BEYOGLU EYE JOURNAL 2018-2

ISSN 5989-6587 ISSN 2459 - 1777

BEYOGLU EYE JOURNAL

BEYOGLU EYE JOURNAL

Volume 3 Issue 2 Year 2018

Volume 3 Issue 2 Year 2018

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INDEXED IN TUBITAK ULAKBIM TR INDEX

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ISSN 2459 - 1777

BEYOGLU EYE JOURNAL

EDITOR-IN-CHIEF

MUHITTIN TASKAPILI, MD University of Health Sciences, Beyoglu Eye Training and Research Hospital

ASSOCIATE EDITORS

ALPER AGCA, MD University of Health Sciences, Beyoglu Eye Training and Research Hospital

CIGDEM ALTAN, MD University of Health Sciences, Beyoglu Eye Training and Research Hospital

PINAR CAKAR OZDAL, MD Ankara Ulucanlar Eye Training and Research Hospital

IRFAN PERENTE, MD University of Health Sciences, Beyoglu Eye Training and Research Hospital SCIENTIFIC ADVISORY BOARD NUR ACAR, Istanbul BANU ACIKALIN, Istanbul ALPER AGCA, Istanbul YUSUF AKAR, Antalya CENGİZ ALAGOZ, Istanbul ZEYNEP ALKIN, Istanbul NILUFER ALPARSLAN, Istanbul TUGRUL ALTAN, Istanbul TULIN ARAS OGREDEN, Istanbul HALIL OZGUR ARTUNAY, Istanbul MELIKE BALIKOGLU YILMAZ, Izmir BERNA BASARIR, Istanbul FIGEN BATIOGLU, Ankara NILUFER BERKER, Ankara CAGRI G. BESIRLI, Michigan, USA ALI BULENT CANKAYA, Ankara FERDA CIFTCI, Istanbul AHMET DEMIROK, Istanbul MURAT DOGRU, Keio, Japan G. MUSTAFA ERDOGAN, Istanbul

KORHAN FAZIL, Istanbul BIRSEN GOKYIGIT, Istanbul G. IBRAHIM GULKILIK, Istanbul HULYA GUNGEL, Istanbul KIVANC GUNGOR, Gaziantep DILEK GUVEN, Istanbul ZIYA KAPRAN, Istanbul ESRA KARDES, Istanbul SAFAK KARSLIOGLU, Istanbul SULEYMAN KAYNAK, Izmir AHMET KIRGIZ, Istanbul R. BERIL KUCUMEN, Istanbul ORKUN MUFTUOGLU, Istanbul OSMAN BULUT OCAK, Istanbul HALIT OGUZ, Istanbul AYŞE ONER, Kayseri ALTAN ATAKAN OZCAN, Adana FERAH OZCELIK, Istanbul HAKAN OZDEMIR, Istanbul

ABDULLAH OZKAYA, Istanbul GAMZE OZTURK KARABULUT, Istanbul AHMET MURAT SARICI, Istanbul BANU SATANA, Istanbul FEVZI SENTURK, Istanbul KUBRA SEREFOGLU CABUK, Istanbul DIDEM SERIN, Istanbul TAMER TAKMAZ, Ankara ARZU TASKIRAN COMEZ, Canakkale MUSTAFA ILKER TOKER, Ankara BETUL TUGCU, Istanbul DIDAR UCAR, Istanbul CANAN ASLI UTINE, Istanbul MURAT UYAR, Istanbul NILUFER YALCINDAG, Ankara MELDA NURSAL YENEREL, Istanbul YUSUF YILDIRIM, Istanbul IHSAN YILMAZ, Istanbul PELIN YILMAZBAS, Ankara

VOLUME 3 ISSUE 2 YEAR 2018

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Drainage. Philadelphia: WB Saunders; 1975.

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Cornea. 2nd ed. Boston, MA: Butterworth-Heinemann; 1998.

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YILIN TECRÜBESİ

ZADITEN® % 0.025 Steril Göz Damlası Etkin madde: 1 ml çözeltide 0,345 mg ketotifen hidrojen fumarat’a eşdeğer 0,25 mg ketotifen içerir. Terapötik endikasyonlar: Alerjik konjonktivit semptomlarının tedavisinde endikedir. Pozoloji ve uygulama şekli: Yetişkinler, yaşlılar ve çocuklarda (3 yaş ve üzeri) konjonktival kese içine günde 2 defa 1 damla damlatılır. Özel popülasyonlara ilişkin ek bilgiler: ZADITEN®’in 3 yaşın altındaki çocuklarda etkinlik ve güvenliliği gösterilmemiştir. Kontrendikasyonlar: Ketotifen veya yardımcı maddelerden herhangi birine karşı aşırı duyarlılığı olduğu bilinen hastalarda kontrendikedir. Özel kullanım uyarıları ve önlemleri: ZADITEN® koruyucu olarak yumuşak kontakt lenslerde birikebilen bir madde olan benzalkonyum klorür ihtiva eder; bu nedenle, ilacın damlatılması esnasında gözde kontakt lens bulunmamalıdır. İlaç damlatıldıktan en az 15 dakika sonra kontakt lensler tekrar göze takılabilir. Diğer tıbbi ürünler ile etkileşimler ve diğer etkileşim şekilleri: ZADITEN®’e ek olarak başka göz ilaçları kullanılması gerektiğinde, iki ilaç en az 5 dakika ara ile uygulanmalıdır. Oral yolla ketotifen fumarat kullanımı, santral sinir sistemi depresanlarının, antihistaminiklerin ve alkolün etkisini potansiyalize edebilir. Bu olgunun ketotifen fumarat ihtiva eden göz ürünleri açısından önemi bilinmemektedir. Gebelik ve laktasyon: Gebelik Kategorisi: C. Ketotifenin gebe kadınlara kullanımına ilişkin yeterli veri mevcut değildir. Oral kullanım ve toksik dozlar için yapılmış hayvan çalışmalarında pre ve postnatal mortalitede artış gözlenirken teratojenitede böyle bir durum gözlenmemiştir. Oküler kullanımı takiben sistemik düzeyler genellikle limitlerin altındadır. ZADITEN® gerekli olmadıkça gebelik döneminde kullanılmamalıdır. Laktasyon dönemi: Oral uygulamayı takiben elde edilen hayvan verilerine göre ilacın anne sütüne geçtiği bildirilmiş olmasına rağmen, insanda topikal uygulamayı takiben anne sütünde tespit edilebilir miktarlarda bulunmamıştır. ZADITEN® emzirme döneminde kullanılırken dikkatli olunmalıdır. Araç ve makine kullanımı üzerindeki etkiler: Bulanık gören veya uyku hali olan hastalar araç ve makine kullanmamalıdırlar. İstenmeyen etkiler: Göz bozuklukları: Gözde yanma/batma, noktasal korneal epitel erozyonu, ilacın damlatılması esnasında bulanık görme, kuru göz, göz kapağı rahatsızlığı, konjonktivit, göz ağrısı, fotofobi, subkonjonktival hemoraji; Bağışıklık sistemi bozuklukları: Alerjik reaksiyon, ağız kuruluğu; Sinir sistemi bozuklukları: Baş ağrısı, somnolans; Deri ve deri altı doku bozuklukları: Deride döküntü, egzama, ürtiker. Doz aşımı ve tedavisi: Klinik sonuçlar 20 mg’a kadar ketotifenin oral yolla alımını takiben hiçbir ciddi belirti ya da semptomun gözlenmediğini göstermiştir. Raf ömrü: 24 aydır. Şişe açıldıktan sonra 4 hafta içinde kullanılmalıdır. Saklamaya yönelik özel tedbirler: 25°C’nin altındaki oda sıcaklığında saklayınız. Ambalajın niteliği ve içeriği: 5 ml’lik polietilen şişe. Ruhsat sahibi: Thea Pharma İlaç Tic. Ltd. Şti.

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DAHA GENİŞ BİLGİ İÇİN FİRMAMIZA BAŞVURUNUZ. Théa Pharma İlaç Tic. Ltd. Şti. Hakkı Yeten Cad. Selenium Plaza No.10/C K.21 Fulya-Beşiktaş 34349 İstanbul, Türkiye. Tel: +90 212 310 80 20, faks: +90 212 310 80 22.

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BEYOGLU EYE JOURNAL CONTENTS

VOLUME 3 ISSUE 2 YEAR 2018 ISSN 2459 - 1777

INVITED REVIEW

Clinical Findings, Pathogenesis, and Treatment in Non-Infectious Peripheral Ulcerative Keratitis Acikalin B, Akova Y, Akkaya S, Garli M, Yamic M........................................................................................................43 ORIGINAL ARTICLES

Distinguishing Non-Arteritic Ischemic Optic Neuropathy from optic Neuritis with Serum Vitamin B12, Ferritin and Folic Acid Level Guclu H, Doganlar ZB........................................................................................................................................................52 The Change in Deviation Measurements After Refractive Surgery for Partially Accommodative Strabismus: Early Postoperative Evaluation Kepez Yildiz B, Ulas MG, Aygit ED, Gurez C, Kandemir Besek N, Yildirim Y, Agca A, Fazil K, Gokyigit B, Demirok A.......................................................................................................................................................58 Visual and Refractive Outcomes of Laser In Situ Keratomileusis in Low to High Myopia: Two Years’ Follow-up Kayaarası Ozturker Z, Kaya V..........................................................................................................................................63 Conjunctival Limbal Autograft Implantation in Primary and Recurrent Pterygium Demircan A...........................................................................................................................................................................71 Deep Anterior Lamellar Keratoplasty Using the Big-Bubble Technique in Keratoconus Ahmet S, Kandemir Besek N, Agca A, Taskapili M......................................................................................................75 The Effects of Age on Pupil Diameter at Different Light Amplitudes Telek HH, Erdol H, Turk A...............................................................................................................................................80 Effects of Intravitreal Injection of Ranibizumab and Aflibercept on Corneal Endothelium and Central Corneal Thickness Coskun M..............................................................................................................................................................................86 Evaluation of Surgical Outcomes, Patient Satisfaction, and Potential Complications after Blepharoplasty Akkaya S.................................................................................................................................................................................91 CASE REPORTS

Anterior Chamber Dislocation of Ozurdex Implant: A Case Report Ertan E, Duman R, Duman R, Dogan M.........................................................................................................................96 Persistent Subretinal Fluid: Wait or Treat?

Yassa ET, Bakbak B..............................................................................................................................................................99

http://beyoglueye.com

Invited Review

DOI:10.14744/bej.2018.10820 Beyoglu Eye J 2018; 3(2): 43-51

Clinical Findings, Pathogenesis, and Treatment in NonInfectious Peripheral Ulcerative Keratitis Banu Acikalin,1 1 2

Yonca Akova,2

Sezen Akkaya,1

Murat Garli,1

Murat Yamic1

Department of Ophthalmology, Fatih Sultan Mehmet Training and Research Hospital, Istanbul, Turkey Department of Ophthalmology, Bayindir Kavaklidere Hospital, Ankara, Turkey

Abstract Peripheral ulcerative keratitis (PUK) is a group of diseases that manifest with ulceration and/or thinning in the peripheral cornea. Although this group of diseases can occur as a result of infection, most cases are of immunological origin and are associated with autoimmune diseases (AID). The most common form of AID associated with PUK is rheumatoid arthritis (RA). However, PUK may also be seen with other AIDs, such as systemic lupus erythematosus and Wegener’s granulomatosis. There are immunological differences between the peripheral and central cornea that may explain the localization of PUK in the peripheral cornea. For example, the proximity to limbal blood vessels and conjunctival lymphatics is different. Both humoral and cellular immunity play a role in the development of PUK. Although the number of CD8+ T cells did not vary significantly in RA patients, the number of CD4+ T cells was significantly greater. As PUK is very serious, early diagnosis and treatment are very important. Local and systemic corticosteroids, immunosuppressants, biological agents, bandage contact lenses, tissue adhesives, and in some cases, surgical treatment can be applied. Adjacent conjunctival excision, patch lamellar grafts, and keratoplasty are options in surgical treatment. It is very important not to forget the possibility of disease progression despite surgery, and the treatment of underlying disease is crucial. Keratoplasty in PUK cases may not be successful as a result of several factors, such as dry eye and the underlying immunological disease..

Keywords: Peripheral ulcerative keratitis, rheumatoid arthritis, systemic lupus erythematosus.

Introduction Peripheral ulcerative keratitis (PUK) includes a group of inflammatory corneal diseases characterized by ulceration and/or thinning in the peripheral cornea, cell infiltration, various degrees of vaso-occlusive disease, and injection of adjacent vessels. This group of diseases can be caused by infection; however, most cases are of immunological origin and more than half are associated with autoimmune diseases (AID). The peripheral corneal localization of these diseases is explained by the immunological differences between the peripheral and central parts of the cornea. To summarize, the peripheral cornea is closer to the conjunctiva than the central cornea, and the conjunctiva has mediators that

can produce an autoimmune reaction (1). The peripheral cornea, limbal blood vessels, and the conjunctiva are also closer to the lymphatic circulation (2). Conjunctival and limbal Langerhans cell density have been found to be similar in studies. Langerhans cell density decreases from the peripheral cornea to the central cornea. Langerhans cells are dendritic cells carrying human leukocyte antigen-D related (HLA-DR). These cells are thought to play a role in the formation of PUK through the release of inflammatory mediators. There are immunoglobulins (Igs) in the cornea. These Igs pass through the limbal blood vessels into the cornea.

While the IgG and IgA concentrations are not different in the peripheral and central cornea, the IgM concentration is

Address for correspondence: Banu Acikalin, MD. Department of Ophthalmology, Fatih Sultan Mehmet Training and Research Hospital, Istanbul, Turkey Phone: +90 216 578 30 00 E-mail: banuoncel@superonline.com Submitted Date: January 30, 2018 Accepted Date: May 21, 2018 Available Online Date: July 07, 2018 Copyright 2018 by Beyoglu Eye Training and Research Hospital - Available online at www.beyoglueye.com

Š

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greater in the peripheral cornea. IgM is the first antibody produced by B cells and has the strongest antibacterial effect among immunoglobulins. As a result of these properties, IgM is thought to be a factor that protects the peripheral cornea against pathogens. The complement component 1 (C1), which activates the classical complement pathway, is more dense in the peripheral cornea than in the central cornea (1, 3).

AIDs are inflammatory diseases that damage not just 1 kind of tissue or organ in the body, but which may damage many organs or systems. The major AID that is the most common cause of PUK is rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) is the second most common cause of PUK. Although the cause of these diseases is not fully understood, it has been established that these diseases cause serious complications in many organs, systems, and tissues, including the eye. The ocular surface is one of the most affected tissues, and the first finding of these diseases may be ocular surface involvement (4). Tauber et al. (5) found that underlying collagen vascular disease was present in 32 (53%) of 61 cases diagnosed as PUK, and in 8 cases (25%) they reported that the diagnosis of collagen vascular disease was made after the diagnosis of PUK. Approximately 34% to 42% of PUK cases develop due to RA. PUK may also be associated with other AIDs, such as Wegener granulomatosis (WG), polyarteritis nodosa, ulcerative colitis, sarcoidosis, and Sweet's syndrome (6). Although it is very rare, PUK has also been reported in cases of Behรงet's disease (7). PUK occurs in Behรงet's disease during the exacerbation period with unilateral and sectoral involvement (6). PUK cases have also occasionally been reported in diseases such as pyoderma gangrenosum and autoimmune hepatitis (8, 9).

Ocular findings in AIDs include dry eye syndrome, episcleritis, scleritis, uveitis, retinal vasculitis, and PUK. The most common finding in these diseases is dry eye syndrome and the most severe finding is the development of PUK, which is very rare (10, 11). Spontaneous or traumatic corneal perforation and visual loss may occur in PUK cases. There are also cases in which perforation develops in a very short time.

A multidisciplinary approach is needed for AID-related PUK cases. Clinical findings of PUK include ocular irritation, redness, pain, photophobia, and decreased vision due to developing astigmatism and corneal opacity (11, 12). In these cases, conjunctival, episcleral, and scleral inflammation is usually seen. Adjacent scleritis is often present in WG (13). Ocular infections, palpebral malformation, lagophthalmia, and neurotrophic factors can also cause PUK (2). In the differential diagnosis, Acanthamoeba keratitis, phlyctenulosis, marginal keratitis, vernal keratoconjunctivitis, immune corneal rings, corneal degeneration, and corneal diseases such as Mooren's

Acikalin et al., Update on non-infectious peripheral ulcerative keratitis

ulcer should be excluded (5, 14-17). Although it has been reported that there is an important link between infectious PUK and tuberculosis in previous publications, staphylococci have been reported to be more frequent in infectious PUK in recent publications (18). Syphilis is a venereal disease that should definitely come to mind in the differential diagnosis of PUK cases. Mooren's ulcer is a painful, chronic unilateral or bilateral peripheral corneal ulceration, usually located in the interpalpebral space and thought to be associated with ocular autoimmunity. Scleritis does not accompany these ulcers and the pain can be very severe. In these cases, iritis and secondary glaucoma may develop. It may spread circumferentially and then centrally, as corneal thickness rapidly diminishes. It should be considered in the differential diagnosis of PUK (17).

Studies have indicated that both humoral and cellular immunity play a role in AIDs (20, 21). The following is the latest information on the pathogenesis and treatment of the diseases that are the most common causes of PUK. Rheumatoid Arthritis A) Clinical findings and pathogenesis RA is a chronic polyarthritis that involves the peripheral small joints. It is 3 times more common in females than in males, and occurs in approximately 3% of the general population. Extra-articular findings are seen in this disease at a rate of some 25%. In 1 study, more than 1 ocular finding was found in 20% of RA patients who had ocular findings. In these cases, a disease that affects the level of vision, such as cataract or dry eye, is present (22). Normally, the immune system is not responsive to autologous antigens. Depending on some factors, such as genetic and environmental factors, synoviocytes are thought to be converted to autoantigens in RA. Autoantigens stimulate T and B cells, causing damage to joints, the ocular surface, and other organs and tissues (20, 21, 23). Although RA can cause many complications in the body, the most serious complication is PUK. Foster et al. (24) reported a 10-year mortality rate of approximately 50% in patients with RA with PUK/necrotizing scleritis. T cells cause continuous antibody formation and the accumulation of immunocomplexes at the corneal border (21, 25).

Proinflammatory cytokines secreted by T cells stimulate the inflammatory cells to accumulate in the corneal stroma. Due to the release of proteolytic and collagenolytic enzymes in the cornea, a crescent-shaped area is formed in the cornea.

Then an epithelial defect and progressive stromal melting is seen in this crescent-shaped area (26). Other factors that play a role in the development of PUK include antigen-presenting host cells (APHC) and chemokines (27). Antigen presentation to T cells is restricted to major histocompatibility complex (MHC) class II (28). HLA-DR is an MHC class II cell

Acikalin et al., Update on non-infectious peripheral ulcerative keratitis

surface receptor found in APHCs. HLA-DR, which presents antigen to T cells, plays a role not only in RA initiation, but also in the entire disease process (29). T cells can be divided into 2 groups according to their receptors: gamma-delta and alpha-beta. The alpha-beta T cells are further classified into 2 groups: CD4+ T cells and CD8+ T cells, according to their surface receptors. CD4+ T cells were found to be significantly more prevalent in RA patients (30-32) CD4+ T cells are transformed into 3 different T-helper (Th) cell subtypes when stimulated by different cytokines and factors. These 3 groups are Th1, Th2, and Th17 cells. Th1 cells secrete tumor necrosis factor (TNF)-Îł, Th2 cells secrete interleukin (IL) 4, IL-5, and IL-13; Th17 cells secrete IL-17 (28). The balance between Th1 and Th2 cells is associated with the onset, progression, and healing processes of the disease. Chemokines help T cells migrate to joints and other areas and T cells secrete proinflammatory cytokines that affect and activate macrophages, monocytes, and other cells in these areas (28, 31). T-cell subtypes (Th1, Th2, Th17) activated in these regions secrete lymphokines and help in the pathogenesis of RA through B cell proliferation and autoantibody construction (32). IL-17 levels are also high in serum and active peripheral blood mononuclear cells other than synovial tissue and synovial fluid (33, 34). It has been demonstrated that the level of IL-17 in tears was higher in cases with ocular surface changes. IL-17 enhances B cell proliferation and leads to the conversion of B cells into plasma cells (35). IL-17 itself, along with other proinflammatory cytokines (such as IL-6, TNF-alpha, IL-1, and IL-8) triggers destructive enzymes such as metalloproteinase (MMP)-9 (35-37). Other T cell subgroups, such as Th17, gamma-delta T cells and natural killer T cells, cause the release of some chemokines, cytokines, and MMPs (22).

Under normal conditions, B cells have a natural tolerance to their own body antigens. In RA, this tolerance doesn't exist. First, rheumatoid factor (RF), an autoantibody that binds to the Fc portion of human IgG, has been shown to be associated with RA. Then anti-citrullinated protein antibodies were discovered. Anti-cyclic citrullinated peptide antibodies (anti-CCP antibodies) have been shown to be more sensitive than RF in RA. Anti-CCP antibodies are the markers specific to systemic involvement in RA and appear to be associated with more intense and severe ocular findings when compared with RF (22, 38). Autoantibodies that occur in RA have been shown to bind to their own antigens to form immune complexes that activate B cells and inflammatory cells (39, 40).

Besides producing autoantibodies, B cells secrete cytokines that stimulate pathological T cell responses (41).

B cells in the peripheral blood are an important source of some cytokines in RA, such as TNF and IL6. IL-6 has been shown to regulate the balance between Th17/regulatory T

45

cells (42). Moreover, B cells regulate the Th1/Th2 cell balance (43).

Corneal epithelial cells in the area of a corneal ulcer or the abnormal production of HLA class II antigens in keratocytes and vasculitis in the adjacent conjunctiva are thought to be responsible for the pathogenesis of PUK in RA (44, 45). The limbic vascular structure causes the accumulation of immunocomplexes and the activation of the classic complement system in the periphery of the cornea. Immunocyte accumulation in the peripheral cornea causes angiogenesis in the periphery of the cornea resulting in a vicious cycle (46).

While the cycle continues, inflammatory cells, especially neutrophils and macrophages, reach the cornea through the veins and produce collagenase and other proteases that cause corneal damage. The release of proinflammatory cytokines, such as IL-1, induces the release of MMP 1 and 2 in stromal keratocytes (2). In the presence of corneal epithelial damage, circulating autoantibodies attack specific corneal proteins and initiate PUK development (47).

MMPs are proteolytic enzymes and the main source of these enzymes is local fibroblasts, mononuclear cells and granulocytes, epithelial cells, and keratocytes in RA (48, 49).

The imbalance between MMPs and their inhibitory factors (MMPIF) results in disease progression (50, 51). MMPIFs are dense in the intact cornea and inhibit MMP activity (49).

MMP-1 has been shown to play a major role in dissolving type 1 collagen in the cornea (52) MMP-1 correlates with corneal perforation in patients with PUK. MMP-2 and MMP9 are enzymes required to hydrolyze type IV collagen, which is a major component of basal membranes (49). These enzymes are thought to limit tissue repair and to facilitate the passage of inflammatory cells and their proteolytic enzymes to the corneal stroma by bypassing the corneal basement membrane (53).

B) Treatment Bandage contact lenses, patching with amniotic membrane, resection of conjunctiva adjacent to PUK, topical steroids, antibiotics, and topical immunosuppressives are the topical treatment options in PUK with unilateral AID (54). Topical use of corticosteroids reduce systemic side effects and improve the lesion significantly, but epithelial healing may be delayed and new collagen production may be inhibited.

Although the immunosuppressive effects of these drugs are strong, it should be remembered that they increase the risk of perforation because they inhibit the production of new collagen. For this reason, the decision to start the use of topical corticosteroids in AID-related PUK cases should be made carefully (55).

Cyclosporin (cyclosporin A) is the most commonly used topical immunosuppressant. Cyclosporin A is an agent that

46

acts on T lymphocytes (56). The topical application of cyclosporin prevents nephrotoxicity on a large scale (57).

Collagenase inhibitors or collagenase synthetase inhibitors inhibit corneal stromal melting by inhibiting collagenase. Topical 1% medroxyprogesterone and topical 20% acetylcysteine have recently been used clinically. Oral tetracycline provides additional benefit because it reduces protease activity (58). When applied in patch or graft fashion, the amniotic membrane can reduce inflammation and accelerate corneal epithelization. This can be achieved by reducing inflammation and activating suppressor T cell functions using substances such as fas-ligand and human leukocyte antigen-G (59-60). When corneal perforation develops, cyanoacrylate glue, conjunctival resection in the inflamed area, conjunctival flap, lamellar patch graft, or penetrating keratoplasty (PK) may be required (61-65). A corneal adhesive may delay the need for immediate keratoplasty. After the application of a tissue adhesive to perforations smaller than 2.0 mm, a bandage contact lens application is preferred. Tissue adhesives have been shown to prevent the loss of stroma by removing acute inflammatory cells from the affected cornea (61).

Conjunctival flaps may be effective in non-progressive perforations and accelerate healing; however, conjunctival flaps may not be effective in the event of ongoing perforation or leakage under the flap in active keratitis. Tectonic lamellar keratoplasty or PK is usually used to provide anatomical integrity of the eyeball in cases of corneal necrosis, thinning, and perforation (62). In the presence of high graft rejection, lamellar patch graft is a good choice when compared to PK. PK is necessary in some cases, depending on the location and size of the perforation (≼3 mm diameter) (63). However, as a result of dry eye and corneal hypoesthesia due to an underlying AID, PK results may not be not successful in PUK cases (64). Maneo et al. (65) reported that despite the cytotoxic agents administered in PUK cases, the risk of recurrence of surgery was significantly higher than in other cases of PK. The keratolytic processes leading to corneal melting continue to occur after transplantation.

Systemic treatment is required for patients with PUK and RA. According to scientific study results, systemic corticosteroid administration is successful in the acute phase when PUK and RA are seen together. However, systemic corticosteroid therapy is not sufficient in most cases. Although there are many corticosteroid options for systemic administration, prednisolone is superior to other steroids and clinically preferred because of moderate-intensity glucocorticoid effects, poor effect on electrolyte metabolism, and reasonable halflife (66). Usually, the initial dose is 1 mg/kg/day. A maximum dose of 60 mg is administered daily. The dose is reduced according to the clinical response. Pulse methylprednisolone (1g/day) can be given for 3 days in severe vision-threatening

Acikalin et al., Update on non-infectious peripheral ulcerative keratitis

cases and then oral treatment can be applied. Common side effects of corticosteroids include osteoporosis, impaired blood pressure and glucose regulation, gastrointestinal bleeding, and elecrolide imbalance that limit the use of these drugs (21).

Less mortality and ocular morbidity were seen in a study examining immunosuppressive medications (cyclophosphamide [CTX], methotrexate [MT]), azathioprine) in patients with PUK and RA (10). If treatment with oral corticosteroids fails to respond or if side effects occur, MTX (7.5-25mg/week) and azathioprine (1.0-2.5 mg/kg/day) are the most appropriate options for treatment (67). MTX causes fewer side effects because it acts only on actively producing cells (68). If side effects occur with MTX and azathioprine, the alternative is oral mycophenolate mofetil (1.0 g, twice a day) (66). Furthermore, there have been reports that leflunomide is successful in controlling inflammation in RA (69). However, in some patients, even high doses of systemic corticosteroids and immunosuppressive agents do not control this disease, and therefore, new agents are being studied (70).

As mentioned earlier, TNF-alpha, IL-1, IL-6 have important roles in the pathogenesis of RA-associated PUK. Treatment targeting these agents is termed biological therapy, and it has been accepted in recent years that biological therapy may be the second or even the first treatment option in PUK cases with RA. Etanercept, infliximab, adalimumab, golimubab, certolizumab pegol proinflammatory cytokine inhibits TNF-alpha.71 Etanercept is the first TNF inhibitor used and binds to soluble TNF to prevent TNF from binding to its own receptor. This drug is administered subcutaneously with a dosage of 50 mg once a week or 25 mg twice a week. Etanersept and MTX have an additive effect when used together (72). Infliximab is another TNF-alpha targeting agent and is administered intravenously by infusion.

This agent is both soluble and a transmembrane TNF-alpha binding chimeric mouse/human IgG1 monoclonal antibody.

It is also more effective than etanercept because it binds to transmembrane TNF-alpha (73). The infliximab dosage for RA is initially 3 mg/kg in the 2nd and 6th weeks and then every 8 weeks for 18 months. This agent has been shown to stop keratolysis in 77.2% of cases, but due to a severe side effect profile, it should be used in serious cases where other treatment has not been not effective (70). Before starting infliximab, tuberculosis must be absolutely excluded (74). It has been reported that infliximab increases the risk of thrombosis, and it can cause diseases such as venous occlusion and pulmonary embolism (75). Antano et al. treated a patient with RA who had PUK while being treated with prednisolone, MTX, and diclofenac. They first increased the dose of systemic treatment, then applied a cyanocrylate adhesive

Acikalin et al., Update on non-infectious peripheral ulcerative keratitis

and bandage contact lenses after bilateral perforation developed. In follow-up, as the systemic treatment was gradually reduced, bilateral perforation developed once again and they applied an amniotic membrane after a tissue adhesive. Bilateral tectonic keratoplasty was performed, given the recurrence of perforation. Systemic treatment doses were once again increased. This time, treatment with 5 mg/kg infliximab was initiated on the postoperative first day and after 18 months, the results were successful in both eyes. In this case, phacoemulsification surgery with intraocular lens implantation in the posterior chamber was performed 9 months after keratoplasty and the initiation of infliximab treatment. There was no problem during or after surgery (76). Adalimumab is a humanized recombinant IgG1 monoclonal antibody that targets TNF-alpha. The subcutaneous delivery ofadalimumab is a significant advantage compared with infliximab, which is delivered by infusion (54). Golimumab is also a biological agent. Initially, it is applied every 4 weeks and then every 8 weeks. Golimumab is used in cases of RA-associated PUK in which MTX alone or with other anti-TNF drugs can not stop PUK progression (77). Another inhibitor of TNF is certolizumab pegol (66). Rituximab is a monoclonal antibody targeting the molecule CD20 on B cells. This agent not only inhibits antigen delivery, but also antibody/cytokine production, and contributes to the depletion of circulating B cells.

It is an appropriate option in cases where at least 2 biological agents, at least 1 of which is an anti-TNF agent, are ineffective (78).

Other agents include anakinra (recombinant human IL-1 receptor antagonist), tosilizumab (humanized anti-human IL-6 receptor antibody of the IgG1 subset), and abatacept (T cell blocking protein Fc fragment of CTLA-4 extracellular domain). Secukinumab and ixekizumab are 2 human monoclonal antibodies that directly block IL-17 (79, 80).

Systemic lupus erythematosus A) Clinic and pathogenesis SLE is most often seen in young women. The joints (arthritis), skin (facial rash, discoid lupus, alopecia, photosensitivity, and Raynaud's phenomenon), kidneys (proteinuria), lungs (pleurisy), blood (anemia, leukopenia and thrombocytopenia), nervous system (psychosis and convulsion), cardiovascular system (pericarditis), and ocular tissues can be involved in SLE (81). Disruption of B cell tolerance leads to the production of antinuclear antibodies (ANAs). The immunocomplexes formed in this case are called CRP (affecting apoptotic cell clearance). Apoptotic cell cleansing is thus impaired in SLE. More nuclear antigens arise from uncleared apoptotic cells and cause intense binding of ANAs. Tissue damage is also seen in the uninvolved area of the immune complexes because of the secretion of C3a and C5a by the activation

47

of an intravascular complement system, the activation of inflammatory cells, and damage to endothelial cells (81). Immune complexes accumulate in the basement membranes of peripheral corneal endothelial cells in SLE and the reactions contribute to melting in the cornea (83). There is an increase in proinflammatory Th17 cells while there is a decrease in anti-inflammatory Treg cells in patients with SLE (82). PUK pathogenesis associated with SLE is similar to PUK pathogenesis in patients with RA in some stages, such as Th17, immune complex and MMP production (84).

B) Treatment As in RA, the treatment of SLE requires medical and surgical treatment. IL-2 is responsible for most of the effects of AIDs. It is a growth, survival, and transformation factor for active T cells, as well as a driving force in the exchange of effector cytolytic T cells and in activation-induced cell death.

Therefore, inhibition of IL-2 is important for SLE treatment and is being investigated (85). Biological agents are widely used in the treatment of SLE. However, only rituximab and belimumab are used in clinical practice and they both target B cells. Belimumab is known to target the B cell survival factor (86).

Wegener granulomatosis A) Clinic and pathogenesis WG is a life-threatening systemic granulomatous vasculitis.

The small vessels, upper and lower respiratory tracts, and kidneys are usually involved in this disease. Ocular findings in WG are similar to those in RA and SLE. The frequency of ocular involvement in WG ranges from 29% to 58%. PUK and necrotizing scleritis can be the first signs of disease. PUK may be bilateral, and PUK is always accompanied by scleral inflammation (87). Watkins et al. (88) reported a PUK ratio of 16.1% in their WG case series.

Autoantibodies and inflammatory cells are responsible for WG. They reach the cornea through the limbal vessels (89, 90). PUK pathogenesis in WG is explained through pathological B and T lymphocytes, and possibly antineutrophil cytoplasmic antibodies (ANCA) (91). The antineutrophil cytoplasmic antibody test in cases of PUK coexisting with WG is a specific and sensitive indicator (92). ANCA binds to receptors in neutrophils and monocytes stimulated by cytokines. The resulting complex releases the lytic enzymes and proinflammatory cytokines such as IL-8. Moreover, the combination of ANCA and neutrophils causes adhesion and cytotoxicity in cultured endothelial cells. In addition, IL-17expressing Th17 cells have been shown to be critical mediators of PUK associated with WG. IL-1, IL-6, IL-17, IL-23, TNF-gamma, and other cytokines have similar effects in the pathogenesis of RA and WG (89).

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B) Treatment Systemic immunosuppressive therapy should definitely be applied in WG patients. Other therapies provide a benefit only if they are given in addition to immunosuppressive treatment (91). Conjunctival excision combined with cryotherapy in addition to immunosuppressive treatment can be effective in these cases. All inflammatory cells and agents that cause necrotic tissue and inflammation are removed from the environment (90). PUK associated with WG is severe and perforation is common. Therefore, surgical treatment is usually required in addition to systemic immunosuppressive treatment (92).

In addition to oral corticosteroids, oral or intravenous CTX is the appropriate treatment choice for these patients.

Hoffman et al. (93) reported successful results in the treatment of PUK associated with WG with 2 mg/kg CTX and 1 mg prednisone per day. Although azathioprine is a safer immunosuppressant than CTX, it has not demonstrated adequate efficacy in these cases compared with RA cases. MTX or azathioprine can be used to provide remission in severe cases (94). Metzler et al. (95) reported that leflunomide was more effective than MTX during attacks. Active ANCA-associated vasculitis responds well to rituximab while limited WG generally responds well to MTX (91).

Differential Diagnosis After excluding all possible causes, including infectious causes, in patients with PUK findings, a detailed personal and family history in terms of AID must be investigated. Treatment choices vary according to the underlying AID (50). A study revealed that the mean time between the onset of RA and the development of ocular findings was 2.1 years, while the time required to develop eye symptoms was 5.4 years.

In the same study, the mean time until the development of severe ocular findings such as PUK and sclerosing keratitis was reported to be 10.5 years (22). PUK is usually seen in patients with RA of long duration. However, cases with PUK detected without arthritis have also been reported (38). In cases of WG and other systemic vasculitis, corneal perforation due to PUK and PUK may occur early. Visual loss can develop even within a few days (21). Since PUK findings are similar in cases of AIDs, we distinguish PUK cases with underlying systemic diseases (such as RA, SLE, and WG).

Results Non-infectious PUK is associated with AIDs, but the pathogenesis is still unclear. The most common disease associated with PUK is RA. PUK requires early diagnosis and treatment because it is a serious and severe disease. The pathogenesis must be understood very well in order to provide the appropriate treatment. Both humoral and cellular immunity play

Acikalin et al., Update on non-infectious peripheral ulcerative keratitis

a role in the pathogenesis. Corticosteroids and immunosuppressives are generally used topically and systemically in treatment. Recently, biological agents have also been introduced. Surgical treatment options are also available in these cases. A multidisciplinary approach is needed.

Disclosures Peer-review: Externally peer-reviewed.

Conflict of Interest: None declared.

Authorship Contributions: Involved in design and conduct of the study (BA, YA MG); preparation and review of the study (BA, YA, MG); data collection (BA, MG, MY); and statistical analysis (BA, MY, SA).

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DOI:10.14744/bej.2018.41736 Beyoglu Eye J 2018;3(2): 52-57

Original Article

Distinguishing Non-Arteritic Ischemic Optic Neuropathy from optic Neuritis with Serum Vitamin B12, Ferritin and Folic Acid Level Hande Guclu,1 1 2

Zeynep Banu Doganlar2

Department of Ophthalmology, Trakya University, Edirne, Turkey Department of Medical Biology, Trakya University, Edirne, Turkey

Abstract Objectives: The aim of this study was to compare the levels of vitamin B12 (Vit B12), folic acid, serum ferritin, serum iron, and total iron binding capacity (TIBC) in patients with optic neuritis (ON) and non-arteritic ischemic optic neuropathy (NAION). It was hoped to determine whether these simple and inexpensive laboratory measurements are indicative for making a distinction between ON and NAION. Methods: In this retrospective study, the data of patients who were diagnosed with ON and NAION between September 2005 and December 2016 were reviewed. In all, 42 patients with NAION, 70 patients with ON, and 76 members of a control group, a total of 188, were enrolled in the study. All of the participants underwent a full ophthalmological examination and complete physical examination, including a detailed medical history and blood count and evaluation of the biochemical parameters, serum ferritin, Vit B12, folic acid, serum iron, and TIBC. Results: The mean serum ferritin level was 236±458.4 ng/mL for the NAION patients, 32.8±34.6 ng/mL for the ON patients, and 76.1±84.6 ng/mL for the control group. The mean serum Vit B12 level was 478±306.3 pg/mL for the NAION patients, 291.7±136.9 pg/mL for the ON patients, and 417.1±163.4 pg/mL for the control group. The mean serum folic acid level was 11.4±6.3 ng/mL for the NAION patients, 6.6±2.7 ng/mL for the ON patients, and 14.5±5.2 ng/mL for the control group.

Conclusion: A higher serum ferritin level was significantly associated with NAION, and lower Vit B12 and folic acid was associated with ON patients. Serum ferritin, Vit B12, and folic acid measurements could be a useful method for distinguishing between NAION and ON before using complicated and invasive methods.

Keywords: Folic acid, non-arteritic ischemic optic neuropathy, optic neuritis, serum ferritin, vitamin B12.

Introduction Optic neuritis (ON) and non-arteritic ischemic optic neuropathy (NAION) are the most common acute optic neuropathies of adults, and they can be difficult to differentiate (1). Distinguishing between these 2 diseases is usually possible using multiple findings, such as pain and typical visual field deficit, as well as with some characteristic clues related to the nature of the diseases, such as age of onset, degree of visual healing, and association with systemic diseases (diabetes, hypertension, multiple sclerosis, neuromyelitis optica) (1-3).

Vitamin B12 (Vit B12) is very important in terms of peripheral and central nervous system functions. A deficiency of Vit B12 has been found to be related to multiple neuro-ophthalmological conditions, including optic neuropathy, bilateral abducens palsy, internuclear ophthalmolplegia, and nystagmus (4-5). Folic acid is required for the formation of tetrahydrofolate, which plays a key role in the detoxification of formate (6, 7). In the case of a folic acid deficiency, formate can block mitochondrial oxidative phosphorylation by inhibiting cytochrome oxidase (6, 8). A folic acid deficiency has been demonstrated to be associated with optic neu-

Address for correspondence: Hande Guclu, MD. Department of Ophthalmology, Trakya University, Edirne, Turkey Phone: +90 284 235 76 41 E-mail: hande83_toprakci@hotmail.com Submitted Date: March 31, 2018 Accepted Date: May 09, 2018 Available Online Date: June 10, 2018 Copyright 2018 by Beyoglu Eye Training and Research Hospital - Available online at www.beyoglueye.com

©

Guclu et al., Ferritin level in ischemic optic

ropathy in multiple studies (7-9). Serum ferritin is an inflammatory marker, which has been reported to be related to the pathogenesis of some diseases, such as diabetes, cancer, heart diseases, neurodegenerative diseases, and age-related macular degeneration (10, 11). Iron plays an important role in cell functions, such as oxygen transport, cell division, mitochondrial adenosine triphosphate formation, and myelin production (12, 13).

Multifocal visual evoked potential, ultrasonography, diffusion-weighted magnetic resonance imaging, visual field tests, fluorescein angiography, optical coherence tomography, and laser speckle flowgraphy have been reported to be helpful in distinguishing ON from NAION in multiple studies. (1, 3, 14-20). The aim of this study was to demonstrate and compare the levels of Vit B12, folic acid, serum ferritin, serum iron, and total iron binding capacity (TIBC) in patients with ON and NAION. The objective was to determine whether these simple and inexpensive laboratory methods could be used to differentiate between ON and NAION.

Methods In this retrospective study, the data of patients who were diagnosed with NAION and ON between September 2005 and December 2016 were reviewed. A total of 188 participants: 42 patients with NAION, 70 patients with ON, and 76 individuals in a control group, were enrolled in the study.

All of the patients underwent a complete neuro-ophthalmological examination, including a detailed medical and ocular history, best corrected visual acuity assessment, pupillary examination, color vision evaluation (Ishihara color vision test), intraocular pressure measurement, automated visual field examination with a Humphrey field analyzer (HFA II 750; Zeiss Medical Technology/Carl Zeiss Meditec AG, Jena, Germany), and slit lamp and fundus examination. In addition, cranial magnetic resonance imaging and visual evoked potential measurements were also performed. The criteria used for NAION were: unilateral disc swelling accompanied by a clinical characterization of NAION, a lack of pain, no improvement in visual acuity in the first month of follow-up, and altitudinal visual field deficit, The criteria used to define ON were: unilateral decreased visual acuity accompanied by or without unilateral disc swelling, pain with ocular movement, and improvement of visual acuity in the first month of follow-up. Exclusion criteria were a positive temporal artery biopsy; a history of any ocular pathology or ocular surgery; the presence of decreased visual acuity of more than 15 days; the presence of inflammatory, rheumatological, or infectious disease; a high sedimentation rate; malignancy; liver disease; kidney disease; hematological disease; coronary artery disease; use of any medications that could cause hematological effects, such as antiaggregants, oral contraceptives, steroids;

53

or the use of any medications that could have an anti-inflammatory effect, such as angiotensin-converting enzyme inhibitors, statins, and beta blockers. Venous blood samples were taken at the time of diagnosis of the NAION and ON patients.

The blood count parameters were measured using a Sysmex XE-2100 automated hematology analyzer (Sysmex Corporation, Kobe, Japan). Serum Vit B12 and folic acid levels were measured with a Centaur XP immunoassay analyzer using original kits (Siemens Healthcare Diagnostics, Erlangen, Germany). Serum iron and unsaturated iron binding capacity (UIBC) levels were measured using an Architect C16000 clinical chemistry analyzer (Abbott Laboratories, Abbott Park, IL, USA) using commercial kits (Archem Diagnostic Ind. Ltd., Istanbul, Turkey) and the TIBC level of patients was calculated according to the following formula: TIBC= Iron + UIBC. Statistical Analysis The results were shown as mean±SD, and categorical variable results were presented as a number (percentage). The Kruskal-Wallis test was used for a comparison of age, ferritin, VitB12, folic acid, TIBC, serum iron, hemoglobin (Hb), and hematocrit (Htc) between groups, and then the Mann-Whitney U test with the Bonferroni adjustment was used for multiple comparisons when a significant difference was found.

Receiver operating characteristic curve (ROC) analysis was used to assess the ION, ON, and control groups. Area under the curve (AUC) values and cut-off points were calculated, and then sensitivity and specificity values at these points were calculated. Moreover, discriminant analysis was used to assess the groups based on the ferritin, Vit B12, and folic acid levels. A p value <0.05 was considered statistically significant. IBM SPSS Statistics for Windows, Version 20.0 (IBM Corp., Armonk, NY, USA) was used to perform the statistical analysis.

Results In this retrospective study, there were 42 ION patients, 70 ON patients, and 76 healthy controls. The mean age was 60.6±16.5 years for the ION patients, 37.3±8.5 years for the ON patients, and 49.1±16.6 years in the control group.

There were statistically significant differences between the ages of the groups (p<0.001).

The serum ferritin level was greater in the ION patients than in the ON patients or the control group. There were statistically significant differences between the groups (p=0.03). Vitamin B12 and folic acid levels were lower in the ON group than in the other groups and the difference was statistically significant. (p=0.001, p<0.001). The serum iron level was lower in the ION patients, but Hb and Htc levels were lower in the ON patients and the differences were

54

Guclu et al., Ferritin level in ischemic optic

statistically significant (p<0.001, p=0.009, p=0.017) (Table 1).

Significant cut-off values were determined to discriminate NAION from ON: >26.3 for ferritin (sensitivity 65.8%, specificity 74.3%), >306 for VitB12 (sensitivity 57.1%, specificity 74.3%), and >11.2 for folic acid (sensitivity 47.6%, specificity 99.0%). Similarly, significant cut-off values were determined to classify the ON group and the control group: ≤26.3 for ferritin (sensitivity 74.3%, specificity 68.4%), ≤306 for VitB12 (sensitivity 74.3%, specificity 78.9%), and ≤11.3 for folic acid (sensitivity 100.0%, specificity 65.8%). The greatest AUC value was determined for folic acid (AUC=0.910; p<0.001) in the analysis of the ON group and the control group. However, cut-off values were not sufficient to distinguish the NAION group from the controls (Table 2, Fig. 1). The classification function coefficients of Fisher's linear discriminant functions Table 1. Laboratory results of non-arteritic ischemic optic neuropathy patients, optic neuritis patients, and controls

NAION ON Control p

(n=42) (n=70) (n=76)

Ferritin

236±458.4

32.8±34.6

76.1±84.6

0.030

Vit B12

478±306.3

291.7±136.9

417.1±163.4

0.001

352.1±69.7 342.7±68.4 324.3±67.7 0.257

Serum iron 57.9±41.4

65.9±34.1

88.8±33.1

<0.001

Hb

13.8±5.1 12.6±1.6 13.6±1.3 0.009

Htc

46.8±34.8 38.1±4.6 41.1±3.6 0.017

Discussion The results of this study demonstrated that there was a higher serum ferritin level in the ION group compared with the ON group and the controls. None of the biomarkers of Vit B12, folic acid, serum iron, TIB, Hb, or Htc was related to a diagnosis of ION. The serum folic acid and Vit B12 levels were found to be significantly lower in the ON group compared with the ION group and the control group.

NAION is an acute ischemic event resulting from interruption of the vascular supply to the optic nerve (1, 21, 22).

Diabetes, hypertension, and atherosclerosis are known to increase the development of this ischemic disease (21). Inflammation has been demonstrated to be related to NAION Table 3. Classification function coefficients of Fisher's linear discriminant analysis

Folic Acid 11.4±6.3 6.6±2.7 14.5±5.2 <0.001 TIBC

are provided in Table 3 and the results are shown in Table 4.

According to the discriminant analysis, overall, 66.0% of the cases were correctly classified in their original group: the individual results were 28.6% in the NAION group, 85.7% in the ON group, and 68.4% in the control group.

Groups

NAION ON Control

Ferritin 0.00016 -0.00236 -0.00443 Vit B12

0.01012

0.00657

0.00822

Folic acid

0.40168

0.26600

0.62811

(Constant) -5.827

Hb: hemoglobin; Htc: hematocrit; NAION: non-arteritic ischemic optic neuropathy; ON: optic neuritis; TIBC: total iron binding capacity;Vit B12: vitamin B12.

-2.899

-7.188

NAION: non-arteritic ischemic optic neuropathy; ON: optic neuritis;Vit B12: Vitamin B12.

Table 2. Diagnostic values of laboratory results of non-arteritic ischemic optic neuropathy patients, optic neuritis patients, and controls

Cut-off

AUC

P

Sensitivity

Specificity

LR+

LR-

NAION vs ON Ferritin

>26.3 0.665 0.050 65.8

74.3

2.59

0.45

Vit B12

>306

0.668

0.030

57.1

74.3

2.22

0.58

Folic Acid

>11.2

0.732

0.002

47.6

99.0

NAION vs Control Ferritin

>155.9 0.543 0.614 33.3

89.5

3.17

0.75

Vit B12

≤308

0.524

0.790

47.6

78.9

2.26

0.66

Folic Acid

≤9.39

0.654

0.054

47.6

84.2

3.02

0.62

Ferritin

≤26.3

0.662

0.014

74.3

68.4

2.35

0.38

Vit B12

≤306

0.774

<0.001

74.3

78.9

3.53

0.33

Folic Acid

≤11.3

0.910

<0.001

100.0

65.8

2.92

0.00

ON vs Control

AUC: Area under the curve; LR +: likelihood ratio positive; LR-: likelihood ratio negative; NAION: non-arteritic ischemic optic neuropathy; ON: optic neuritis;Vit B12: vitamin B12.

Guclu et al., Ferritin level in ischemic optic

55

Table 4. Results of discriminant analysis

100

Predicted group membership

Total

NAION ON Control

80

membership n

Sensitivity

Original group 60 40

NAION 12

16

14 42

ON

6

60

4 70

Control 12

12

52 76

20 0

Ferritine Folic acid VitB12

% NAION

28.6

38.1

33.3 100.0

ON

8.6

85.7

5.7 100.0

Control

15.8

15.8

68.4 100.0

40 60 100-Specificity NAION vs Control 0

NAION: non arteritic ischemic optic neuropathy, ON: optic neuritis.

80

100

100

Sensitivity

80 60 40

Ferritine Folic acid VitB12

20 0 40 60 100-Specificity ON vs Control 0

20

80

100

100 80 Sensitivity

in multiple studies (23, 24). Bernstein et al. (24) reported findings of early inflammatory alterations and stressed that inflammatory-based treatments could be useful in the early phase of the disease (24). Salgado et al. (23) suggested that NAION-related optic nerve damage is associated with thrombosis or hypoperfusion. These 2 conditions result in tissue edema in the sheath of optic nerve, which causes a compartment syndrome. The damage mechanism is similar to central nervous system white matter stroke. Bernstein et al. (25) claimed that NAION is a stroke of the optic nerve.

Middle cerebral artery occlusion leads to cortical cellular inflammation; therefore, NAION could result in inflammation similar to central nervous system strokes (23, 26). Serum ferritin is a well-known marker of iron body stores, iron-related oxidative stress, and inflammation (10, 27, 28). Gye et al. (10) observed higher serum ferritin levels in male glaucoma patients; however, other iron-related markers, such as iron, transferrin, and TIBC were not associated with glaucoma. Similarly, in this study, we detected a higher serum ferritin level in the NAION patients, but we found no relationship between the other biomarkers of serum iron, TIBC, Vit B12, and folic acid level with NAION. We theorized that NAIONâ&#x20AC;&#x2122;s inflammatory character could be a result of this higher ferritin level and that this laboratory test could be useful to distinguish between NAION and ON in older age patients. In addition, the increased incidence of atherosclerosis and diabetes that are accompanied by inflammation in NAION patients may have contributed to the detection of high ferritin levels in the NAION patients.

ON is also an inflammatory demyelinating disease of the myelin sheath surrounding the retinal ganglion cell axons of the optic nerve (29). ON may be immune-mediated with known antibodies, such as neuromyelitis optica, or associat-

20

60 40

Ferritine Folic acid VitB12

20 0 40 60 100-Specificity NAION vs ON 0

20

80

100

Figure 3. ROC analysis for discriminating the NAION, ON, and control groups.

NAION: non-arteritic ischemic optic neuropathy; ON: optic neuritis; Vit B12: Vitamin B12.

56

ed with other systemic diseases, like multiple sclerosis (29).

Vit B12 is a coenzyme in multiple cell reactions, including DNA synthesis and folate metabolism (30). Vit B12 deficiency is a well-known cause of optic neuropathy that occurs due to insufficient myelin production, resulting in axonal degeneration and demyelination (31). In the present study, we found significantly lower Vit B12 levels in ON patients; however, the mean Vit B12 level was within normal limits. In the literature, Vit B12 concentrations have been reported as normal at ≥200 pmol/L, borderline when 150–200 pmol/L, and low when the level is <150 pmol/L (32). It was also demonstrated in a previous study that 42.6% of aquaporin-4 antibody-positive neuromyelitis optica patients had a Vit B12 level of <300 pmol/L. Folic acid concentration is important for myelin basic protein methylation, which is required for nerve myelination and nerve function (8, 33). Multiple studies have reported that folic acid deficiency could lead to nutritional optic neuropathy (6-8). We found significantly lower folic acid levels in the ON patients; however, similar to the VitB12 level, the folic acid level was within normal limits and was not at the level of deficiency. In a previous study, the folic acid level was classified as normal at ≥7 nmol/L, borderline when 5-7 nmol/L, and low <5 nmol/L (32).

Although older patients have an increased risk of Vit B12 and folic acid deficiency (32), interestingly, in the present study, the ON patients (who were younger than the NAION patients and the controls) had lower Vit B12 and folic acid levels. Also, in our study, significant cut-off values were determined to discriminate ON from the controls: ≤306 for Vit B12 and ≤11.3 for folic acid. We suggest that lower (but not of deficiency level) folic acid and Vit B12 levels could be related to ON. The higher serum ferritin levels observed in NAION patients could be associated with that additional risks for inflammation, such diabetes and atherosclerosis in comparison with the younger ON patients. Yet it is noteworthy that more aggressive local inflammation of the optic nerve would typically be seen in NAION patients than in cases of ON aside from the relationship to other systemic diseases.

The greatest limitation of the present study is its retrospective nature, which meant that we could not measure methylmalonic acid and homocysteine levels, 2 markers that are important for Vit B12 and folic acid deficiency. However, to the best of our knowledge, this is the first study to analyze the use of serum ferritin, Vit B12, and folic acid levels to distinguish between 2 diseases that can be difficult to differentiate: NAION and ON. In conclusion, instead of using complicated, invasive, and expensive methods, measurement of serum ferritin, Vit B12, and folic acid levels are useful, inexpensive, noninvasive, and effective laboratory methods for distinguishing NAION from

Guclu et al., Ferritin level in ischemic optic

ON. Further studies will reveal additional relationships between the levels of serum ferritin, Vit B12, and folic acid and NAION, ON, and treatment.

Disclosures Peer-review: Externally peer-reviewed.

Conflict of Interest: None declared.

Authorship Contributions: Involved in design and conduct of the study (HG, ZBD); preparation and review of the study (HG, ZBD); data collection (HG); and statistical analysis (ZBD).

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14. Chen JJ, AbouChehade JE, Lezzi R Jr, Leavitt JA, Kardon RH. Optical coherence angiographic demonstration of retinal changes from chronic optic neuropathies. Neuroophthalmology 2017;41:76–83 15. Giambene B, Virgili G, Menchini U. Retinal nerve fiber layer thickness by Stratus and Cirrus OCT in retrobulbar optic neuritis and nonarteritic ischemic optic neuropathy. Eur J Ophthalmol 2017;27:80–5.

16. Jayaraman M, Gandhi Ra, Ravi P, Sen P. Multifocal visual evoked potential in optic neuritis, ischemic optic neuropathy and compressive optic neuropathy. Indian J OPhthalmol 2014;62:299–304.

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Original Article

DOI:10.14744/bej.2018.57060 Beyoglu Eye J 2018; 3(2): 58-62

The Change in Deviation Measurements After Refractive Surgery for Partially Accommodative Strabismus: Early Postoperative Evaluation Burcin Kepez Yildiz, Nilay Kandemir Besek,

Mehmet Goksel Ulas, Yusuf Yildirim,

Ebru Demet Aygit,

Alper Agca,

Ceren Gurez,

Korhan Fazil,

Birsen Gokyigit,

Ahmet Demirok University of Health Sciences Prof. Dr. N.Resat Belger Beyoglu Eye Training and Research Hospital, Istanbul, Turkey

Abstract Objectives: The aim of this study was to evaluate the postoperative change in the angle of deviation in patients with partially accommodative esotropia or exotropia who underwent keratorefractive surgery.

Methods: The records of patients with partially accommodative esotropia or exotropia who underwent keratorefractive surgery (small incision lenticule extraction [SMILE], laser in situ keratomileusis [LASIK]) at Beyoglu Eye Training and Research Hospital between January 2017 and June 2017 were retrospectively reviewed. Preoperative and postoperative third month uncorrected and best corrected visual acuity, the angle of deviation in prism diopters, and titmus stereoacuity measurements were compared. Any preoperative strabismus surgery was also recorded.

Results: A total of 19 eyes of 11 patients with partially accommodative esodeviation or exodeviation who underwent keratorefractive surgery between January 2017 and June 2017 were included in the study. Eight patients had bilateral surgery and 3 patients had unilateral surgery. The mean age of the patients was 24.9Âą5.78 years. Eight patients (72%) were men and 3 (28%) were women. Four patients had esotropia (36%), 5 had exotropia (45%) and 2 (18%) had exophoria. Five patients (45%) underwent a SMILE procedure and 6 patients underwent femtosecond LASIK surgery. No complications occurred preoperatively or postoperatively. One patient (0.9%) had a history of strabismus surgery before the keratorefractive procedure. No significant difference was detected in the ocular alignment and angle of deviation before and after keratorefractive surgery at postoperative third month.

Conclusion: Refractive surgery seems to be ineffective at providing orthophoria for patients with partially accommodative esodeviation or exodeviation.

Keywords: Binocularity, refractive surgery, strabismus.

Introduction Refractive surgery is a procedure commonly used to correct myopia, hypermetropia, astigmatism, and anisometropia. Refractive surgery in strabismus patients is a special subject that continues to be studied (1-3). It has been reported in the literature that strabismus and diplopia can also occur de novo after different refractive procedures performed in ametropic patients (4, 5). This has led ophthalmologists to

perform preoperative orthoptic examinations to identify patients at risk (6). In myopic and hypermetropic patients with accommodative strabismus, refractive surgical applications have the potential to heal ocular misalignment by correcting refractive errors (7). There are case series with different results for nonaccommodative and partially accommodative deviations (8-10). It is well known that it is very important to inform the patient about how the deviation will change after refractive surgery.

Address for correspondence: Burcin Kepez Yildiz, MD. University of Health Sciences Prof. Dr. N.Resat Belger Beyoglu Eye Training and Research Hospital, Istanbul, Turkey Phone: +90 532 460 06 50 E-mail: burcinkepez@hotmail.com Submitted Date: May 31, 2018 Accepted Date: July 31, 2018 Available Online Date: August 08, 2018 Copyright 2018 by Beyoglu Eye Training and Research Hospital - Available online at www.beyoglueye.com

Š

Kepez Yildiz et al., Ocular misalignment and refractive surgery

The objective of this study was to evaluate changes in preoperative manifest and latent ocular misalignments following keratorefractive surgery in patients with esodeviations or exodeviations.

Methods The files of patients who had been treated by the University of Health Sciences Prof. Dr. Reşat Nuri Belger Beyoglu Eye Training and Research Hospital strabismus and refraction departments and who had undergone corneal refractive surgery between January 2017 and June 2017 were evaluated retrospectively. The study adhered to the tenets of the Declaration of Helsinki. Detailed anamnesis of our patients, including family history was taken in terms of strabismus. A fundus examination, detailed ophthalmological examination, and orthoptic examination were routinely performed. Preoperative and postoperative third-month corrected and uncorrected visual acuity, manifest refraction spherical equivalents, orthoptic examinations with deviation values in prism diopter (PD), stereoacuity, and diplopia examination findings were recorded. Any complications occurring during refractive surgery and any history of preoperative strabismus surgery were recorded. Visual acuity was measured using a Snellen chart projector and recorded in decimals. Uncorrected and corrected best visual acuity was recorded for distance (6 m) and near (33 cm) vision. Cycloplegic refraction with 1% cyclopentate was evaluated in each patient. Ocular misalignment examinations were performed for distance (6 m) and near (33 cm) vision, and for 9 diagnostic positions using the prism cover test. Alignment deviation values were evaluated both with and without refractive correction. During the stereoacuity evaluation, a titmus stereoacuity test was used after correction of refractive errors with contact lenses or glasses. The dominant eye was identified for each patient.

Inclusion criteria for the study were 1) age greater than 20 years, 2) no ocular/systemic disease, 3) normal topographical findings with regular retinoscopic reflexes, 4) central corneal thickness >500 µm, 4) stable refraction for the last 2 years, 5) latent hypermetropia (if any) <2 D, 6) registered near and distance deviation in PD. Informed consent was obtained from all of the patients for refractive surgery procedures.

In cases of bilateral refractive surgery, the procedure was performed on both eyes on the same day with a goal of emmetropia. Corneal refractive surgery was performed under bupivacaine topical anesthesia. The devices used were a Schwind Amaris 750 laser (Schwind eye-tech-solutions GmbH & Co. KG, Kleinostheim, Germany) and VisuMax laser (Carl Zeiss Meditec AG, Jena, Germany). Topical fluorometholone, topical moxifloxacin, and artificial tears were prescribed for 10 days after the operation. All statistical analyses were performed using SPSS version 20 (SPSS Inc, Chi-

59

cago, IL, USA). The mean values were standardized to within 1.0 standard deviation for all determined values. Statistically significant differences were determined using a paired t-test.

Values were considered statistically significant if p was less than 0.05. Since there was a small number of cases with exophoria, statistical analyses of these patients were performed together with exotropia patients.

Results Refractive surgery was performed on 19 eyes of 11 patients.

Eight patients underwent bilateral surgery and 3 patients underwent unilateral refractive surgery. The mean age of the patients was 24.90±5.78 years. Of the group, 8 (72%) were male and 3 (28%) were female. The etiology of strabismus was esotropia (ET) in 4 (36%), exotropia (XT) in 5 (45%), and exophoria (XF) in 2 patients (18%). Small incision lenticule extraction (SMILE) was performed on 5 patients (45%) and femtosecond-assisted laser in situ keratomileusis (femto-LASIK) on 6 patients (55%). One patient (0.9%) had a history of strabismus surgery before the refractive procedure.

Detailed demographic features of the patients are presented in Table 1.

The mean manifest refraction spherical equivalence was 3.29±2 D preoperatively and 0.37±0.75 D postoperatively in esotropic eyes (n=8). In exotropic eyes, the preoperative mean manifest refraction spherical equivalent was -2.98±4.74 D and -0.57±1.42 D postoperatively (n=10) In eyes with exophoria, (n=4) the mean manifest spherical equivalent was -3.53±0.79 D preoperatively and -0.28±0.35 D postoperatively. Four patients (2 patients with ET, 1 patient with XT, 1 patient with XF) had successful outcomes with <10 PD angle of deviation in both distance and near vision after the refractive surgery procedure.

The distance and near vision testing values and the preoperative and postoperative deviation measurements are shown in Table 1. There were no statistically significant differences between groups in terms of preoperative and postoperative values (Table 2) There were no significant changes in the preoperative and postoperative titmus stereoacuity test results in our patients, and no patients complained of diplopia in the postoperative period (Table 1).

Discussion In 1983, Trokel et al. (11) presented excimer laser corneal refractive surgery for the first time and corneal refractive surgery became increasingly popular in the treatment of refractive errors. Patients with strabismus have a much more specific status as candidates for refractive surgery as the correction of the refractive error and removal of the prismatic effect of glasses on ocular alignment can have unpredictable effects on deviation values. Previous studies revealed that

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Kepez Yildiz et al., Ocular misalignment and refractive surgery

Table 1. Demographic and clinical features of the patients (esotropia, exotropia, exophoria) a. Preoperative Patient Gender Age No

Previous Misalignment

BCVA (Snellen)

strabismus values (PD) Right surgery

1 M 39 NO

2 M 21 NO

3 M 21 NO

4 M 21 YES

5 M 21 NO

6 M 22 NO

7 F 26 NO

8 M 20 NO

9 M 23 NO

10 F 29 NO

11 F 31 NO

Refractive

Left

surgery

N 14 ET 20/20 14/20 D 10 ET N 30 ET 18/20 18/20 D 30 ET N 12 ET 18/20 12/20 D 6 ET N 18 ET 20/20 20/20 D 14 ET N 30 XT 18/20 18/20 D 40 XT N 4 XT 18/20 18/20 D 35 XT N 10 XT 20/20 20/20 D 18 XT N 30 XT 14/20 10/20 D 25 XT N 6 XT 20/20 4/20 D 14 XT N 16 XF 20/20 16/20 D 14 XF N 6 XF 18/20 16/20 D 8 XF

MRSE (Diopter) Right

Stereoacuity

Left

Bilateral

0.5

4.63

TITMUS -

Bilateral

4.25

5.5

TITMUS +

Unilateral

3.63

4.63

TITMUS +

Bilateral

3.25

3.25

TITMUS +

Bilateral

-4.5

-4.25

TITMUS +

Bilateral

-8.75

-5.5

TITMUS +

Bilateral

-7.5

-7

TITMUS +

Bilateral

-0.25

0.13

TITMUS +

Bilateral

1,5

6.25

TITMUS -

Bilateral

-2.62

-4.5

TITMUS +

Unilateral

-3.75

-3.25

TITMUS +

(+glasses)

b. Postoperative third month

UCVA (Snellen chart)

Right

Left

MRSE

Right

Left

Misalignment values (PD)

20/20 12/20 1.25 1

18/20 18/20 0.75 1

18/20 12/20 1.38 0.38

20/20 20/20 -1 0

18/20 18/20 -0.12 -0.12

16/20 16/20 -2.75 -1.75

20/20 20/20 -1.75 -1.5

14/20 10/20 -0.75 0

20/20 4/20 2 1

20/20 16/20 -0.37 0.25

18/20 16/20 -0.5 -0.5

Stereoacuity

N 10 ET TITMUS - D 6 ET N 25 ET TITMUS + D20 ET N 0 TITMUS + D 0 N 14 ET TITMUS + D 10 ET N 20 XT TITMUS + D 30 XT N 0 TITMUS + D 30 XT N 14 XT TITMUS + D 20 XT N 45 XT TITMUS + D 50 XT N 4 XT TITMUS D 10 XT N 16 XF TITMUS + D 12 XF N 4 XF TITMUS + D 4 XF

CVA: best corrected visual acuity; D: distance; ET: esotropia; EXT: exotropia; F: female; M: male; MRSE: manifest refraction spherical equivalent; N: near; PD: B prism diopter; UCVA: uncorrected visual acuity; XF: exophoria.

Kepez Yildiz et al., Ocular misalignment and refractive surgery

Table 2. Preoperative and postoperative misalignment values a. Patients with esotropia Esotropia (ET)

Preop ET

Postop 3d

p (n=4)

Month ET

(paired t-test)

15±9.73

12±7.78

0.164

18.5±7.46

14.2±9.57

0.097

(p=4)

DISTANCE (PD) NEAR (PD)

b. Patients with exotropia and exophoria Exophoria

Preop XT

(n=2)/Exotropia

Postop 3rd

p (n=7)

month XT (paired t-test)

(n=5) (XT) (n=7) DISTANCE (PD)

11±3.46

11±5.77

0.706

NEAR (PD)

8±4.61

10±6.92

0.837

ET: esotropia; Preop: preoperative; Postop: postoperative; XT: exotropia+exophoria.

in particular, patients with accommodative esotropia benefit from refractive surgery, and it becomes possible to eliminate both refractive errors and misalignments at the same time in this group of patients. High hypermetropia can lead to increased convergence, and greater convergence can lead to esotropia, even though the fusional divergence amplitude is acceptable. The underlying reason for this cascade is hypermetropia. Correction of hypermetropia with refractive surgery disrupts this sequence and results in orthophoria or microesotropia (12). In our study, there were no patients with fully accommodative esotropia. All were classified as partially accommodative esotropia.

There are quite a number of case series in the literature related to these groups of patients. Hutchinson et al. (13) studied 40 patients with a preoperative deviation value of 18.6 PD (distance-near) esotropia who underwent photorefractive keratectomy surgery, and they reported orthophoria after a mean follow-up of 3.4 years. Hoyos et al. (12) reported outcomes of LASIK surgery used to treat refractive accommodative esotropia in 9 adults ranging in age from 18 to 38 years. Postoperatively, all of the patients were orthophoric without optical correction or maintained their eyeglasses-corrected pre-operative microesotropia. Shi et al. (14) performed LASEK and LASIK surgeries on 26 eyes of 13 patients with accommodative esotropia and amblyopia and reported that the preoperative 37.92±9.12 PD of deviation regressed to 2.76±2.8 PD after 6 months of postoperative follow-up. Sabetti et al. (15) observed that after excimer laser surgery, refractive errors substantially decreased accompanying the improvement in misalignment in 18 patients at the second year; however, this decrease was not statistically significant.

61

Studies in patients with partially accommodative or nonaccommodative esotropia have noted that there is usually a decrease in the degree of misalignment after refractive surgery, but not as dramatic as that seen in the accommodative group. Polat et al. (8) reported a decrease in deviation values in 5 patients with partially accommodative esotropia after LASIK surgery. Nemet et al. (2) also reported a slight decrease in the misalignment of eyes with partially accommodative esotropia and exotropia after a LASIK procedure.There are also studies with less encouraging results. Godts et al. (16) found no change in misalignment values in 42% of a groupu of 14 patients with partially accommodative or nonaccommodative esotropia who underwent LASIK surgery. In our study, we found a decrease in the misalignment for both near and distance after corneal refractive surgery in our patient group with esotropia, but this decrease was not statistically significant (p=0.097, p=0.164, respectively) Furthermore there was no statistically significant difference in patients with exotropia or exophoria after refractive surgery (p=0.706, p=0.837, respectively). The postoperative distance and near deviation of 1 patient in the exotropia group increased.

In the literature, among these patients, those who are myopic with anisometropia benefit most from this procedure (2, 16). Alio et al. (17) and Singh (18) reported that excimer laser surgery can be valuable for pediatric amblyopic patients because of the positive effects on the prognosis of amblyopia. In our study, 1 patient in the exotropia group had bilateral myopia and anisometropia, and another patient in the same group had bilateral hypermetropia and anisometropia.

Both of these patients had substantially decreased deviation values postoperatively. If corneal refractive surgery is considered in patients with misalignment, it is important to expect the patient to stabilize for accommodative and refractive aspects. In our clinical practice, we perform refractive surgery on patients aged 21 years or older and the average age of the patients included in our study was 24 years. However, there are also pediatric studies in the literature. For example, in a study of 30 eyes of 15 patients with a mean age of 13.9 years, patients with high hypermetropia and partially or complete accommodative esotropia underwent LASIK surgery. Seven patients developed inadequate correction and diplopia, but despite this, all of the patients were reported to have continued orthophoria at the postoperative 15th month (9).

Accurate evaluation of stereopsis is helpful in assessing the effects of treatment. Some authors have reported a change in stereopsis before and after surgery (19-21). In our study, no patient with preoperative stereopsis (titmus fly test) lost stereopsis postoperatively.

Another problem of refractive surgeries performed on strabismic patients is postoperative diplopia. This condition can be due to deterioration of binocularity after refractive

62

surgery, myopic hypercorrection, residual hypermetropia, and visual instability as a result of change in dominance (22).

In our study, no diplopia developed in any of the patients.

Only 2 patients had unilateral refractive surgery and they had successful outcomes with <10 PD angle of deviation postoperatively. It should be emphasized that any refractive surgery on a single eye can cause a disparity between the 2 eyes and may result in impairment of fusion, leading to strabismus (23). Our patients who underwent unilateral surgery had no problems postoperatively.

The limitations of our study are the number of patients and the length of follow-up. Further studies with larger patient groups and longer follow-up will give more precise results.

In conclusion, we found that keratorefractive surgery alone is not effective to provide orthophoria for patients with partially accommodative esotropia or exotropia. A detailed preoperative orthoptic examination should be performed and the patient should be informed about the possibility of misalignment after refractive surgery to prevent unrealistic expectations.

Disclosures Acknowledgement: This study was presented as an oral presentation at the Turkish Ophthalmology Foundation 51st National Congress (October 24-29, 2017).

Peer-review: Externally peer-reviewed.

Conflict of Interest: None declared.

Authorship Contributions: Involved in design and conduct of the study (BKY, EDA, YY, MGU); preparation and review of the study (BKY, AA, BG, AD); data collection (NKB, EDA, CG, MGU); and statistical analysis (BKY, KF, CG).

References 1. Bilgihan K, Akata F, Or M, Hasanreisoğlu B. Photorefractive keratectomy in refractive accommodative esotropia. Eye (Lond) 1997;11:409–10.

2. Nemet P, Levenger S, Nemet A. Refractive surgery for refractive errors which cause strabismus. A report of 8 cases. Binocul Vis Strabismus Q 2002;17:187–90.

3. Nucci P, Serafino M, Hutchinson AK. Photorefractive keratectomy for the treatment of purely refractive accommodative esotropia. J Cataract Refract Surg 2003;29:889–94.

4. Marmer RH. Ocular deviation induced by radial keratotomy.

Ann Ophthalmol 1987;19:451–2.

5. Kushner BJ, Kowal L. Diplopia after refractive surgery: occurrence and prevention. Arch Ophthalmol 2003;121:315–21.

6. Godts D, Tassignon MJ, Gobin L. Binocular vision impairment after refractive surgery. J Cataract Refract Surg 2004;30:101–9.

7. Minnal VR, Rosenberg JB. Refractive surgery: a treatment for and a cause of strabismus. Curr Opin Ophthalmol 2011;22:222–5.

Kepez Yildiz et al., Ocular misalignment and refractive surgery

8. Polat S, Can C, Ilhan B, Mutluay AH, Zilelioğlu O. Laser in situ keratomileusis for treatment of fully or partially refractive accommodative esotropia. Eur J Ophthalmol 2009;19:733–7.

9. Phillips CB, Prager TC, McClellan G, Mintz-Hittner HA. Laser in situ keratomileusis for high hyperopia in awake, autofixating pediatric and adolescent patients with fully or partially accommodative esotropia. J Cataract Refract Surg 2004;30:2124–9.

10. Kirwan C, O'Keefe M, O'Mullane GM, Sheehan C. Refractive surgery in patients with accommodative and non-accommodative strabismus: 1-year prospective follow-up. Br J Ophthalmol 2010;94:898–902.

11. Trokel SL, Srinivasan R, Braren B. Excimer laser surgery of the cornea. Am J Ophthalmol 1983;96:710–5 12. Hoyos JE, Cigales M, Hoyos-Chacón J, Ferrer J, Maldonado-Bas A. Hyperopic laser in situ keratomileusis for refractive accommodative esotropia. J Cataract Refract Surg 2002;28:1522–9.

13. Hutchinson AK, Serafino M, Nucci P. Photorefractive keratectomy for the treatment of purely refractive accommodative esotropia: 6 years' experience. Br J Ophthalmol 2010;94:236–40.

14. Shi M, Jiang H, Niu X, Dai H, Ye Y. Hyperopic corneal refractive surgery in patients with accommodative esotropia and amblyopia. J AAPOS 2014;18:316–20.

15. Sabetti L, Spadea L, D'Alessandri L, Balestrazzi E. Photorefractive keratectomy and laser in situ keratomileusis in refractive accommodative esotropia. J Cataract Refract Surg 2005;31:1899–903.

16. Godts D, Trau R, Tassignon MJ. Effect of refractive surgery on binocular vision and ocular alignment in patients with manifest or intermittent strabismus. Br J Ophthalmol 2006;90:1410–3.

17. Alió JL, Artola A, Claramonte P, Ayala MJ, Chipont E. Photorefractive keratectomy for pediatric myopic anisometropia. J Cataract Refract Surg 1998;24:327–30.

18. Singh D. Photorefractive keratectomy in pediatric patients. J Cataract Refract Surg 1995;21:630–2.

19. Stidham DB, Borissova O, Borissov V, Prager TC. Effect of hyperopic laser in situ keratomileusis on ocular alignment and stereopsis in patients with accommodative esotropia. Ophthalmology 2002;109:1148–53.

20. Magli A, Iovine A, Gagliardi V, Fimiani F, Nucci P. LASIK and PRK in refractive accommodative esotropia: a retrospective study on 20 adolescent and adult patients. Eur J Ophthalmol 2009;1:188–95.

21. Nucci P, Serafino M, Hutchinson AK. Photorefractive keratectomy followed by strabismus surgery for the treatment of partly accommodative esotropia. J AAPOS 2004;8:555–9.

22. Gómez de Liaño-Sánchez R, Borrego-Hernando R, Franco-Iglesias G, Gómez de Liaño-Sánchez P, Arias-Puente A. Strabismus and diplopia after refractive surgery [Article in Spanish]. Arch Soc Esp Oftalmol 2012;87:363–7.

23. Kim SK, Lee JB, Han SH, Kim EK. Ocular deviation after unilateral laser in situ keratomileusis. Yonsei Med J 2000;41:404–6.

Original Article

DOI:10.14744/bej.2018.26349 Beyoglu Eye J 2018; 3(2): 63-70

Visual and Refractive Outcomes of Laser In Situ Keratomileusis in Low to High Myopia: Two Years’ Follow-up Zeynep Kayaarası Ozturker,1 1 2

Vedat Kaya2

Department of Ophthalmology, Başkent University Faculty of Medicine, Istanbul, Turkey Department of Ophthalmology, Istanbul Kemerburgaz University Faculty of Medicine, Istanbul, Turkey

Abstract Objectives: The purpose of this study was to determine the refractive and visual acuity changes in myopic eyes after laser in situ keratomileusis (LASIK) surgery and to evaluate the stability, predictability, efficacy, and safety of the procedure.

Methods: A total of 199 eyes of 113 patients were evaluated retrospectively at the Beyoğlu Eye Training and Research Hospital in terms of myopia and/or myopic astigmatism correction with LASIK surgery. The cases were classified as low to moderate myopia/myopic astigmatism (-0.50 to -6.00 diopters [D]) (Group 1) and high myopia (-6.25 to -16.00 D) (Group 2). Uncorrected visual acuity (UCVA), best corrected visual acuity (BCVA), the rate of achieving the planned diopter value, and insufficient and excessive correction were investigated. In all cases, the laser procedure was performed with an LSX (LaserSight, Inc., FL, USA) device, and keratome incisions with a Carrazio-Barraquer or a Moria M2 microkeratome.

Results: The patients were followed up for a median of 18.82±6.06 months. In the group, 52 were male (46.0%), 61 were female (53.9%), and the mean age was 30.5±8.76 years. At the last visit, the mean spherical and cylindrical refractive error in Group 1 regressed from the preoperative values of -3.31±1.54 D and -1.00±1.08 D to -0.17±0.56 D and -0.71±0.57 D, respectively. In Group 2, the mean spherical and cylindrical refractive error regressed from the preoperative values of -8.55±2.26 D and -1.64±3.36 D to -1.53±1.06 D and -0.66±0.71 D, respectively. Preoperative UCVA increased from 0.07±0.46 D to 0.83±0.75 D in Group 1 (p<0.001), and 0.03±0.58 D to 0.43±0.54 D in Group 2 (p<0.001). There was no statistically significant change in the BCVA in either group at the final visit (p>0.05 for each group). Five eyes (10%) in Group 1 and 6 eyes (18%) in Group 2 had a loss of ≥1 line on the Snellen chart with best correction. Four eyes (8%) in Group 1 and 7 eyes (21%) in Group 2 gained ≥1 line on the Snellen chart with best correction.

Conclusion: LASIK surgery yielded better results in cases of low to moderate myopia, and had acceptable results in high myopia. Although refractive improvement may be achieved in high myopia, considering the low visual quality obtained and the possibility of regression, the results of high dioptric correction can be variable.

Keywords: Laser in situ keratomileusis, myopia, visual acuity.

Introduction With the advent of corneal ablation with an excimer laser, photorefractive keratectomy began to be widely used. However, complications, such as stromal haze, refractive regression, and a decrease in visual acuity especially seen in high diopters (D), led to the quick adoption of the laser in situ keratomileusis (LASIK) procedure (1, 2). This method demonstrated earlier refractive stability as a result of the combination of the early healing property of automated

lamellar keratoplasty and the sensitivity of photorefractive keratectomy. Nonetheless, because LASIK requires the creation of flap in the cornea, the ability to use a microkeratome is important for the success of surgery (3).

Numerous studies have demonstrated good efficacy, safety, stability, and predictability in the use of LASIK for the treatment of myopia (4-6). However, one-third of the studies did not provide information on a gain or loss of best corrected visual acuity (BCVA), an important safety measure

Address for correspondence: Zeynep Kayaarası Ozturker, MD. Department of Ophthalmology, Başkent University Faculty of Medicine, Istanbul, Turkey Phone: +90 532 393 64 32 E-mail: zeynepkayaa@yahoo.com Submitted Date: Ay gün, 2017 Accepted Date: Ay gün 28, 2017 Available Online Date: August 06, 2018 Copyright 2018 by Beyoglu Eye Training and Research Hospital - Available online at www.beyoglueye.com

©

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for refractive surgery (7). The aim of this study was to evaluate the visual outcomes of LASIK surgery performed on all levels of myopic patients and to improve understanding of the impact of the surgery in terms of safety, stability, predictability, and efficacy.

Methods The charts of 186 consecutive patients who underwent LASIK surgery at the Beyoglu Eye Research and Training Hospital (ZKO) were systematically evaluated. Of these patients, 78 had low to moderate myopia and myopic astigmatism, and 35 had high myopia and myopic astigmatism. Patients were followed for at least 6 months after the surgery (mean: 18.82±6.06 months).

Patients who met the following criteria were eligible for the study: preoperative corneal thickness of ≥400 µm and estimated residual thickness of the stromal bed ≥250 µm after laser ablation, severe dry eye, progressive corneal degeneration, forme fruste keratoconus, cataract, glaucoma, uveitis, and no history of ocular surgery. Eyes that had a progressive refractive error for 1 year or that had previous LASIK surgery were excluded. The retrospective review of the data was approved by the Institutional Review Board of Beyoglu Eye Research and Training Hospital and followed the tenets of the Declaration of Helsinki.

Prior to the operation, the patients underwent a complete ophthalmological examination. Rigid contact lens users were asked not to use the lenses for 4 weeks before their examination, and soft lens users for 2 weeks. The following data were collected for each patient: age, gender, uncorrected visual acuity (UCVA) and BCVA with Snellen chart, cycloplegic refraction, biomicroscopic examination, intraocular pressure of both eyes with Goldmann applanation tonometer, detailed evaluation of the fundus with 3-mirror Goldmann lens under full dilation, corneal topography with EyeSys, keratometric measurement with Javal keratometer, measurement of corneal thickness with a DGH 4000 ultrasonic pachymeter, and axial length measurement with an Axis II A-scan ultrasound device.

A total of 138 eyes of 78 patients with low to moderate myopia and/or myopic astigmatism (-0.50 D to -6.00 D), and 61 eyes of 35 patients with high myopia and/or myopic astigmatism (-6.25 D to -16.00 D) were included in the study.

Visual acuity was determined using the Snellen chart, and scores were converted to logMAR units for statistical analysis. Eyes with a peripheral retinal hole or lattice degeneration were treated with argon laser photocoagulation. If the eyes were considered safe enough to proceed after 1 month, LASIK was then applied. Corneal topography performed with EyeSys was evaluated using the Holladay Diagnostic Summary 2000 program. In all eyes, flap formation

Kayaarası Ozturker et al., LASIK in myopia

was performed with a Carrazio-Barraquer and a Moria M2 microkeratome and the laser application was performed with an LSX (LaserSight Inc., FL, USA) excimer laser using the spot scan technique.

Operation Technique All of the patients were fully informed about the procedure in order to facilitate cooperation, including advisement that there would be a sensation of pressure and a loss of vision for a short time. Prior to the operation, anesthesia was provided with a 0.5% proparacaine drop 3 times at 5-minute intervals.

After topical anesthesia was achieved, a corneal flap of 130 µm thickness was lifted toward the nasal hinge. The laser was applied with a broad beam profile in a 6-mm optical zone. In all eyes, the preoperative manifest refraction was selected as the target for myopic correction. A daily dose of 5x1 tobramycin sulfate, 5x1 prednisolone acetate, and 6x1 artificial tear drops were prescribed for 1 week. Tobramycin sulfate was discontinued at the end of the first week and prednisolone acetate was discontinued gradually within 1 month.

Follow-up of the patients was performed on the postoperative first day, first week, first month, third month, and sixth month, and continued every 6 months afterward. In each examination, the UCVA and the BCVA, biomicroscopic examination, and intraocular pressure measurement were evaluated. Corneal topography with Orbscan II and corneal pachymetry measurements were also included in the follow-up of new patients who were not included in the present study since the length of the follow-up was shorter.

The final refractive errors and UCVA and BCVA measurements were compared with preoperative values. The rate of success in achieving the planned diopter and insufficient and excessive correction were also investigated. SPSS for Windows, Version 11.5 (SPSS Inc., Chicago, IL, USA) was used for the statistical analysis. A t-test was used to compare means and a chi-square test was used to compare ratios. A p value of <0.05 was considered statistically significant.

Results A total of 199 eyes of 113 patients (52 men, 61 women) were evaluated in the study. The mean patient age was 30.5±8.7 years (range: 17-57 years). The preoperative refractive error and UCVA and BCVA values are shown in Table 1.

Group 1 Improvement in preoperative refractive error and changes in visual acuity can be seen in Table 2. In 138 eyes with low to moderate myopia, the mean spherical and cylindrical refractive error decreased from -3.31±1.54 D to -0.17±0.56 D (correction rate: 94.8%) (p<0.001) and from -1.00±1.08

Kayaarası Ozturker et al., LASIK in myopia

65

D to ±0.71±0.57 D (correction rate: 29.0%) (p<0.05), respectively, at the final examination (Fig. 1). Among 41 eyes examined at the postoperative second year, 40 eyes (97.6%) had a spherical refractive error within ±1.00 D and all eyes were within ±2.00 D. Thirty-eight eyes (92.7%) had a cylindrical refractive error within ±1.00 D and 1 eye (2.4%) was within ±2.00 D. Table 1. The clinical characteristics of myopic patients undergoing LASIK surgery Characteristics Low to moderate myopia

High myopia

(Group 1)

(Group 2)

Mean spherical RE

-3.31±1.54

-8.55±2.26

-1.00±1.08

-1.64±3.36

(diopter) Mean cylindrical RE (diopter) UCVA

0.07±0.46 0.03±0.58

BCVA

0.92±0.13 0.61±0.67

BCVA: best corrected visual acuity; LASIK: laser in situ keratomileusis; RE: refractive error; UCVA: uncorrected visual acuity.

The mean UCVA increased from 0.07±0.46 D to 0.83±0.75 D (p<0.001), and there was no statistically significant increase in the BCVA (p>0.05) at the final visit (Fig. 2).

The UCVA was 20/20 or better in 24 (48%) of 50 eyes and 20/40 or better in all eyes. Three eyes (6%) had a loss of 1 line, 1 eye (2%) had a loss of 3 lines, and 1 eye (2%) had a loss of 4 lines on the Snellen chart with best correction. One eye (2%) had a gain of 2 lines, and 3 eyes (6%) had a gain of 1 line (Fig. 3).

There was undercorrection in 19 eyes (13.7%), overcorrection in 7 eyes (5%) and regression in 6 eyes (4.3%). Of the undercorrected eyes, 17 had a second LASIK procedure at an average of 3.3±3.3 months, and 13 of these eyes had a mean spherical and cylindrical refractive error within ±1.00 D at the last visit. No further operation was applied in eyes with overcorrection or regression in the 2-year period.

Group 2 Data of the improvement in preoperative refractive error and changes in visual acuity are provided in Table 3. In 61 eyes with high myopia, the mean spherical and cylindrical refractive error decreased from -8.55±2.26 D to -1.53±1.06 D (correction rate: 82.1%) (p<0.001) and from -1.64±3.36 D to ±-0.66±0.71 D (correction rate: 59.7%) (p<0.05), respec-

Table 2. The preopeartive and postoperative spherical and cylindrical refractive error and uncorrected and best corrected visual acuity in patients with low to moderate myopia in 2 years of follow-up after LASIK Parameters

Preoperative Postoperative

p

1 month

(n=125)

(n=138)

3 months (n=115)

6 months (n=108)

1 year (n=109)

2 years (n=50)

Mean spherical RE (diopter)

-3.31±1.54

-0.41± 1.09

-0.12±0.95

-0.14±0.90

-0.17±0.80

-0.17±0.56

<0.001

Mean cylindrical RE (diopter)

-1.00±1.08

-0.62± 0.69

-0.75±0.65

-0.73±0.57

-0.78±0.70

-0.71±0.57

<0.05

UCVA

0.07±0.46

0.69±0.66

0.72±0.65

0.77±0.67

0.76±0.63

0.83±0.75

<0.001

BCVA

0.92±0.13

0.81±0.77

0.79±0.78

0.81±0.80

0.82±0.79

0.87±0.80

>0.05

BCVA: best corrected visual acuity; LASIK: laser in situ keratomileusis; RE: refractive error; UCVA: uncorrected visual acuity.

Table 3. The preopeartive and postoperative spherical and cylindrical refractive error and uncorrected and best corrected visual acuity in patients with high myopia in 2 years of follow-up after LASIK Parameters

Preoperative Postoperative

p

(n=61)

1 month (n=61)

3 months

6 months

(n=59)

(n=60)

1 year

2 years

(n=57)

(n=57)

Mean spherical RE (diopter)

-8.55±2.26

-2.98±2.32

-2.50±1.47

-2.27±1.67

-1.46±1.55

-1.53±1.06

<0.001

Mean cylindrical RE (diopter)

-1.64±3.36

-0.63±0.61

-0.66±0.73

-0.57±0.70

-0.67±0.76

-0.66±0.71

<0.05

UCVA

0.03±0.58 0.30±0.40 0.34±0.43 0.40±0.47 0.50±0.52 0.43±0.54 <0.001

BCVA

0.61±0.67 0.60±0.64 0.65±0.68 0.63±0.68 0.61±0.62 0.65±0.58 >0.05

BCVA: best corrected visual acuity; LASIK: laser in situ keratomileusis; RE: refractive error; UCVA: uncorrected visual acuity.

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Kayaarası Ozturker et al., LASIK in myopia

Spherical

-3.5

Cylindrical

-3 -2.5 -2 -1.5 -1 -0.5 0

1st week

1st month

3rd month

6th month

1st year

2nd year

Figure 1. The preoperative and postoperative spherical and cylindrical refractive error of patients with low to moderate myopia in 2 years of follow-up after LASIK.The rate of spherical and cylindrical refractive correction was 94.8% and 29.0%, respectively.

UCVA

BCVA

1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

Preop

1st month

3rd month

6th month

1st year

2nd year

Figure 2. The preoperative and postoperative uncorrected visual acuity (UCVA) and best corrected visual acuity (BCVA) in patients with low to moderate myopia in 2 years of follow-up after LASIK. The UCVA improved from 0.07±0.46 D to 0.83±0.75 D with no change in BCVA.

tively, at the final examination (Fig. 4). Among 44 eyes examined at the postoperative second year, 24 eyes (54.4%) had a spherical refractive error within ±1.00 D, 31 eyes (70.5%) were within ±2.00 D, and in 12 eyes (27.3%) it was greater than ±2.00 D. Thirty-four eyes (77.3%) had a cylindrical refractive error within ±1.00 D, 39 eyes (88.6%) were within ±2.00 D and it was greater than ±2.00 D in 5 eyes (11.4%).

The mean UCVA increased from 0.03±0.58 D to 0.43±0.54 D (p<0.001), and there was no statistically significant increase in the BCVA (p>0.05) at the final visit (Fig. 5).

The UCVA was 20/20 or better in 3 (9.0%) of 33 eyes and

20/40 or better in 19 eyes (57.5%). Two eyes (6%) had a loss of 1 line, 3 eyes (9%) had a loss of 2 lines, and 1 eye (3%) had a loss of 4 lines on the Snellen chart with best correction.

Two eyes (6%) had a gain of 1 line, three eyes (9%) had a gain of 2 lines, and 2 eyes (6%) had a gain of 4 lines (Fig. 6).

There was undercorrection in 25 eyes (40.9%), overcorrection in 1 eye (1.6%), and regression in 15 eyes (24.5%).

Of those that were undercorrected, 15 eyes had a second LASIK procedure at an average 2.7±2.3 months and 9 had a mean spherical and cylindrical refractive error within ±1.00 D at the last visit. Seven eyes with regression had secondary

Kayaarası Ozturker et al., LASIK in myopia

67

100% 80% 60% 40% 20% 0%

-4

-3

-1

0

1

2

Figure 3. The percentage of eyes with a loss or gain of best corrected visual acuity Snellen lines postoperatively in patients with low to moderate myopia.

Spherical

Cylindrical

-9 -8 -7 -6 -5 -4 -3 -2 -1 0

Preop

1st month

3rd month

6th month

1st year

2nd year

Figure 4. The preoperative and postoperative spherical and cylindrical refractive error of patients with high myopia in 2 years of follow-up after LASIK. The rate of spherical and cylindrical refractive correction was 82.1% and 59.7%, respectively.

LASIK and 5 had a mean spherical and cylindrical refractive error within ±1.00 D at the last visit. No operation was applied in the eyes with overcorrection.

Discussion In this study, we retrospectively reviewed myopic patients who were followed up regularly for 2 years after LASIK surgery and evaluated the visual and refractive results. We found that 97.6% of eyes with low to moderate myopia and 54.5% of eyes with high myopia were within ±1.00 D 2 years after undergoing LASIK surgery. It has been reported that low to moderate myopic patients show a manifest spheric equivalent refraction within ±1.00 D in 94% to 100% of eyes in the early postoperative period (8). In longer follow-up studies with similar groups of patients, 96% of eyes after 2 years5, 94% after 5 years, (9) and 95% after 10 years (5) had a spherical equivalent refractive error within ±1.00 D at the

final examination. In one study, the authors reported only minimal regression between the third postoperative month to 10 years postoperatively, suggesting that the visual outcome at the third month gives an estimate of the last visual results at 10 years (10).

In our study, the higher myopic treatment group had lower refractive stability. Sekundo et al. (11) demonstrated that 46% of eyes with high myopia that underwent LASIK surgery had a mean spherical refractive error within ±1.00 D at the end of 6 years of follow-up. In a recent study, a similar result was found at 15 years (12). These findings were attributed to myopic regression, as described previously (13).

A final UCVA of 20/20 or 20/40 is a measure of the effectiveness of LASIK surgery. Of eyes with low to moderate myopia in our study, 48% achieved an UCVA of 20/20 or better and all eyes achieved 20/40 or better. However, 20/20 vision was detected in only 9% of eyes in the high myopic

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Kayaarası Ozturker et al., LASIK in myopia

UCVA

BCVA

1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

Preop

1st month

3rd month

6th month

1st year

2nd year

Figure 5. The preoperative and postoperative uncorrected visual acuity (UCVA) and best corrected visual acuity (BCVA) in patients with high myopia in 2 years of follow-up after LASIK. The UCVA improved from 0.03±0.58 D to 0.43±0.54 D with no change in BCVA. 100% 50% 0%

-4

-2

-1

0

1

2

1

2

Figure 6. The percentage of eyes with a loss or gain of best corrected visual acuity Snellen lines postoperatively in patients with high myopia.

group, while 57% achieved 20/40 vision. Clinical trials have shown that in cases of low myopia of ≥-6.00 D, 66% to 86% of eyes achieved a UCVA of 20/20 and 93% to 100% achieved 20/40 (5, 9). In moderate myopia, results from large series indicate that 26% to 71% of eyes achieved a UCVA of 20/20 (14, 15). In the highest myopia group, the results were unfavorable in terms of efficacy, safety, and refractive predictability compared with other myopic levels. Over the 10-year period, the mean was 30% for 20/20, and 79% for 20/40 vision (5, 10). This may be due to slower wound healing associated with a greater cutting depth, and myopic regression due to excessive central ablation (8).

Regarding lost or gained Snellen lines in our patients, 8% of the low to moderate myopic eyes gained lines and 10% lost lines with best correction. In the high myopic group, 21% of eyes gained lines, and 18% lost lines with best correction. In a similar study of patients with different degrees of myopia, it was concluded that although visual results were better in patients with lower myopia, high myopic eyes showed better improvement in visual acuity (16). Our study found that the

rate of gain of Snellen lines in high myopic eyes was more than twice that of the low to moderate myopic eyes. This may confirm reports that high myopic patients treated with LASIK have satisfaction rates as high as 96.3% (11, 17).

The clinical results of low to moderate myopic correction seem to be slightly better than high myopic correction.

The disadvantage of keratorefractive surgery is the inability to maintain long-term refractive stability in high myopic patients. Several studies have shown the occurrence of myopic regression after LASIK, especially when there is a large myopic correction. Regression was found in the early post-LASIK period (3 and 6 months) in high myopia and was attributed to epithelial hyperplasia (18-20). In one study, myopic eyes over -15.00 D showed regression without evidence of stromal ectasia (12). Magallanes et al. (21) reported regression at the postoperative second year, although the refraction was stable at the postoperative first year. High myopic eyes may respond to LASIK surgery differently than low myopic eyes because of the greater corneal elasticity and relatively thinner sclera. In addition, different mediators may play role in

Kayaarası Ozturker et al., LASIK in myopia

wound healing in these eyes.

Residual myopia after LASIK has also been detected more frequently in eyes with high myopia, and it was found to be -1.00 D higher in high myopic eyes after LASIK (22, 23). This may be due to insufficient correction, which involves incorrect data entry and calibration, and differences between manifest and cycloplegic refraction values.

We chose a follow-up period of 2 years after the operation to analyze the results. Long-term studies indicate that the effectiveness of laser refractive surgery is usually stable at 6 months, and this finding provides an estimation of the final visual outcome (10, 24-26). Studies with longer follow-up may involve the development of other age-related ocular disease and additional ocular surgery, such as cataract procedures, which may affect visual outcomes. For this reason, 2 years is an appropriate time frame for evaluating the results in our study. Other studies of postoperative safety, efficacy, and stability may have better outcomes. However, differences in the study population, dioptric correction, and the model of the laser device and the microkeratome may influence the results.

Although a range of visual results have been evaluated in this study, other results, such as ocular surface-related symptoms or patient satisfaction were not included. It is not uncommon for patients who have undergone refractive surgery to have visual complaints, even if their visual acuity is 20/20. This indicates the need for future research.

In conclusion, our findings show that LASIK surgery is predictable for mild to moderate myopia. However, its efficacy decreases with a trend toward myopia over 2 years, particularly in higher myopic eyes. Treatment protocols and technologies in challenging cases are developing, and future studies may provide additional evidence in this evolving field.

Disclosures Peer-review: Externally peer-reviewed.

Conflict of Interest: None declared.

Authorship Contributions: Involved in design and conduct of the study (ZKO VK); preparation and review of the study (ZKO, VK); data collection (ZKO); and statistical analysis (ZKO).

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Original Article

DOI:10.14744/bej.2018.35229 Beyoglu Eye J 2018; 3(2): 71-74

Conjunctival Limbal Autograft Implantation in Primary and Recurrent Pterygium Ali Demircan Prof. Dr. N. Resat Belger Beyoglu Eye Training and Research Hospital, Istanbul, Turkey

Abstract Objectives: The aim of this study was to evaluate the clinical results and recurrence rate after pterygium excision with a conjunctival limbal autograft in patients with primary and recurrent pterygium.

Methods: Patients who had primary (Group 1) or recurrent (Group 2) pterygium and who underwent pterygium excision with a conjunctival limbal autograft implantation (with interrupted 10-0 nylon sutures or fibrin glue) were retrospectively reviewed. Only patients with a follow-up of at least 6 months were included. The primary outcome measures were the spherical equivalent (SE) of manifest refraction, uncorrected distance visual acuity, distance corrected visual acuity, topographical astigmatism, and keratometry values measured preoperatively and at 3- and 6-month follow-up visits. Complication and recurrence data were also recorded.

Results: A total of 145 patients were included in the study. There were no statistically significant differences between the groups preoperatively. When all of the cases were evaluated, there was a statistically significant correlation between pterygium length and corneal astigmatism. After surgery, SE, corneal astigmatism, and topographical astigmatism measurements had decreased significantly in both groups when compared with the preoperative values. Postoperative visual acuity, corneal astigmatism, and manifest cylinder values were similar between the groups. There was no recurrence in Group 1.

The recurrence rate was 1.75% in Group 2.

Conclusion: Pterygium excision with a conjunctival limbal autograft is a safe and effective method for the surgical treatment of primary and recurrent pterygium. The recurrence rate was very low.

Keywords: Autograft, fibrin glue, pterygium, suture.

Introduction Pterygium is a common ocular surface disease originating in the conjunctiva and extending to the cornea; the incidence rate is between 0.7% and 31% (1-3). The standard treatment option for pterygium is surgical excision, but the recurrence rate after surgery has been quite high (24%-89%) (4). The average length of time after the surgery before recurrence has been reported as 3.13 months. Therefore, multiple strategies and new techniques have been developed to reduce the high rate of pterygium recurrence, including limbal conjunctival

autograft, human amniotic membrane grafting, beta-irradiation, stem cell transplantation, and the use of mitomycin-C and fibrin glue (FG) (5-11).

Conjunctival or limbal conjunctival autograft is currently thought to be the best treatment, with a low recurrence rate ranging from 1.9% to 5.3%, and a high degree of safety, according to some studies (12â&#x20AC;&#x201C;15). These treatments have also been demonstrated to be more effective at treating recurrent pterygium than other techniques (16). Although the most common method of conjunctival autograft fixation in pterygium surgery is the use of absorbable or non-ab-

Address for correspondence: Ali Demircan, MD. Prof. Dr. N. Resat Belger Beyoglu Eye Training and Research Hospital, 34421 Istanbul, Turkey Phone: +90 506 854 42 99 E-mail: alidemircanctf@yahoo.com Submitted Date: May 18, 2018 Accepted Date: May 29, 2018 Available Online Date: July 03, 2018 Copyright 2018 by Beyoglu Eye Training and Research Hospital - Available online at www.beyoglueye.com

Š

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Demircan, Conjunctival autograft in pterygium

sorbable sutures, FG is an alternative to sutures for conjunctival autograft fixation.

The aim of this study was to evaluate and compare the effectiveness of conjunctival autograft implantation using sutures and FG in primary and recurrent pterygium.

Intergroup comparisons were conducted using Student’s ttest for parametric variables, and the Mann-Whitney U for non-parametric data.

Methods

In all, 145 patients were included in the study. The mean length of follow-up was 10.92±4.18 months for Group 1 and 11.20±4.25 months for Group 2. The preoperative characteristics of the patients are shown in Table 1 and Table 2.

There were no statistically significant differences between the groups preoperatively. When all of the cases were evaluated, it was observed that there was a statistically significant correlation between pterygium length and corneal astigmatism (Pearson correlation analysis: r=0.657; p<0.001).

There was a statistically significant increase in UCVA and CDVA after the operation in both groups (p<0.001 for UCVA and CDVA in Group1 and Group 2). SE, corneal astigmatism, and topographical astigmatism decreased significantly in both groups when compared with the preoperative values (p<0.001 for UCVA and CDVA in Group1 and Group 2). The postoperative visual acuity, corneal astigmatism, and manifest cylinder values were similar between the groups.

The postoperative findings are presented in Table 3 and the postoperative complications are provided in Table 4.

This study adhered to the tenets of the Helsinki Declaration, and it was approved by the institutional review board of Beyoglu Training and Research Hospital. Patients who had primary (Group 1) or recurrent (Group 2) pterygium and who underwent pterygium excision with conjunctival autograft implantation between September 2011 and July 2012 were included in the study. Only patients with a follow-up of at least 6 months were included. Patients with a history of trauma, use of a topical agent, or previous ocular surgery were not included in this study. The main outcome measures were spherical equivalent (SE) of manifest refraction, uncorrected distance visual acuity (UCVA), distance corrected visual acuity (DCVA), topographical astigmatism, and keratometry values preoperatively and at postoperative 3- and 6-month follow-up visits. The Sirius corneal topography system (Costruzioni Strumenti Oftalmici, Florence, Italy) was used for corneal topography examinations. Anterior segment photography was taken preoperatively and at each postoperative visit. The length of the pterygium tissue over the cornea was measured from the limbus in anterior segment images.

Surgical Methods All of the procedures were performed by a single surgeon using subconjunctival anesthesia. The leading edge of the pterygium was avulsed from the cornea and the pterygium tissue over the corneal surface was dissected with a crescent knife. Remaining pterygium tissue over the bulbar conjunctiva was removed with scissors. The superotemporal bulbar conjunctiva was used to harvest a rectangular limbal conjunctival autograft to match the size of the bare sclera left after the pterygium excision. The conjunctival graft was sutured in place with 10-0 interrupted nylon sutures or FG (Tisseel; Baxter International, Inc., Deerfield, IL, USA). All of the patients received a topical antibiotic and a topical steroid 4 times a day for 1 month. Suture removal was performed 2 weeks postoperatively in patients with sutured conjunctival grafts.

Statistical Methods IBM SPSS Statistics for Windows, (Version 22.0; IBM Corp., Armonk, NY, USA) was used to perform the statistical analysis. Mean and SD were used for descriptive statistics. The Shapiro-Wilks test was used to test the normality of data.

Results

Table 1. Preoperative demographic data

Fibrin glue Nylon suture Age (years) Mean±SD Gender (male/female) Pterygium length (mm) Mean±SD

Group 1

Group 2

p

(n=88) (n=57) 43

26

n/a

45

31

n/a

48.79±12.9 50.94±11.5 0.78 55/33

36/21

0.82

3.46±0.9

3.1±1.05

0.69

n/a: not applicable.

Table 2. Preoperative clinical data of the groups

Group 1

Group 2

p

Mean±SD Mean±SD

Mean keratometry (D)

43.6±1.95

42.99±1.60

0.08

Mean topographic cylinder (D)

-3.77±2.81 -5.03±5.59

0.1

UCVA (decimal)

0.52±0.27

0.66±0.31

0.07

DCVA (decimal)

0.68±0.28

0.77±0.26

0.07

SE (D)

0.86±1.87

0.86±1.28

0.97

Mean manifest cylinder (D)

-2.81±2.56 -2.23±-2.21

0.16

D: diopters; DCVA: distance corrected visual acuity; SE: spherical equivalent; UCVA: uncorrected distance visual acuity.

Demircan, Conjunctival autograft in pterygium

73

Table 3. Postoperative clinical findings Group 1

Group 2

p

Mean±SD Mean±SD

Mean keratometry (D)

44.4±1.7

44.1±1.3

>0.05

Mean topographic cylinder (D)

-1.5±1.6

-0.84±0.7

>0.05

UCVA (decimal)

0.76±0.2

0.84±0.3

>0.05

DCVA (decimal)

0.90±0.02

0.92±0.07

>0.05

SE (D)

0.04±0.02

0.11±0.04

>0.05

Mean manifest cylinder (D)

-1.03±0.3

0.66±0.2

>0.05

D: diopters; DCVA: distance corrected visual acuity; SE: spherical equivalent; UCVA: uncorrected distance visual acuity.

Table 4. Complications Primary

Recurrent

pterygium pterygium

Fibrin Glue Suture Fibrin Glue Suture

Hematoma

1 1

0 1

Dellen

1 0

0 1

Tenon’s granuloma 1 1

0 2

Folding of graft

1 0

1 0

Conjunctival cyst 1 2

1 0

in the literature varies (12-15, 13). These differences are probably related to surgical technique and the definition of recurrence. As in our study, Kenyon et al. (12) reported that none of the patients with primary pterygium experienced recurrence, while Allan et al. (20) reported a recurrence rate of 6.5%. Although there was a lower rate of recurrence in the primary pterygium group in our study, the small number of recurrences (only 1) prevents us from drawing a statistically significant conclusion. The low recurrence rate in this study is probably related to a wide excision of pterygium tissue with the surrounding conjunctiva, a large conjunctival graft with limbal tissue, and the surgeon’s experience. Furthermore, we may have found a higher rate of recurrence with a longer follow-up period.

The most important limitation of this study is the relatively short length of follow-up and the retrospective design.

However, the large number of cases performed by a single surgeon is a major strength.

In conclusion, we evaluated the surgical results of pterygium surgery and found that excision with a conjunctival limbal autograft is a safe and effective method for the surgical treatment of pterygium in primary and recurrent cases. The recurrence rate was very low, whether the graft was fixed in place using interrupted nylon sutures or FG. Disclosures Peer-review: Externally peer-reviewed.

Discussion

Conflict of Interest: None declared.

In this study, we evaluated the results of pterygium surgery with a conjunctival limbal autograft in cases of primary and recurrent pterygium. We found a statistically significant relationship between preoperative corneal astigmatism and preoperative pterygium length. Other studies in the literature have reported similar findings (17,18). After the surgery, visual acuity and corneal topographical findings improved as expected, and no sight-threatening complications were seen in this study in either group.

The most important problem after pterygium surgery is recurrence. Accordingly, multiple strategies and new techniques have been developed to reduce the high rate of pterygium recurrence. In this study, the recurrence rate in Group 1 and Group 2 was 0% and 1.75%, respectively. It is well established in the literature that recurrence is more frequent in younger patients (19). In this study, the only patient to experience recurrence was younger than 40 years of age.

Various studies in the literature have evaluated recurrence rates after pterygium surgery with a conjunctival limbal autograft (12-15). Consistent with our study results, several other authors have reported lower recurrence rates in cases of primary pterygium (12, 13). However, the recurrence rate after surgery in primary and recurrent pterygium cases seen

References 1. Hirst LW. Recurrent pterygium surgery using pterygium extended removal followed by extended conjunctival transplant: recurrence rate and cosmesis. Ophthalmology 2009;116:1278– 86.

2. Shiroma H, Higa A, Sawaguchi S, Iwase A, Tomidokoro A, Amano S, et al. Prevalence and risk factors of pterygium in a southwestern island of Japan: the Kumejima Study. Am J Ophthalmol 2009;148:766–71.e1.

3. Srinivasan S, Dollin M, McAllum P, Berger Y, Rootman DS, Slomovic AR. Fibrin glue versus sutures for attaching the conjunctival autograft in pterygium surgery: a prospective observer masked clinical trial. Br J Ophthalmol 2009;93:215–8 4. Xu Y, Zhou HM, Li J, Ke BL, Xu X. Efficacy of treatment for pterygium by autologous conjunctival transplantation and mitomycin C. Chin Med J (Engl) 2012;125:3730–4.

5. Huerva V, March A, Martinez-Alonso M, Muniesa MJ, Sanchez C. Pterygium surgery by means of conjunctival autograft: long term follow-up. Arq Bras Oftalmol 2012;75:251–5.

6. Kucukerdonmez C, Karalezli A, Akova YA, Borazan M. Amniotic membrane transplantation using fibrin glue in pterygium surgery: a comparative randomised clinical trial. Eye (Lond)

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2010;24:558–66.

7. Chui J, Coroneo MT, Tat LT, Crouch R, Wakefield D, Di Girolamo N. Ophthalmic pterygium: a stem cell disorder with premalignant features. Am J Pathol 2011; 178:817–27.

8. Sekundo W, Droutsas K, Cursiefen C. Operative techniques for surgical treatment of primary and recurrent pterygia. [Article in German]. Ophthalmologe 2010;107:525–8.

9. Jiang J, Gong J, Li W, Hong C. Comparison of intra-operative 0.02% mitomycin C and sutureless limbal conjunctival autograft fixation in pterygium surgery: five-year follow-up. Acta Ophthalmol 2015;93:e568–72.

10. Kurian A, Reghunadhan I, Nair KG. Autologous blood versus fibrin glue for conjunctival autograft adherence in sutureless pterygium surgery: a randomised controlled trial. Br J Ophthalmol 2015;99:464–70.

11. Taylan Sekeroglu H, Erdem E, Dogan NC, Yagmur M, Ersoz R, Dogan A. Sutureless amniotic membrane transplantation combined with narrow-strip conjunctival autograft for pterygium.

Int Ophthalmol 2011;31:433–8.

12. Kenyon KR, Wagoner MD, Hettinger ME. Conjunctival autograft transplantation for advanced and recurrent pterygium.

Ophthalmology 1985;92:1461–70.

13. Prabhasawat P, Barton K, Burkett G, Tseng SC. Comparison of conjunctival autografts, amniotic membrane grafts, and primary closure for pterygium excision. Ophthalmology 1997;104:974–

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85.

14. Sanchez-Thorin JC, Rocha G, Yelin JB. Meta-analysis on the recurrence rates after bare sclera resection with and without mitomycin C use and conjunctival autograft placement in surgery for primary pterygium. Br J Ophthalmol 1998;82:661–5.

15. Young AL, Leung GY, Wong AK, Cheng LL, Lam DS. A randomised trial comparing 0.02% mitomycin C and limbal conjunctival autograft after excision of primary pterygium. Br J Ophthalmol 2004;88:995–7.

16. Al Fayez MF. Limbal versus conjunctival autograft transplantation for advanced and recurrent pterygium. Ophthalmology 2002;109:1752–5.

17. Ermiş SS, İnan Ü, Öztürk F. Analysis of the correlation between pterygium size and induced astigmatism [Article in Turkish]. T Klin J Ophthalmol 2001;10:171–4.

18. Oner FH, Kaderli B, Durak I, Cingil G. Analysis of the pterygium size inducing marked refractive astigmatism. Eur J Ophthalmol 2000;10:212–4.

19. Güler M, Sobaci G, Ilker S, Oztürk F, Mutlu FM, Yildirim E. Limbal conjunctival autogreft transplantation in cases with recurrent pterygium. Acta Ophthalmol 1994;72:721–6.

20. Allan BD, Short P, Crawford GJ, Barrett GD, Constable IJ. Pterygium excision with conjunctival autografting: an effective and safe technique. Br J Ophthalmol 1993;77:698–701.

Original Article

DOI:10.14744/bej.2018.29292 Beyoglu Eye J 2018; 3(2): 75-79

Deep Anterior Lamellar Keratoplasty Using the Big-Bubble Technique in Keratoconus Sibel Ahmet,1 1 2

Nilay Kandemir Besek,2

Alper Agca,2

Muhittin Taskapili2

Department of Ophthalmology, Agri State Hospital, Agri, Turkey University of Healty Sciences, Beyoglu Eye Training and Research Hospital, Istanbul, Turkey

Abstract Objectives: The aim of this study was to evaluate the visual outcomes and complications of deep anterior lamellar keratoplasty (DALK) performed using the big-bubble technique in patients with keratoconus.

Methods: In this case series, 57 eyes of 57 patients with moderate to advanced keratoconus underwent DALK. All of the participants were contact lens-intolerant or had an unacceptable contact lens fitting as a result of advanced keratoconus.

DALK was performed using the big-bubble technique. Full thickness donor corneas devoid of Descemet’s membrane were sutured to the recipient bed. Preoperative and postoperative best spectacle-corrected visual acuity (BSCVA), corneal topography, and intra-postoperative complications were evaluated.

Results: The mean age of 40 male (70%) and 17 female (30%) patients who had an average follow-up of 48.84±18.12 months (range: 12–60 months) in this study was 28±11.3 years (range: 7–63 years) at the time of the DALK procedure.

The mean BSCVA increased from 1.41±0.44 logMAR to 0.87±0.37 logMAR at the final follow-up (p<0.001). The mean preoperative value of flat (K1) and steep (K2) curvature power was 53.5±8.8 diopters (D) and 60.6 ± 8.5 D, respectively, while the postoperative mean K1 and K2 value was 42.8±1.2 D and 46.06±1.3 D. Microperforation was seen in 6 patients (10.5%) during the suturation as an intraoperative complication. Postoperatively, 8 patients (14%) underwent suture revision and 1 patient (0.2%) underwent amniotic membrane transplantation.

Conclusion: DALK using the big-bubble technique appears to be a safe and effective procedure in patients with keratoconus.

Keywords: Big-bubble, deep anterior lamellar, keratoconus, keratoplasty.

Introduction There are 3 basic approaches to keratoconus treatment.

There are methods that provide rehabilitation of the patient’s vision (glasses, hard contact lenses, intracorneal segment insertion), stop the progression of the disease (crosslinking), and remove the source of the disease (keratoplasty).

Surgery is required when the disease has become advanced and the patient’s vision can no longer be rehabilitated with glasses or contact lenses (1).

The surgical treatment technique of keratoplasty for keratoconus can be applied using 2 methods: penetrating keratoplasty (PK) or deep anterior lamellar keratoplasty (DALK).

Though PK adversely affects the structure and integrity of the eye, it has commonly been used as the definitive treatment for many corneal pathologies, such as keratoconus and corneal degeneration or dystrophy (2).

DALK is a method that doesn’t affect the endothelium or Descemet’s membrane (DM), so it can be used in cases of corneal disease located above the DM (3). Although DALK is a time-consuming procedure and a method that requires experience, it has advantages, including the elimination of endothelial graft rejection, reduction of graft failure, faster visual rehabilitation, and longer graft survival due to lower rates of endothelial cell loss (4). Rather than manual dis-

Address for correspondence: Sibel Ahmet, MD. Department of Ophthalmology, Agrı State Hospital, Agri, Turkey, Turkey Phone: +90 506 744 88 33 E-mail: dr.sibelahmet@gmail.com Submitted Date: July 20, 2018 Accepted Date: July 25, 2018 Available Online Date: July 26, 2018 Copyright 2018 by Beyoglu Eye Training and Research Hospital - Available online at www.beyoglueye.com

©

76

section, the injection of air or viscoelastic material into the deep corneal stroma in DALK provides for easier separation of the DM from the stroma and leaves a smoother and more uniform interface, thus reducing the likelihood of complications, such as interface opacity (5). The purpose of this study was to report and assess the results of DALK using the bigbubble technique in patients with keratoconus.

Methods The medical records of patients who had undergone DALK with the big-bubble technique for moderate to advanced keratoconus between February 2012 and February 2017 were retrospectively reviewed. The study was conducted according to the tenets of the Declaration of Helsinki. Written informed consent was obtained from all of the patients before the DALK procedure was performed. Keratoconus was diagnosed clinically based on slit lamp findings (stromal thinning, Fleischer ring, Vogt’s striae) and keratometry, and was confirmed by corneal topography. The study inclusion criteria were moderate to advanced keratoconus with poor best spectacle-corrected visual acuity (BSCVA), rigid gas-permeable contact lens intolerance, or inappropriate contact lens fit. Exclusion criteria included ocular diseases that may affect measurements or visual acuity gains, such as vernal keratoconjunctivitis (VKC), or the presence of hydrops, cataracts, retinal disorders, or glaucoma. Preoperatively, all of the patients had a full ophthalmological examination to determine uncorrected visual acuity (UCVA), BSCVA, manifest and cycloplegic refractions, slit lamp evaluation, Goldman applanation tonometry, and fundoscopy. Using the Sirius topography system (Costruzioni Strumenti Oftalmici, Florence, Italy), the following topographic parameters were recorded and evaluated preoperatively and postoperatively: the flattest keratometric reading (K1) and the steepest keratometric reading (K2). All of the patients were operated on using the big-bubble technique. The diameter of trephination was chosen according to the size of the cone and vertical corneal diameter. After trephination to approximately 80% of the corneal thickness with a Hessburg-Barron suction trephine (Katena Products Inc., Denville, NJ, USA), a 27-gauge needle attached to a 5-cc syringe and bent at 100° (bevel facing downward) was inserted into the stroma up to the center of the cornea. Air was gently injected into the midstroma until a big bubble was formed extending to the border of trephination. If no big bubble was formed the first time, the injection was repeated until a big bubble was formed. After bubble formation, debulking of the anterior two-thirds of the corneal stroma was performed with a crescent blade (Alcon Laboratories, Fort Worth, TX, USA). Thereafter, peripheral paracentesis was performed to reduce intraocular pressure, and the bubble was punctured with a 15° slit-knife

Ahmet et al., DALK using the big-bubble technique

(Alcon Laboratories, Fort Worth, TX, USA) to allow for air to escape and collapse of the bubble. Viscoelastic material (Coatel, Bausch & Lomb, Inc., Bridgewater, NJ, USA) was injected to keep the DM away from the manipulations. Vannas scissors were used to divide the rest of the corneal stroma into 4 quadrants and each quadrant was completely excised using left and right transplantation scissors, taking care not to leave any posterior lip. The viscoelastic material was then completely washed out before proceeding to graft suturing.

If DM perforation occurred and was large enough to preclude lamellar keratoplasty, the procedure was converted to PK. Data related to these eyes were excluded from the study. The donor cornea was punched from the endothelial side using the Barron punch (Katena Products Inc., Denville, NJ, USA). The donor material was oversized by 0.5 mm. The donor DM and endothelium were gently stripped off with a dry cellulose sponge or forceps. The donor cornea was initially fixed with 4 cardinal 10–0 nylon sutures (Sharpoint, Angiotech Pharmaceuticals, Inc. Vancouver, Canada) at the 3, 6, 9, and 12 o’clock positions. Three different suturing techniques were employed based on the surgeon’s preference. These consisted of 16 interrupted sutures, a single running suture with 16 to 18 bites, or a combined technique (8 interrupted sutures accompanied by a single 16-bite running suture). The suture bites encompassed approximately 90% of the thickness of the recipient and donor tissues in all of the suturing techniques. Intraoperative keratoscopy was performed to adjust suture tension. At the conclusion of surgery, dexamethasone 4 mg was injected subconjunctivally.

Patients received topical moxifloxacin 0.5% drops every 6 hours for 30 days and topical prednisolone 1% every 6 hours tapered over 2 to 3 months. If indicated, sodium chloride 5% drops were prescribed to reduce graft edema and filamentary keratitis, and topical lubricants were administered to hasten epithelial healing. In intractable cases, other interventions, such as bandage contact lens fitting (OmniFlex; Hydron International Co., Ltd., Shanghai, China) or amniotic membrane transplantation were used to treat non-healing epithelial defects. Postoperatively, patients were examined on the first day after surgery and every alternating day postoperatively to assess the status of corneal epithelial healing.

Follow-up examinations were scheduled 1, 3, 6, 12, 24, 36, 48, and 60 months postoperatively, with an appointment at least once every 3 months until complete suture removal, and 6 months thereafter. BSCVA, corneal topography, biomicroscopic slit lamp examination, Goldman applanation tonometry, and fundoscopy were performed at each visit.

An automated phoropter (CV-5000; Topcon Corp., Tokyo, Japan) and a back-illuminated 19” LED LCD monitor chart (CC-100 XP; Topcon Corp., Tokyo, Japan) were used for visual acuity examinations. Visual acuity was converted to

Ahmet et al., DALK using the big-bubble technique

77

logMAR for statistical analysis. BSCVA, K1, and K2 readings, as well as intra- or postoperative complications or secondary interventions (such as resuturing) were recorded and evaluated. When more than 1 procedure was required (such as resuturing), the final results were considered for analysis.

The mean and SD were used for descriptive statistics of variables with normal distribution. The Kolmogorov-Smirnov test was used to test the normality of the datasets. A dependent sample t-test was used in the statistical analysis of the comparisons of preoperative and postoperative repeated measures. The level of statistical significance was set at p<0.05.

Statistical analysis was performed using IBM SPSS Statistics for Windows, Version 20.0. (IBM Corp, Armonk, NY, USA).

Results Fifty-seven eyes of 57 (40 male) patients with moderate to advanced keratoconus underwent surgery. The mean age of the patients was 28±11.3 years (range: 7–63 years) at the time of the DALK procedure, and were followed for a mean of 48.84±18.12 months (range: 12–60 months) (Table 1).

Table 1. Patient characteristics and preoperative data of deep anterior lamellar keratoplasty surgery patients Age (mean±SD), years

28±11.3 (range 7–63)

Follow-up (mean±SD), months

48.84±18.12 (range 12–60)

Male/female 40/17 Right/left eye

30/27

The recipient trephination size was 7.25 to 8.0 mm.

The sutures were removed between the 6th and 12th postoperative month. The final outcome analysis was performed after complete suture removal.

The mean BSCVA increased from 1.41±0.44 logMAR to 0.87±0.37 logMAR at the final follow-up (p<0.001) (Fig.1).

The mean preoperative K1 and K2 value was 53.5±8.8 diopters (D) and 60.6 ±8.5 D, respectively, while the postoperative K1 and K2 value was 42.8±1.2 D and 46.06±1.3 D (Fig. 2).

Intraoperatively, microperforations in the DM occurred in 6 eyes (10.5%). Postoperatively, 8 eyes (14%) required resuturing, and 1 patient (0.2%) underwent amniotic membrane transplantation (Table 2).

Discussion Keratoconus is the most common indication for PK in some countries (6). Several advantages and disadvantages have been published for DALK in comparison with PK (2, 7). Some studies (8, 9) have published comparable visual outcomes following DALK and PK, while others (2, 10) have reported superior visual outcomes after PK. This difference can be attributed to irregularity at the host-donor interface in DALK. DM perforation and conversion to PK have been reported at a rate of 4% to 39.2% and 0% to 14%, respectively (11). The difficult learning curve for the surgical technique may also contribute to differences in success rates of big-bubble formation seen in various studies. We decided to include only successful big-bubble formation cases in this study.

Visual Acuity

1.5 1.4

LogMAR

1.3 1.2 1.1 1 0.9 0.8

BSCVA

Preop

12. month

24. month

36. month

48. month

60. month

1.42

0.92

0.9

0.88

0.89

0.88

Follow Up Interval

Figure 1. Visual acuity over the entire follow-up period.

BSCVA: Best spectacle-corrected visual acuity.

Ahmet et al., DALK using the big-bubble technique

Diopters

78

Topographic Changes

62 61 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 Preop

12. month

24. month

36. month

48. month

60. month

K1

53.55

43.13

42.7

42.75

42.65

42.81

K2

60.61

47.2

46.89

46.81

46.28

46.06

Follow Up Interval

Figure 2. Topographic changes.

Table 2. Complications of deep anterior lamellar keratoplasty Complication

n %

Microperforation

6 10.5

Loose suture

14

Resuturation

8 14

Persistent epithelial defect

1

1.7

Amniotic membrane transplantation

1

1.7

24.5

Although DALK rules out the risk of endothelial rejection, other types of graft rejection (subepithelial and stromal) may still spring up. The clinical features of subepithelial and stromal graft rejections after DALK are very similar to those following PK (12). In this study, there was no rejection; which may be explained by excluding eyes with a history of VKC, and having too few patients to see rejections.

In our study, the mean BSCVA increased from 1.41±0.44 logMAR to 0.87±0.37 logMAR at the final follow-up (p<0.001). Romano et al. (13) observed a corrected distance visual acuity (CDVA) of 20/25 (0.09±0.1 logMAR) at the last control examination after DALK surgery in 158 eyes/150 consecutive patients with keratoconus with a postoperative follow-up time equal to or greater than 4 years when the CDVA was 20/50 (0.7±0.2 logMAR) at the beginning. The length of the follow-up was longer in that study than in ours (76.9±23.2 months [range: 48-120 months]) and the study included a larger number of patients.

Javadi et al. (14) found a mean preoperative BSCVA of 1.23±0.4 logMAR (range: 0.0–2.0 logMAR), equivalent to

20/400, which improved to 0.26±0.2 logMAR (range 0.0– 1.4 logMAR), equivalent to 20/40, at the final follow-up (p<0.001). In our study, the preoperative visual acuity and the BSCVA at the last follow up were lower, but there was a statistically significant increase in visual acuity change.

In this study, the mean preoperative K1 keratometry was 53.55±8.85 D in the flattest meridian, whereas it was 42.81±1.29 D at the last follow-up. The mean preoperative K2 keratometry measurement at the steepest meridian was 60.61±8.51 D and 46.06±1.31 D at the last control examination. The changes in K1 and K2 values were statistically significant. (p<0.05) In 77 eyes, Javadi et al. (14) reported a mean preoperative keratometry measurement of 55.51±5.33 D (range: 44.25–71.5 D) and a postoperative value of 47.04±2.27 D (range: 42.25–55.5 D) (p<0.001).

Behesht-Nejad et al. (15) performed DALK using the bigbubble technique in 17 eyes with a mean preoperative keratometry of 60.1±7.3 D and observed a result of 44.86±2.4 D 9 months after the procedure (p<0.0001). Although our follow-up period was longer and our research included 57 eyes, the outcomes were similar, particularly the K2 readings.

The complications experienced are provided in Table 2. A total of 6 eyes (10.5%) had a microperforation in the DM, which occurred during air injection or removal of residual corneal stroma, though it was still possible to continue the DALK procedure because the defect was small. Several studies have reported DM perforation during DALK, ranging from 4% to 39.2%. Microperforation rates are highest with manual dissection (26.3%) and lowest with the Anwar bigbubble technique (5.48%). This variation likely reflects differences in surgeon experience, indications for keratoplasty,

Ahmet et al., DALK using the big-bubble technique

and surgical technique (11).

In the Javadi et al. (14) study, perforation in the DM occurred in 5 eyes during air injection or removal of residual corneal stroma, and 3 required conversion to PK. Zhang et al. (16) performed DALK in 75 eyes and observed microperforation of the DM in 7 eyes (9.3%) and a large tear in the DM in 1 eye (1.3%).

In our study, loose sutures were noted in 14 patients (24.5%) over the follow-up period; however, only 8 cases required resuturing. This rate was similar to that seen in the Behesht-Nejad (15) study. A persistent epithelial defect was noted in 1 patient (1.7%) and was successfully managed with amniotic membrane transplantation. Reepithelialization was completed at 2 weeks, with some subepithelial haze present.

There was no instance of subepithelial or stromal graft rejection, interface wrinkling, vascularization or opacification, fixed dilated pupil, suture abscess, or suture tract vascularization as a complication.

Abdel Hakeem et al. (17) compared the big-bubble technique with manual dissection in DALK and found that in the big-bubble group, the mean BCVA was significantly better (p = 0.006), whereas the mean residual stroma was significantly lower (p = 0.0001) and the interface haze was significantly less (p = 0.018) than that found in the predescematic DALK group.

In another study, Keane et al. (18) compared DALK with PK and found that no evidence to support a difference in outcome in the treatment of keratoconus with regard to BCVA at 3 months post-graft or at any of the other time points analyzed (GRADE rating: very low). They also found no evidence of a difference in outcomes with respect to graft survival, final UCVA, or keratometric outcome. They found some evidence that rejection was more likely to occur following PK than DALK (GRADE rating: moderate).

The principal limitations of our study are the retrospective design and the fact that it does not include a comparison with other keratoplasty techniques.

In conclusion, DALK is an appropriate alternative to PK in patients with keratoconus. It eliminates the risk of endothelial graft rejection, preserves globe integrity, and provides acceptable visual function. More extensive studies with a longer follow-up period are required to better understand all of the advantages and disadvantages of DALK. Disclosures Financial Disclosure: This retrospective study was not supported by any company. None of the authors has financial or proprietary interests in any material or method mentioned. These data have not been previously published.

Peer-review: Externally peer-reviewed.

Conflict of Interest: None declared.

Authorship Contributions: Involved in design and conduct of the study (NKB, AA, SA); preparation and review of the study (AA, NKB, MT); data collection (SA, NKB); and statistical analysis (NKB).

79

References 1. Arnalich-Montiel F, Alió Del Barrio JL, Alió JL. Corneal surgery in keratoconus: which type, which technique, which outcomes?

Eye Vis (Lond) 2016;3:2.

2. Watson SL, Ramsay A, Dart JK, Bunce C, Craig E. Comparison of deep lamellar keratoplasty and penetrating keratoplasty in patients with keratoconus. Ophthalmology 2004;111:1676–82.

3. Shimmura S, Tsubota K. Deep anterior lamellar keratoplasty.

Curr Opin Ophthalmol 2006;17:349–55.

4. Benson WH, Goosey CB, Prager TC, Goosey JD. Visual improvement as a function of time after lamellar keratoplasty for keratoconus. Am J Ophthalmol 1993;116:207–211.

5. Manche EE, Holland GN, Maloney RK. Deep lamellar keratoplasty using viscoelastic dissection. Arch Ophthalmol 1999;117:1561–5.

6. Edwards M, Clover GM, Brookes N, Pendergrast D, Chaulk J, McGhee CN. Indications for corneal transplantation in New Zealand: 1991-1999. Cornea 2002;21:152–5.

7. Terry MA. The evolution of lamellar grafting techniques over twenty-five years. Cornea 2000;19:611–6.

8. Coombes AG, Kirwan JF, Rostron CK. Deep lamellar keratoplasty with lyophilised tissue in the management of keratoconus. Br J Ophthalmol 2001;85:788–91.

9. Sugita J, Kondo J. Deep lamellar keratoplasty with complete removal of pathological stroma for vision improvement. Br J Ophthalmol 1997;81:184–8.

10. Funnell CL, Ball J, Noble BA. Comparative cohort study of the outcomes of deep lamellar keratoplasty and penetrating keratoplasty for keratoconus. Eye 2006;20:527–32.

11. Karimian F, Feizi S. Deep Anterior Lamellar Keratoplasty: Indications, Surgical Techniques and Complications. Middle East Afr J Ophthalmol 2010;17:28–37.

12. Watson SL, Tuft SJ, Dart JK. Patterns of rejection after deep lamellar keratoplasty. Ophthalmology 2006;113:556–60.

13. Romano V, Iovieno A, Parente G, Soldani AM, Fontana L. Longterm clinical outcomes of deep anterior lamellar keratoplasty in patients with keratoconus. Am J Ophthalmol 2015;159:505–11.

14. Javadi MA, Feizi S, Jamali H, Mirbabaee F. Deep Anterior Lamellar Keratoplasty Using the Big-Bubble Technique in Keratoconus. J Ophthalmic Vis Res 2009;4:8–13.

15. Behesht-Nejad AH, Alimardani A, Amoozadeh J, Hashemi H. Deep Anterior Lamellar Keratoplasty Using the Big-bubble Technique. Iranian Journal of Ophthalmology 2009;21:15–22.

16. Zhang YM, Wu SQ, Yao YF. Long-term comparison of full-bed deep anterior lamellar keratoplasty and penetrating keratoplasty in treating keratoconus. J Zhejiang Univ Sci B 2013;14:438–50.

17. Abdel Hakeem AS, Katamish TA, Khalil DH, Alaaeldin HA. Comparative study between big-bubble technique and manual dissection in deep anterior lamellar keratoplasty. J Egypt Ophthalmol Soc 2016;109:93-7.

18. Keane M, Coster D, Ziaei M, Williams K. Deep anterior lamellar keratoplasty versus penetrating keratoplasty for treating keratoconus. Cochrane Database Syst Rev 2014:CD009700.

Original Article

DOI:10.14744/bej.2018.43534 Beyoglu Eye J 2018; 3(2): 80-85

The Effects of Age on Pupil Diameter at Different Light Amplitudes Hande Husniye Telek,1 1 2

Hidayet Erdol,2

Adem Turk2

Department of Ophthalmology, Ankara Training and Researching Hospital, Ankara, Turkey Department of Ophthalmology, Karadeniz Technical University Faculty of Medicine, Trabzon, Turkey

Abstract Objectives: This study was an evaluation of pupil response at different light amplitudes in healthy individuals in different age groups.

Methods: A total of 210 eyes of 105 healthy individuals were included in the study. The participants were divided into 4 groups at 15-year age intervals: 15-30, 31-45, 46-60, and over 60 years. The dimensions of the pupil were measured with a pupillometer at 5 different light amplitudes: 0, 1, 10, 100, and 200 cd/m2. The average pupil diameter in the groups was compared and changes in pupil diameter were correlated for each light amplitude according to age.

Results: The mean pupil diameter was 4.96+0.82 mm in males, and 4.95+0.87 mm in females at 0 cd/m2 light amplitude, and 2.44+0.19 mm and 2.40+0.19 mm, respectively, at 200 cd/m2 light amplitude. The differences were not statistically significant (p>0.05). In addition, there was no significant difference in pupil size between the right and left eye at any light amplitude (p>0.05). Pupil diameters were found to be smaller at all light amplitudes with advanced age. There was a negative significant correlation between pupil size and age at all light amplitudes (p<0.05). The correlation was stronger at low light amplitudes.

Conclusion: Pupil response to light is influenced by age. This should be taken into consideration when evaluating pupil reaction.

Keywords: Electrophysiology, light amplitude, pupil diameter, pupil reaction.

Introduction The iris regulates the amount of light reaching the retina by changing pupil diameter. Thus, it can decrease aberrations, increasing the depth of the focus by decreasing pupil diameter (1, 2). The most influential factors on pupil diameter are the amplitude of the light reaching the retina and the accommodation made for near vision (2, 3). Several factors, such as age, attention level, changes in sympathetic and parasympathetic efferent pathways, and tone dominance, can be listed as other factors affecting pupil diameter (1, 3).

Pupil diameter is very important for the quality of vision. A small pupil diameter allows for a clear image of high quality by decreasing spherical aberrations. The best retinal image for most eyes is obtained at a pupil diameter of 2.4

mm, where the balance between aberration and diffraction is considered to be optimal (4-7). Campbell and Gregory (7) demonstrated that by adjusting the pupil diameter in a reflex manner in response to ambient light, one can achieve the most appropriate visual acuity.

The pupil functions via sympathetic and parasympathetic stimuli. Any pathology that appears in the pupil reflex arc distorts the light response by altering the adjustability of the pupil (1). The response to light can differ between healthy individuals. Pupil dimension can also be different in healthy individuals, and it decreases in size with advancing age. Compiling information about normal pupil response in different age groups and at different light amplitudes may add to a more objective evaluation of these responses.

Address for correspondence: Hande Husniye Telek, MD. Department of Ophthalmology, Ankara Training and Researching Hospital, Ankara, Turkey Phone: +90 312 595 34 67 E-mail: handetelek@gmail.com Submitted Date: January 30, 2018 Accepted Date: May 21, 2018 Available Online Date: July 14, 2018 Copyright 2018 by Beyoglu Eye Training and Research Hospital - Available online at www.beyoglueye.com

Š

Telek et al., The effects of age on pupil diameter

81

The participants in this study were divided into 4 subgroups and pupil diameter at 5 different light amplitudes was measured.

The aim of this study was to evaluate the pupil response at different light amplitudes in healthy individuals according to age group. Unlike other studies in the literature, it was observed that at advanced ages, especially under low illumination (0 and 1 cd/m2), there was a slowing of the pupillary response.

the pupillometry mode. The measurements were performed both unilaterally and bilaterally. When measurements were made unilaterally, 1 eye of the participant was covered in order not to let in any light. After adapting to the dark environment (5 minutes), the computer automatically measured the pupil diameter in millimeters at light amplitudes of 0, 1, 10, 100, and 200 cd/m2. Each light amplitude was applied for at least 10 seconds, with 1-minute intervals between each measurement of the next intensity. The measurements were repeated 3 times for each light intensity level and the mean of all of the measurements was used as the final value.

Methods This retroprospective study was performed at the Karadeniz Technical University Faculty of Medicine Ophthalmology Clinic between December 2009 and March 2009. All of the participants were informed about the study and their consent was obtained. The research was approved by the ethics committee of Karadeniz Technical University Faculty.

Statistical Evaluation The mean pupil size values obtained at 5 different amplitudes were separately compared within the group using Student’s ttest. Pearson correlation analysis was used to evaluate whether age was correlated with pupil diameter at all light amplitudes.

A p value of <0.05 was accepted as statistically significant.

Study Group To be eligible for the study the subjects had to fulfill the following criteria: 1. No previous history of ocular surgery, 2. Refractive error of ±1.00 diopters (D) range, 3. No visual defect, 4. Absence of any other systemic or ocular disease that might affect pupil response.

Results A total of 105 healthy individuals (49 male, 56 female) were admitted into the study. The mean age of the participants was 49.8+19.3 years (range: 16-76 years). There was no significant difference between males (49.8+18.3 years) and females (48.6+19.6 years) in terms of age (p>0.05). Pupil response was measured under both unilateral and bilateral illumination. No significant difference in pupil response was observed between males and females (p>0.05). When the light amplitude increased from 0 cd/m2 to 200 cd/m2, pupil size decreased nearly 50% in all subjects.

The differences in pupil diameter obtained at different light amplitudes were compared, and there was no significant difference in the response from the left and the right eye in bilateral and unilateral illumination. Similarly, there was no significant difference between the right and the left eye at different illuminations (p>0.05).

The mean bilateral and unilateral pupil size obtained according to amplitude is summarized in Table 1.

Under unilateral illumination, the mean pupil diameter

All the participants underwent a detailed ophthalmological examination (corrected visual acuity, biomicroscopic anterior-posterior segment examination, measurement of intraocular pressure). To evaluate the influence of age on pupil response, the cases in the study group were divided into 4 subgroups: 15-30 years (Group 1), 31-45 years (Group 2), 46-60 years (Group 3), and over 60 years (Group 4).

Measurement Technique The participants were taken into a dark room in the electrophysiology unit in order to evaluate their pupil response.

Measurements were carried out with a Monpack II (Metrovision, Pérenchies, France) electrophysiology device using

Table 1. The mean pupil size obtained in the right and left eye, bilaterally and unilaterally, at 5 different light amplitudes

Pupil size (Mean±SD)

Bilateral illumination Unilateral illumination Light amplitude (cd/m2)

Right eye

0

4.67±0.84

4.74±0.85

4.96±0.82

4.83±0.89

1

3.76±0.60

3.85±0.67

4.07±0.61

4.07±0.76

10

2.88±0.53

2.87±0.65

3.37±0.58

3.21±0.49

100

2.51±0.38 2.55±0.57 2.70±0.44

2.60±0.25

200

2.44±0.42 2.47±0.51 2.55±0.49

2.44±0.19

Left eye

Right eye

Left eye

82

Telek et al., The effects of age on pupil diameter

was 4.96±0.82 mm in the right eye and 4.83±0.89 mm in left eye, while it was 4.67±0.84 mm and 4.74±0.85 mm, respectively, with bilateral illumination at 0 cd/m2 light amplitude.

The differences were not statistically significant (p>0.05).

Although the pupil size was smaller with bilateral illumination than with unilateral illumination, the difference was not statistically significant (p>0.05) (Table 1). Pupil size was smaller by 4% to 6% under bilateral illumination compared with unilateral illumination. This difference was more obvious at 1, 10, and 100 cd/m2 light amplitudes, whereas it was much smaller at 0 cd/m2 and 200 cd/m2 (1.45% and 2.11%, respectively).

When the groups were compared, there was a statistically significant difference in pupil size at all light amplitudes between Group 1 (15-30 years) and Group 4 (over 60 years) (p<0.05). In particular, the difference at low light amplitudes was more obvious.

In a comparison of Group 1 with Group 2, the difference in pupil size was significant at 0, 1, and 10 cd/m2 (p=0.03, 0.02, and 0.02, respectively), while it was not significant at high light amplitudes (100 and 200 cd/m2) (p=0.16 and 0.21, respectively).

Likewise, when comparing Group 1 with Group 3, at 0, 1, 10 cd/m2 light amplitudes, there was a significant difference, whereas at 100 and 200 cd/m2 light amplitudes, the difference was not significant.

No significant difference in pupil response at any light amplitude was seen in a comparison of Group 2 with Group 3 or between Group 3 and Group 4 (p>0.05). There was a significant difference only at 0 cd/m2 light amplitude between Group 2 and Group 4 (p=0.001). (Table 2) When the correlation between pupil size and age was evaluated, a statistically significant negative correlation was

observed at all light amplitudes. The statistical results were summarized in Table 3.

The correlation with increased age is stronger at low illuminations (Tables 2 and 3). At low light amplitudes, pupil diameter was smaller in the older participants.

Discussion Pupillary light reflex appears at about 5 months postpartum and becomes active after 6 months. Pupil size is small during infancy; it becomes larger with age and reaches its maximum diameter in adolescence. It gradually decreases in the following years. The pupil has a diameter of 2.5-5.0 mm in normal individuals at rest. Pupil diameter is influenced by the age of the individual, psychogenic condition, and status of expirium or inspirium (3, 4). In this study, the pupil diameter of older adults was smaller at all light amplitudes compared with younger individuals.

The iris controls the amount of light entering the eye by dilating or contracting. Pupil diameter created by the iris can enlarge to 8 mm under dim light and decrease to 1.5 mm unTable 3. Correlation between illumination intensity and age

Right eye

Light amp-

Pearson

Left eye

p

Pearson

litude (cd/m ) correlation

correlation

2

p

0

-0.60 0.000

-0.66 0.000

1

-0.40 0.000

-0.55 0.000

10

-0.33 0.000

-0.42 0.000

100

-0.31 0.001

-0.21 0.029

200

-0.31 0.001

-0.22 0.022

Table 2. The pupil diameter obtained in the right and left eye at different light amplitudes according to group Light amplitude Illumination (cd/m2)

Group 1 Group 2 Group 3 Group 4 RE

LE

RE

LE

RE

LE

RE

LE

0

Unilateral

5.80 5.74

5.06 5.16

4.67 4.71

4.52 4.20

Bilateral

5.63 5.70

4.96 5.05

4.51 4.42

4.28 4.30

1

Unilateral

4.55 4.70

3.95 4.13

3.96 3.87

3.87 3.61

Bilateral

4.25 4.36

3.80 3.88

3.69 3.57

3.49 3.54

10

Unilateral

3.53 3.47

3.30 3.26

3.20 3.07

3.10 2.93

Bilateral

3.19 3.38

2.76 2.83

2.77 2.78

2.79 2.74

100

Unilateral

2.87 2.69

2.54 2.54

2.56 2.50

2.55 2.55

Bilateral

2.51 2.68

2.43 2.48

2.44 2.42

2.50 2.41

200

Unilateral

2.70 2.47

2.40 2.46

2.45 2.39

2.39 2.38

Bilateral

2.41 2.55

2.33 2.38

2.36 2.36

2.38 2.38

LE: Left eye; RE: Right eye.

Telek et al., The effects of age on pupil diameter

der very bright light. On a bright, sunny day, the light intensity is 34.260-103.000 cd/m2 and there is maximal pupillary contraction. There is a strong relationship between pupil diameter and visual acuity. When background illumination was increased to 3400 cd/m2, greater visual acuity has been demonstrated. When the eye is focused on a near object, pupil diameter decreases (4-6).

The pupil size of individuals with myopia is larger than that of individuals with emmetropia and hypermetropia. This is probably due to the fact that myopes do not need to make accommodation for near sight (1-6). In order to eliminate the discrepancies that might arise from errors of refraction, we excluded eyes with refractive errors outside Âą1.00 D range.

In recent years, various technologies have been developed to objectively evaluate pupil light reflex. Among these technologies, infrared videography and computerized pupillometry are most often employed (4-7). Pupil measurements in our study were carried out with the advanced Monpack II electrophysiology device using its pupillometry program.

Age is one of the most important factors affecting the activity and the shape of the pupil. Scotopic, mesopic, and photopic pupil diameters decrease with age. This decrease is thought to be due to the increased effort to accommodate to conditions seen at advanced ages, as accommodative capability decreases with age (8-15). Together with age, the shape of the pupil changes from a regular circular form to an irregular form. Pupil response is influenced by the initial pupil diameter, and the relationship between pupil response and the initial pupil diameter changes with age. The dynamics of pupillary response slow with age. Pupillary hippus at high frequencies also decreases with age. This means that the maximum speed of pupil contraction and dilatation decreases with age as well (16-18). Consistent with the data in the literature, the pupil diameter of elderly patients (Group 4) was smaller than that of the younger patients at all light amplitudes.

Glaucoma is a disease thought to affect pupil reactions; the dilatation speed of the affected eye is slower than that of the healthy eye. However, contraction speed is not influenced by this neuronal loss. No explanation has yet been found for this. Glaucoma patients are reported to have relative afferent pupillary defect (RAPD). Cataract is thought to affect light reactions through a different mechanism and results in less light reaching the retina. Cataract is reported to cause RAPD as well (19).

As in previous reports (20-25), we have shown that older people have a smaller resting pupil diameter in the dark than younger individuals. The reduction in darkness reflex amplitude and the prolongation of recovery time of the light reflex are consistent with the notion of a decrease in sympathetic activity occurring with old age. Such a mechanism may also explain the decline in resting pupil size with age. There is

83

independent evidence that the sympathetic and parasympathetic components of the autonomic nervous system change differentially with age. Pagani et al. (26) reported that during tilt, aging is progressively associated with attenuation of the low frequency (sympathetic) component of the heart rate power spectrum, whereas the parasympathetic response to tilt, detectable in the high frequency band, is relatively well preserved.

The observed changes in static and dynamic characteristics of the pupil in older subjects are probably mediated by alterations in autonomic function, which may form part of a more general change in autonomic activity in old age. The precision and linearity of the decline of pupil size with age (27, 28) suggest that the pupillary system is very sensitive and most reliably reflects the normal aging process. It has been suggested that the decline in resting pupil size with age was due to senile iris degeneration leading to increased rigidity (25). Such a mechanism could perhaps account for a reduced light reflex amplitude or constrictive velocity, either directly or via a reduction in resting pupil size because of the floor effect mentioned earlier (29-33).

Older people have a reduced pupil diameter, consistent with a sympathetic deficit and/or parasympathetic disinhibition. There is reduced darkness reflex amplitude and dilatation velocity, consistent with a sympathetic deficit. Furthermore, older subjects have a prolonged pupillary light reflex recovery time, consistent with a sympathetic deficit (8). It has been reported that the dynamics of pupil responses are influenced by the biomechanics of the iris muscle plant (12).

The form of the pupil also shows age-related change, presumably due to structural alterations (28), such as changes in the contractility of the muscle fibers, stromal atrophy with loss of connective tissue, and hyaline degeneration (9).

The physiological aspects of the effect of pupil size should be considered in terms of both behavioral and underlying neural mechanisms. Under photopic light levels, regulation of light flux is important; the pupil is small and demonstrates pupillary capture. With a step change in light level, there is a large gain in response and the pupil size change is maintained. The pupil is an effective (low pass) regulator. Gain, as first described for the pupil by Stark and Sherman (16), is the percentage change in aperture divided by the percentage change of light.

Under scotopic light levels it is less important for the pupil to regulate long-term light flux onto the retina; the pupil is large and demonstrates pupillary escape. With a step change in light level, the response has a smaller, but relatively high, gain for a brief period, and then with redilatation, the gain is greatly reduced, becoming almost insignificant. Thus, a large quantity of light can enter the eye in these mesopic and scotopic conditions. The pupil can only be considered a

84

partial (or band pass) regulator for brief changes of light (13).

As mentioned in other studies, we have shown that pupil responses to light can be influenced by age. This should be taken into consideration when evaluating pupil reactions.

There are studies about pupil reaction, but unlike other studies, we found that at advanced ages, especially under low illumination (0 and 1 cd/m2), there is a slowing of the pupillary response.

In conclusion, advanced age affects pupil reaction. At advanced ages, especially under low illumination (0 and 1 cd/ m2), the pupillary response is slower. We think that more advanced electrophysiological studies are needed to identify the etiology behind differences in pupil diameter.

Disclosures Peer-review: Externally peer-reviewed.

Conflict of Interest: None declared.

Authorship Contributions: Involved in design and conduct of the study (HHT, AT, HE); preparation and review of the study (HHT, HE); data collection (HHT); and statistical analysis (HHT).

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pupil dynamics by recurrence quantification analysis. Biomed Res Int 2013;2013:420509.

32. Ebitz RB, Pearson JM, Platt ML. Pupil size and social vigilance in rhesus macaques. Front Neurosci 2014;8:100.

33. Bieniek MM, Frei LS, Rousselet GA. Early ERPs to faces: aging, luminance, and individual differences. Front Psychol 2013;4:268.

Original Article

DOI:10.14744/bej.2018.03521 Beyoglu Eye J 2018; 3(2): 86-90

Effects of Intravitreal Injection of Ranibizumab and Aflibercept on Corneal Endothelium and Central Corneal Thickness Mehmet Coskun Department of Ophthalmology, Karabük University Faculty of Medicine, Karabük, Turkey

Abstract Objectives: This study was an evaluation of intravitreal injections of ranibizumab (IVR) and aflibercept (IVA) administered to the corneal endothelium.

Methods: Thirty eyes of 30 patients made up the IVR injection group and 30 eyes of another 30 patients were recruited as the IVA injection group. Specular microscopy results before the injection, on the 1st, 7th, and 30th days were examined.

Central corneal thickness (CCT), endothelial cell density (CD), coefficient of variation (CV), and hexagonality (HEX) values were recorded.

Results: No difference was seen between the groups with respect to gender (p=0.057). No significant difference was seen in CCT measurements in the IVR or the IVA group (p=0.08, p=0.16, respectively). Nor was a significant difference seen in the IVR group in terms of CD (p=0.85); however, a statistically significant difference was detected in the IVA group (p=0.03). Furthermore, no significant difference was seen in the IVR or the IVA group with regard to CV (p=0.12, p=0.17, respectively), and no significant difference was seen in the IVA group with respect to HEX values between measurements intervals (p>0.05); however, a significant difference was found in the IVR group (p=0.02).

Conclusion: Neither IVR nor IVA affected the CCT or CV values. The CD did not change significantly in the IVR group, whereas in the IVA group, the CD values of the first day after the injection were high, although they had returned to normal on the 30th day. In the IVR group, a statistically significant difference was seen in terms of the HEX values.

Keywords: Aflibercept, anti-vascular endothelial growth factor, intravitreal injection, ranibizumab, specular microscopy.

Introduction Vascular endothelial growth factor (VEGF) is the most important factor in ocular angiogenesis. Recently developed anti-VEGF agents have revolutionized the treatment of many retinal diseases. These agents affect both neovascularization and permeability, and therefore, in many diseases that could result in vision loss, visual acuity can be preserved or increased (1, 2).

Under normal physiological conditions, VEGF is secreted by the stroma, epithelium, and the endothelial layers of the

cornea. VEGF is produced in large amounts by the vessels of the limbus and nascent stromal vessels, as well as by keratocytes, but to a lesser extent. Moreover, it has been determined in experimental studies that VEGF receptors exist on the corneal endothelium (3). Anti-VEGF agents could be used for the treatment of pathological conditions in the cornea, such as corneal neovascularization, as well as retinal disease.

Petsoglou et al. (4) observed a significant regression of corneal neovascularization after subconjunctival bevacizumab injections with no adverse effects in terms of central corneal

Address for correspondence: Mehmet Coskun, MD. Department of Ophthalmology, Karabük University Faculty of Medicine, Karabük, Turkey Phone: +90 505 293 44 04 E-mail: drmehmetcoskun@mynet.com Submitted Date: May 08, 2018 Accepted Date: July 02, 2018 Available Online Date: July 12, 2018 Copyright 2018 by Beyoglu Eye Training and Research Hospital - Available online at www.beyoglueye.com

©

Coskun, Effects of intravitreal injection on the cornea

thickness, intraocular pressure, or the number of endothelial cells when compared with saline injections. Chalam et al.

(5) reported in their in vitro safety profile study that bevacizumab had no cytotoxic effect in human corneal cells up to a concentration of 4 mg/mL. The aim of the present study was to evaluate the potential adverse effects of intravitreal injections of different antiVEGFs in patients with nonproliferative diabetic retinopathy and macular edema and to compare the results by investigating changes to the corneal endothelium.

Methods Sixty eyes of 60 patients who received intravitreal injections due to diabetic retinopathy and macular edema were investigated retrospectively. The patients were recruited from among individuals who presented at the eye disease clinic of the Medical Faculty Hospital of Karabuk University. Approval for the study was obtained from the ethics committee of Karabuk University. IVR was injected into 30 eyes of 30 patients, and IVA was injected into 30 eyes of another 30 patients. Ranibizumab (Lucentis; Novartis International AG, Basel, Switzerland) and aflibercept (Eylea; Bayer AG, Leverkusen, Germany) were injected at doses of 0.5 mg/0.05 mL and 2 mg/0.05 mL, respectively. Patients with an ocular disease, those who had used an ocular medication or who had previously undergone ocular surgery were excluded.

Specular microscopy measurements were performed using an SP-1P device (Topcon Medical Systems, Inc., Oakland, NJ, USA). Central corneal thickness (CCT), endothelial cell density (CD), coefficient of variation (CV), and hexagonality (HEX) parameter values were recorded before the injection (O), on the 1st day (1), 7th day (7), and the 30th day (30) after the injection. The parameters during the intervals were compared between the groups.

SPSS for Windows, Version 16.0 (SPSS, Inc., Chicago, IL, USA) was used for the statistical analysis. A chi-square test was used to compare the groups with respect to gender.

Student’s t-test was used to determine differences between the groups. Measurements before the injection, on the 1st day, 7th day, and the 30th day after injection were compared using Friedman analysis of variance (ANOVA). Wilcoxon’s matched-pairs test was used as a post hoc test after the ANOVA analysis. A 2-tailed technique was used and the significance level was set at p<0.05.

Results The mean age of the IVR and IVA groups was 60.70±5.70 years and 61.30±6.29 years, respectively. There was no significant difference between the therapy groups with respect to age (p=0.75). Eighteen men and 12 women were included in IVR group, and 17 men and 13 women comprised the

87

IVA group. There was no significant difference between the groups with respect to gender (p=0.057).

There was no statistically significant difference in the CCT value after the injection between the IVR and the IVA groups (p=0.08 and p=0.16, respectively) (Table 1 and 2).

No statistically significant difference was observed in the IVR group in terms of CD values between measurement intervals (p=0.85) (Table 3); however, a significant difference was observed in the IVA group (p=0.03). Binary comparisons made with the Wilcoxon test revealed that this difference began in the earliest period: the CD value in the first week Table 1. Median, minimum, and maximum values of central corneal thickness measurements before injection (OCCT), on the 1st day after injection (1CCT), 7th day after injection (7CCT), and the 30th day after injection (30CCT) in the ranibizumab group.

OCCT

1CCT

7CCT

30CCT

N Valid

30 30 30 30

Missing 0 0 0 0 Median

537.00 538.00 536.50 537.50

Minimum

502 479 496 492

Maximum

562 560 590 553

Table 2. Median, minimum, and maximum values of central corneal thickness measurements before injection (OCCT), on the 1st day after injection (1CCT), 7th day after injection (7CCT), and the 30th day after injection (30CCT) in the aflibercept group.

OCCT

1CCT

7CCT

30CCT

N Valid

30 30 30 30

Missing 0 0 0 0 Median

522.50 520.50 519.00 518.50

Minimum

467 467 470 468

Maximum

597 600 596 582

Table 3. Median, minimum, and maximum endothelial cell density measurements in the ranibizumab group before injection (0CD), on the 1st day after injection (1CD), 7th day after injection (7CD), and the 30th day after injection (30CD).

OCD

1CD

7CD

30CD

N Valid

30 30 30 30

Missing 0 0 0 0 Median

2667.50 2729.00 2689.00 2695.00

Minimum

1078 1139 1144 1154

Maximum

3015 2942 3324 3161

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Coskun, Effects of intravitreal injection on the cornea

(2515.00 cells/mm²) was significantly higher than the posttreatment level (2342.00 cells/mm²) at week 1 (p=0.02). The differences between the other intervals were not significant (Table 4). This result indicated that the earlier CD disorder was resolved quickly.

No statistically significant difference was observed in terms of CV between the measurement intervals in either the IVR or the IVA group (p=0.12 and p=0.17, respectively) (Table 5 and Table 6).

In the IVR group, a statistically significant difference was seen in the HEX values (p=0.02). The median 0HEX value Table 4. Median, minimum, and maximum endothelial cell density measurements in the aflibercept group before injection (0CD), on the 1st day after injection (1CD), 7th day after injection (7CD), and the 30th day after injection (30CD).

OCD

1CD

7CD

30CD

N Valid

30 30 30 30

Missing 0 0 0 0 Median

2342.00 2515.00 2372.00 2331.50

Minimum

1969 2006 1974 2038

Maximum

2975 3012 2670 3030

was greater than the 30HEX value as a result of progressive changes in HEX from the pretreatment period to the last examination (p=0.007) (Table 7). There were no statistically significant differences in HEX values in the IVA group between measurement intervals (p=0.69) (Table 8).

Discussion Anti-VEGFs are effective, recent agents used for the treatment of many ocular diseases. Ranibizumab, which is produced with recombinant monoclonal antibody technology, is a human anti-VEGF antibody fragment that is able to bind to all isoforms of VEGF (6). Aflibercept binds VEGFR-1 and VEGFR-2, which are on VEGF-A, with a higher affinity than bevacizumab (7, 8). It also inhibits VEGF-B and placental growth factor. In vitro studies demonstrated that VEGF and its receptor were expressed on the cornea and anterior chamber (9, 10). In vitro conditions revealed that neither bevacizumab nor ranibizumab had a toxic effect on the corneal epithelium or the retina, and to date, routine clinical applications have not caused toxicity (11-13). However, only a limited number of in vivo studies have evaluated the effects of intravitreal anti-VEGF injections on the corneal epithelium (14-16). Furthermore, we found no studies investigating the effects of aflibercept on the corneal epithelium.

Table 5. Median, minimum, and maximum coefficient of variation before injection (0CV), on the 1st day after injection (1CV), 7th day after injection (7CV), and the 30th day after injection (30V) in the ranibizumab group.

Table 7. Median, minimum, and maximum hexagonality values before injection (0HEX), on the 1st day after injection (1HEX), 7th day after injection (7HEX), and the 30th day after injection (30HEX) in the ranibizumab group.

OCV

1CV

7CV

30CV

ÖHEX

1HEX

7HEX

30HEX

N

N Valid

Valid

30 30 30 30

Missing 0 0 0 0

Missing 0 0 0 0 Median

31.50 32.00 30.00 31.00

30 30 30 30

Median

52.50 54.50 53.00 49.50

Minimum 27 23 25 29

Minimum 29 35 38 19

Maximum 39 42 38 42

Maximum 66 68 68 62

Table 6. Median, minimum, and maximum coefficient of variation before injection (0CV), on the 1st day after injection (1CV), 7th day after injection (7CV), and the 30th day after injection (30V) in the aflibercept group.

Table 8. Median, minimum, and maximum hexagonality values before injection (0HEX), on the 1st day after injection (1HEX), 7th day after injection (7HEX), and the 30th day after injection (30HEX) in the aflibercept group.

OCV

1CV

7CV

30CV

OHEX

1HEX

7HEX

30HEX

N

N Valid

30 30 30 30

Missing 0 0 0 0 Median

30.00 30.00 31.00 31.00

Valid

30 30 30 30

Missing 0 0 0 0 Median

52,00 51,50 51,00 52,00

Minimum 22 23 25 24

Minimum 41 48 47 30

Maximum 41 38 38 45

Maximum 60 65 62 61

Coskun, Effects of intravitreal injection on the cornea

Yourek et al. (9) reported that although VEGF, VEGF1, and VEGF-2 receptors were present in avascular tissue, such as the cornea, corneal avascularization was protected by balancing fms-related tyrosine kinase 1.In a series of 5 cases, Bayar et al. (17) observed condensed corneal edema after a bevacizumab injection, which might have been the result of inhibition of the immune system activation feature of VEGF in limbal vessels. However, no pathological corneal endothelium was detected and corneal edema was treated with steroids in conjunction with antibiotics within 10 days in all cases. According to their study, it could be concluded that bevacizumab might cause morphological and immunological changes in the corneal endothelium.

VEGF is normally secreted by the stroma, the epithelium, and the endothelium of the cornea, but it is also secreted from limbal vessels and keratocytes, albeit to a lesser extent.

It can be secreted in large amounts in pathological conditions by newly developed stromal vessels. In experimental studies, it has been observed that VEGF receptors were present in the corneal endothelium. It was reported that 1 week after an intravitreal injection of either bevacizumab (IVB) orranibizumab (IVR), VEGF levels decreased by at least 10fold in the aqueous humour, and anti-VEGF antibodies were detected in the aqueous humour 29 days after injection (18).

Cho et al. (19) compared the CD in patients aged 23 to 83 years with type 1 and non-type 1 diabetes mellitus (DM). The CD was significantly lower in diabetics (2577.2±27.3 cells/ mm²) compared with nondiabetic subjects (2699.9±38.7cells/ mm²) (p=0.01). The CD was 2617.6±34.3 cells/mm² in patients with ≤10 years of DM and 2525.7±38.3 cells/mm² in those with >10 years of DM. In terms of CD, the difference was not significant (p=0.07). Other parameters, such as CV, HEX, irregularity, and CCT were significantly higher in patients with DM than in the non-DM group (p=0.001). However, Arslan et al. (20) reported that DM had no negative effect on endothelium morphology.

Chen et al. (21) reported that they found no significant difference in terms of corneal endothelium count, polymorphism, polymegathism ratio, or CCT after a single dose of 2.5 mg bevacizumab after 6 months. Benitez-Herrero et al.

(14) reported no significant difference with regard to CD, CCT, CV, or HEX ratios when they compared these parameters before injection, following 3 monthly injections, and 6 months after the last injection in 52 patients with age-related macular degeneration.

Hosny et al. (22) showed that intracameral injections of 1.25 mg/0.05 mL IVB caused no structural changes of corneal endothelium morphology. Furthermore, Lichtinger et al. (23) found no statistically significant difference in terms of CD, CV, HEX, or CCT parameters before and 6 months after 3 combined subconjunctiva bevacizumab injections for the

89

treatment of corneal neovascularization. Kim et al. (24) also compared intracameral injections of 0.05 mL bevacizumab with 0.05 mL bevacizumab plus balanced salt solution and concluded that bevacizumab had no negative effect on CCT or CD, and thus it could be used safely.

In our study, we observed no significant differences in CV over time between the IVR and IVA groups. In the IVA group, HEX values in the post-injection periods showed no significant difference compared with the pre-injection period. However, HEX values were significantly decreased at the 30thday measurement in the IVR group.

The limitations of our study are the number of patients included and the short period of patient follow-up. Furthermore, the tissue area analyzed with specular microscopy was just a 3-mm thick layer of cornea. Thus, evaluation of the cornea periphery was not possible, especially the area close to the limbus, which is rich for another blind side.

To the best of our knowledge, this is the first study to investigate the effect of aflibercept. Moreover, the decrease in HEX values in the IVR group is a new topic of discussion. We offer this study as a contribution to the current literature.

Disclosures Peer-review: Externally peer-reviewed.

Conflict of Interest: None declared.

References 1. Kim LA, D'Amore PA. A brief history of anti-VEGF for the treatment of ocular angiogenesis. Am J Pathol 2012;181:376–9.

2. Kaiser PK. Antivascular endothelial growth factor agents and their development: therapeutic implications in ocular diseases.

Am J Ophthalmol 2006;142:660–8.

3. Gan L, Fagerholm P, Palmblad J. Vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 in the regulation of corneal neovascularization and wound healing. Acta Ophthalmol Scand 2004;82:557–63.

4. Petsoglou C, Balaggan KS, Dart JK, Bunce C, Xing W, Ali RR, et al. Subconjunctival bevacizumab induces regression of corneal neovascularisation: a pilot randomised placebo-controlled double-masked trial. Br J Ophthalmol 2013;97:28–32.

5. Chalam KV, Agarwal S, Brar VS, Murthy RK, Sharma RK. Evaluation of cytotoxic effects of bevacizumab on human corneal cells. Cornea 2009;28:328–33.

6. Costa RA, Jorge R, Calucci D, Cardillo JA, Melo LA Jr, Scott IU. Intravitreal bevacizumab for choroidal neovascularization caused by AMD (IBeNA Study): results of a phase 1 dose-escalation study. Invest Ophthalmol Vis Sci 2006;47:4569–78.

7. Stewart MW, Rosenfeld PJ, Penha FM, Wang F, Yehoshua Z, Bueno-Lopez E, et al. Pharmacokinetic rationale for dosing every 2 weeks versus 4 weeks with intravitreal ranibizumab, bevacizumab, and aflibercept (vascular endothelial growth factor

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Trap-eye). Retina 2012;32:434–57.

8. Browning DJ, Kaiser PK, Rosenfeld PJ, Stewart MW. Aflibercept for age-related macular degeneration: a game-changer or quiet addition? Am J Ophthalmol 2012;154:222–6.

9. Yoeruek E, Spitzer MS, Tatar O, Aisenbrey S, Bartz-Schmidt KU, Szurman P. Safety profile of bevacizumab on cultured human corneal cells. Cornea 2007;26:977–82.

10. Ambati BK, Nozaki M, Singh N, Takeda A, Jani PD, Suthar T, et al. Corneal avascularity is due to soluble VEGF receptor-1.

Nature 2006;443:993–7.

11. Spitzer MS, Wallenfels-Thilo B, Sierra A, Yoeruek E, Peters S, Henke-Fahle S, et al; Tuebingen Bevacizumab Study Group. Antiproliferative and cytotoxic properties of bevacizumab on different ocular cells. Br J Ophthalmol 2006;90:1316–21.

12. Luthra S, Narayanan R, Marques LE, Chwa M, Kim DW, Dong J, et al. Evaluation of in vitro effects of bevacizumab (Avastin) on retinal pigment epithelial, neurosensory retinal, and microvascular endothelial cells. Retina 2006;26:512–8.

13. Kernt M, Welge-Lüssen U, Yu A, Neubauer AS, Kampik A. Bevacizumab is not toxic to human anterior- and posteriorsegment cultured cells [Article in German]. Ophthalmologe 2007;104:965–71.

14. Pérez-Rico C, Benítez-Herreros J, Castro-Rebollo M, GómezSangil Y, Germain F, Montes-Mollón MA, et al. Effect of intravitreal ranibizumab on corneal endothelium in age-related macular degeneration. Cornea 2010;29:849–52.

15. Chiang CC, Chen WL, Lin JM, Tsai YY. Effect of bevacizumab on human corneal endothelial cells: a six-month follow-up study. Am J Ophthalmol 2008;146:688–91.

16. Pérez-Rico C, Benítez-Herreros J, Castro-Rebollo M, Gómez-

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SanGil Y, Germain F, Montes-Mollón MA, et al. Endothelial cells analysis after intravitreal ranibizumab (Lucentis) in age-related macular degeneration treatment: a pilot study. Br J Ophthalmol 2010;94:267–8.

17. Bayar SA, Altinors DD, Kucukerdonmez C, Akova YA. Severe corneal changes following intravitreal injection of bevacizumab.

Ocul Immunol Inflamm 2010;18:268–74.

18. Bakri SJ, Pulido JS, Reid JM, Singh RJ, Snyder MR. Pharmacokinetics of intravitreal bevacizumab(Avastin). Ophtalmology 2007;114:855–9.

19. Cho BM, Choi HY, Lee JE, Lee JS, Oum BS. Differences in corneal thickness and corneal endothelium related to duration in diabetes. Eye (Lond) 2006;20:315–8.

20. Arslan OS, Doğan İ, Ermiş SS, Sakarya Y. İnsüline Bağimli Diyabetes Mellitusda Kornea Endotel Morfolojisinin Diyabetik Retinopati İle İlişkisi. Oftalmoloji Dergisi 2002;9:33–6.

21. Chen WL, Chiang CC, Lın JM, Tsai YY. Effect of bevacizumab on human corneal Endothelial Cells: a six-month follow-up study. Am J Ophtalmol 2008;146:688–91.

22. Hosny MH, Zayed MA, Shalaby AM, Eissa IM. Effect of intracameral bevacizumab injection on corneal endothelial cells: an in vivo evaluation. J Ocul Pharmacol Ther 2009;25:513–7.

23. Lichtinger A, Yeung SN, Kim P, Amiran MD, Elbaz U, Slomovic AR. Corneal endothelial safety following subconjunctival and intrastromal injection of bevacizumab for corneal neovascularization. Int Ophthalmol 2014;34:597–601.

24. Kim HK, Kim YS, Lee JW, Shin JP, Sohn BJ. In vivo corneal endothelial safety of intracameral bevacizumab and effect in neovascular glaucoma combined with Ahmed valve implantation. J Glaucoma 2009;18:589–94.

DOI:10.14744/bej.2018.08208 Beyoglu Eye J 2018; 3(2): 91-95

Original Article

Evaluation of Surgical Outcomes, Patient Satisfaction, and Potential Complications after Blepharoplasty Sezen Akkaya Department of Ophthalmology, Fatih Sultan Mehmet Training and Research Hospital, Istanbul,Turkey

Abstract Objectives: This study is an evaluation of the surgical outcomes, patient satisfaction, and potential complications following blepharoplasty surgery.

Methods: A total of 128 patients who underwent blepharoplasty surgery between 2015 and 2017 were included in this study. A postoperative lid crease difference of at least 1 mm was considered asymmetrical. Pre- and postoperative tear break-up time (TBUT) was evaluated. All of the patients were asked to complete a satisfaction assessment form prepared by the authors. The scar tissue that developed along the incision line was evaluated and graded by a single observer.

Results: The mean age of the patients was 62.70±9.73 years, and all of the patients were monitored for a period of least 6 months. In combination with blepharoplasty, 17 patients underwent eyebrow surgery, 6 underwent lower eyelid surgery, and 4 underwent levator surgery. Lid crease asymmetry of 1 mm was determined in 8 patients, and a 2-mm asymmetry was identified in 2 patients, although the pre- and postoperative TBUT was not significantly different (p≥0.05). A total of 107 (83.59%) patients reported a very high level of satisfaction at the postoperative sixth month, 15 (11.71%) patients reported a high level of satisfactıon, and 6 (4.68%) reported a moderate level of satisfaction. In the postoperative sixth month, 87 (67.97%) patients had no scar tissue at the incision line, while 36 (28.13%) patients had noticeable scar tissue upon close inspection, and 5 (3.91%) patients had apparent scar tissue. None of the patients developed serious complications, such as severe hematoma, lagophthalmos, or wound separation.

Conclusion: In the present study, the patients generally expressed long-term satisfaction with the results of blepharoplasty surgery for dermatochalasis. A comprehensive preoperative assessment, and combining surgeries when necessary and appropriate, ensures a high rate of success in blepharoplasty procedures.

Keywords: Blepharoplasty, patient satisfaction, potential complications.

Introduction Blepharoplasty surgery is performed to correct changes to the eyelid that may be caused by aging or genetic disposition.

Among middle-aged and elderly individuals, the removal of the orbicular muscle and fat tissue during an upper eyelid blepharoplasty provides a younger look and increases the field of vision, particularly in the upper temporal region (1).

Surgical success depends primarily on meeting the patients’ expectations and achieving a uniform, symmetrical appearance after the operation (2). An eyebrow elevation during blepharoplasty may also be appropriate in cases where dermatochalasis is accompanied by eyebrow ptosis, as it may

negatively affect the cosmetic outcome by reducing the distance between the eyebrow and the eyelid (3). The surgeon should also be able to manage potential postoperative complications, such as lagophthalmos, asymmetry, and eyebrow ptosis (4). While blepharoplasty surgery is often successful, rarely, complications may arise. The frequency of dry eye after blepharoplasty is higher among individuals with preoperative tear insufficiency, but it may also develop due to insufficient postoperative blinks and lagophthalmos. In previous studies, the reported frequency of dry eye following blepharoplasty ranged between 8% and 21% (5, 6). Aside from the possible negative cosmetic outcomes, such as eyelid

Address for correspondence: Sezen Akkaya, MD. Department of Ophthalmology, Fatih Sultan Mehmet Training and Research Hospital,Istanbul,Turkey Phone: +90 216 578 30 00 E-mail: drsezenakkaya@gmail.com Submitted Date: April 15, 2018 Accepted Date: June 19, 2018 Available Online Date: July 10, 2018 Copyright 2018 by Beyoglu Eye Training and Research Hospital - Available online at www.beyoglueye.com

©

92

asymmetry, lagophthalmos, or changes in facial expression, complications such as dry eye syndrome and superior limbic keratoconjunctivitis may also emerge after blepharoplasty, and retro-orbital bleeding is a potential complication that may, in rare cases, result in vision loss (7-11).

In the present study, the long-term outcomes regarding scar development, asymmetry, findings of dry eye, and the level of satisfaction among patients who underwent blepharoplasty surgery were evaluated.

Methods The study included a total of 128 patients who underwent upper eyelid blepharoplasty surgery at least 6 months earlier due to ptosis associated with a decreased visual field. Informed consent forms were obtained from all of the patients prior to their inclusion in the study. The pre- and postoperative examinations of all of the patients were carried out by the same physician, and tear break-up time (TBUT) was recorded. The need to perform simply upper eyelid or also lower eyelid surgery, and internal-external eyebrow surgery and correction for ptosis were all evaluated according to the specific problems of each patient. The staging of the scar tissue along the incision line was performed in the postoperative sixth month, in accordance with the following stage definitions, 0: no scar tissue along the incision line, 1: scar tissue can be seen upon close inspection, 2: scar tissue is apparent, 3: marked hypertrophic scar.

Before administering a local anesthetic, the surgical site was marked on the patients while they were sitting up straight on the operating table. In patients who had a visible lid crease, the first line of incision was the lid crease. In patients who lacked visible a lid crease, the eyelid was turned out, and the line corresponding to the upper boundary of the tarsal plate was used as the first line of incision. Excess skin tissue was determined with a pair of forceps, and care was taken to leave at least 22 to 24 mm of tissue, in total, on the upper part of the excised region toward the lower boundary of the eyebrow and the lower part to the eyelid boundary. To ensure that the eyes were symmetrical, the distance between the inner parts of the eyebrow, the middle highest part of the eyebrow, and the end of the eyebrow and the lid creases (estimated saturation line) were measured and equalized.

A local anesthetic (50% lidocaine [with adrenaline], 50% bupivacaine mixture) was administered subcutaneously using a dental needle. The skin on the marked line was incised using a number-11 surgical scalpel blade to the level of the orbicular muscle, and both the skin and the muscle were excised simultaneously. Hemostasis was achieved through unipolar/bipolar cauterization. Pressure was applied to the globe to check for fat tissue prolapsus, and when necessary, the septum was opened to clamp and excise fat tissue, after which hemostasis was achieved through cauterization. To

Akkaya, Surgical outcomes of blepharoplasty surgery

form the lid crease, 6-0 Prolene (Ethicon, Inc., Somerville, NJ, USA) sutures were used through skin-tarsus-orbicular muscle-skin lines, with 3 vertical sutures applied in women, and 2 in men. The skin was sutured using 6-0 Prolene sutures while the wound lips were kept opposite.

All of the patients were prescribed an antibiotic ointment to be used postoperatively twice-daily, and all of the sutures were removed on the 10th day of follow-up. The patients were, at a minimum, followed-up in the first, third, and sixth postoperative months. The patients were asked to complete a satisfaction assessment form that comprised 3 yes-no questions.

The patients were asked to classify their postoperative level of satisfaction as 0: I am not satisfied, 1: I am moderately satisfied, 2: I am satisfied, 3: I am very satisfied, and I would recommend it to another.

Statistical analyses of the mean values were performed using Statistics for Windows, Version 18.0 (SPSS, Inc., Chicago, IL, USA). A p value that was â&#x2030;¤0.05 was considered statistically significant.

Results A total of 128 patients with a mean age of 62.70Âą9.73 years were included in the study. Among the patients, 118 (92.1%) were women, while 10 (7.8%) were men. The mean duration of follow-up was 12.9Âą5.6 months.

In combination with blepharoplasty, 17 patients underwent eyebrow surgery, 6 underwent lower eyelid surgery, and 4 underwent levator surgery. In all, 11 patients underwent combined internal eyebrow surgery, while 6 underwent external eyebrow surgery.

When the degree of asymmetry was assessed, a 1-mm lid crease asymmetry was identified in 8 patients, and a 2-mm asymmetry was observed in 2 patients. One patient underwent repeat surgery due to asymmetry, which was corrected with no scar development.

Table 1 illustrates the postoperative satisfaction assessment form. In the late postoperative period, 6 (4.68%) paTable 1. Post-operative satisfaction assessment form and results Yes (%)

Are you satisfied with the results of your operation?

Very good

83.59

Good 11.72 Moderate Would you have the same surgery again, knowing

4.68 95

what it involves?

Do you feel more energetic and awake during the day since the surgery?

89

Akkaya, Surgical outcomes of blepharoplasty surgery

93

Figure 1. A preoperative photo of a patient.

Figure 2. A postoperative photo of the same patient.

Figure 3. Scar tissue visible on close inspection.

tients reported being “moderately satisfied,” 15 (11.72%) reported being “satisfied,” and 107 (83.59%) reported being “very satisfied” with the surgery, while none responded that they were not satisfied. Of the 6 patients who reported being moderately satisfied, the cause of discomfort was asymmetry in 3 of the patients, and the appearance of scar tissue in the remaining 3 patients. One patient with asymmetry was re-operated on, and symmetry was achieved. A second surgery was not deemed necessary for the remaining 2 patients.

Figures 1 and 2 are photographs of a patient before and after surgery. He reported being very satisfied with the results.

In the late postoperative period, 87 (67.97%) patients

had no scar tissue on the incision line, 36 (28.13%) had some scar tissue that was noticeable upon close inspection, and 5 (3.91%) had apparent scar tissue. None of the patients had marked hypertrophic scar tissue (Table 2). Figure 3 is a photograph of a patient with scar tissue that was noticeable upon close inspection. Figure 4 is a patient photograph demonstrating apparent scar tissue.

The mean preoperative and postoperative TBUT was 13.48±2.4 seconds and 12.5±1.9 seconds, respectively. The difference was not statistically significant (p>0.05). Among the patients, 19 (14.8%) developed milia along the wound boundaries during the early postoperative term.

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Akkaya, Surgical outcomes of blepharoplasty surgery

Table 2. Post operation scar staging and results Scar stage

Patients (%)

0: No scar tissue along the incision line

87 (67.97)

1: Scar tissue can be seen upon close inspection

36 (28.13)

2: Scar tissue is apparent 3: Marked hypertrophic scar

5 (3.91) 0 (0)

Figure 4. Visible scar tissue.

Discussion While blepharoplasty is a surgical intervention with a high success rate, it is still essential to perform a detailed examination of the patient before surgery and to devise a sound surgical plan in advance. The most common complications associated with blepharoplasty include asymmetry, edema, infection, lagophthalmos, and secondary keratopathy, canthal folds, and ectropion. While these complications can be treated, loss of vision is still a very serious complication that has been reported in the literature at a rate of 0.004% (11, 12). These severe complications are more common after lower eyelid blepharoplasty operations, and are seen only rarely following upper eyelid blepharoplasty.

Although a symmetrical appearance was achieved in 92.19% of the patients operated on in our clinic, asymmetry was still the most commonly encountered complication.

A total of 10 patients had lid crease asymmetry: there was a difference of 2 mm in 2 patients, but only 1 required a second operation. The remaining patients did not undergo additional interventions, given that they had no complaints and did not elect to have a second surgery.

Following blepharoplasty, dry eye syndrome develops in 8% to 21% of patients (6, 13), and lower eyelid malpositioning, increased eyelid space, lagophthalmos, eyelid retraction, and decreased blink reflex may play a role in its development (14).

Previous studies have indicated that the symptoms associated

with dry eye syndrome develop more frequently after lower eyelid surgeries. In their study that reported the outcomes of blepharoplasty surgery in 892 patients, Prischmann et al. (13) reported a rate of postoperative dry eye of 12.9% of the patients who underwent upper eyelid blepharoplasty alone, and 21.9% in patients who underwent lower eyelid surgery.

In the present study, the rate of postoperative dry eye syndrome requiring treatment did not significantly increase, and there was no significant postoperative change in TBUT. This was probably due to the fact that our patients were not operated on for cosmetic reasons, but required surgery due to dermatochalasis limiting the field of vision. In addition, we made only limited skin excisions in all cases. The need to use artificial tears was greater during the postoperative first due to limited eyelid movement during this period, but this returned to normal after the postoperative 10th day. To prevent the development of postoperative dry eye, a serious potential complication of surgery, the decision to operate must be considered very carefully in patients with severe dry eye syndrome; and most importantly, excisions must be limited in order to avoid lagophthalmos.

Achieving a symmetrical appearance after surgery depends on adequate evaluation of the preoperative eyebrow position, the eyebrow-eyelash edge distance, the appearance of the tarsal plate, and the eyelid edge-corneal reflex distance. Among these parameters, the amount of tarsal plate contributes most to symmetry, and is the most no-

Akkaya, Surgical outcomes of blepharoplasty surgery

table element with respect to appearance. For this reason, in patients with unnoticeable lid creases, it is crucial that the eyelid is turned out preoperatively and that a lid crease is formed symmetrically between the 2 eyes based on the upper boundary of the tarsal plate.

Although a visible incision site tends to be less frequent after upper eyelid blepharoplasty procedures, patient satisfaction is still linked to the absence of incision marks. To reduce the appearance of scars, the wound edges should be uniformly and smoothly joined while suturing, the sutures should not be too tight, and the minimal number of lines possible should be used. In patients who will undergo concomitant eyebrow surgery, it is important to avoid extra incisions and to pay attention to achieving symmetry. As ectropion is far more frequent in lower eyelid blepharoplasties, it is essential that preoperative measurements and marks be made very carefully before these procedures.

A similar study was previously conducted by Schulz et al. (15), who reported the results of blepharoplasty in 47 patients and identified a surgery success rate of 91.5% in terms of symmetry. The symmetry success rate in the present study was similar at 92.19%. Schulz et al. identified a patient satisfaction ratio of 95.7%, and the 95.31% total ratio of satisfied and highly satisfied patients in the present study was consistent with those results. Schulz et al. also assessed patient quality of life, and found that it increased after blepharoplasty.

Lèclere et al. (16) published the asymmetry ratio identified in laser-assisted blepharoplasty performed on 52 patients, and they determined that 8 patients had 1 mm of asymmetry. In all, 6 were re-operated on. Leclere et al. had a comparatively higher ratio of asymmetry.

In this study, the patients expressed long-term satisfaction with the outcome of blepharoplasty surgery performed due to dermatochalasis. A comprehensive preoperative assessment and combination surgery when appropriate can ensure a high rate of success in blepharoplasty procedures.

Disclosures Peer-review: Externally peer-reviewed.

Conflict of Interest: None declared.

References 1. Lee JW, Baker SR. Esthetic enhancements in upper blepharoplasty. Clin Plast Surg 2013:40;139–46.

2. Yang P, Ko AC, Kikkawa DO, Korn BS. Upper Eyelid Blepharo-

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plasty: Evaluation, Treatment, and Complication Minimization.

World J Plast Surg 2016;5:58–61.

3. Hassanpour SE, Khajouei Kermani H. Brow Ptosis after Upper Blepharoplasty: Findings in 70 Patients. Semin Plast Surg 2017;31:51–7.

4. Leatherbarrow B, Saha K. Complications of Blepharoplasty. Facial Plast Surg 2013;29:281–8.

5. Hamawy AH, Farkas JP, Fagien S, Rohrich RJ. Preventing and managing dry eyes after periorbital surgery: a retrospective review. Plast Reconstr Surg 2009;123:353–3.

6. Floegel I, Horworth-Winter J, Mueller K, Haller-Schober EM. A conservative blepharoplasty may be a means of alleviating dry eye symptoms. Acta Ophthalmol Scand 2003;81:230–2.

7. Witney S, Witherow H, Waterhouse. One hundred cases of endoscopic brow lift. Br J Plast Surg 2002;55:20–4.

8. Jones BM, Grover R. Endoscopic brow lift: a personal review of 538 patients and comparison of fixation tecniques. Plast Reconstr Surg 2004;113:1242-50.

9. Saadat D, Dresner SC. Safety of blepharoplasty in patients with preoperative dry eyes. Arch Facial Plast Surg 2004;6:101–4.

10. Sheu MC, Schoenfield L, Jeng BH. Development of superior limbic keratoconjunctivitis after upper eyelid blepharoplasty surgery: support for the mechanical theory of its pathogenesis.

Cornea 2007; 26:490–2.

11. Hass AN, Penne RB, Stefanyszyn MA, Flanagan JC. Incidence of postblepharoplasty orbital hemorrhage and associated visual loss. Ophthal Plast Reconstr Surg 2004;20:426–32.

12. Patrocinio TG, Loredo BA, Arevalo CE, Patrocinio LG, Patrocinio JA. Complications in blepharoplasty: how to avoid and manage them. Braz J Otorhinolaryngol 2011;77:322–7 13. Prischmann J, Sufyan A, Ting JY, Ruffin C, Perkins SW. Dry eye symptoms and chemosis following blepharoplasty: a 10-year retrospective review of 892 cases in a single-surgeon series.

JAMA Facial Plast Surg 2013;15:39–46.

14. Korn BS, Kikkawa DO, Schanzlin DJ. Blepharoplasty in the postlaser in situ keratomileusis patient: preoperative considerations to avoid dry eye syndrome. Plast Reconstr Surg 2007;119:2232– 9.

15. Schulz CB, Nicholson R, Penwarden A, Parkin B. Anterior approach white line advancement: technique and long-term outcomes in the correction of blepharoptosis. Eye (Lond) 2017;31:1716–23.

16. Leclère FM, Alcolea J, Mordon S, Servell P, Kolb F, Unglaub F, et al. Long-term outcomes of laser assisted blepharoplasty for ptosis: about 104 procedures in 52 patients. J Cosmet Laser Ther 2013;15:193–9.

Case Report

DOI:10.14744/bej.2018.91885 Beyoglu Eye J 2018; 3(2): 96-98

Anterior Chamber Dislocation of Ozurdex Implant: A Case Report Elif Ertan,1 1 2

Rahmi Duman,2

Resat Duman,2

Mustafa Dogan2

Department of Ophthalmology, Siirt Kurtalan State Hospital, Siirt, Turkey Department of Ophthalmology, Afyon Kocatepe University, Afyonkarahisar, Turkey

Abstract Anterior chamber dislocation of an Ozurdex (Allergan plc, Dublin, Ireland) implant from the vitreous cavity is unusual. The risk factors for dexamethasone implant migration into the anterior chamber include a defective posterior lens capsule, aphakia, and a prior history of pars plana vitrectomy. Presently described is a case of corneal toxicity occurring after the migration of a dexamethasone implant into the anterior chamber.

Keywords: Anterior migration, corneal edema, cystoid macular edema, dexamethasone implant.

Introduction Implantation of dexamethasone (DEX) (Ozurdex; Allergan, Inc., Dublin, Ireland) is an approved treatment for macular edema due to branch or central retinal vein occlusion, diabetic macular edema, or noninfectious uveitis affecting the posterior segment (1). Ozurdex is associated with ocular side effects, such as conjunctival hemorrhage, endopthalmitis, cataracts, glaucoma, and retinal detachment (2). There may also be complications due to the implant itself, such as desegmentation (fracture) of the implant, accidental injection of Ozurdex into the crystalline lens, and migration of the Ozurdex implant into the anterior chamber (3-5). This report describes a case of corneal toxicity occurring after migration of a DEX implant into the anterior chamber.

Case Report The patient was a 78-year-old woman with diabetic macular edema (DME), a best-corrected visual acuity (BCVA) of 20/200, intraocular pressure (IOP) measured at 18 mmHg, and a central macular thickness (CMT) of 450 mikron in the

left eye. The patient had undergone a complicated cataract surgery 2 years earlier with a scleral-fixated posterior chamber lens implant and a defective iris. She had previously received 5 intravitreal injections of ranibizumab and 1 DEX implant (Ozurdex) in the left eye for the DME. The implant was injected via the pars plana route 3.5 mm from the limbus following topical anesthesia with proparacaine. An uneventful intravitreal DEX implant injection was performed.

However, 3 weeks after the injection, the patient presented at the clinic complaining of pain and vision loss in her left eye ongoing for a week. The intraocular pressure measured during the first visit was 18 mmHg. An anterior segment examination revealed corneal edema and the rod implant adhered to the corneal endothelium (Fig. 1). The implant was surgically removed from the anterior chamber 24 hours later. After the removal of the DEX implant, the patient was administered an eye drop formula consisting of 5% hypertonic solution to reduce the edema in the cornea, 5 times per day for 6 months. Six months after the DEX injection, BCVA was measured at 20/400, and the corneal edema had not resolved. The patient is awaiting corneal transplantation.

Address for correspondence: Elif Ertan, MD. Department of Ophthalmology, Siirt Kurtalan State Hospital, 56000, Siirt, Turkey Phone: +90 505 264 22 34 E-mail: elif-ertan@hotmail.com Submitted Date: April 04, 2018 Accepted Date: May 22, 2018 Available Online Date: June 06, 2018 Copyright 2018 by Beyoglu Eye Training and Research Hospital - Available online at www.beyoglueye.com

Š

Ertan et al., Anterior chamber dislocation of ozurdex implant

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Figure 1. Slit-lamp biomicroscopy showing the dexamethasone implant dislocated in the anterior Chamber with diffuse corneal edema.

Discussion In the GENEVA (Global Evaluation of implantable dexamethasone in retinal vein occlusion with macular edema) phase III clinical trial evaluating the DEX implant for treatment of macular edema secondary to retinal vein occlusion in 1256 patients and in the Ozurdex MEAD Study group phase III trial examining the efficacy of a DEX implant in 1048 patients with diabetic macular edema (DME), no cases of the steroid implant migrating into the anterior chamber occurred.

However, in both studies, eyes with aphakia and those with a history of pars plana vitrectomy (PPV) were excluded (6, 7). The risk factors for DEX implant migration into the anterior chamber include a defective posterior lens capsule, aphakia, and a prior history of PPV. Anterior migration of a DEX implant in pseudophakic and aphakic eyes with corneal decompensation and increased IOP has been previously reported. Khurana et al. (5) reported 15 cases including eyes with aphakia and pseudophakia with anterior chamber, iris-fixated, scleral-fixated, and intracapsular posterior chamber intraocular lens. Pardo et al. (8) reported a case of anterior dislocation of the DEX implant in a pseudophakic patient who had an iris-claw intraocular lens. Bansal et al. (9) reported 3 cases of anterior dislocation of the DEX implant in aphakic vitrectomized eyes. The authors reported that the implant was repositioned in the vitreous cavity in 2 cases.

However the third case required surgical removal with postsurgery persistence of corneal edema.

Corneal edema is the most serious complication of DEX

implant migration in the anterior chamber. Corneal endothelial toxicity may be due to mechanical trauma from the implant as well as chemical toxicity. In the setting of migration of the DEX implant into the anterior chamber, there are a few management strategies. The surgical management strategies include the repositioning of the implant into the vitreous, Neodymium-doped yttrium aluminum garnet (NdYAG) laser to fragment the implant, aspiration of the disintegrated implant, and forceps are used to remove the implant (5). Pacella et al. (10) also reported a case of an effective repositioning of a DEX implant through mobilization and subsequent balanced saline solution injection in the anterior chamber.

We did not elect to reposition the DEX; we preferred complete removal because the patient had a defective iris, which could cause recurrence of anterior chamber migration. If the implant migrates into the anterior chamber and there is corneal edema, we recommend immediate removal of the DEX implant.

Disclosures Informed consent: Written informed consent was obtained from the patient for the publication of the case report and the accompanying images.

Peer-review: Externally peer-reviewed.

Conflict of Interest: None declared.

Authorship Contributions: Involved in design and conduct of the study (EE); preparation and review of the study (EE, RD, RD, MD); data collection (EE, RD, RD, MD).

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References 1. London NJ, Chiang A, Haller JA. The dexamethasone drug delivery system: indications and evidence. Adv Ther 2011;28:351–66.

2. Schmitz K, Maier M, Clemens CR, Höhn F, Wachtlin J, Lehmann F, et al; German Retinal Vein Occlusion Group. Reliability and safety of intravitreal Ozurdex injections. The ZERO study [Article in German]. Ophthalmologe 2014;111:44–52.

3. Agrawal R, Fernandez-Sanz G, Bala S, Addison PK. Desegmentation of Ozurdex implant in vitreous cavity: report of two cases. Br J Ophthalmol 2014;98:961–3.

4. Coca-Robinot J, Casco-Silva B, Armadá-Maresca F, GarcíaMartínez J. Accidental injections of dexamethasone intravitreal implant (Ozurdex) into the crystalline lens. Eur J Ophthalmol 2014;24:633–6.

5. Khurana RN, Appa SN, McCannel CA, Elman MJ, Wittenberg SE, Parks DJ, et al. Dexamethasone implant anterior chamber migration: risk factors, complications, and management strategies. Ophthalmology 2014;121:67–71.

6. Haller JA, Bandello F, Belfort R Jr, Blumenkranz MS, Gillies M,

Ertan et al., Anterior chamber dislocation of ozurdex implant

Heier J, et al; Ozurdex GENEVA Study Group. Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion twelve-month study results. Ophthalmology 2011;118:2453–60.

7. Boyer DS, Yoon YH, Belfort R Jr, Bandello F, Maturi RK, Augustin AJ, et al; Ozurdex MEAD Study Group. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology 2014;121:1904–14.

8. Pardo-López D, Francés-Muñoz E, Gallego-Pinazo R, Díaz-Llopis M. Anterior chamber migration of dexametasone intravitreal implant (Ozurdex®). Graefes Arch Clin Exp Ophthalmol 2012;250:1703–4.

9. Bansal R, Bansal P, Kulkarni P, Gupta V, Sharma A, Gupta A. Wandering Ozurdex(®) implant. J Ophthalmic Inflamm Infect 2012;2:1–5.

10. Pacella F, Agostinelli E, Carlesimo SC, Nebbioso M, Secondi R, Forastiere M, et al. Management of anterior chamber dislocation of a dexamethasone intravitreal implant: a case report. J Med Case Rep 2016;10:282.

Case Report

DOI:10.14744/bej.2018.86580 Beyoglu Eye J 2018; 3(2): 99-100

Persistent Subretinal Fluid: Wait or Treat?

Ertugrul Tan Yassa,1 1 2

Berker Bakbak2

Department of Ophthalmology, Asya Eye Medical Centre, Istanbul, Turkey Department of Ophthalmology, Selcuk University Faculty of Medicine, Konya, Turkey

Abstract Persistent subretinal fluid (SRF) may occur even after successful surgery for rhegmatogenous retinal detachment (RRD).

In most cases, persistent SRF resolves spontaneously within a year, but persistent SRF may cause poor central vision, photoreceptor damage, and the irreversible loss of visual function. Therefore, a variety of interventions have been developed to manage persistent SRF, including the prophylactic use of steroids. As far as we know, an intravitreal steroid injection has never been used in the treatment of persistent SR. This report is a description of steroid treatment used in the case of a 46-year-old male patient with SRF persisting for 15 months after pars plana vitrectomy surgery for the treatment of macula-off RRD. A single-dose intravitreal triamcinolone acetonide (IVTA) injection (4 mg/0.1 mL) was administered; however, no improvement was seen in the lesions. It was concluded that an IVTA injection should be used in a limited fashion in patients with persistent SRF. Keywords: Persistent subretinal fluid, rhegmatogenous retinal detachment, visual dysfunction.

Introduction

Case Report

Persistent subretinal fluid (SRF) may be observed even after successful surgery for rhegmatogenous retinal detachment (RRD); the incidence of this well-known phenomenon varies in the literature (1). Persistent SRF after successful RRD surgery has been reported to occur in 47% to 100% of cases of macula-off retinal detachment (1-3). Long duration of persistent SRF after RRD surgery is probably multifactorial.

Possible causes include buckling surgery, cryocoagulation, and the high viscosity of SRF due to long-standing retinal detachment (2). Other reasons may be the breakdown of the blood-retinal barrier, and surgical trauma to the retinal pigment epithelium-Bruch's membrane complex (3).

In most cases, persistent SRF disappears spontaneously within 1 year (4). However, delayed absorption of SRF may not occur in some cases. This case is presented as an example of steroid treatment in a patient with persistent SRF.

A 46-year-old male patient presented with SRF persisting for 15 months after experiencing a right superior maculaoff RRD. Pars plana vitrectomy surgery with sulfur hexafluoride (SF6) gas was performed. Resorption of the peripheral SRF was achieved within 1 month. His right visual acuity was 20/40 and the patient had metamorphopsia. Optical coherence tomography of the right eye revealed multiple, subretinal, bleb-like lesions beneath the fovea (Fig. 1). The lesions were demonstrated to be only minimally hyperfluorescent, with no leakage or staining. The patient’s findings remained stable for 15 months. A single-dose intravitreal triamcinolone acetonide (IVTA) injection (4 mg/0.1 mL) was performed; however, no improvement in the lesions was seen.

Discussion While several studies have concluded that persistent SRF delays visual recovery without affecting one’s final outcome

Address for correspondence: Ertugrul Tan Yassa, MD. Department of Ophthalmology, Asya Eye Medical Centre, Istanbul, Turkey Phone: +90 212 593 97 00 E-mail: ertugrultanyassa@yahoo.com Submitted Date: April 11, 2018 Accepted Date: July 02, 2018 Available Online Date: July 12, 2018 Copyright 2018 by Beyoglu Eye Training and Research Hospital - Available online at www.beyoglueye.com

©

100

Yassa et al., Persistent subretinal fluid

from the patient for the publication of the case report and the accompanying images.

Peer-review: Externally peer-reviewed.

Conflict of Interest: None declared.

Authorship Contributions: Involved in design and conduct of the study (ETY, BB); preparation and review of the study (ETY, BB); data collection (ETY, BB).

References

Figure 1. Optical coherence tomography of the right eye revealed multiple, subretinal, bleb-like lesions beneath the fovea.

(1, 5), patients with persistent SRF-such as in our case-have cause for complaint due to poor central vision and metamorphopsia. Furthermore, persistent SRF may cause photoreceptor damage and the irreversible loss of visual function (6). As a result, several interventions have been used to manage persistent SRF. First, Koinzer et al. (7) found that selectively damaging retinal pigment epithelial cells using a neodymium: yttrium lanthanum fluoride laser is both safe and effective. Second, Itakura et al. (8) demonstrated that persistent SRF can be treated using an intravitreal injection of SF6 gas. Third, Wu et al. (9) noted that an oral dose of 0.5 or 1 mg prednisolone/ kg for 3 days postoperatively lowered the incidence of SRF and facilitated the absorption of SRF. In addition, the patients in that study demonstrated heightened improvement in their best-corrected visual acuity (BCVA) postoperatively. Finally, Mirshahi et al. (10) reported that the prophylactic injection of single-dose of IVTA at the end of the RD surgery might increase one’s final BCVA, despite the presence of persistent SRF. In our case, an intravitreal steroid injection was used 15 months after RRD surgery to treat persistent SRF. As far as we know, an intravitreal steroid injection has never been used in the treatment of persistent SRF that occurred following RRD. Our patient showed no improvement in terms of either optical coherence tomography findings or BCVA following the injection. Therefore, we can conclude that, other than the role that inflammation plays, other mechanisms must exist in this case and an IVTA injection should be used in a limited fashion in patients with persistent SRF occurring after surgery.

Further supportive data are required to reveal the role that steroids play in the treatment of persistent SRF. Disclosures Informed consent: Written informed consent was obtained

1. Kim JM, Lee EJ, Cho GE, Bae K, Lee JY, Han G, et al. Delayed Absorption of Subretinal Fluid after Retinal Reattachment Surgery and Associated Choroidal Features. Korean J Opthalmol 2017;31:402–11.

2. Hagimura N, Iida T, Suto K, Kishi S. Persistent foveal retinal detachment after successful rhegmatogenous retinal detachment surgery. Am J Ophthalmol 2002;133:516–20.

3. Kim YK, Ahn J, Woo SJ, Hwang DJ, Park KH. Multiple subretinal fluid blebs after successful retinal detachment surgery: incidence, risk factors, and presumed pathophysiology. Am J Ophthalmol 2014;157:834–41.

4. Kang SW, Kim JH, Shin WJ, Kim JI. Subretinal fluid bleb after successful scleral buckling and cryotherapy for retinal detachment. Am J Ophthalmol 2008;146:205–10.

5. Ricker LJ, Noordzij LJ, Goezinne F, Cals DW, Berendschot TT, Liem AT, et al. Persistent subfoveal fluid and increased preoperative foveal thickness impair visual outcome after maculaoff retinal detachment repair. Retina 2011;31:1505–12.

6. Veckeneer M, Derycke L, Lindstedt EW, van Meurs J, Cornelissen M, Bracke M, Van Aken E. Persistent subretinal fluid after surgery for rhegmatogenous retinal detachment: hypothesis and review. Graefes Arch Clin Exp Ophthalmol 2012;250:795– 802.

7. Koinzer S, Elsner H, Klatt C, Pörksen E, Brinkman R, Birngruber R, et al. Selective retina therapy (SRT) of chronic subfoveal fluid after surgery of rhegmatogenous retinal detachment: three case reports. Graefes Arch Clin Exp Ophthalmol 2008;246:1373–8.

8. Itakura H, Kishi S. Intravitreal injection of 0.3 ml of SF6 gas for persistent subfoveal fluid after scleral buckling for rhegmatogenous retinal detachment. Graefes Arch Clin Exp Ophthalmol 2009;247:1147–50.

9. Wu JS, Lin CJ, Hwang JF, Chen SN. Influence of systemic steroids on subretinal fluid after scleral buckle surgery for maculaoff retinal detachment. Retina 2011;31:99–104.

10. Mirsahi A, Karkhaneh R, Zamani Amir J, Movassat M, Azadi P. Influence of intravitreal triamcinolone acetonide injection in scleral buckling surgery for macula-off retinal detachment.

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