Romanian Journal of Ophthalmology

EDITOR-IN-CHIEF Mihail Zemba, M.D., Ph.D. Bucharest, Romania

E-mail: mhlzmb@yahoo.com

ASSOCIATE EDITOR Ovidiu Musat, M.D., Ph.D. Bucharest, Romania

E-mail: ovidiu.musat@yahoo.com

EXECUTIVE EDITOR Prof. Victor Lorin Purcarea, Ph.D. Bucharest, Romania

E-mail: victor.purcarea@gmail.com

ASSISTANT EDITORS Horia Stanca, M.D., Ph.D. Bucharest, Romania

E-mail: hstanca@yahoo.com Daniel Branisteanu, M.D., Ph.D. Iasi, Romania

E-mail: dbranisteanu@yahoo.com

INTERNATIONAL EDITORIAL ADVISORY BOARD Prof. Khaled al Rakhawy, M.D., Ph.D. Cairo, Egipt Daniel Baron M.D., Ph.D. Nantes, France Prof. Zsolt Biro M.D., Ph.D. Pecs, Hungary Prof. Derald Brackmann M.D., Ph.D. Los Angeles, USA Thierry Chazalon M.D., Ph.D. Nantes, France Prof. Gabriel Coscas M.D., Ph.D. Paris, France Prof. J.J. De Laey M.D., Ph.D. Gent, Belgium Prof. Fabian Hoehn M.D., Ph.D. Pforzheim, Germany

Prof. Christian Paul Jonescu-Cuypers M.D., Ph.D. Berlin, Germany Prof. Slobodanka Latinovic M.D., Ph.D. Novi Sad, Serbia Prof. Dan Milea M.D., Ph.D. Angers, France Gabor Rado M.D., Ph.D. Budapest, Hungary Prof.Gabor Scharioth M.D., Ph.D. Recklinghausen, Germany Prof. Wolfgang Schrader M.D., Ph.D. Wuerzburg, Germany Prof. Fankhauser Franz M.D., Ph.D. Bern, Switzerland

NATIONAL EDITORIAL ADVISORY BOARD Assoc.Prof. Florian Balta, M.D., Ph.D. Bucharest, Romania Prof. Dorin Chiselita M.D., Ph.D. Iasi, Romania Assoc. Prof. Mircea Filip M.D., Ph.D. Bucharest, Romania Prof. Mihnea Munteanu M.D., Ph.D. Timisoara, Romania Daniela Selaru M.D., Ph.D. Bucharest, Romania

Assoc.Prof. Cristina Stan M.D., Ph.D. Cluj Napoca, Romania Prof. Adriana Stanila M.D., Ph.D. Sibiu, Romania Cornel Stefan M.D., Ph.D. Bucharest, Romania Calin Tataru M.D.,Ph.D. Bucharest, Romania Prof.Dr. Cristina Vladutiu M.D., Ph.D. Cluj Napoca, Romania

NATIONAL EDITORIAL BOARD Gheorghe Anghel M.D., Ph.D. Bucharest, Romania Eugen Bendelic M.D., Ph.D. Chisinau, Republic of Moldova Camelia Bogdanici M.D., Ph.D. Iasi, Romania Daniel Branisteanu M.D., Ph.D. Iasi, Romania Marian Burcea M.D., Ph.D. Bucharest, Romania Catalina Corbu M.D., Ph.D. Bucharest, Romania Mihaela Coroi M.D., Ph.D. Oradea, Romania Valeria Coviltir M.D., Ph.D. Bucharest, Romania Valeriu Cusnir M.D., Ph.D. Chisinau, Republic of Moldova Danut Costin M.D., Ph.D. Iasi, Romania Monica Gavris M.D., Ph.D. Cluj Napoca, Romania Karin Horvath M.D., Ph.D. Tg. Mures, Romania Sanda Jurja M.D., Ph.D. Constanta, Romania

Carmen Mocanu M.D., Ph.D. Craiova, Romania Cristina Nicula M.D., Ph.D. Cluj Napoca, Romania Monica Pop M.D., Ph.D. Bucharest, Romania Mihai Pop M.D., Ph.D. Bucharest, Romania Alina Popa-Cherecheanu M.D., Ph.D. Bucharest, Romania Vasile Potop M.D., Ph.D. Bucharest, Romania Speranta Schmitzer M.D., Ph.D. Bucharest, Romania Horia Stanca M.D., Ph.D. Bucharest, Romania Ioan Stefaniu M.D., Ph.D. Bucharest, Romania Simona Talu M.D., Ph.D. Cluj Napoca, Romania Liliana Voinea M.D., Ph.D. Bucharest, Romania Mihail Zemba, M.D., Ph.D. Bucharest, Romania

PUBLISHING EDITORS Consuela Madalina Gheorghe, Bucharest, Romania Dodu Petrescu, Bucharest, Romania Petrut Radu, Bucharest, Romania

EDITORIAL OFFICE "Dr. Carol Davila"Central Military University Emergency Hospital 134 Calea Plevnei Street, District 1, Bucharest, Romania Phone number/Fax: +40.21.3137189 E-mail:editors@rjo.ro, Typesetting and cover graphic: P. Radu

Volume 61, Issue 1 January-March 2017

© All the rights on the journal belong to the Romanian Society of Ophthalmology. The partial reproduction of the articles or of the figures is possible only with the written consent of the Romanian Society of Ophthalmology. The responsibility of the articles’ originality belongs entirely to the authors.

Print ISSN 2457 – 4325 ISSN-L 2457 - 4325

Online ISSN 2501-2533 ISSN–L 2457-4325

Printed at ''Carol Davila'' University Press, 8 Eroilor Sanitari Blvd., 050474 Bucharest, Romania

Romanian Journal of Ophthalmology Volume 61, Issue 1, January-March 2017

Contents

Editorial

Empowering education for ophthalmologists Stanca T. Horia

1

Reviews Matrix regenerative therapy Timaru Cristina-Mihaela, Stefan Cornel, Iliescu Daniela Adriana, De Simone Algerino, Batras Mehdi

2

Uveitis–Glaucoma–Hyphaema Syndrome. General review Zemba Mihail, Camburu Georgiana

11

General articles

Is Laser Assisted Capsulotomy better than standard CCC? Gavriș Monica, Mateescu Radu, Belicioiu Roxana, Olteanu Ioana

18

One year refractive outcomes of Femtosecond-LASIK in mild, moderate and high myopia Tabacaru Bogdana, Stanca Horia Tudor

23

Topical administration of Metamizole and its implications on vascular reactivity in Wistar rats- Experimental research Coman Ioana-Cristina, Paunescu Horia, Stamate Alina Cristina, Cherecheanu Alina Popa, Ghita Isabel, Barac Cosmina, Vasile Danut, Tudosescu Ruxandra, Fulga Ion

32

Schirmer test changes after 20 gauge and 23 gauge pars plana vitrectomy Ghasemi Falavarjani Khalil, Shaheen Yahya, Karimi Moghaddam Arezoo, Aghaei Hossein, Parvaresh Mohammad Mehdi, Bahmani Kashkouli Mohsen, Farrokhi Hosein, Abri Aghdam Kaveh

39

Case reports

Terson’s Syndrome – case report Moraru Andreea, Mihailovici Ruxandra, Costin Dănuţ, Brănişteanu Daniel

44

Necrotizing retinitis of multifactorial etiology Pirvulescu Ruxandra Angela, Popa Cherecheanu Alina, Romanitan Mihaela Oana, Obretin Dana, Iancu Raluca, Vasile Danut

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Penetrating corneal wound with traumatic cataract and intraocular foreign body-case report Căciulă Dorin, Gavriș Monica, Tămășoi Irina

54

Diagnosis difficulties in a patient with progressive loss of vision - a case report - Cristescu Teodor Razvan

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Intraocular ossification. Case report Maftei Ciprian, Stanca Horia Tudor

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Scheimpflug topographical changes after Femtosecond LASIK for mixed astigmatism – theoretical aspects and case study Tabacaru Bogdana, Stanca Horia Tudor

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Subconjunctival ocular filariasis-Case report- Macarie Sorin Simion, Dobre Cristina, Suciu Marilena-Cristina, Ionica Angela-Monica, Cernea Mihai-Sorin, Tarcău Paul, Bodea Flaviu

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EDITORIAL

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doi:10.22336/rjo.2017.1

Empowering education for ophthalmologists

Romanian Society of Ophthalmology (RSO) and its Partner, the American Academy of Ophthalmology (AAO) are empowering education for Romanian Ophthalmologists by online clinical education resources.

There have already been 2 years since RSO signed a partnership with AAO in order to provide access to ONE Network for every Romanian ophthalmologist, this opportunity being welcomed by our members, and being more and more used.

Ophthalmic News and Education (ONE) Network is a Global Education Platform for Ophthalmologists launched in November 2007, which nowadays offers access to more than 400 courses and interactive cases, more than 15000 pages of ophthalmic content, more than 3600 clinical images, more than 1800 instructional videos and podcasts, 10 leading scientific journals, these numbers increasing constantly. ONE Network is a great resource for innovative education addressed to trainees offering 24 courses in all subspecialties, more than 100 videos and AAO lectures and more than 1000 self-assessment questions. This online resource for clinical information and instruction also includes up-to-date clinical guidelines translated into 15 languages, including Romanian.

AAO collaborates with the Ophthalmology Societies Worldwide and ONE Network, through the Global Alliances, which is an outstanding project that had a significant impact on both clinical education and the delivery of eye care.

Last year, during the 2016 AAO Meeting in Chicago, Richard L. Abbott, MD, Secretary for Global Alliances and Past President of the American Academy of Ophthalmology, has unveiled the “Global Directory of Training Opportunities”, a service that will help the ophthalmologists worldwide identify the training opportunities (observership, fellowship or preceptorship) outside their country and expand their knowledge and instruction in the United States and internationally. Working with the AAO’s Regional Advisors Committee, the Global Alliances has succeeded in just one year to plan and launch a Global Observership Listing Service and this tremendous option can be accessed by every Romanian ophthalmologist through ONE Network platform (aao.org/training-opportunities).

The Romanian Society of Ophthalmology is proud to be one of the 70 national Societies that can offer ONE Network as a benefit for their members to stay updated and get the most comprehensive schooling.

In addition, dear Romanian Ophthalmologists, feel free to expand your knowledge and identify the best educational opportunities by using ONE Network platform!

Stanca T. Horia MD, PhD RSO Member of the Board

AAO’s Regional Advisors Committee Member

Romanian Journal of Ophthalmology, Volume 61, Issue 1, January-March 2017. pp:2-10

REVIEW

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Matrix regenerative therapy

Timaru Cristina-Mihaela*, Stefan Cornel*, Iliescu Daniela Adriana*, De Simone Algerino*, Batras Mehdi* *Ophthalmology Department, “Dr. Carol Davila” Central Military Emergency University Hospital, Bucharest, Romania Correspondence to: Timaru Cristina Mihaela, MD, Ophthalmology Department, “Dr. Carol Davila” Central Military Emergency University Hospital, Bucharest, 134 Calea Plevnei Street, District 1, Bucharest, Romania, Phone/ Fax: +4021 313 71 89, E-mail: cristinamihaelatimaru@yahoo.com Accepted: February 20, 2017

Abstract The extracellular matrix (ECM) is responsible for many of the cell behavior processes, including cell proliferation and growth, survival, change in cell shape, migration, and differentiation. The most important component of the ECM is heparan sulfate (HS), because it insures the storage of many cell communication proteins, necessary for the continuous and identical renewal of cells and thus for tissue regeneration. Regenerating agents (RGTA®) are bioengineered structural analogues of heparan sulfate glycosaminoglycans that replace the degraded endogenous HS of the ECM. In the ophthalmological field, RGTA® represents an innovative approach for the improvement of the ocular surface wound healing and matrix remodeling and plays a role in controlling and regulating the wound healing process in various ocular diseases. Keywords: regenerating agents, RGTA, extracellular matrix, wound healing

Introduction

Corneal pathologies remain a major health concern in the ocular surface diseases. Improving both the quality and the speed of healing and controlling the inflammation are goals in treating the corneal injuries.

The cornea is a complex structure responsible for three quarters of the optical power of the eye as well as one of the first lines of immunologic defense. The normal cornea is transparent, free of blood vessels, and densely innervated. It consists of the following layers:

1. The epithelium: stratified squamous and non-keratinized; the cells are interconnected

by hemidesmosomes, critical in maintaining a physiological barrier.

2. The Bowman layer: acellular superficial layer formed by collagen fibers.

3. The stroma: layers of collagen fibrils whose spacing is maintained by proteoglycan ground substance (glycosaminoglycans-GAGs: chondroitin sulfate, keratin sulfate, heparin sulfate) (the extracellular matrix); the regular arrangement and spacing is critical for optical clarity; 90% of corneal thickness; the mechanical response of the cornea to injury is dominated by the stroma; the stroma is approximately 78% water, 15% collagen and 7% non-collagenous proteins, proteoglycans and salts.

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4. The Descemet membrane: fine layer of collagen fibrils, different from the stromal collagen.

5. The endothelium: monolayer of polygonal cells that pump excess fluid out of the stroma.

6. The Dua layer: a sixth layer between the stroma and the Descemet membrane; its existence was suggested by Harminder Singh Dua et al. in 2013, but many scientists are still conflicted [1,2].

The RGTA-based technology is a new therapeutic approach also named “Matrix Therapy”, aiming to preserve the extracellular matrix (ECM) and providing encouraging results in tissue regeneration.

ECM is an organized complex macromolecule network of proteins such as collagen and elastin that are linked together through polymers called glycosaminoglycans (GAGs).

The most important component of the ECM is heparan sulfate (HS). It insures the storage of many cell communication proteins such as growth factors and cytokines, necessary for the continuous and identical renewal of cells and thus for tissue regeneration. HS also provides a mechanical protection of the matrix signaling proteins against proteolytic degradation.

Corneal lesions healing and regenerating process

ECM is responsible for many of the cell behavior processes, including cell proliferation and growth, survival, change in cell shape, migration, and differentiation.

Corneal homeostasis (replacing a dead cell by a new identical cell) is regulated by the local cellular microenvironment. The initial endogenous signals needed for tissues to regenerate come from the matrix. They are expected to trigger the natural onset of events, signaling cells to migrate and multiply with the cascades and equilibrium found in tissue homeostasis to achieve a perfect replacement or regeneration.

Within the cornea, the ECM is continuously remodeled by cells via the degradation of the ECM components trough proteases, followed by

the reassembly of the newly synthesized protein components secreted by cells.

Corneal healing is a complex process involving cellular interaction and various molecules (proteases, growth factors, and epithelial and stromal cytokines).

When a lesion is produced, the GAGs are destroyed by the glycanases and can no longer be bound by the proteins, leaving them sensitive to proteases. The ECM architecture is disorganized and its function is disrupted. The inflammatory process determines inflammatory cells migration and release of less specific factors that replace growth factors. The homeostasis can no longer be effective and a healing process is starting [3].

The process of corneal epithelial wound healing can be divided into phases that occur in sequence, but may overlap in time:

1. Latent Phase: cellular remodeling and changes to tear composition in preparation for healing; there is an increased production of enzymes that decrease cellular adhesion and help enhance cellular migration; they are also important in the degradation and remodeling of normal extracellular matrix (ECM) maintenance [4,5].

2. Migration Phase. The next phase occurs as cells near the wound edge flatten and spread; contractile elements pull the cell forward toward the defect. Adjacent cells remain attached by desmosomes and maintain their position relative to each other as they slide across the denuded area. This cycle continues until the defect is completely sealed by a single layer of cells. The process typically takes place over 24 to 36 hours, though time can vary depending on the defect’s location and size [6].

3. Proliferation Phase. After migration is complete, the monolayer of cells covering the defect proliferates to restore the normal thickness and fill in the defect. Tight junctions form to re-establish the cornea’s barrier function, and gap junctions, adherens junctions and desmosomes reform between cells [5,6]. The reepithelization is initiated by the keratinocytes that proliferate, grow, and reform the tissue in depth. The deep tissue is reconstituted by proliferating fibroblasts that re-colonize the wound, synthesize a new temporary ECM, and form new blood vessels.

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4. Remodelling Phase: can last for several years and consists of an ECM reorganization, vascular regression, and cell density reduction. Fibroblasts produce collagen as well as glycosaminoglycans and proteoglycans, which are major components of the ECM. One critical feature of the remodeling phase is ECM remodeling to an architecture that approaches that of the normal tissue [7].

Chronic and acute wounds heal very differently because of their physiology and repair characteristics.

Acute wound repair is a systematic process, consisting of homeostasis, inflammation, migration, proliferation and remodeling, while chronic wound repair is much more complex. Chronic wounds have a prolonged inflammatory phase, thus delaying the healing and repair process. In such wounds, an endless cycle of deterioration-healing-deterioration takes place. This precise action of the ECM is a potential target for RGTA® [8].

ReGeneraTing Agents (RGTA)

The RGTA concept Regenerating agents (RGTA®) are

bioengineered structural analogues of heparan sulfate glycosaminoglycans (HS GAGs) that replace the degraded endogenous HS of the ECM. They are obtained by controlled grafting of carboxymethyl and sulfate groups on dextran polymers. Unlike naturally occurring HS, these polymers are stable and resistant to degradation [9].

They are adapted to interact with, and protect against proteolytic degradation of cellular signaling proteins (growth factors, cytokines, interleukins, colony stimulating factors, chemokines, and neurotrophic factors) and re-establish the intercellular links.

When a tissue is attacked, stressed cells release proteases and glycanases, which destroy this matrix architecture. Tissue-regenerating agents (RGTA) mimic the action of destroyed heparan-sulfate molecules, thereby recreating a matrix microenvironment in which cells can migrate and multiply. Moreover, these agents

break the negative repair-destruction cycle occurring in chronic lesions [10].

The result is the preservation of the tissue natural endogenous signaling and is reflected by spectacular tissue regeneration or by a very greatly improved tissue repair.

These effects allow the creation of a suitable microenvironment for cells to respond properly to the cascade of signals needed for the tissue regeneration process to take place.

Mechanism of action RGTA®s were designed to be a matrix

therapy that restores the natural cellular microenvironment. They enhance both speed and quality of the tissue healing and lead in some cases to a tissue regenerating process.

The goal of this therapy is to block the cycle of ECM destruction and reconstruction that characterizes the chronic wounds by introducing a glycanases-resistant biopolymer engineered to mimic HS to improve tissue healing. This ECM stability is critical to the health and healing of wounds [11].

When applied topically to a wound, RGTA® penetrates into the micro-clefts of the damaged ECM, where it replaces the endogenous HS that have been degraded by glycanases. By binding to structural matrix proteins (collagen, elastin, fibronectin), the scaffolding properties of the ECM, and the mechanical protection of the matrix signaling proteins (heparin-binding growth factors, cytokines, neurotrophic factors) against proteolytic degradation, are restored [12]. This, in turn, prevents the degradation of the extracellular matrix proteins, and promotes stromal and, subsequently, epithelial healing [13,14].

Regenerative medicine

There are multiple studies on a variety of animal species and tissue injury models including bone, gastrointestinal, muscular (including cardiac muscle), gingival, mouth and skin lesions, which proved that local or systemic administration of RGTA® improve the speed and

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quality of wound healing, in both epithelial and connective tissues.

RGTA®s in ophthalmology In the ophthalmological field, the available

RGTA® is alfa 1-6 poly (carboxymethyl glucose sulfate) (CACICOL® – Laboratoires Thea). Several studies tested and proved the ability of RGTA® to promote the healing of chronic and severe corneal dystrophies, and healing of chronic corneal ulcers in humans. The heparan sulfate analog was shown to enhance re-epithelialization after corneal ulcer, reduce corneal inflammation and neovascularization, and suppress the antioxidant/ pro-oxidant imbalance in the injured corneal epithelium [17,18].

RGTA (Cacicol) is supplied as a sterile single-dose solution (0.33ml) of alpha 1-6 poly carboxymethyl glucose sulfate, with dextran T40 and sodium chloride as excipients. It contains no component of animal or biological origin, and penetrates into the cornea without crossing Descemet’s membrane. It was approved in the UE in 2008.

It is distributed in an aluminum foil for protection against light, being stable for 36 months at a temperature between 4 and 25 degrees Celsius.

RGTA®s studies The first evidence of the efficacy of a

RGTA® ophthalmic solution was obtained in a series of in vivo experiments on rabbit eyes that presented with alkali-induced severe corneal ulcers. A single drop of RGTA solution at a concentration of 100 µg/ mL was able to optimize the healing process, restoring an almost normal corneal histology after one week [15].

Since then, a high number of preclinical studies were performed by testing the efficacy of RGTA®s in different types of corneal lesions.

Using the same lesion model, Takesue et al. (2005) revealed an improved healing with a decreased corneal opacity in mice after the topical application of RGTA® on corneal wound healing after burn injury [19].

A similar study was published by Cejkova J in 2014 on the effects of RGTA® therapy in

rabbit corneas injured with alkali. The study demonstrated that RGTA® facilitates the healing of the alkali-injured corneas via a reduction of proteolytic, oxidative and nitrosative damage. The corneal thickness increased after the alkali injury and decreased during the corneal healing after RGTA treatment faster than after the placebo application. Following the injury with the high alkali concentration, corneal inflammation and neovascularization were highly pronounced in placebo-treated corneas, whereas in RGTA-treated corneas they were significantly suppressed. In conclusion, RGTA facilitates the healing of injured corneas via a reduction of proteolytic, oxidative and nitrosative damage [16].

Aifa et al. published a single-center, uncontrolled, prospective study in 2012 concerning the efficacy of RGTA therapy in corneal neurotrophic ulcers in 11 patients. The defect in 72.7% (8 patients) was completely healed in 8.7 weeks, the area of the lesion diminishing with 50% or more in the first week. No local or systemic side effects were noticed and the treatment was very well tolerated [11].

Indications in ophthalmology

This heparan mimetic, which stimulates extracellular matrix healing, may be a possible alternative therapy to heavy and invasive treatments such as autologous serum or amniotic membrane transplantation in patients suffering from:

- chronic corneal wound healing - persistent and recurrent epithelial

chronic defects - corneal ulcers - corneal dystrophies - chemical burns - traumatic injuries - chronic wearing of contact lenses - hereditary factors: familial

dysautonomia, Riley-Day syndrome (loss of sensitivity, loss of tear secretion)

- limbus stem cells destruction - viral keratitis

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- sever dry eye syndrome - old age (reduces corneal sensitivity,

modifies the tear film, reduces the autonomous nervous system response)

- corneal surgery: refractive surgery, corneal transplant, cataract surgery

- toxic iatrogenic keratitis: topical anesthetics, preservatives, chronic medication (for glaucoma)

- autoimmune diseases (Sjogren syndrome, Lyell syndrome)

- corneal lesions in diabetes, malnutrition, alcoholism

- corneal ulcer in neovascular glaucoma.

Administration

The number of heparan-binding sites available in wound tissue is limited, and once all these sites are occupied by RGTA, excess RGTA may compete with heparan-binding growth factors for sites on the matrix-bound RGTA. Thus, heparan-bound growth factors/ cytokines stored in the matrix could be removed from the matrix by this excess, hence reducing the amount of the growth factor available, and healing

efficacy. For this reason, daily, or more than daily, addition does not seem to be needed [11].

The dosage depends on the etiology of the lesion. It can vary between:

- 1 drop/ week, for 1-2 months - 1 drop/ 2 days, for 10 days - 1 drop/ 2-3 days for 2-3 months or 1

drop/ day for a month in very difficult cases. It has to be administered 15 minutes after

another topical treatment, in the absence of an infectious disease and not associated with topical aminoglycosides (neomycin, gentamicin).

Our experience

26 patients with corneal lesions of various etiologies (infectious, posttraumatic, severe dry eye syndrome, post transplant, viral, linear corneal dystrophy, and post refractive surgery) were treated with RGTAs, 1 drop/ week for 2-4 months.

Follow-ups concentrated on symptoms evolution (cloudy vision, foreign body sensation, pain, excessive tearing), visual acuity and quality of life improvement, slit-lamp examination of the anterior segment, with fluorescein staining of the defect and defect measurements at each visit (maximum diameter) [20].

Fig. 1 47-year-old female patient, infectious corneal ulcer; 1 - day 1 of treatment, 2a,b - follow-up day 30, 3a,b - follow-up day 60

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Fig. 2 42-year-old male patient, linear corneal dystrophy; 1a,b - day 1 of treatment, 2a,b - follow-up day 30, 3 - follow-up day 90

Fig. 3 57-year-old male patient, post corneal transplant; 1a,b - day 1 of treatment, 2 - follow-up 60 days

Fig. 4 59-year-old male patient, post corneal transplant, 1a,b - day 1 of treatment, 2a,b - follow-up 90 days

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Fig. 5 39-year-old female patient, post refractive surgery, 1 - day 1 of treatment, 2 -follow-up 30 days

Fig. 6 45-year-old female, severe dry eye syndrome, 1 - day 1 of treatment, 2 - follow-up 30 days, 3 - follow up 90 days, 4 - follow-up 120 days

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Results

The results are very promising. All the patients confirmed an improvement

or even disappearance of symptoms and a better quality of life due to that effect.

Objectively, visual acuity improved in all cases and the defect was cured in 73% (19 patients) of the cases and reduced by 50% or more in 27% (7 patients).

The easy way of administering it and the weekly dosage insured a good adherence to treatment of all patients. No side effects, local or systemic, were noticed and the therapy was well tolerated by patients [21].

Conclusions

In the ophthalmological field, RGTA® represents an innovative approach for the improvement of the ocular surface wound healing and matrix remodeling and plays a role in controlling and regulating the wound healing process in various ocular diseases, such as those involving corneal epitheliopathy, chemical or physical trauma, severe dry eye syndrome, scarring conjunctivitis, or after refractory surgery.

It is effective in improving subjective and objective symptoms, corneal healing and the patient’s comfort, has no noticed side effects and it is well tolerated by the patients. This therapy enhances both speed and quality of tissue healing, promoting tissue regeneration.

References

1. Bowling B. Kanski’s Clinical Ophthalmology. eight edition, 2016, 168-169.

2. Dua HS, Faraj LA, Said DG, Gray T, Lowe J. Human corneal anatomy redefined: a novel pre-Descemet’s layer (Dua’s layer). Ophthalmology. 120 (9):1778–85. doi:10.1016/j.ophtha.2013.01.018.

3. Badylak S. Regenerative medicine and developmental biology: The role of the extracellular matrix. The Anatomical Record. 2005.

4. Tsirogianni AK, Moutsopoulos NM, Moutsopoulos HM. Wound healing: immunological aspects. Injury. 2006 Apr; 37 Suppl 1:S5-12.

5. Liu CY, Kao WW. Corneal Epithelial Wound Healing. Prog Mol Biol Transl Sci. 2015; 134:61-71.

6. Lu L, Reinach PS, Kao WW. Corneal epithelial wound healing. Exp Biol Med (Maywood). 2001 Jul; 226(7):653-64.

7. Guo S, Dipietro LA. Factors affecting wound healing. J Dent Res. 2010 Mar; 89(3):219-29. doi: 10.1177/0022034509359125.

8. Colombier ML, Lafont J, Blanquaert F, Caruelle JP, Barritault D, Saffar JL. A single low dose of RGTA®, a new healing agent, hastens wound maturation and enhances bone deposition in rat craniotomy defects. Cells Tissues Organs. 1999; 164:131-40.

Fig. 7 40-year-old female patient, viral keratitis, 1a,b - first day of treatment, 2a,b - follow-up at 30 days, 3 - follow-up at 90 days

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9. Stefan C. Matrix regenerative therapy. SRO. 2016. 10. Groah SL, Libin A, Spungen M, Nguyen KL, Woods

E, Nabili M, Ramella-Roman J, Barritault D. Regenerating matrix-based therapy for chronic wound healing: a prospective within-subject pilot study. Int Wound J. 2011 Feb; 8(1):85-95. doi: 10.1111/j.1742-481X.2010.00748.x.

11. Aifa A, Gueudry J, Portmann A, Delcampe A, Muraine M. Topical Treatment with a New Matrix Therapy Agent (RGTA) for the Treatment of Corneal Neurotrophic Ulcers. Investigative Ophthalmology & Visual Science. December 2012; Vol. 53,8181-8185. doi:10.1167/iovs.12-10476.

12. Rouet V, Meddahi-Pellé A, Miao HQ, Vlodavsky I, Caruelle JP, Barritault D. Heparin-like synthetic polymers, named RGTAs, mimic biological effects of heparin in vitro. J Biomed Mater Res A. 2006 Sep 15; 78(4):792-7.

13. Chebbi CK, Kichenin K, Amar N, Nourry H, Warnet JM, Barritault D, Baudouin C. Pilot study of a new matrix therapy agent (RGTA OTR4120) in treatment-resistant corneal ulcers and corneal dystrophy. J Fr Ophtalmol. 2008 May; 31(5):465-71.

14. Aslanides IM, Selimis VD, Bessis NV, Georgoudis PG. A pharmacological modification of pain and epithelial healing in contemporary transepithelial all-surface laser ablation (ASLA). Clin Ophthalmol. 2015; 9:685–690.

15. Brignole-Baudouin F, Warnet JM, Barritault D, Baudouin C. RGTA-based matrix therapy in severe experimental corneal lesions: safety and efficacy studies. J Fr Ophtalmol. 2013 Nov; 36(9):740-7. doi: 10.1016/j.jfo.2013.01.012.

16. Cejkova J, Olmiere C, Cejka C, Trosan P, Holan V. The healing of alkali-injured cornea is stimulated by a novel matrix regenerating agent (RGTA, CACICOL20): a biopolymer mimicking heparan sulfates reducing proteolytic, oxidative and nitrosative damage. Histol Histopathol. 2014 Apr; 29(4):457-78.

17. Cochener B, Muraine M. A new matrix therapy agent in the treatment of corneal ulcers resistant to conventional treatments. Poster. e2522 – EVER. 2012.

18. Cochener B and al. New medical device for chronic corneal ulcers healing. ARVO. 2013.

19. Takesue Y, Huet E, Gabison E, Racine L, Hoang-Xuan T, Barritault D, Caruelle JP, Menashi S. Heparan Mimetics (RGTA®) Promote Corneal Wound Healing in vivo and in vitro. E-Abstract 2134/B903. 2005 May 1-5, Fort Lauderdale, USA.

20. Stefan C, Timaru CM, Anghel G, Burcea M, Selaru D, Muşat O, Zemba M, Manole H, Macovei L, Pulbere L, Armegioiu M. ReGeneraTing Agents (RGTAs)- Matrix therapy in ophthalmology. Balkanic Medicine. 2016.

21. Timaru CM, Stefan C, Iliescu DA, De Simone A, Batras M. Corneal matrix therapy trough regenerative agents. SRO. March 2017.

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REVIEW

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Uveitis–Glaucoma–Hyphaema Syndrome. General review

Zemba Mihail, Camburu Georgiana *Ophthalmology Department, “Dr. Carol Davila” Central Military Emergency University Hospital, Bucharest, Romania Correspondence to: Georgiana Camburu, MD, Ophthalmology Department, “Dr. Carol Davila” Central Military Emergency University Hospital, Bucharest, Romania, 134 Plevnei Street, District 1, Bucharest, Romania, Phone: +4021 313 71 89, E-mail: georgiana.camburu@yahoo.com Accepted: January 19, 2017

Abstract Uveitis-Glaucoma-Hyphaema Syndrome (UGH syndrome, or “Ellingson” Syndrome) is a rare condition caused by the mechanical trauma of an intraocular lens malpositioned over adjacent structures (iris, ciliary body, iridocorneal angle), leading to a spectrum of iris transillumination defects, microhyphaemas and pigmentary dispersion, concomitant with elevated intraocular pressure (IOP). UGH Syndrome can also be characterized by chronic inflammation, secondary iris neovascularization, cystoid macular edema (CME). The fundamental step in the pathogenesis of UGH syndrome appears to arise from repetitive mechanical iris trauma by a malpositioned or subluxed IOL. These patients have uncomplicated cataract implants and return for episodes of blurry vision weeks to months after surgery. This may be accompanied by pain, photophobia, erythropsia, anterior uveitis, hyphaema along with raised intraocular pressure. A careful history and examination, as well as appropriate investigations can confirm the diagnostic. Treatment options are IOL Explantation exchange, topical and systemic medication, and cyclophotocoagulation, the placement of a Capsular Tension Ring to redistribute zonular tension and Anti–vascular endothelial growth factor (anti-VEGF) Therapy. Keywords: UGH syndrome, uveitis, glaucoma,hyphema , cystoid macular edema, IOL, anti-VEGF Therapy

Background

Uveitis-Glaucoma-Hyphaema Syndrome (UGH syndrome, or “Ellingson” Syndrome) is a rare condition caused by the mechanical trauma of an intraocular lens malpositioned over adjacent structures (iris, ciliary body, iridocorneal angle), leading to a spectrum of iris transillumination defects, microhyphaemas and pigmentary dispersion, concomitant with elevated intraocular pressure (IOP). UGH Syndrome can also be characterized by chronic inflammation, secondary iris neovascularization, and cystoid macular edema (CME) [1].

The term UGH Syndrome was originally described by Ellingson in 1977 as a result of excessive lens movement by small lens size or lens dislocation. Poorly manufactured edges, iris-clipped IOLs, or rigid closed looped haptics were also found as promoting factors. Along with the upgrade of the lens design, fabrication, surgical techniques, and the use of posterior chamber IOLs, the incidence of UGH has sharply decreased from a mean of 2.2 to 3% to 0.4 to 1.2% over a one-year period [2].

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Epidemiology

The UGH Syndrome is a triad that commonly occurs in adults, nonetheless it was reported a case of postoperative uveitis-glaucoma-hyphaema syndrome following pediatric cataract surgery [3].

Speaking at the ASCRS 2016, Dr. Albert Cheung stated that UGH is a rare, but potentially devastating complication. Dr. Cheung’s 10-years (2005-2015) retrospective chart review is the result of 249 patients who had been referred for evaluation for IOL reposition or exchange, 53 of them (56 eyes) having UGH at presentation [4].

Although it was mainly described with rigid anterior chamber lenses, the UGH syndrome has also been described with posterior-chamber and iris-supported lenses. In a retrospective review from Gainesville, University of Florida, 97 patients who had some form of UGH were studied and 54% had an ACIOL, while 34% had an iris-fixed lens. UGH syndrome can occur in cases with PCIOLs, however, it is much less likely due to the added stability provided by the lens capsule [5].

The same result was found in Hong Kong Eye Hospital’s medical records of the patients who underwent IOL explantation during January 2008 and March 2013. The reasons for lens removal from a total of 98 explanted IOLs included in the study were due to lens malposition (71.4%), isolated uveitis-glaucoma-hyphaema (UGH) syndrome (9.1%), refractive surprise (6.1%), and pseudophakic bullous keratopathy (4.1%), “In-the-bag” IOL malposition associated with intraocular complications during cataract extraction (28.9%) and high myopia (22.2%). Sulcus-

fixated 3-piece lenses had the UGH Syndrome as a complication in 7.1% of the cases, whereas Sulcus implantation of a single-piece acrylic (SPA) was involved in all cases [6].

Pathophysiology

As the overall pathogenesis of the UGH syndrome remained unclear for a long period of time, some hypotheses were made. These theories were based on the activation of the innate immunity: cytokine and eicosanoides synthesis, triggered by a mechanical excoriation of the angle or iris, by the haptics or optics, plasma-derived enzyme (especially complement or fibrin) activated by the surface of the IOLs (especially PMMA), adherence of bacteria and leukocytes to the IOL surface, toxicity caused by contaminants on the IOL surface during manufacturing implantation were suggested [5].

Ultrasonic biomicroscopy has enabled a better understanding of the mechanism of this disorder. In a review of 20 suspected cases, ultrasonic biomicroscopy showed the haptic in contact with the iris in 75% of the cases, extending to the ciliary body in 35% and to the pars plana in 10% of the cases [7]. The lenses have surface imperfections that may render them more capable of traumatizing the tissue and cause symptoms. Vaulting, decentration, and excessive movement of the lens may cause the breakdown of the blood-aqueous barrier. Intermittent contact with the fragile vascular uveal tissue may then lead to chafing, erosion, and pigment dispersion; consequently, with signs of anterior uveitis and recurrent episodes of hyphaema, and raised intraocular pressure. Elevated intraocular pressure is a result of persistent inflammation, pigment dispersion and deposition, or secondary to macrophages containing degraded red blood cells blocking the trabecular meshwork. Further, the patient may develop glaucomatous atrophy and visual field loss.

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Previous studies suggested that the low-grade chronic inflammation was the effect of a foreign-body reaction to the lens material or to a toxic compound on the lens surface. Lately it has been proved that cause is the avirulent organisms that are sequestrated within the lens haptic. Performing the scanning electron microscopy of cellular findings on explanted IOLs in patients with UGH, revealed coccoid-like structures on the haptic surface. Moreover, transmission electron microscopy made the spherical structures turn into melanosomes, possibly derived from the damaged pigment epithelial cells or stromal melanocyte in consequence of recurrent contact of the haptic against the anterior or posterior part of the iris [8].

The fundamental step in the pathogenesis of the UGH syndrome appears to arise from repetitive mechanical iris trauma by a malpositioned or subluxed IOL.

Cheng et al., Jacobs et al., and Miller and Doane determined the movements of IOLs by using high-speed-imaging, for short-distance eye movements. Previously, position-determining investigations of IOLs in various positions or during accommodation were made, but not during fast eye movements.

A Pilot Study was conducted in the Centre for Ophthalmology, University Eye Hospital, Eberhard Karls University of Tübingen, Germany to measure this condition in a more realistic manner, and aimed to evaluate the kinetic influences, in fast direction changes and at lateral end points, with a digital high-speed camera along with digital morphometric software for dynamic measurements of phakic intraocular lens movements. The selected “peak lens deviation” images that were analyzed in the study revealed a low-lying lens position relative to the pupil center in nine of ten eyes. Possible explanations for this result were described as implantation position, looseness of the iris or fixation points, shifting haptic phenomenon, and gravity forces “pulling” the lenses. Other studies also showed decentrations of the ICIOL models. Menezo et al. asserted decentrations of up to 1 mm, and, at the same time, Pérez-Santonja et al. decentrations were greater than 0.5 mm in 14 (43%) of 32 eyes [9].

Fig. 1 Scanning electron micrograph showing material attached to the tip of a haptic lens. R. H. Y. ASARIA J. F. SALMON Oxford

Fig. 2 Details of the surface of the material attached to the haptic tip showing densely packed coccoid-like structures. R. H. Y. ASARIA , J. F. SALMON, Oxford - Electron microscopy findings on an intraocular lens in the uveitis, glaucoma, hyphaema syndrome

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UGH is most commonly caused by anterior chamber intraocular lenses, but can occur from any type of pseudophakic lens. Angle supported anterior chamber implants have been in use since the 1950’s for the correction of aphakia. 75% of the patients with this type of implant manifested symptoms that can relate to the UGH syndrome. The lens direct contact with the iridocorneal angle structures produces continuous mechanical damage and pigment dispersion. The liberated pigment occludes the trabecular meshwork and rise IOP. Since ACIOL were promoted for their cosmetic use, there have been a growing number of cases with UGH [10].

The frequency of UGH syndrome as a complication of posterior chamber lens implantation is very low. Although Percival reported a case with an implantation of a Rayner-Pearce tripod lens, Van Liefferinge described two cases with the implantation of an Anis-type lens. In most of these cases, the implanted lenses were modern single-piece or 3-

piece lenses. In these cases, the unstable sulcus fixation caused mechanical irritation and trauma to the surrounding tissues and vessels. Although electron microscopy did not show any deterioration of the haptic material, the decreased size of the lens might have caused the rotation. Cases of UGH Syndrome were described even with an adequate positioning in the bag for a single block IOL with square edged haptics in specific situations, such as zonular latitude and plateau iris [11].

Presentation

UGH is a complication that can occur after post-op cataract surgery. These patients have uncomplicated cataract implants and return for episodes of blurry vision weeks to months after surgery. This may be accompanied by pain, photophobia, erythropsia, red eyes, anterior uveitis along with raised intraocular pressure. There is never a complete loss of light perception. Regarding the slit lamp examination,

Fig. 3 Images of different positions with overlays of the pupil shape and lens positions. Leitritz, Ziemssen-Tübingen, Germany, Using a slit lamp-mounted digital high-speed camera for the dynamic observation of phakic lenses during eye movements: a pilot

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the presence of microscopic hyphaema can conduct the diagnose. Occasionally, the intraocular bleed is sufficient to produce a macroscopic hyphaema, which is visible without a slit-lamp. Neovascularization of the iris or corneal edema (apposition of the prolapsed intraocular lens over the corneal endothelium) can also be included as other features. Gonioscopy can be valuable because it may disclose blood in the trabecular meshwork between attacks [12].

A careful history and examination, as well as appropriate investigations can confirm the diagnostic.

Variations of UGH syndrome include UGH Plus and IPUGH (Incomplete Posterior UGH). IPUGH is defined as bleeding into the posterior chamber with/ without glaucoma and no uveitis. UGH Plus is defined as a UGH syndrome plus a vitreous hemorrhage and occurs more frequently with anterior chamber lenses with iris support, and it is also described with posterior chamber lenses positioned in the sulcus or in the capsular bag. The loss of anterior hyaloids integrity (spontaneous, degenerative or after surgery) enables communication between the aqueous humor and the vitreous, allowing the passage of blood and giving rise to the possibility of simultaneous bleeding in both chambers. The coexistence of VH should not delay the diagnose [13].

Investigations

OCT-SD and/ or BMC-US supports the diagnose by showing the IOL position and its relationship with the surrounding ocular structures. Ultrasound biomicroscopy (UBM) is often used in the diagnosis of UGH syndrome to visualize the malpositioned IOLs, to confirm the haptics position and their contact with the uveal tissue. In addition, ocular coherence tomography (OCT) can aid in the guidance of diagnosing CME [13].

Differential Diagnosis Trauma Vascular abnormalities Rubeosis iridis Ocular ischemic syndrome Diabetes mellitus Retinal artery occlusion Retinal vein occlusion Swan Syndrome (NV wound) Juvenile Xanthogranuloma Iris Varices

Vascular tufts Hereditary hemorrhagic telangiectasia Inflammation (Iritis) Fuchs heterochromic iridocyclitis Herpes simplex Herpes zoster Iatrogenic Causes Intraocular surgery Laser trabeculoplasty

Iridotomy Neoplasm Retinoblastoma Melanoma Iris hemangiomas Systemic Disorders Sickle cell trait or disease Coagulation disorders Anticoagulation medications

Complications Pseudophakic bullous keratopathy (PBK) Corneal straining Chronic inflammation Vitreous hemorrhage Glaucomatous nerve damage Cystoid macular edema

Treatment

In patients with UGH syndrome, topical and systemic medication (Corticosteroids along with IOP lowering medication) reduce the intraocular pressure, control the anterior inflammation and bring symptomatic relief in the short term [14]. Parasympathomimetics should be avoided because of its miotic effect and increase in the

Fig. 4 Uveitis-Glaucoma-Hyphaema Syndrome, Zemba M, Camburu G, Ophthalmology Department, “Dr. Carol Davila” Central Military Emergency University Hospital, Bucharest, Romania

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mechanical chaffing to the iris. The management of patients with hyphaema should be limited activity, head elevation, and cycloplegics for ciliary spasm [15].

IOL exchange should be performed if the vision is reduced, or raised intraocular pressure and inflammation cannot be controlled or progressive glaucomatous atrophy is demonstrated.

Out of 259 surveys, the IOL Explantation indications given at ASCRS & ESCRS 2000 were the following: ACIOL & Iris fixated lenses (PBK with corneal decompensation, UGH syndrome with CME), Older PCIOL & PMMA PCIOL (Decentration, Corneal edema and inflammation), Foldable 3pc monofocal silicone PCIOL (40% incorrect lens power 32% decentration, 9% damaged IOL during insertion), Foldable 3 on acrylic PCIOL (39% incorrect lens power, 24% optical aberration, 15% decentration), Foldable plate-haptic silicone PCIOL (> 50% decentration, 22% incorrect lens power, 18% damaged IOL during insertion), Foldable 3 on multifocal silicone PCIOL (89% optical aberration, 11% others). Besides the IOL Explantation exchange, topical and systemic medication, and cyclophotocoagulation, new treatment options can be the placement of a Capsular Tension Ring to redistribute zonular tension and Anti–vascular endothelial growth factor (anti-VEGF) Therapy. Intravitreal and intracameral bevacizumab have demonstrated to induce the regression of iris neovascularization and the inflammation in uveitic macular edema. An increase in acute and sustained intraocular pressure can be a potential complication of this therapy. To avoid an immediate increase in the intraocular pressure, an anterior chamber paracentesis can be performed along with the intracameral injections. Corneal endothelium has demonstrated a good tolerance to bevacizumab for doses of up to 2.5 mg, but repeated intracameral injections may cause endothelial cell loss. In defiance of the potential side effect, serial intracameral bevacizumab could offer a temporizing or long-term option to high-risk IOL manipulation cases [16].

Conclusions

In the 1950s, rigid ACIOLs were used in cataract extractions, Bullous keratopathy, inflammation, and cystoid macular edema were very common complications. Today, PMMA, acrylate, and silicone lenses are often used and many choices exist for implantable lenses, from toric lenses to multifocal and accommodating IOLs.

In conclusion, it is important to know the severe effects, signs, and management course for UGH syndrome. UGH syndrome is a severe complication of cataract extraction and a cause for blurry vision weeks to months after surgery. The hyphaema may obscure the doctor’s view of the anterior chamber, posterior chamber, and IOL, a B-scan ultrasound being useful. Lately, the explantation of the IOL has been necessary.

Prior to the operation, all the factors that could affect the difficulty of the surgery should be noticed: zonular laxity, small pupil, medications (anticoagulants), patient’s ability to lay flat, co-existing conditions. These characteristics could become risk factors that cause the decreased vision post-op.

There are advantages and disadvantages in selecting the lens design. Single piece acrylic lenses allow the use of smaller incisions while large haptics lens do not provide the best fit in the sulcus. The 3-piece lens design will fit well in the sulcus but they require a large incision. Overall, it is important to recognize the pros/ cons of the lens designs and adapt that to the patient [17].

References

1. Foroozan R. Tabas JG, Moster ML. Recurrent microhyphaema despite intracapsular fixation of a posterior chamber intraocular lens. J Cataract Refract Surg. 2003; 29:1632-5.

2. Apple DJ, Mamlis N, Loftfield K, Googe JM, Novak LC, Kavka-van Norman D, Brady SE, Olson RJ. Complications of Intraocular Lenses. A Historical and Histopathological Review. Surv Ophthalmol. 1984; 29:1-54.

3. Lin CJ, Tan CY, Lin SY, Jou JR. Uveitis-glaucoma-hyphaema syndrome caused by posterior chamber intraocular lens—a rare complication in pediatric cataract surgery. Ann Ophthalmology. 2008; 40(3-4):183-4.

4. Dalton M, Cheung A. UGH rare, but potentially devastating complication. Ophthalmlogy Times.

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5. Hanh M, Nguyen T. Uveitis-glaucoma-hyphaema syndrome. New England Medical Center Grand Rounds, Tufts University.

6. Chan TC, Lok JK, Jhanji V, Wong VW. Intraocular lens explantation in Chinese patients: different patterns and different responses. Int Ophthalmol. 2015 Oct; 35(5):679-84. doi: 10.1007/s10792-014-9996-7.

7. Lima BR, Pichi F, Hayden BC, Lowder CY. Ultrasound biomicroscopy in chronic pseudophakic ocular inflammation associated with misplaced intraocular lens haptics. Am J Ophthalmol. 2014 Apr; 157(4):813-817.e1. doi: 10.1016/j.ajo.2013.12.025.

8. Asaria RH, Salmon JF, Skinner AR, Ferguson DJ, McDonald B. Electron microscopy findings on an intraocular lens in the uveitis, glaucoma, hyphaema syndrome. Eye. 1997; 11(Pt 6):827-9.

9. Leitritz MA, Ziemssen F, Bartz-Schmidt KU, Voykov B. Centre for Ophthalmology. University Eye Hospital. Eberhard Karls University of Tübingen, Tübingen, Germany Using a slit lamp-mounted digital high-speed camera for dynamic observation of phakic lenses during eye movements: a pilot.

10. Shweikh Y, Ameen S, Mearza A. Complications secondary to cosmetic artificial iris anterior chamber implants: a case report. BMC Ophthalmology. 2015; 15:97. doi 10.1186/s12886-015-0084-1.

11. Aonuma H, Matsushita H, Nakajima K, Watase M, Tsushima K, Watanabe I. Uveitis-Glaucoma-Hyphaema Syndrome After Posterior Chamber Intraocular Lens Implantation. Japanese Ophthalmological Society. Jpn J Ophthahnol. 1997; 41:98-100 0 1997.

12. Cates CA, Newman DK. Transient monocular visual loss due to uveitis-glaucoma-hyphaema (UGH) syndrome. J Neurol Neurosurg Psychiatry. 1998; 65:131–132.

13. Alfaro-Juárez A, Vital-Berral C, Sánchez-Vicente JL, Alfaro-Juárez A, Muñoz-Morales A. Uveitis-glaucoma-hyphaema syndrome associated with recurrent vitreous hemorrhage. Arch Soc Esp Oftalmol. 2015; 90:392-4. doi: 10.1016/j.oftale.2015.08.007.

14. Bodh SA, Kumar V, Raina UK, Ghosh B, Thakar M. Inflammatory glaucoma. Oman J Ophthalmol. 2011 Jan-Apr; 4(1):3–9.

15. Crowell EL. Uveitis-Glaucoma-Hyphaema Syndrome. http://eyewiki.aao.org.

16. Rech L, Heckler L, Damji KF. Serial intracameral bevacizumab for uveitis glaucoma hyphaema syndrome: a case report. Can J Ophthalmol. 2014; 49:e160–e162.

17. Phi K. Uveitis-Glaucoma-Hyphaema (UGH) Syndrome - A Complex Complication. Adv Ophthalmol Vis Syst. 2015; 2(2): 00036. doi: 10.15406/aovs.2015.02.00036.

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GENERAL ARTICLE

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doi:10.22336/rjo.2017.4

Is Laser Assisted Capsulotomy better than standard CCC?

Gavriș Monica, Mateescu Radu, Belicioiu Roxana, Olteanu Ioana Optisan Laser Clinic, Cluj-Napoca, Romania Correspondence to: Gavriș Maria Monica, MD, Ophthalmologist, Associated member of Optisan Laser Clinic, Optisan Laser Clinic, Cluj-Napoca, Romania, 55 General Traian Mosoiu Street, Code 400132, Cluj-Napoca, Romania, Mobile phone: +40745 654 595, +40745 239 595, E-mail: gavrismonica@yahoo.com Accepted: January 21, 2017

Abstract Objectives: To compare the safety and intraoperative difficulties of two capsulorhexis techniques for white intumescent cataract: Femtolaser-assisted capsulorhexis and manual capsulorhexis performed in 2-3 stages, with the Utrata forceps. Materials and methods: A prospective comparative study that included 28 eyes divided into 2 equal groups in which capsulorhexis was performed by using the 2 methods. In the first group, the capsulorhexis was executed by using LenSx Femtolaser. In the second group, an Utrata forceps was used to perform a manual 2-3 steps capsulorhexis as follows: a small 2-3 mm capsulorhexis was performed after the staining of the anterior capsule with Trypan Blue along with a good pressurization with viscoelastic substance. The liquefied cortex was aspirated, followed by the enlargement of the capsulorhexis. In some cases, the enlargement was made after IOL implantation. Results: In the Femtolaser group, the capsule was completely detached in 13 cases and only in one case, the capsule had a few bridges which detached easily, without endangering the capsulorhexis integrity. Its size was 4,9 mm in all cases. In the group in which capsulorhexis was performed with the Utrata forceps in 2-3 stages, this was complete, circular and relatively well centered in all cases, but the size varied between 4,5 and 5,5 mm. Conclusions: Femtosecond laser-assisted capsulorhexis was round, well centered and of a desired size of 4,9 mm. The manual capsulorhexis with the Utrata forceps depends on the surgeon’s skill and experience and requires a good local anesthesia, the coloring of the anterior capsule with Tripan Blue, using a large quantity of cohesive viscoelastic substances and sometimes using micro incision forceps for helpful maneuvers. The size and centering of the capsulorhexis are not always identical with the intended ones. Keywords: capsulorhexis, Utrata forceps, Femtosecond laser, white intumescent cataract

Introduction

Cataract surgery is one of the safest and most efficient surgical interventions, but it is extremely dependent on the surgeon’s

experience, especially in challenging cases as intumescent cataract, subluxated lens cataract, hypermature cataract, cataract in the myopic or vitrectomized eye, etc.

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Capsulorhexis is considered the most important step in cataract surgery and offers the lens bag more resistance during hydrodissection, phacoemulsification, and cortex aspiration, reducing the risk of capsular tears and improving the postoperative stability of the IOL. Capsulorhexis was first described in 1987 by Gimbel and Neuhann, as a circular, centered, curvilinear opening in the anterior capsule. These aspects help in maintaining a good positioning of the IOL in the capsular bag while decreasing the incidence of radial tears at the same time [1].

In a study by Gavris et al. in 2003, on 70 eyes with intumescent cataract, capsulorhexis skidding frequency was 11.43%, and in one case, 1.43% respectively, the posterior capsule rupture occurred [2].

These unfavorable results determined us to improve our method, by performing a 2-3 stages capsulorhexis as described by Gimbel et al. [3], or by implementing a new technological solution like Femtolaser-capsulotomy. Once Lasers were introduced in cataract surgery, a well-controlled and reproducible capsulorhexis was obtained, by laser-tissue interaction called photodisruption. In 2008, Zoltan Nagy performed the first laser capsulotomy during the first femtosecond laser-assisted cataract surgery [4].

Objectives of the study

The objectives were to compare the safety and intraoperative difficulties of two capsulorhexis techniques for white intumescent cataract: the capsulorhexis performed with the LensEx femtosecond laser and the capsulorhexis performed in 2-3 stages with Utrata forceps.

Materials and method

This is a prospective and comparative clinical study, which included a total of 28 patients (28 eyes) with white intumescent cataract.

The patients were operated on by the same surgeon at Optisan Laser Clinic, Cluj-Napoca, between July and December 2016. Patients were divided into 2 equal groups.

The first group was made up of 6 women and 8 men, aged between 20 and 73 years old,

with an average age of 56,64 years and the second group was made up of 5 men and 9 women, aged between 57 and 78 years old, with an average age of 68,14 years.

A 4,9 mm Femtolaser capsulotomy was performed in the first group by using the LenSx laser, and in the second group, a 2-3 steps manual capsulorhexis was performed by using the Utrata forceps.

Surgery was performed under local anesthesia (Oxibuprocaine 0,4%) and pupil dilation was obtained with Tropicamide 1% and Neosynephrine 10%, one drop every 15 minutes, 60-90 minutes preoperatively.

For the first group, the first step was the Laser procedure and included:

Surgical steps programming (4,9 mm capsulorhexis and 2,2 mm incision) (Fig. 1).

- Performing the docking (Fig. 2).

- Centering the treatment plan and starting the Laser (Fig. 3).

Fig. 1 Surgical steps programming

Fig. 2 Performing the docking

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The docking is the most important step in Femtolaser assisted cataract surgery and it determines the safety and accuracy of the entire procedure. Once it is properly done and the position of the eye is checked on the screen, suction is applied by simply pressing a button.

In the second group, the capsulorhexis was performed in 2-3 stages by using the Utrata forceps, after the staining of the anterior capsule with Tripan Blue under an air bubble. Thus, after a good anterior capsule pressurization with viscoelastic substance, a 2-3 m small, centered, round capsulorhexis was performed (Fig. 4) and the liquefied cortex was aspirated, obtaining the decompression of the capsular bag. In some cases, the capsulorhexis widening was performed as the next step (Fig. 5) and in other cases, the widening was made after IOL implantation.

In the next stage, the same surgeon performed the phacoemulsification of the nucleus in both groups, by using the Centurion vision system, in the same operating room.

Pre- and postoperative patient evaluation was complex and included the determination of the visual acuity, measurement of the IOP, slit-lamp examination of the anterior segment, B-scan, ultrasound biometry, and endothelial cell counting. All the cases were evaluated the second day, at 1 week and at 6 months postoperatively.

No intra- or postoperative complications occurred. Postoperative topical therapy included topical antibiotics and steroidal anti-inflammatory drops for 6 weeks.

Results

Preoperatively, there were no differences in the number of cases and disease staging in these 2 groups. Only the mean age was smaller in the group in which Femtosecond-capsulorhexis was performed (56,64 vs. 68,14).

Obtaining a curvilinear, continuous, intact capsulorhexis at the end of the surgery was considered a surgical success.

Out of 28 operated eyes, a Femtosecond capsulorhexis was performed on 14 eyes, and a 2-3 stages Utrata forceps capsulorhexis was performed on the other 14.

In the group in which the capsulorhexis was performed with the LenSx Laser, the capsule was completely detached in 13 cases (92,86%)

Fig. 3 Centering the treatment plan and starting the Laser

Fig. 4 Creation a 2-3 m small, centered, round capsulorhexis

Fig. 5 Widening of the capsulorhexis

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(free-floating capsulotomy) and only in one case (7,14%), the capsule had a few bridges which detached easily, without endangering the capsulorhexis integrity. Its size was 4,9 mm in all cases (Fig. 6).

In the group in which capsulorhexis was performed with the Utrata forceps in 2-3 stages, this was complete, circular and relatively well centered in all cases, but the size varied between 4,5 and 5,5 mm. Several maneuvers for capsular bag decompression were made to insure the optimal size of the rhexis, and a lot of cohesive viscoelastic substance was used.

Discussions

Peer-review studies have already demonstrated that the Femtolaser capsulotomy is better centered and more precise compared to manual capsulorhexis. A 360-degree overlapping capsular edge was thought to be an important feature for standardizing refractive results, preventing the optic decentration, shifts toward myopia or hyperopia, tilt or capsular opacification due to symmetric contractile forces of the capsular bag [5].

While performing the 1-stage capsulorhexis in white intumescent cataracts, the surgeon perceives the high intracapsular pressure and the leakage of the liquefied cortex, which can lead to discontinuities or tearing of the anterior or posterior capsule and difficulties in centering the capsulorhexis.

Newton Kara-Junior et al. compared the results of the 1-stage versus the 2-stage capsulorhexis in intumescent white cataracts and found anterior capsule tears in 23,07% of the cases in which the 1-stage capsulorhexis was performed (11 cases) and no ruptures of the anterior capsule were evidenced in which capsulorhexis was done in 2 stages (13 cases) [6].

In 1991, Gimbel analyzed 2967 cataract cases, out of which 34 were intumescent white cataracts and performed a 2-stages capsulorhexis in these cases. He found that in 4 out of the 34 cases, the anterior capsule tore [7].

The very good results we obtained by performing Femtosecond laser-capsulorhexis, as well as by a 2-3 stages capsulorhexis are owed to the surgeon’s experience and her concern in perfecting the capsulorhexis technique in intumescent white cataract, using the proper microsurgery instruments, and implementing new technological solutions [8].

Conclusions

The achieved results confirmed the safety and efficacy of both techniques in performing the capsulorhexis in intumescent white cataracts.

The manual capsulorhexis with the Utrata forceps depends on the surgeon’s skill and experience and requires good local anesthesia, coloring of the anterior capsule with Trypan Blue, using a large quantity of cohesive viscoelastic substances, and sometimes using micro incision forceps for helpful maneuvers. Nevertheless, the size and centering of the capsulorhexis are not always identical with the intended ones.

Femtosecond laser-assisted capsulorhexis was round, well centered and of the desired size, 4,9 mm respectively.

The perfection of the Femtosecond laser-assisted capsulorhexis, along with the surgeon’s increased comfort, make this type of capsulorhexis a superior option or the technique of choice in intumescent white cataract cases, in which the risk of capsulorhexis skidding is greater than in other types of cataract.

Fig. 6 Capsule with a size of 4,9 mm

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References 1. Neuhann T. Theory and surgical technic of

capsulorhexis. Klin Monbl Augenheilkd. 1987 Jun; 190(6):542-5.

2. Gavris M, Popa D, Caraus C, Gusho E, Kantor E. Facoemulsificarea in cataracta alba, intumescenta. Oftalmologia. 2004; 48(2),81-87.

3. Gimbel HV, Willerscheidt AB. What to do with limited view: the intumescent cataract. J Cataract Refract Surg. 1993 Sep; 19(5):657-61.

4. Cimberle M. Femtosecond laser assisted surgery could revolutionize cataract removal in europe. March 2012. http://www.healio.com/ophthalmology/cataract-surgery/news/print/ocular-surgery-news-europe-edition/%7B8c96c397-a54f-4766-9bab-aec7612bbac4%7D/femtosecond-laser-assisted-surgery-could-revolutionize-cataract-removal-in-europe.

5. Nagy ZZ, Kranitz K, Takacs A, Mihaltz K, Kovacs I, Knorz MC. Comparison of intraocular lens decentration parameters after femtosecond and manual capsulotomies. J Refract Surg. 2011 Aug; 27(8):564-9.

6. Kara-Junior N, de Santhiago MR, Kawakami A, Carricondo P, Hida WT. Mini-rhexis for white intumescent cataracts. Clinics. 2009; 64(4):309-12.

7. Gimbel HV, Willerscheidt AB. What to do with limited view: the intumescent cataract. J Cataract Refract Surg. 1993 Sep; 19(5):657-61.

8. Gavris MM, Belicioiu R, Olteanu I, Horge I. The advantages of Femtosecond Laser-Assisted Cataract Surgery. Rom J Ophthalmol. 2015 Jan-Mar; 59(1):38-42.

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GENERAL ARTICLE

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Romanian Society of Ophthalmology © 2017 doi:10.22336/rjo.2017.5

One year refractive outcomes of Femtosecond-LASIK in mild, moderate and high myopia

Tabacaru Bogdana* **, Stanca Horia Tudor* ** *** *”Prof. Dr. Agrippa Ionescu” Emergency Hospital, Bucharest, Romania **“Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania ***”Metropolitan” Hospital, Bucharest, Romania Correspondence to: Bogdana Tabacaru, MD, Department of Ophthalmology, “Prof. Dr. Agrippa Ionescu” Emergency Hospital, Bucharest, 7 Ion Mincu Street, Code 011356, Bucharest, Romania, Mobile phone: +40741 111 238, E-mail: bogdana_gt@yahoo.com Accepted: January 14, 2017

Abstract Purpose: To evaluate the safety, efficacy, predictability and stability for a cohort of myopic eyes treated by Femtosecond-LASIK procedure. Methods: 60 eyes (36 patients) with different degrees of myopia that underwent refractive surgery by using the Femtosecond-LASIK technique were prospectively evaluated for 12 months. The mean preoperative spherical equivalent value was –3.827 ± 1.410 diopters (D) (range: –8.125 to –1.375 D). VisuMax femtosecond laser was used for cutting the corneal flap and then the Mel80 excimer laser for the stromal ablation. Results: Mean age was 30.80 ± 5.745 years (range: 21 to 46 years) with 75% female patients. Postoperative spherical equivalent at 12 months was within ±0.25 D of emmetropia in 90% of the eyes and within ±0.50 D of emmetropia in 100% of the eyes. All the eyes achieved an uncorrected distance visual acuity (UDVA) of 1.0 (decimal scale). No eye lost lines of preoperative corrected distance visual acuity (CDVA). No major intraoperative or postoperative complications were encountered. Conclusions: Femtosecond-LASIK seems to be a suitable option for the correction of mild, moderate, and high myopia, as the procedure showed to be safe, effective, and predictable for the treatment of myopic refractive errors. Keywords: Femtosecond-LASIK, FemtoLASIK, Refractive Surgery, Myopia

Introduction

Femtosecond Laser-Assisted In Situ Keratomileusis (FemtoLASIK) is a modern method for the correction of refractive errors, being introduced in our country for the first time in September 2011. The procedure requires two lasers, a femtosecond laser (wavelength in infrared light at 1043 nm [1]) for flap creation and an excimer laser (wavelength in ultraviolet light at 193 nm [2]) for refractive ablation.

The purpose of our study was to evaluate the safety, efficacy, predictability, and stability for a cohort of myopic eyes treated by FemtoLASIK procedure.

Patients and Methods

66 eyes (40 patients) were treated for mild, moderate, and high myopia by FemtoLASIK technique. All the surgeries were performed between September 1, 2011 and October 31,

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2015. After being informed about the benefits and risks of the procedure, all the patients signed an informed consent.

Inclusion criteria for surgery were the patients’ wish of not wearing glasses for nearsightedness, age of 20 years or over, good general health, stable refraction for at least two years before surgery, no previous ocular trauma or ocular surgery, no ocular diseases. Exclusion criteria for surgery were estimated residual thickness of the stromal bed of less than 300 µm after the treatment, evidence, or suspect of keratoconus, severe dry eye syndrome, pregnancy, lactation, general diseases, and poor compliance. When the fundus examination revealed at-risk peripheral lesions, FemtoLASIK surgery was delayed until photocoagulation treatment was performed.

Patients had to discontinue contact lens wearing for two weeks prior to all the corneal investigations and then again, for two weeks before the surgery.

The preoperative ocular examination included uncorrected (UDVA) and corrected distance visual acuity (CDVA), manifest and cycloplegic refraction, keratometry, anterior segment slit-lamp biomicroscopy and mydriatic fundoscopy, noncontact tonometry, corneal pachymetry, corneal topography and white-to-white (WTW) corneal diameter.

The surgical attempted result was emmetropia in all cases. The Femtosecond laser (VisuMax, Carl Zeiss Meditec, Germany) treatment was done first. The corneal flap thickness varied between 100 to 120 µm and the hinge was located superiorly. After the flap dissection, an excimer laser (MEL 80, Carl Zeiss Meditec, Germany) treatment was performed. The mean ablation depth was 57.27 ± 23.032 µm (range: 21 to 130 µm). After laser ablation, a plano soft contact lens was applied.

The flap position was checked at the slit-lamp 30 minutes after the surgery in all patients.

The first appointment was in the first day postoperative when the bandage contact lens was removed. Next follow-up visits were at one month, three months, six months, and one year. UDVA and CDVA, manifest refraction and

noncontact tonometry were measured and slit-lamp examination was performed at each visit. Topographies were performed at one month, six months, and one year.

Twelve patients who underwent FemtoLASIK for mild, moderate, and high myopia in one eye were also treated in the fellow eye but for compound myopic astigmatism.

Patient data were stored into an Excel database (version 14.0, Microsoft Corp.). Statistical analysis was performed by using SPSS statistical software (version 20, IBM SPSS Statistics, IBM Corp.).

After testing the normality of continuous variables distributions with the Shapiro-Wilk test, statistical analysis evaluated the postoperative outcomes based on the Paired-Samples T-Test or the Wilcoxon Signed-Rank Test.

The statistically significance level was fixed at P-value ≤ 0.05.

Results

As three patients who were treated in both eyes were lost to follow-up after the first month postoperative visit, our study included 60 eyes (31 right eyes and 29 left eyes) from 36 patients (27 females and 9 males). The mean age of included patients was 30.80 ± 5.745 years (range: 21 to 46 years).

Visual acuity Preoperative CDVA was 1.0 (decimal scale)

in all eyes. At the one year postoperative visit, the

UDVA of 1.0 (decimal scale), equivalent to the preoperative CDVA, was obtained in all eyes. The efficacy index [3,4] (postoperative UDVA/ preoperative CDVA) was 1. The safety index [3,4] (postoperative CDVA/ preoperative CDVA) was also 1. No eye lost lines of preoperative CDVA.

Refraction The preoperative manifest and cycloplegic

refraction data are presented in Table 1.

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Table 1. Preoperative manifest and cycloplegic refraction data of the 60 myopic eyes before FemtoLASIK surgery

Manifest sphere (D) –3.629 ± 1.397 (range: –7.75 to –1.00)

Manifest cylinder (D) –0.395 ± 0.212 (range: –1.00 to 0)

Manifest spherical equivalent (D)

–3.827 ± 1.410 (range: –8.125 to –1.375)

Cycloplegic sphere (D) –3.254 ± 1.448 (range: –7.50 to –1.00)

Cycloplegic cylinder (D) –0.362 ± 0.192 (range: –0.75 to 0)

Cycloplegic spherical equivalent (D)

–3.435 ± 1.452 (range: –7.875 to –1.125)

*D=diopters; As the cylinder value was low and the

spectacle corrections for CDVA and laser treatment were performed only with spherical diopters, our statistical analysis was focused on the manifest spherical equivalent.

Comparing the preoperative manifest and the cycloplegic mean spherical equivalent refraction data, we concluded that there was a statistically significant difference from –3.827 ± 1.410 D to –3.435 ± 1.452 D (P<0.0005) according to the paired samples t-test, the hyperopic shift being 0.391 ± 0.468 D. In order to determine the relationship between the preoperative manifest and the cycloplegic mean spherical equivalent refraction, we performed a Pearson product-moment correlation and we found a positive correlation which was statistically significant (r=0.947, P<0.0005). The

refractive data for laser ablation were set according to the manifest refraction, cycloplegic refraction, and spectacle correction for CDVA.

The refractive outcomes data reported below are in accordance with the Standard Reporting in Refractive Surgery [3,4].

Fig. 1 shows the evolution of manifest refraction (spherical equivalent) after the surgery and its stability in time.

The mean preoperative manifest spherical

equivalent significantly decreased in the first postoperative day. Comparing refractive parameters as pairs of successive postoperative visits, we found no statistically significant difference until the 1-year follow-up, meaning that the spherical equivalent refraction remained stable (Table 2).

Table 2. Mean values ± SD of the manifest spherical equivalent (shown in diopters) preoperatively, and at one and 12 months after FemtoLASIK surgery, for the 60 myopic eyes of our study. P-values represent the statistical significance of the difference between two consecutive visits.

Manifest Spherical Equivalent Diopters (mean±SD) P-valuea Preoperative Postoperative 1 day Postoperative 1 month Postoperative 12 months

–3.827 ± 1.410 +0.079 ± 0.486 –0.008 ± 0.394 –0.064 ± 0.186

<0.0005b 0.247b 0.236c

aStatistical significance of the difference when compared to the previous visit bWilcoxon Signed Rank Test cPaired Samples T-Test

In order to analyze the predictability of the

refractive results, we considered the attempted spherical equivalent refraction and the achieved spherical equivalent refraction. The Sperman’s correlation coefficient showed a strong

correlation (r=0.971, P<0.0005). Fig. 2 shows the linear correlation, based on the following formula: achieved spherical equivalent refraction = 0.1214 + 1.0158 * attempted spherical equivalent refraction (r2=0.943).

Fig. 1 Stability – Mean change in manifest spherical equivalent during one year after FemtoLASIK surgery for the 60 myopic eyes of our study

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The accuracy of postoperative 1-year spherical equivalent refractions compared to the intended preoperative spherical equivalent refractions is shown in Fig. 3. Postoperative spherical equivalent values 12 months after surgery were within ±0.25 D and ±0.5 D of emmetropia in 90% and 100% of the eyes, respectively.

Corneal Thickness The preoperative corneal thickness was

547 ± 25.295 µm (range: 499–619 µm). It

significantly decreased to 488.90 ± 28.208 µm (range: 415–554 µm) at one month postoperatively (P<0.0005, paired samples t-test) and afterwards did not significantly change at 12 months postoperatively (P=0.451, paired samples t-test).

Complications Neither intraoperative events nor major

postoperative complications such as flap dislocation, epithelial ingrowth, diffuse lamellar keratitis or flap melting, were encountered. After 12 months of follow-up, none of the eyes developed keratectasia.

The aim of our study was to report the refractive outcomes after laser surgery; therefore, the adverse events as haze, night visual disturbances, reduced corneal sensitivity, reduced contrast sensitivity, or dry eye syndrome were not analyzed.

Clinical Case

We presented the case of a 27-year-old female (V.I.C.), with a CDVA of 1.0 (-5.75 Dsf) in both eyes. Cycloplegic refraction for the right eye was -5.75 Dsf ^ -0.50 Dcyl x 174o and for the left eye it was -5.75 Dsf ^ -0.50 Dcyl x 10o. Keratometry for the right eye was: K flat 44.21 D x 176o and K steep 45.03 x 86o and for the left eye it was: K flat 44.50 D x 2o and K steep 44.90 x 92o. Pachymetry for the right eye was 552 µm and for the left eye, it was 547 µm. We have chosen a flap thickness of 110 µm for both eyes and an optical zone for excimer ablation of 6.5 for both eyes. The estimated residual stromal bed was 348 µm for the right eye and 343 µm for the left eye. We further presented the preoperative corneal thickness and tangential anterior maps for the right eye (Fig. 4) and for the left eye (Fig. 5).

Fig. 2 Predictability – Attempted versus achieved graph at 12 months after the FemtoLASIK surgery, for the 60 myopic eyes of our study

Fig. 3 Accuracy – Spherical Equivalent Refraction to the Intended Target (D) at 12 months after the FemtoLASIK surgery, for the 60 myopic eyes of our study

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Table 3 (for the right eye) and Table 4 (for the left eye) present the postoperative results, for all postoperative visits: visual acuities,

manifest refraction, keratometry and pachymetry (when measured).

Table 3. Postoperative data for the right eye of the patient V.I.C.

Postoperative visits

Uncorrected visual acuity

Manifest refraction K flat K steep Pachymetry

1 day 1.0 +0.25^-1.00 x 164o 40.00 x 170o 40.75 x 80o - 1 month 1.0 +0.25^-0.75 x 166o 40.25 x 170o 41.00 x 80o 477 µm 3 months 1.0 +0.25^-0.50 x 171o 40.25 x 173o 40.75 x 83o - 6 months 1.0 +0.25^-0.75 x 165o 40.25 x 167o 41.00 x 77o 478 µm 12 months 1.0 +0.25^-0.50 x 170o 40.25 x 170o 41.00 x 80o 474 µm

Fig. 4 Preoperative corneal thickness map (left) and tangential anterior map (right) for the right eye of the patient V.I.C.

Fig. 5 Preoperative corneal thickness map (left) and tangential anterior map (right) for the left eye of the patient V.I.C.

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Table 4. Postoperative data for the left eye of the patient V.I.C. Postoperative

visits Uncorrected visual acuity

Manifest refraction K flat K steep Pachymetry

1 day 1.0 +0.75^-0.25 x 1o 39.50 x 4o 40.00 x 94o - 1 month 1.0 +0.75^-0.75 x 7o 39.50 x 5o 40.75 x 95o 455 µm 3 months 1.0 +0.25^-0.50 x 0o 40.00 x 5o 40.75 x 95o - 6 months 1.0 +0.00^-0.25 x 5o 40.25 x 8o 40.75 x 98o 460 µm 12 months 1.0 +0.25^-0.50 x 7o 40.00 x 6o 40.75 x 96o 457 µm

Postoperative corneal thickness and

tangential anterior maps for the right eye (Fig. 6) and for the left eye (Fig. 7) showed a good ablation profile. Twelve months after laser

surgery, there was no sign of corneal ectasia in both eyes, neither on the anterior elevation map nor on the posterior elevation map (Fig. 8,9).

Fig. 6 Twelve months postoperative corneal thickness map (left) and tangential anterior map (right) for the right eye of the patient V.I.C.

Fig. 7 Twelve months postoperative corneal thickness map (left) and tangential anterior map (right) for the left eye of the patient V.I.C.

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The differential anterior elevation map between the postoperative visit at 1 month and the postoperative visit at 12 months are presented in Fig. 10 (right eye) and Fig. 11 (left

eye), which best show no change in the corneal shape (no risk of anterior corneal ectasia) during one year follow-up.

Fig. 8 Twelve months postoperative anterior elevation map (left) and posterior elevation map (right) for the right eye of the patient V.I.C.

Fig. 9 Twelve months postoperative anterior elevation map (left) and posterior elevation map (right) for the left eye of the patient V.I.C.

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Fig. 10 Up-left: Anterior elevation map for the right eye of the patient V.I.C. at 1-month postoperative visit. Up right: Anterior elevation map for the right eye of the patient V.I.C. at 12 months postoperative visit. Bottom: Differential anterior elevation map between postoperative 1 month and postoperative 12 months for the right eye of the patient V.I.C.

Fig. 11 Up-left: Anterior elevation map for the left eye of the patient V.I.C. at 1-month postoperative visit. Up right: Anterior elevation map for the left eye of the patient V.I.C. at 12 months postoperative visit. Bottom: Differential anterior elevation map between postoperative 1 month and postoperative 12 months for the left eye of the patient V.I.C.

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Discussion

Compared to the other nowadays techniques of correcting myopic refractive errors, Femtosecond-LASIK was comparable with Small Incision Lenticule Extraction (SMILE) [5-7] and Transepithelial Photorefractive Keratectomy (Transepithelial-PRK) [8] in terms of safety, efficacy and predictability. After Femto-LASIK, the corneal sensitivity was lower and the dry eye syndrome was more frequent than after SMILE [5] but compared to Transepithelial-PRK had a shorter recovery time [8].

Referring to the flap cutting, either the Femtosecond laser (in Femto-LASIK procedure) or the mechanical microkeratome (in LASIK procedure) demonstrated to be safe and effective in correcting myopia, with stable results and no significant difference in postoperative UCVA and CDVA [9]. However, the femtosecond laser may have advantages over the microkeratome in better flap thickness predictability, fewer induced high order aberrations, and longer tear break-up time [9].

To the best of our knowledge, in our country, this is the first study on Femtosecond-LASIK refractive results for myopia correction.

We achieved maximum UDVA and manifest refraction close to emmetropia at all postoperative visits with no major intraoperative or postoperative complication for all the treated eyes in our study cohort.

Our study’s weaknesses included the small number of study eyes and the short period of follow-up. According to J.Alió et al., myopic regression is possible up to 5 years of follow-up and it is correlated with the achieved correction [10]. Further reports will be salutary after following-up the patients for a longer period of time.

In conclusion, Femtosecond-LASIK seems to be a suitable option to correct mild, moderate, and high myopia, as the procedure showed to be safe, effective, and predictable for the treatment of myopic refractive errors.

Financial Disclosure

None of the authors has any financial or proprietary interests to disclose.

References

1. VisuMax Brochure, Carl Zeiss Meditec AG, Germany, www.meditec.zeiss.com/VisuMax.

2. Mel80 Brochure, Carl Zeiss Meditec AG, Germany, www.meditec.zeiss.com/MEL80.

3. Koch DD, Kohnen T, Obstbaum SA, Rosen ES. Format for Reporting Refractive Surgical Data. J Cataract Refract Surg. 1998; 24(3):285-287.

4. Waring GO. Standard Graphs for Reporting Refractive Surgery. J Refract Surg. 2000; 16(4):459-466. Erratum in: J Refract Surg. 2001 May-Jun; 17(3):following table of contents.

5. Zhang Y, Shen Q, Jia Y et al. Clinical Outcomes of SMILE and FS-LASIK Used to Treat Myopia: A Meta-analysis. J Cataract Refract Surg. 2016; 32(4):256-265.

6. Shen Z, Shi K, Yu Y et al. Small Incision Lenticule Extraction (SMILE) versus Femtosecond Laser-Assisted In Situ Keratomileusis (FS-LASIK) for Myopia: A Systematic Review and Meta-Analysis. PLoS One. 2016; 11(7):e0158176.

7. Liu M, Chen Y, Wang D et al. Clinical Outcomes After SMILE and Femtosecond Laser-Assisted LASIK for Myopia and Myopic Astigmatism: A Prospective Randomized Comparative Study. Cornea. 2016; 35(2):210-216.

8. Luger MH, Ewering T, Arba-Mosquera S. Myopia correction with transepithelial photorefractive keratectomy versus femtosecond-assisted laser in situ keratomileusis: One-year case-matched analysis. J Cataract Refract Surg. 2016; 42(11):1579-1587.

9. Xia LK, Yu J, Chai GR et al. Comparison of the femtosecond laser and mechanical microkeratome for flap cutting in LASIK. Int J Ophthalmol. 2015; 8(4):784-790.

10. Alió JL, Muftuoglu O, Ortiz D et al. Ten-year Follow-up of Laser In Situ Keratomileusis for High Myopia. Am J Ophthalmol. 2008; 145(1):55-64.

Romanian Journal of Ophthalmology, Volume 61, Issue 1, January-March 2017. pp:32-38

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doi:10.22336/rjo.2017.6

Topical administration of Metamizole and its implications on vascular reactivity in Wistar

rats- Experimental research

Coman Ioana-Cristina*, Paunescu Horia*, Stamate Alina Cristina*, Cherecheanu Alina Popa**, Ghita Isabel*, Barac Cosmina**, Vasile Danut***, Tudosescu Ruxandra**, Fulga Ion* *Pharmacology and Pharmacotherapy Department, ”Carol Davila” University of Medicine and Pharmacy, Faculty of Medicine, Bucharest, Romania **Ophthalmology Department, Emergency University Hospital, Bucharest, Romania ***Surgery Department, Emergency University Hospital, Bucharest, Romania Correspondence to: Ioana-Cristina Coman, MD, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania, 129 Calea 13 Septembrie Street, bl. T3A, ap. 6, District 5, Bucharest, Romania, Mobile phone: +40724 282 715, E-mail: cristinaioanacoman@gmail.com

Accepted: February 21, 2017

Abstract Aim: The aim of this paper was to describe the possible implications of topical (ocular) administration of Metamizole on vascular reactivity of the iris in Wistar rats. No other study regarding its topical use was found. Methods: Male adult Wistar rats were anaesthetized with Ketamine 100 mg /kg body weight - injected intraperitoneally - while maintaining spontaneous respiration and the blink reflex. After selecting the area of interest (long posterior ciliary artery – LPCA), manual adjustments of the image magnitude, clarity, and brightness were made, and the experiment began. The image recording lasted 10 minutes. Results: Metamizole induced a slight vasoconstriction that started with the initial moment for all the doses used. After the topical administration of Metamizole, we did not observe an increase of the vascular diameter of LPCA in a dose dependent manner. The saline solution used as a negative control did not modify the vessel diameter. Conclusions: Metamizole (dipyrone) is a non-opioid drug, which is commonly used in human and veterinary medicine. It is the most popular first-line analgesic in various populations. In some cases, this agent is still incorrectly classified as a non-steroidal anti-inflammatory drug. The high analgesic efficacy of metamizole, as well as its spasmolytic effect, makes it a very important pharmaceutical agent that could be used in the therapy of various eye disorders in humans and in animals. Keywords: Metamizole, vascular reactivity, iris, long posterior ciliary artery Abbreviations: COX = Cyclooxygenase; LPCA = Long Posterior Ciliary Artery; PRP = panretinal photocoagulation; PDR = proliferative diabetic retinopathy; Sec = second(s); VSPR = very severe non proliferative diabetic retinopathy

Introduction

Metamizole is a pro-drug, which spontaneously breaks down to structurally

related pyrazolone compounds after oral administration. Besides its analgesic effect, Metamizole is an antipyretic and spasmolytic agent. The mechanism responsible for the

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analgesic effect is complex and most probably based on the inhibition of a central cyclooxygenase-3 and the activation of the opioid system and the cannabinoid system. The mechanism responsible for the spasmolytic effect of metamizole is associated with the inhibited release of intracellular Ca2+ as a result of the reduced synthesis of inositol phosphate [1]. All the studies in the ophthalmological field focused on its effectiveness in reducing pain after laser procedures (panretinal photocoagulation- PRP) [2,3]. For example, it has been described that the use of 1000 mg of metamizole 40 min before PRP significantly reduces the pain associated with proliferative diabetic retinopathy (PDR) and very severe non proliferative diabetic retinopathy (VSPR) [2].

The aim of this paper was to describe the effects of Metamizole on iris vascular bed after the topical (ocular) administration in Wistar rats. It is important to mention that Metamizole (dipyrone) is commonly used in human and veterinary medicine; no other study regarding its local/ topical use was found.

Materials & Methods

Adult male Wistar rats, weighing 250 g to 350 g, were used for the experiments and were brought in the laboratory facilities with a minimum of three days before the experiments began, being kept on a standard diet, with water and food supply ad libitum. All the experiments were performed during daytime (9:00 AM to 6 PM), and conducted in a noise-attenuated environment. All the animal procedures were carried out with the approval of the Local Ethics Committee of “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania, in accordance with the European Community Council Directive 86/609/EEC on the protection of animals used for scientific purposes.

The substances used were: Ketamine 5% (Calypsol 50mg/ml produced by Gedeon Richter PLC HU), Pancuronium Bromide Hospira (GB), Metamizole sodium monohydrate (Algocalmin solution 1g/ 2ml produced by Zentiva) and sodium chloride 0.5%. All rats were anaesthetized with Ketamine 5% -100 mg/ kg body weight - injected intraperitoneally - while maintaining spontaneous respiration and the

blink reflex; after five minutes, Pancuronium Bromidum 0.02%, 0.1 mL/ 100 g body weight –injected intraperitoneally - was used to induce myorelaxation. Data recording was started after 10 minutes. After selecting the area of interest (long posterior ciliary artery – LPCA), manual adjustments of the image magnitude (maximum 400 X), clarity, and brightness were made, and the experiment began. The image recording lasted 10 minutes; two instillations at 30 and 330 seconds were used. The test solutions were applied topically without touching the ocular surface. The temperature of substances instilled was 37°C. The first drug was saline (sodium chloride 0.5%), the second one was the active substance (Metamizole 2.5%, 5%, 10% and equimolar doses of Metamizole 3.33%, 6.66%, 13.33%). Each subject served as his own control. The experiment design was parallel. The number of rats per group was 6, testing only the right eye (see Fig. 1).

The image acquisition system was composed of a CCD camera (Toshiba IK–642E) and an AD converter interface (Pinnacle microVideo DC10+) connected to an ASUS PC compatible system. The camera was fitted with a magnifying objective (Nikon) aided by an adapter (Navitar 1X Adapter 1–6015), allowing for resolutions within the optical microscopy range. Cold light was provided by a circular (ring-type fiber optics) source (Dolan–Jenner Industries Inc. model FiberLite series 180). The camera was mounted on a holder (produced by IOR, Romania) allowing it to focus on the eye of the animal. The maximum optical resolution attained by the system was 12400 dpi (a pixel representing around 2×2 micrometers). After immobilizing the animal, the optical system was adjusted manually until the image on the screen was adequately rich in blood vessels and its clarity was optimal. For maximum accuracy, the lighting conditions and the adjustment of the optical system were kept constant during the recording. To avoid the possible capture of image errors, the image adjustment, and acquisition was made for a single iris vascular area for each animal.

The image analysis was carried out by using VirtualDub and Adobe PhotoShop CS6 (see Fig. 1 and 2) and by measuring the variations of the vessels diameters before and after topic administration, at fixed time intervals: 0(T0i),

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30(T1i), 120(T2i), 210(T3i), 300(T0), 330(T1), 420(T2), 510(T3), 600(T4) seconds (so nine different measurements were made for each eye). The first value of vessels diameter, at 0 seconds (D0i) was considered as control value for each eye registration. Five diameters (mm) were measured at equidistant intervals of 10 pixels and the average value and standard deviation value were calculated for each of the 5 vascular diameters. Microsoft Excel was used for statistical processing of data. The comparison was made solely at the same target area according to the initial conditions at 0s and 300s (e.g. T1i vs T1, T2i vs T2, T3i vs T3, T4i vs T4.) Thereby, the relative variations of the vascular diameter were calculated.

Actual values (Da) were analyzed in relation with the initial value (D0i) by the following formulas:

Vrel = (Da-Di0)/ Di0*100 For all the 6 rats, the Vrel. values and the

mean standard error were analyzed by using the T-test.

Results

The results were presented in Fig. 1-4. The saline solution used as a negative

control did not modify the vessel diameter. We could not recognize a pattern of vasodilation or vasoconstriction during the first 5 minutes of our recordings.

a

b

a

Fig. 1 The aspect of LPCA diameter before and after topic administration of Metamizole 5%; a-Vascular diameter at T0i (0 sec); b- Vascular diameter at T4 (600 sec); we could observe a visible vasoconstriction between the initial and the final moment

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b

Fig. 2 The aspect of LPCA diameter before and after topic administration of Metamizole 6.66%; a- Vascular diameter at T0i (0 sec); b- Vascular diameter at T4 (600 sec)

Fig. 3 Relative variation (based on T0i value) of the vascular diameter of LPCA when using Metamizole 2.5%, 5% and 10%. Each value represents the percent of variation of vascular diameter at 30s (T1i), 120s (T2i), 210s (T3i), 300s (t4i), 330s (T1), 420s (T2), 510 s (T3), 600s (T4) and standard error

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As it was seen in Fig. 3 and 4, Metamizole induced a slight vasoconstriction that started with the initial moment for all doses used; a significant vasoconstriction was obtained only for the medium doses used (5% and 6.66%) and only for the final moment (T4). A statistical significance for Metamizole 5% was obtained at the final moment (T4) (p=0.04) and for Metamizole 6.66% at T4 (p=0.02); also, for Metamizole 10% a tendency towards vasoconstriction at T2 (420 sec) was observed, the values being at the limit of the statistical significance (p=0.053).

Discussion

This particular experimental model was chosen to observe the local effects of the topical administration of Metamizole on vascular reactivity. The reason for this choice was the diversity of effects Metamizole provides and the lack of similar studies from literature. Also, its systemic reactions are partially known, but there is no research made on its local effects associated with topical administration. Metamizole is a relatively safe pharmaceutical preparation although it is not completely free from undesirable effects. Among these side effects, the most serious one that raises most

controversy is the myelotoxic effect. It seems that in the past, the risk of metamizole-induced agranulocytosis was exaggerated. Despite the evidence showing no risk of teratogenic and embryotoxic effects, the drug must not be administered in pregnant women, although it can be given to pregnant and lactating animals. The mechanism of action of Metamizole, especially the one responsible for the analgesic effect, is complex [1,4]. Although for years it has been claimed to be part of non-steroidal anti-inflammatory drugs (NSAIDs), apart from its analgesic effect, the medication has antipyretic and spasmolytic effects as well. The drug produces only a very weak anti-inflammatory effect, which is most probably the consequence of its weak inhibition on cyclooxygenase1 (COX-1) and 2 (COX-2) [5].

The mechanism responsible for the analgesic effect of Metamizole most probably rests on the inhibition of a central cyclooxygenase-3 and activation of the opioidergic system and cannabinoid system; the mechanism responsible for the spasmolytic effect is associated with the inhibited release of intracellular Ca2+ as a result of the reduced synthesis of inositol phosphate [1,6].

The topical administration of drugs is the most preferred route for the management of

Fig. 4 Relative variation (based on T0i value) of the vascular diameter of LPCA when using Metamizole 2.5%, 5% and 10%. Each value represents the percent of variation of vascular diameter at 30s (T1i), 120s (T2i), 210s (T3i), 300s (t4i), 330s (T1), 420s (T2), 510 s (T3), 600s (T4) and standard error

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eye disorders because it provides higher ocular drug concentrations, avoiding powerful systemic side effects associated with oral administration [7]. Considering that Dipyrone is detectable in the serum for only about 15 min following the intravenous administration, and it is not detectable after oral intake [5], a considerable part of its side-effects can be avoided when using topical pathway.

Our findings suggested a tendency towards the vasoconstriction on iris territory, probably via prostaglandin-induced vasoconstrictor tonus (at the level of LPCA), COX1-mediated, the latter being the main functional enzyme in the platelets which couples preferentially, with thromboxane synthase [8]. Some studies suggested that the analgesic effect of dipyrone may be partly mediated by a dual mechanism of action: the inhibition of COX enzyme activity and the stimulation of CB receptors [5,9]. Thus, further studies should focus on the neuropathic pain from Dry Eye Syndrome and the effects of topical Metamizole. Local side-effects of topical ophthalmic NSAIDs, which are often used in Dry Eye Syndrome, include transient burning, stinging, conjunctival hyperemia and corneal anesthesia [10].

According to relatively recent reports, a more severe complication involves the association of topical ophthalmic NSAIDs with indolent corneal ulceration and full-thickness corneal melting [10]. There might be many risk factors for NSAIDs-associated adverse reactions in diverse populations. Autoimmune diseases, such as and Sjögren’s syndrome, bacterial infections, rheumatoid arthritis, chronic dry eye syndrome and rosacea are common disorders associated with corneal ulcer-formation [11]. On the other hand, the side effects of NSAIDs are preferred over those of opioids, whose sedative and anesthetic effects could interfere with ocular homeostasis. That being considered, the use of topical Metamizole could exclude or diminish the numerous side effects of these two types of drugs and improve the outcome in those particular cases. For example, a comparative study that focused on the preemptive analgesia associated with the oral administration of metamizole versus ibuprofen in patients going through retinal laser photocoagulation stipulated that both medications are equivalent or equinumerous in

controlling the pain produced by photocoagulation [3]. Keeping in mind the side effects of Ibuprofen, especially the gastrointestinal adverse reactions and the short period of drug administration, we could say that the first drug of choice should be Metamizole. It is now well established that inflammation plays a pathogenic role in age-related macular degeneration, diabetic retinopathy and diabetic macular edema, but clinical data demonstrating a therapeutic effect of NSAIDs for these diseases is limited and derived mostly from small, retrospective studies [12].

Conclusions

- Metamizole induced a slight vasoconstriction (at the level of long posterior ciliary artery), probably COX1-mediated, for all doses used.

- Statistical significance of LPCA constriction was obtained only for the final moment (T4), after 5 minutes from the topical instillation and only for the Metamizole 5% and 6.66%.

- Metamizole administration did not increase the arterial diameter of LPCA in a dose dependent manner.

- The greatest concern related to the administration of metamizole is the risk of causing agranulocytosis [1], which is excluded in case of topical (ocular) administration.

- The high analgesic efficacy of metamizole, as well as its spasmolytic effect, makes it a very important pharmaceutical agent that could be used in the therapy of various eye disorders (dry eye syndrome, anterior pole inflammatory disorders, retinal vascular occlusions, or other retinal conditions) in humans and in animals.

Conflict of interests The authors declare that they have no

conflict of interests.

References 1. Jasiecka A, Maślanka T, Jaroszewski JJ.

Pharmacological Characteristics of Metamizole. Polish Journal of Veterinary Sciences. 2014; 17.1. https://doi.org/10.2478/pjvs-2014-0030.

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2. Barbosa de Araújo R, Zacharias LC, Marques de Azevedo B, Schmidt Giusti B, Pretti RC, Walter Y. Takahashi and Mário Luiz Ribeiro Monteiro. Metamizole versus Placebo for Panretinal Photocoagulation Pain Control: A Prospective Double-Masked Randomized Controlled Study. International Journal of Retina and Vitreous. 2015; 1.1. https://doi.org/10.1186/s40942-015-0021-8.

3. Macaferri Del Santo A, Maluf Auge R, Amaral Ferraz C. Preemptive Analgesia of Metamizole versus Ibuprofen in Retinal Laser Photocoagulation. Revista Brasileira de Oftalmologia. 2016; 75.1. https://doi.org/10.5935/0034-7280.20160003.

4. Schug SA, Manopas A. Update on the Role of Non-Opioids for Postoperative Pain Treatment. Best Practice & Research Clinical Anaesthesiology. 2017; 21.1,15–30. https://doi.org/10.1016/j.bpa.2006.12.002.

5. Maślanka J, Rogosch JT et al. Novel Bioactive Metabolites of Dipyrone (Metamizol). Bioorganic & Medicinal Chemistry. 2012; 20.1,101–7. https://doi.org/10.1016/j.bmc.2011.11.028.

6. Vazquez E, Hernandez N, Escobar W, Vanegas H. Antinociception Induced by Intravenous Dipyrone (Metamizol) upon Dorsal Horn Neurons: Involvement of Endogenous Opioids at the Periaqueductal Gray Matter, the Nucleus Raphe Magnus, and the Spinal Cord in Rats. Brain Research. 2005; 1048.1–2,211–17. https://doi.org/10.1016/j.brainres.2005.04.083.

7. Ahuja M, Dhake AS, Sharma SK, Majumdar DK. Topical Ocular Delivery of NSAIDs. The AAPS Journal. 2008; 10.2,229–41. https://doi.org/10.1208/s12248-008-9024-9.

8. Ricciotti E, FitzGerald GA. Prostaglandins and Inflammation. Arteriosclerosis, Thrombosis, and Vascular Biology. 2011; 31.5,986–1000. https://doi.org/10.1161/ATVBAHA.110.207449.

9. Păunescu H, Coman OA, Coman L, Ghiţă I, Georgescu SR, Drăia F, Fulga I. Cannabinoid System and Cyclooxygenases Inhibitors. Journal of Medicine and Life. 2011; 4.1,11–20.

10. Schalnus R. Topical Nonsteroidal Anti-Inflammatory Therapy in Ophthalmology. Ophthalmologica. Journal International D’ophtalmologie. International Journal of Ophthalmology. Zeitschrift Fur Augenheilkunde. 2003; 217.2,89–98. https://doi.org/68563.

11. De Paiva C, Coursey T. Managing Sjögren’s Syndrome and non-Sjögren Syndrome dry eye with anti-inflammatory therapy. Clinical Ophthalmology. 2014; 1447. https://doi.org/10.2147/OPTH.S35685.

12. Schoenberger SD, Kim SJ. Nonsteroidal Anti-Inflammatory Drugs for Retinal Disease. International Journal of Inflammation. 2013; 1–8. https://doi.org/10.1155/2013/281981.

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GENERAL ARTICLE

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7doi:10.22336/rjo.2017.

Schirmer test changes after 20 gauge and 23 gauge pars plana vitrectomy

Ghasemi Falavarjani Khalil, Shaheen Yahya, Karimi Moghaddam Arezoo, Aghaei Hossein, Parvaresh Mohammad Mehdi, Bahmani Kashkouli Mohsen, Farrokhi Hosein, Abri Aghdam Kaveh Eye Research Center, Rassoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran Correspondence to: Kaveh Abri Aghdam, MD, PhD Eye Research Center, Rassoul Akram Hospital, Sattarkhan-Niayesh Street, Tehran 14456-13131, Iran, Phone: +9821 665 588 11, Fax: +9821 665 09 16 2, E-mail: kaveh.abri@gmail.com Accepted: November 15, 2016

Abstract Objective: To evaluate the short-term changes in Schirmer I test (ST) after pars plana vitrectomy and to compare the results between 23 gauge and 20 gauge vitrectomy surgeries. Methods: 42 patients who underwent pars plana vitrectomy for posterior segment diseases were included in this prospective, non-randomized, comparative study. The choice of sclerotomy gauge was at the surgeons’ discretion. ST values were recorded before and at 1 and 3 months after vitrectomy. Results: 20 patients in 23 gauge and 22 patients in 20-gauge group with a mean age of 59.9 ± 13.5 years were included. The mean preoperative ST values decreased significantly in both groups at 1 and 3 months after surgery (all P < 0.01). The ST values in the fellow eyes were the same, at baseline and during the follow up (P > 0.05). At 3 months visit, 15 eyes (35.7%) had abnormal ST measurements. There was no statistically significant difference in the changes in the ST measurements between the two groups at one month (P = 0.7), however, 3 months after surgery, the mean decrease in the ST measurements was significantly higher in the 20 gauge group (P = 0.03). At 3 months, 4 eyes in the 23 gauge group (20%) and 11 eyes in the 20 gauge group (50%) had abnormal ST measurements (P = 0.05). Conclusions: Although both 20 and 23-gauge vitrectomy decrease the ST measurements postoperatively, the value is less affected by the 23-gauge vitrectomy. Keywords: 20 gauge, 23 gauge, dry eye, pars plana vitrectomy, Schirmer test

Introduction

Dry eye is a common condition, with an increased prevalence in the elderly and in patients with different systemic diseases including autoimmune diseases and diabetes mellitus [1,2]. Previous studies have shown that surgical trauma to the external ocular surface results in significant changes in the tear film

characteristics, leading to the postoperative dry eye [3-6]. The changes are especially prominent in patients with preoperative signs of dry eye [7]. The effect of corneal refractive surgery and cataract surgery on the tear film is well understood. However, limited studies have reported ocular surface changes after pars plana vitrectomy [8-11]. Moreover, the effect of transconjunctival small gauge vitrectomy, which

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is associated with less manipulation of the ocular surface on the tear film and the incidence of dry eye after surgery, remains unclear [12].

The diagnosis of dry eye is based on the clinical features and some diagnostic tests such as tear break-up time, tear meniscus height, and rose Bengal staining. The assessment of tear production by Schirmer I test (ST) is the most common test in the evaluation of dry eye [13]. It measures the basal tear secretion and the function of the main lacrimal gland. In a literature search using the Pubmed database, no study reporting the ST measurements after pars plana vitrectomy could be found.

The aim of this study was to evaluate the short-term effect of pars plana vitrectomy on the ST measurements in patients with no preoperative dry eye. Also, the ST changes after conventional 20 gauge versus microincision 23 gauge vitrectomy surgery were compared.

Methods

42 patients who underwent pars plana vitrectomy for various posterior segment diseases were included in this prospective, non-randomized case series study, from January 2012 to September 2013, and the Eye Research Center Ethics Committee approval and consent form from the subjects were obtained. Patients with clinical signs of dry eye, including preoperative ST values < 10 mm in either vitrectomy or fellow eyes, previous intraocular surgery, except for phacoemulsification more than 6 months before, known ocular surface disease (e.g. cicatricial conditions), acute inflammatory and/ or infectious ocular problems, and patients with a history of systemic autoimmune diseases (e.g. rheumatoid arthritis, systemic lupus erythematosus, Sjӧgren’s syndrome), were excluded. Also, patients who needed repeated surgery during the first 3 months after vitrectomy were excluded.

The ST value without anesthesia was determined by measuring the length of the wetted part of the standardized filter paper strip (Whatman no. 41) at 5 minutes after inserting one end of the paper into the lateral side of the lower conjunctival fornix. The patients were instructed to keep the eyes closed during the test. Instillation of eye drops and extraocular

surface manipulations were avoided at least 1 hour before the measurements. ST measurements were performed in both eyes before, and at 1 and 3 months after surgery. A ST measurement of < 10 mm was considered abnormal.

All surgeries were performed by one surgeon (KGF). Standard 3-port pars plana vitrectomy was performed. The choice of the gauge depended on the surgeons’ decision. Generally, 20-gauge vitrectomy was selected in eyes with severe proliferative vitreoretinopathy or proliferative diabetic retinopathy, so that an extensive scleral depression or a circumferential buckle was necessary. In 20-gauge surgery, limited 30 and 90-degree limbal peritomies were performed at the superonasal and temporal part of the globe, respectively. A 360-degree peritomy was performed in eyes with forniceal shortening and when a circumferential buckle was needed. At the end of the surgery, the sclerotomy and conjunctiva were closed separately, by using 7-0 Vicryl sutures. In 23-gauge surgery, the trocars were inserted transconjunctival and no peritomy was performed. If there was a continuous leakage from the sclerotomy site at the end of the surgery and after removing the trocars, a 7-0 transconjunctival suture was used for closure. Subtenon injection of triamcinolone acetonide was performed for both groups at the conclusion of the surgery. Postoperative medication was similar between the two groups. Topical antibiotic eye drops were administered 4 times daily for 4 weeks and topical betamethasone eye drops were prescribed at every 2 hours for 1 week and then 4 times daily for the next 3 weeks. The Vicryl sutures were absorbed or removed within one month after surgery.

Data were entered by using SPSS software (version 15, Chicago IL). Paired t-test, independent sample t-test, Fisher’s exact test, and Chi square test were used for statistical analysis and a P value of less than 0.05 was considered statistically significant.

Results

Forty-two patients including twenty women and twenty-two men, with a mean age of 59.9 ± 13.5 years, were included. The surgical indications were complications of diabetic

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retinopathy, rhegmatogenous retinal detachment, vitreous hemorrhage due to retinal vascular occlusion, macular hole, and macular pucker. The ST measurements at baseline were statistically the same for men and women (15.5 ± 4.4 and 18.1 ± 6.5, respectively, P = 0.1), and when eyes with diabetic retinopathy complications were compared with other surgical indications (18.5 ± 6.3 and 15.5 ± 4.2, respectively, P = 0.07). The baseline mean ST value was statistically similar between the vitrectomy eyes and fellow eyes (16.7 ± 5.6 and 14.9 ± 1.3 mm, respectively, P = 0.1).

The mean preoperative ST value of 16.7 ± 5.6 mm decreased to 11.9 ± 4.9 mm and 11.9 ± 4.8 mm at 1 and 3 months after surgery, respectively (both P < 0.001), in the operated eyes. The ST values were the same at baseline and during the follow up (P > 0.05), in the fellow eyes. The mean decrease in the ST values at 1 and 3 months (5.01 ± 5.5 and 4.7 ± 4.2 mm, respectively) were significantly different from the fellow eyes (1.1 ± 3.3 and 0.2 ± 2.9 mm,

respectively, both P < 0.001). No significant difference was found in one and 3 months changes in the ST measurements between the eyes operated for diabetic retinopathy complications and those operated for other indications (P = 0.4 and P = 0.5, respectively). At 3 months visit, 15 eyes (35.7%) had abnormal ST measurements; however, all ST measurements in the fellow eyes were higher than 10 mm.

Baseline characteristics and results of ST measurements in 20 and 23 gauge groups are summarized in Table 1. The mean ST values were decreased significantly at 1 and 3 months after surgery (all P < 0.01), in both groups. There was no statistically significant difference in the changes in ST measurements between the two groups at one month (P = 0.7). However, the mean decrease in the ST measurements was significantly higher in 20 gauge group at 3 months (P = 0.03). At 3 months, 4 eyes in the 23 gauge group (20%) and 11 eyes in the 20 gauge group (50%) had abnormal ST measurements (P = 0.05).

Table 1. Demographics and Schirmer I test results in 20 and 23 gauge vitrectomy groups

20 gauge 23 gauge P value Number of patients 22 20 Age (year) 58.1 ± 14.4 62.6 ± 12.3 0.4** Gender (Male/ Female) 9/ 13 11/ 9 0.4† Surgical indication (Complications of diabetic retinopathy/ other indications)

13/ 9 6/ 14 0.06 †

Baseline Schirmer test (mm) 17.6 ± 6.2 15.7 ± 4.8 0.3** One month Schirmer test (mm) 13.2 ± 5.8 10.3 ± 2.9 0.06** Three months Schirmer test (mm)

11.5 ± 5.7 12.4 ± 3.7 0.6**

Schirmer test measurement changes at 1 month (mm)*

5.2 ± 4.1 4.6 ± 6.7 0.7**

Schirmer test measurement changes at 3 months (mm)*

6.1 ± 4.6 3.3 ± 3.3 0.03**

Eyes with Schirmer test value < 10 mm at 3 months

4 (20%) 11 (50%) 0.05‡

* Compared to the baseline ** Independent sample t-test † Chi square test ‡ Fisher’s exact test

Discussion

Several mechanisms have been described for the tear film changes after intraocular surgery. Destruction of goblet cells, decrease in corneal sensation, and decrease in lacrimal gland

secretion, alteration of the tear cytokines and disruption of corneal epithelium are amongst the reasons proposed to be responsible for postoperative dry eye [3,5,8,14].

Preoperative patient and ocular characteristics have been reported to affect the development of dry eye after surgery. These

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include age, sex, presence of dry eye and history of diabetic retinopathy [2,7,9]. Intraoperative factors such as the amount of exposure to microscope light, surgical trauma to the corneal epithelium, conjunctiva, eyelids, and lacrimal glands may cause significant changes in tear film [2,5,7,9,14,15]. Also, after surgery, some factors including topical eye drops and the presence of sutures may aggravate the tear dysfunction [3,4]. The patients were carefully selected to have a normal ST, being free of dry eye at baseline, to reduce the confounding effect of these variables.

ST measurements were performed with eyes closed. Closing the eyes during ST results in less blinking, reducing the role of the lid margins and eyelashes in stimulating tear secretion and eliminating the influence of external factors such as temperature, evaporation, and humidity, and may help maintain more stable and uniform conditions [13]. Also, ST was performed on the fellow eyes and showed that the mean ST measurements remained the same after surgery. This showed that the effect of extraocular factors was negligible on ST measurements. Our results showed that the ST values significantly decreased after pars plana vitrectomy in both groups. Considering less than 10 mm of ST as abnormal [16], more than one third of this series had an abnormal ST at 3 months after surgery.

Previous studies have reported higher rates of dry eye and corneal epitheliopathy after intraocular surgery in patients with diabetic retinopathy [9,17,18]. We did not observe any statistically significant difference between the eyes operated for the complications of diabetic retinopathy and others.

Sutureless microincision vitrectomy has rapidly been replaced by the conventional 20-gauge system. The advantages of microincision vitrectomy include decreased surgical time, early postoperative rehabilitation and less postoperative discomfort [12]. Our study showed that compared to 20-gauge vitrectomy, the ST values are less affected after 23-gauge surgery, and the proportion of eyes with abnormal ST values was higher in 20-gauge group. The size and structure of the incisions obviated the need for a separate peritomy and reduced the conjunctival manipulation. Although the suture closure of the leaking sclerotomies might sometimes be necessary, a small

transconjunctival suture is usually enough. Also, since the retina pathology is usually less severe in 23 gauge vitrectomy, the depression necessary for the anterior vitreous dissection is usually less extensive in 23 gauge surgeries. Other surgical characteristics including operation time, circumferential buckling, and epithelial debridement might further explain the difference in the ST results.

Our study had several limitations. The follow up period was short and the time interval needed for the normalization of the ST values was not clear. The small sample size might explain the absence of statistically non-significant results observed in some analyses. We did not match the 20 and 23 gauge groups based on the conjunctival opening, and sclera depression and did not randomize the study population. Moreover, ST could be affected by several factors including environment, age, and gender. However, to the best of our knowledge, this is the first study reporting the ST measurement changes after 20 and 23 gauge vitrectomy surgeries. Our results showed significant tear dysfunction after vitrectomy, which was more prominent in 20-gauge surgery. Future randomized studies with larger sample size are needed to confirm our results.

References

1. Wang TJ, Wang IJ, Hu CC, Lin HC. Comorbidities of dry eye disease: a nationwide population-based study. Acta Ophthalmol. 2012; 90(7):663-8.

2. Perry HD, Donnenfeld ED. Dry eye diagnosis and management in 2004. Curr Opin Ophthalmol. 2004; 15:299–304.

3. Khanal S, Tomlinson A, Esakowitz L, Bhatt P, Jones D, Nabili S, Mukerji S. Changes in corneal sensitivity and tear physiology after phacoemulsification. Ophthalmic Physiol Opt. 2008; 28(2):127-34.

4. Li XM, Lizhong H, Jinping H, Wei W. Investigation of dry eye disease and analysis of the pathologic factors in patients after cataract surgery. Cornea. 2007; 26:S16-20.

5. Kohlhaas M. Corneal sensation after cataract and refractive surgery. J Cataract Refract Surg. 1998; 24:1399-409.

6. Oh T, Jung Y, Chang D, Kim J, Kim H. Changes in the tear film and ocular surface after cataract surgery. Jpn J Ophthalmol. 2012; 56(2):113-8.

7. Ram J, Gupta A, Brar G, Kaushik S, Gupta A. Outcomes of phacoemulsification in patients with dry eye. J Cataract Refract Surg. 2002; 28(8):1386-9.

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8. Heinrich H, Sarah E, Rinata G. Alterations in expression of mucin following retinal surgery and plaque radiotherapy. Graefe’s Arch Clin Exp Ophthalmol. 2001; 239:488-95.

9. Chen WL, Lin CT, Ko PS, Yeh PT, Kuan YH, Hu FR, Yang CM. In vivo confocal microscopic findings of corneal wound healing after corneal epithelial debridement in diabetic vitrectomy. Ophthalmology. 2009; 116(6):1038-47.

10. Chung H, Tolentino FI, Cajita VN, Acosta J, Refojo MF. Reevaluation of corneal complications after closed vitrectomy. Arch Ophthalmol. 1988; 106(7):916-9.

11. Chiambo S, Baílez Fidalgo C, Pastor Jimeno JC, Coco Martín RM, Rodríguez de la Rúa Franch E, De la Fuente Salinero MA, Herreras Cantalapiedra JM. Corneal epithelial complications after vitrectomy: a retrospective study. Arch Soc Esp Oftalmol. 2004; 79(4):155-61.

12. Thompson JT. Advantages and limitations of small gauge vitrectomy. Surv Ophthalmol. 2011; 56(2):162-72.

13. Kashkouli MB, Pakdel F, Amani A, Asefi M, Aghai GH, Falavarjani KG. A Modified Schirmer Test in Dry Eye and Normal Subjects: Open Versus Closed Eye and 1-Minute Versus 5-Minute Tests. Cornea. 2010; 29:384–387.

14. Stern ME, Beuerman RW, Fox RI, Gao J, Mircheff AK, Pflugfelder SC. The pathology of dry eye: the interaction between the ocular surface and lacrimal glands. Cornea. 1998; 17:584–589.

15. Cho YK, Kim MS. Dry Eye After Cataract Surgery and Associated Intraoperative Risk Factors. Korean J Ophthalmol. 2009; 23:65-73.

16. Vitali C, Moutsopoulos HM, Bombardieri S. The European community study group on diagnostic criteria for Sjogren’s syndrome. Sensitivity and specificity of tests for ocular and oral involvement in Sjogren’s syndrome. Ann Rheum Dis. 1994; 53:637-47.

17. Hiraoka M, Amano S, Oshika T, Kato S, Hori S. Factors contributing to corneal complications after vitrectomy in diabetic patients. Jpn J Ophthalmol. 2001; 45(5):492-5.

18. Liu X, Gu Y, Xu Y. Changes of tear film and tear secretion after phacoemulsification in diabetic patients. J Zhejiang Univ Sci B. 2008; 9(4):324-328.

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CASE REPORT

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doi:10.22336/rjo.2017.8

Terson’s Syndrome – case report

Moraru Andreea* **, Mihailovici Ruxandra* **, Costin Dănuţ* **, Brănişteanu Daniel*

*“Grigore T. Popa” University of Medicine and Pharmacy, Iaşi, Romania **“Prof. N. Oblu” Hospital, Iaşi, Romania

Correspondence to: Dănuţ Costin, MD, PhD, “Prof. N. Oblu” Emergency Hospital, Iaşi, 2 Ateneului Street, Iaşi, Romania Mobile phone: +40728 728 729, E-mail: costin_danut@yahoo.com Accepted: February 13, 2017

Abstract Terson’s Syndrome is represented by a vitreous, retrohyaloid, retinal, or subretinal hemorrhage occurring consequent to an acute intracranial hemorrhage or elevated intracranial pressure. The outcome may include a complete clearing of the blood and the restoration of VA or persistent hemorrhage. This report presents the case of a 43-year-old woman who underwent bilateral surgery for a persistent vitreous hemorrhage and a hematoma underneath the internal limiting membrane in the left eye. The event followed shortly after a subarachnoid hemorrhage due to the rupture of a posterior communicating artery aneurism. Vitrectomy was performed in both eyes, together with the peeling of the internal limiting membrane in the left eye, followed by a bilateral good outcome. Keywords: Terson’s syndrome, persistent hemorrhage, epiretinal membrane, vitrectomy

Introduction

Terson’s syndrome is represented by a vitreous, retrohyaloid, retinal, or subretinal hemorrhage occurring consequent to an acute intracranial hemorrhage or elevated intracranial pressure.

It was first described by the French ophthalmologist Albert Terson in the beginning of the 1900’s [1]. Terson’s syndrome has been most commonly described in subarachnoid hemorrhages due to cerebral aneurisms, head trauma, intracranial elevated pressure, and tumors and intracranial hemorrhage, which occurs during or post operatively.

The pathogenesis of Terson’s Syndrome has been controversial, but there are 2 main accepted mechanisms [2,3]. One of them states that elevated intracranial pressure has a crucial role, causing the raise of intraocular venous pressure and the rupture of the superficial vessels, hence the hemorrhage. The other one

asserts that the accumulated blood form the subarachnoid space enters the eye along the optic nerve and retinal vessels space, producing a vitreous or retrohyaloid hemorrhage.

Case report

A 43-year-old woman referred to the Ophthalmology Clinic complaining of a sudden decrease in visual acuity, which occurred after she had surgery for a ruptured intracranial aneurism.

The patient was admitted to the Neurosurgery Department, a few weeks prior for loss of consciousness. She was diagnosed with rupture of a posterior communicating artery aneurism, which was clipped along with its origin from the internal carotid artery. Two weeks postoperatively, the patient accused a sudden decrease of visual acuity in both eyes and

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she was directed towards the Ophthalmology Clinic.

Upon examination, the patient presented with BCVA RE = 0,3 and BCVA LE = 0,02, normal IOP and no significant changes in the anterior pole.

Fundoscopic examination revealed diffuse vitreous hemorrhage in both eyes, denser in the right eye (Fig. 1). Also, the left eye had a double hemorrhagic level: retrohyaloid hemorrhage in the macular area and hematoma under the internal limiting membrane (Fig. 2).

Taking into account the fact that both eyes have been affected by vitreous hemorrhage in this young patient for over three weeks, we decided to perform vitrectomy. 23G Pars plana posterior vitrectomy was performed in the right eye. Three weeks postoperatively, the fundoscopic aspect of the right eye was normal (Fig. 3).

Due to the persistence of the hemorrhage, vitrectomy was also performed in the left eye. Tissue plasminogen activator was injected intravitreal one day before surgery, to breakdown the blood clot (25 µg in 0,05 mL). Subsequently, 23G pars plana posterior vitrectomy and peeling of the internal limiting membrane was performed.

Postoperative outcome was favorable with a normal aspect of the retina and the entire fundus (Fig. 4).

At 1, 3 and 6 months follow-ups the BCVA of the RE was 1 and the BCVA of the LE was 0,8 and the fundus aspect of both eyes was stationary.

A few pathological entities could be discussed for the purpose of differential diagnosis. Regarding the vitreous hemorrhage, the differential diagnosis could be made with:

1. Advanced stage diabetic retinopathy: the patient had no prior history of diabetes;

2. Trauma: there was no history of trauma;

Fig. 1 RE Fundus: diffuse hemorrhage

Fig. 2 LE Fundus: double hemorrhagic level and hematoma in the macular area

Fig. 3 RE Fundus: normal aspect

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3. Hemoglobinopathies: the blood count was within normal limits.

The differential diagnosis of the sub- internal limiting membrane hematoma comprised:

1. Purtscher’s retinopathy: it has a varied etiology, such as severe head trauma, acute pancreatitis, lupus, chronic renal disease. The mechanism of this disease consists of intravascular micro particles occluding the arterioles (fibrin clots, platelet – leukocyte aggregates, fat emboli, gaseous emboli). Its manifestations consist of intraretinal hemorrhages and cotton-wool exudates surrounding the optic nerve head and later on, the optic nerve atrophies [4];

2. Valsalva retinopathy: it is secondary to a sudden increase in intrathoracic or intraabdominal pressure (weight lifting, coughing, sneezing, vomiting). This mechanism causes an elevation in the intraocular venous pressure and further on, a spontaneous rupture of the retinal capillaries. Ocular findings are classically described as uni/ bilateral hemorrhages in the macular area, underneath the internal limiting membrane, retinal/ subretinal/ vitreous hemorrhages, which evolve towards spontaneous clearing of the blood without long-term complications.

3. Hypertensive retinopathy: it represents the ophthalmic findings secondary to systemic arterial hypertension, which, in an acute,

significant rise of pressure may cause the constriction of arterial vascular beds and the obstruction of retinal arterioles. These results in cotton-wool spots near the optic nerve head, nerve fiber layer hemorrhages in the peripapillary region, lipid exudates in the macula, macular edema, and retinal hemorrhages [4].

Discussions

Terson syndrome is usually described in correlation with ruptured cerebral vessel aneurysms, mainly in three locations: in the internal carotid artery, the middle cerebral artery bifurcation, and in the upper part of the basal artery [5].

The sudden elevation of the intracranial pressure has a crucial role in Terson’s syndrome. It causes the raise of intraocular venous pressure and the rupture of the superficial vessels, hence the hemorrhage. Also, the pressure is transmitted along the optic nerve sheath and retinal vessels space, occluding the retinal and choroidal anastomoses at the lamina cribrosa.

Approximately 20% of the patients diagnosed with subarachnoid hemorrhage present with Terson’s syndrome. This association has a negative influence on the mortality rate. Patients diagnosed with Terson syndrome have a 40-60% mortality rate, 3 to 9 times higher comparative to the patients who only present with subarachnoid hemorrhage unaccompanied by ocular manifestations [6].

Most often, the patient is neurologically impaired and the visual acuity cannot be tested, but the degree of vision loss is usually related to the extent of the intraocular hemorrhage. It can range from 20/ 20 to light perception. Also, the amount of intraocular hemorrhage is influenced by the speed of accumulation and magnitude of the intracranial pressure elevation [7].

Usually, the intraocular hemorrhage is bilateral and superficial and infrequently intraretinal or subretinal. A preretinal hemorrhage can cause a vitreous hemorrhage weeks after the initial event.

According to literature data, the incidence of intraocular hemorrhage associated with subarachnoid hemorrhage is 10-50% [8].

Fig. 4 LE Fundus: normal aspect

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Vitreous hemorrhage incidence is lower: 3-13% [9].

The histopathological specimens obtained from patients with Terson’s syndrome have displayed the presence of erythrocytes and leukocytes in the vitreous, subhyaloidal, and subinternal limiting membrane space and in the retina. Although not as common, some studies report the presence of subretinal blood. Also, the examinations of epiretinal membranes showed glial cells and basement membrane material [10].

The formation of an epiretinal membrane is one of the most common complications which can occur in Terson’s, with an incidence of up to 78%. It is a result of the fibroblast and glial cell proliferation, which can occur in the subhyaloidal or subinternal limiting membrane space created by the intraocular hemorrhage [10]. It can critically affect the patients’ vision after the clearing of the hemorrhage and it can become significant even 4 years after the hemorrhagic episode. Other reported long-term complications include retinal pigment epithelium mottling, optic atrophy, macular holes, retinal folds, cystoid retinal changes, proliferative vitreoretinopathy, retinal detachment, and cataract formation [11].

Glatt și Machemer have demonstrated that blood has a toxic effect over the retina’s photoreceptors, especially in the first 7 days after the hemorrhage [12]. The iron from the hemoglobin catalyses the conversion of hydrogen peroxide into hydroxyl radical, which is the most destructive species of reactive oxygen. The destruction caused by this radical consists of the peroxidation of lipids, breaking of DNA chains and biomolecular degradation. Since the main function of the retinal pigment epithelium (RPE) is to phagocyte the photoreceptors external segments, which are rich in lipids, the retina, and the RPE are prone to oxidative damage [13].

The visual prognosis of the patients who survive a subarachnoid hemorrhage is favorable. Most of the vitreous hemorrhages spontaneously clear up [14]. Only 40% of the cases need a vitrectomy and only half of these also need a peeling of the internal limiting membrane [15]. Vitrectomy is indicated in the cases showing persistent or bilateral vitreous or macular hemorrhages. Recent studies suggest that an

early vitrectomy may help with a fast restoration of vision, thus reducing the incidence of complications that can occur, such as proliferative vitreoretinopathy and glaucoma [16].

Kuhn et al. have described the accumulation of blood underneath the internal limiting membrane in Terson’s syndrome and reported a 39% incidence of macular hemorrhages [17]. Proceeding with a vitrectomy has lead to good results in all these cases, over 80% of the patients having a final VA of 0,8 or more. The best results were achieved in young patients (under 45 years) and in those who were operated on during the first 3 months [16].

In 1991, Lewis has introduced the tissue plasminogen activator (tPA) in the treatment plan, helping with the breaking down of the blood clot in cases of submacular hemorrhages [18]. The tPA is a protease that transforms plasminogen in plasmine which, subsequently, breaks the fibrin clot. It can be used as a subretinal injection during the vitrectomy or it can be injected intravitreously along with the pneumatic displacement of the clot [19]. It has been demonstrated that intravitreously administered tPA is toxic in doses over 100 µg [20].

Taking into account the young age of our patient and the fact that the vitreous hemorrhage was persistent and bilateral, with macular involvement in the left eye, we decided that vitrectomy was necessary in this case in order to prevent the occurrence of further complications and to improve the quality of life. The results achieved in this case were comparable to those described in the specialty literature. Both eyes regained a good visual acuity immediately after surgery. The final VA of the left eye was lower than the VA of the other eye (0,8 comparative to 1), suggesting that the persistence of blood in the macular area influenced the functional prognosis.

The final functional prognosis is influenced by many factors: the age of the patient, the rate of pre and postoperative complications such as epiretinal membranes and cataract formation. Some authors suggest that the final visual acuity influences the neurological condition of the patient, regarding the damage to brain structures associated with Terson syndrome [21,22].

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Conclusions

Vitrectomy is a safe and efficient procedure of treating intraocular hemorrhage, which is secondary to a ruptured intracranial aneurism, and has also enabled a quick recovery of visual acuity in this young patient.

References

1. Terson A. De l’hemorrhagie dans le corps vitre au cours del’hémorrhagie cerebrale. Clin Ophthalmol. 1900; 6:309–12.

2. Michalewska Z, Michalewski J, Nawrocki J. Possible methods of blood entrance in Terson syndrome. Ophthalmic Surg Lasers Imaging. Nov-Dec 2010; 41 Suppl:S42-9.

3. Ko F, Knox DL. The Ocular Pathology of Terson’s Syndrome. Ophthalmology. 2010 Jul; 117(7):1423-9.

4. Yanoff M, Duker JS. Ophthalmology. Fourth Edition, 2014, Elsevier Saunders.

5. Ou R Jr., Talavera F, Charles S, Roy H, Phillpotts B, Yoshizumi M. Terson Syndrome treatment and management. Med Scape. 2014; 13:312–318.

6. Skevas C, Czorlich P, Knospe V, Stemplewitz B, Richard G, Westphal M, Regelsberger J, Wagenfeld L. Terson’s Syndrome-Rate and Surgical Approach in Patients with Subarachnoid Hemorrhage: A Prospective Interdisciplinary Study. Ophthalmology. 2014 Mar 31.

7. Kapoor S. Terson syndrome: an often overlooked complication of subarachnoid hemorrhage. World Neurosurg. 2014 Jan; 81.

8. Stienen MN, Lücke S, Gautschi OP, Harders A. Terson haemorrhage in patients suffering aneurysmal subarachnoid haemorrhage: a prospective analysis of 60 consecutive patients. ClinNeurolNeurosurg. 2012 Jul; 114(6):535-8.

9. Middleton K, Esselman P, Lim PC. Terson syndrome: an underrecognized cause of reversible vision loss in patients with subarachnoid hemorrhage. Am J Phys Med Rehabil. 2012 Mar; 91(3):271-4.

10. Garcia-Arumi J, Corcostegui B, Tallada N et al. Epiretinal membranes in Tersons syndrome. A clinicopathologic study. Retina. 1994; 14(4):351-5.

11. Rubowitz A, Desai U. Nontraumatic macular holes associated with Terson syndrome. Retina. 2006 Feb; 26(2):230-2.

12. Glatt H, Machemer R. Experimental subretinal hemorrhage in rabbits. Am J Ophthalmol. 1982; 94:762-773.

13. Song D, Dunaief JL. Retinal iron homeostasis in health and disease. Front Aging Neurosci. 2013; 5:24.

14. Toosi SH, Malton M. Terson’s syndrome - significance of ocular findings. Ann Ophthalmol. 1987; 19:7-12.

15. Skevas C, Czorlich P, Knospe V, Stemplewitz B, Richard G, Westphal M, Regelsberger J, Wagenfeld L. Terson’s Syndrome-Rate and Surgical Approach in Patients with Subarachnoid Hemorrhage: A Prospective Interdisciplinary Study. Ophthalmology. 2014 Mar 31.

16. Garweg JG, Koerner F. Outcome indicators for vitrectomy in Terson syndrome. Acta Ophthalmol. 2009; 87(2):222-6.

17. Kuhn F, Morris R, Mester V, Witherspoon CD. Terson’s syndrome. Results of vitrectomy and the significance of vitreous hemorrhage in patients with subarachnoid haemorrhage. Ophthalmology. 1998; 105:472–477.

18. Lewis H, Resnick SC, Flannery JG, Straatsma BR. Tissue plasminogen activator treatment of experimental subretinal hemorrhage. Am J Ophthalmol. 1991; 111:197-204.

19. Hillenkamp J, Surguch V, Framme C, Gabel VP, Sachs HG. Management of submacular hemorrhage with intravitreal versus subretinal injection of recombinant tissue plasminogen activator. Graefes Arch Clin Exp Ophthalmol. 2010; 248:5-11.

20. Chen SN, Yang TC, Ho CL, Kuo YH, Yip Y, Chao AN. Retinal toxicity of intravitreal tissue plasminogen activator: case report and literature review. Ophthalmology. 2003; 110:704-708.

21. Czaplicka E, Grabska-Liberek I, Rospond I, Kocięcki J. Zespół Tersona — omówienie przypadków klinicznych i postępowania leczniczego. Borgis — Postępy Nauk Medycznych 2013; 12:901–903.

22. Nacef L, Zghal-Mokni I, Allagui I. Indications and results of vitrectomy in Terson syndrome. Tunis Med. 2004; 82:461–464.

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Necrotizing retinitis of multifactorial etiology Pirvulescu Ruxandra Angela* **, Popa Cherecheanu Alina* **, Romanitan Mihaela Oana***, Obretin Dana****, Iancu Raluca* **, Vasile Danut* **** *“Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania **Ophthalmology Clinic, University Emergency Hospital, Bucharest, Romania ***Department for Clinical Research, Karolinska Institute, Sodersjukhuset, Stockholm, Sweden ****Infectious Diseases Department, “Dr. Victor Babes” Clinical Hospital “, Bucharest, Romania *****Surgery 1 Clinic, University Emergency Hospital, Bucharest, Romania Correspondence to: Pirvulescu Ruxandra Angela, MD, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania, 8 Eroii Sanitari Blvd., District 5, Code 050474, Bucharest, Romania, Phone: +40 (0) 721746351 E-mail: ruxandra.pirvulescu@umf.ro Accepted: February 23, 2017

Abstract Introduction. We present the case of a 73-year-old woman with osteoporosis, who presented to the emergency room with a sudden vision loss and ocular pain in the right eye, which appeared two days before. The patient mentioned loss of appetite, weight loss for three months and low fever for two weeks. Materials and methods. Among the ophthalmological findings, the most important were panuveitis, and large confluent necrotic areas in the peripheral retina. The patient was diagnosed with RE Panuveitis and acute necrotizing retinitis. Results. Blood exams showed leukocytosis and monocytosis, thrombocytosis and anemia. Further investigations showed high levels of Cytomegalovirus (CMV) anti IgG and Herpes Simplex (HS) type 1 virus anti IgM, urinary infection, and secondary hepatic cytolysis. The CT and MRI of the thorax and abdomen showed no sign of neoplastic disease, and no explanation for the CMV infection was found. The patient received general corticotherapy and antiviral therapy, and, after one month, RE BCVA was 20/ 30. Particularity of the case. Acute necrotizing retinitis in an old patient with CMV and HSV type 1, associated with secondary hepatic cytolysis, without any other immunosuppressive disease and very good outcome. Keywords: acute necrotizing retinitis, panuveitis, vasculitis, Cytomegalovirus, Herpes Simplex Type 1, corticotherapy

Introduction

We present the case of a 73-year-old woman with osteoporosis, who presented to the emergency room with sudden vision loss and ocular pain in the right eye, two days before. The patient mentioned loss of appetite and weight loss for three months and low fever for two weeks. The personal medical history of the

patient showed no significant general or ocular pathology.

Clinical eye exam showed: - RE BCVA = c.f. at 50 cm; - LE BCVA = 20/ 20; - RE IOP = 16 mmHg; - LE IOP = 15 mmHg; The Goldmann visual field in right eye

showed central scotoma on 20 degrees.

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Slit lamp examination of the right eye revealed perikeratic injection, posterior synechiae at 180 degrees inferiorly which deformed the pupil, endothelial keratic precipitates in a triangular pattern, flare in the anterior chamber and Tyndall ++.

The eye fundus showed vitreal floaters and vitritis (Fig. 1), slightly blurred margins of the optic nerve (unclear due to the inflammation or the vitreal flare), macula with absent foveal reflex, very narrow blood vessels, phantom vessels especially in peripheral retina, perivascular cuffing (vasculitic aspect) (Fig. 2), large cotton-wool spots and rare hemorrhages on the retinal periphery (Fig. 3), and, most important, large confluent necrotic areas in the periphery and mid-periphery of the retina (Fig. 2,4). The left eye had a normal aspect (Fig. 5).

Fig. 1 Eye fundus (RE) - vitritis

Fig. 2 Eye fundus (RE) – large confluent areas of retinal necrosis, narrowed vessels

Fig. 3 RE - narrowed vessels, peripheral retinal hemorrhage

Fig. 4 Peripheral retinal necrosis (RE)

Fig. 5 LE Fundus - within normal limits

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We established the diagnosis: RE Panuveitis; Necrotizing retinitis

The blood exam revealed: - LEUCOCITOSIS 11800/ µl (normal range

4000 – 10000/ µl) - NEUTROPHILIA 10300/ µl (normal range

2000-7000/ µl) - LYMPHOCYTES 800/ µl (normal range

1000-4000/ µl) - THROMBOCITOSIS 683000/ µl (normal

range 100000-400000/ µl) - VSH 68 mm/ h (normal range 1-30 mm/

h) - PCR 3.98 mg/ dl (normal range <0.5 mg/

dl) - TGO 44 U/ L (normal range 0-32 U/ L) - TGP 79 U/ L (normal range 0-65 U/ L) Given the results of the blood test, the

patient was referred to hematology and infectious diseases department. Further exams showed:

- AND-CMV 4554 copies/ mL (quantitative test) – latent infection (<200 copies/ mL)

- HSV 1 Ig M 1.8 (positive >1) - Uroculture - urinary infection (E. Coli) - Abdominal ultrasound – hepatomegaly,

most likely due to secondary hepatic cytolysis - CT and MRI of the thorax and abdomen

showed no sign of neoplastic disease. The final diagnosis set was RE Necrotizing

retinitis.

Discussion

Acute necrotizing retinitis (ARN) and Progressive Outer Retinal Necrosis (PORN) represent a spectrum of rapidly progressing necrotizing herpetic retinopathies. ARN usually strikes in immunocompetent hosts and continues with vasculitis, iridocyclitis, and vitritis. On the other hand, PORN occurs in immunocompromised persons due to HIV infection or other immunosuppressive conditions. These patients develop a necrotizing retinitis that may rapidly involve the macula as well as the peripheral retina, without significant

intraocular inflammation or vasculopathy. The outcomes in both these entities can be devastating and include blindness from complicated retinal detachment and optic atrophy [1,2].

Clinical eye fundus aspect of necrotizing retinitis includes:

- Vitritis (that can be severe); - Disk edema and retrobulbar optic nerve

disease are not uncommon early in the course of ARN;

- Single/ multiple areas of retinal necrosis with distinct borders;

- Necrotic foci in peripheral retina; - Extension/ coalescence of foci of retina;

necrosis in a circumferential fashion; - Occlusive vasculopathy with arteriolar

involvement (retinal vasculitis is common, usually, primarily we could have arteritis);

- Prominent anterior chamber and vitreous inflammation;

- Characteristics that support but are not required for the diagnosis:

• optic neuropathy or atrophy, scleritis, • ocular pain - Inflammation in the anterior and

posterior segments [1,3]; - Anterior granulomatous or non

granulomatous uveitis with keratic precipitates; - ARN may also present with diffuse

scleritis; - Therefore, it is imperative to perform a

dilated fundoscopic examination of every patient with scleritis [2,3].

A differential diagnosis is made with several infectious and noninfectious entities, most of these conditions (with the exception of Behcet disease, atypical toxoplasmosis, and bacterial endophthalmitis) progressing at a much slower pace than ARN.

The retinitis of Behcet’s disease may be indistinguishable from ARN. However, Behcet’s disease is most common in patients of Japanese, Middle-Eastern, or Mediterranean origin, history of oral aphthous ulcers, genital ulcers, or skin lesions (HLA B-51, CD4+, CD8+) [1,3].

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The management of necrotizing retinitis refers, first, to treating the cause of the retinitis. Because most cases of ARN are thought to be caused by Varicella Zoster Virus and HSV, the standard therapy is usually with intravenous acyclovir for 10 to 14 days, followed by a maintenance therapy with oral acyclovir, famciclovir, or valacyclovir. However, more recent data support the induction with oral therapy, for example valacyclovir 1 g three times a day (Aizman, Aslanides). The maintenance therapy for ARN is usually employed for 3 months, in order to reduce the risk of the disease in the fellow eye. It may be used longer in the setting of immunosuppression or multiple recurrences [4].

After the first 24 to 48 hours of antiviral therapy, systemic corticosteroids may be introduced to minimize vitritis and the development of vitreous bands, which may contribute to the development of tractional retinal detachment [3].

Since the viral involvement was revealed the next day, we considered our patient’s situation as severe, so we decided to administer corticotherapy until the results of the tests came out. The patient received general corticotherapy (Solumedrol 1g/ d for 3 days, then Medrol 0.8mg/ kg in a decreased dosage), and antibiotherapy (Ciprofloxacin 200 mg/ 8h). Antiviral therapy was set the next day, as we had the blood exam final results (Acyclovir 2g/ d for 2 months) [3,4].

Complications of ARN may be devastating. Usually, the eye is frequently left with 360° of peripheral retinal atrophy, with multiple posterior retinal breaks secondary to retinal necrosis. A combination of rhegmatogenous and tractional retinal detachment may develop secondary to retinal breaks. Optic atrophy frequently develops in patients who suffered from disc edema earlier in the disease [4,5].

The evolution of our patient was quite good, considering the severity of the condition. After one month, RE BCVA was 20/ 30, vitritis disappeared, the vascular aspect normalized and the necrotic areas vanished (Fig. 6).

Conclusion and particularity of the case The early diagnosis and treatment of

necrotizing retinitis remains the key to a successful management while the prognosis for patients with severe immune dysfunction remains guarded.

The prognosis of untreated ARN has traditionally been poor, with two-thirds of eyes having a visual acuity of 20/ 200 or worse due to retinal detachment, optic atrophy, or retinal pathology [3,4]. While there are reports of aggressive intervention resulting in better outcomes, overall the prognosis for patients with ARN remains guarded.

The particularity of our case is acute necrotic retinitis in an immunosuppressed old patient, with a strong panuveitis component associated with CMV, HSV type 1 and secondary hepatic cytolysis, without any other associated

Fig. 6 Eye fundus aspect of the RE

Fig. 7 RE eye fundus peripheral aspect

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immunosuppressive disease and any other obvious cause of immunodepression, and with a good outcome. Patient is still under the supervision of the infectious disease department.

References

1. http://eyewiki.aao.org/Necrotizing_Herpetic_Retinitis 2. https://en.wikipedia.org/wiki/Acute_retinal_necrosis 3. https://www.aao.org/focalpointssnippetdetail.aspx?id

=6442888a-c135-4a1c-88c5-88753ed3bd0a 4. Duker JS, Blumenkranz MS. Diagnosis and management

of the acute retinal necrosis (ARN) syndrome. Survey of Ophthalmology. March–April 1991; 35(5),327-343.

5. Cernea P. Tratat de Oftalmologie, 2002, Editura Medicala.

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doi:10.22336/rjo.2017.10

Penetrating corneal wound with traumatic cataract and intraocular foreign body-case report

Căciulă Dorin*, Gavriș Monica*, Tămășoi Irina** *”Dr. Constantin Papilian” Military Emergency Hospital, Cluj-Napoca, Cluj, Romania **Dej City Hospital, Dej, Romania Correspondence to: Tămășoi Irina-Diana, MD, Ophthalmologist, 4 Govora Street, Code 400664, Cluj-Napoca, Romania, Mobile phone: +40743 416 245, E-mail: iri_dia@yahoo.com Accepted: January 17, 2017

Abstract Open globe injuries complicated with the presence of an intraocular foreign body mostly affect young males and represent a vision threatening condition. We presented the case of a 48-year-old male who presented to our emergency service due to ocular pain and blurred vision in his right eye. A metallic foreign body situated between 1 and 12 o’clock, near the corneoscleral limbus, that perforated the cornea, the iris, the anterior capsule of the lens and the lens, was detected at the slit-lamp examination. We decided to immediately remove the foreign body that was approximately 20 mm long. The following day, traumatic cataract had already developed, so we performed cataract extraction. Despite the dimensions of the intraocular foreign body, the retina was attached and there were no sign of retinal tears or vitreous haemorrhage. The proper management in this case led to good results in spite of the dimensions of the intraocular foreign body. Abbreviations: IOFB = Intraocular Foreign Body, IOL = Intraocular Lens, PVR = Proliferative Vitreo-Retinopathy Keywords: corneal wound, intraocular foreign body, cataract, iris-claw intraocular lens

Introduction

The incidence of ocular trauma is relatively common despite the anatomical and functional protective mechanisms of the eye. The orbital rim prevents many direct injuries from affecting the eye, and reflex closure of the lids aids in insulating the globe [1].

Open globe injuries complicated with the presence of an intraocular foreign body represent a vision threatening condition [2].

Patients may have an intraocular foreign body without being aware that the eye was penetrated. A history of hammering metal on

metal should alert the clinician to search for an intraocular foreign body. The material will dictate the type of reaction: silver, aluminum, platinum, and gold are rather inert and cause little reaction, but iron can lead to siderosis bulbi and eventual loss of the eye [1].

Surgical intervention with or without pars plana vitrectomy combined with intraocular foreign body removal and cataract extraction may preserve severely traumatized eyes and maintain or even improve vision [2].

The choice of the type of cataract surgery performed in such cases depends on the surgeons’ experience and the particularity of the

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case. Frequently traumatic cataract is associated with anterior or posterior luxation or subluxation of the lens, anterior or posterior capsular rupture, ectropion uveae, corneal wounds, vitreous in the anterior chamber, vitreous, or iris loss. When facing a very complex case it is advisable to restore the anatomical integrity of the eye first and perform cataract surgery later when we have the comfort of a stable anterior chamber.

Visual recovery after ocular trauma also depends on the involvement of the retina. The extraction of the opacified lens has a great importance as it allows the vitreoretinal surgeon to detect and cure associated retinal complications.

Besides the right management of the corneal or scleral wound, retinal complications and traumatic cataract, another important step in managing these patients is the choice of the type of artificial intraocular lens.

There are several options in placing the intraocular lens: in the posterior chamber - iris fixation, scleral suture, placing it in the sulcus or in the anterior chamber. It is advisable to place the artificial IOL in the posterior chamber.

Transscleral fixation of a posterior chamber IOL is technically challenging, requiring more surgical time and has an increased possibility of associated complications such as retinal detachment, IOL decentration and endophthalmitis. Angle – supported anterior chamber IOLs are associated with long-term complications such as bullous keratopathy.

Posterior iris-claw fixated IOL is a viable option due to less surgical time and minimal complications. Progressive pigment dispersion and secondary pigmentary glaucoma are not a common late complication of this type of IOL [3-5].

Case report

Herein we presented the case of a 48-year-old male who presented to our emergency service due to ocular pain and blurred vision in

his right eye. While cleaning an oven with a metallic brush, the patient felt a foreign body sensation in the right eye. Best-corrected visual acuity of his right eye was 0.9.

Slit lamp examination of the anterior pole of the right eye revealed conjunctival congestion, watery discharge. Around 12 o’clock, a metallic foreign body was detected near the corneoscleral limbus, which perforated the cornea, the iris, the anterior capsule of the lens and the lens (Fig. 1). We could not perform the full examination of the posterior pole, so we could not establish the trajectory of the intraocular foreign body. Ocular B-scan was not performed because of the penetrating corneal wound. X-ray of the orbit did not offer enough details and computed tomography could not be performed at that time in our service.

After performing an anti-tetanic

prophylaxis, we decided to extract the intraocular foreign body by using a forceps. Since it had a helicoidal shape, we had to perform several circular movements (Fig. 2 a,b). We were surprised to find out that the wire that perforated the eye was almost 20 mm long (Fig. 3). We injected an antibiotic in the anterior chamber and placed a contact lens to protect the cornea and facilitate the healing of the point-like corneal wound.

Fig. 1 IOFB at presentation

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On the first day postoperatively, the slit lamp examination revealed a stable anterior

chamber and a totally opacified lens with anterior capsule rupture. B-scan ultrasound showed no sign of vitreous haemorrhage and an attached retina. Visual acuity of the right eye was hand motion determined because of the traumatic cataract. We decided to extract the opacified lens. Due to the age of the patient, the lens was very soft so we performed its extraction with a blunt cannula under viscoelastic protection, with good results (Fig. 4). We noticed a posterior capsule break because the foreign body passed through the lens into the vitreous cavity. Surgical aphakia was corrected with an intraocular lens fixated to the posterior face of the iris. At one week follow-up, the best corrected visual acuity was 0.8 and the retina was attached.

Discussion

Penetrating corneal wounds with intraocular foreign bodies are challenging situations, as they require very complex therapeutic management. Sometimes, the surgeon can extract the foreign body and cure the associated complications in one surgical intervention, but there are times when several interventions are needed. In our case, we performed the extraction of the intraocular foreign body and the management of the corneal wound at once, postponing the cataract extraction and IOL implantation.

Fig. 2 a,b Intraoperative aspects - extraction of the helicoidal IOFB with the forceps

Fig. 3 IOFB measuring almost 20 mm in length

Fig. 4 Postoperative aspect (after cataract extraction). We noticed the round pupil and the iris defect between 12 and 1 o’clock

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A thorough examination of the patient with penetrating corneal wound should be made as most of the times one or several intraocular foreign bodies may be associated. Patel et al. suggested that 14% of the patients with penetrating globe trauma have intraocular foreign bodies. Radiological examinations can be performed to detect intraocular foreign bodies: X-ray, ultrasound, computed tomography of the orbit. CT examination at presentation identified IOFB in more than 90% of the cases, B-scan ultrasound revealed an IOFB in 51.9% of the cases and clinical eye examination in 45.6% of the cases [6,7]. In our case report, the intraocular foreign body was visible at the clinical examination. CT or B-scan ultrasound could have revealed the depth and complications associated with the IOFB: vitreous hemorrhage, retinal detachment, and endophthalmitis.

A B-scan ultrasound was performed the day after the IOFB extraction. The retina was attached and the vitreous was clear and homogeneous.

Another important fact is the management of the cornel perforation. In our case, it was point-like, with the diameter of less than 1 mm. After extracting the intraocular foreign body, the anterior chamber was stable. That was why we decided to place a contact lens instead of a corneal suture, avoiding the irregular astigmatism and the corneal scar due to the suture.

Most of the patients with intraocular foreign bodies already have traumatic cataract when they address to the ophthalmology service. In our case, since we saw our patient one hour after the accident, the lens was clear. Traumatic cataract developed later, after IOFB extraction.

We decided to extract the opacified lens. This led to the improvement of the visual acuity and to a better visualization of the posterior pole, which helped in the detection and treatment of retinal complications [8].

There are several methods of treating traumatic cataract: extracapsular, intracapsular extraction and phacoemulsification. Because of the anterior capsule tear, in our case, capsulorhexis was more challenging than usual. We also had to pay attention to hydrodissection because posterior capsule tear might also be present. Ocular hypotony and posterior capsule break makes the surgical intervention difficult and risky [9].

In this particular case, the traumatic cataract was intumescent. This led to the extension of the anterior capsule break caused by the IOFB. We used trypan blue to stain the anterior capsule. Capsulorhexis was followed by gentle hydrodissection and extraction of the soft lens with a cannula (Fig. 5 a,b,c). Repeated viscoelastic injections were performed in the anterior chamber during the procedure in order to maintain its stability and protect the corneal endothelium. Vitreous could be found in the anterior chamber due to a posterior capsule break. Triamcinolone straining and anterior vitrectomy were used for its removal.

Choosing the right type of intraocular artificial lens is very important when appropriate capsular support is absent. Several types are available: IOL with scleral fixation, anterior chamber IOL and iris-claw IOL. Several studies revealed that fixating an iris-claw IOL on the posterior face of the iris result in reduced surgical time and good stability of the IOL on long-term.

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According to Labeille et al., the complications associated with this type of IOL were: cystoid macular edema, retinal detachment, transient intravitreal hemorrhage, secondary glaucoma and choroidal detachment, but with a lower incidence in comparison with the scleral fixation IOL [10]. Placing the IOL on the posterior face of the iris reduces the risk of endothelial cells loss and of bullous keratopathy. These are some of the reasons that determined us to use this type of IOL to correct the surgical aphakia in our case. Postoperative best-corrected visual acuity was 0.8.

Even if surgical outcome was good, long-term complications could arise.

The most important complication of open globe injury is endophthalmitis. The frequency of endophthalmitis after open globe injury is 6.8% [11] and the etiology is mostly Staphylococcus spp. The following factors were associated with the subsequent development of endophthalmitis: dirty wound, retained intraocular foreign body, lens capsule breach, delayed primary repair [11]. Our patient underwent a prompt surgical intervention for IOFB extraction followed by the irrigation of the anterior chamber with vancomycin and systemic antibiotic therapy. It did not develop any signs or symptoms of endophthalmitis.

Secondary glaucoma is another complication. There is a strong correlation between traumatic cataract, angle recession of minimum 180 degrees, iris trauma, traumatic

ectopia of the lens and secondary traumatic glaucoma [12]. According to Bojikian et al., traumatic IOP elevation and glaucoma are common after visually salvageable open-globe injury. Most cases develop within 6 months, although longer follow-up remains important for case detection [13].

Between 15-32% of the patients with IOFB may develop retinal detachment [8]. In our case report, retinal injury was not associated even though the IOFB was almost 20 mm long.

Young patients can develop proliferative vitreoretinopathy in the absence of retinal breaks, leading to vitreoretinal tractions, secondary retinal breaks, tractional retinal detachment, and decreased visual acuity. It is important to perform a thorough follow up of young patients with open globe injury and address them to the vitreoretinal surgeon at the first signs of PVR.

Macular pucker is frequent when the IOFB touches the retina near the macula or the temporal vascular arcades [14]. Vitreous hemorrhage is present in almost all the cases of IOFB following open globe injury. Sometimes, it reabsorbs by itself but most of the times it requires posterior vitrectomy.

We must not neglect the risk of sympathetic ophthalmia. In our case, the risk was low because of the good surgical management without vitreous or iris loss.

Conclusions

Ocular trauma occurs mostly in young, active males.

Open globe injuries with IOFB require a thorough examination of the eye. The detection and treatment of the associated complications can determine a favorable outcome with the restoration of the anatomical integrity of the eye and a good visual acuity.

References

1. Nichols BD. Ocular Trauma: Emergency Care and Management. Can Fam Physician. 1986 Jul; 32:1466–1471.

2. Chorągiewicz T, Nowomiejska K, Wertejuk K et al. Surgical treatment of open globe trauma complicated with the presence of an intraocular foreign body. KlinOczna. 2015; 117(1):5-8.

Fig. 5 a,b,c Intraoperative aspects: extraction of the traumatic cataract

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3. Condon GP. Simplified small-incision peripheral iris fixation of an AcrySof intraocular lens in the absence of capsule support. J Cataract Refract Surg. 2003; 29:1663–7.

4. Schein OD, Kenyon KR, Steinert RF, Verdier DD, Waring GO 3rd, Stamler JF et al. A randomized trial of intraocular lens fixation techniques with penetrating keratoplasty. Ophthalmology. 1993; 100:1437–43.

5. Zeh WG, Price FW Jr. Iris fixation of posterior chamber intraocular lenses. J Cataract Refract Surg. 2000; 26:1028–34.

6. Patel SN, Langer PD, Zarbin MA, Bhagat N. Diagnostic value of clinical examination and radiographic imaging in identification of intraocular foreign bodies in open globe injury. Eur J Ophthalmol. 2012 Mar-Apr; 22(2):259-68.

7. Suthar Pokhraj P, Patel Jigar J, Chetan M, Patel Narottam A. Intraocular Metallic Foreign Body: Role of Computed Tomography. J Clin Diagn Res. 2014 Dec; 8(12):RD01–RD03.

8. Mahapatra SK, Rao NG. Visual outcome of pars plana vitrectomy with intraocular foreign body removal through sclerocorneal tunnel and sulcus-fixated intraocular lens implantation as a single procedure, in cases of metallic intraocular foreign body with traumatic cataract. Indian J Ophthalmol. 2010 Mar-Apr; 58(2):115–118.

9. Veselinović D, Stefanović I, Jovanović M, Veselinović A, Trenkić-Bozinović M. Operation of traumatic cataract with metal foreign body in the lens. Srp Arh Celok Lek. 2011 Mar-Apr; 139(3-4):216-20.

10. Labeille E, Burillon C, Cornut PL. Pars plana vitrectomy combined with iris-claw intraocular lens implantation for lens nucleus and intraocular lens dislocation. J Cataract Refract Surg. 2014 Sep; 40(9):1488-97.

11. Essex RW, Yi Q, Charles PG, Allen PJ. Post-traumatic endophthalmitis. Ophthalmology. 2004 Nov; 111(11):2015-22.

12. Sihota R, Sood NN, Agarwal HC. Traumatic glaucoma. Acta Ophthalmol Scand. 1995 Jun; 73(3):252-4.

13. Bojikian KD, Stein AL, Slabaugh MA, Chen PP. Incidence and risk factors for traumatic intraocular pressure elevation and traumatic glaucoma after open-globe injury. Eye. 2015 Sep 18. doi: 10.1038/eye.2015.173.

14. Feghhi M, Dehghan MH, Farrahi F, Moghaddasi A, Rastegarpour A. Intraretinal foreign bodies: surgical techniques and outcomes. J Ophthalmic Vis Res. 2013 Oct; 8(4):330-6.

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Diagnosis difficulties in a patient with progressive loss of vision - a case report

Cristescu Teodor Razvan Ploiesti County Hospital, Ploiesti, Romania; Miroptic Med, Ploiesti, Romania Correspondence to: Cristescu Teodor Razvan, MD, Ploiesti County Hospital, Ploiesti, Romania, 108 Matei Basarab Street, bl. 74, st. 1, 1st floor, ap. 7, District 3, Bucharest, Romania, Mobile phone: +40769 287 827, E-mail: razvancristescu@ymail.com Accepted: December 19, 2016

Abstract The paper presents the case of a 57-year-old male patient who complained of slow progressive loss of visual acuity. Anamnesis revealed he was a heavy drinker and he was previously diagnosed with a pancreatic cancer, observed on the MRI. The clinical examination revealed ocular features that made the diagnosis difficult. Initially, it seemed to be a case of narrow angle glaucoma but further ocular examinations revealed macular thinning. Keywords: cancer-associated retinopathy, paraneoplastic retinopathy, autoimmune retinopathy

Introduction Case report

A 57-year-old man presented to the ophthalmology department complaining of progressive visual loss, which he had been suffering from for the last few weeks, wishing to undertake surgery for cataract. Anamnesis revealed he was a heavy drinker and that he was recently discovered with pancreatic cancer (observed on the MRI). He was not taking any medication but he mentioned he was scheduled for a consultation with the oncologist. At presentation, his visual acuity was 1/ 10 with his own corrective glasses at both eyes. Measured refraction was around +4 spherical diopters (Fig. 1) but the maximal correction did not provide a better visual acuity. Intraocular pressure measured by a non-contact tonometer was 9 in his right eye and 14 in his left eye.

Fig. 1 Refraction

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The biomicroscopic examination revealed a shallow anterior chamber and a clear lens (Fig. 2). Due to this anatomical conformation, narrow angle glaucoma was suspected but the patient did not recall any episodes of ocular pain, redness, and acute loss of visual acuity. The fundus examination was performed under a careful dilatation, with tropicamide and revealed a few soft macular drusen in the right eye, and a curious sectorial temporal pallor of both optic nerve heads (Fig. 3,4). Red free images of the posterior pole were taken but did not reveal any loss of ganglionar nerve fibers suggestive of glaucoma (Fig. 5,6).

Fig. 2 Anterior aspect

Fig. 3 Fundus examination RE

Fig. 4 Fundus examination LE

Fig. 5 Red free image REF

Fig. 6 Red free image LEF

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Humphrey visual field examination revealed central scotomas in both eyes. The patient was unable to fixate, hence a lot of fixation errors (Fig. 7,8) appeared. These results, which were not specific for glaucoma, oriented more towards a macular disease or some kind of optic nerve disease (neuritis or AION). Optical coherence tomography for both maculae and optic nerve heads was recommended for further investigation.

Optical coherence tomography revealed a macula thinner than average, highlighted by the red color on the thickness map (Fig. 9,10). OCT of the optic nerve head and RNFL analysis showed a thick neuroretinal rim, with no evidence of optic nerve atrophy. The results suggested a macular disease.

Fig. 7 Visual field RE

Fig. 8 Visual field LE

Fig. 9 OCT LE

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Diagnosis

The clinical signs and paraclinical examinations alone were not sufficient for a positive diagnosis, but as the patient revealed documents about his general health, mentioning that he was diagnosed with pancreatic cancer, the diagnosis of a cancer associated retinopathy (CAR) seemed plausible. No diagnostic criteria were set for this type of paraneoplastic retinopathy. Apart from the above mentioned criteria, one of the most important was the identification of serum anti-retinal antibodies, the most important of these being the anti-recoverin (a 23-kDa protein) and the anti-alpha-enolase antibody (46-kDa) [6,7]. USA has tests for the identification of these antibodies. On the other hand, these antibodies are not diagnostic tools for CAR themselves because they were also identified in normal individuals, so they must be correlated with the clinical findings.

Differential diagnosis

1. subacute or intermittent angle closure glaucoma - visual field defects were not characteristic for glaucomatous damage. The optic nerve OCT revealed a normal width of the neuroretinal rim.

2. toxic neuropathy - the patient was a heavy drinker

3. retrobulbar neuritis or ischemic neuropathy - the paraclinical investigations localized the disease at the level of the macula and not at the level of the optic nerve.

4. retinal dystrophies 5. optic nerve tumors - The MRI revealed

only the pancreatic mass, with no sign of other affected organs.

Treatment

The patient followed the oncologist for the treatment of his cancer. At this moment, there is no known effective treatment for CAR. The treatment of systemic cancer does not lead to the improvement of vision. Many systemic immunosuppressive medications have been tried

Fig. 10 OCT RE

Fig. 11 OCT optic nerve

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with mild and transient improvement in the visual acuity but no long lasting improvement has been recorded [1].

Evolution and prognostic

The patient could not be followed-up for more than a few weeks because he did not come to the ophthalmological evaluations anymore. The prognosis for visual recovery in CAR was poor, but, on the other hand, complete or further progressive visual loss did not occur. Usually, disease stabilization occurs in such a case.

Case particularities

Although initially the patient seemed to have a form of angle closure glaucoma due to his shallow anterior chamber, further exams showed a thinned macula and no objective signs of nerve damage.

Cancer associated retinopathy is a rare disease that is most often associated with colon or gynecologic cancers. The presented case associated a maculopathy and a pancreatic cancer.

Discussions

The presented case closely resembled 2 other cases that were recently presented by Eadie et al. They reported the cases of 2 women with localized foveal flattening and history of cancer. The OCT findings showed the flattening of the foveal depression in both eyes with the disruption of the inner retinal layers [2].

Cancer associated retinopathy is a specific type of paraneoplastic disease of the eye, associated with the presence of extraocular malignancy and circulating autoantibodies against retinal proteins. It is hypothesized that some tumors express protein antigens that are the same or cross-react with retinal proteins [3].

CAR is triggered by an alteration of the immune system. The autoimmune reaction leads to retinal photoreceptor cell death. In patients with a diagnosis of systemic cancer, screening should be done for anti-retinal antibodies, in particular anti-recoverin (23-kDa protein) [4] and anti-alpha-enolase (46-kDa) [5].

The first retinal antigen shown to represent the source of autoimmunity in CAR was a 23 kDa protein named recoverin [6], but many other proteins were found to be antigenic (alfa-enolase [7], transducin).

Electroretinography (ERG) is very important to highlight the retinal dysfunction. Full field ERG is abnormal in most cases (attenuated or absent photopic and scotopic response) [8]. In cases in which only the cones are affected, full field ERG may be normal but multifocal ERG reveals the macular disease. OCT is helpful in evaluating patients with CAR and the studies published so far showed reduced central macular and foveal thickness [9].

References 1. Ferreyra HA, Jayasundera T, Khan NW, He S, Lu Y,

Heckenlively JR. Management of autoimmune retinopathies with immunosuppression. Arch Ophthalmol. 2009; 127(4):390–397.

2. Eadie JA, Ip MS, Ver Hoeve JN. Localized retinal manifestations of paraneoplastic autoimmune retinopathy. Retin Cases Brief Rep. 2014 Fall; 8(4):318-21.

3. Thirkill CE, Roth AM, Keltner JL. Cancer-Associated Retinopathy. Arch Ophthalmol. 1987; 105(3):372-375.

4. Whitcup SM, Vistica BP, Milam AH, Nussenblatt RB, Gery I. Recoverin-associated retinopathy: a clinically and immunologically distinctive disease. Am J Ophthalmol. 1998; 126(2):230–237.

5. Adamus G, Aptsiauri N, Guy J, Heckenlively J, Flannery J, Hargrave PA. The occurrence of serum autoantibodies against enolase in cancer-associated retinopathy. Clin Immunol Immunopathol. 1996; 78(2):120–129.

6. Adamus G, Guy J, Schmied JL, Arendt A, Hargrave PA. Role of anti-recoverin autoantibodies in cancer-associated retinopathy. Invest Ophthalmol Vis Sci. 1993 Aug; 34(9):2626-33.

7. Dot C, Guigay J, Adamus G. Anti-alpha-enolase antibodies in cancer-associated retinopathy with small cell carcinoma of the lung. Am J Ophthalmol. 2005 Apr; 139(4):746-7.

8. Hiroshi O et al. Clinical and immunologic aspects of cancer-associated retinopathy. American Journal of Ophthalmology. 2004; 137.6:1117-1119.

9. Mohamed Q, Harper CA. Acute optical coherence tomographic findings in cancer-associated retinopathy. Arch Ophthalmol. 2007; 125(8):1132-3.

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Intraocular ossification. Case report Maftei Ciprian*, Stanca Horia Tudor* ** *“Prof. Dr. Agrippa Ionescu” Clinical Emergency Hospital, Bucharest, Romania **“Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania Correspondence to: Horia Tudor Stanca, MD, PhD, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania, 8 Eroii Sanitari Blvd., District 5, Code 050474, Bucharest, Romania, Phone +40722 761 454, E-mail address: hstanca@yahoo.com Accepted: January 19, 2017

Abstract Objective: To report a case of intraocular ossification, describe its particularities and review some of the pathogenesis theories. Methods: We described the case of a 31-year-old woman with a history of perforating trauma ten years before, who presented in our clinic for right eye pain. The patient wanted a cosmetic improvement so an evisceration was proposed. An intraocular hard yellowish mass, which had a histopathological examination, was found intraoperatively. Results: We diagnosed the case as an intraocular ossification, based on the medical history and histopathological specimen examination, which proved to be an ossified structure. Conclusions: In spite of a rare occurrence, our case emphasized the theory that trauma and subsequent neurogenic inflammation could lead to osseous metaplasia. Keywords: intraocular ossification, osseous metaplasia, bone formation

Introduction

Eyeball structures ossification is a rare type of metaplasia. Chronic inflammation, trauma, or a long-standing retinal detachment can be an etiologic factor for the heterotopic bone formation. We reported a case of a 31-year-old woman with a history of perforating trauma ten years before, who complained of right eye pain and wanted a cosmetic appearance improvement. During the evisceration, a hard, yellowish mass was discovered in the eyeball. We diagnosed the case as an intraocular ossification, based on the histopathological specimen examination, which proved to be an ossified structure.

Ectopic bone formation can be found in any soft, highly vascularized tissue, but has a rare

intraocular occurrence. In a study conducted by Finkelstein and Boniuk [1] on 2486 enucleated eyes, an intraocular ossification was described in only 119 (4.8%) cases. An association between ectopic ossification and long-standing retinal detachment, chronic inflammation, phthisis bulbi, microphthalmia, buphthalmos, or some intraocular tumors [2-4] was found. A case of intraocular ossification was reported and some of the theories about it were reviewed.

Case report

A 31-year-old woman presented to our clinic complaining of right eye pain and cosmetic appearance. She had a history of perforating trauma of the right eye due to a car crash ten

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years before. At that time, she underwent vitrectomy for rhegmatogenous retinal detachment and had several reattachment procedures over the years. On the eye exam, the right eye had no light perception, the right cornea had a central epithelial defect, with fine dust-like subepithelial deposits, emulsified silicone oil in the anterior chamber, a round, nonreactive pupil and corectopia, and it revealed postoperative aphakia (Fig. 1). The fundus examination of the right eye revealed full-thickness fixed retinal folds in three quadrants and subretinal strands. The left eye was normal.

A standard evisceration technique with a polymethylmethacrylate implant was used. When the eyeball content was removed, a hard mass could be palpated covering the temporal inner sclera. With a successive dissection, a hard, white, 30 x 3 x 1 mm mass was exposed (Fig. 2 a,b). It was difficult to distinguish the origin of the mass considering the medical history. We had a histopathological specimen evaluation done, which described an ossified structure with areas of thin retinal tissue attached that could be a posttraumatic ossification.

Discussion

Intraocular abnormal bone formation is an entity that occurs in degenerative tissues, chronic eye disease, tumors, or congenital disorders [1-6]. Generally, there are two types of osteogenic precursor cells that induce ossification: one can be determined, found in the bone marrow stroma; others are inducible, found in the circulating blood and the connective tissue framework of many other tissues [7]. Inducible osteogenic cells need an agent to induce bone formation, which could be cells from the retinal pigment epithelium (RPE) or some types of morphogenic multifunctional cytokines [8,9]. The retinal epithelium cells in the eye are considered to be pluripotent and have the capacity to differentiate the mesenchymal phenotype, including fibroblasts and osteoblasts which are osteogenesis inducing cells [1,10].

Fig. 1 Intraoperative aspect of the anterior segment

Fig. 2 a,b Intraoperative aspect of the intraocular mass

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Intraocular ossification has an incidence reported in large series of enucleated eyes, that varies from 5% to 18%, but there are unpublished studies that report an occurrence rate of more than 38% [1,11]. The osseous metaplasia is diagnosed differently depending on the date of onset and the examination methods [12]. Generally, the studies found that a 10 to 20 year period is needed. In some rare cases, an intraocular bone is formed in less than two years after the initial injury [1,11]. Choroidal ossification can be histopathologically diagnosed one year after the ocular trauma, but it needs 10 to 20 years to be radiologically identified [13]. The correlation between age and the etiological factors of this condition was pointed out in one of the studies. Trauma was the leading cause for the 10 to 50 years old age group, while for the 51-90 years old group, the inflammation was the leading etiological factor [5].

The first studies reported the site of intraocular ossification only external to the neurosensory retina [1,5]. With the advance of surgical techniques, it became possible to conduct histopathological studies on epiretinal membranes. Such studies reported osseous metaplasia in epiretinal membranes obtained at vitreoretinal surgery [14,15]. Now, we can assume that the location of heterotopic bone can be pre-retinal, sub retinal or in both location and in some certain conditions there could be intraretinal ossification [11].

Complex pathogenic mechanisms are suggested for every different site of intraocular ossification. The principal source of fibrous and osseous metaplasia appears to be retinal pigment epithelium [9]. Growth differentiation factor-5 (GDF-5), bone morphogenic protein-7 (BMP-7), and transforming growth factor beta-1 (TGF β1) are multifunctional cytokines that have important roles in bone formation [9]. A model for bone formation was proposed in a study conducted by Toyran S et al. [9]. Chronic end-stage eye disease is often accompanied by intraocular inflammation. The inflammatory cells release interleukin-1 (IL-1) or tumor necrosis factor alpha (TNF-α), stimulating the RPE to produce TGF β1 and BMP-7. TGF β1 triggers epithelial-mesenchymal transformation of RPE cells into RPE fibrous metaplasia. BMP-7 inhibits this transformation by counteracting the effect of TGF β1. Additionally, BMP-7 promotes the

transformation of metaplastic RPE into osteoblasts. It is likely that GDF-5, which was co-localized with BMP-7 in areas of RPE metaplasia, also stimulates osseous metaplasia.

Preretinal ossification occurs after the migration of retinal pigment epithelium from the sub-retinal space to the retinal surface, along the back surface of the detached retina (through retinal breaks) [14,15]. Bone formation could occur within the fibrous membranes or the proliferating vitreoretinal mass, suggesting the possibility of multi-directional metaplasia of the retinal pigment epithelial cells [11].

Drusen are an abnormal accumulation of extracellular material in Bruch’s membrane that is suggested to be an important step in the transdifferentiation of retinal pigment epithelium following retinal detachment [16]. As drusen have various morphologies, there is a possibility that some components within to act like an inducing agent for osteogenesis in earlier stages.

A different possible theory suggested by Munteanu M et al. [12] describes the ossification of the choroid. Some of the factors that cause bone formation within the choroid are BMPs, growth factors, and in particular, pericytes and/ or circulant mesenchymal stem cells (MSCs). The pluripotent MSCs can differentiate between different cell types like osteoprogenitor cells that secrete bone matrix. Bone matrix regeneration and remodeling leads to the formation of spicules and thereafter osseous trabeculae which, by interconnection, generate primary spongy bone, later replaced by lamellar bone. The histopathological aspect of ossified choroidal tissue reveals a spongy type, consisting of osseous lamellae, osteocytes, bone canaliculi, and adipose tissue. This lamellar bone structure supports the hypothesis of endoconjunctive/ desmal ossification, without passing through the cartilage phase. This theory seems to explain more suitable our findings – a hard mass with a semicircular configuration, perfectly adapted to the eye wall and located between the retina and the sclera.

To summarize, intraocular ossification is a rare finding, with complex pathogenic mechanisms not entirely understood. Specialists came to an agreement that chronic inflammation, posttraumatic neurogenic inflammation, bone morphogenic proteins, drusen components, and

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the differentiation of mesenchymal stem cells are parts of the pathogenesis.

Financial Disclosures

None of the authors has any financial or proprietary interests to disclose.

References

1. Finkelstein EM, Boniuk M. Intraocular ossification and hematopoiesis. Am J Ophthalmol. 1969; 68:683-90.

2. Duke-Elder S, Perkins ES. Diseases of the uveal tract. In Duke-Elder S, ed. System of ophthalmology. vol. 9, 1966, St. Louis: CV Mosby, 740-7.

3. Samuels B. Ossification of the choroid. Trans Am Acad Ophthalmol. 1938; 43:193-244.

4. Reese AB. Tumors of the eye. 3rd ed., 1976, Hagerstown: Harper & Row, 318-22.

5. Monselise M, Rapaport I, Romem M et al. Intraocular ossification. Ophthalmologica. 1985; 190:225–9.

6. Pecorella I, Vingolo E, Ciardi A, Grenga P. Scleral Ossification in Phthisical Eyes’. Orbit. 2006; 25:1,35-38.

7. Vaughan J. Osteogenesis and hematopoiesis. Lancet. 1981; 2:133-36.

8. Friedenstein AJ. Determined and inducible osteogenic precursor cells. In: Hard Tissue Growth, Repair, and Remineralization. Ciba Foundation Symposium II. 1973, New York: Elsevier, 69-81.

9. Toyran S, Lin AY, Edward DP. Expression of growth differentiation factor-5 and bone morphogenic protein-7 in intraocular osseous metaplasia. Br J Ophthalmol. 2005; 89:885-890.

10. Park HS, Kong TS, Jang KY, Chung MJ, Moon WS, Lee DG, Kang MJ. Intraocular Ossification: A Case Report. The Korean Journal of Pathology. 2004; 38(3):188-190.

11. Vemuganti GK, Honavar SG, Jalali S. Intraocular osseous metaplasia. A clinico-pathological study. Indian J Ophthalmol. 2002 Sep; 50(3):183-8.

12. Munteanu M, Munteanu G, Giuri S, Zolog I, Motoc AG. Ossification of the choroid: three clinical cases and literature review of the pathogenesis of intraocular ossification. Rom J Morphol Embryol. 2013; 54(3 Suppl):871-7.

13. Zografos L, Uffer S, Girard-Othein BCh. Tumeurs osseoses de la choroide. In: Zografos L (ed)., Tumeurs intraoculaires. 2002, Masson, Paris, 335–350.

14. Yoon YD, Aeberg TM, Wojno TH, Grossniklaus HE. Osseous metaplasia in proliferative vitreoretinopathy. Am J Ophthalmol. 1998; 125:558-59.

15. Lowenstein JI, Hogan RN, Jakobiec FA. Osseous metaplasia in a preretinal membrane. Arch Ophthalmol. 1997; 115:117-19.

16. Rohrbach JM, Liesenhoff E, Steuhl KP. Principles of intraocular ossification exemplified by secondary choroid ossification. Klin Monatsbl Augenheilkd. 1990; 197:397-403.

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Scheimpflug topographical changes after Femtosecond LASIK for mixed

astigmatism – theoretical aspects and case study

Tabacaru Bogdana* **, Stanca Horia Tudor* ** *** *”Prof. Dr. Agrippa Ionescu” Emergency Hospital, Bucharest, Romania **“Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania ***”Metropolitan” Hospital, Bucharest, Romania

Correspondence to: Bogdana Tabacaru, MD, Department of Ophthalmology, “Prof. Dr. Agrippa Ionescu” Emergency Hospital, Bucharest 7 Ion Mincu Street, Code 011356, Bucharest, Romania, Mobile phone: +40741 111 238, E-mail: bogdana_gt@yahoo.com

Accepted: February 13, 2017

Abstract Objective: To evaluate the corneal topographical changes after Femtosecond-LASIK surgery in eyes with mixed astigmatism. Methods: We present the analysis of the corneal Scheimpflug topographies of a patient treated with Femtosecond-LASIK technique for bilateral mixed astigmatism. Results: Three-dimensional reconstruction maps and differential anterior curvature maps were used to demonstrate the ablation profile and its stability in time. Conclusions: Visual and refractive results were very good after surgery, being topographically confirmed by the corneal reshaping which was performed as planned, the achieved ablation being stable during the one-year follow-up period. Keywords: Femtosecond-LASIK, Mixed Astigmatism, Scheimpflug Analysis, Corneal Topography, Tangential Anterior Map

Introduction

Astigmatism is the condition of refraction in which the rays of light coming from a point source cannot produce a point on the retina [1,2]. Cornea is the major source of astigmatism in the optical system as it is responsible for about 74% of the total dioptric power of a normal eye [3]. The optical power of the mixed astigmatic eye is different in two principal meridians, perpendicular to one other, one meridian being myopic and the other being hyperopic [4]. The aim of corneal refractive surgery in mixed astigmatism is to reshape the cornea, flattening it in the myopic meridian and steepening it in the hyperopic meridian [5].

After the corneal refractive surgery, changes in the corneal shape and curvature can be evaluated by using a variety of devices based on Placido-disc systems and elevation analyzers [6]. The Schwind Sirius (Schwind Eye-Tech-Solutions GmbH&Co, Germany) is a device that combines a Scheimpflug camera with a Placido disc corneal topographer [7]. Placido-based videokeratoscopy measures the corneal reflection of mires (circles of light) of known radius, the corneal power being estimated mathematically. Rotating Scheimpflug camera system uses the slit illumination to obtain an optical section that is captured in a side view, the camera being oriented according to the Scheimpflug principle, in order to create sharp

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images from anterior corneal surface to depth [8]. Data obtained after corneal scanning are converted to computerized color scale maps [6].

The axial (or sagittal) map is the most commonly used map for routine screening, as it easily classifies the normal and abnormal corneas and differentiates between spherical, astigmatic or irregular corneas. Due to the Placido rings configuration and to the axial acquisition which intersects with the instrument axis, the sagittal map fails to describe the true shape and power of the peripheral cornea [6,9].

The tangential map (also called “instantaneous radius of curvature”) has a better accuracy in the evaluation of the peripheral changes in shape and curvature but has the

tendency to reveal excessive details that are not always clinically relevant. It may be very useful in detecting mild corneal changes that could not be detected by the sagittal maps [6,9].

The three-dimensional reconstruction maps, available in both sagittal and tangential acquisitions, offer an overall view and a better understanding of the real corneal shape with steep and flat areas [9]. Normal corneas are prolate, being steeper centrally and flatter peripherally, with a medium anterior refractive power of 43.00-43.50 diopters [10]. Fig. 1 shows the three-dimensional tangential anterior and sagittal anterior configuration of a normal spherical cornea.

Material and methods – Case study

A 23-year-old white woman (P.A.M.), underwent bilateral Femtosecond-LASIK with the VisuMax – Mel80 platform (Carl Zeiss Meditec, Germany), to correct mixed astigmatism. Preoperative manifest refractive errors were +1.75 – 3.25 x 0o in the right eye and +1.75 – 3.75 x 175o in the left eye. The best-corrected visual acuity of both eyes was 20/20. The patient underwent refraction with fogging and refraction under cycloplegia, which demonstrated a hyperopic shift of 0.5 and 1.25, respectively in both eyes. Keratometry values for

the right eye were K flat 41.23 x 8o, K steep 44.28 x 98o and for the left eye K flat 41.20 x 177o, K steep 45.05 x 87o. Corneal pachymetry in the thinnest location was 0.565 mm in the right eye and 0.561 mm in the left eye. Topographies were performed with the Schwind Sirius topographer. Preoperative slit-lamp biomicroscopy and mydriatic fundoscopy revealed no pathological findings.

Femtosecond laser parameters for the anterior corneal flap cutting were chosen as it follows: depth of 120 µm, diameter of 8.8 mm, hinge of 3.84 located superiorly and side cut angulation of 50o. We have chosen a refraction of

Fig. 1 Scheimpflug topography of a spherical cornea. Left image – tangential anterior map; Right image – sagittal anterior map

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+2.25 – 3.25 x 0o in the right eye and +2.25 – 3.75 x 175o in the left eye for the excimer treatment plan, with an optical zone of 6.5 mm for both eyes. Surgery was uneventful.

Postoperative examinations were carried out on the first day following the surgery and then after one, six and twelve months. We evaluated the uncorrected distance visual acuity (UDVA), the manifest refraction and we performed slit-lamp examinations at each visit. Except for the first postoperative day,

topographies were achieved at each follow-up visit.

Results

Postoperative results were good, with full recovery of uncorrected vision and a manifest refraction very close to emmetropia. The keratometry was constant over the follow-up period (Table 1).

Table 1. Postoperative visual acuities, manifest refraction and keratometric measurements for patient P.A.M.

Postoperative visit UDVA Manifest refraction K flat K steep Right eye:

- 1 day - 1 month - 6 months - 12 months

20/ 20 20/ 20 20/ 20 20/ 20

+0.75 –1.00 x 87o

+0.50 –0.25 x 44o

+0.75 –0.25 x 33o

+0.75 –0.25 x 19o

42.50 x 97o 42.75 x 90o

42.75 x 0o

42.50 x 110o

43.25 x 7o 43.00 x 180o

42.75 x 90o

43.00 x 20o Left eye:

- 1 day - 1 month - 6 months - 12 months

20/ 20 20/ 20 20/ 20 20/ 20

+0.25 –0.75 x 173o

+0.25 –0.50 x 168o

+0.75 –0.25 x 177o

+0.50 –0.50 x 176o

42.75 x 179o

42.50 x 163o

42.75 x 168o

42.75 x 167o

43.00 x 89o

43.25 x 73o

43.25 x 78o

43.25 x 77o

We further present the corneal topographies performed pre and postoperatively and their analysis regarding the corneal shape and curvature changes occured after the refractive surgery and their stability over the follow-up period.

Fig. 2 and 3 demonstrate the results of the calculated ablation we have performed for the right eye and the left eye respectively. The preoperative tangential anterior map was on the upper-left and the one-month postoperative tangential map was on the upper-right. As the

color scale was the same for both topographical aquisitions, we were able to directly compare the two scans on a differential map, visualizing the ablation profile. The relative shape of the corneas was changed with flattened areas in the myopic meridians and steepened areas in the hyperopic meridians. As a result of the surgery, the corneas theoretically looked as if they were spheres. The corneal shape changing result can be better understood in the three-dimensional reconstruction, shown in Fig. 4 for the right eye and in Fig. 5 for the left eye.

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Fig. 2 Up-left: Tangential anterior map for the right eye of the patient P.A.M. at the preoperative visit. Up right: Tangential anterior map for the right eye of the patient P.A.M. at 1-month postoperative visit. Bottom: Differential tangential anterior map between preoperative and postoperative 1 month visits, for the right eye of the patient P.A.M.

Fig. 3 Up-left: Tangential anterior map for the left eye of the patient P.A.M. at the preoperative visit. Up right: Tangential anterior map for the left eye of the patient P.A.M. at 1-month postoperative visit. Bottom: Differential tangential anterior map between preoperative and postoperative 1 month visits, for the left eye of the patient P.A.M.

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Two postoperative corneal topographical maps were also compared in order to demonstrate the ablation stability in time. The postoperative differential maps for both eyes were achieved by substracting the 12-months postoperative map from the one obtained at the 1-month follow-up visit. The postoperative

differential maps displayed on the bottom of Fig. 6 (for the right eye) and Fig. 7 (for the left eye) show exactly the changes that had occured in every corneal point during the 1-year follow-up. The ablation profile was stable, with unsignificant changes of the radius of curvature inside the optical zone.

Fig. 4 Tangential anterior map of Scheimpflug topography of the right eye of patient P.A.M. Left image – Preoperative; Right image – one-month postoperative

Fig. 5 Tangential anterior map of Scheimpflug topography of the left eye of patient P.A.M. Left image – Preoperative; Right image – one-month postoperative

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Fig. 6 Up-left: Tangential anterior map for the right eye of the patient P.A.M. at 1-month postoperative visit. Up right: Tangential anterior map for the right eye of the patient P.A.M. at 12 months postoperative visit. Bottom: Differential tangential anterior map between postoperative 1 month and 12 months visits, for the right eye of the patient P.A.M.

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Discussion

Nowadays, corneal topography is an indispensable investigation in the preoperative and postoperative refractive surgery management. The curvature maps, available in bi- and three-dimensional imaging are very useful to better understand the corneal shape changes that occur after surgery. Modern software allows a comparative analysis of the corneal corresponding points and generates differential maps that are useful in the precise evaluation of changes between preoperative and postoperative visits or between two postoperative moments.

In the presented case, Femtosecond-LASIK technique was a suitable option for the correction of mixed astigmatism. During the entire follow-up period of one year, the uncorrected vision was 20/20, the manifest refraction was very close to emmetropia and the keratometry had constant values. The topographical maps used in the analysis demonstrated a proper ablation profile and its stability within at least one year. Disclosures

The authors have no financial or proprietary interest in any device presented in this study.

References 1. Remington LA. Clinical Anatomy And Physiology Of The

Visual System. 3rd ed., 2012, Elsevier, USA, 10. 2. Renu J. Basic Ophthalmology. 4th ed., 2009, New Dehli,

Jaypee Brothers Medical Publishers (P) Ltd., 53. 3. Basic and Clinical Science Course. American Academy

of Ophthalmology. Section 8. External Disease and Cornea. 2011, Singapore, 6.

4. Grovè JD, Meyer D. Refractive Errors of the Eye, in: Instant Clinical Diagnosis in Ophthalmology (Refractive Surgery). Garg A, Rosen E ed., Chapter 11st ed., 2009, New Dehli, Jaypee Brothers Medical Publishers (P) Ltd., 8.

5. Alio JL, Pachkoria K, El Aswad A, Plaza-Puche AB. Laser-assisted in Situ Keratomileusis in High Mixed Astigmatism with Optimized. Fast-repetition and Cyclotorsion Control Excimer Laser. Am J Ophthalmol. 2013; 155(5):829-836.

6. Basic and Clinical Science Course. American Academy of Ophthalmology. Section 13. Refractive Surgery. 2011, Singapore, 10-19.

7. Savini G, Barboni P, Carbonelli M, Hoffer KJ. Repeatability of Automatic Measurements by a New Scheimpflug Camera Combined with Placido Topography. J Cataract Refract Surg. 2011; 37:1809–1816.

8. Smith GT, Dart JKJ. Cornea In: Jackson TL ed. Moorfields Manual of Ophthalmology. 2nd ed., 2014, New Delhi, India: JP Medical Ltd., 161-162.

9. Simón-Castellvi GL, Simón-Castellvi S, Simón-Castellvi HM, Simón-Castellvi C. Fundamentals on Corneal Topography In: Agarwal AM, Agarwal AT, Jacob S eds. Dr Agarwal’s Textbook on Corneal Topography Including Pentacam and Anterior Segment OCT. 2nd ed., 2010, New Delhi, India, Jaypee Brothers Medical Publishers (P) Ltd., 14.

10. Ayad AF, McDermott ML, Soong HK. Cornea and Ocular Surface Diseases. in: Yanoff M, Duker JS eds., Chapter 4, 3rd ed., 2008, Yanoff & Duker: Ophthalmology, Elsevier Inc.

Fig. 7 Up-left: Tangential anterior map for the left eye of the patient P.A.M. at 1-month postoperative visit. Up right: Tangential anterior map for the left eye of the patient P.A.M. at 12 months postoperative visit. Bottom: Differential tangential anterior map between postoperative 1 month and 12 months visits, for the left eye of the patient P.A.M.

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CASE REPORT

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doi:10.22336/rjo.2017.14

Subconjunctival ocular filariasis -Case report-

Macarie Sorin Simion*, Dobre Cristina**, Suciu Marilena-Cristina**, Ionica Angela-Monica***, Cernea Mihai-Sorin***, Tarcău Paul**, Bodea Flaviu** *Department of Ophthalmology, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania **County Emergency Hospital, Cluj-Napoca, Romania ***Faculty of Veterinary Medicine, University of Agricultural Sciences and Veterinary Medicine, Cluj-Napoca, Romania Correspondence to: Sorin Macarie, MD, PhD, Department of Ophthalmology, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania 8 Victor Babes Street, Code 400012, Cluj-Napoca, Romania, Mobile phone: +40722 499 041, E-mail: sorin_macarie@yahoo.com Accepted: January 27, 2017

Abstract We are presenting the case of a patient who was clinically diagnosed with subconjunctival ocular dirofilariasis, confirmed by the parasitological examination. The treatment consisted in the surgical extraction of the parasite, a local treatment with antibiotics and steroidal anti-inflammatory mydriatic and general treatment with antihelminthic, antibiotic, analgesic, and anti-inflammatory drugs. The intraoperative and postoperative evolution of the case was favorable. Keywords: Dirofilaria repens, ocular dirofilariasis, ocular parasite

Introduction

Dirofilaria repens (Spirurida, Onchocercidae) is a nematode that parasitizes mainly dogs (Canis lupus familiaris) and other mammals, but may also infect humans, being considered a zoonotic agent [1]. The parasite’s most frequent localization in humans is in subcutaneous and ocular tissue (75.8%), especially in the ocular area, which is accessible to mosquitoes that act as vectors [2].

Adult parasites are found in subcutaneous tissues while the larvae (known as microfilariae) are found in the blood of the infested animals. They are ingested by mosquitoes of genera Aedes, Anopheles, or Culex during the blood meal. The larvae grow and become infective inside the mosquito’s body. Infective L3 larvae

may be transferred to humans through inoculation when the mosquitoes feed [3].

Case report

A 54-year-old female patient, living in a rural area in Salaj county, Romania, having contact with dogs, cats, pigs, rabbits in the household, presented to the emergency room of Cluj Ophthalmology Clinic, complaining of a sudden ocular pain that persisted from the previous day, with burning, itching and epiphora in the left eye (LE).

Family history and personal history were not relevant to the condition for which the patient presented to our clinic.

Functional ocular examination revealed a visual acuity of 20/ 20 in both eyes, normal

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intraocular pressure (14 mmHg in the right eye (RE) and 17 mmHg in the LE).

A round formation containing a mobile larva in the subconjunctival temporal region of bulbar conjunctiva was observed at the slit lamp examination of the LE, overlying a conjunctival congestion and underlying the episcleral tissue.

Examination of the fundus of the eye revealed a well-defined vital papilla, a macula with reduced foveolar reflex, and normal blood vessels without the presence of other larval forms at the back of the eyeball.

Based on clinical examination, the LE diagnose was subconjunctival ocular parasitosis. General clinical examination did not reveal the presence of subcutaneous nodules, which might be also present in Dirofilaria repens infestation. Heart ultrasound, abdominal ultrasound, and chest X-ray showed normal relations.

Laboratory examinations: blood picture with unimportant changes, normal liver enzymes, creatinine, glucose, cholesterol, triglycerides and coagulation, increased fibrinogen (520.3 mg/ dl, VN: 200-400 mg/ dl), CIC U x 10 ^ 95 3 normal C3, C4 slightly increased, IgA and IgG normal, IgM slightly decreased.

We decided to surgically extract the parasite. The surgery resulted in the extraction of a white, translucent parasite with a length of about 10 cm and a diameter of about 0.5 mm (Fig. 1-3). Both the surgical and the postsurgical evolution were favorable.

The parasitological examination revealed that the parasite was an immature male of Dirofilaria repens (L5). Nematode identification was based on morphological characters described in the literature: rounded ends, the presence of longitudinal cuticular ridges, the shape and arrangement of caudal papillae [3,4] (Fig. 6); sex was determined by emphasizing the male genitalia (spikes) which were not yet fully developed (Fig. 5,6).

During hospitalization, the patient received treatment with local antibiotic, anti-inflammatory steroid, mydriatics and general treatment with antibiotics, pain relievers, and anti-inflammatories. After the identification of the parasitic species, the patient received treatment with 400 mg albendazole two times daily, for three days.

No short term or long-term complications were noticed in the evolution of this patient.

Fig. 1 The appearance of the subconjunctival parasite

Fig. 2 The surgical extraction of the parasite

Fig. 3 Measurement of the parasite

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Conclusions

The geographical distribution of Dirofilaria repens has changed considerably in recent decades. Before 2001, the area mainly consisted of scattered areas of Italy, Greece, Spain, and southern France [5]. In correlation with a variety of factors, mainly climate change, this area has expanded into many countries in Central, Northeast, and East Europe, including Romania [6,7].

Similar to canine heartworm (D. immitis), most human cases in Europe were recorded in Italy and France [2]. There is a positive correlation between the prevalence of infestation in canine species and the risk of human infection [8]. Sporadic cases have been reported in Belgium, Bulgaria, Greece, Romania, Russia, Serbia, Slovakia, Slovenia, Spain, Ukraine, and Hungary [2,9].

After 2005, 16 other human cases have been reported in Romania [10-14], most of which involved patients living in the SE of the country, which correlates with local climatic conditions and the high infestation rates that were found in dogs from that area [15].

In the past, it was thought that man is an accidental and terminal host for this parasite and that full development cannot be achieved in the human body. More recent studies based on the discovery of microfilariae in subcutaneous nodules in humans, suggested, however, that man would be a favorable host for reaching sexual maturity [16]. In the clinical presented

Fig. 4 The appearance of the anterior extremity of the Dirofilaria repens (x20)

Fig. 5 The appearance of Dirofilaria repens posterior end with spikes visible (x20)

Fig. 6 Dirofilaria repens posterior end with spikes visible (x20)

Fig. 7 Dirofilaria repens posterior end, caudal papillae (x20)

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case, the immature parasite was located under the conjunctiva of the eye, without the presence of any subcutaneous nodules being revealed.

Previous studies have revealed high levels of specific IgG in the serum of patients infected with Dirofilaria repens [17]. In the subcutaneous forms, they are described by the presence of 26-40 kDa polypeptide fragments belonging to adult parasite antigenic complex in serum and changes in blood picture, with increased eosinophilia [17,18]. The presented case showed insignificant changes in the blood picture, the eosinophilia being within normal limits. Given that a single male parasite, that did not reach sexual maturity, was revealed under the conjunctiva of the eye, it was not considered necessary to carry out a determination of specific IgG or measurements of the antigenic fragments from serum. There is no data in literature to correlate the changes in fibrinogen, C4, IgM with the nematode’s presence.

References

1. Orihel TC, Eberhard ML. Zoonotic filariasis. Clin Microbiol Rev. 1998; 11:366-381.

2. Pampiglione S, Rivasi F. Human dirofilariasis due to Dirofilaria (Nochtiella) repens: an update of world literature from 1995 to 2000. Parassitologia. 2000; 42:231-254.

3. Manfredi MT, Di Cerbo A, Genchi M. Biology of filarial worms parasitizing dogs and cats. In: Genchi C, Rinaldi L, Cringoli G (eds), Mappe Parassitologiche 8 - Dirofilaria immitis and D. repens in dog and cat and human infections. 2007, Rolando Editore, Naples, Italy, 41-45.

4. Demiaszkiewicz AW, Polańczyk G, Osińska B, Pyziel AM, Kuligowska I, Lachowicz J. Morphometric characteristics of Dirofilaria repens Railliet et Henry, 1911 parasite of dogs in Poland. Wiadomooeci Parazytologiczne. 2011; 57:253–256.

5. Trotz-Williams LA, Trees AJ. Systematic review of the distribution of the major vector-borne parasitic infections in dogs and cats in Europe. Vet Rec. 2003; 152:97-105.

6. Genchi C, Rinaldi L, Mortarino M, Genchi M, Cringoli G. Climate and Dirofilaria infection in Europe. Vet Parasitol. 2009; 163:286-292.

7. Otranto D, Dantas-Torres F, Brianti E, Traversa D, Petrić D, Genchi C, Capelli G. Vector-borne helminthes of dogs and humans in Europe. Parasites & Vectors 2013. 2013; 6:16.

8. Montoya-Alonso JA, Mellado I, Carretón E, Cabrera-Pedrero ED, Morchón R, Simón F. Canine dirofilariosis caused by Dirofilaria immitis is a risk factor for the human population on the island of Gran Canaria,

Canary Islands, Spain. Parasitol Res. 2010; 107:1265-1269.

9. Harizanov RN, Jordanova DP, Bikov IS. Some aspects of the epidemiology, clinical manifestations, and diagnosis of human dirofilariasis caused by Dirofilaria repens. Parasitol Res. 2014; 113:1571-1579.

10. Mănescu R, Bǎrǎscu D, Mocanu C, Turculeanu A. Nodul subconjunctival cu Dirofilaria repens. Chirurgia. 2009; 104(1):95–97.

11. Popescu I, Tudose I, Racz P, Muntau B, Giurcaneanu B, Poppert S. Human Dirofilaria repens Infection in Romania: A Case Report. Case Reports in Infectious Diseases. 2012; Article ID 472976.

12. Lupșe M, Mircean V, Cavasi A, Mihalca AD. Recurrent subcutaneous human Dirofilariasis due to Dirofilaria repens after surgical removal of the worm and anthelmintic treatment. Parasites & Vectors. 2014; 7(Suppl 1):P3.

13. Rascanu A, Chiotan C, Hrisca RM, Gheorghita V, Constantin C, Bacescu B, Morot R. Dirofilaria repens in humans – an emerging antropozoonosis in a central European Country - Romania: Case-series. Proceedings of ECCMID. 24, At P0634, 10-13 May 2014, Barcelona, Spain.

14. Ionică AM, Mihalca AD. Human Dirofilaria infection in Romania: How much do we really know? Proceedings of 13th USMV International Symposium “Prospects for 3rd Millennium Agriculture”. 25-27 September 2014, Cluj-Napoca, Romania, 453.

15. Ionică AM, Matei IA, Mircean V, Dumitrache MO, D’Amico G, Győrke A, Pantchev N, Annoscia G, Albrechtová K, Otranto D, Modrý D, Mihalca AD. Current surveys on the prevalence and distribution of Dirofilaria spp. and Acanthocheilonema reconditum infections in dogs in Romania. Parasitology Research. 30 Dec. 2014. doi: 10.1007/s00436-014-4263-4.

16. Sergiev VP, Suprjaga VG, Morozov EN, Jukova LA. Human dirofilariasis: diagnosis and character of the relationship between causative agent and host. Med Parasitol and Parasit Dis. 2009; 3:3-6.

17. Simón F, Prieto G, Muro A, Cancrini G, Cordero M, Genchi C. Human humoral immune response to Dirofilaria species. Parassitologia. 1997 Dec; 39(4):397–400.

18. Glavan N, Pećanić S, Bosak A, Gacanin L, Abram M, Jonjić N. Dirofilaria repens infection in a ten-year-old boy from the Istria Peninsula: case report. Acta Clin Croat. 2013 Dec; 52(4):533–6.

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Disclosures In the Disclosures section, authors must disclose any and all relationships that could be perceived as real or apparent conflict(s) of interest. If authors have nothing to disclose, they must state "None." Conflicts of interest pertain to relationships with and/or ownership interests in pharmaceutical companies, biomedical device manufacturers, or other corporations whose products or services are related to the subject matter of the article. Relationships include, but are not limited to, employment by an industrial concern, ownership of stock, membership on a standing advisory council or committee, being on the board of directors, or being publicly associated with the company or its products. Ownership interest includes any stock, stock option, partnership, membership or other equity position in an entity regardless of the form of the entity, or any option or right to acquire such position, and any rights in any patent or other intellectual property. Other areas of real or perceived conflict of interest could include receiving honoraria or consulting fees or receiving grants or funds from such corporations or individuals representing such corporations. References References must conform to Pubmed requirements. Authors must ensure accuracy of reference data. Verify all entries against original sources. All authors must be listed in each reference. Do not use "et al". Cite references in numerical order according to first mention in the text. Personal communications, unpublished observations, and submitted manuscripts are not legitimate references and must be cited in the text only (not in the reference list) as "(author name, unpublished data, [year])." All submitted manuscripts that are pertinent to the manuscript under consideration must accompany the submission. Personal communications and unpublished observations must be accompanied by a letter from the source approving use of the information. All references will be written in the following order: name (of the author), initial letter of the surname (of the author), title of the article, source (name of the book, magazine, etc), year of publication, volume, issue (if applicable), first page, last page (of the source). Example: Langlois J, Rutland-Brown W, Wald M. The epidemiology and impact of traumatic brain injury: a brief overview.J Head Trauma Rehabil. 2006; 21: 375-378. The references will not contain internet sources. All references which are originally taken from an international database (i.e. Scopus, MedLife, etc.), should respect the same order of the elements mentioned above, but should necessarily contain a “doi” after the year of the publication, instead of the page numbers of the paper. Example: Langlois J, Rutland-Brown W, Wald M. The epidemiology and impact of traumatic brain injury: a

brief overview. 2006; doi:10.1111/j.1464-410X.2009.08495.x. All references which are originally taken from books, should contain the following details in this specific order: name(s) and surname(s) of the author(s), chapter of the book (if applicable), the title of the book, year of publication, the city of publication, the name of the publishing house, first page, last page (of the source). Example: Hojat M. Does empathy predict career choice and professional success? Empathy in Patient Care, 2006, New York, Springer Verlag, 205-209 We recommend you to use only peer-reviewed journals. Figures Acceptable electronic figure file formats for publication are: jpg and .tiff Color figures must be in CMYK mode, not RGB mode. Color figures and line drawings must be at least 600 dpi resolution. Grayscale and black/white figures must be at least 300 dpi resolution. Combination color, grayscale and line art must be 600 dpi or higher. The use of digital media for image acquisition and processing introduces the potential for inadvertent distortion of data. To prevent such distortion, data should neither be added to, nor removed from, an image by digital manipulation. Figures assembled from multiple images must indicate the separation of the parts by lines. Linear adjustment of contrast, brightness or color must be applied equally to all parts of an image. Authors must be prepared to submit the original, unaltered files from which the submitted figures were derived, if requested by the editorial office. Graphics downloaded from the Web are not acceptable for print. Web graphics, usually in GIF or JPEG format, have a resolution of only 72 dpi, which does not meet the standard for peer review nor publication. Figure parts should be clearly labeled. Letters and labels must be uniform in size and style within each figure and, when possible, between figures. The font size must be 10 point or higher. Symbols and abbreviations must be defined in the figure or its legend. Avoid headings on the figure. Heading information should appear in the figure legend. Provide a short title (in the legend, not on the figure itself) and an explanation in brief but sufficient detail to make the figure intelligible without reference to the text (unless a similar explanation has been given in another figure). Figure legends are included in the word limit.

Tables Include table(s) in the main manuscript document as text, not as an image. Table(s) are included in the word limit. Number tables using Arabic numerals, and supply a brief, informative title for each table. Table text must be consistent in size and style with main manuscript text. Supply brief column headings. Indicate footnotes in this order: *, †, ‡, §, ||, #, ** Use only horizontal borders above, and below the column headings and at the bottom of the table. Use extra space to delineate rows and columns. Abbreviations/symbols used in a table but not already defined in the main text must be defined in the table or table legend. Do not use colors for tables, use only default .1 black borders. Tables must be placed 1 per page at the end of the manuscript, after the references. Copyright information A letter signed by the main author of the article, which will be sent via mail together with the manuscript, will contain copyright transfer to Romanian Journal of Ophthalmology. The full responsibility for all written information in the article belongs to authors. Conflict of Interest Policy Authors are responsible for the published materials and other conflicts of interests regarding subjects included in their work. Authors must mention all the funding received for research and other financial or personal connections linked to the article, in their work. Order of publication The order in which the articles appear in the journal is determined by: • date of arrival • editorial priorities • compliance with the above mentioned

recommendations • peer-review recommendations

Priorities can be decided for some articles, requested either by the editors or by being of special interest. For urgent communications (phone, fax, e-mail), the following address may be used as well: " Dr. Carol Davila"Central Military University Emergency Hospital 134 Calea Plevnei Street, District 1, Bucharest, Romania Phone number/Fax: +40.21.3137189, E-mail: editors@rjo.ro Please also consider downloading the following documents: Authors' recommendations Authorship responsibility form Copyright transfer agreement

Sponsors of Romanian Journal of Ophthalmology

Alcon, Allergan, Amaoptimex, Argusoptik, Biosooft, BK Medical, Essilor, Euromedex France, HOYA, Kemblimed, Laboratoire Thea, Nova Lenti, Opticiris, RECKITT BENCKISER, Romger General, Santen, Sifi, Sover Optica, Sun Wave Pharma, Unimed Pharma, Valeant Bausch Lomb