



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Interferon Induced Retinopathy - References

References

Ophthalmological side effects of interferon therapy of chronic hepatitis C., Medhat E,Esmat G,Hamza E,Abdel Aziz A,Fouad Fathalah W,Darweesh SK,Zakaria Z,Mostafa S,, Hepatobiliary surgery and nutrition, 2016 Jun     [PubMed]
Retinopathy associated with interferon therapy in patients with hepatitis C virus., Abd El-Badie Mohamed M,Abd-El Azeem Eed K,, Clinical ophthalmology (Auckland, N.Z.), 2012     [PubMed]
Literature systematic review on the ophthalmological side effects of interferons., Fragoso YD,Paggiaro MS,Mastromauro R,Jacondino Gda S,Wilson HM,, Arquivos brasileiros de oftalmologia, 2011 Jul-Aug     [PubMed]
Rentiya ZS,Wells M,Bae J,Chen KJ,Chao AN,Turgeon N,Shah SM,Hanout M, Interferon-α-induced retinopathy in chronic hepatitis C treatment: summary, considerations, and recommendations. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 2019 Mar;     [PubMed]
Heath G,Airody A,Gale RP, The Ocular Manifestations of Drugs Used to Treat Multiple Sclerosis. Drugs. 2017 Mar;     [PubMed]
Bourgeois N,Chavant F,Lafay-Chebassier C,Leveziel N,Pérault-Pochat MC, [Drugs and retinal disorders: A case/non-case study in the French pharmacovigilance database]. Therapie. 2016 Sep;     [PubMed]
Lückoff A,Caramoy A,Scholz R,Prinz M,Kalinke U,Langmann T, Interferon-beta signaling in retinal mononuclear phagocytes attenuates pathological neovascularization. EMBO molecular medicine. 2016 Jun;     [PubMed]
Zarbin MA,Jampol LM,Jager RD,Reder AT,Francis G,Collins W,Tang D,Zhang X, Ophthalmic evaluations in clinical studies of fingolimod (FTY720) in multiple sclerosis. Ophthalmology. 2013 Jul;     [PubMed]
Kashif M,Saleem MK,Farooka IK,Husnain A,Siddiqui AM, Incidence of retinopathy in chronic hepatitis C patients treated with pegylated interferon alpha 2a and ribavirin combination therapy. Pakistan journal of medical sciences. 2015 Jan-Feb     [PubMed]
Hayasaka S,Nagaki Y,Matsumoto M,Sato S, Interferon associated retinopathy. The British journal of ophthalmology. 1998 Mar     [PubMed]
Fouad YM,Khalaf H,Ibraheem H,Rady H,Helmy AK, Incidence and risk factors of retinopathy in Egyptian patients with chronic hepatitis C virus treated with pegylated interferon plus ribavirin. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases. 2012 Jan     [PubMed]
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