Volume 62, Issue 1, 2018

Romanian Journal of Ophthalmology Volume 62, Issue 1, 2018

Romanian Society of Ophthalmology www.rjo.ro INDEXED BY: MEDLINE/PUBMED Romanian Journal of Volume 62, Issue 1 January-March 2018 Ophthalmology

EDITOR-IN-CHIEF EXECUTIVE EDITOR Mihail Zemba, M.D., Ph.D. Bucharest, Romania Prof. Victor Lorin Purcarea, Ph.D. Bucharest, Romania E-mail: [email protected] E-mail: [email protected]

ASSOCIATE EDITOR ASSISTANT EDITORS Ovidiu Musat, M.D., Ph.D. Bucharest, Romania Horia Stanca, M.D., Ph.D. Bucharest, Romania E-mail: [email protected] E-mail: [email protected] Daniel Branisteanu, M.D., Ph.D. Iasi, Romania E-mail: [email protected]

INTERNATIONAL EDITORIAL ADVISORY BOARD Prof. Khaled al Rakhawy, M.D., Ph.D. Cairo, Egipt Prof. Slobodanka Latinovic M.D., Ph.D. Novi Sad, Serbia Daniel Baron M.D., Ph.D. Nantes, France Prof. Dan Milea M.D., Ph.D. Angers, France Prof. Zsolt Biro M.D., Ph.D. Pecs, Hungary Gabor Rado M.D., Ph.D. Budapest, Hungary Prof. Derald Brackmann M.D., Ph.D. Los Angeles, USA Prof.Gabor Scharioth M.D., Ph.D. Recklinghausen, Germany Thierry Chazalon M.D., Ph.D. Nantes, France Prof. Wolfgang Schrader M.D., Ph.D. Wuerzburg, Germany Prof. Gabriel Coscas M.D., Ph.D. Paris, France Prof. Fankhauser Franz M.D., Ph.D. Bern, Switzerland Prof. J.J. De Laey M.D., Ph.D. Gent, Belgium Tina Xirou, M.D., Ph.D. Athens, Greece Prof. Fabian Hoehn M.D., Ph.D. Pforzheim, Germany Prof. Dr. Andreas Wedrich, M.D., Ph.D. Graz, Austria Prof. Christian Paul Jonescu-Cuypers M.D., Ph.D. Berlin, Germany NATIONAL EDITORIAL ADVISORY BOARD Assoc.Prof. Florian Balta, M.D., Ph.D. Bucharest, Romania Assoc.Prof. Cristina Stan M.D., Ph.D. Cluj Napoca, Romania Prof. Dorin Chiselita M.D., Ph.D. Iasi, Romania Prof. Adriana Stanila M.D., Ph.D. Sibiu, Romania Assoc. Prof. Mircea Filip M.D., Ph.D. Bucharest, Romania Cornel Stefan M.D., Ph.D. Bucharest, Romania Prof. Mihnea Munteanu M.D., Ph.D. Timisoara, Romania Prof. Calin Tataru M.D.,Ph.D. Bucharest, Romania Daniela Selaru M.D., Ph.D. Bucharest, Romania Prof. Cristina Vladutiu M.D., Ph.D. Cluj Napoca, Romania NATIONAL EDITORIAL BOARD Gheorghe Anghel M.D., Ph.D. Bucharest, Romania Carmen Mocanu M.D., Ph.D. Craiova, Romania Eugen Bendelic M.D., Ph.D. Chisinau, Republic of Moldova Cristina Nicula M.D., Ph.D. Cluj Napoca, Romania Camelia Bogdanici M.D., Ph.D. Iasi, Romania Monica Pop M.D., Ph.D. Bucharest, Romania Daniel Branisteanu M.D., Ph.D. Iasi, Romania Mihai Pop M.D., Ph.D. Bucharest, Romania Marian Burcea M.D., Ph.D. Bucharest, Romania Alina Popa-Cherecheanu M.D., Ph.D. Bucharest, Romania Catalina Corbu M.D., Ph.D. Bucharest, Romania Vasile Potop M.D., Ph.D. Bucharest, Romania Mihaela Coroi M.D., Ph.D. Oradea, Romania Speranta Schmitzer M.D., Ph.D. Bucharest, Romania Valeria Coviltir M.D., Ph.D. Bucharest, Romania Horia Stanca M.D., Ph.D. Bucharest, Romania Valeriu Cusnir M.D., Ph.D. Chisinau, Republic of Moldova Ioan Stefaniu M.D., Ph.D. Bucharest, Romania Danut Costin M.D., Ph.D. Iasi, Romania Simona Talu M.D., Ph.D. Cluj Napoca, Romania Monica Gavris M.D., Ph.D. Cluj Napoca, Romania Liliana Voinea M.D., Ph.D. Bucharest, Romania Karin Horvath M.D., Ph.D. Tg. Mures, Romania Mihail Zemba, M.D., Ph.D. Bucharest, Romania Sanda Jurja M.D., Ph.D. Constanta, Romania

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Romanian Journal of Ophthalmology Volume 62, Issue 1, January-March 2018

Contents

Editorial Romanian Journal of Ophthalmology is indexed in PMC and PUBMED. 1 More to come on the indexing processes soon Gheorghe Consuela-Mădălina

Reviews The role of Optical Coherence Tomography in optic neuropathies 3 Iorga Raluca Eugenia, Moraru Andreea, Ozturk Manuela Ramona, Costin Dănuţ Ocular implants-methods of ocular reconstruction following radical surgical interventions 15 Catalu Corina Teodora, Istrate Sanziana Luminita, Voinea Liliana Mary, Mitulescu Costin, Popescu Viorela, Radu Ciuluvica

General articles Effect of sevoflurane preconditioning on light-induced retinal damage in diabetic rats 24 Iliescu Daniela Adriana, Ciubotaru Alexandra, Ghiţă Mihai Aurelian, Dumitru Adrian, Zăgrean Leon Electrophysiologic evaluation of the visual pathway at different depths of sevoflurane 34 anesthesia in diabetic rats Iliescu Daniela Adriana, Ciubotaru Alexandra, Ghiţă Mihai Aurelian, Păun Adrian Marius, Ion Tudor, Zăgrean Leon Correlations between internal and external ocular factors and macular 42 pigment optical density Tudosescu Ruxandra, Alexandrescu Cristina Mihaela, Istrate Sânziana Luminiţa, Vrapciu Alexandra Diana, Ciuluvică Radu Constantin, Voinea Liliana Medical and legal point of view for low-vision patients 48 Bogdănici Camelia-Margareta, Bogdănici Ştefan Tudor, Săndulache Diana Elena, Diaconu Carmen-Mariana Measuring the perceived quality of ophthalmology services in private organizations. 54 A marketing perspective Gheorghe Iuliana Raluca, Gheorghe Consuela-Mădălina, Purcărea Victor Lorin

Case reports Leber’s hereditary optic neuropathy - Case report 64 Iorga Raluca Eugenia, Mihailovici Ruxandra, Ozturk Manuela Ramona, Costin Dănuţ Leukemic retinophaty, the first manifestation in a case of acute myelogenous leukemia 72 Scripcă Oana Roxana, Pădurariu Cristina, Boricean Neacșu Gheorghe, Botoș Loredana Multiple sclerosis with ophthalmologic onset - case report 78 Costin Dănuţ, Pînzaru Gabriela Mirela, Pătraşcu Andra Mădălina, Moţoc Anca, Moraru Andreea Dana Various therapies for ocular surface diseases 83 Gheorghe Alina, Rosoga Ancuţa Teodora, Mrini Fildys, Vărgău Iulia, Gherghiceanu Florentina

Romanian Journal of Ophthalmology, Volume 62, Issue 1, January-March 2018. pp:1-2

EDITORIAL

Romanian Journal of Ophthalmology is indexed in PMC and PUBMED. More to come on the indexing processes soon

Three years have passed since Romanian Journal of Ophthalmology has changed its name from Oftalmologia and begun being published in English. At that time, the aim was to obtain a better visibility and quotation, which has been partly achieved. Starting 2017, a contract has been signed with The National Library of Medicine (NLM), thus, all the articles up to date have been indexed in PMC and PubMed. PubMed Central (PMC) is a free digital repository that archives publicly accessible full-text scholarly articles that have been published within the biomedical and life sciences journal literature (source: https:// en.wikipedia.org/ wiki/ PubMed_Central). PubMed is a free search engine accessing primarily the MEDLINE database of references and abstracts on life sciences and biomedical topics (source: https:// en.wikipedia.org/ wiki/ PubMed). In other words, we managed to fulfill our desideratum of making our journal popular and increase its visibility. Of course, this change has brought more value to our journal, now being indexed in an international database. In addition, we welcome scientists, academic personalities, etc., from Romania and the whole world to send their articles to be published in Romanian Journal of Ophthalmology. The process of indexing was a lengthy one, starting with the indexing of the abstracts of the articles in MEDLINE, continuing with the conversion of all the articles in a specific format (XML) and their uploading on PMC platform and in PubMed database. Regarding process of indexing, MEDLINE indexers describe the content of biomedical articles by assigning subject terms to them. These subject terms are selected from the controlled vocabulary, Medical Subject Headings (MeSH). The MeSH terms assigned to an article appear on the bibliographic citation in PUBMED. They can be used in PUBMED searches and retrieval (source: https:// www.nlm.nih.gov/ bsd/ indexing/ training/ INT_010.html). The MeSH controlled vocabulary, developed at NLM (National Library of Medicine), contains over 27,000 terms covering life sciences, medicine, as well as many other areas. MeSH vocabulary reflects the progress in biomedical sciences. Every year, several hundred new terms are added to the MeSH vocabulary, and some existing terms are modified. In addition to the MeSH descriptors, MEDLINE indexers also use 79 topical subheadings or qualifiers (source: https: // www.nlm.nih.gov/ bsd/indexing/ training/ INT_010.html). For the full participation in PMC, which is a full text archive, a journal must meet the scientific quality standards established by the National Institutes of Health (NIH) and National Library of Medicine. The members of the latter will decide if the scientific and editorial scope and quality of a journal merit its inclusion in PMC. Moreover, the opinions of expert consultants will also count in the final evaluation of the journal (source: https:// onlinelibrary.wiley.com/ doi/ pdf/ 10.1002/ rth2.12047). The journal must also meet the technical standards of the database by providing high-quality digital files (full text articles in XML format) (source: https:// onlinelibrary.wiley.com/ doi/ pdf/ 10.1002/ rth2.12047). The PMC application requires that a journal publish at least 25 peer-reviewed research articles before being indexed (source: https:// onlinelibrary.wiley.com/ doi/ pdf/ 10.1002/ rth2.12047). Regarding the inclusion of a journal in MEDLINE, there is a condition that a journal has been publishing for 12 months and has published at least 40 articles. The more content the journal has published, the stronger the application. The journal needs to appear sustainable by publishing

Romanian Society of Ophthalmology 1 © 2018 doi:10.22336/rjo.2018.1 Romanian Journal of Ophthalmology 2018; 62(1): 1-2 quality content at a regular rate. Other elements taken into consideration include scope and coverage of the journal, quality of content and editorial work, production quality, and audience (source: https://onlinelibrary.wiley.com/doi/pdf/10.1002/rth2.12047). MEDLINE requires that all published articles include declarations of conflict of interest by authors, confirmation that informed consent was sought from research subjects, and that animal welfare was taken into consideration (source: https:// onlinelibrary.wiley.com/ doi/ pdf/ 10.1002/ rth2.12047). What sets MEDLINE apart from the rest of PubMed is the added value of using the NLM controlled vocabulary, Medical Subject Headings (MeSH®), to index citations. PubMed has been available since 1996. Its more than 27 million references include the MEDLINE database plus different types of citations. PubMed citations often include links to the full-text article on the publishers’ Web sites and/ or in PMC and the Bookshelf. MEDLINE is the largest subset of PubMed (source: https://www.nlm.nih.gov/pubs/factsheets/dif_med_pub.html). This indexing has been greatly appreciated so far by the academic community and we hope that this will result into more articles of Romanian and international authors being published in the future, taking into account that we intend to index the journal in many other international databases, including Thomson Reuters (ISI). However, in order to succeed, we need the help and collaboration of all the authors who send their articles to be published in the journal. In addition, before submitting, an author should be well acquainted with the editorial recommendations for writing an article (information that can be found in the Guidelines for Authors section both in the printed version and on the journal’s website – www.rjo.ro). In addition, when writing an article the authors should properly mention the complete name and surname, address of the corresponding author, etc., and they should also comply with the IMRAD form: introduction, methods, results, discussion and conclusion, including acknowledgements, disclosures and all the references, which should be all cited with no exception and at all times. It was a tremendous effort for us to get where we are, but we must continue, improve, be better, and the rewards will surely be the ones expected. We have managed to publish an issue at every three months, which means that on one hand, we have kept our promise and on the other, the ophthalmology field is still interesting for many authors. We are very confident that together with the Romanian Society of Ophthalmology and the ophthalmological academic community, Romanian Journal of Ophthalmology can be the best journal in this field in Romania and abroad. The steps taken so far have required and are still requiring the further improving of the quality of the published articles. Our recommendation to the authors, readers, members of the academic community, etc., is to get more involved in the effort of promoting the journal both in Romania and in the whole world and to encourage their peers to write and send articles to be published in our journal, to achieve visibility.

Assist. Prof. Gheorghe Consuela-Mădălina, PhD, Philologist, Authorized translator

REVIEW

The role of Optical Coherence Tomography in optic neuropathies

Iorga Raluca Eugenia*, Moraru Andreea* **, Ozturk Manuela Ramona**, Costin Dănuţ* ** *Department of Ophthalmology, “N. Oblu” Clinical Emergency Hospital, Iaşi, Romania **Department of Ophthalmology, “Gr. T. Popa” University of Medicine, Iaşi, Romania

Correspondence to: Iorga Raluca Eugenia, MD, PhD, Department of Ophthalmology, “N. Oblu” Clinical Emergency Hospital, Iaşi 35 Lascăr Catargiu Street, Code 700107, Iaşi, Romania, Mobile phone: +40733 792 259, E-mail: [email protected]

Accepted: February 14th, 2018

Abstract Optical neuropathies are neuro-ophthalmologic disorders, the main symptoms of which are the decrease of visual acuity and the alteration of the color vision. Optical coherence tomography has been one of the most important innovations in ophthalmology, which offered the possibility to analyze specific structures of the retina. Optical coherence tomography performs in vivo, real-time, noncontact scanning and provides cross- sectional and volumetric images with a resolution approaching that of histology. Optical coherence tomography offers the opportunity to study neurological diseases in an objective and non-invasive manner. The measurements of retinal nerve fiber layer can be an objective measurement of nerve swelling or nerve atrophy. By analyzing the ganglion cell complex, optical coherence tomography can help detect early axonal damage and may predict the visual outcome. It can be useful for diagnosis and follow-up of optic nerve and chiasmal compressive diseases. Furthermore, optical coherence tomography is useful in patients with multiple sclerosis in distinguishing macular disease from optic neuritis and in monitoring the treatment. Multiple studies and clinical observations support the importance of optical coherence tomography in the diagnosis, treatment, and follow-up of optic neuropathies. Keywords: optical coherence tomography OCT, optic neuropathy, multiple sclerosis MS, retinal nerve fiber layer RNFL, ganglion cells layer GCL Abbreviations: OCT = optical coherence tomography, VA = visual acuity, RNFL = retinal nerve fiber layer, GCL = ganglion cells layer, MS = multiple sclerosis, ON = optic neuropathy, NAION = non-arteritic ischemic anterior optic neuropathy, LHON = Leber hereditary optic neuropathy, RE = right eye, LE = left eye

Introduction colors appearing subtly washed out in the affected eye. On clinical examination, the optic Optic neuropathy refers to damage to nerve head appears edematous in early stages. A the optic nerve due to multiple causes. Damage pale disc is characteristic of long-standing optic and death of these neurons leads to neuropathy. Optic atrophy is the end result of characteristic features of optic neuropathy. The any disease that damages nerve cells anywhere main symptoms are a decrease of visual acuity between the retinal ganglion cells and the lateral (VA) and the alteration of the color vision, with geniculate body.

Optical Coherence Tomography (OCT) is a 6. The internal nuclear layer non-invasive method that makes the 7. Internal plexiform layer introduction to high-tech medicine, a technique 8. Ganglion cells layer (GCL) that revolutionizes the early detection of ocular 9. Nerve fibers layer and central nervous system disorders 10. Internal limiting membrane (Alzheimer’s, Parkinson’s, multiple sclerosis or vascular dementia). OCT is a method capable of OCT in different optic neuropathies producing two-dimensional cross-sections of the 1. Optic neuritis in multiple sclerosis retina with very good spatial resolution. OCT has Optic neuropathy (ON) may be the first a wide use in ophthalmology, especially in the clinical demyelinating event in up to 20% of the diagnosis and monitoring of a wide variety of patients with multiple sclerosis (MS) and the retinal diseases affecting the macula, as well as probability of developing clinically-definite MS calculates the thickness of the retina [1]. The was 50% by 15 years after the onset of acute ON operation of the OCT is based on an optical [5]. While visual recovery from ON is considered measurement technique called “low coherence as a first demyelinating event [6], studies interference”. When light emitted by the source showed that patients would have deficits that are of the device is directed to the eye, it is reflected not well captured by high-contrast visual acuity by intraocular structures with different optical alone [7]. properties. The OCT uses coherent laser light to The OCT exam allows a correlation sweep the retina and analyze the light reflected between the structural aspect (neuronal loss) by the retinal layers. This way, an in vivo and visual dysfunction. The OCT exam shows a “biopsy” of the retina provides information of thinning of the RNFL and the ganglion cells layer high quality resolution about all its layers [2,3]. GCL, and can be used as a marker in the follow The OCT allows qualitative (localization, shape, up of multiple sclerosis patients. Trip et al. structure) and quantitative analyzes (retinal reported a 33% reduction in peripapillary RNFL measurements, especially of the retinal thickness thickness in eyes with a history of ON and and retinal nerve fiber layer RNFL) [4]. incomplete recovery. There was a 27% reduction in the affected eyes compared to the unaffected Retinal layers: fellow eyes [8]. The OCT measurements showed 1. Retinal pigment epithelium layer both axonal loss and retinal ganglion cells loss. 2. Layer of the external segment of The decrease in the peripapillary RNFL photoreceptor cells thickness by approximately 10-40μ is maximal at 3. External limiting membrane 3-6 months after the acute episode, and a 4. The external nuclear layer stabilization is observed at 7-12 months [9] (Fig. 5. External plexiform layer 1).

Fig. 1 Bilateral RNFL thinning in MS patient with no optic neuritis (from Andrzej Grzybowski, Piero Barboni, OCT in central nervous system disease. The eye as a window to the brain, 2016, Switzerland, Springer International Publishing, ISBN 978-3-319-24083-1, pg 97)

OCT was able to identify mild and even 2. Non-arteritic ischemic anterior optic clinically undetectable optic disc edema in eyes neuropathy with acute ON [10]. In 2006, Fisher et al. Non-arteritic ischemic anterior optic compared the RNFL thickness among MS eyes neuropathy NAION is characterized by abrupt with a history of ON, MS eyes without a history of decrease of VA, associated with papillary edema ON and disease-free eyes. The RNFL thickness and peripapillary hemorrhage. NAION is was reduced significantly among MS eyes as a secondary to the reduction of blood flow to the group overall (92 μ) vs. controls (105 μ) and head of the optic nerve by the phenomenon of particularly reduced in MS ON eyes (85 μ) [11]. crowding on a small excavation disc. OCT plays a role in monitoring the At presentation, the OCT shows the RNFL treatment with fingolimod and INF-β. edema. Histopathological studies have shown a Fingolimod can cause macular edema (0.3-1.2% doubling of RNFL in NAION [15]. In time, the of the patients) and uveitis [12], while INF-β can edema reduces, and we can observe a thinning of cause exudates and retinal hemorrhage [13]. An the RNFL corresponding to optic nerve atrophy, OCT exam is recommended before treatment, on OCT. At 2 months post acute episode, the and one at every 3-4 months (Fig. 2). RNFL thickness in the affected eye is similar to Patients with DeVic disease can present that of the congenital eye and at 3-4 months, microcysts in the internal nuclear layer on OCT - there is a 40% decrease in the thickness of the signs of inflammation, autoantibodies against RNFL compared to the healthy eye. At 12 aquaporin 4, microglial activation, months, the RNFL thickness stabilizes [16,17] neurodegenerative changes [14]. (Fig. 3).

Fig. 2 Fingolimod related macular edema (from Andrzej Grzybowski, Piero Barboni, OCT in central nervous system disease. The eye as a window to the brain, 2016, Switzerland, Springer International Publishing, ISBN 978-3-319-24083-1, pg 98)

Fig. 3 Right Eye RE Optic disc edema secondary to NAION (from Andrzej Grzybowski, Piero Barboni, OCT in central nervous system disease. The eye as a window to the brain, 2016, Switzerland, Springer International Publishing, ISBN 978-3-319-24083-1, pg 54)

Certain patients with secondary papillary correlation between macular thickness and edema NAION develop subretinal fluid. OCT visual field sensitivity. Macular thickness may be shows peripapillary subretinal hyporeflectivity a surrogate marker for determining the extent of adjacent to RNFL thickening and subfoveolar optic nerve damage [19]. Ganglion cells hyporeflectivity [18]. Hedges observed that 8 out thickness correlates with visual field parameters, of 76 eyes with NAION had subfoveal fluid, at 4 both in acute and chronic phase. Ganglion cells weeks after the acute phase [18]. In NAION, it thickness measured by OCT can detect axonal appears to be a more significant damage to the damage when the RNFL is edematous [20] (Fig. maculopapillary fibers, which corresponds to a 4). central defect. Papchenko found a strong

Fig. 4 RE Thinning of the GCL in a patient with NAIO (from Andrzej Grzybowski, Piero Barboni, OCT in central nervous system disease. The eye as a window to the brain, 2016, Switzerland, Springer International Publishing, ISBN 978-3-319-24083-1, pg 53)

3. Leber hereditary optic neuropathy edema, with mitochondrial redistribution at (LHON) dysfunctional ganglion cells, affecting the Leber hereditary optic neuropathy is an prelaminar unmyelinated portion of the optic optic neuropathy associated with mutations in nerve axons [22]. mitochondrial DNA that affects young men. It is In the acute phase and in the first 6 months associated with retinal ganglion cell of onset, the RNFL analysis shows thickening in degeneration and axonal loss in the optic nerve, the upper and lower segments, compared to the leading to optic atrophy. control group [23] (Fig. 5). At the atrophic stage, In healthy carriers, the OCT test showed a RNFL thinning appears in all segments (Fig. 6). RNFL thickening in temporal quadrants and in Patients who recover from VA have a higher asymptomatic men in the inferior sector [21]. RNFL thickness than those who do not recover RNFL thickening is correlated with axonal [23].

Fig. 5 Acute phase of LHON with a. peripapillary RNFL thickening and b. early GCL atrophy (from Andrzej Grzybowski, Piero Barboni, OCT in central nervous system disease. The eye as a window to the brain, 2016, Switzerland, Springer International Publishing, ISBN 978-3-319- 24083-1, pg 188)

Fig. 6 RNFL thinning in atrophy phase in a patient with LHON

The OCT analysis of macular thickness of patients with compressive optic neuropathies. showed a thinning of the GCL at the early stage in Among the causes, the intrinsic causes are listed the sectors of the inner ring [24]. 6% of the - glioma, optic nerve meningioma, and extrinsic, patients had microcystic degeneration and were compressive causes - orbital tumor, Graves associated with focal retinoschisis induced by disease, intracranial tumors (pituitary adenoma, vitreomacular tractions in combination with craniopharyngioma), aneurysm. RNFL atrophy [25]. Meningioma occurs with the progressive decrease of VA. The OCT exam is 4. Compressive optical neuropathies important in predicting the visual prognosis: Compressive optical neuropathies are when the VA decrease occurs in a patient with among the most important anterior optical minimal RNFL loss, the prognosis is favorable. pathways diseases that can lead to severe Loo evaluated 14 eyes of 12 patients with impairment of visual function if they are pretreatment and post-treatment OCT, along discovered late. The diagnosis is made through a with clinical examination. After treatment, the progressive decline of VA associated with group with normal RNFL experienced imaging exams. Axonal loss can be quantified by improvement in VA, color vision, visual field, peripapillary RNFL measurements, as well as by compared with the group with altered RNFL [26] measuring the macular thickness. OCT is useful (Fig. 7). in the diagnosis, follow-up, and visual prognosis

Fig. 7 Left Eye LE optic nerve meningioma IRM and OCT. A. Thinning of the RNFL on OCT. B. Reduced GCL on OCT (from Andrzej Grzybowski, Piero Barboni, OCT in central nervous system disease. The eye as a window to the brain, 2016, Switzerland, Springer International Publishing, ISBN 978-3-319-24083-1, pg 73)

Glioma - Avery et al. studied 62 patients for proptosis, diplopia, congestive signs, and with NF-1 and optic nerve glioma. OCT showed a dysthyroid optic neuropathy. Because prognosis reduction in RNFL thickness, which significantly is significantly improved when early diagnosis is associates with VA decrease and sensitivity to made, OCT can be used to detect high-risk contrast [27]. Fard et al. included 38 eyes from patients. The OCT measurements of the RNFL 23 children with optic nerve glioma and they can predict axonal losses. Forte et al. observed correlated the OCT exam with clinical and RNFL losses in 30% of the patients with radiological changes. The RNFL and macular OCT dysthyroid optic neuropathy and intraocular measurements were significantly different in hypertension [29]. After decompression, an patients with tumor progression [28]. improvement in VA and visual field in patients Graves Orbitopathy is an autoimmune with normal retinal integrity was marked, as inflammatory disorder that affects extraocular assessed by OCT [29] (Fig. 8). muscles and orbital fat, which are responsible

Fig. 8 Patient with Graves’ orbitopathy - IRM and OCT. IRM shows enlarged medial and inferior rectus muscles. OCT shows normal peripapillary RNFL, normal macular full-thickness (A) and normal GCL (B). (from Andrzej Grzybowski, Piero Barboni, OCT in central nervous system disease. The eye as a window to the brain, 2016, Switzerland, Springer International Publishing, ISBN 978-3-319-24083-1, pg 76)

Chiasmal lesions may be caused by RNFL losses in all optic nerve quadrants and a pituitary adenoma, craniopharyngioma, macular thinning nasal from the fovea [30] (Fig. meningioma, and aneurysm. Chiasmatic lesions 9). Danesh-Meyer evaluated 40 patients with can cause changes ranging from minimal to chiasmatic lesions, with OCT and visual field, pre severe, with optic nerve atrophy and ganglion and post decompression treatment. Patients with cells loss. The OCT measurements of retinal thin RNFL did not demonstrate significant thickness can detect neuronal loss from onset. improvement in VA and visual field as compared Patients with bitemporal hemianopsia show to those with normal RNFL [31].

Fig. 9 IRM and OCT of a patient with large pituitary adenoma with chiasmal compression. OCT shows reduced peripapillary RNFL - temporal in the RE and nasal and temporal in the LE (upper image) and thinning of the nasal macula (lower image). (from Andrzej Grzybowski, Piero Barboni, OCT in central nervous system disease. The eye as a window to the brain, 2016, Switzerland, Springer International Publishing, ISBN 978-3-319-24083-1, pg 82)

Using OCT to quantify axonal losses by susceptible due to the large unmyelinated measuring RNFL and macular thickness can be segment and thin gauge [35]. considered a predictor for vision recovery. Jacob In early stages, toxicity accumulates in the et al. showed that the increase in RNFL thickness mitochondria of the ganglion cells, causing correlated with visual field improvement [32]. axonal thickening, which is detectable in OCT. In the subacute stage, the OCT shows RNFL 5. Nutritional and Toxic Optic thinning of the papillomacular bundle in the Neuropathies inferior-temporal sector. In the late stage, RNFL Nutritional Optic Neuropathy is common in thinning is observed in all layers [35,36]. patients with chronic diseases and malnutrition, Toxic optic neuropathy to ethambutol may being associated with deficiency of B1, B12, folic become clinically manifested between 2 and 12 acid, Cu. Deficiency in these elements affects months after the onset of treatment. It is mitochondrial oxidative phosphorylation [33]. reversible if it is recognized on time. Permanent The OCT measurements show a thickening of the toxic effects may occur at standard doses of 15- RNFL, followed by a more pronounced thinning 25 mg/ kg/ day. Early animal experiments have in the temporal sector [34]. demonstrated ethambutol toxicity affecting the Toxic Optic Neuropathies occur due to retinal ganglion cells, the optic nerve, chiasm, accidental ingestion of substances such as and optic tracts [37]. In the late-stage, the OCT alcohol (methanol, ethylene glycol), anti- changes are the thinning of the RNFL in the tuberculosis drugs, antimalarial drugs, inferior-temporal sector and significant thinning antiarrhythmic (digital, amiodarone), and of the ganglion cells layer [38]. antibiotics. They present with painless, Methanol optic neuropathy is due to a progressive, bilateral visual acuity decrease, cytotoxic edema at the retinal level and at the dyschromatopsia, and central scotoma. The site optic nerve, which appears at 48h post ingestion. can be variable, including the retina, intraocular OCT is used for the exploration of the macula and nerve fiber axons, and chiasm. The peripapillary retina, showing early peripapillary symptomatology is due to the damage of the RNFL edema, subsequent optic nerve atrophy, papillomacular bundle, which is more and intraretinal fluid accumulation [39] (Fig. 10,11).

Fig. 10 Methanol optic neuropathy - OCT shows thinning of peripapillary RNFL in both eyes (from Andrzej Grzybowski, Piero Barboni, OCT in central nervous system disease. The eye as a window to the brain, 2016, Switzerland, Springer International Publishing, ISBN 978-3-319-24083-1, pg 221)

Fig. 11 Methanol optic neuropathy - OCT shows decreased volume of GCL (from Andrzej Grzybowski, Piero Barboni, OCT in central nervous system disease. The eye as a window to the brain, 2016, Switzerland, Springer International Publishing, ISBN 978-3- 319-24083-1, pg 222)

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REVIEW

Ocular implants-methods of ocular reconstruction following radical surgical interventions

Catalu Corina Teodora*, Istrate Sânziana Luminiţa*, Voinea Liliana Mary*, Mitulescu Costin*, Popescu Viorela*, Radu Ciuluvică** *Ophthalmology Department, University Emergency Hospital, Bucharest, Romania **Anatomy Department, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania

Correspondence to: Istrate Sânziana, MD, PhD, Ophthalmology Department, University Emergency Hospital, Bucharest, 169 Splaiul Independentei Street, District 5, Bucharest, Romania, Mobile phone: +40726 535 515, E-mail: [email protected]

Accepted: February 8th, 2018

Abstract The main motivation of an ocular-orbital reconstruction after a radical surgical intervention (evisceration, enucleation) is represented by the psychological and socioeconomic impact of such interventions on life conditions of patients. The current methods for ocular prosthesis are based on a new concept, which is nanotechnology, and its main objectives represent the reconstruction of the remaining orbital volume, reduction of postoperative complications and maintaining a satisfactory esthetical aspect. This review will discuss the numerous types of ocular implants that have been used throughout history as well as the most recent methods used by ophthalmic surgeons, also taking into consideration the advantages and disadvantages from a cosmetic, functional and short and long term postoperative complications point of view. Keywords: ocular implant, evisceration, enucleation, exenteration, orbital reconstruction, hydroxyapatite, polyethylene, postoperative complications

Introduction an ocular implant (fat, bone fragments, cartilage, silver, titanium, glass, porous materials, silicone, The psychological support of the patient etc.) for more than a century [1-3]. pre and post-operatively is important after a When discussing the biocompatibility of a radical intervention. It is fundamental that in certain nanostructured material, we have to such cases, the patients’ re-adaptation to social consider 3 aspects: bio-adaptability, bio- life and the esthetic aspect is taken into tolerability and bio-functionality [4]. Progress in consideration. this field led to improved designs of ocular There has been an increasing desire to implants. create the ideal ocular implant as well as to An ideal ocular implant should be non- improve surgical techniques, in favor of reducing allergenic, nontoxic, not provoking host tissue the frequency of postoperative complications. immune response, mechanically stable with Different materials have been used to improve satisfying motility and a suitable quality to price the biocompatibility and aesthetic appearance of ratio [5].

For improved motility of ocular prosthesis, most surgeons attach the extrinsic muscles to the ocular implant also reducing the risk of exposure or extrusion. This is why types of implants integrated and non-integrated are being discussed [6].

General considerations of orbital anatomy The orbit is a pyramid-shaped cavity, with the anterior base and the posteromedial apex, and four walls: lateral, medial, floor and the orbital roof. There are communications to the orbit with neighboring regions through orifices located on the orbital walls. Due to low resistance areas, there is a high frequency of fractures located in the zygomaticomaxillary and zygomaticofrontal sutures. Fractures of the Fig. 1 Post corneal fungal ulcer with a conjunctival orbital plane and the medial wall are common in flap diffuse traumas [7-9]. Anatomically speaking, there is a space between the orbit and the periosteum that allows the ablation of the orbital content. Orbital content consists of the eyeball with its annexes (Tenon capsule, conjunctiva, lacrimal apparatus, eyelids, oculomotor muscles), optic nerve, ophthalmic artery, ophthalmic vein, peripheral nerves, periorbital fat [10]. The adult orbital volume is about 30 cm³ and has a depth of 45-55 mm. Constitutionally, the male orbit is larger than in women. Also, the Broca index, which represents the ratio between the orbital cavity height and its length, is very variable depending on race [11-13]. Fig. 2 Neovascular glaucoma Radical interventions: surgery Depending on the ocular pathology (Fig. Regardless of the surgical technique, there 1,2), the removal of the eyeball can be is always a preoperative assessment, taking into account the history of ocular pathology accomplished by three surgical techniques, (congenital or acquired ocular affection), namely: evisceration, enucleation or objective and paraclinical examination, patient exenteration. There are pros and cons in requirements (discomfort, aesthetic aspect), applying these surgical methods, but the main associated general disorders, explanation of purpose remains the preserving of the patient’s pathology and surgical technique (pre- and post- life and the increase of the quality of life through operative psychological counseling), and, last but various methods of ocular prosthesis. not least, written consent of the patient [14,15]. Evisceration and enucleation can be

16 Romanian Society of Ophthalmology © 2018 Romanian Journal of Ophthalmology 2018; 62(1): 15-23 performed under local or general anesthesia, the Table 1. Radical intervention indications [20-22] latter having the advantage of not modifying the EVICERATION neovascular glaucoma, infectious anatomy of the orbital vicinity [16]. endophthalmitis, disorganized Moreover, evisceration is a procedure in globe, eye injury without uveal which the globular content is removed, keeping involvement, corneal perforation ulcers, etc. the sclera, Tenon capsule, conjunctiva, extrinsic ENUCLEATION intraocular tumors without local muscles, and the optic nerve (Fig. 3) [17]. extrascleral invasion Enucleation is another surgical option (melanomas, retinoblastomas), represented by removing the ocular globe and painful eyes with important keeping only the bulbar conjunctiva and damage to VA, the need of extrinsic ocular muscles [16,18]. histopathological examination, Evisceration has been considered superior important ocular traumas with to enucleation for a long time, due to the significant uveal involvement, esthetical aspect and motility, but current risk of sympathetic ophthalmia, surgical methods suggest the attachment of the etc. EXENTERATION malignant ocular tumors extrinsic muscles at the implant after an (palpebral spine cell carcinoma, enucleation [18,19]. conjunctival or lacrimal sac, Exenteration is a more complex procedure basal cell carcinoma, involving collaboration in a multidisciplinary adenocarcinomas, melanomas, team (ophthalmologist, plastic surgeon, rhabdomyosarcoma, etc.); neurosurgeon, oncologist, ENT), and involves aggressive benign tumors removing the eyeball with its attachments and (meningiomas, gliomas, etc.); the orbital content of the periosteum that vascular facial malformations, associates the eyelid removal or not [20]. massive orbital varicose veins, In cases of intraocular tumors, i.e. orbital pseudotumor, aggressive orbital mycosis, trauma orbital melanoma or retinoblastoma, evisceration is causing orbital cellulite that does contraindicated due to high dissemination risk not respond to treatment, etc. [16,21,22]. Complications occurring either intraoperatively or postoperatively (Fig. 4, Table 2) should be considered. In case of evisceration, there is a risk of local intraoperative hemorrhage, especially when a coagulation disorder is associated, as well as the risk associated with general or local anesthesia [20]. In terms of enucleation, intraoperative incidents are uncommon, but the following are possible: puncture of sclera in patients with malignant intraocular tumors, loss of extrinsic eye muscles in orbital fat, etc. Sino-orbital fistula is a complication quite

commonly encountered intraoperatively in the

Fig. 3 Evisceration, one of radical surgical exenteration approach, and dural rupture is a vital risk complication involving extrusion of the interventions cerebrospinal fluid [23].

Fig. 4 One day after evisceration (palpebral edema)

Table 2. Different postoperatory complications [15,20,22,23] Evisceration Enucleation Exenteration

- extrusion of the ocular implant - extrusion of the ocular implant - postoperative infections - postoperative infections - postoperative infections (especially in the neglected sino- - increased eye pressure - palpebral edema (Fig. 4) orbital fistula) - local pain (due to corneal - tumor recurrence (most preservation) important) - delayed healing (frequent in patients post-radiotherapy or those with diabetes) - graft failure - cutaneous and mucous hypoesthesia (often by infraorbital nerve injury, nerve supraorbital and anterior and posterior ethmoidal nerve.

The procedure ends by placing an ocular fibrovascular invasion of the mentioned implant implant in the ocular cavity. In the case of ocular [24,45]. integrated (HA) implant, prosthesis is placed in about 6 months post-op, prior to which, a CT Types of ocular implants scan is performed by visualizing the The search for an ideal ocular implant also

18 Romanian Society of Ophthalmology © 2018 Romanian Journal of Ophthalmology 2018; 62(1): 15-23 led to a progress regarding the surgical which potentially reduces the risk of migration, procedure as well as reducing post-operative extrusion and infection [37,38]. complications after an evisceration or In a prospective study of 60 patients with enucleation. For instance, Sami et al. mentioned different ocular pathologies, it was found that three categories based on the nature of each type 14% of the patients with primary ocular implant of implant: buried, exposed-integrated, and showed ocular implant extrusion and only 1% of buried-integrated implants [6]. Integrated ocular the patients with secondary ocular implants. Of implants offer the appropriate dimensions unlike the 60 patients included in the study, 27 received the ocular prosthesis that has a volume of 4,2 ml primary ocular implant after enucleation and less than the volume needed for ocular one after evisceration, and 32 ophthalmic reconstruction [26,27]. patients received secondary implant [39]. Regarding the silicone sphere implant, it HA implant includes the intrinsic cost of the has been used for over 50 years [30]. Many implant, which is often the most significant cost – surgeons argue that it would be a less favorable the need for a wrapping material, the assessment choice if it were implanted without attachment of implant vascularization with a confirmatory of extrinsic muscles, due to extrusion risk and MRI study and, optionally, a secondary drilling reduction in motility [28,29]. procedure for peg placement with the Looking at the chemical, physical, and consequent modification of the ocular prosthesis structural characteristics of orbital implants, [40]. comparative studies on such topics are quite rare Lower-cost versions of these materials in the literature. It has been recognized that have been developed and are currently in use adequate fibro-vascularization is vital for a around the world. Therefore, it is generally porous implant to achieve long-term success: recommended that HA implants are placed chemical composition, microstructure, and within a wrapping material before being mechanical features are all factors that play a introduced into the orbit [24,25,41]. It was role, but there is a wide variation in these shown that the majority of the exposed HA characteristics among the available materials implants can be successfully treated by using [31]. patch grafts of different origin (e.g. scleral graft, dermis graft, oral mucosa graft) without the Hydroxyapatite need for implant removal [42-45]. Porous orbital implants spread worldwide Youn-Shen Bee et al. have shown in a study after the introduction of modern HA orbital that the increased number of preoperative implants, which are not based on treated bone leukocytes may be associated with the increased derived from animal sources. HA formally risk of extrusion of the ocular implant belongs to the class of calcium orthophosphates (approximately 13%). This study was conducted and, especially in the form of coralline or on 85 patients with ocular infections in whom synthetic HA, has been widely used for more radical surgery was performed (evisceration or than 50 years in orthopaedics and dentistry for enucleation) [46]. bone repair, thanks to its chemical and In the case of orbital implant infections, compositional similarity to the biological apatite administration of systemic antibiotics and of hard tissues [32–34]. topical eye drops can solve the problem, but if no In the mid-1980s, Perry [35] improvement in the symptoms is noticed, experimentally introduced the coralline porous implant removal should be considered [47]. HA sphere and it has been commonly adopted in Other reported complications include clinical practice since the early 1990s, eventually conjunctival thinning (followed or not by becoming the most frequently used implant after exposure), socket discharge, pyogenic granuloma primary enucleation [36]. Porous HA implants formation, mid-term to chronic infection of the have been widely studied, and many implant, and persistent pain or discomfort retrospective reviews on patients’ outcomes are [45,48,49]. available in the literature [28]. The In summary, porous HA implants remain interconnected porous structure of the HA the most commonly used in anophthalmic implant allows host fibrovascular in-growth, surgery, together with their advantages and

19 Romanian Society of Ophthalmology © 2018 Romanian Journal of Ophthalmology 2018; 62(1): 15-23 suitability [50]. However, in the search for an with facial deformities, orbital fractures, but also “ideal” porous orbital implant with a reduced from the aesthetic point of view. complication profile and diminished surgical and In an animal model study, Goldbag et al. postoperative costs, alternative materials have [57] showed that the HA implant induces a high been also explored over the last two decades. risk of inflammation and local fibrosis versus porous polyethylene. Poly (methyl methacrylate) In a study of two patient groups, Sadiq et al. PMMA is known in ophthalmology as well [58] found that the rate of postoperative as rigid and semi-rigid contact lenses [51], due complications after implantation of an HA or PE to its excellent biocompatibility with ocular was similar, but the PE implant showed better tissues and transparency to visible light. motility. In 1976, Frueh and Felker first described By looking at the future of PE orbital the use of the so-called “baseball implant”. implants, Kozakiewicz et al. [59] implanted Although originally described as a secondary ultrahigh-molecular-weight PE implants in three implant, its design might allow primary patients with orbital reconstructions. Based on implantation as well [52]. the CT scanning, Kozakiewicz et al. prepared a In 1985, Tyers and Collin implanted 35 virtual model of both orbits (injured and secondary and six primary baseball implants and uninjured). The two resulting surfaces were then monitored the patients over a 24 months follow- overlapped and the outer surface was used to up period [53]. Complications occurred in 59% design the external surface of the implant. This of the cases, but most of them were resolved by new procedure could also be applied in the pharmaceutical treatment. The authors future for the design and manufacture of orbital concluded that the baseball implant showed implants that closely mimic the original shape good potential and might be recommended both and size of the anophthalmic socket [59,60]. as the secondary implant and as the first approach to a volume deficit in the anophthalmic Quasi-integrated implants socket. On the other hand, they acknowledged In terms of fibrovascular in-growth and that the reported series of primary baseball motility, Girard and co-workers [61,62] merged implants were too small to allow them to draw the advantages of porous and quasi-integrated definite conclusions [52,53]. implants for the first time. In 1994, Leatherbarrow et al. [54] Guthoff et al. [63] developed a composited reviewed 44 patients receiving the baseball implant composed of two parts (anterior part implant and reported six cases of severe made of synthetic porous HA and posterior part complications (unacceptable pain, implant made of silicone rubber). The eye muscles were migration and implant exposure). In the late sutured crosswise in front of the implant to 1990s, Christmas et al. [55] implanted the guarantee a better motility and stability [64,65]. baseball implant in six patients (primary This type of ocular implant is considered a good enucleation) and after 14 days appeared as option, especially in Europe. exposure of ocular implants. A preliminary study of 24 patients showed In summary, PMMA is an excellent no cases of “quasi” implant extrusion and one of biomaterial for ophthalmic applications. In an ten cases of enucleated pediatric patients had interesting study, Groth et al. [56] treated nine complications, but not significant [66]. severely injured patients implanting CT-based biomodelled, prefabricated, heat cured PMMA Aluminium Oxide implants that were well tolerated Aluminium oxide (Al2O3) has been used for postoperatively. decades in orthopaedics thanks to mechanical properties, biocompatibility, and bio inertness Polyethylene [67]. Since the late 1990s, alumina has also been The advantages of porous polyethylene are proposed, in a porous form, and was approved mainly the low cost in comparison to HA and the by the US Food and Drug Administration in 2000 possibility of suturing extrinsic muscles directly and has been marketed under the commercial from the implant. It has been used in patients name of “Bioceramic implant”.

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GENERAL ARTICLE

Effect of sevoflurane preconditioning on light-induced retinal damage in diabetic rats

Iliescu Daniela Adriana* ***, Ciubotaru Alexandra*, Ghiţă Mihai Aurelian* ****, Dumitru Adrian**, Zăgrean Leon* *Physiology Department, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania **Pathology Department, University Emergency Hospital, Bucharest, Romania ***Ophthalmology Department, “Dr. Carol Davila” Central Military University Emergency Hospital, Bucharest, Romania ****Ophthalmology Department, University Emergency Hospital, Bucharest, Romania

Correspondence to: Iliescu Daniela Adriana, MD, Ophthalmology Department, “Dr. Carol Davila” Central Military University Emergency Hospital, Bucharest, 134 Calea Plevnei Street, District 1, Bucharest, Romania Phone/Fax: +40213 137 189, E-mail: [email protected]

Accepted: January 15th, 2018

Abstract Hyperglycemia and bright light are powerful stress agents that produce an enhanced retinal damage, when simultaneously acting on retina. Previous studies have shown that preconditioning with sevoflurane anesthesia offers a certain degree of protection to retinal cells against light damage. The objective of this study was to explore the effect of sevoflurane anesthetic preconditioning on a model of light-induced retinal degeneration in diabetic rats. Wistar rats that were randomly divided into four groups: control (rats exposed to photostress), group 1 (rats exposed to photostress and sevoflurane preconditioning), group 2 (diabetic rats exposed to photostress), group 3 (diabetic rats exposed to photostress and sevoflurane preconditioning) were used for this experiment. We recorded basal electroretinogram (ERG), at 36 h and 14 days after photostress and performed histological analysis of the retina. Results showed that sevoflurane has a protective effect on light-induced neuroretinal degeneration proved by significantly less variations of the ERG before and after photostress. Diabetes appears to increase the damaging effect of photostress on retina and attenuate the protection provided by sevoflurane preconditioning. Keywords: diabetes, photostress, preconditioning, sevoflurane

Introduction determine if sevoflurane has a neuroprotective role for retinal cells. In order to prove our Light induced retinal injury is an important theory, we further increased the stress load on iatrogenic complication that can occur during the retina, by inducing diabetes to rats and ophthalmologic surgery. In order to prevent or subjecting them to the same protocol. attenuate it, strategies to protect the retina Light induced retinal injury: Clinical should be developed. The main purpose of this context study was to explore the effect of sevoflurane The eye has many physiological defensive anesthesia preconditioning on a model of light- mechanisms against light damage, for example: induced retinal degeneration in rats and to squint, blink and miosis reflexes, the cornea

24 Romanian Society of Ophthalmology © 2018 doi:10.22336/rjo.2018.4 Romanian Journal of Ophthalmology 2018; 62(1): 24-33 reflecting most of the non-incidental light and molecules [7] and other mammals have a similar absorbing UV-B, UV-C, furthermore, the lens order of magnitude. Hence, from the light absorbing most of the UV-A and some of the near absorption and implicit energy perspective, it is infrared. The light absorption process is also an important aspect that we will integrate later presented in the other eye optical media, but to a in the context of oxidative stress. On the other lesser extent [1]. hand, traces of all-trans- and 9-cis retinoic acid Most of the inherent protection have been found in dark reared rat retinas mechanisms of the eye are abolished during exposed to intense light [8]. Knowing that cataract, refractive, corneal transplant, and retinoids are transcription regulators during above all vitreoretinal surgery. Although retina development and mediate retinal cell has its own additional defenses, high power, and differentiation and apoptosis [9] and that prolonged radiation from very close sources, like retinoic acid receptor and retinoid X receptor are operating microscope or fiber optic expressed in various cell types in mature retina, endoilluminator, can cause serious photic lesions including photoreceptors, might suggest a link [2]. A light induced retinal injury is first detected between light exposure and transcriptional by fluorophotometry, due to a transitory blood- events. retinal barrier dysfunction, an area of retinal Close metabolic and anatomical edema appearing after 1-2 days, followed by a relationships between neuroretina and RPE link focal hyperpigmentation of RPE (retinal pigment damage in one tissue to degeneration in the epithelium), ophtalmoscopically observable, other. Light induced reactive oxygen species lead after 1 week [3]. to: cytotoxic oxysterols formation [10], protein It is noteworthy that retinal phototoxicity coupling with other unsaturated lipids oxidation exists without clinically visible lesions. Studies products, that impair several metabolic functions have shown a statistically significant reduction [11] and eventually, shading of this of visual acuity in patients operated under photoproducts along with rod outer segment higher light intensity in comparison with those (ROS) tips, followed by phagocytosis inside RPE operated under lower light intensity [4]. and finally inducing RPE toxicity. Chromophores, Light induced retinal injury: such as rhodopsin bleaching products, RPE Physiopathological mechanisms residues like A2E (bis-retinaldehyde- Like radiation, light can damage tissues phosphatidylethanolamine) and other retinal through ablation, overheating, and phototoxicity, containing molecules, induce retinal damage by depending on frequency spectrum and power. In increasing the likelihood of high-energy photons our study, we were mostly interested in absorption and consequent oxidative stress [12]. phototoxicity, i.e. the processes triggered by Another strong argument, for oxidative stress intense light exposure that could eventually involvement, is that treatment with antioxidants promote an apoptotic cell death in like ascorbic acid reduces phototoxicity [13,14] photoreceptors and other retinal cells. We and promoters of glutathione (GSH) synthesis intended to interfere with phototoxicity, attenuate oxidative stress and decrease cell attenuating and preventing its damaging death [15]. consequences. Phototoxicity comprises multiple A metabolic survey, made on rat retinas pathological mechanisms, such as light-induced exposed to mild photostress, highlighted an oxidative reactions, toxic photoproducts increase in amino acids and biogenic amines generated by vitamin A exposure to light and specific to nitric oxide (NO) pathway [16]. metabolic abnormalities [5]. Another previously made study gave NO a Taking into consideration that our study central role in mouse rods apoptosis induced by was made on Wistar rats, which have a rod- acute light damage. Specific inhibition of dominant retina, we can attribute a central role neuronal isoform of nitric oxide synthase in photoreceptor injury to rhodopsin bleaching (nNOS), not only prevents apoptosis, but it also [6]. The lack of rhodopsin in KO mice, or low blocks its early photoreceptor specific signs, like levels of proteins involved in its regeneration, intracellular Ca2+ concentration increase. The e.g. RPE-65, prevent light damage [5]. A human postulated downstream pathway involves rod has approximately 4x107 rhodopsin enhancement of the guanylate cyclase activity by

NO, subsequent raised intracellular cGMP promising [20]. Another encouraging evidence is concentration, followed by cationic cGMP-gated the up-regulation of antioxidant enzymes in rat channels opening and Ca2+ influx, which furthers brain following sevoflurane treatment [32], the apoptotic program through mitochondrial especially knowing that reactive oxygen species membrane depolarization and apoptotic and oxidative stress play an important role in promoters realizing. The authors additionally light induced retinal damage [13,14]. suggested the possibility of Ca2+ dependent endonuclease activation [17]. Diabetes as a retinal stress load increase Apart from classic physiopathological Sevoflurane preconditioning mechanisms involved in diabetic retinopathy, In general, preconditioning is a method such as endothelial tight junction disassembly, through which prior subjection to certain stimuli that leads to increase in vascular permeability can induce ulterior protection against a and leukostasis, known as glucose-induced subsequent stressor. Volatile anesthetics have a microvascular disease [33], important roles are long history as preconditionants, firstly used in played by oxidative stress and inflammation cardiology against myocardial ischemic injury [34], both present in photic injury. The and then in neurology against ischemic and coexistence of light stress and diabetes mellitus reperfusion injury [18-20]. was recently proved to potentiate retinal Retinal preconditioning history is also damage [35]. The increment in basal oxidative starting to take shape [21-27] and we decided to stress is due to the decrease of intracellular explore the yet unknown potential of antioxidant glutathione (GSH). GSH biosynthesis sevoflurane as a shield against photostress. is dependent on NADPH as a hydrogen donor. At Literature presents both ischemia and light as the same time, glucose excess is converted to preconditioning agents for retina and not only sorbitol by aldose reductase, an enzyme that also stressors. But their protective mechanisms uses NADPH as a cofactor. Since retinal glucose involve synthesis of neurotrophic molecules like uptake is insulin-independent, it increases basic fibroblast growth factor (bFGF) and ciliary significantly when the blood levels are high. The neurotrophic factor (CNF), for light excess is converted to sorbitol, hence the preconditioning [21] and Heat-shock protein 27 diabetic retina sensibility to oxidative stress (Hsp 27), for ischemic preconditioning [28]. At [36]. Furthermore, several inflammation the same time, sevoflurane acts directly on the markers are present in diabetic retinopathy: existing receptors, modulating the cells activity microglia activated morphology and more promptly. proinflammatory cytokines secretion, elevated With a number of advantages over complement levels, increased expression of isoflurane, sevoflurane is gaining popularity in growth factors, including vascular endothelial clinical practice. The already existing growth factor (VEGF) [34]. infrastructure would be the upper hand in Taking into consideration both the instituting preconditioning therapy with physiopathology and the high prevalence of sevoflurane before ophthalmologic surgery, if diabetes mellitus, 8.5% in the adult population in proven efficient. A meta-analysis split the 2014, we concurred that diabetes would be a neuroprotective effects of sevoflurane and other suitable additional stressor to test our theory inhalational anesthetics in three main and to gain insight into the interaction between paradigms: anti-excitotoxicity, anti- preconditioning, photostress, and diabetes. inflammation, and anti-apoptosis [29]. Sevoflurane diminishes neuron excitotoxicity by attenuating excitation and enhancing inhibition, Materials and methods i.e. it is an antagonist for ionotropic glutamate 20 male Wistar rats, weighting 350 g and of receptor and a positive modulator for GABA-A approximately 3 months old were used in our receptor [30,31]. Inflammation is as well present study, which were reared in a normal 12h light/ in light damage, so the fact that sevoflurane dark cycle, with food and water ad libitum. Rats suppresses the expression of inflammatory were divided equally and randomly into four cytokines, NF-kappa B and p38 MAPK is

26 Romanian Society of Ophthalmology © 2018 Romanian Journal of Ophthalmology 2018; 62(1): 24-33 groups: control (rats exposed to photostress), monitored the temperature inside the box and group 1 (rats exposed to photostress and ensured that the animals had the eyes opened at sevoflurane preconditioning), group 2 (diabetic every 20 minutes during the experiment. The rats exposed to photostress) and group 3 exposure time to photostress for all groups was (diabetic rats exposed to photostress and 1 hour. ERG were performed at 36 h and 14 days sevoflurane preconditioning). For ERG after photostress in all groups. ERG a- and b- recording, we made use of electrodes, positioned waves latencies and amplitudes were compared as it follows: the active electrode on the between groups. stimulated eye, the reference on the mouth and Sevoflurane preconditioning was obtained the ground on the tail. The tips of the electrodes by 1h exposure to 2% inhalational concentration were made from nickel-chromium Alloy through a specially adapted mask, at an oxygen (ni80cr20, diameter 0.15 mm). Before ERG flow rate of 2L/ min. The photostress was recording, we instillated oxibuprocaine performed at one hour after sevoflurane hydrochloride (Benoxi 4 mg/ ml, preconditioning to ensure awakening from UnimedPharma), a corneal anesthetic, and anesthesia before light exposure. Diabetic groups tropicamide (Mydriacyl, 0.5%, Alcon). For the were formed by an intraperitoneal injection of ERG set-up, we connected the electrodes to streptozotocin at a dose of 50 mg/ kg body Biopac MP150 System. We used Acq.Knowledge weight, one month before ERG baseline 4.2 for data acquisition and analysis. We recording. Glycemia was measured 2 days after recorded ERG for a 200 s period and waveforms streptozotocin injection and after every ERG were acquired by averaging 150 ms of the raw recording. Only glycemic values over 400 mg/ dl data after light stimulus. All recordings were were considered suitable. done in a dark room after proper dark After ERG recordings were done, animals adaptation. The ERG recordings were done were sacrificed with an overdose of chloral under anesthesia with chloral hydrate (0.4 g/ kg) hydrate. Eyes were enucleated for histological injected intraperitoneally. assessment. After enucleation, the eyes were Photostress was performed with previous fixed in paraformaldehyde 4%. Retinal sections pupillary dilation with tropicamide (Mydriacyl, and staining with hematoxylin and eosin were 0.5%, Alcon). For light exposure, we used an done. Analysis of retinal layers was performed. aluminium foil covered box, which contained For statistical analysis, parameters were four LED lamps that produced a mean brightness compared by using the one-way ANOVA test of 20.000 lux. The box was provided with a (IBM SPSS Statistics 22). cooling system to prevent overheating. We

Table 1. Sequence of events conducted in our study Day 1 Day 7 Day 8 Day 21 Control group Baseline ERG Photostress ERG recording – 36h ERG recording – 14 recording Exposure after photostress days after photostress Group 1 Baseline ERG Photostress ERG recording – 36h ERG recording – 14 recording Exposure + after photostress days after sevoflurane photostress preconditioning Group 2 Baseline ERG Photostress exposure ERG recording – 36h ERG recording – 14 (diabetic) recording after photostress days after photostress Group 3 Baseline ERG Photostress ERG recording – 36h ERG recording – 14 (diabetic) recording Exposure + after photostress days after sevoflurane photostress preconditioning

Results wave latency and b wave latency in the diabetic group (4 weeks after streptozotocin injection). Only the a-b amplitude showed a slight decrease, but it was not statistically significant.

Fig. 2 Baseline ERG averaging from one animal recording (specific morphology of the ERG waves)

Fig. 1 Glycemia and weight in control and diabetic animals. A mean glycemia of 500 mg/ dl and a decrease in weight over the course of the experiment in diabetic animals can be observed. *Day 1 represents the date of baseline ERG

recording and corresponds to 4 weeks of streptozotocin (STZ) induced diabetes

We assessed the differences in ERG Fig. 3 Variability of mean a-b wave amplitude in response between diabetic and non-diabetic relation to sevoflurane preconditioning and diabetes after photostress (DM – diabetes groups, with or without prior sevoflurane preconditioning, after light-induced retinal mellitus, PS – photostress, PC – sevoflurane preconditioning) damage. No statistical significant differences were found between the control group and the experimental groups at baseline measurement.

ERG maintained the same measurements for a

Fig. 5 ERG recording at baseline, after photostress or photostress and sevoflurane preconditioning at 36 h (NDM – non-diabetic, DM - diabetes mellitus, PS–photostress, PC– sevoflurane preconditioning)

Fig. 4 Mean a-b wave amplitude at baseline and after photostress in the studied groups (DM – diabetes mellitus, PS – photostress, PC – sevoflurane preconditioning)

The amplitude of the ERG showed a statistically significant decrease after photostress for both normal and diabetic animals (control and group 2). This decrease was more important in the diabetic group. For the photostress and preconditioning group (experimental group 1), the decrease was not statistically significant when baseline and post- Fig. 6 Mean a-wave latency at baseline and after photostress ERG were compared. Group 3 photostress in the studied groups (DM – diabetes showed a statistically significant decrease of the mellitus, PS – photostress, PC – sevoflurane preconditioning) ERG amplitude after photostress when compared to baseline. The mean amplitude values obtained after light damage were similar at 36 h and 14 days post-photostress for each of the studied groups.

Fig. 7 Mean b-wave latency at baseline and after sevoflurane preconditioning and photostress in photostress in the studied groups (DM – diabetes the non-diabetic groups at 36 h and 14 days after mellitus, PS – photostress, PC – sevoflurane light damage. In the diabetic groups, the preconditioning) latencies of the composing ERG waves increased

after 14 days post-photostress (not statistically

Both a- and b-wave latency showed no significant), without additional shifts done by statistical changes after photostress or sevoflurane preconditioning.

Fig. 8 Hematoxylin & eosin staining of retinal layers in non-diabetic rats after photostress (A), non-diabetic rats after sevoflurane preconditioning and photostress (B), diabetic rats after photostress (C) and diabetic rats after sevoflurane preconditioning and photostress (D). In diabetic animals, sections reveal loss of retinal ganglion cell and a swollen appearance of the remaining cells. Additionally, the diabetic groups (C, D) show a decrease in cell density in ONL. A comparison between diabetic (D) and non-diabetic (B) groups, both with preconditioning and photostress, also exhibits a decrease in ONL thickness (OS PR – photoreceptor outer segment; ONL – outer nuclear layer; INL – inner nuclear layer; IPL – inner plexiform layer; GC – ganglion cell layer)

Discussions amplitude by 4 weeks post-streptozotocin. Some studies have reported early visual function Our results showed that baseline ERG was deficits in diabetic rats after 12 weeks following not changed in any of the studied groups. This streptozotocin treatment [37] or even at one indicated that streptozotocin induced diabetic month following streptozotocin treatment [38]. rats did not exhibit any ERG delay or decrease in On the other hand, electrophysiological studies

30 Romanian Society of Ophthalmology © 2018 Romanian Journal of Ophthalmology 2018; 62(1): 24-33 done on female diabetic rats showed no visual retinal deterioration due to white light was so function abnormalities after 12 weeks of severe in diabetic group after 42 days of light streptozotocin-induced hyperglycemia [39]. Our exposure to 1500-2000 mW/ m² during a 12 to study supported the fact that ERG was not 12 hour light-dark cycle, that ERG could not be modified after 4 weeks of streptozotocin induced recorded. Such severe light damage cannot be diabetes in rats. A slight delay in a- and b-wave determined by other types of light, like red light, latency could be noted at 14 days post- attenuated brown light, or attenuated yellow photostress only in the diabetic groups but it did light [35]. not reach statistical significance. This delay could Sevoflurane preconditioning with 2% be attributed to diabetes and not to photostress inhalational concentration for 1 hour before because it did not appear in the non-diabetic photostress did provide some retinal protection group after light damage. against light-induced damage in diabetic animals The response to light induced damage was but this effect was attenuated when compared to different in diabetic vs. control group. In the the non-diabetic group. The relationship control group, our model of photostress between glycemia and anesthetic concentration produced a decrease to approximately half the has been speculated as an important mean amplitude value of the baseline ERG. This determinant during anesthetic preconditioning susceptibility to light damage is known to be in diabetes, higher concentrations of anesthetic much higher in albino rats, like Wistar rats, than having a more protective effect in diabetes [45]. in pigmented rodents [40]. Preconditioning with Further studies should clarify if a higher sevoflurane anesthesia provided a protective inhalation concentration of sevoflurane (more action on photoreceptors (represented by the a- than 2%) would offer a better retinal protection wave of the ERG) and the bipolar cells against light damage in diabetes. (represented by the b-wave). This was indicated Beside anesthesia, other factors like by the increased amplitude of the ERG after ischemia conditioning have shown to provide photostress when compared to control group. some protection in diabetes [46,47]. This gives Positive effects of other anesthetics on the “preconditioning” concept a launching pad protecting the retina against light-induced for the development of new treatment strategies retinal damage have been described. Combined in diabetes. Nevertheless, other studies showed ketamine-xylazine and halothane anesthesia opposite results regarding diabetes and have been shown to be neuroprotective and preconditioning [48]. reduce photoreceptor cell death [41,42]. Also sevoflurane has been recognized as having retinoprotective effects in rats by References preconditioning in a model of retinal ischemia by 1. Boettner EA, Wolter JR. Transmission of the ocular permanent bilateral common artery occlusion media. Invest Ophthalmol Vis Sci. 1962; 776-83:1. [25]. 2. Jaffe GJ, Wood I. Retinal phototoxicity from the Light-induced retinal damage produced a operating microscope: Protective effect by the fovea. severe decrease of the a-b wave amplitude in the Arch Ophthalmol. 1988; 445-6:106. 3. Azzolini C, Brancato R, Venturi G, Bandello F, Pece A, diabetic group indicating that diabetes is an Santoro P. Updating on intraoperative light-induced additional stressor factor to photostress. This retinal injury. International Ophthalmology. 1995; 269- effect of summation between hyperglycemia in 276:18. diabetes and light exposure interacts to induce a 4. Berler PR. Light intensity and visual acuity following cataract surgery. Ophthalmology. 1983; 993-6:90. severe damage to retinal cells. This is consistent 5. Organisciak DT, Vaughan DK. Retinal light damage: with other studies that have shown Mechanisms and protection. Progress in Retinal and electrophysiological changes of ERG and VEP Eye Research. 2010; 113-134:29. after photostress in diabetes type 1 without 6. Noell WK, Walker VS, Kang BS, Berman S. Retinal retinopathy [43]. Also histological analyses have damage by light in rats. Invest. Ophthalmol. 1966; 450- 473:5. shown reduced outer nuclear layer after a period 7. Nathans J. Rhodopsin: Structure, Function, and of 9 days of light exposure in streptozotocin Genetics. Biochemistry. 1992; 4924-4931. injected animals when compared to control 8. Duncan T, Wiggert B, Whittaker N, Darrow R, group [44]. Other studies have reported that Organisciak DT. Effect of visible light on normal and

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GENERAL ARTICLE

Electrophysiologic evaluation of the visual pathway at different depths of sevoflurane anesthesia in diabetic rats

Iliescu Daniela Adriana* **, Ciubotaru Alexandra*, Ghiţă Mihai Aurelian* ***, Păun Adrian Marius*, Ion Tudor*, Zăgrean Leon* *Physiology Department, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania **Ophthalmology Department, “Dr. Carol Davila” Central Military University Emergency Hospital, Bucharest, Romania ***Ophthalmology Department, University Emergency Hospital, Bucharest, Romania

Accepted: March 13rd, 2017

Abstract Our study investigated the changes produced by diabetes on the visual pathway in a Wistar rat model. The impact of diabetes at 10 weeks after intraperitoneal streptozotocin (STZ) injection was evaluated through electrophysiological methods like visual evoked potentials (VEP) and electroretinogram (ERG). VEP and ERG were recorded simultaneously under different sevoflurane anesthetic depths. In all tested concentrations, sevoflurane affected the amplitude and latency of VEP and ERG component elements. With increasing anesthetic depths, sevoflurane increased the latencies of VEP N1, P1 and N2 peaks and ERG a- and b- waves in both control and diabetic animals. On the other hand, the amplitude of VEP showed enhancement in higher concentrations of sevoflurane, contrariwise to the drop of amplitude seen in the ERG. Diabetes additionally increased the latencies of VEP peaks and decreased the N1-P1 amplitude of the VEP when compared to control at the same anesthetic depth. The a- and b- waves were also delayed by diabetes at 10 weeks post-STZ diabetic induction, with the exception of highly profound anesthetic depth in which the result for the b wave were conflicting. We found a reduction in amplitude of the a-b wave in diabetic animals, when ERG was recorded under 6% and 8% sevoflurane concentration. In conclusion, neurophysiological studies like VEP and ERG are useful in the assessment of retinal and optic nerve dysfunctions produced by diabetes, yet considering the alterations that occur during anesthesia if this is used. Keywords: visual evoked potential, electroretinography, diabetes, sevoflurane

Introduction evoked potential) and ERG (electroretinogram) recorded under sevoflurane anesthesia in The purpose of our study was to investigate diabetic animals. More than 60% of the diabetic the influences of moderate and deep levels of patients were expected to develop a form of sevoflurane anesthesia on optic nerve retinopathy in the first decade of the disease. conduction and retinal function in diabetic rats. This could be the cause of several abnormalities: Our research followed the changes of VEP (visual increased polyol pathway, activation of protein

34 Romanian Society of Ophthalmology © 2018 doi:10.22336/rjo.2018.5 Romanian Journal of Ophthalmology 2018; 62(1): 34-41 kinase C pathway, increased expression of dark cycle, with food and water ad libitum. Rats growth factors, hemodynamic changes, were divided equally and randomly into two accelerated formation of advanced glycation end groups, control (non-diabetic), and diabetic. For products, oxidative stress, or activation of the each group we used 2%, 4%, 6% and 8% renin-angiotensin-aldosterone system [1]. The inhalational concentration of sevoflurane for effects of these abnormalities could lead to anesthesia and recorded simultaneous ERG and retinal microaneurysms with microhemorrhages VEP, during flash stimulation. or microthrombosis, hyaline deposits or angiogenesis. Recent studies have pointed Electrodes settings towards the role of activated microglia in Both ERG and VEP recordings were diabetic patients in the release of pro- performed using electrode tips from nickel- inflammatory mediators and proliferation chromium alloy (ni80cr20, diameter 0.15 mm). resulting in severely affected retinal neurons [2]. The electrodes for VEP recordings were Besides diabetic retinopathy, optic nerve implanted through and fixed in the cranial bones, neuropathy manifested as a delay in neural one week before the rats in diabetic group were conduction of the post-retinal visual pathways, made diabetic, in order to give time to the another complication of diabetes that leads to surgical wound to heal without complications. impaired vision. The surgical procedure was performed under Neurophysiological techniques are anesthesia with intraperitoneal solution of available to assess both optic nerve and retinal chloral hydrate (0.4g/ Kgc). The withdrawal dysfunction generated by diabetes [3]. VEP is an reflex to noxious stimuli was periodically electroencephalographic pattern, which shows assessed during the procedure, and we adjusted the electrical signals generated by the occipital the chloral hydrate dose whenever required. The cortex, during flash light stimulation of the actual surgery had the following steps: a median retina. The amplitude of the signal is related to incision was performed on the scalp, then the the integrity of the visual pathways and of the tegument and connective tissue were sideways occipital area itself. VEP abnormalities have been shifted, periosteum was easily scraped from the described in patients with Diabetes Mellitus, bone, the head of the rat was fixed in a more important in those who already suffer from stereotaxic apparatus, the bregma was identified, diabetic retinopathy [4]. On the other hand, ERG two trepanations were done for each electrode is a noninvasive method that assesses the using a dental drill, retaining between them 1 bioelectrical response to the visual stimuli of the mm bone bridge for anchoring the electrode, the retina, reflecting events associated to electrodes were placed in their final position photoreceptors, bipolar cells, amacrine cells and crossing the epidural space from one trepanation Muller cells [3]. Changes produced in a and b to the immediately close one and the last step wave amplitude and latency can have a role in was the suturing the scalp around the electrodes. scaling the severity and prognosis of the diabetic The sites of the electrodes were decided in disease [5]. The clinical importance of our study agreement with the atlas of Paxinos and Watson is that exploration of VEP and ERG during (Paxinos G, 1998). Two active electrodes were anesthesia can be disturbed by the depth of the placed over the right and left occipital area (6 anesthesia, especially in diabetic patients. mm dorsal to bregma, 4 mm lateral to midline). The reference electrode was placed over the Materials and methods olfactory bulb (7 mm anterior to bregma, on the midline). For our study, we used 16 male Wistar rats For the ERG, the electrodes were of approximately 3 months old (medium weight positioned as it follows the active electrode on 350 g), which were reared in a normal 12h light/ the stimulated eye, the reference on the mouth and the ground on the tail. The active and

35 Romanian Society of Ophthalmology © 2018 Romanian Journal of Ophthalmology 2018; 62(1): 34-41 reference electrodes were loop-shaped nickel- 100 Hz, amplified by 10000 times. Data was chromium wires. The active electrode was acquired and digitalized at 1000fps on a placed around the rim of the eyeball in the computer through AcqKnowledge 4.2 software. conjunctival sack of the stimulated eye and the Amplitudes and latencies of the ERG a- and b- reference electrode in the mouth of the animal. waves and VEP N1, P1, N2 peaks were analyzed Before the ERG recording we instilled using IBM SPSS Statistics 22. Mean values and oxibuprocaine hydrochloride (Benoxi 4 mg/ ml, standard deviation were calculated. One-way UnimedPharma), a corneal anesthetic, and ANOVA and unpaired T-test were used to tropicamide (Mydriacyl, 0.5%, Alcon). compare the differences between groups (p<0.05 was interpreted as statistically significant). Diabetic induction We induced diabetes in the diabetic group by specifically destroying the pancreatic β-cells, achieved by an intraperitoneal injection of streptozotocin (STZ) at a dose of 50 mg/ kg body weight, after overnight fasting. Two days after the injection, the glycemia was measured with a glucometer (ACCU-CHEK Performa Nano; Roche, Germany). Rats were considered diabetic only if glycemic values were over 300 mg/ dl. We kept monitoring glycemic values at every two weeks.

ERG and VEP recordings All our recording settings were placed in a dark and soundproof room. During anesthesia Fig. 1 Spontaneous activity of ERG, occipital EEG, induction, the rat was placed for 1 minute in a and EKG recorded under 4% sevoflurane during custom-built anesthetic induction chamber flash stimulation. Please note that ERG and VEP where 8% sevoflurane was vaporized in 2L/ min can be identified after light pulses without oxygen. Afterwards, the animal was immediately averaging. The EEG shows burst-suppression pattern that facilitated VEP appearance placed in a gas delivery system. ERG and VEP electrodes were set in the above-mentioned positions, connected to Biopac MP150 system. We simultaneously recorded ERG and VEP for every rat, at each inhalational concentration of sevoflurane (2%, 4%, 6% and 8%), consecutively. After switching from one concentration to another, a waiting period of 5 minutes was followed so that the anesthetic concentration in the rat system would equalize the one delivered. In the diabetic group, ERG and VEP were recorded at 10 weeks after streptozotocin induced diabetes. Light flashes were delivered at a rate of 30 stimuli/ min with o a duration of 0.015 s, by a LED placed at 1 cm distance from the stimulated Fig. 2 Representative ERG and VEP obtained by eye. Both retinal and visual cortex responses to averaging of a 300 sec sample under 4% the stimuli were recorded in 300 s epochs. The sevoflurane; a and b waves could be identified for signals were band-pass filtered between 1 and ERG and N1, P1 and N2 peaks for VEP

Results Animals that did not achieve > 300 mg/ dl after 3 days post-STZ injection were excluded from the The glycemic values in the diabetic group study. Diabetic rats developed polyuria and were maintained over the accepted threshold polydipsia and decreased in weight over the (>300 mg/ dl) during the whole experiment. course of the 10-week experiment.

Table 1. Glycemic values obtained in NDM and DM groups during the experiment (NDM-non-diabetic, DM–diabetic) Glycemia (mg/ dl)* Baseline 2 weeks** 4 weeks** 6 weeks** 8 weeks** 10 weeks ** NDM 122±8 116±5 118±10 117±8 121±13 122±8 Group DM Group 510±66 542±12 499±62 489±28 495±37 481±31

*Mean value ± standard deviation ** Period after STZ injection

Sevoflurane affected the amplitude and latency of VEP and ERG component elements in all tested concentrations. Sevoflurane increased the latencies of N1, P1 and N2 VEP peaks (statistically significant for both groups, p<0.05) with increasing anesthetic depths. When diabetic and control groups were compared, N1 and N2 latency values showed a statistically significant increase in diabetic animals for all analyzed sevoflurane concentrations, except for 6% (p>0.05). For P1 peak, diabetes increased the latency in all four studied anesthetic concentrations. On the other hand, the amplitude of N1-P1 and P1-N2 of the VEP showed enhancement with A higher concentrations of sevoflurane. The increase of amplitude of the VEP recorded with deeper anesthesia levels reached statistical significance only for N1-P1, both for non-diabetic and diabetic groups. Even though the same tendency for amplitude enhancement with higher anesthetic concentrations was observed in diabetic animals, when compared to the non- diabetic group, the amplitude of N1-P1 was decreased at the same level of anesthesia (p<0.05). For the P1-N2 amplitude, this decrease was observed only for the 8% sevoflurane level.

Deviation 6% Mean 229.9091 345.2727 Std. 265.82906 427.88388 Deviation 8% Mean 387.4286 537.1429 Std. 344.43957 539.82480 Deviation

The latencies of a and b ERG waves increased with anesthetic deepening for both non-diabetic and diabetic groups (except for a wave latency in the control group, where no statistical difference was noted between recordings under 6% and 8% sevoflurane concentrations). When the two groups were

C compared at various anesthetic depths, the diabetic group showed increased a wave latency Fig. 3 Variability of N1 (A), P1 (B) and N2 (C) peak (statistical significant for 2%, 4% and 8% latencies of the VEP in relation to sevoflurane sevoflurane concentrations, p<0.05) and b wave anesthetic concentration for NDM (non-diabetic) latency (statistical significant for 2% and 4% and DM (diabetic) groups sevoflurane concentrations, p<0.05). On the

other hand, the a-b wave amplitude decreased

Table 2. Changes of VEP amplitude (N1-P1 and P1-N2 with increasing anesthetic depth. Diabetes amplitude) for NDM (non-diabetic) and DM (diabetic) diminished even more the amplitude for 6% and groups in accordance with sevoflurane anesthetic 8% sevoflurane concentrations. concentration NDM Group N1-P1 P1-N2 Sevoflurane Amplitude Amplitude concentration (μV) (μV) 2% Mean 148.6667 252.3333 Std. 72.55251 108.05122 Deviation 4% Mean 186.7500 230.0000 Std. 139.30392 186.03046 Deviation 6% Mean 330.7500 281.0000 Std. 237.26409 267.14540 Deviation 8% Mean 705.6667 1006.3333 Std. 514.86050 603.99365 Deviation

DM Group N1-P1 P1-N2 Sevoflurane Amplitude Amplitude A concentration (μV) (μV) 2% Mean 116.5000 311.5000 Std. 65.76093 246.78027 Deviation 4% Mean 168.8750 359.6250 Std. 104.66469 212.72312

during medium and deep anesthetic levels. High doses of sevoflurane increase the N1, P1, and N2 peak latencies of the VEP but also potentiate the amplitude of the VEP in a dose-dependent manner in both control and diabetic groups, especially for the N1-P1 amplitude. The P1-N2 amplitude showed a great increase when the highest sevoflurane concentration was reached (8% inhalational concentration) but the amplitude difference between 2%, 4%, and 6% was not prominent. Overall, higher concentrations of sevoflurane increase latency and enhance amplitude of VEP. VEP changes, produced by volatile anesthetics, including sevoflurane, that show increased latency with more profound anesthesia, have been reported

B in literature, and are well-known facts [6-9]. On the other hand, our results showed an unexpected enhancement of VEP amplitude with Fig. 4 Variability of a wave (A), and b wave (B) increasing concentration of sevoflurane, latencies of the ERG in relation to sevoflurane suggesting a facilitated visual cortical reactivity anesthetic concentration for NDM (non-diabetic) and DM (diabetic) groups to light stimulation during increased anesthetic depth. As most volatile anesthetics do,

sevoflurane silences the brain cortical activity

but as indicated by our results it also facilitates the sensory evoked responsiveness of the occipital cortex to light stimulation. This finding is similar to recent research results that confirm the increment of visual sensory response during cortical silencing produced by increased sevoflurane anesthesia. One possible suggested explanation is that in awake state, the high spontaneous activity of the brain processed in the occipital cortex depresses the input and output synapses, inhibiting the generation of the VEP. On the contrary, anesthetics like sevoflurane would potentiate the response to visual stimulation by counteracting the synaptic depression [10]. Older reports are not in agreement with these results, showing a decrease of VEP amplitude with an increase in sevoflurane anesthetic concentration [7,8]. Fig. 5 Changes of a-b wave amplitude of the ERG It has been shown that diabetes is an for NDM (non-diabetic) and DM (diabetic) groups additional stress factor for the optic nerve in accordance with sevoflurane anesthetic function causing optic neuropathy at 10 weeks concentration after STZ injection. This has been proven by increased latencies of the N1, P1, and N2 peaks and by decreased N1-P1 amplitude of the VEP Discussions when compared to control at the same anesthetic depth. For the P1-N2 amplitude, we Our results supported the fact that found an actual increase for diabetic animals at sevoflurane and diabetes affect the VEP and ERG 2%, 4%, and 6% sevoflurane concentrations but

39 Romanian Society of Ophthalmology © 2018 Romanian Journal of Ophthalmology 2018; 62(1): 34-41 a significant decrease at 8%. At increasing diabetic. These results were recorded in female anesthetic depths in the diabetic group, we found rats, so gender should also be taken into the same tendency of amplitude enhancement of consideration when evaluating diabetic induced VEP as in the control group. Thus, we conclude abnormalities [20]. that in the diabetic group, we have a general In conclusion, neurophysiological studies reduction of nerve transmission compared to like VEP and ERG are useful in the assessment of control, but the facilitation of sensory evoked retinal and optic nerve dysfunctions produced by signaling is maintained. diabetes, yet considering the alterations that Dark-adapted ERG showed waveform occur during anesthesia if this is used [3,21]. changes induced by sevoflurane anesthesia in both control and diabetic groups. 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Arena A, Lamanna J, Gemma M, Ripamonti M, Ravasio timing at 12 weeks of diabetes [18]. We found a G, Zimarino V, De Vitis A, Beretta L, Malgaroli A. Linear reduction in the amplitude of the a-b wave only transformation of the encoding mechanism for light when ERG was recorded under 6% and 8% intensity underlies the paradoxical enhancement of sevoflurane concentration. This showed a cortical visual responses by sevoflurane. J Physiol. sensitivity of the ERG in diabetic animals to 2017; 595(1):321–39. 11. Yanase J, Ogawa H. Effects of halothane and profound anesthesia. Some studies have found sevoflurane on the electroretinogram of dogs. Am J early retinal damage at only 2 weeks after Vet Res. 1997; 58(8):904-9. diabetic induction showed by reduced amplitude 12. Raitta C, Karhunen U, Seppäläinen AM. Changes in the of the ERG compared to control, b-wave being electroretinogram and visual evoked potentials during general anaesthesia using enflurane. Graefes Arch Clin more affected [19]. Other reports that indicated Exp Ophthalmol. 1982; 218(6):294-6. opposite results found no statistical differences 13. Iohom G, Gardiner C, Whyte A, O'Connor G, Shorten G. in a and b waves of the ERG between control and Abnormalities of contrast sensitivity and

electroretinogram following sevoflurane anaesthesia. Eur J Anaesthesiol. 2004; 21(8):646-52. 14. Iohom G, Whyte A, Flynn T, O'Connor G, Shorten G. Postoperative changes in the full-field electroretinogram following sevoflurane anaesthesia. Eur J Anaesthesiol. 2004; 21(4):272-8. 15. Aung MH, Kim MK, Olson DE, Thule PM, Pardue MT. Early visual deficits in streptozotocin-induced diabetic long evans rats. Investig Ophthalmol Vis Sci. 2013; 54(2):1370–7. 16. Xie TY, Li Q, Chen XY. Histopathological changes in retinas and F-ERG features of streptozotocin-induced diabetic rats treated with ozone. Int J Ophthalmol. 2016; 9(6):816–20. 17. Hiramatsu N, Deguchi S, Yoshioka C, Otake H, Yamamoto N, Nagai N. Evaluation of Retinal Function in Streptozotocin-induced Diabetic Rats by Using the Electroretinography and Immunohistochemistry Methods. Yakugaku Zasshi. 2017; 137(9):1169-1175. 18. Hancock HA, Kraft TW. Oscillatory potential analysis and ERGs of normal and diabetic rats. Invest Ophthalmol Vis Sci. 2004; 45(3):1002-8. 19. Li Q, Zemel E, Miller B, Perlman I. Early retinal damage in experimental diabetes: electroretinographical and morphological observations. Exp Eye Res. 2002; 74(5):615-25. 20. Ramsey DJ, Ripps H, Qian H. An Electrophysiological Study of Retinal Function in the Diabetic Female Rat. Investig Opthalmology Vis Sci. 2006; 47(11):5116. 21. Ghita AM, Parvu D, Sava R, Georgescu L, Zagrean L. Electrophysiological changes in optic neuropathy of streptozotocin induced diabetic rats. J Med Life. 2013; 6(3):340–8.

GENERAL ARTICLE

Correlations between internal and external ocular factors and macular pigment optical density

Tudosescu Ruxandra*, Alexandrescu Cristina Mihaela** ***, Istrate Sânziana Luminiţa* ** ***, Vrapciu Alexandra Diana** ****, Ciuluvică Radu Constantin****, Voinea Liliana** *** *Ophthalmology Department, “Regina Maria” Private Health Care Network, Dorobanţi Hyperclinic, Bucharest, Romania **Ophthalmology Department, University Emergency Hospital, Bucharest, Romania ***Ophthalmology Department, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania ****Division of Anatomy, Faculty of Dental Medicine, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania

Correspondence to: Istrate Sanziana, MD, PhD, Ophthalmology Department, University Emergency Hospital, Bucharest, 169 Splaiul Independentei Street, District 5, Bucharest, Romania, Mobile phone: +40726 535 515, E-mail: [email protected]

Accepted: February 15th, 2018

Abstract Aim. To assess the relationship between the macular pigment optical density and blue- light issued by computers, glare sensibility, with iris color, age, sex, or refractive errors. Material and methods. 83 patients (166 eyes) were enrolled in a prospective observational study. They were divided into 2 groups: group 1 (study group) - computer using patients (time spent in front of the computer for minimum 8 hours per day, 5 days per week, 2 years) - 43 patients and group 2 (control group) - 40 patients. The following investigations were conducted in all the selected cases: visual acuity, refraction, biomicroscopy, measurement of the MPOD, glare sensitivity, assessment of eye color. Results. 51.81% of the patients were included in group 1, while the rest, 48.19%, were in group 2. Thus, the MPOD had a mean value of (+/ -SD) 0.42+/ -0.13 (t = -1.08, p = 0.28) in group 1, and 0.44+/ -0.16 on the LE. The results showed a MPOD mean value of 0.51+/ - 0.16 in group 2 and 0.51+/ -0 .16. (t = 0.49, p = 0 .62) on the LE. 55.77% of the patients with light colored iris and 56.14% of those with dark iris had a low MPOD. Conclusions. The data from our study failed to illustrate a significant correlation between MPOD and blue-light issued by computers. Furthermore, a statistic significant relationship regarding iris color, refractive errors, glare, and MPOD was not observed. Keywords: macular pigment optical density, blue-light, iris colour, refractive erros, computer using patients Abbreviations: L = lutein, Z = zeaxanthin, MZ = meso-zeaxanthin, AMD = age related macular degeneration, MPOD = macular pigment optical density, MP = macular pigment, HFP = Heterochromatic Flicker Photometry, RE = right eye, LE = left eye

Introduction resolution central vision. The center of the macula contains a small pit – the fovea - that has The macula lutea is the region of the retina the highest density of cone photoreceptors, thus that is responsible for the sharp and high – providing the best visual acuity. Lutein (L),

42 Romanian Society of Ophthalmology © 2018 doi:10.22336/rjo.2018.6 Romanian Journal of Ophthalmology 2018; 62(1): 42-47 meso-zeaxanthin (MZ) and zeaxanthin (Z) are The primary aim of the study was to the components of the macular pigment. The investigate if there are any relationships predominant location of the macular pigment is between MPOD and computer using patients. in the inner plexiform layer and the The secondary aim was to see if there are photoreceptor axon layer of the macula [1]. any correlations with glare and contrast The primary role of these natural sensibility, with iris color, age, sex or refractive xanthophylls is supposed to be the protection errors. against the development of age related macular degeneration (AMD) [2]. Among individuals, their concentration and spatial distribution can Material and methods be very variable [3]. Even though the optical The study was conducted in agreement density of the macular pigment (MPOD) can have with the declaration of Helsinki, with an wide ranges, it is very rare to have a MPOD informed consent practice, good clinical and below 0.2 and, in a healthy person, it is not medical practice and the institutional review totally absent [4,5]. board regulations. We enrolled a number of 83 Another important role of these patients (166 eyes) in a prospective carotenoids is the protection against light- observational study, conducted from May 2017 induced oxidative stress by the free oxygen to August 2017 in the University Emergency radicals, them being antioxidants [6]. This way Hospital, Bucharest, Romania – the they are involved in the protection of the Ophthalmology Clinic. photoreceptors located in the macula. The including criteria for all patients were The third major role is the improvement of subjects over 18 years old and under 65 years the visual performance (glare, contrast) [7]. old, with a minimum BCVA of 0.8. Exclusion The concentrations of the MP can depend criteria for all patients included: corneal diseases on various factors such as smoking, exposure to that might impair the visual acuity, retinal blue light at 499-530 nm, the low intake of L and diseases that might interfere with the Z. and obesity, lifestyle, the color of the iris, measurement of the MPOD, presence of cataract. refractive errors like myopia, low carotenoid After providing an informed consent, patients levels in the serum and possibly ageing [8,9-13]. were divided into 2 groups: Group 1 (study Oxidative stress and blue light might be group) consisted of 43 patients. Group 2 (control involved in the development of ARM with a group) consisted of 40 patients. The including possible connection with a low density of the criteria for group 1 - the computer using patients macular pigment [14,15]. was: time spent in front of the computer for a Nowadays, an important source of blue minimum of 8 hours per day, 5 days per week, 2 light are the computers and the prevalence of years. In group 2 - the normal group, we people working with these devices is more and included subjects who did not fit the criteria for more high. group 1. Regarding glare, there are recent studies All the patients in group 1 worked in the which suggest that a low MP can influence visual informatics industry and the subjects in group 2 performance [16]. There are 2 types of glare: worked in the medical field. discomfort glare – when there is too bright The following investigations were illumination and disability glare - when stray conducted in all the selected cases: visual acuity, light reduces contrast on the image quality [7]. refraction, biomicroscopy, and measurement of Glare dysfunctions are reported in the MPOD, sensitivity to contrast and to glare. glaucoma and in several retinal disorders such as We also assessed the color of the eyes, the use of AMD or retinitis pigmentosa [17-19]. glasses with or without filters against the blue Furthermore, photostress recovery, light of the computers. Refraction values were disability glare, and visual discomfort can be calculated using the spherical equivalent, which influenced by low levels of MP in normal subjects represents the sphere’s value plus half the and can be improved by oral supplementation cylinder’s value. with carotenoids [16].

Measurement of MPOD The values of the measured MPOD in the MPOD was measured using right and left eye varied from 0.10 to 0.77, with a Heterochromatic Flicker Photometry (HFP), with means (+/ -SD) of 0.44 +/ - 0.14 in the right eye Macular Pigment Screener MPS II (Electron eye (RE), and 0.45 +/ -0.16 in the left eye (LE). technology, Cambridge, United Kingdom) at 0.5° 39.76% of the subjects had a higher MPOD of retinal eccentricity. The MPOD can be on the LE, 34.94% had it on the RE, while calculated through this method by measuring the 25.30% did not have a RE-LE difference. absorbance of the blue light by the MP. The results of MPOD are values on a scale of 0-1. If the value is low, the level of blue light that reaches the macula is higher. HFP technique needs patients to match flicker using two wavelengths a blue one at 465 nm absorbed by the MP and a green one, at 530 nm which does not. The determination of the minimum flicker point by flicker matches is done by the MPS II in a quick and easy way. All the patients were naive to the testing. They were instructed by a trained examiner regarding the technique and were shown a demonstration. They had to press a button at the detection of the flicker [20]. Fig. 1 From the statistical data, no significant The MPOD values results were divided into 4 groups: 0-0.25 - very low, 0.25-0.5 - low, 0.5- correlation was found regarding the difference in MPOD between the 2 eyes (p>0.05) 0.75 - good, 0.75-1 - very good.

Statistical analysis The MPOD difference between the 2 eyes All data was analyzed using SPSS. Using the Shapiro–Wilk test and Kolmogorov-Smirnov test, was between a minimum of 0.04 and a maximum the data was interpreted for normality. For the of 0.34, with a mean of (+/ -SD) 0.08 +/ -.06. normally distributed data, student t test and The mean value of the MPOD of the 2 eyes Pearson correlation coefficient were used for was between 0.16 and 0.77 in hypermetropic analysis and a p-value < 0.05 was considered as patients, with a mean value (+/ -SD) of 0.44 +/ - being statistically significant. A descriptive 0.15, while in myopic patients the mean value analysis, which included means, medians, and standard deviations, was performed. was between 0.14 and 0.72, with a mean value (+/ -SD) of 0.45 +/ - 0.13. Results The mean value of the MPOD of the 2 eyes was between 0.14 and 0.62 in male patients, 166 eyes of 83 patients were analyzed in with a mean value (+/ -SD) of 0.42 +/ -0.11, the present study. A number of 63 female while in female patients, the mean value was patients and 23 male patients were included, 3 between 0.16 and 0.77, with a mean value (+/ - times more females than males (female/ male = 60/ 23 = 2.6). SD) of 0.45 +/ - 0.15. Taking into consideration The mean age for the women was 35.85 +/ the parametric distribution of the data, a t test -0.99 years, and for the men was a 33.13 +/ -1.93 was performed, showing no statistical significant years. correlation. Regarding optical correction, 63% of the patients did not have any optical corrections. We analyzed glare in patients in both Regarding the main type of ametropia, groups. According to the glare test, the score 63.9% of the patients were hypermetropic while results were divided into poor, average and the rest of 36.1% were myopic. good. The results are illustrated in table 2.

Table 1. There was no significant statistic correlation 51.81% of the patients were included in between the MPOD and glare of each eye (p>0.05) group 1 - computer using group (>8 hours/ day), %patients poor average good while the rest, 48.19%, were in group 2 (<8 Glare RE 0% 8.43% 91.57% hours/ day). Glare LE 1.20% 3.61% 95.18% The mean age of group 1 was (+/ -SD) of 36.02 +/ - 7.8, and that of those in group 2 (+/ - Regarding the color of the iris, the subjects SD) was de 34.10 +/ - 8.60. were divided into 2 groups, dark colored iris, and We analyzed if the time spent in front of the light colored iris (green and blue). The results computer influenced the type of ametropia and are illustrated in fig. 2 and table 2. the results are shown in table 2.

Table 2. 55.77% of the patients with light colored Table 2. There was no statistical correlation between iris and 56.14% of those with dark iris had a low the type of ametropia and the hours spent using the MPOD computer when using a Chi-square test Percentage % light colored dark colored Refraction iris iris hypermetropia myopia very low 7.69 10.53 Group1 26 17 low 55.77 56.14 good 34.62 31.58 Group2 27 13 very good 1.92 1.75 We analyzed the MPOD value to see if there was any correlation regarding each eye, the means, and the difference between the 2 eyes. Thus, in group 1, the MPOD value of the RE was between 0.10 and 0.67, with a mean of (+/- SD) 0.42 +/ - 0.13 (t = -1.08, p = 0.28) and between 0.10 and 0.77 on the LE, with a mean of (+/ -SD) 0.44 +/ -0.16. In group 2, the results showed a MOPD on the RE, between 0.19 and 0.77, with a mean of (+/ -SD) 0.51 +/ -0.16, and between 0.10 and 0.77 on the LE, with a mean of (+/ -SD) 0.51 +/ -0.16 (t = 0.49, p =0.62). The difference of MPOD between the 2 eyes was between 0.00 and 0.34 with a mean of (+/ - SD) = 0.06 +/ -0.06 in group 1, and between 0.00 and 0.24 in group 2, with a mean of (+/ - SD) 0.07 +/ - 0.06 (t = -0.61, p = 0.54). The mean values of the MPOD in group 1 had a range between 0.14 and 0.72, with a mean of (+/ -SD) 0.45 +/ - 0.14, while in group 2, it was between 0.19 and 0.77, with a mean of (+/ -SD) 0.44 +/ - 0.14 (t = 0.41, p = 0.68). The statistical analysis showed no significant correlation. Therefore, our study revealed that there was no influence of the blue light issued by the computer on the MPOD.

Discussions

Fig. 2 No statistical significant correlation was The results that interest MP determinants

found between the MPOD value and the color of are very variable and still inconclusive [21]. It

the iris (p value two- tail 0.72) seems that there is no consistency between

45 Romanian Society of Ophthalmology © 2018 Romanian Journal of Ophthalmology 2018; 62(1): 42-47 different studies and the results cannot be subjects who did not meet the group 1 criteria, replicated. The causes can be multiple from showed no significant statistical difference sampling to insufficient subjects or between the 2 groups. Yet, there are limitations measurement issues that prevent us from to our study such as small sampling. achieving a significant statistical correlation. Moreover, the MPOD can vary in different geographical areas. Conclusions In our study, we tried to see if we could find The role of the macular pigment is to some significant correlations regarding various safeguard the photoreceptors from the oxidative determinants that can influence the MPOD in the stress, improving the visual performances and Romanian population. possibly providing a long-term protection from We would like to note that the the development of AMD. The MPOD can be measurements in our study were done using a influenced by various determinants like the HFP method, the most common one used for the intake of L and Z, gender, age, obesity, iris color measurement of the MPOD. and others, although there are inconsistencies in Various studies have tried to see if the iris studies results. color can influence the MPOD. In their report, In conclusion, the data from our study Bone and Sparrock (1971) [22] showed no failed to illustrate a significant correlation significant association between MPOD and the between MPOD and blue-light issued by color of the iris, but later on, in their study, computers. Furthermore, no statistically Hammond et al. (1996) showed that light colored significant relationship was observed regarding irises (blue and green) had less MP density than iris color, refractive errors, glare, and MPOD. dark colored ones [8,23]. In our study, the Although these are negative findings, they results showed no statistical difference between are important in further studies regarding the these 2 types of eye color. distribution of MP and the effects of blue- light In consistency with current literature [24- on MPOD. 26], our study did not reveal any significant correlation between MOPD and the type of Acknowledgements ametropia. Myopic patients did not show a MP 1. AMD Nobel Pharmaceutical is gratefully density smaller than the hypermetropic ones. acknowledged for all the support offered in data Previous studies tried to see if ocular collection. dominance can influence MP density [27]. Even 2. All the authors have equally contributed though it is known that ocular dominance can to this study. influence visual performances, there is no proven data that can demonstrate a significant Disclosures relationship between MP density and ocular None dominance [24]. The results from our study were consistent with these results, showing that there is no difference in MPOD between the 2 eyes. Furthermore, our data showed that the References difference in MPOD between the 2 eyes is not statistically significant between males and 1. Snodderly DMBP, Delori FC, Auran JD. The macular females. pigment. I. Absorbance spectra, localization, and discrimination from other yellow pigments in primate To our knowledge, no other study has tried retinas. Invest Ophthalmol Vis Sci. 1984; (25):660-73. to find differences in MPOD in patients who used 2. Hammond BRJE Jr., Russell RM et al. Dietary computers for a long period of time, these modification of human macular pigment density. devices being one of the most important sources 1997; (38):1795–801. of blue–light. So, we hypothesized that there 3. Berendschot TT W-AJ, Bastiaanse M et al. Macular pigment and melanin in age-related maculopathy in a could be a low MPOD in normal subjects who general population. Invest Ophthalmol Vis Sci. 2002; have spent more than 8 hours/ day for at least 2 (43):1928–32. years exposed to computers. However, our 4. Trieschmann MSG, Lommatzsch A et al. Macular statistical data comparing them with normal pigment: quantitative analysis on autofluorescence

images. Graefes Arch Clin Exp Ophthalmol. 2003; supplementation in the intervention of atrophic age- (241):1006–12. related macular degeneration: the veterans LAST 5. Delori FCGD, Hammond BR et al. Macular pigment study (Lutein Antioxidant Supplementation Trial). density measured by autofluorescence spectrometry: Optometry. 2004; (75):223–9. comparison with reflectometry and heterochromatic 20. 20. R de Kinkelder RLPvdV, Verbaak FD, Faber DJ, van flicker photometry. J Opt Soc Am A Opt Image Sci Vis. Leeuwen TG, Berendschot TTJM. Macular pigment 2001; (18):1212–30. optical density measurements: evaluation of a device 6. Sommerburg OGSW, Hurst JS et al. Lutein and using heterochromatic flicker photometry. Eye. 2011; zeaxanthin are associated with photoreceptors in the (25(1)):105–12. human retina. 1999; (19):491–5. 21. 21. Paul S, Bernstein FCD, Richer S, van Kuijk FJM, 7. Estera Igras JL, Matthew Ratzlaff, Rónán O’Caoimh, Wenzel AJ. The Value of Measurement of Macular Colm O’Brien. Evidence of lower macular pigment Carotenoid Pigment Optical Densities and optical density in chronic open angle glaucoma. Br J Distributions in Age-Related Macular Degeneration Ophthalmol. 2013; (97):994–8. and Other Retinal Disorders. Vision Res. 2010 Mar 31; 8. Hammond BRJ, Fuld K, Snodderly M. Iris Color and 50(7):716–28. Macular Pigment Optical Density. Exp Eye Res. 1996; 22. 22. Bone RASJ. Comparison of macular pigment (62):293-7. densities in human eyes. Vision Res. 1971; 9. Algvere PVMJ, Seregard S. Age-related maculopathy 11(10):1057-64. and the impact of blue light hazard. Acta Ophthalmol 23. Billy R, Hammond JMCA. Macular Pigment Optical Scand. 2006; (84):4–15. Density in a Southwestern Sample. Investigative 10. Hammond BRWB Jr., Snodderly DM. Individual Ophthalmology & Visual Science. 2000; 41(6):1492-7. variations in the spatial profile of human macular 24. Kumari Neelam JN, Loane E, Stack J, O’Donovan O, Au pigment. J Opt Soc Am A Opt Image Sci Vis. 1997; Eong KG, Beatty S. Macular pigment and ocular (14):1187–96. biometry. Vision Research. 2006; (46):2149–56. 11. Broekmans WMR, Berendschot TTJM, Klopping- 25. Jongenelen SRJ, Tassignon MJ. Influence of macular Ketelaars IAA, de Vries AJ, Goldbohm RA, Tijburg LBM, pigment on retinal straylight in health eyes. Invest Kardinaal AFM, van Poppel G. Macular pigment Ophthalmol Vis Sci. 2013; 54:3505–9. density in relation to serum and adipose tissue 26. Liew SHMGC, Spector TD et al. Central retinal concentrations of lutein and serum concentrations of thickness is positively correlated with macular zeaxanthin. American Journal of Clinical Nutrition. pigment optical density. Exp Eye Res. 2006; (82):915– 2002; (76):595-603. 20. 12. Curran-Celentano J, Hammond BR, Ciulla TA, Cooper 27. Davey PAS, Lee J. Macular pigment optical density: DA, Pratt LM, Danis RB. Relation between dietary repeatability, intereye correlation, and effect of ocular intake, serum concentrations and retinal dominance. Clinical Ophtalmology. 2016; 10:1671-8. concentrations of lutein and zeaxanthin in adults in a midwest population. American Journal of Clinical Nutrition. 2001; (74):796-802. 13. Hammond BR, Ciulla TA, Snodderly DM. Macular pigment density is reduced in obese subjects. Investigative Ophthalmology &Visual Science. 2002; (43):47-50. 14. 14. Beatty S, Koh HH, Henson D, Boulton M. The role of oxidative stress in the pathogenesis of age-related macular degeneration. Survey of Ophthalmology. 2000; (55):115-34. 15. 15. John M, Nolan JS, O’Donovan O, Loane E, Beatty S. Risk factors for age-related maculopathy are associated with a relative lack of macular pigment. Experimental Eye Research. 2007; (84):61-74. 16. 16. James M, Stringham PVG, Smith PA, McLin LN, Foutch BK. Macular Pigment and Visual Performance in Glare: Benefits for Photostress Recovery, Disability Glare, and Visual Discomfort. Invest Ophthalmol Vis Sci. 2011; 52:7406–15. 17. 17. Loughman JDP, Akkalli M et al. Visual performance and macular pigment. J Optom. 2010; (3):73–89. 18. 18. Loughman JNJM, Howard AN, Connolly E, Meagher K, Beatty S. The impact of macular pigment augmentation on visual performance using different carotenoid formulations. Invest Ophthalmol Vis Sci. 2012; (53):7871–80. 19. 19. Richer SSW, Laisvyde S. Double-masked, placebo controlled, randomized trial of lutein and antioxidant

GENERAL ARTICLE

Medical and legal point of view for low-vision patients

Bogdănici Camelia-Margareta*, Bogdănici Ştefan Tudor**, Săndulache Diana Elena*, Diaconu Carmen-Mariana*** *”Grigore T. Popa” University of Medicine and Pharmacy, Iaşi, Romania; Surgery II Department, Discipline of Ophthalmology, “Sf. Spiridon” Hospital, Iași, Romania **Preventive Department and Interdisciplinarity Department, Discipline of Public Health and Sanitary Management, ”Grigore T. Popa” University of Medicine and Pharmacy, Iași, Romania ***“Ion Ionescu de la Brad” University of Agricultural Sciences and Veterinary Medicine, Agriculture Faculty, Iași, Romania

Correspondence to: Camelia-Margareta Bogdănici, MD, PhD ”Grigore T. Popa” University of Medicine and Pharmacy, Iaşi, 16 Universităţii Street, Code 700115, Iaşi, Romania, Phone: +0232 217 781, E-mail: [email protected]

Accepted: December 19th, 2017

Abstract The aim of the study was to highlight the medical and legal difficulties in framing low- vision patients for certification. We performed a retrospective observational study conducted from January 2013 to January 2016, on 63 patients with the mean age of 16.37±3.34 years, evaluated at the Ophthalmology Clinic from “Sf. Spiridon” Hospital, Iași, in order to release a medical certificate required at the Expertise Board. The clinical parameters observed were visual acuity (VA) with correction, objective refraction (in Spherical Equivalent - SEq), intraocular pressure, slit lamp examination of the anterior pole, fundus examination, orthoptic eye exam, and ocular ultrasonography (in selected cases). The main causes for the decreased visual acuity found are refractive or strabic amblyopia determined by: high myopia (28.57%), esotropia (19.04%), astigmatism (17.46); congenital diseases - congenital nystagmus (12.69%), congenital cataract (7.93%), microphthalmia (7.93%); acquired diseases - retinopathy of prematurity (9.52%), optic nerve atrophy (7.93%), bandelette keratopathy (6.34); ocular trauma (7.93%). In 52.38% of the cases for the RE and 53.96% of the cases for the LE, decreased visual acuity was caused by an irreversible condition and could not be improved. Patients come every year for reevaluation in order to receive the medical certificate required at the Expertise Board. Evaluating the patient for a certificate for visual impairment is a time consuming process due to the high number of investigations necessary and, sometimes, difficult collaboration with the patient with associated general pathology. It also requires knowledge of frequently changing legislation to complete legal forms for patients with visual impairment. A medical certificate may now be issued with a validity of up to four years, given that certain diseases are irreversible and visual functional status does not change over time. Keywords: low-vision, ocular parameters, medical legislation, visual impairment

Introduction Symptoms felt by the patient are reduced visual acuity or contrast sensitivity, visual field loss, Visual impairment is defined as a functional diplopia, photophobia, visual perceptual limitation of the eye(s) or visual system. difficulties or visual distortion [1].

There are 285 million people estimated to Material and methods be visually impaired worldwide. Of these, 39 million are blind and 246 have low vision [2]. It The study was a retrospective is estimated that there are 19 million children of observational one conducted from January 2013 less than 15 years worldwide who are visually to January 2016, on 63 patients with a mean age impaired, and that 12 million have a refractive of 16.37±3.34 years (limits 13 - 27 years), error, which can be easily corrected and 1.4 million are irreversibly blind for the rest of their evaluated at Ophthalmology Clinic from “Sf. lives [2]. Spiridon” Hospital, Iasi, in order to release a Patients with visual impairment are medical certificate required at the Expertise divided into two categories: individuals with low Board. In the selected cases, the majority of vision and individuals with blindness with patients (68%) were male. 63.76% were from distinct characteristics [3] (Table 1). Students rural areas, which highlighted the late with low vision have residual vision and they are addressability of patients for a specialized able to use special equipment to read printed examination. The clinical parameters observed materials. Blindness is characterized by a total were: loss of vision and conditions in which individuals  visual acuity (VA) with correction (with need to rely predominantly on vision Snellen chart), substitution skills, meaning that a blind student  objective refraction (OR) (Topcon does not use vision in the learning process [4]. autorefractometer),

Table 1. Classification of visual impairment  intraocular pressure (Goldmann (after World Health Organization, 2016) aplanotonometer), Category Presenting distance visual acuity  slit lamp examination of the anterior Worse than: Equal to or pole, better than:  fundus examination (direct 0 Mild or no 6/18 ophthalmoscopy), visual 3/10 (0.3)  orthoptic eye exam (synoptophore and impairment 20/70 prims), 1 Moderate 6/18 6/60 visual 3/10 (0.3) 1/10 (0.1)  ocular ultrasonography (in selected impairment 20/70 20/200 cases). 2 Severe visual 6/60 3/60 Refraction values were calculated using the impairment 1/10 (0.1) 1/20 (0.05) spherical equivalent (SEq), which represents the 20/200 20/400 sphere’s value plus half of the cylinder’s value. 3 Blindness 3/60 1/60* The study showed the difficulties for an 1/20 (0.05) 1/50 (0.02) ophthalmologist to known the changing of legal 20/400 5/300 parameters and laws to complete all the papers (20/1200) for the Expertise Board. These parameters 4 Blindness 1/60* Light 1/50 (0.02) perception change very often and make difficulties for 5/300 criteria for visual handicap. It is necessary to be (20/1200) in a permanent connection with a lawyer to 5 Blindness No Light perception complete all the papers for the Expertise Board 9 Undetermined or unspecified in good condition. *or counts fingers (CF) at 1 metre Results Visual impairment causes unfavorable Mean visual acuity on Snellen chart (with consequences for both the individual and the correction) for the right eye (RE) was 0.32±0.35 collectivity. Blindness generates psychological, (limits between 0 and 1.2) (Fig. 1). For the left social, and economic difficulties and it can lead to eye (LE), the mean visual acuity with correction was 0.23±0.31, with the same limits as the RE loss of autonomy and self-esteem [3]. (Fig. 2). For the RE (after World Health Organization, 2003), 17.7% of the cases had

49 Romanian Society of Ophthalmology © 2018 Romanian Journal of Ophthalmology 2018; 62(1): 48-53 moderate visual impairment, 14.51% had severe Regarding the optical correction, it was visual impairment and 27.41% fit into a necessary in 50% of the cases for the RE and in blindness category. For the LE, 24.19% of the 50% of the cases for the LE. The refractive errors cases had moderate visual impairment, 11.29% (in SEq) for the RE had a mean value of 4±7.64 D had severe visual impairment, and 35.47% fit (limits between -17.5 D and +14 D) (Fig. 3.a) and into a blindness category. Bilateral visual for the LE 4.4±8.57 D (limits between -19.25 D impairment was present in 51.61% of the cases; and +13) (Fig. 3.b). unilateral visual impairment in 27.41% and 20.9% had mild or no visual impairment.

A Fig. 1 VA – distribution RE

B Fig. 3 Refractive errors: a - refractive errors for RE and b - refractive errors for LE

Of the 63 patients, 44.4% had changes in fundus examination for the RE and 47.61% for the LE. Changes in the anterior pole were found in 28.5% of the cases for the RE and in 28.5% of the cases for the LE. For 10 patients (15.87%),

eye ultrasound (Mode A and B) was required, 9.2% showed changes in the RE and 7.93% in the Fig. 2 VA – distribution LE LE.

Certification depending on the value of sight impaired and 8% slightly sight impaired visual acuity (by Order no. 707/538/2014) was (Table 2). the following: for the RE - 8% were slightly sight impaired, 18% medium sight impaired and 24% Table Classification of visual impaired severely sight impaired; for the LE - 11.29% Vision RE LE were slightly sight impaired, 19.35% medium sight impaired and 27.42% severely sight slightly sight impaired 8% 11.9% impaired. In 52.38% of the cases for the RE and 53.96% of the cases for the LE, decreased visual medium sight impaired 18% 19.35% acuity was caused by an irreversible condition and could not be improved. The main causes for the decreased visual severely sight impaired 24% 27.42% acuity found were (Fig. 4): refractive or strabic amblyopia - high myopia (28.57%), esotropia

(19.04%), astigmatism (17.46%), myopic anisometropia (6.34%), high hyperopia (4.76%), Discussions hyperopic anisometropia (1.58%); congenital diseases - congenital nystagmus (12.69%), Visual impairment is defined as blindness congenital cataract (7.93%), microphthalmia or low vision [5] and is associated with an (7.93%), persistent of primitive vitreous important limitation in ocular function. (6.34%), Stargardt disease (6.34%), pigmentary Psychological distress, difficulties in activities of retinopathy (3.17%), congenital glaucoma daily living and low health-related quality of life (3.17%); acquired diseases - retinopathy of has been reported in patients with visual prematurity (9.52%), optic nerve atrophy impairment [6,7]. Amblyopia, from the Greek (7.93%), bandelette keratopathy (6.34%), ocular amblus (dull) and ops (eye), is a common cause toxoplasmosis (4.76%), secondary glaucoma of vision loss affecting between 1% and 3% of (3.17%); ocular trauma (7.93%). Most patients the population. It has been reported to be more had multiple causes for decreased visual acuity. common in left eyes than right eyes [8] and is, according to the National Eye Institute, the leading cause of unilateral vision loss in the under-70 population. Amblyopia affects both near and distance visual acuity equally [9]. The early detection and treatment improve multiple quality of life indicators and treatments are very cost-effective in terms of benefits derived compared with costs of care [10,11]. According to the data for 2010, 80% of the visual impairment including blindness is avoidable. The two main causes of visual impairment in the world are uncorrected refractive errors (42%) and cataract (33%) [2]. The leading cause of unilateral vision loss in under-70 years old population [10]. It has been

Fig. 4 Causes of decreased visual acuity reported to be more common in left eyes than in the right eyes [8]. The prevalence of childhood blindness Patients come every year for reevaluation varies according to socioeconomic status [12]. In in order to receive the medical certificate very low income countries with high mortality required at the Expertise Board. After rates in children younger than 5 years, the certification depending on the value of visual prevalence may be as high as 1.5 per 1000 acuity Order no. 707/538/2014, 27,42% of the children, in contrast with high-income countries patients had severe sight impaired, 18% medium where the prevalence is five times less [13].

Strabismus or strabismus surgery history is disability, who attest the impossibility of present in 37,5% of the children with amblyopia, acquiring work capacities in relation to the anisometropia in 34,4%, both conditions in already performed medical tests, not to re-take 18,8% of the cases [14]. The prevalence of visual those specific tests, unless the received medical impairment in European populations shows a treatment could have restored one’s work definite increasing trend from north to South capacity. [15]. Visually impaired persons experience Conflict of interest mental health problems related to their vision The authors do not have a financial loss and they might need and want help for this interest/arrangement or affiliation with one or [16]. Vision loss is significantly associated with more organizations that could be perceived as a depression and certain traits of personality real or apparent conflict of interest in the context (specifically neuroticism and conscientiousness), of the subject of the manuscript. independent of the severity of vision loss, and duration of vision loss [17]. References In Romania, the certificates for visual impairment are given according to three 1. Freeman KF, Cole RG, Faye EE, Freeman PB, Goodrich National Orders: 762/ 1992 from August 2007, GL, Stelmack JA. Statement of the problem. In: Care of 707/ 538 from May 2014 and 874/ 554/ 2016 the Patient with Visual Impairment. 2007, St. Louis, American Optometric Association, 1-10. from April 2016. Given the large number of 2. World Health Organization. Media Centre, 2014; normative acts that also include the orders of the http://www.who.int/mediacentre/factsheets/fs282/e Ministry of Health, public policies generate the n/. implementation of problems in the absence of 3. Alves CC, Monteiro GB, Rabello S, Gasparetto ME, de training for medical professionals. It is necessary Carvalho K. Assistive technology applied to education of students with visual impairment. Rev Panam Salud to create a center coordinated by the Public Publica. 2009; 26(2):148-152. Health Department, subordinated to the Ministry 4. World Health Organization. Consultation on of Health. This center would inform medical development of standards for characterization of visual professionals about the specific documents and functioning. WHO/PBL/03.91. 2003, Geneva, WHO. 5. World Health Organization. International Statistical forms required for the issuance of a medical Classification of Diseases and Related Health Problems certificate to patients with a degree of disability, -10-th Revision (ICD-10)-2016-WHO, Version for 2016. assessed according to the legislation on the 6. Leissner J, Coenen M, Froehlich S, Loyola D, Cieza A. matter. Also, this center would help both in the What explains health in persons with visual continuous professional training of medical staff impairment?. Health and Quality of Life Outcomes. 2014; 12:65. and in the benefit of patients, who would receive 7. Bogdanici ST, Costin D, Bogdanici C. Quality of life for a complete file for the specific assessment amblyopic children and their parents. Rev Med Chir Soc required for the issuance of the certificate Med Nat. 2015; 119(1):214-220. attesting a certain degree of disability. 8. Repka MX, Simons K, Kraker RT. Laterality of Amblyopia. Am J Ophthalmol. 2010; 150:20–274. 9. Christoff A, Repka MX, Kaminski BM et al. Distance versus near visual acuity in amblyopia. J AAPOS. 2011; Conclusions 15:342–344. 10. Ostrow G, Friedlaender D. Amblyopia: Current Evaluating the patient for certification is a Evidence-based Therapeutic Options. Int Ophthalmol time consuming process due to the high amount Clin. 2014; 54(3):33-40. of investigations necessary and, sometimes, 11. Bogdanici ST, Martinescu G, Sandulache CM, Bogdanici difficult collaboration with the patient with an CM. Socio-professional integration for amblyopic associated general pathology. It also requires patients. RCIS. 2016; 52:187-194. knowledge of frequently changing legislation. A 12. deVerdier K, Ulla E, Lofgren S, Fernell E. Children with blindness – major causes, developmental outcomes medical certificate may now be issued with a and implications for habilitation and educational validity of up to four years, given that certain support: a two-decade, Swedish population-based diseases are irreversible and visual functional study. Acta Ophthalmol. 2017; doi: status does not change over time. From a 10.1111/aos.13631. legislative point of view, it is necessary for 13. Gilbert C. Changing challenges in the control of patients already confirmed with a degree of blindness in children. Eye. 2007; 21:1338-1343.

14. Robaei D, Kifley A, Rose KA, Mitchell P. Refractive error and patterns of spectacle use in 12-yeay-old Australian children. Ophthalmology. 2006; 113(9):1567-1573. 15. Seland JH, Vingerling JR, Augood CA, Betham G, Chakravarthy U, deJong PTVM, Rahu M, Soubrane G, Tomazzoli L, Topouzis F, Fletcher AE. Visual impairment and quality of life in the older European population, the EUREYE study. Acta Ophthalmol. 2011; 89:608-613. 16. Bruijning JE, van Rens GHMB, Fick M, Knol DL, van Nispen RMA. Longitudinal observation, evaluation and interpretation of coping with mental (emotional) health in low vision rehabilitation using the Dutch ICF Activity Inventory. Health and Quality of Life Outcomes. 2014; 12:182. 17. Tabrett DR, Latham K. Adjustment to vision loss in a mixed sample of adults with established visual impairment. Invest Ophthalmol Vis Sci. 2012; 53(11):7227-7234.

GENERAL ARTICLE

Measuring the perceived quality of ophthalmology services in private organizations. A marketing perspective

Gheorghe Iuliana Raluca, Gheorghe Consuela-Mădălina, Purcărea Victor Lorin “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania

Correspondence to: Gheorghe IR, PhD, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania, 8 Eroii Sanitari Bld., District 5, Bucharest, Romania, E-mail: [email protected]

Accepted: January 14th, 2018

Abstract Nowadays, the competition registered on the Romanian markets regarding the activity of private ophthalmology organizations has raised their interest in developing consumer- oriented strategies. The key factor that assures a differentiation as well as a competitive advantage is the service quality from a marketing perspective. Objectives: From a marketing perspective, service quality is measured as a perceived discrepancy between the consumers’ expectations and was actually performed in health care services. The most widely and validated measurement is the SERVQUAL scale. However, a variety of SERVQUAL scales have been applied in different health care environments without taking into consideration the specialty of the health care service. Thus, the objective of this paper was to measure the service quality in the Romanian ophthalmology private organizations using the SERVQUAL measurement, by identifying the SERVQUAL dimensions, which register the highest and the lowest gap scores. Materials and methods: The instrument for data collection was the SERVQUAL self- administered questionnaire that consisted of 22 items measured on a 5-point Likert scale. The sample size encompassed 100 participants and the sampling technique was the snowball. The internal consistency, validity and the reliability of the SERVQUAL scale was determined by the Cronbach’s alpha coefficients and factor analysis. The SERVQUAL questionnaire focused on 5 dimensions (tangibles, reliability, assurance, empathy and responsiveness) and each dimension, in its turn, was characterized by different items. Results: The mean age of the participants was 49.52 years, with a mean income of 3031 Romanian Currency and the mean period of wearing eyeglasses was 5 years (±2). Further, there were 47% females and 53% males. The overall internal consistency of the SERVQUAL scale, as well as the dimensions’ internal consistency were all above 0.7 and the factor analysis revealed that the items loaded properly on each dimension. Moreover, the gap scores of the SERVQUAL scale’s dimensions pinpointed that the highest gap score was registered by the Tangibles dimension and the lowest gap score was registered by the Reliability dimension. Conclusions: Performing the ophthalmology service right the first time, contributes significantly to the improvement of the marketing effectiveness and the operating efficiency. Keywords: ophthalmology services, service quality, SERVQUAL scale

1. Introduction 1. Literature review From a marketing perspective, perceived Nowadays, the competition in private service quality is a concept that measures the health care ophthalmology organizations has discrepancy between the consumers’ increased and, in order to survive, they have to expectations and their perceptions related to a health care service [8]. As such, expectations are deliver services that satisfy the consumer’s reflected in the desires of the consumers that needs [1,2]. The key factor in differentiating they believe a health care organization should services, which also assures a competitive provide. Once formed, expectations become advantage as well as consumer retention, important for consumers as they will help them positive word-of-mouth, increased profitability, make comparisons between what they financial performance and consumer anticipated and what they actually received [9]. satisfaction, is the service quality [3-5]. On the other hand, perceptions refer to the Studies in the health care field confirmed consumer’s evaluation of the health care service that high quality services are linked directly to provider, being considered, in fact, a increased market share, profits, and savings for combination between what is delivered and how an organization [6]. More exactly, since the 90s, it is delivered [9,10]. the patients’ quality perceptions have accounted Still, like quality in most services, health for 17-27% of the variation in a health care quality is difficult to measure owing to the organization’s net revenue and asset returns [7]. characteristics of services, namely intangibility, By nature, healthcare is a credence service, heterogeneity, and inseparability. Moreover, patients being unable to assess the technical health quality perceptions rise according to the service quality accurately, therefore, functional service size, complexity, specialization, and quality is the primary judgmental feature. Thus, expertise within the health care organizations quality is a judgmental concept [12] and patients [11]. form their perceptions on the operational part of the quality [13]. 1.1. Measures of service quality In ophthalmology, service quality takes the Considering the importance of service same shape and has similar meaning to what was quality in health services, there is no surprise aforementioned about health services, in that many experts still spend a lot of their time general, but it may register some differences understanding the underlying dimensions of the related to the measurement scale. concept [8]. During the 1980s, the service quality Many researchers concluded that from a research increased and led to different empirical consumer’s perspective service quality should be methods because service quality is almost defined by two dimensions [15-17]. For impossible to measure [14]. However, the example, Lehtinen and Lehtinen [15] determined marketing experts determined the service the service quality in terms of corporate quality, quality based on the consumer perceptions. The interactive quality and physical quality whereas most widely and validated scale in scientific Gronroos [16] revealed the components of literature is the SERVQUAL scale. Despite being a service quality as technical quality and reliable instrument, many specialists consider it functional quality, meaning what is delivered inappropriate, if used in health care services. and how the service is delivered, respectively. In Therefore, the objective of this paper was the same vein as Gronroos’ model approach [16], to measure the service quality in the Romanian Berry [17] observed that service quality should ophthalmology private organizations using the encompass outcome quality and process quality. SERVQUAL instrument. More specifically, we Following the research of other marketing wanted to assess whether the SERVQUAL scale specialists, Parasuraman et al. [18] elaborated could be successfully applied in private the most widely used, validated and generally ophthalmology services in Romania and accepted service quality measurement in the determine the dimensions that register the services literature, the SERVQUAL scale [19]. highest gap scores. The SERVQUAL measure is a multi-item instrument that consists of 5 dimensions,

55 Romanian Society of Ophthalmology © 2018 Romanian Journal of Ophthalmology 2018; 62(1): 54-63 determined in their turn, by 22 paired items beneficial not only for the patients but also for [18]. In fact, the SERVQUAL scale measures the the health care organizations. Investigating expectation-perception gap of consumers [20]. patients’ expectations would provide useful Moreover, the gap score is the outcome of the information for the health care provider who difference between perception and expectation wishes to control and improve his service scores. Thus, a positive gap score suggests that performance. the expectations of consumers have been In the health care sector, the traditional exceeded whereas a negative gap score indicates method to assess service quality is Donabedian’s failure. Further, gap scores are usually analyzed structure-process-outcome model that includes as aggregated scores giving an overview of each the following dimensions [23]: dimension and emphasize the strengths and - Structure- includes the setting of the weaknesses embedded in the actual service health care organizations; quality performance. - Process- suggests how health care is The five dimensions that define the technically delivered; SERVQUAL instrument are the following [18]: - Outcome emphasizes the result of - The Tangibles dimension that focuses on medical care on the health and welfare of the the physical facilities, the equipment used and patient. the appearance of the personnel; Donabedian’s model described quality as - The Reliability dimension suggests the being more technical in nature rather than ability of the service provider to perform the functional. In other words, it is not that delivery of the service as accurately as promised; commonly employed, as patients do not have the - The Responsiveness dimension indicates necessary medical knowledge to evaluate an organization’s employees’ willingness to whether the health care service has been provide the consumers a prompt service; delivered properly. Moreover, there have been - The Assurance dimension concentrates several attempts to assess the quality of a health on an organization’s employees’ knowledge and care service based on two dimensions, but courtesy as well as their ability to inspire trust without any real success. For instance, even if and confidence to consumers; technical quality has the highest priority, - The Empathy dimension consists of the researchers resorted to measure it by proxy, ability of the organization’s employees to helping patients make a difference between provide caring and personalized attention to “curing” and “caring” services [24]. consumers. Despite all controversies related to the Despite the fact that SERVQUAL has been validity and reliability of the SERVQUAL scale, it widely spread and has been considered a reliable proved to be efficiently applied in health care as instrument, many specialists criticized it both well. Therefore, there have been shortened or methodologically and conceptually. The most extended versions of SERVQUAL with application important criticism brought to light was that the in health care services in the scientific literature. five dimensions cannot be universally applied in For instance, Lim and Tang [25] extended the all service industries and should be carefully scale with 2 more dimensions, namely implemented on each service market [21]. accessibility and affordability, Tucker and Adams Moreover, the five dimensions should be [26] added caring and outcome while Johnston restrained to two dimensions, namely the core [27] shortened the initial SERVQUAL services and augmented services [22] or to measurement, regrouping the items of the scale. technical and functional dimensions [16]. Similarly, Tomes and Ng [28] integrated in the empathy dimension items that reflected 1.2. Health Service Quality understanding of the illness, relationship and As mentioned before, service quality mutual respect, dignity, physical environment remains a critical issue in most service industries and religious needs. and even more in health care services. Today, According to a research conducted by patient’s expectations changed as they became Purcărea et al. [29], who used the 22-item scale more informed and involved in the delivery of in measuring the health care service quality, it the service. As such, ensuring service quality is was concluded that the SERVQUAL scale might

56 Romanian Society of Ophthalmology © 2018 Romanian Journal of Ophthalmology 2018; 62(1): 54-63 be successfully applied in this field as well. The The internal consistency, validity, and mixed outcomes resulted from previous studies reliability of the SERVQUAL measurement was made us posited that the health service quality is assessed by using the Cronbach’s alpha far from being solved, more crucially if we were coefficient and the factor analysis was performed to take into consideration each medical specialty, in SPSS version 20. such as ophthalmology. In order to determine the SERVQUAL scale’s consistency and reliability, the threshold 2. Materials and methods for the Cronbach’s alpha value was 0.7, which is the accepted limit [32], whereas for the factor After the elaboration of the SERVQUAL analysis, we eliminated values of items lower scale, many specialists applied it on health care than 0.4, which did not load properly on any services in the shape of 22-item format or latent factor, in our case being the SERVQUAL modified, proving its usefulness in assessing the scale dimensions. Before performing the factor service quality as perceived by consumers in hospitals, clinics and other medical centers analysis, a preliminary statistical test was [30,31]. Further, most studies used the employed, namely the Kaiser-Meyer-Olkin SERVQUAL self-administered questionnaire, (KMO) index accompanied by the Bartlett’s test selecting the sample participants from the lists of sphericity in order to examine the inter- with patients of the health care organizations, correlated items. Moreover, the KMO test has to regardless of the medical specialty and their have values greater than 0.5 and the Bartlett’s geographic location. In this research, we selected our sample respondents using the snowball test has to have a significant statistical level technique but taking into consideration the lower than 0.05. Consequently, the method used following criteria: to uncover the latent variables, or in our case, - The respondents’ ages should have been the SERVQUAL scale’s dimensions, was the more than 18 years; correlation matrix, with the Varimax rotation. - The respondents should have been wearing eyeglasses for more than 2 years; - The respondents’ last consultation 3. Findings should have taken place in a private ophthalmology organization from Bucharest. 3.1 Demographic profile of the respondents The sample size was determined by using The mean age of the participants was 49.52 G*Power software and we concluded that a years (±19.84), their mean income was 3031, 00 number of 150 participants should be enough to give us a clear overview of our researched (± 1088) Romanian Currency and their mean objectives. From 150 participants, we validated period of wearing eyeglasses was 5 years (±2) 100 questionnaires, as many were not (Table 1). Moreover, from 100 participants, 47% completely filled in or the respondents did not were females whereas 53% were males and pay attention when filling in the questionnaire. went for a consultation to an ophthalmologist The instrument for data collecting was the due to a routine check-up (22%), surgery (42%) SERVQUAL self-administered questionnaire, consisting of two sections, as it follows: and even asking for second opinions (36%) - The first section collected information (Table 2). about the demographic profile of the respondents such as age, gender, marital status, Table 1. The mean age, income and the period of income, reason for visiting an ophthalmology wearing eyeglasses of the respondents organization and the period of wearing Age of the Income of Period of eyeglasses. respondent the wearing - The second section encompassed the 22- respondent eyeglasses paired questions that measured both Mean 49,52 3031,61 5,00 expectations and perceptions on a 5-point Likert Std. 19,847 1088,277 2,005 scale ranging from strongly agree (5) to strongly Deviation disagree (1). Minimum 18 711 2 Maximum 85 4922 8

Table 2. The distribution of the respondents’ genders Table 3. Cronbach’s alpha coefficients of the overall according to the marital status and the reasons for SERVQUAL scale, the expectation, and the perception seeing an ophthalmologist scales as well as of every dimension included Gender Female Male Dimensions No of Expectatio Perceptio Demographic Frequency Frequency item n n variable s Marital status Tangibles 4 0,86 0,87 Not married 53.2% 45.3% Reliability 5 0,90 0,89 Married 29.8% 26.4% Responsivenes 4 0,86 0,87 Separated 17.0% 28.3% s Reasons for seeing an ophthalmologist Assurance 4 0,89 0,87 Routine check-up 25.5% 18.9% Empathy 5 0,86 0,89 Surgery 36.2% 47.2% 0,78 0,73 Second opinion 38.3% 34% SERVQUAL scale: 0,82

1.1 The SERVQUAL scale applied in 3.1.1 Factor analysis private ophthalmology services According to the KMO index and the 1.1.1 Internal consistency of the Bartlett’s test of sphericity, both the expectation SERVQUAL scale scale and the perception scale had values higher The overall internal consistency of the than 0.80 with a significant level higher than SERVQUAL scale, as well as the dimensions’ 0.05., suggesting that the items included in the internal consistency, was determined by the questionnaire were inter-correlated and the Cronbach’s alpha coefficients as illustrated in factor analysis was suitable to be performed. As table 3. As it can be observed, none of the scales such, the factor analysis for the expectation scale had a Cronbach’s alpha coefficient lower than and the perception scale revealed that every 0.7. item of the questionnaire loaded accordingly on each dimension (table 4 and table 5). The dimensions of the expectation scale showed a 72.20% explanation of the variance whereas the dimensions in the perception scale explained 72.85% of the variance. Table 4. The Rotated Matrix of the Expectation Scale Component Reliability Empathy Assurance Responsiveness Tangibles Dimension Dimension Dimension Dimension Dimension e_ta1 0,843 e_ta2 0,807 e_ta3 0,872 e_ta4 0,829 e_rel1 0,844 e_rel2 0,854 e_rel3 0,829 e_rel4 0,829 e_rel5 0,850 e_resp1 0,813 e_resp2 0,822 e_resp3 0,846 e_resp4 0,867 e_ass1 0,879

e_ass2 0,830 e_ass3 0,851 e_ass4 0,858 e_emp1 0,818 e_emp2 0,859 e_emp3 0,844 e_emp4 0,790 e_emp5 0,723

Table 5. The Rotated Matrix of the Perception Scale Component Empathy Reliability Assurance Tangibles Responsiveness Dimension Dimension Dimension Dimension Dimension p_ta1 0,842 p_ta2 0,869 p_ta3 0,808 p_ta4 0,854 p_rel1 0,853 p_rel2 0,828 p_rel3 0,805 p_rel4 0,810 p_rel5 0,848 p_resp1 0,853 p_resp2 0,857 p_resp3 0,841 p_resp4 0,822 p_ass1 0,862 p_ass2 0,859 p_ass3 0,844 p_ass4 0,821 p_emp1 0,807 p_emp2 0,862 p_emp3 0,849 p_emp4 0,851 p_emp5 0,848

1.1.1 The Gap analysis dimension, namely the “gap” analysis. Tables 6- As mentioned earlier, the service quality is 10 indicate the gaps assessed for every measured as the difference between the dimension included in the SERVQUAL scale. perception and the expectation of each

Table 6. The Tangibles Dimension Gap Score Items included in the Expectation Scale Perception Scale Gap Score (Expectation- Tangibles Dimension Perception) IT1 3,06 3,09 -0,03 IT2 3,08 2,95 0,13 IT3 3,18 2,97 0,21 IT4 3,13 3,09 0,04 Tangibles Dimension Gap Score: 0.35

Table 7. The Reliability Dimension Gap Score Items included in the Expectation Scale Perception Scale Gap Score (Expectation- Reliability Dimension Perception) IT1 3,05 3 0,05 IT2 3 3,07 -0,07 IT3 2,99 3,03 -0,04 IT4 2,97 2,98 -0,01 IT5 3,07 3,08 -0,01 Reliability Dimension Gap Score: -0,08

Table 8. The Responsiveness Dimension Gap Score Items included in the Expectation Scale Perception Scale Gap Score Responsiveness Dimension (Expectation- Perception) IT1 2,83 2,87 -0,04 IT2 2,94 2,82 0,12 IT3 2,93 2,90 0,03 IT4 3,02 2,96 0,06 Responsiveness Dimension Gap Score: 0,17

Table 9. The Assurance Dimension Gap Score Items included in the Expectation Scale Perception Scale Gap Score (Expectation- Assurance Dimension Perception) IT1 3,07 3,05 0,02 IT2 2,90 3,05 0,25 IT3 2,96 3,07 -0,11 IT4 3,06 3,14 -0,08 Assurance Dimension Gap Score: 0,08

Table 10. The Empathy Dimension Gap Score Items included in the Expectation Scale Perception Scale Gap Score (Expectation- Empathy Dimension Perception) IT1 3,07 3,12 0,04 IT2 3,08 3,01 0,07 IT3 2,91 2,87 0,04 IT4 3,03 3,12 -0,09 IT5 3,04 2,99 0,05 Empathy Dimension Gap Score: 0,11

4. Discussion the most widely used and employed in a vast array of fields. As such, the SERVQUAL scale is The investigation of the quality in health materialized in a gap measured between the care services has raised many controversies expectations and perceptions of a consumer regarding their implementation and validation related to a health care service. owing to their credence particularities. Based on From a marketing perspective, different studies, the SERVQUAL scale has been understanding the health care consumer in a

60 Romanian Society of Ophthalmology © 2018 Romanian Journal of Ophthalmology 2018; 62(1): 54-63 competitive market, is highly essential as it may wanted to identify whether the SERVQUAL scale bring new insights in the health care industry could be successfully applied in ophthalmology overall. For instance, an improvement in the services in Romania and determine the health care delivery of services can reduce the dimensions that register the highest gap scores. in-patient stays and lower mortality as well as deliver value to consumers. Therefore, Thus, the highest gap score was registered by the identifying the dimensions’ gap scores may turn Tangibles Dimension and the lowest gap score out to be useful from a strategic perspective, as was registered by the Reliability Dimension (Fig. they will indicate which components should be 1). used as a competitive advantage. The SERVQUAL scale has been frequently applied in health care services without keeping in mind the specialty of the medical service but the type of health care organization. For example, Mangold and Babakus [31] measured the service quality in a US hospital, concluding that the assurance dimension has the lowest gap score whereas the empathy dimension has the highest gap score. Further, according to Lam [30], who applied the SERVQUAL scale in a hospital in Hong Kong, the highest gap score was registered by the empathy dimension and in a Fig. 1 The SERVQUAL Scale’s Gap Score hospital located in Singapore, the dimension Dimensions with the highest gap score was responsiveness [25]. In Romania, Popa et al. [33] determined the quality of health care services using the According to some specialists, assuring SERVQUAL scale in a hospital in Oradea and reliability is paramount for every service indicated that the empathy dimension registered industry and, in addition, is the essence of the the highest gap score whereas Purcarea et al. service quality, which, in turn, is the core pillar for services marketing excellence [34]. [29] confirmed that the tangibles dimension Consequently, performing the ophthalmology should be considered a competitive advantage. service right the first time contributes As mentioned earlier, none of the above significantly to the improvement of marketing studies took into consideration the specialty of effectiveness and the operating efficiency as well the health care service. The objective of this as to achieving higher current-consumer paper was to measure the service quality in the retention rates, increased word of mouth Romanian ophthalmology private organizations communication, and reduction in the need to using the SERVQUAL scale. More specifically, we reperform the service (Fig. 2).

Improved Service Reliability

Increased positive Higher employee word of mouth morale and communication enthusiasm

Higher retention Greater Reduced cost of Lower employee of current opportunity for reperforming the turnover consumers charging different service prices

Imporved marketing effectiveness Increased productivity and lower and higher sales revenues costs

Higher profits for the ophthalmology organization

Fig. 2 The benefits of performing a reliable ophthalmology service from a marketing perspective [35, p. 18]

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7. Nelson EC, Rust RT, Zahorik A, Rose RL, Batalden P, 27. Johnston R. The determinants of service quality: Siemanski BA. Do patient perceptions of quality relate satisfiers and dissatisfiers. International Journal of to hospital financial performance?. Journal of Health Service Industry Management. 1995; 6(5): 53-71. Care Marketing. 1992; 12(4): 6-13. 28. Tomes A, Ng SCP. Service quality in hospital care: the 8. Parasuraman A, Zeithaml VA, Berry LL. A conceptual development of in-patient questionnaire. International model of service quality and its implications for future of Health Care Quality Assurance. 1995; 8(3): 25-33. research. Journal of Marketing. 1985; 49: 41-50. 29. Purcărea VL, Gheorghe IR, Petrescu CM. The 9. Lovelock C, Wright L. Principles of service marketing assessment of perceived service quality of public and management. 2002, New Jersey, Prentice Hall. health care services in Romania using the SERVQUAL 10. Zeithaml V, Berry L, Parasuraman A. The nature and scale. Procedia Economics and Finance. 2013; 6: 573- determinants of customer expectations of service. 585. Journal of the Academy of Marketing Science. 1993; 30. Lam SSK. Servqual: A tool for measuring patients’ 21(1): 1-12. opinions of hospital service quality in Hong Kong. Total 11. Eiriz V, Figueiredo JA. Quality evaluation in health care Quality Management. 1997; 8(4): 145-152. services based Customer provider relationships. 31. Mangold WG, Babakus E. Service quality: The front- International Journal of Health Care. 2005; 18(6):404- stage vs. the back-stage perspective. Journal of Services 12. Marketing. 1991; 5(4): 59-70. 12. Turner P, Pol L. Beyond patient satisfaction. Journal of 32. Nunnally JC. Psychometric Theory, 1978, New York, Health Care Marketing. 1995; 15 (3): 45-53. McGraw-Hill. 33. Popa AL, Rosca RD, Mihoc F. Investigating the Patient 13. Taylor SA Cronin JJ. Modeling patient satisfaction and satisfaction within Romanian Public and Private service quality. Journal of Health Care Marketing. Hospitals. 2011. 1994; 14(1): 34-44. http://core.kmi.open.ac.uk/display/1057879. 14. Harvey J. Service quality: a tutorial. Journal of 34. Berry LL, Parasuraman A, Zeithaml V. Improving Operations Management. 1998; 16: 583-597. service quality in America: lessons learned. Academy 15. Lehtinen U, Lehtinen J. Service Quality: a study of of Management Executive. 1994; 8(2):32-52. quality dimensions. Service Management Institute, 35. Berry LL, Parasuraman A. Marketing Services. Helsinki, 1982. Competing through quality, 1991, The Free Press. 16. Gronroos C. Strategic Management and Marketing in the Service Sector. Boston: Marketing Science Institute, 1983. 17. Berry L. Services Marketing is different. Business. 1983; 30: 23-26. 18. Parasuraman A, Zeithaml V, Berry L. SERVQUAL: a multiple-item scale for measuring consumer perceptions of service quality. Journal of Retailing. 1988; 64(1):12-40. 19. Ladhari R. A review of twenty years of SERVQUAL research. International Journal of Quality and Service Sciences. 2009; 1: 172-198. 20. Babakus E, Mangold W.G. Adapting the SERVQUAL scale to hospital services: An empirical investigation. Health Services Research. 1992; 26: 768-786. 21. Carman JM. Consumer perceptions of service quality: an assessment of the SERVQUAL dimensions. Journal of Retailing. 1990; 66(1): 33-55. 22. McDougall G, Levesque T. A revised review of service quality dimension: an empirical investigation. Journal of Professional Service Marketing. 1994; 11(1): 189- 210. 23. Donabedian A. Criteria and standards for quality assessment and monitoring. Quality Research Bulletin. 1986; 12 (3): 99-108. 24. Gabbott M, Hogg G. Consumers and Services. 1998, Chichester, Wiley. 25. Lim PC, Tang NKH. A study of patients’ expectations and satisfaction in Singapore hospitals. International Journal of Health Care Quality Assurance. 2000; 13: 290-299. 26. Tucker JL Adams SR. Incorporating patients’ assessments of satisfaction and quality: an integrative model of patients’ evaluations of their care. Managing Service Quality. 2001; 11(4): 272-287.

CASE REPORT

Leber’s hereditary optic neuropathy - Case report

Iorga Raluca Eugenia*, Mihailovici Ruxandra* **, Ozturk Manuela Ramona**, Costin Dănuţ* ** *Department of Ophthalmology, ”N. Oblu” Clinical Emergency Hospital, Iaşi, Romania **Department of Ophthalmology, ”Gr. T. Popa” University of Medicine and Pharmacy, Iaşi, Romania

Correspondence to: Iorga Raluca Eugenia, MD, PhD, Department of Ophthalmology, ”N. Oblu” Clinical Emergency Hospital, Iaşi 35 Lascăr Catargiu Street, Code 700107, Iaşi, Romania, Mobile phone: +40733 792 259, E-mail: [email protected]

Accepted: March 18th, 2018

Abstract Leber’s hereditary optic neuropathy is the most common mitochondrial condition and is characterized by bilateral, painless, subacute visual loss that develops during young adult life. LHON is a rare condition and this lack of knowledge can make doctors suspect and treat for other causes of vision loss. Typically, a series of tests are performed to confirm LHON diagnosis or exclude any other conditions. We presented the case of two brothers, HB, of 40 years old and HF, of 38 years old, who presented with a decrease in visual acuity in both eyes. The patients had been diagnosed with optic atrophy of unknown cause a long time ago, but no further investigations were made. They were treated with corticosteroids, antioxidants and vasodilators, but with no significant benefit. A blood test of the mitochondrial DNA, a magnetic resonance imaging and an optic coherence tomography of the optic nerve and macula were part of the following assessment of our patients. The mitochondrial DNA analyses revealed the 3460 G>A mutation on the mtND1 gene in both patients. Based on the medical history, the fundus aspect, the optic coherence tomography and the paraclinical investigations of the diagnosis of Leber’s hereditary optic neuropathy were established in both patients. We started the treatment with idebenone and we evaluated the patients after three months. Keywords: Leber’s hereditary optic neuropathy, mitochondrial DNA test, optic coherence tomography, idebenone Abbreviations: LHON = Leber’s hereditary optic neuropathy, mtDNA = mitochondrial DNA, VA = visual acuity, CF = count fingers, OCT = optical coherence tomography, RNFL = retinal nerve fiber layer, GCL = ganglion cells layer, MS = multiple sclerosis, MRI = magnetic resonance imaging, MTI = magnetization transfer imaging, MTR = magnetization transfer ratio

Introduction LHON is the most common mitochondrial condition and about 45 mutations have been Leber’s hereditary optic neuropathy linked to LHON. A person may carry a (LHON) was first described in 1871 by the mitochondrial DNA (mtDNA) mutation without German ophthalmologist Theodore Leber and experiencing any signs or symptoms of vision was subsequently named after him. LHON is loss; therefore, it is hard to predict which characterized by bilateral, painless, subacute members of a family who carry a mutation will visual loss that develops during young adult life. eventually become affected [1].

Clinically, most patients with LHON go age, the hereditary aspect and no other medical through pre-symptomatic ophthalmoscopic history and risk factors, we made a stage changes before the acute phase, characterized by diagnosis of Hereditary optic neuropathy. visual loss. LHON mainly affects the central vision, leading to large bilateral centrocecal scotoma. By 6 months after onset, optic atrophy is evident and visual loss stabilizes. The chronic phase is reached by 1 year after onset. In some rare cases, patients do experience a significant recovery of vision and this is more likely to happen if you have the 14484 mutation [2]. If LHON is suspected, a blood test can determine if an individual has one of the primary mutations. However, LHON is a rare condition and most doctors can easily pass over this mtDNA test. This lack of knowledge can make doctors suspect and treat for other causes of vision loss. Typically, a series of tests are performed to confirm LHON diagnosis or exclude any other conditions.

Fig. 1 Fundus left eye: optic atrophy, narrow

Case report vessels, no macular reflex

We present the case of two brothers, HB, of 40 years old and HF, 38 years old, who presented with a decrease in visual acuity. From the medical history, we found that the onset of symptoms was about 3 years before in HB and 5 years before in HF, when a diagnosis of optic atrophy of unknown cause was made. They followed treatment with corticosteroid intravenously iv in the beginning and then vasodilators at every 3 months, and antioxidants but with no significant benefit. At presentation, the patient HF had best corrected visual acuity (VA) in both eyes count fingers (CF) at 2 m, normal intraocular pressure IOP (15 mmHg). On slit lamp examination, the findings of the anterior pole were within normal limits. The fundus of each eye was examined after mydriasis with tropicamide and revealed Fig. 2 Fundus right eye: optic atrophy, narrow vessels, no macular reflex optic atrophy in both eyes, with narrow vessels and no macular reflex (Fig. 1,2). The patient HB presented with a VA of CF at 1m and an IOP The usual blood test and inflammatory within normal limits. The anterior segment tests were within normal limit. A blood test of examination at the slit lamp was normal. Fundus the mtDNA, a magnetic resonance imaging MRI examination showed a bilateral optic atrophy, and an optic coherence tomography of the optic narrowed vessels and no macular reflex, similar nerve and macula were part of the following with the fundus examination of his brother. In assessment of our patients. The mtDNA analyses this context, we thought of the multiple causes of revealed the 3460 G>A mutation on the mtND1 optic atrophy, but taking into account the young gene in both patients.

The MRI exam in HB showed (Fig. 3):  the symmetric enlargement of the  in the sequence axial 3 D, the optic intergiral grooves nerves had similar thickness, but  no pathologic contrast fixation slightly reduced in 3 segments  asymmetric enlargement of the (retrobulbar 2 mm - normal 1.5-4.4 perivascular spaces with milimetric cysts. mm, the middle segment of the

intraorbital part 1.5 mm - normal 1.8- 2.5 mm, in the optic channel 2 mm - normal 3.6-6.5 mm, prechiasmatic 4 mm - normal 4.7-5.5 mm)  the symmetric enlargement of the intergiral grooves, mostly parieto- occipital  no pathologic contrast fixation.

Fig. 4 MRI in HF - The MRI in our patient showed

that the mean values of optic nerve volumes were significantly lower

The OCT exam revealed a normal size optic disc, but with severely affected retinal nerve fiber layer RNFL in both eyes of the two patients, mostly in the superior, inferior, and nasal quadrants (Fig. 5,6). The macular region was Fig. 3 MRI HB - The MRI in our patient showed normal, without microcystic degeneration (Fig. that the mean values of optic nerve volumes were significantly lower 7), but with affected ganglion cells layer (Fig. 8). Based on the medical history, the fundus aspect, the OCT and the paraclinical investigations (mtDNA, MRI, blood tests), the The MRI in HF showed (Fig. 4): diagnosis of Leber’s hereditary optic neuropathy  in the sequence axial 3 D, the optic were established in both patients. nerves had similar thickness, but We started a treatment with systemic slightly reduced in only 2 segments idebenone, 6 tablets a day (900 mg/ day), for 1 (retrobulbar 2 mm - normal 1.5-4.4 year. We examined the patients 3 months later. mm, the middle segment of the Subjectively, the 2 patients were pleased with an intraorbital part 2 mm improvement in clarity and contrast sensitivity.  normal 1.8-2.5 mm, in the optic In HF, we noticed a VA of CF at 4 m, with no channel 3.3 mm - normal 3.6-6.5 mm, modification on fundus examination and OCT. In prechiasmatic 4 mm - normal 4.7-5.5 HB, the VA recovery was slightly smaller, only CF mm) in 2 m, with the same fundus and OCT. The usual blood test in both patients was within normal limits.

Fig. 5 OCT left eye: reduced peripapillary RNFL in the superior, inferior, and nasal segments

Fig. 6 OCT right eye: reduced peripapillary RNFL in the superior, inferior, and nasal segments

Fig. 7 OCT macula normal

Fig. 8 OCT macula affected GCL in both eyes

Discussions isolated optic neuropathies or in association with systemic diseases. LHON is an inherited Hereditary optic neuropathies are diseases form of vision loss, which leads to the selective affecting the optic nerve. They may appear as loss of retinal ganglion cells and axons, in

68 Romanian Society of Ophthalmology © 2018 Romanian Journal of Ophthalmology 2018; 62(1): 64-71 particular of the papillomacular bundle [3]. affected patients may be related to the Although this condition usually begins in a mechanical compression of the papillomacular person’s teens or twenties, rare cases may bundle fibers, which represent the trigger appear in early childhood or later in adulthood. dysfunction and axonal death [10]. The OCT LHON is a maternally inherited disorder analysis of macular thickness showed a thinning that has been associated with mtDNA mutations. of the GCL at the early stage in the sectors of the The most common is the 11778 mutation, inner ring [11]. accounting for about 50% of all LHON In our patients, the OCT exam revealed cases. About 45% of the remaining LHON cases normal size optic disc, but with severely affected are 14484 or 3460 mutations [4]. Changes in RNFL in both eyes mostly in the superior, mitochondrial DNA mtDNA appear in every inferior, and nasal quadrants and with affected generation of a family and can affect both males GCL. and females, but fathers do not pass The severity of optic nerve pathology in mitochondrial traits to their children. The LHON is measurable in vivo using MRI and mtDNA mutation is necessary but not sufficient magnetization transfer imaging MTI. A subtype to induce the disease. Other, still poorly defined, of LHON presents additional clinical and MRI genetic, or environmental factors may be aspects indistinguishable from those of multiple implicated. About 40% of the individuals affected sclerosis (MS) (LHON-MS). In patients with with LHON do not have a clear family history of LHON or LHON-MS, an assessment was made of this condition [5]. the severity of optic nerve damage, using MRI In the pre-symptomatic stage, the and MT, and the presence and extent of ophthalmoscopic changes are peripapillary macroscopic and microscopic pathology in the microangiopathy, small vessel tortuosity, brain and cervical cord, using MRI and MT ratio swelling of the retinal nerve fiber layer RNFL. A (MTR). The mean values of optic nerve volumes sudden painless blurring and clouding of vision and MTR were significantly lower in patients are usually the first symptoms of the acute phase with LHON than in healthy controls [12]. An of LHON. These vision problems may begin in association between LHON and MS has been one eye or simultaneously in both eyes. If vision suggested and evidence for such an association loss starts in one eye, the other eye is usually has been found by recent studies with MRI [13]. affected within several weeks or months. The In another study, 26% of the patients with LHON rate of progression can vary from rapid to over 2 had white matter lesions. Additionally, a years but most people are severely impaired by quantitative MRI study of patients with LHON 3 or 4 months. Over time, vision in both eyes found abnormalities of the normal-appearing worsens with a severe loss of visual acuity and brain tissue consistent with that previously color vision, due to optic atrophy [2]. reported in MS. A hypothesis as to why LHON OCT has been used to investigate the RNFL may be a risk factor for MS is that mitochondrial of LHON unaffected carriers, as well as LHON defects trigger the autoimmune process. A affected patients in all stages. In healthy carriers, further possibility is that mitochondrial the OCT showed RNFL thickening in temporal dysfunction is a final common pathway in neural quadrants and in asymptomatic men in the damage [14]. inferior sector [6]. RNFL thickening is correlated The MRI in our patients showed that the with axonal edema and mitochondrial mean values of optic nerve volumes were redistribution at dysfunctional ganglion cells, significantly lower than in healthy controls. affecting the prelaminar unmyelinated portion of Regarding the treatment, some patients are the optic nerve axons [7]. In the acute phase and self-medicating with a range of mostly in the first 6 months of onset, the RNFL analysis antioxidant food supplements. Early studies shows thickening in the upper and lower testing a range of antioxidants and other segments, compared to the control group [8,9]. supplements including curcumin, lutein, At the atrophic stage, a RNFL thinning appears in brimonidine, and others have proved all segments. The optic disc analysis showed that inconclusive and most scientific research into carriers had larger discs than the affected this area seems to have ceased. Idebenone patients. The smaller optic nerve head in the (Raxone(®)), a short-chain benzoquinone, has

69 Romanian Society of Ophthalmology © 2018 Romanian Journal of Ophthalmology 2018; 62(1): 64-71 been the only disease-specific drug approved to idebenone gave the patients hope for visual treat visual impairment in adolescents and improvement. adults with LHON, since September 2015. The mechanism of action of idebenone involves its antioxidant properties and ability to act as a mitochondrial electron carrier. Idebenone References overcomes mitochondrial complex I respiratory 1. Yu-Wai-Man P, Griffiths PG, Chinnery PF. chain deficiency in patients with LHON by Mitochondrial optic neuropathies disease transferring electrons directly to mitochondrial mechanisms and therapeutic strategies. Prog Retin complex III (by-passing complex I), thereby Eye Res. 2011; 30:81-114. restoring cellular energy production and re- 2. Carelli V. Leber’s hereditary optic neuropathy. In: Schapira Ahv, DiMauro S. Mitochondrial disorders in activating inactive, but viable retinal ganglion neurology. Blue books of practical neurology. vol. 26, cells, which ultimately prevent further vision 2nd ed., 2002, Boston, Butterworth-Heinemann, 115- loss and promote vision recovery. 42. Klopstock T conducted a 24-week multi- 3. Pan BX, Ross-Cisneros FN, Carelli V, Rue KS, Salomao centre double blind, randomized, placebo- SR, Moraes-Filho MN. Mathematically modeling the involvement of axonxs in Leber hereditary optic controlled trial in 85 patients with LHON. This neuropathy. Invest Ophthalmol Vis Sci. 2012; first randomized controlled trial in the 53:7608-17. mitochondrial disorder provides evidence that 4. Carelli V, Giordano C, d’Amati G. Pathogenic patients with discordant visual acuities are the expression of homoplasmic mtDNA mutations needs a complex nuclear-mithocondrial interaction. Trends most likely to benefit from idebenone treatment, Genet. 2003; 19:257-62. which is safe and well tolerated. They 5. Sadun AA, La Morgia C, Carelli V. Mithocondrial optic investigated the treatment effect among patients neuropathies: our travels from bench to bedside and with the 11778G>A and 3460G>A mutations back again. Clin Experiment Ohthalmol. 2013; [15]. 41:702-12. 6. Savini G, Barboni P, Valentino ML, Montagna P, Heitz et al. described that in mice, Cortelli P, De Negri AM. Retinal nerve fiber layer idebenone penetrated into the eye at evaluation by optical coherence tomography in concentrations equivalent to those that unaffected carriers with Leber’s hereditary optic protected retinal ganglion cells from complex I neuropathy mutations. Ophthalmology. 2005; dysfunction in vitro. Consequently, they 112:127-31. 7. Carelli V, Ross-Cisneros FN, Sadun AA. Mithocondrial investigated the protective effect of idebenone in dysfunction as a cause of optic neuropathies. Prog a mouse model of LHON, whereby mitochondrial Retin Eye Res. 2004; 23:53-89. complex I dysfunction was caused by exposure 8. Barboni P, Savini G, Valentino ML, Montagna P, to rotenone. In this model, idebenone protected Cortelli P, De Negri AM. Retinal nerve fiber layer evaluation by optical coherence tomography in against the loss of retinal ganglion cells, Leber’s hereditary optic neuropathy. Ophthalmology. reduction in retinal thickness and gliosis. 2005; 112:120-6. Furthermore, consistent with this protection of 9. Zhang Y, Huang H, Wei S, Qiu H, Gong Y, Li H. retinal integrity, idebenone restored the Characterization of retinal nerve fiber layer thickness functional loss of vision in this disease model changes associated with Leber’s hereditary optic neuropathy by optical coherence tomography. Exp [16]. After a 3 months treatment, we observed a Ther Med. 2014; 7:483-7. slightly increase of VA and an improvement in 10. Ramos C doV, Bellusci C, Savini G, Carbonelli M, contrast sensitivity in our patients. Berezovsky A, Tamaki C. Association of optic disc size with development and prognosis of Leber’s hereditary optic neuropathy. Invest Ophthalmil Vis Case particularity Sci. 2009; 50:1666-74. The patients were diagnosed a long time 11. Zhang Y, Huang H, Wei S, Gong Y, Li H, Dai Y. ago with optic atrophy of unknown cause, but no Characterization of macular thickness changes in further investigations were made. They were Leber’s hereditary optic neuropathy by optical coherence tomography. BMC Ophthalmol. 2014; treated with corticosteroids, antioxidants and 14:105. vasodilators, but with no significant benefit. A 12. Inglese M, Rovaris M, Bianchi S. Magnetic resonance blood test, the mtDNA test, helped us make the imaging, magnetization transfer imaging, and correct diagnosis and the new treatment with diffusion weighted imaging correlates of optic nerve, brain, and cervical cord damage in Leber’s hereditary

optic neuropathy. J Neurol Neurosurg Psychiatry. 2001; 70:444–9. 13. Horvath R, Abicht A, Shoubridge EA. Leber’s hereditary optic neuropathy presenting as multiple sclerosis-like disease of the CNS. J Neurol. 2000; 247:65–67. 14. Palace J. Multiple sclerosis associated with Leber’s hereditary optic neuropathy. J Neurol Sci. 2009; 286:24–7. 15. Thomas Klopstock T, Yu-Wai-Man P, Dimitriadis K, Rouleau J, Heck S, Maura Bailie M, Atawan A. A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy. Brain. 2011 Sep; 134(9):2677–2686. 16. Heitz FD, Erb M, Anklin C, Robay D, Pernet V, Gueven N. Idebenone protects against retinal damage and loss of vision in a mouse model of Leber’s hereditary optic neuropathy. PLoS One. 2012; 7(9):e45182.

CASE REPORT

Leukemic retinophaty, the first manifestation in a case of acute myelogenous leukemia

Scripcă Oana Roxana*, Pădurariu Cristina*, Boricean Neacșu Gheorghe*, Botoș Loredana** *Ophthalmology Department, County Emergency Hospital, Brașov, Romania **Haematology Department, County Emergency Hospital, Braşov, Romania

Correspondence to: Scripcă Oana Roxana, MD, Ophthalmology Department, County Emergency Hospital, Brașov, Romania 25-27 Calea București Street, Brașov, Romania, Mobile phone: +40727 848 467, E-mail: [email protected]

Accepted: March 1st, 2018

Abstract A 42-year-old woman, without a specific medical history presented at the Department of Emergency Ophthalmology accusing marked decrease of vision for the left eye (VA 1/ 100). The eye examination revealed an optic neuropathy with multiple retinal hemorrhages at the level of both eyes, but more acutely on the left eye. The brain computer tomography (CT) excluded the suspicion of increasing intracranial pressure. The common blood tests such as complete blood count (CBC), erythrocyte sedimentation rate, and inflammatory markers raised a high suspicion of a malignant haematological disease. Keywords: LAM3-Acute promyelocytic leukemia, bone marrow aspiration and biopsy, leukemic retinopathy, sepsis, disseminated intravascular coagulation (DIC), all-trans retinoic acid

Introduction history. She presented at the Department of Emergency Ophthalmology, claiming a drop of Two of the most common pathologies vision in the left eye (LE), which gradually investigated in ophthalmology are optic disc installed during the last 48 hours before she oedema and retinal vascular diseases. In this presented at the Emergency Department. There context, the imagistic evaluation often was no history of ocular trauma or surgery. transcends the diagnosis, the clinician having The ophthalmic evaluation at the time of high-performance technology in his hands, such admission revealed a well-contoured and as CT, MRI, OCT, but there are situations in which normally colored optic disc, retinal hemorrhage common assays such as CBC and the radiating from the inferotemporal optic disc inflammatory markers can be the only medical margin with a flame shaped aspect, dot-spot investigation that clearly suggests the existence of a life-threatening haematological disorder. retinal hemorrhages and low foveolar reflex, at the right eye (RE). At the left eye (LE), an elevated optic disc with moderate retinal Case report oedema marked retinal hemorrhages, and preretinal hemorrhage with no foveolar reflex. We present the case of a 42-year-old The slit lamp examination of the anterior female patient with no significant pathological

72 Romanian Society of Ophthalmology © 2018 doi:10.22336/rjo.2018.10 Romanian Journal of Ophthalmology 2018; 62(1): 72-77 segment was normal for the RE and delayed RFM sequence in moderate hyposignal, which almost for the LE. totally interests the vitreous body, possibly The visual acuity (VA) for the RE was 0.9 hemorrhagic. with correction and for the LE was counting At the CT for thorax and abdomen, we fingers at 1 meter, not correctable. found multiple pulmonary outbreaks spread in In the first stage of biohumoral status both lungs, parapneumonic pleurisy of 6 mm on assessment, we performed blood tests such as the right and 5 mm on the left, pelvic ascites fluid CBC, erythrocyte sedimentation rate, C-reactive with infiltrative appearance around the genitals. protein, fibrinogen, blood glucose test, lipid Blood culture test was negative; RT-PCR Sepsis profile, total serum protein and thyroid markers. test was negative for S. aureus, Enterococcus The results of blood test showed a severe pancytopenia with 1.43 X 10³/ µl leukocytes, 24 faecalis, Streptococcus agalactiae, X 10³/ µl thrombocytes and severe low levels of Enterobacteriaceae, Candida spp and Hb 5 g/ dl, inflammatory markers were high, Pseudomonas aeruginosa. erythrocyte sedimentation rate ESR 60 mm/ h, CPR 17.63 mg/ l, lower fibrinogen levels 94.77 mg/ dl. Given the analyses, we suspected disseminated intravascular coagulation and we performed D- Dimeri test with positive result. Interdisciplinary medical evaluations were made by colleagues from internal medicine, cardiology and hematology departments. In the multidisciplinary team, we decided to complete the investigations with Hemostasis Analyzer Markers (Pts, Ptr, INR, and APTT), which suggested a hemostasis disorder. Lactate dehydrogenase test, Polymerase chain reaction (PCR) and ferritin were on high levels, serum iron was on low levels, negative serology for HIV, Hepatitis B and Hepatitis C, anti-thyroid peroxidase antibodies (anti-TPO antibodies) and the thyroid hormones within normal limits. At the time of admission, the CT for head segment did not indicate pathological changes. A bone marrow aspiration and biopsy were made. Leukocyte concentrate, cytological blood smear test, and the cytological examination of the spinal cord were inconclusive because they showed a low percentage of Fig. 1 CT for head segment promyelocytes of approximately 8% and blasts of approximately 6%. Due to the patient’s general condition changing with the onset of The examination of the posterior pole fever we decided to transfer her to the intensive revealed marked changes of the retina and optic care unit. Given the unfavorable evolution, we disc with massive hemorrhages that practically repeated the CT for head segment, which showed multiple supratentorial lesional processes covered a large part of the posterior pole for the predominantly in the white matter and calf body LE and for the RE extensive retinal hemorrhage, and a few isolated thalamic lesions that raised marked papillary edema, both eyes with vitreous the suspicion of brain microabscesses in a septic condensation (Fig. 2,3). It was difficult to context (Fig. 1). The head CT also revealed a determine the patient’s VA given the general modulation of signal diffusion in the left eye- altered status. viewable on the hemosiderin-susceptible

Fig. 3 Fundus of the left eye, showing a big retinal hemorrhage that covers the optic disc and multiple dot-spot hemorrhages, 6 days after admission

Fig. 2 Fundus of the right eye, showing a massive retinal hemorrhage 6 days after admission The patient was transferred to the hematology department having an extended mucosal cutaneous hemorrhage syndrome (Fig. 4), hepatic cytolysis syndrome and started the specific treatment for LAM3 with Vesanoid 45 mg/ m2 - 80 mg/ day. The general status of the patient worsened, becoming confused, jaundice with haematological status in the collapse with WBC=55.76 X 10³/ µl, Neutrophils 0.00 X 10³/ µl, Lymphocytes 0.00 X 10³/ µl, Monocytes 0.00 X 10³/ µl, Eosinophils 0.00 X 10³/ µl, Basophils 0.02 X 10³/ µl, she had PLT=8 X 10³/ µl, Hb=7.7 g/ dl.

dominated by the promyelocytes. There are two types of classification, the French-American- British (FAB) composed of the morphological and cytochemical aspects of the cells notes the acute promyelocytic leukemia as AML M3 and the World Health Organization (WHO) classification system noted as APL with translocation between chromosomes 15 and 17, t(15;17) [1,2]. The first reference about APL associated with disseminated intravascular coagulation (DIC) was made in 1959 by Jean Bernard, who described the disease like a hyperacute fatal illness associated with a hemorrhagic syndrome [3]. Disseminated intravascular coagulation is a haematological syndrome characterized by the activation of circulating thrombin and plasmin, which can cause thrombosis and hemorrhage in the small and midsize vessels (Fig. 5). Depending on the haematological and metabolic status of the patient with disseminated intravascular coagulation, the failure of multiple organs may occur [4]. The clinical pathology associated with

disseminated intravascular coagulation is Fig. 4 Extended cutaneous hemorrhage syndrome myeloproliferative diseases, trauma, and sepsis.

In the hematology department, the test battery was extended with flow cytometer, PML RAR alpha transcript t 15, 17, and immunohistochemistry. The result of PML RAR alpha screening transcript (15;17) was positive. The patient received antibiotics, red blood cell transfusion, freshly frozen plasma platelets, cryoprecipitate, corticosteroid, and haemostatic. Due to severe coagulopathy and severe fibrinogenemia, she received treatment with Haemocomplettan fibrinogen concentrate. Thirteen days after admission, the patient suffered a respiratory cardiac arrest and died. Later on, after the patient died, the result of Bone Marrow Biopsy revealed a hypercellularity with Fig. 5 The Mechanism of disseminated intertrabecular infiltration of blastic cells with cytoplasmic granulations and Auer rods, about intravascular coagulation [4]

80-90% of the total cells. Course Discussions The patients with LAM3 diagnostic are generally young. The onset is sudden with Background hemorrhagic syndrome. It is characterized by Acute promyelocytic leukemia is the type of mucosal, cutaneous hemorrhage and thrombotic acute leukemia with myeloid population manifestations.

DIC and thrombosis can be a clinical (fluorescence in situ hybridization) analysis of manifestation in LAM3. Clinically deep PML/ RARA fusion genes [7]. thrombophlebitis, pulmonary embolism, cerebral thrombosis, and renal thrombosis Prognosis occur. In this situation, secondary fibrinolysis is A study made by Reddy, Quah, Low and damaged or there is a vascular lesion, which Jackson [8] on seventy-seven patients with acute favors accumulation of fibrin. Hypercoagulability leukemia who presented intraretinal is induced by tissular factors of the leukemic M3 hemorrhages (IRH), white-centered cells. This factors binds of FVII in the presence of hemorrhages, cotton-wool spots and macular Calcium and activates the X factor (extrinsic hemorrhages, concluded that the hemorrhagic pathway) inducing thrombin and then fibrin pathological changes in the retina lead to a poor production [5]. prognosis [8]. LAM3 is a medical emergency; therefore, the treatment should be initiated as soon as Treatment possible. In the absence of treatment, the Treatment of acute promyelocyte leukemia prognosis is very poor [1]. should consider both the increased frequency of The leukocyte count prior to the onset of DIC, which requires sustained therapy as well as therapy is the most relevant prognostic factor for the therapeutic response to a non-cytostatic survival (high risk WBC > 10.000/ µl). Age is agent: isotretinoin (all-trans retinoic acid, another important factor. Prognosis of LAM3 ATRA). ATRA 45 mg/ m2/ day P.O. can induce after treatment is favorable with very high rates full remission within the induction protocol in of complete remission, more than 90% [6]. patients with LAM3 possessing translocation t(15;17). Remission is not long lasting and Differential diagnosis therefore LAM classical chemotherapy should be Differential diagnosis is mainly made with associated to the treatment [9]. other type of acute leukemia especially LAM2 and LAM4, aplastic anemia, folic acid deficiency and myelodysplastic syndrome. Conclusions Pancytopenia can be caused by a large There are a few pathologies described in variety of diseases of varying severity, including literature that associate bilateral retinal vitamin deficiencies, agranulocytosis with hemorrhagic changes. C Ling, PL Atkinson, and arrested maturation at the promyelocyte stage CG Munton [10] mention the appearance of and autoimmune disease. It is important to bilateral retinal hemorrhages following epidural review the peripheral blood smear at the time of injection. A case of acute bilateral retinal initial evaluation of all patients with hematologic hemorrhages occurring after injection of oxygen- disorders [7]. ozone (O2O3) mixture for lumbar disc herniation Diagnosis relies on laboratory findings was described by Giuseppe Lo Giudice, Franco showing pancytopenia or hyperleukocytosis in Valdi, Maurizio Gismondi, Giovanni Prosdocimo around 20% (complete blood cell count with and Valentinade Belvis [11] in American Journal differential cell counts), bone marrow of Ophthalmology, 2014. examination that shows large blasts, numerous There are situations in which a granules, Auer rods often in bundles, faggot cells, subarachnoid hemorrhage (SAH) or traumatic promyelocytic cells, and strong positive on brain injury can cause retinal changes either by myeloperoxidase staining, bone marrow direct blood flow to the optic nerve sheath or by histology and on coagulation status [7]. cerebrospinal fluid (CSF) leakage in the optic Immunophenotyping of promyelocytic cells nerve sheath, which will cause compression in shows positivity for CD13, CD33, CD117, MPO, the central vein of the retina and subsequently and negativity for HLA-DR, CD 2, and CD 34 [7]. retinal hemorrhage in the vitreous, subhyaloid The diagnosis is confirmed by molecular or intraretinal/ sub-internal limiting membrane screening (RT-PCR), immunofluorescence anti- [12]. PML antibody and cytogenetic or FISH

From a hematological point of view, the 8. Reddy SC, Quah S, Low S et al. Prognostic significance particularity of this case is that the diagnosis was of retinopathy at presentation in adult acute leukemia. Ann Hematol. 1998; 76:15. based on bone marrow biopsy since the https://doi.org/10.1007/s002770050354. cytological examination of blood smear and bone 9. All-trans retinoic acid and chemotherapy in the marrow aspiration were inconclusive. After treatment of acute promyelocytic leukemia. treatment with All-Trans Retinoic Acid (ATRA PierreChristineChomienne12LamentDegos12 Vesanoid) and fibrinogen concentrate https://doi.org/10.1016/S0037-1963(01)90002-2. 10. Ling C1, Atkinson PL, Munton CG. Bilateral retinal (Haemocomplettan), the disseminated haemorrhages following epidural injection. Br J intravascular coagulation did not resolve and the Ophthalmol. 1993 May; 77(5):316-7. coagulopathy continued leading to the death of 11. Lo Giudice G, Valdi F, Gismondi M, Prosdocimo G, de the patient. Belvis V. Acute bilateral vitreo-retinal hemorrhages following oxygen-ozone therapy for lumbar disk Another particularity of the case is that herniation. Am J Ophthalmol. 2004 Jul; 138(1):175-7. although the patient presented at the hospital doi: 10.1016/j.ajo.2004.02.059. invoking only decreased vision, a thorough 12. Czorlich P, Skevas C, Knospe V, Vettorazzi E, Richard G, posterior pole examination revealed the Wagenfeld L, Westphal M, Regelsberger J. Terson presence of acute bilateral retinal vascular signs, syndrome in subarachnoid hemorrhage, intracerebral hemorrhage, and traumatic brain injury. Neurosurg these being the only hint that we might be Rev. 2015 Jan; 38(1):129-36. discussion 136. doi: dealing with in a hematological malignant 10.1007/s10143-014-0564-4. disease. All these draw attention to the importance of routine blood tests that were the first steps for a prompt and correct diagnosis.

References

1. Current management of newly diagnosed acute promyelocytic leukemia. Cicconi L, Lo-Coco F. Ann Oncol. 2016 Aug; 27(8):1474-81. doi: 10.1093/annonc/mdw171. 2. Acute Myelogenous Leukemia And Acute Promyelocytic Leukemia. Union for International Cancer Control 2014 Review of Cancer Medicines on the WHO List of Essential Medicines. http://www.who.int/selection_medicines/committees /expert/20/applications/AML_APL.pdf. 3. Bernard J, Mathe G, Boulay J, Ceoard B, Chome J. Acute promyelocytic leukemia: a study made on 20 cases. Schweiz Med Wochenschr. 1959 Jun 6; 89:604-8. 4. Levi M, ten Cate H. Disseminated intravascular coagulation. N Engl J Med. 1999; 341:586-592; August 19, 1999; doi: 10.1056/NEJM199908193410807. 5. Ikezoe T. Pathogenesis of disseminated intravascular coagulation in patients with acute promyelocytic leukemia, and its treatment using recombinant human soluble thrombomodulin. International Journal of Hematology. July 2014; 100, Issue 1,27–37. doi: https://doi.org/10.1007/s12185-013-1463-0. 6. Testa U, Lo-Coco F. Prognostic factors in acute promyelocytic leukemia: strategies to define high-risk patients. Ann Hematol. 2016 Apr; 95(5):673-80. doi: 10.1007/s00277-016-2622-1. 7. Lengfelder E, Niederwieser D, Platzbecker U, Schlenk RF, Wörmann B. Acute Promyelocytic Leukemia (APL) Guideline. February 2012. https://www.onkopedia- guidelines.info/en/onkopedia/guidelines/acute- promyelocytic-leukemia- apl/@@view/html/index.html.

CASE REPORT

Multiple sclerosis with ophthalmologic onset - case report

Costin Dănuţ* **, Pînzaru Gabriela Mirela**, Pătraşcu Andra Mădălina**, Moţoc Anca**, Moraru Andreea Dana* ** *“Grigore T. Popa” University of Medicine and Pharmacy, Iaşi, Romania **Department of Ophthalmology, “Prof. N. Oblu” Emergency Hospital, Iaşi, Romania

Correspondence to: Moraru Andreea Dana, MD, PhD, Ophthalmology Department, “Prof. N. Oblu” Emergency Hospital, Iaşi, Romania, 2 Ateneului Street, Iaşi, Romania, Mobile phone: +40723 504 701, E-mail: [email protected]

Accepted: January 15th, 2018

Abstract Ophthalmological and neurological signs and symptoms were assessed in a patient diagnosed with retrobulbar optic neuritis associated with multiple sclerosis (MS). The patient presented with progressive decrease of visual acuity, intermittent diplopia, paresthesia of the left arm and equilibrium disturbances. The complete ophthalmologic examination (clinical examination, visual field, optical coherence tomography) along with an MRI exam supported the diagnosis of MS with active lesions associated with retrobulbar optic neuritis. The corticosteroid therapy, followed by betaferon led to the remission of both ophthalmological and neurological signs. The multidisciplinary approach of the case played an important role in the early establishment of the diagnosis as well as the functional recovery of this patient. Keywords: optic neuritis, multiple sclerosis, diplopia

Introduction optic neuritis have an excellent prognosis for recovery of central visual acuity [2]. Multiple sclerosis (MS) is a chronic The diagnosis is essentially clinical, inflammatory disease of the central nervous although MRI, cerebrospinal fluid system (CNS), of unknown etiology, in which loss measurements, and visual evoked potential of neurological functions occurs due to an studies are often useful for confirmation [1]. autoimmune demyelination. Multiple sclerosis presents several clinical manifestations Case report associated to brainstem lesions such as impaired motor and sensory functions, cognitive, visual, A 30-year-old white male presented with urogenital, and mental disorders. Periods of decrease of visual acuity, intermittent diplopia, remission and exacerbation may alternate [1]. photophobia in both eyes and paresthesia of left Ocular findings in MS include optic neuritis, hand. Family medical history was non- retinitis, pars planitis, peripheral vasculitis, and contributory. ocular motility dysfunction, manifested as Ocular and medical history of this patient nystagmus or diplopia. Optic neuritis, the most included: keratoconus in both eyes, operated in common ocular manifestation of multiple the right eye and craniocerebral trauma (at 2 sclerosis, may represent the first clinical sign of years old) followed by right brachial the disease. Recent long-term follow-up data hemiparesis. In June 2017, after an excessive shows that most patients with demyelinating

78 Romanian Society of Ophthalmology © 2018 doi:10.22336/rjo.2018.11 Romanian Journal of Ophthalmology 2018; 62(1): 78-82 food and alcohol intake, an acute diarrhea Ocular motility examination revealed syndrome and vertigo installed. A native CT impaired adduction and abduction in both eyes, found no cerebral lesions. After the treatment of with the maintenance of vertical movements, the hydroelectrolytic imbalance, the patient was variable angle (+10-+12 degrees) esophoria at discharged. Fourteen days after this event, he distance and dyschromatopsia in the red-green presented in the Ophthalmology Clinic reporting axis. decrease in visual acuity for 5 days, intermittent The visual field exam showed a slight diplopia, photophobia, and vertigo. narrowing in the inferior-nasal sector to 40 Visual acuity was 0,12 in the right eye and degrees from fixation in the right eye and up to 0,3 in the left eye. Intraocular pressure was 15 50 degrees from fixation in the inferior-nasal mmHg in both eyes. Slit lamp examination sector in the left eye. revealed segments of intrastromal rings in the right eye and a tight therapeutic contact lens in the left eye. Fundoscopic exam was normal.

Fig. 2 The inferior-nasal visual field defect in both eyes

The optical coherence tomography (OCT)

showed reduction of the retinal nerve fiber layer (RNFL) thickness in the inferior sector in both

Fig. 1 Fundus photography in both eyes eyes.

Fig. 3 The OCT shows thinning of RNFL in the inferior quadrant in both eyes

Native and contrast cerebral MRI were significant for multiple sclerosis, showing both inactive subtentorial and supratentorial lesions and 4 active, peripheral, gadolinophilic lesions, located posterior median in the pons, in the knee of the right callous body and in the left frontal Fig. 4 Cerebral MRI showing active lesions and occipital lobes. The sequences of angio-MRI revealed no autoimmune vasculitis lesions.

Differential diagnosis Optic neuritis associated with MS typically Although an underlying systemic disease is presents as a monocular, sometimes painful not often found on the initial evaluation in vision loss that occurs over hours to days and patients with retrobulbar neuritis, the following lasts for a few weeks. The neuro-ophthalmologic entities are taken into account in establishing the manifestations of multiple sclerosis can be differential diagnosis, when neurologic signs are divided into two main categories: those that present: Devic’s disease, infectious diseases affect the visual sensory system and those that (Lyme Borreliosis, hepatitis B, cytomegalovirus, affect the ocular motor system [3]. Disturbances and herpes simplex), toxic neuropathy, and of visual sensory function are caused by the autoimmune disorders. In this case, the cerebral impairment of the optic nerve in prechiasmal, MRI supported the diagnosis of multiple chiasmal and retrochiasmal sectors. sclerosis with ophthalmological onset. Disturbances of ocular motility or alignment may Tests for other autoimmune disorders develop during the course of MS and usually (pANCA, cANCA, totalANCA) and for Borreliosis result from demyelinating lesions in the have been performed and the results were brainstem that affect supranuclear, internuclear, negative. nuclear, or fascicular pathways [6]. In cooperation with the neurologist, the Virtually any type of visual field loss can treatment with intravenous (iv) corticosteroids occur, including altitudinal, arcuate, central or (CS) was initiated: Methylprednisolone 500 mg/ cecocentral scotoma, unilateral hemianopsia or day for 5 days, then 250 mg/ day for 2 days, quadranopsia. Visual field defects are often followed by oral cortico-therapy. found also in the contralateral eye [7,8]. At discharge, BCVA increased to 0,3 in the Acquired dyschromatopsia, in red-green right eye and 0,5 in the left eye, with the axis is also present, the color deficit often being persistence of a slight limitation of adduction in greater than the degree of visual acuity loss [9]. both eyes. Contrast sensitivity seems to reflect disease This case was included in the National progression and can be a valuable prognostic Multiple Sclerosis Treatment Program and the marker. Recent studies have demonstrated patient started the Betaferon treatment. abnormalities even in patients who had a normal At the 3 months evaluation, BCVA vision [10]. increased to the values of 0,5 and 1 for the right OCT is a useful tool in the evaluation of the and left eye, respectively. The fundus exam was retinal nerve fiber layer (RNFL) and the ganglion normal and dyschromatopsia in red-green axis cell layer thickness. OCT studies have persisted in both eyes. The immunomodulatory demonstrated the thinning of RNFL in patients treatment was continued according to the diagnosed with optic neuritis due to multiple indication of the neurologist. sclerosis. RNFL thickness reduction reflects the axonal degeneration and atrophy of the ganglion cells. OCT findings are related both to visual Discussions impairment as well as to disease progression [11,12]. OCT is also useful for the evaluation of Most often, the term retrobulbar optic treatment efficacy [13]. neuritis (ON) refers to the optic neuropathy Magnetic resonance imaging (MRI) associated with a demyelinating disease. Optic showing active lesions is compulsory for the neuritis is often present at the onset of MS and establishment of the MS diagnosis. The represents a common cause of visual loss in characteristics of the demyelinating lesions these patients [3]. include 3 mm ovoid lesions with T2 high-signal It is estimated that in 15-20% of the MS that are mostly located in periventricular area of cases, the onset manifests as optic neuritis and the white matter and radiate toward the 75% of the patients have at least one episode ventricular space [14,15]. Studies showed that throughout the course of their lives [4]. patients with a first episode of ON, who have According to Rizzo and Lessel, more than 50% of normal brain MRI, seem to have a lower risk of the patients diagnosed with ON would develop developing MS at 15 years [16]. MS in the following 15 years [5].

The case discussed in this article presented first attack of optic neuritis. Can J Neurol Sci. 2011; with typical retrobulbar optic neuritis signs as 38:887–895. 5. Rizzo JF, Lessel S. Risk of developing MS after the initial manifestation of MS, preceding other uncomplicated optic neuritis. Neurology. 1988; 38:185- neurological signs and symptoms. 190. The visual field defect registered in this 6. Serra A, Derwenskus J, Downey DL, Leigh RJ. Role of eye patient showed a slight narrowing in the movement examination and subjective visual vertical in inferior-nasal quadrant of both eyes. These signs clinical evaluation of multiple sclerosis. J Neurol. 2003 May; 250(5):569-75. are specific to demyelinating lesions of the 7. Tsuda H, Ishikawa H, Matsanuga H, Mizutani T, sensory visual pathways, although the visual Shinkeigaku R. A neuro-ophthalmological analysis in 80 function damage at that moment was minimal cases of multiple sclerosis. Rinsho Shinkeigaku. 2004 due to early diagnosis of the disease. Acquired Aug; 44(8):513-21. 8. Killer HE, Flammer J, Wicki B, Laeng RH. Acute dyschromatopsia, in the red-green axis, was asymmetric upper nasal quandrantanopia caused by a more important than the decrease of VA at the chiasmal colloid cyst in a patient with multiple sclerosis moment of diagnosis. and bilateral retrobulbar neuritis. Am J Ophthalmol. A short course of intravenous 2001 Aug; 132(2):286-8. 9. Schneck ME, Haegerstrom-Portnoy G. Color vision corticosteroids, followed by a 2-week course of defect type and spatial vision in the optic neuritis oral prednisone hastened the visual function treatment trial. Invest Ophthalmol Vis Sci. 1997 Oct; recovery and the remission of diplopia in this 38(11):2278-89. young patient. 10. Balcer LJ. Clinical practice. Optic neuritis. N Engl J Med. Often, the diagnosis of optic neuritis is the 2006 Mar 23; 354(12):1273-80. 11. Frohman E, Costello F, Zivadinov R, Stuve O, Conger A, main factor that contributes to the decision to Winslow H, Trip A, Frohman T, Balcer L. Optical initiate therapy in these patients. Without prior coherence tomography in multiple sclerosis. Lancet treatment with high doses of Neurol. 2006 Oct; 5(10):853-63. methylprednisolone, oral prednisone alone may 12. Costello F, Coupland S, Hodge W, Lorello GR, Koroluk J, Pan YI, Freedman MS, Zackon DH, Kardon RH. increase the risk for recurrent ON and should be Quantifying axonal loss after optic neuritis with optical avoided [17,18]. coherence tomography. Ann Neurol. 2006 Jun; 59(6):963-9. 13. Swanton JK, Fernando KT, Dalton CM, Miszkiel KA, Conclusions Altmann DR, Plant GT, Thompson AJ, Miller DH. Early MRI in optic neuritis: the risk for disability. Neurology. The cooperation between the 2009 Feb 10; 72(6):542-50. ophthalmologist and the neurologist plays an 14. Optic Neuritis Study Group. Multiple sclerosis risk after optic neuritis: final optic neuritis treatment trial follow- important role for both early diagnosis and up. Arch Neurol. 2008 Jun; 65(6):727-32. periodic clinical evaluation of MS patients. As a 15. Chan JW. Optic neuritis in multiple sclerosis. Ocul result, the case discussed in this article benefited Immunol Inflamm. 2002 Sep; 10(3):161-86. from inclusion in the national MS therapy 16. Dooley MC, Foroozan R. Optic neuritis. J Ophthalmic Vis program and early initiation of therapy. Both the Res. 2010 Jul; 5(3):182-7. 17. Beck RW, Trobe JD. What we have learned from the neurological and the visual prognosis are Optic Neuritis Treatment Trial. Ophthalmology. 1995 favorable on long term. Oct; 102(10):1504-8. 18. Optic Neuritis Study Group The 5-year risk of MS after optic neuritis: experience of the optic neuritis References treatment trial. Neurology. 1997; 49(5):1404–1413.

1. Maria AM, Sibinelli F, Cohen R, Ramalho AM, Tilbery CP, Lake JC. Ocular manifestations in patients with multiple sclerosis in São Paulo. Arq. Bras. Oftal. 2000; 63(4),311. 2. Chen L, Gordon LK. Ocular manifestations of multiple sclerosis. Curr Opin Ophthalmol. 2005; 16(5):315-20. 3. Cerovski B, Vidovic T, Petricek I, Popovic-Suic S, Kordic R, Bojic L, Cerovski J, Kovacevic S. Multiple Sclerosis and Neuro-Ophthalmologic Manifestations. Coll. Antropol. 2005; 29(Suppl.1):153–158. 4. Mamarabadi M, Razjouyan H, Mohammadi F, Moghaddasi M. Assessment of outcome predictors after

CASE REPORT

Various therapies for ocular surface diseases

Gheorghe Alina*, Rosoga Ancuţa Teodora**, Mrini Fildys*, Vărgău Iulia*, Gherghiceanu Florentina*** *Clinical Emergency Eye Hospital, Bucharest, Romania **Sanamed Hospital, Bucharest, Romania ***”Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania

Correspondence to: Alina Gheorghe, MD, PhD, Clinical Emergency Eye Hospital, Bucharest, 1 Alexandru Lahovari Square, Bucharest, Romania, Mobile phone: +40722 661 401, E-mail: [email protected]

Accepted: March 13rd, 2017

Abstract This paper aims to discuss various therapeutical strategies (corneal cross-linking, amniotic membrane transplantation with or without autologous serum application, medical regenerative therapy) for treating ocular surface diseases according to medical indications, etiology, local and general status of the patient. Besides the evolution and treatment of the lesions induced by corneal foreign body, ocular burns, neurotrophic keratitis, pterygium removal, Mooren’s ulcer, this paper also follows and evaluates the migration, stratification and development of corneal epithelium. Of course, the success of the treatment depended on the therapeutic approach, the cause of the disease, the status of the eye and the patients’ compliance. All cases presented had good results, proving once again, that a well-chosen therapeutic approach ensures the improvement or cure for many ocular surface diseases nowadays. Keywords: cornea, optical coherence tomography, cross-linking, amniotic membrane Abbreviations: BVCA = best corrected visual acuity, OCT = optical coherence tomography, CLX = corneal cross-linking

Introduction Therefore, a judicious therapy from the beginning of the disease or according to its Being the first and most important complications underlies a successful treatment. refractive component of the eye, the cornea is essential for human vision. Regardless of the Case report etiology, traumatic, infectious, degenerative, or secondary to a systemic disease, ocular surface We present three cases of different lesions affect vision either directly or due to etiologies that underwent different types of complications. Repair and restoration of treatment according to pathology, medical eye damaged cornea is a current topic in history, stage of the disease. ophthalmology but also in regenerative medicine The first case was of a single eye of a 63- and tissue engineering. Successful treatment year-old male patient who had a non-healing depends on the lesion, etiology, presence of corneal ulcer with corneal melting developed in limbal stem cells status or other complications. the last 3 months. BCVA was 0.1 (Snellen chart) Fig. 1.

Fig. 2 Therapeutic contact lens on the corneal defect

Fig. 3 Removal of therapeutic contact lens

Fig. 1 Non-healing corneal ulcer

The failure of proper and complete re- epithelialization of the corneal epithelium was highlighted by the OCT images 1 day after the removal of the therapeutical corneal contact lens. The images show a fragile and unstable epithelium (Fig. 2-4).

Fig. 4 Fragile and unstable epithelium

For this case, we chose to perform corneal cross-linking. One month after the procedure, the corneal epithelium was well organized and stable without tendency to break (Fig. 5).

Fig. 5 Pre and post CLX intervention

The second case was of a male who had a tried. In this case, the amniotic membrane acted large corneal defect 1 month after the removal of as a scaffold for host cells to populate, thus an intracorneal foreign body. BCVA was 20/ 20 facilitating healing and repair. It also acted as a (Snellen chart) Fig. 6 SLD7. The OCT image (Fig. space filler to increase stromal thickness [1]. 6) showed a defect of 316 microns and a Five weeks after the surgery, the corneal defect perilesional corneal thickness of 495 microns. healed and a normal corneal architecture was Amniotic membrane surgery was performed achieved (Fig. 6). after all the medical therapeutic options were

Fig. 6 Large corneal defect after foreign body removal treated with amniotic membrane; pre and postoperatory images

The last case to be presented was of a 14- was 0.05 (Snellen chart). OCT images showed year-old female with neurotrophic keratitis and large epithelial defect and corneal edema corneal ulcer after Bell’s palsy and surgery for ranging from 642 microns to 755 microns (Fig. venous malformation of cerebral vessels. BCVA 7).

Fig. 7 Large epithelial defect and corneal edema

Together with medical therapy (hyaluronic membrane graft assured a complete corneal acid, vitamins, carboxymethyl glucose sulfate, epithelization and remission of corneal edema hypromellose) surgical therapy with amniotic (Fig. 8,9).

Fig. 8 Complete epithelization and reduction of corneal edema from approx. 700 microns to 520 microns

Fig. 9 Slit lamp image of the healed neurotrophic keratitis

Discussion depends not only on the clinical experience but also on the well-chosen therapy. A combined Ocular surface disorders represent a broad therapy, pharmaceutical and surgical, should not spectrum of conditions. Thanks to the advances exclude each other, but should be in this pathology, treatment options have complementary. improved in the last decade. Various methods of ocular surface healing and reconstruction are nowadays available for patients, giving them a References real chance of minimizing their visual loss [2-4]. Regarding our first patient, the causes and 1. Rahman I, Said DG, Maharajan VS, Dua HS. Amniotic mechanisms of his non-healing corneal ulcer membrane in ophthalmology: indications an were complex. Perhaps a neurotrophic cause, limitations. Eye. 2009; 23:1954-1961. 2. McGrath D. Regeneration Revolution, Advances in limbal stem cells deficiency, and systemic regenerative medicine leading to paradigm shift in condition that led to melting cornea treating ocular surface disorders. Eurotimes. 2016; phenomenon contributed to his ocular 4:4-6. pathology. Cross-linking procedure offered the 3. Gheorghe A, Pop M, Burcea M, Serban M, Zemba M. possibility of intervening on the microstructure New clinical application of amniotic membrane of the stromal collagen, increasing the fibril transplant for ocular surface disease. Journal of interconnections and microfibrils. After CLX, the Medicine and Life. April- June 2016; 9(2):177-179. corneal cells were more stable and the 4. Gheorghe A, Pop M, Mrini F, Vargau I, Barac R. Ocular surface reconstruction in limbal stem cell deficiency. architecture more durable, preventing corneal Romanian Journal of Ophthalmology. March-June 2016; perforation. 60(1):2-5. Corneal epithelium cells renewal follows 5. Muraine M, Gueudry J, Duchesne B, Majo F. Ulceres several theories; the main theory is the one of chroniques de la Cornee. Laboratoires Thea. 2015. limbal stem cell that renews the epithelium at 6. Gheorghe A, Pop M, Tataru CP, Mihai C, Cioboata M. Human every 15 days by cell migration from the limbus amniotic membrane for sever alkali burn-100% visual to the centre of cornea. Also the normal healing recovery. Research and Science Today. November 2015; 2(10):200-206. of a corneal erosion or ulcer implies the 7. Keelan JA, Sato T, Mitchell MD. Interleukin (IL)-6 and IL-8 migration of epithelial basal cells in a production by human amnion: regulation by cytokines, monocellular layer that covers the denuded growth factors, glucocorticoids, phorbol esters, and corneal stroma in a centripetal way. Deep bacterial lipopolysaccharide. Biol Reprod. 1997; 57:1438– corneal ulcers need medical and surgical therapy 1444. for healing because the stroma is also affected 8. Koizumi NJ, Inatomi TJ, Sotozono CJ, Fullwood NJ, Quantock [5]. AJ, Kinoshita S. Growth factor mRNA and protein in preserved human amniotic membrane. Curr Eye Res. 2000; Amniotic membrane is very conducive to 20:173–177. epithelial cell migration and attachment; 9. Kubo M, Sonada Y, Muramatsu R, Usui M. Immunogenicity of keratocytes have been shown to re-populate the human amniotic membrane in experimental amnion stroma, thus building corneal stromal xenotransplantation. Invest Ophthalmol Vis Sci. 2001; tissue. The mechanisms of action of the 42:1539–1546. membrane are attributed to and inferred from its physical structure and its molecular constituents. The amniotic membrane is composed of a single layer of epithelial cells, basement membrane, and avascular stroma.

Enzymes, cytokines (IL-6, IL-10), growth factors (EGF, KGF, HGF, and TGF), metalloproteases, and inhibitors of metalloproteases have been identified in amniotic membrane layers [6-9].

Conclusion

Ocular surface diseases have multiple causes, so a successful therapeutic approach

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Romanian Journal of Ophthalmology, Volume 62, Issue 1, January-March 2018. pp:88-89

ERRATUM to the article entitled “NON-PARAMETRIC TESTS IN DETECTING GLAUCOMA PROGRESSION”, published in Romanian Journal of Ophthalmology, 2017; 61 (3): 212-218 by Anca Pantalon and Crenguta Feraru

The authors would like to express the deepest apologies not to have mentioned in their manuscript the following paper: “Glaucoma Monitoring in a Clinical Setting Glaucoma Progression Analysis vs Nonparametric Progression Analysis in the Groningen Longitudinal Glaucoma” by Wesselink et al. published in 2009 as a result of Groningen Longitudinal Glaucoma Study.

In consequence, we would like to rectify the references by adding the following citation in the 22nd position of the list:

22. Wesselink C., Heeg G., Jansonius N. Glaucoma Monitoring in a Clinical Setting Glaucoma Progression Analysis vs Nonparametric Progression Analysis in the Groningen Longitudinal Glaucoma Study Archives of Ophthalmology 127(3):270-274;

Additionally, the following corrections to the manuscript have been made in order to acknowledge the remarkable work of Wesselink et al. Page 213-214, section “Material and Method”

The paragraph containing the phrase:

“For GPA, visual field progression was based on glaucoma change probability maps [5]. In glaucoma change probability maps, the threshold value of each test point location in every follow-up field is compared with a mean of the values from the same test point in 2 baseline fields. Points that have changed more than might be expected from random variability at P<0.05 are flagged as significantly changing. To limit the effect of increasing media opacities, GPA uses pattern deviation probability plots [6]. Likely progression is reached when 3 or more test point locations at any location in the field, not necessarily contiguous, show a significant deterioration in 3 consecutive tests. Possible progression occurs when 3 or more such locations have been identified in 2 consecutive tests [7,8]. Nonparametric progression analysis (NPA) is based on an algorithm ranking MD values during the follow up interval (see algorithm in the table below)”.

should be:

For GPA, visual field progression was based on glaucoma change probability maps [5, 22]. In glaucoma change probability maps, the threshold value of each test point location in every follow-up field is compared with a mean of the values from the same test point in 2 baseline fields. Points that have changed more than might be expected from random variability at P<0.05 are flagged as significantly changing. To limit the effect of increasing media opacities, GPA uses pattern deviation probability plots [6, 22]. Likely progression is reached when 3 or more test point locations at any location in the field, not necessarily contiguous, show a significant deterioration in 3 consecutive tests. Possible progression occurs when 3 or more such locations have been identified in 2 consecutive tests [7, 8, 22]. Nonparametric progression analysis (NPA) is based on an algorithm ranking MD values

88 Romanian Society of Ophthalmology © 2018 Romanian Journal of Ophthalmology 2018; 62(1): 88-89 during the follow up interval, as described by Wesselink et al. in Groningen Longitudinal Glaucoma Study [22] (see algorithm in the table below) [2].

In the discussions section, page 216, the first paragraph containing the following phrase:

“The development of cataract is presumably a common cause of a general decrease in sensitivity. Insensitivity to cataract is obviously an advantage in a glaucoma trial. However, in a clinical setting, patients may benefit from the fact that a clinician has to evaluate the lens before he or she can interpret perimetry results”.

should be:

The development of cataract is presumably a common cause of a general decrease in sensitivity. Insensitivity to cataract is obviously an advantage in a glaucoma trial. However, Wesselink et al suggested that, in a clinical setting, patients may benefit from the fact that the clinician needs to evaluate the lens before interpreting visual field results [22].

In the discussions section, page 217, paragraph 2 containing the following phrase:

“Neither GPA nor NPA provides information regarding the speed of deterioration. Hence, after progression was diagnosed by using either technique, the amount of deterioration and its localization (toward fixation or not) should be evaluated”

should be:

In the conclusions section, the paragraph containing the following phrase “As shown in this study, NPA is an easy tool for screening likely progression in glaucoma; it can be used with any perimeter at any disease stage, without the need for additional software”. should be: “As shown [22], NPA is an easy tool for screening likely progression in glaucoma; it can be used with any perimeter at any disease stage, without the need for additional software.