Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy — a Review

REVIEW ARTICLE DOI: 10.5603/OJ.2019.0002 Autosomal dominant neovascular inflammatory vitreoretinopathy — a review

Małgorzata Kowalczyk, Robert Rejdak

Department of General Ophthalmology and Pediatric Ophthalmology Service, Medical University in Lublin, Lublin, Poland

ABSTRACT Autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) is a hereditary autoimmune disorder of the eye caused by mutations in the CAPN5 gene. It is characterized by non-specific uveitis in the anterior chamber and vitreous leading to panuveitis, iris and retinal neovascularization, cystoid macular edema, abnormal retinal pigmentation, vitreous hemorrhage, intraocular fibrosis, membrane formation and tractional retinal detachment. ADNIV is a progressive disease leading to complete blindness despite of treatment. Confirmation is made by genetic analysis demonstrating mutations of the CAPN5 gene. Key words: autosomal dominant neovascular inflammatory vitreoretinopathy; ADNIV; uveitis; neovascularization; proliferative vitreoretinopathy; cystoid macular edema; CAPN5; calpain-5 Ophthalmol J 2019; Vol. 4, 15–21

Introduction of approximately one in 1 000 000 births and has Autosomal dominant neovascular inflammatory been found worldwide [9]. The pathophysiology vitreoretinopathy (ADNIV) is a very rare, autoim- and immunopathology are not yet well known. The mune uveitis belonging to inherited vitreoretinal first symptoms can occur at all ages [9]. The disease dystrophies [1]. The disease is caused by the muta- is very progressive despite the treatment and leading tions in the CAPN5 gene (calpain-5) [2, 3]. Ge- to complete blindness. netic locus for ADNIV was mapped to chromosome Loss of the b-wave amplitude on electroretinog- 11q13 in 1992 by Stone et al. [4, 5]. This gene raphy (ERG) is a characteristic feature of ADNIV encodes a protein, calpain-5, which is an intracel- disease [8]. lular calcium-activated cysteine protease [2, 3, 6]. The pathophysiology of the illness has not been CAPN5 is the first nonsyndromic gene for autoim- known well; therefore, the condition is given a de- mune uveitis and among the very few Mendelian scriptive name autosomal dominant neovascular in- autoimmune diseases where the gene is identified flammatory vitreoretinopathy. [6]. There is significant phenotypic variance in AD- NIV causes by different mutations in CAPN5 gene. Recent genetic tests have discovered two new muta- Diagnosis tions which were described in literature in 2017 [7]. The diagnosis of the disease is difficult due to The first scientific work describing ADNIV was several causes. Firstly, ADNIV is classified as a rare published in 1990 by Steven Bennett and co-work- disease; secondly, the first signs can occur at any ers. The authors presented symptoms and causes of age and cannot be detected in childhood; there- the illness illustrated with an example of large group fore, unfortunately, the diagnosis is delayed in most of affected 28 of 61 members of a six generation cases. The symptoms of the disorder mimic sev- family [8]. The ADNIV occurs with a frequency eral much more common eye diseases, including

Corresponding author: Małgorzata Kowalczyk, Department of General Ophthalmology and Pediatric Ophthalmology Service, Medical University in Lublin, Lublin, Poland, e-mail: [email protected]

non-specific uveitis, retinitis pigmentosa, rod-cone due to localization of CAPN5 to the photoreceptor dystrophy, proliferative diabetic retinopathy and synapse [10]. With progression of the disease there proliferative vitreoretinopathy [8]. Because of its is also a reduction of the a-wave and in the last stage similarity to these disorders, ADNIV patients are the ERG is extinguished; it shows non-recordable often misdiagnosed. The very characteristic sign of cone and rod responses due to severe photoreceptor the ADNIV is a lack of systemic features unlike in dysfunction [2, 3]. some of the disorders mentioned above [1]. It is Genetic analysis or ERG testing is performed in important sign in differential diagnosis. patients who do not demonstrate classic features of The family history is very important because ADNIV or those who are younger than 30 years of helps to recognize hereditary nature of the disease age [10]. and suggests a genetic etiology. If the patient lacks a family history of ADNIV and presents with vitreous inflammation, a thorough evaluation for infec- Symptoms tious and inflammatory etiologies should be per- There are 5 stages in the course of ADNIV, each formed [10]. lasting approximately ten years. Key findings in correct diagnosis are molecular The first stage begins in the second or third dec- genetic examination and ERG testing. ADNIV is ade of life and is asymptomatic for the patient. In inherited in an autosomal dominant manner. It the first stage we observe inflammatory cells in the means that each child has a 50% chance of inher- vitreous, minimal far peripheral arteriolar closure, iting the condition from an affected parent. It is pigmentation and mild peripheral ischemia. In this present in every generation of affected family. The stage, ADNIV is clinically indistinguishable from disease is caused by the mutations in CAPN5 gene an autoimmune, non-infectious uveitis. localized on chromosome 11q13. The electroretinogram demonstrates early retinal Best’s vitelliform dystrophy, another disease in- and photoreceptor dysfunction. The most character- herited in autosomal dominant manner, is caused ized feature is reduction of b-wave. by the gene mutation mapped also to chromosome In the second stage, patients become sympto- 11q13 [11]. We do not know yet, whether there are matic, the anterior chamber shows mild inflamma- any other common features with ADNIV disease. tory cells and there is early development of cata- Different molecular genetic testing is necessary ract. The inflammatory cells are still observed in the to detect mutations. If there is no possibility to con- vitreous. The posterior segment shows pigmentary duct comprehensive genetic testing, the diagnosis of retinal degeneration and some macular and optic ADNIV unfortunately is delayed. nerve head edema. Retinal degeneration in ADNIV patients can Stage three of the disease usually develops during be detected by examining fundus autofluorescence the third or fourth decades, but in some cases can (FAF) and infrared reflectance (IR) of the fun- start earlier [14]. There are moderate inflammatory dus. The fundus displays enhanced FAF observed cells, progressive cataract and iris synechiae. Some- during mid-to-late stage ADNIV and is associated times peripheral iris stromal atrophy and thinning with photoreceptor or RPE cell dysfunction. IR occur. Development of band keratopathy is some- imaging of the retina shows pigmentary changes in- times seen in the patients. The posterior segment dicative of reactive retinal pigment epithelium cells shows cystoid macula edema (Fig. 1AB), progressive and photoreceptor degeneration [12]. vascular closure with neovascularization of the far Another important examination confirming the peripheral retina or optic disc. With the develop- diagnosis of the disease is ERG testing. The abnor- ment of inflammation in the vitreous, epiretinal and mality is detectable with electroretinography very subretinal membranes start to develop (Fig. 2AB). early in the course of the disease despite the nor- There are extensive pigmentary and atrophic chang- mal appearing of the retina. ERG signaling defects es throughout the fundus. Optical coherence tom- precedes the signs of photoreceptors degeneration ography reveals distortion of the retinal layers. There [13]. In early stages, we observe a reduced b-wave is a decline of peripheral vision with progressively on ERG, later it is selective loss of the b-wave in the constricted visual field, which indicates reduced scotopic bright flash [3]. This indicates dysfunc- retinal light sensitivity. In some cases despite of the tion of signal transmission from photoreceptors to significant disease progression, the limited central membranes of the inner retina such as bipolar cells vision is observed [14].

16 www.journals.viamedica.pl/ophthalmology_journal Małgorzata Kowalczyk, Robert Rejdak, Autosomal dominant neovascular inflammatory vitreoretinopathy

A B

Figure 1AB. Optical coherence tomography (OCT) presenting cystoid macular edema (CME) in patients with autosomal dominant neovascular inflammatory vitreoretinopathy

A B

Figure 2AB. Fundus images showing vitritis in a patient with autosomal dominant neovascular inflammatory vitreoretinopathy

In stage four neovascular and angle closure no evidence for systemic autoimmune or systemic glaucoma caused by inflammation in the anterior inflammatory conditions in ADNIV patients. chamber is observed; next, epiretinal membranes The development of secondary glaucoma is ob- formation and proliferative vitreoretinopathy served in ADNIV patients. The IOP management is starts. Profound visual loss is due to ongoing neo- connected with uveitic glaucoma, steroid-response vascularization of the retina that causes vitreous glaucoma, angle closure glaucoma and hypotony. hemorrhage, tractional retinal detachment and neo- The chronic uveitis can cause aqueous hyposecre- vascular glaucoma. In the last fifth stage, the eyes tion, due to inflammation of the ciliary body, but become hypotonous and subsequently phthisical, this IOP-lowering effect is usually overpowered by leading to complete blindness. the increased resistance to trabecular drainage from Patients with ADNIV have night blindness only inflammatory infiltrates and endothelial dysfunc- as a very late manifestation of the disease. There is tion [15]. Necessary steroids therapy is the result of

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steroid-induced glaucoma. Furthermore, develop- hypoxia, retinitis pigmentosa, retinal detachment ment of neovascularization in the anterior chamber and glaucoma [18]. Retinal damage from these causes angle closure glaucoma. In late stages, some pathologies can be lessened by administering the ADNIV eyes become hypotonous [15]. Interesting- calpain inhibitor SJA6017, but it is not known ly, some ADNIV patients do not develop elevated which isoform(s) exert(s) an inhibitory effect [18]. IOP or glaucoma despite decades of ADNIV and CAPN5 is widely expressed in the human body in steroid therapy. the colon, kidney, liver, trachea, uterus, eye and The rate of disease progression, specific features brain, but the ADNIV is restricted just to the eye and vision loss vary between the affected members [13]. Retinal expression of CAPN5 may be suffi- of a given family and is also asymmetrical between cient to generate an autoimmune response. Study eyes. For example, some of the ADNIV patients of CAPN5 mutations can provide insight into develop blindness in one eye before the other, re- mechanisms of this disease and help us develop maining partially sighted for years [16]. treatments for ADNIV and more common eye diseases with inflammation and neovascularization. Calpains have been implicated in the pathogen- Pathophysiology esis of different diseases including cancer, multiple Autosomal dominant neovascular inflammatory sclerosis, Alzheimer’s disease, cataract, diabetes and vitreoretinopathy is also an autoimmune disorder muscular dystrophy [3]. Several human neuro- but pathophysiology and immunopathology is not logical disorders have been associated with excess well known. Immunohistological stain revealed T- calpain activity. Wort et al. generated transgenic cell infiltrated in ADNIV patients; hence, there mice expressing human CAPN5(R243L) only in is a suggestion that T-cell may play main role in the retina and observed a clinical, histologic and immunopathology of the disease [17]. No specific molecular phenotype consistent with human AD- antibodies were detected in ADNIV patients so far. NIV [12]. This mouse model can be used to ex- It was noted that despite organ atrophy in the late plore protease mechanism, disease progression and stages of the disease, antigen reactions may still be possible therapies and have utility for other types active. The phthisis in the ADNIV eye seems to of uveitis. be immunologically different from that observed Uveitis in ADNIV is characterized by infiltrating in eyes with phthisis from other conditions [17]. CD3+ and CD4+ inflammatory cells in the vitreous, It is reported that cell-mediated rather than anti- the uvea and the retina, suggesting a predominantly body-mediated autoimmunity may be the primary T-cell process [13, 6]. Mutation in calpain-5 causes inflammatory mechanism [17]. Studies of human both early CD3+, T-cell migration into the retina autopsy eyes indicated that ADNIV uveitis is pri- and reduction in ERG b-wave amplitudes and later marily driven by cell-mediated immunity [12]. The photoreceptors degeneration. vitreous biopsy revealed that interleukin-6 was el- The Mahajan et al. described enucleated eye of evated, suggesting a stimulated inflammatory or ADNIV patient due to phthisis and pain. Exami- autoimmune response [12]. nation of the enucleated eye revealed a shrunken The physiologic role of calpain-5 is not well distorted phthisical globe. The intraocular con- known. Calpain-5 was found to be located in the tents were grossly disorganized. A segment of optic inner and outer segments of the photoreceptor nerve was unremarkable. The cornea was depressed, cells and also within the outer plexiform layer brown and opaque, anterior chamber filled with [13]. The mutations alter its location inside the hemorrhage. The posterior segment showed a vit- cells and probably its proteolytic activity or spe- reous filled with a red-brown material, a detached cificity. So CAPN5 could account for the various retina and subretinal hemorrhage. The optic nerve inflammatory degenerations, vascular and fibrotic was atrophic with replacement of axons with colla- phenotypes observed in ADNIV patients. Wert et genous bands. The iridocorneal angle was occluded al. report that the effect of the ADNIV mutation by fibrous membranes. The retina showed extensive is to increase CAPN5 catalytic activity. This insight degeneration and retinal pigment epithelium sig- was next supported by physiologic testing of the nificant cell loss [6]. CAPN5(R243) mutation in vivo [12]. Increased Despite organ atrophy in the late stages of dis- calpain activity is a feature of many eye-related ease, antigens that instigate autoimmune reactions pathologies including retinal degeneration, retinal may still be active. The ADNIV autoimmune reac-

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tion continues through end-stage disease when the The disorder is dominant, highly penetrant and eye becomes shrunken and blind [17]. displays severe and different phenotype. Phenotypic The molecular mechanisms that initiate neuroin- discordance may be due to epigenetic, postzygotic flammation are poorly understood. or environmental differences [16]. Immunological mechanisms in the eye are also poorly understood. Treatment Treatment of ADNIV patients is very difficult Differential diagnosis and many of them are refractory to it. One of the The differential diagnosis should include au- major reasons is a chronic, severe and non-specific toimmune uveitis, retinitis pigmentosa, rod-cone autoimmune uveitis in the course of ADNIV. An- dystrophy, proliferative vitreoretinopathy and dia- other reason is iris and retina neovascularization betic retinopathy [8, 13, 19, 20]. At different stag- leading to hemorrhage and fibrosis causing trac- es ADNIV mimics this diseases but most of them tional retinal detachment and ongoing outer reti- are characterized with systemic features otherwise nal degeneration. then in ADNIV. Comparing neovascularization Uveitis accounts for as much as 10–15% of seen in proliferative diabetic retinopathy and AD- blindness in the USA and is the fifth leading cause NIV, significant capillary dropout or evidence of of vision loss in developed world. The manage- ischemia is absent in ADNIV. This suggests that ment of uveitis is often ineffective especially in a non-ischemic signaling pathway activates neo- non-specific uveitis, like in ADNIV patients [14]. vascularization. There is not a crisp demarcation Immunohistopathological findings suggest that un- line of vascular closure in the peripheral retina derlying ocular immune dysfunction is present. The as can be seen in other peripheral retinal vascular treatment should be directed at major causes of diseases [8]. profound vision loss such as photoreceptor degen- Retinal pigmentation in ADNIV begins in the eration, cataract, cystoid macular edema, vitreous area of vascular closure and becomes large deep hemorrhage, dense membrane formation leading round spots rather than the bone spicule pattern in to tractional retinal detachment, neovascular and the midperiphery seen in retinitis pigmentosa. steroid-responsive glaucoma. Another disease to be considered in the dif- Initial proceeding of ADNIV is directed to ferential diagnosis is familial exudative vitreoretin- reduce active inflammation in anterior and pos- opathy. In this condition, we observe abrupt termi- terior segment and prevent serious complication nation of the retinal vessels at the equator. Vessels of ongoing inflammation and neovascularization. probably never develop normally. In contrast, AD- The therapy of ADNIV involves steroids including NIV patients initially have normal vessels which topical, periocular and intravitreal injections. Long gradually become occluded. Another difference is term local and systemic therapies are limited be- absence of vitreous cells and loss of the b-wave on cause of the numerous side effects like cataracts, ERG testing in patients with familial exudative infections and glaucoma. Periocular and intrav- vitreoretinopathy [8]. itreal steroids require injections at regular inter- There are other conditions in which we observe vals in order to control inflammation and cystoid a selective loss of the b-wave, including retinal vas- macula edema. Some authors report the benefit cular diseases such as central retinal artery or vein of the fluocinolone acetonide (FA) implant in the occlusions, quinine and methanol intoxication and treatment of chronic uveitis in ADNIV patients siderosis. Inherited conditions in which the b-wave [14]. It provides continuous release of intraocular is affected include X-linked retinoschisis, myotonic corticosteroid for approximately 2.5 years. It is dystrophy and forms of nonprogressive night blind- surgically implanted through the pars plana into ness [8]. the vitreous and sutured to the sclera. FA implant Autosomal dominant neovascular inflammatory reduces inflammation, neovascularization and, vitreoretinopathy is a unique eye disease, because it which is important, the need for systemic or lo- shows pathological symptoms of several eye diseases cal therapy, but it does not stabilize long-term that normally do not occur together. Recognition vision, retinal thickening and fibrosis [21]. The of familial nature of ADNIV is very helpful to di- corticosteroid therapy in ADNIV is a non-specific agnose properly. therapy. Like some other uveitic conditions, AD-

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NIV eventually becomes resistant to conventional gations. Despite the aggressive treatment the visual steroid immunosuppression. improvement is only transient — as the disease This nonspecific therapy might be optimized progresses patients progressively lose vision. AD- by medications directed at the specific mediators of NIV patients need careful, continuous long-term ADNIV. One study suggests that therapeutic strate- follow-up to address ongoing chronic inflamma- gies targeting T cells may be more effective than tion, membrane formation, neovascularization and nonspecific therapy. For example drugs such as cy- retinal degeneration. closporin A, FK06, anti-CD3 and rapamycin that To better understand ADNIV pathogenesis fur- target T cell activation and downstream T cell path- ther investigations including immunology, physiol- ways might have greater effect than B cell drugs such ogy and genetic are necessary. as cyclosphamide and mycophenylate mofetil [17]. Immunohistopathological findings suggest that Treatment of ongoing iris and retinal neovas- an underlying ocular immune dysfunction is present cularization apart from steroids therapy includes in ADNIV patients. The creation of a pre-clinical also anti-VEGF medication. Some authors reported model of ADNIV could be used to study mecha- applying of bevacizumab for recurrent uveitis [15]. nisms of ADNIV disease progression and therapy. The laser photocoagulation of the peripheral retina Further study of mechanisms of ADNIV will is only partially effective. Likewise, vitrectomy sur- provide important new insight into some of the gery is related to recurrent membranes and detach- most important causes of irreversible human blind- ments. ness, such as autoimmune uveitis, retinitis pigmen- ADNIV patients could be candidates for retinal tosa, proliferative vitreoretinopathy and diabetic gene therapy, but if disease allele expression in the retinopathy. In-depth investigation of this disorder eye is not sufficient, therapies directed to cells out- will hopefully lead to better understanding of its side the eye as calpain-5 expressing T-cells might be pathogenesis and ultimately result in effective treat- required [13]. ment. There is no therapy for retinal degeneration and References there are no specific therapies for calpains [13]. To 1. Michaelides M, Moore AT. Vitreous. In: Hoyt C, Taylor D. ed. Pediatric develop specific treatment for ADNIV an animal Ophthalmology and Strabismus. Elsevier, London 2012: 410–411. 2. Bassuk A, Yeh S, Wu S, et al. Structural Modeling of a Novel CAPN5 model is needed [13]. Mutation that Causes Uveitis and Neovascular Retinal Detach- The development of secondary glaucoma is asso- ment. PLOS ONE. 2015; 10(4): e0122352, doi: 10.1371/journal. ciated with the need of applying antiglaucoma ther- pone.0122352, indexed in Pubmed: 25856303. 3. Mahajan V, Skeie J, Bassuk A, et al. 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