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SA Ophthalmology Journal The official journal of the Ophthalmological Society of South Africa Earn 3 CPD points

SUMMER 2021 | Vol 16 • No 1

A REVIEW OF NECROTISING HERPETIC RETINOPATHIES: ACUTE RETINAL NECROSIS AND PROGRESSIVE OUTER RETINAL NECROSIS I Walters, A Makgotloe

COMMON OPHTHALMIC DISEASE PRESENTATIONS AT A REFERRAL HOSPITAL IN RURAL SOUTH AFRICA N Ally, S Ismail, HD Alli

COMPARISON OF AMPLITUDE OF ACCOMMODATION IN TYPE 1 AND TYPE 2 DIABETES MELLITUS PS Makunyane, SD Mathebula

ADENOVIRUS AND HUMAN PAPILLOMAVIRUS IN THE PATHOGENESIS OF PTERYGIUM EB van der Merwe, J Maritz, KE Delaney, D Smit

IDIOPATHIC INTERSTITIAL KERATITIS IN A CHILD DA Erasmus, R Höllhumer

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References: 1. Pavesio CE, et al. Treatment of ocular inflammatory conditions with loteprednol etabonate. Br J Ophthalmol 2008;92:455–459. 2. Ilyas H, et al. Long-term safety of loteprednol etabonate 0.2% in the treatment of seasonal and perennial allergic conjunctivitis. Eye Contact Lens 2004;30(1):10-13. 3. Comstock TL, et al. Advances in corticosteroid therapy for ocular inflammation: loteprednol etabonate. Int J Inflam 2012;789623:1-11. 4. Dell SJ, et al. A randomized, double-masked, placebo-controlled parallel study of 0.2% loteprednol etabonate in patients with seasonal allergic conjunctivitis. J Allergy Clin Immunol 1998;102:251-255. Scheduling status: S4 Proprietary name and dosage form: Lotemax Ophthalmic Suspension, Eye Drops. Composition: Each 1 ml contains: Loteprednol etabonate 5,00 mg (0,5 % m/v) and Benzalkonium chloride (preservative) 0,01 % m/v. Pharmacological classification: A 15.2 Ophthalmic preparations with corticosteroids. Registration number: 37/15.2/0588. Scheduling status: S4 Proprietary name and dosage form: Alrex Ophthalmic Suspension. Composition: Each 1 ml contains: Loteprednol etabonate 2,00 mg (0,2 % m/v) and Benzalkonium chloride (preservative) 0,01 % m/v. Pharmacological classification: A 15.2 Ophthalmic preparations with corticosteroids. Registration number: 38/15.2/0203. For full prescribing information, refer to the professional information as approved by the South African Health Products Regulatory Authority (SAHPRA). © 2003 Bausch & Lomb Incorporated. ® / TM denote trademarks of Bausch & Lomb Incorporated. Applicant: Soflens (Pty) Ltd. Reg. no.: 1968/011787/07. 254 Hall Street, Centurion, 0157. Tel: +27 10 025 2100. www.bausch.co.za. BL395/19

SA Ophthalmology Journal The official journal of the Ophthalmological Society of South Africa ISSN: 2218-8304

Contents

Summer 2021 Vol 16 • No 1

Editor-in-Chief

Prof Nagib du Toit journaleditor@ossa.co.za

Managing Editor

Patricia Botes | 083 266 8200 pat.botes@ponynet.co.za

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Expert Board

Professors: Trevor Carmichael, Colin Cook, Nagib du Toit, Prisilla Makunyane, Ismail Mayet, Anthony Murray, Derrick Smit, Sue Williams Doctors: Eric Albrecht, Hassan Alli, Naseer Ally, Stephen Cook, Linett du Toit, Leonard Heydenrych, Mpopi Lenake, Aubrey Makgotloe, Hamza Mustak, James Rice, Chris Tinley, Linda Visser

Subscriptions

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Publishing Team

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COVER PIC: Left eye showing multifocal areas of inflammation and deep vascularisation. Note the ‘salmon-patch’ lesion inferiorly

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FROM THE EDITOR

Expert help needed with peer review N du Toit

6 9

GUIDELINES FOR AUTHORS REVIEW ARTICLE

A review of necrotising herpetic retinopathies: acute retinal necrosis and progressive outer retinal necrosis I Walters, A Makgotloe

ORIGINAL STUDY

Common ophthalmic disease presentations at a referral hospital in rural South Africa N Ally, S Ismail, HD Alli

Tel: +27 (0)21 406 2002 www.newmedia.co.za

The reproduction, without permission of any articles or photographs in this publication is forbidden and copyright is expressly reserved to NewMedia under the Copyright Act of 1978 as amended. The views expressed by contributors to and advertisers in the journal and the inclusion or exclusion of any medicine or procedure, do not necessarily reflect the views of the publisher or editorial board. While every effort is made to ensure accurate reproduction, the authors, advisers, publishers and their employees or agents shall not be responsible or in any way liable for errors, omissions or inaccuracies in the publication, whether arising from negligence or otherwise or for any consequences arising therefrom.

22 27

ORIGINAL STUDY

Comparison of amplitude of accommodation in type 1 and type 2 diabetes mellitus PS Makunyane, SD Mathebula

ORIGINAL STUDY

Adenovirus and human papillomavirus in the pathogenesis of pterygium EB van der Merwe, J Maritz, KE Delaney, D Smit

CASE STUDY

Idiopathic interstitial keratitis in a child DA Erasmus, R Höllhumer

Vol 16 | No 1 • Summer 2021 SA Ophthalmology Journal

From t he Editor

Expert help needed with peer review

e welcomed 2021 in much the same way that we ushered out 2020 – with another wave of the Covid-19 pandemic. Masks, social distancing, working from home and ‘keeping safe’ have become the new normal. Vaccination is next on the global agenda in the ongoing struggle to end the pandemic and return our lives to the way they used to be. In this, our first edition of the year, we have included a review article on the necrotising herpetic retinopathies – acute retinal necrosis and progressive outer retinal necrosis. The article gives a good overview of the two conditions and an up-to-date summary on management. We are fortunate to publish a submission, once again, from one of our esteemed optometry colleagues. Prof Solani wrote a review article for our last issue and now returns with an interesting original study on the reduced amplitude of accommodation in diabetics. Another of the original studies published here, is authored by Dr Naseer Ally, who has a good background in research and recently joined us as a member of the Expert Board of the SA Ophthalmology Journal. Dr Ally is working on improving the submission process for authors and switching to an online submission platform, instead of using

our current email system. Using the new system, authors will be able to track their papers from submission to peer review and finally, publication. Board members are required to perform regular reviews of work that has been submitted for publication in the SA Ophthalmology Journal and may be required to write the occasional review article. Each of our published articles is reviewed by two independent reviewers as part of the peerreview process. Since this process places a load on the Board, in future, we will be inviting members of our ophthalmology community, who are familiar with research and are well published, to assist us with the peer-review process. We hope that we can look forward to the support of our colleagues in this regard. Please note that at present, we have an average six-month wait from time of submission of original studies and case reports to publication in the SA Ophthalmology Journal. The period is shorter for review articles, as we receive a lower number of these submissions. We have included one further original study on pterygia and the role of human adenovirus and human papillomavirus in their pathogenesis – based on findings in a Namibian population. The case report included in this edition sheds light on idiopathic interstitial keratitis

in a paediatric case of known juvenile idiopathic arthritis, which responded to topical steroid therapy with full recovery of vision. Please note that SA Ophthalmology Journal publications can be found on Google Scholar and we can only initiate the process of achieving listing on PubMed/Medline, Scopus and SciELO around March 2022, once we have a twoyear record post-accreditation. Please continue to support us with your valuable submissions. The SA Ophthalmology Journal team encourages all our readers to take care and we hope for a productive year ahead. 

Prof Nagib du Toit

MBChB(UCT), DipOphth(SA), FRCS(Ed), FCOphth(SA), MMed(UCT), PhD(UCT)

Editor-in-Chief: South African Ophthalmology Journal

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Vol 16 | No 1 • Summer 2021 SA Ophthalmology Journal

Guideline s for aut hor s

South African Ophthalmology Journal guidelines for authors

he SA Ophthalmology Journal is a peer-reviewed scientific journal and the official mouthpiece of the Ophthalmological Society of South Africa. It appears on a quarterly basis. 1. A cover sheet is to be submitted with each manuscript. It should contain the title of the manuscript, the names of all authors in the correct sequence, their academic status and affiliations. The main author should include his/her name, address, phone and email address. 2. The South African Ophthalmology Journal invites review articles, original studies and case reports for submission. Articles should be the original, unpublished work of the stated author. All materials submitted for publication must be submitted exclusively for publication in this journal. Written permission from the author or copyright holder must be submitted with previously published figures, tables or articles. 3. The Editor reserves the right to shorten and stylise any material accepted for publication. 4. Authors are solely responsible for the factual accuracy of their work. 5. Articles should be between 2 000

and 3 000 words in length. A 200word abstract should state the main conclusions and clinical relevance of the article. 6. All articles are to be in English and are to follow the Vancouver style. 7. Abbreviations and acronyms should be defined on first use and kept to a minimum. 8. Tables should carry Roman numerals, I, II etc., and illustrations Arabic numbers 1, 2 etc. 9. References should be numbered consecutively in the order that they are first mentioned in the text and listed at the end in numerical order of appearance. Identify references in the text by Arabic numerals in superscript after punctuation, e.g. …trial.13 10. The following format should be used for references: Articles: Kaplan FS, August CS, Dalinka MK. Bone densitometry observation of osteoporosis in response to bone marrow transplantation. Clin Orthop 1993;294:173-78. Chapter in a book: Young W. Neurophysiology of spinal cord injury. In: Errico TJ, Bauer

RD, Waugh T (eds). Spinal Trauma. Philadelphia: JB Lippincott; 1991: 377-94. 11. Articles are to be submitted by email to the Editor-in-Chief, Prof Nagib du Toit at the following email address: journaleditor@ossa.co.za The text should be in MS Word. Pages should be numbered consecutively in the following order wherever possible: Title page, abstract, introduction, materials and methods, results, discussion, acknowledgements, tables and illustrations, references. 12. All figures, tables and photographs should also be submitted electronically. Each figure must have a separate self-explanatory legend. The illustrations, tables and graphs should not be embedded in the text file, but should be provided as separate individual graphic files, and clearly identified. The figures should be saved as a 300 dpi jpeg file. Tables should be saved in a PowerPoint document or also as a 300 dpi jpeg. 13. Authors should declare any interests, financial or otherwise, regarding the publication of their article and should also indicate whether the submission forms part of an 'MMed dissertation by publication' by stating so clearly on the title page. 

The CPD questions now have to be completed online. To complete the questionnaire, go to https://www.medicalacademic.co.za/courses/ sa-ophthalmology-journal-cpds-summer-2021

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1. Arrata M. Fusidic acid viscous eye drops, Fucithalmic®, in bacterial con�unc�vi�s. A review of three controlled clinical studies with chloramphenicol and framyce�n eye drops. Acta XXV Concilium Ophthalmologicum. Proceedings of the XXVth Interna�onal Congress of Ophthalmology, Rome, May 4-10, 1986; 1038-1042. 2. Medicines.org.uk. (2019). Fusidic Acid 1% Viscous Eye Drops - Summary of Product Characteris�cs (SmPC) - (eMC). h ps://www.medicines.org.uk/emc/product/5188/smpc. Accessed 28.06.2019. 3. Optometric clinical prac�ce guideline. Care of the pa�ent with con�unc�vi�s. Reference guide for clinicians. © American Optometric Associa�on 1995, 2002. 4. Epling J. Bacterial Con�unc�vi�s. BMJ Clin Evid 2012; pii: 0704. 5. Orden Mar�nez B, Mar�nez Ruiz R, Millán Pérez R. Bacterial con�unc�vi�s: most prevalent pathogens and their an�bio�c sensi�vity. An Pediatr (Barc). 2004;61(1):32-36. 6. Centre for Disease Control (CDC). Pink Eye. h ps://www.cdc.gov/con�unc�vi�s/clinical.html. Accessed 28.06.2019. 7. Dirdal, M. (1987). Fucithalmic® in acute con�unc�vi�s. Acta Ophthalmologica, 65(2), pp.129-133. 8. Fucithalmic package insert. Approved by MCC 02 April 2013. 9. Jackson WB, Low DE, Da ani D, Whitsi PF, Leeder RG, Macdougall R. Treatment of acute bacterial con�unc�vi�s: 1% fusidic acid viscous drops vs 0.3% tobramycin drops. Can J Ophthalmol 2002; 37:228-237. FUC_A4 20_01

Re v ie w ar t icle Necrotising herpetic retinopathies

Summer 2021 • Vol 16 | No 1 SA Ophthalmology Journal

A review of necrotising herpetic retinopathies: acute retinal necrosis and progressive outer retinal necrosis I Walters MBBCh(Wits), B Optom(RAU/UJ); Registrar in the Division of Ophthalmology, University of the Witwatersrand, Johannesburg, South Africa ORCID: https://orcid.org/0000-0001-9159-8930 A Makgotloe MBBCh(Wits), MMed(Wits), FCOphth(SA); Academic Head: Division of Ophthalmology, University of the Witwatersrand, Johannesburg, South Africa ORCID: https://orcid.org/0000-0002-8193-3245 Corresponding author: Dr Ingrid Walters, PO Box 52281, Saxonwold, 2132; tel: +27 82 573 1023; email: ingrid.walters@yahoo.co.uk

Abstract Purpose of review: Necrotising herpetic retinopathies are a group of debilitating retinal disorders of which acute retinal necrosis and progressive outer retinal necrosis are important examples. They are uncommon, rapidly progressive, and devastating posterior segment syndromes caused by human herpes viruses. The clinical picture is influenced by the patient’s immunological status and viral factors. The authors present a review article on the epidemiology, clinical features, diagnosis and management of acute retinal necrosis and progressive outer retinal necrosis. Recent findings: Although a clinical diagnosis, polymerase chain reaction has become a diagnostic modality of choice in the management of patients with necrotising herpetic retinopathies. Treatment is high dose induction dual intravitreal and systemic antiviral therapy followed by a prolonged period of maintenance therapy. Prophylactic laser retinopexy and

Introduction

Acute retinal necrosis (ARN) was first described in immunocompetent, healthy adults in Japan by Urayama et al. (1971). They described acute unilateral panuveitis with retinal periarteritis and rapidly progressive diffuse retinal necrosis with subsequent retinal detachment.1 Culbertson et al. (1982) first described histologic evidence of a likely herpetic aetiology. 2 It was not until 1994 that the Executive Committee of the American Uveitis Society developed and published standardised diagnostic criteria for ARN. 3 Progressive outer retinal necrosis (PORN), the variant of necrotising herpetic

early vitrectomy are no longer advocated, as there is lack of supporting evidence. Despite early diagnosis and best treatment, acute retinal necrosis and progressive outer retinal necrosis carry guarded prognoses and patients should be counselled appropriately. Keywords: progressive outer retinal necrosis syndrome, acute retinal necrosis syndrome, necrotising herpetic retinopathy, varicella zoster virus, retinitis, polymerase chain reaction Funding: All research was funded by the principal author. Conflict of interest: The authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article.

retinopathy, found almost exclusively in profoundly immunosuppressed patients, was first described by Forster et al. (1990). The condition is characterised by multifocal areas of retinal opacification originating in the outer retinal layers, little to no ocular inflammation, rapid progression of lesions to confluence and early posterior pole involvement.4 Margolis et al. (1991) presented clinical and laboratory evidence suggesting this was a form of varicella zoster virus (VZV) retinopathy. 5 Guex-Crosier et al. (1997) concluded that ARN and PORN, while being distinct clinical entities, fell on opposite ends of the spectrum of necrotising herpetic

retinopathies as they share a causative viral aetiology. The degree of host-immune impairment seems to determine the type and severity of the syndrome with various intermediary clinical forms in between.6

Methods

A Pubmed database search was conducted to find recently published, original English articles concerned with the topic of necrotising herpetic retinopathies. Relevant articles including reviews were included. All important publications, mostly retrospective studies and case reports, were reviewed and included. All research included is in accordance with the declaration of Helsinki.

Re v ie w ar t icle Necrotising herpetic retinopathies

Epidemiology

ARN is rare, comprising approximately 1–2% of endogenous uveitis cases.7 It affects woman and men equally. Typically described as affecting healthy young adults, it can also affect the elderly, as well as children.7-9 Although ARN often occurs acutely in healthy, immunocompetent patients, ARN has been described in patients with HIV infection and in those taking immunosuppressive agents.7,9 Studies suggest possible specifically diminished cellular immunity to VZV in the absence of systemic immunosuppression or a possible diminished local immunity in the eye.6,9 Genetic predispositions may exist.9 Most ARN sufferers have no preceding prodrome and no relevant systemic diseases; however, cases of ARN occurring with past or concurrent herpetic encephalitis or meningitis have been reported.9,10 In 1978, Young and Bird coined the phrase bilateral acute retinal necrosis (BARN), which is now known to occur in up to 70% of untreated patients.10,11 In immunocompromised patients PORN is the second most common infectious retinitis after cytomegalovirus (CMV) retinitis.12 It generally affects young adults with an equal sex distribution.12,13 PORN has most commonly been described in immunosuppressed individuals secondary to advanced HIV infection, with mean CD4 T-lymphocyte counts of 21 cells/µL (range 0–130 cells/µL).13 In a large South African case series of PORN patients by Gore et al., all patients were found to be HIVpositive with mean CD4 lymphocyte count of 30 cells/µL.14 PORN has also occasionally been described in other settings of immunosuppression such as lymphoma, immunosuppressive medications like corticosteroids or chemotherapy, nephrotic syndrome, rheumatoid arthritis, and graft-versushost disease.12 Approximately 66% of cases are associated with preceding or concurrent cutaneous herpes zoster infection.13,14 PORN, like ARN, typically manifests unilaterally before affecting the fellow eye in 71% of cases.12,13

Aetiology

ARN results from a reactivated latent herpes viral infection. Varicella zoster virus (VZV) remains the most frequent cause and tends to affect older patient populations as VZV immunity wanes.9 Human herpes virus 1 and 2 (HSV-1 and HSV-2) are usually acquired in childhood.

Reactivation of HSV-1 tends to cause retinitis in older patients and HSV-2 tends to affect younger populations. 8,9 Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are reported, albeit exceedingly rare causes of ARN.7 Evidence proving that VZV is the commonest cause of ARN, followed by HSV-1 and 2 and very rarely CMV and EBV is strong. The viruses have been isolated and identified using polymerase chain reaction (PCR) based techniques, serum and intraocular fluid antibody testing, viral culture, immunohistochemistry and retinal biopsy. 8,9 Histology demonstrates intranuclear viral inclusions within inner layer retinal cells, full thickness retinal necrosis and arteritis.9 PORN is caused almost exclusively by reactivation of latent VZV and, in extremely rare circumstances, by HSV or CMV reactivation. 5,12,13 Using electron microscopy and immunohistochemical methods Margolis et al. (1991) first demonstrated VZV in vitreous and retinal specimens of patients with PORN. 5 The localisation of isolated viral capsids and VZV antigens in the outer retinal layers of retina in enucleated specimens coincided with the deep retinal necrosis seen in PORN.12 Subsequently, investigators have cultured VZV from chorioretinal biopsies and isolated VZV DNA using PCR from aqueous, vitreous and retinal specimens.12

Clinical presentation

Presenting symptoms of ARN are classically acute, unilateral loss of vision, hyperaemia, photophobia, floaters and pain. Fellow eye involvement will occur in 36% of cases, usually before six weeks from when the initial eye developed symptoms, but involvement can be delayed for an extended period of up to 20 years.7-9 The pain experienced may be worse with eye movements due to optic nerve and extraocular muscle involvement.9 Anterior segment signs include acute and significant inflammation. The inflammation may be fibrinous with keratic precipitates (granulomatous or non-granulomatous) and mild to moderately elevated intraocular pressure in 36.3% cases.7-9 Posterior synechiae may occur but iris atrophy is not typically seen which differentiates it from herpetic iridocyclitis. Diffuse scleritis may be present.9 Dilated fundus examination is crucially important and if not performed, the classically described ARN triad of

Vol 16 | No 1 • Summer 2021 SA Ophthalmology Journal

vitritis, occlusive retinal arteritis and retinal necrosis would be missed.

The American Uveitis Society Diagnostic Criteria for ARN3

1. Clinical characteristics that must be seen: a) One or more foci of retinal necrosis with discrete borders located in the peripheral retina (outside of the major temporal vascular arcades) b) Rapid progression (advancement of lesion border or development of new foci of necrosis) in the absence of antiviral therapy c) Circumferential spread d) Occlusive vasculopathy with arteriolar involvement e) Prominent inflammation of the vitreous and anterior chamber 2. Clinical characteristics that are supportive but not required for the diagnosis: a) Optic neuropathy or atrophy b) Scleritis c) Pain 3. The definition does not depend on the extent of the necrosis 4. The definition does not depend on the immunologic status of the host 5. The diagnosis is not influenced by isolation of any virus from ocular tissues or fluid The American Uveitis Society also recommended, in the event that the above diagnostic criteria are not met, that the terms previously used such as ‘limited or atypical ARN’ be replaced with the term ‘necrotising herpetic retinopathy’. 3 The retinitis initially typically begins as numerous yellow white foci in the peripheral retina which then progress towards well-delineated, scalloped-edged plaques. When untreated these lesions coalesce and spread circumferentially within 5–10 days, advancing posteriorly. The posterior pole and macula are spared until late in the disease process.7,9,10 In general, ARN caused by VZV progresses more rapidly than HSV- ARN.9,10 Optic nerve involvement in ARN is quite common and can precede the onset of retinitis. Signs could include a papillitis, dyschromatopsia or relative afferent pupillary defect.9 The vasculitis in the acute stage is mainly arterial and occlusive in nature; however, phlebitis is also frequently observed. Retinal haemorrhages, if present, are not a prominent feature as in CMV retinitis.7-9 The extensive necrosis, which results in peripheral retinal atrophy and retinal breaks, as well as the vitreoretinal

Re v ie w ar t icle Necrotising herpetic retinopathies

Summer 2021 • Vol 16 | No 1 SA Ophthalmology Journal

tractional bands (that result from the resolved vitritis), predispose to combined tractional-rhegmatogenous retinal detachments. The rate of these in the literature ranges from 50–75%. 8,9 Presenting symptoms of PORN include sudden onset, usually unilateral loss of vision, or visual field loss. Importantly, unlike ARN, PORN is usually painless and asymptomatic.12 Patients reported previous cutaneous zoster infection in 67–78% of cases, depending on the study.13,14 Classically, intraocular inflammation is minimal or absent. Anterior chamber inflammation was seen in 38% of eyes and was usually mild.13 Most cases had 1+ cells. Keratic precipitates were only observed in 11% and were fine and nongranulomatous.13,14 Vitreous inflammation was only present in a quarter of patients and tended to be mild.13 Newer case series report even lower rates of inflammation.14 The retinitis is described as starting as multifocal, discrete lesions without granular borders arising in the outer retinal layers of the peripheral retina. These lesions progress and coalesce rapidly to involve the posterior pole early on, unlike ARN.12-14 Approximately a third of patients will have macular involvement at presentation. There is no consistent direction of disease spread13 (Figures 1 and 2). Retinal vasculitis and haemorrhages are typically absent and this is an important distinguishing feature in PORN.12,13 PORN characteristically has perivascular sparing from retinitis which gives the fundus a ‘cracked mud’ appearance.12,13 Optic nerve involvement including disc swelling, hyperaemia and optic atrophy can occur, although less frequently than in ARN.13 Resolution of the retinitis in PORN results in multiple atrophic posterior retinal holes and breaks that predispose to rhegmatogenous retinal detachments which are reported to occur in 70% of affected eyes.12,13 The median time to retinal detachment is three weeks, usually occurring within the active necrotic phase, although retinal detachment can occur many months later during the inactive phase.13,14

a Figure 1. A case of PORN in the right (a) and left (b) eyes before initiation of both systemic and intravitreal antiviral therapy. The widespread retinal necrosis and early posterior pole involvement is evident. A vitreous tap on the right eye which was no light perception on presentation revealed positive PCR for varicella zoster virus.

Investigations and work-up

Both ARN and PORN are clinical diagnoses. If the presentation is typical or if clinical suspicion is sufficiently high, then therapy is to be commenced immediately while waiting for confirmatory laboratory testing, usually PCR, which is the current gold standard. 8,9,15

Re v ie w ar t icle Necrotising herpetic retinopathies

a Figure 2. Fundus photographs of the right eye (a and b) of the same case after treatment with intravenous acyclovir and intravitreal ganciclovir treatment demonstrating widespread scarring

Vol 16 | No 1 • Summer 2021 SA Ophthalmology Journal

1. Polymerase chain reaction (PCR): PCR has largely supplanted all other historically performed diagnostic procedures. The sensitivity of PCR testing is as high as 79–100%.15 Multiplex PCR, a qualitative PCR test, can accurately detect multiple different types of minute viral nucleic acid fragments in only 90 minutes.15 Real‑time PCR, a quantitative PCR test, is now readily available and can accurately quantify viral load allowing clinicians to monitor response to treatment.15 Studies have looked at initial viral loads and postulate that high viral loads may be linked to worse disease severity and poorer final visual outcomes.15,16 A few studies have been performed comparing diagnostic pick-up rates of aqueous sampling versus the gold standard vitreous sampling using PCR testing. Advantages of aqueous sampling via paracentesis is that it is easier, safer and more convenient. Apart from a single outlying study, the consensus is that there is no significant difference between sampling techniques. 8,10,16 2. Retinochoroidal biopsy: In rare cases with a negative PCR in the presence of high clinical suspicion for a necrotising herpetic retinopathy, biopsy can be performed.10 3. Goldmann-Witmer coefficient: This is a type of indirect testing tool that compares the amount of intraocular antibody to the amount serum antibodies. It has largely fallen out of popular use.9 4. Fluorescein angiography: In ARN, although the quality may be limited by the overlying vitritis, angiography may demonstrate the occlusive vasculitis. Initial hypofluorescence and late staining may indicate choroidal involvement. Optic nerve involvement may also be demonstrated.10 In PORN, choroidal involvement may also be evident, and characteristic features are that of arteriolar narrowing and widespread retinal staining. The perivenous capillary network remains spared.12 5. B-scan ultrasonography: This is useful in ARN for detecting retinal detachment when view of the fundus is obscured by vitritis.7,8 6. Optical coherence tomography: Although not useful in the acute stage, later it may detect complications such as cystoid macular oedema, macular atrophy and epiretinal membranes. 8,9

Re v ie w ar t icle Necrotising herpetic retinopathies

Summer 2021 • Vol 16 | No 1 SA Ophthalmology Journal

7. Laboratory and serum testing: Baseline full blood count, liver and kidney function testing are useful prior to initiation of systemic treatment and for dosing considerations. HIV status and CD4 lymphocyte count need to be obtained.10 It is important to exclude differentials such as syphilis, etc. 8,10

Medical therapy Antivirals

Prompt initiation of a systemic antiviral agent is needed to treat the affected eye as well as protect the fellow eye. Systemic antivirals have been shown to reduce fellow eye involvement from 70% at two years down to 13%.9,10 High dose induction therapy is given either intravenously or orally for 10–14 days. Clinical stability should be seen approximately 48–72 hours after initiation although it may take up to 6–12 weeks for resolution of the inflammation. Maintenance therapy is given for a minimum of six months and is crucial as antiviral medication cannot eradicate herpetic viruses and recurrences and reactivations are common.7,8,10 ARN is traditionally treated with intravenous acyclovir induction followed by oral maintenance. New evidence suggests oral antiviral therapy, usually valacyclovir, reaches acceptable plasma drug levels and vitreous concentrations and can be used as an effective alternative induction modality. 8,10 Oral induction is popular as it avoids hospitalisation and the subsequent costs incurred. No formal direct comparison between oral and intravenous treatment modalities has been done although there are a number of retrospective reviews which suggest that their outcomes are comparable and either may be used.10 Adjunctive intravitreal antivirals (foscarnet and ganciclovir) have been studied as part of the induction regimen to attain immediate therapeutic vitreous drug levels. This may reduce severe vision loss as well as diminish retinal detachment risk from 60% to 35%. Intravitreal antivirals are not to be used as monotherapy as this puts the fellow eye at risk. 8,10 Acyclovir, famciclovir and valacyclovir constitute first-line therapy and demonstrate good activity against both VZV and HSV. They are competitive viral DNA polymerase inhibitors and are generally well tolerated in both intravenous and oral forms.8,10 The drugs are excreted renally and dose adjustments are required in geriatric and renal-failure patients.

Table I: First-line antivirals in the treatment of necrotising herpetic retinitis and recommended doses Drug

Induction

Maintenance

Acyclovir

10 mg/kg IV 8 hrly 10–14 days

800 mg orally 5×/day

Valacyclovir

1 000–2 000 mg orally 3×/day

1 000 mg orally 3×/day

Famciclovir

500 mg orally 3×/day

The most common reported side effects of these first-line antivirals are gastrointestinal disturbances, headaches and rash. Intravenous acyclovir can cause nephrotoxity or central nervous system disturbances.7,8,10 Generally accepted doses for induction and maintenance are given in Tables I and II.10 ARN cases that respond poorly to acyclovir could be due to the HSV, or rarely drug-resistant VZV. Acyclovir resistant HSV is described in the literature in less than 1% of immunocompetent patients but in as high as 14% of immunocompromised cases.10 Acyclovirresistant VZV is uncommon and has rarely been described in the literature. Other reasons for first-line treatment failure are suboptimal dosing or misdiagnosed CMV which responds poorly to acyclovir. 8,10 The antivirals ganciclovir, valganciclovir and foscarnet which serve as secondline treatment for CMV retinitis can also be used to treat acyclovir-resistant HSV and to a lesser extent VZV. 8,10 Ganciclovir is available in oral, intravenous preparations, and off label as intravitreal therapy. Valganciclovir, an oral prodrug of ganciclovir, is a good alternative to parenteral ganciclovir. 8,10 The main side effects of both drugs include bone marrow suppression and neutropaenia. Doses also require adjustment in renal patients.7,10 Foscarnet is only available as an intravenous formulation or as intravitreal therapy. Side effects include nephrotoxicity and hypocalcaemia.10 Additional adverse effects of intravitreal injection include endophthalmitis, vitreous haemorrhage and retinal detachment.10 Initially the same acyclovir induction and maintenance regimen that yielded good outcomes in ARN was applied to treating PORN with appalling effect.

Moreover, multiple reports exist of patients developing PORN while on acyclovir prophylaxis or treatment for cutaneous zoster infection.12,14 Various combinations of one or more systemic antiviral agents are usually used and may yield slightly better outcomes but no single agreed-upon treatment regimen exists.12 Bi-weekly adjunctive intravitreal antiviral injections have been shown to be beneficial.12,14 After initial induction therapy which can consist of two systemic antivirals (usually from the second-line group) as well as twice weekly intravitreal injections, long-term maintenance therapy (which may include systemic antivirals and intravitreal injections every two weeks) is required to protect against recurrences which are extremely common.12-14 Newer antivirals such as sorivudine, vadarabine and bromovinyldeoxyuridine (BVDU) have been proposed to possibly treat PORN but evidence is insufficient at this stage.12

Adjunctive medical therapy

Oral prednisone (0.5–1.0 mg/kg/day) started 1–2 days after the initiation of antiviral therapy has been recommended in the literature.7 The rationale is to treat the severe inflammatory response and optic neuropathy associated with ARN. Intravitreal dexamethasone or triamcinolone has been used and may decrease vitritis as well as improve final visual outcomes, but may worsen the retinal necrosis. Topical corticosteroids are also often utilised.7,10 Aspirin and other anticoagulants such as warfarin have been used as adjuvant in the management of ARN. This treatment is postulated to treat the hypercoagulable state, extensive occlusive vasculitis and ischaemic optic neuropathy.

Table II: Second-line antivirals in the treatment of necrotising herpetic retinitis and recommended doses Drug

Induction

Foscarnet

Intravitreal 2.4 mg/0.1 mL repeated 1–2×/week

Maintenance

Intravenous 90 mg/kg IV 8 hrly Ganciclovir

Intravitreal 2 mg/0.1 mL repeated 1–2×/week Intravenous 5–10 mg/kg/day

Valganciclovir

900 mg orally 2×/day for 3 weeks

900 mg orally daily

Re v ie w ar t icle Necrotising herpetic retinopathies

Strong evidence for their use and benefit is lacking and their safety should be carefully considered before use.10 Highly active antiretroviral therapy (HAART) is an important adjunct in PORN treatment.12 Studies have reported a correlation in that patients who are already on HAART at time of presentation of PORN are less likely to develop retinal detachments.14 The degree of immune recovery required before discontinuing systemic antiviral maintenance therapy has not been established. Some authors consider a CD4 lymphocyte count of more than 100 cells/µL sufficient based on data from CMV-retinitis studies while others advocate for lifelong antiviral prophylaxis.12,14

Prophylactic laser retinopexy

The use of prophylactic laser in ARN was initially advocated for as several small retrospective comparative series demonstrated the apparent benefit and protection against retinal detachment. However, in these studies, laser was usually performed on eyes with better initial presenting visual acuities, less extensive retinitis and had clearer media to allow for laser retinopexy. The selection bias confounds the results and therefore no strong evidence currently exists to suggest there is any benefit to prophylactic laser retinopexy. 8,10 In the few studies evaluating prophylactic laser retinopexy in PORN, laser was deemed non-beneficial in preventing retinal detachments.12,13

Surgical management

Large retrospective reviews have demonstrated no anatomic or visual benefit to early vitrectomy in either ARN or PORN.8,10 Retinal reattachment surgery is done through a standard three-port pars plana vitrectomy and the tamponade of choice is silicone oil. Successful anatomical reattachment in PORN is reported in 70–87% of cases.12,10 The decision to operate on a retinal detachment depends on the extent of retinal necrosis and whether the patient would derive any visual improvement. Other factors to consider are optic nerve involvement, the state of the fellow eye, as well as general patient fitness and life expectancy.12

Outcomes and prognosis

Visual outcomes in ARN are typically poor, although still better than PORN. Fortyeight per cent of affected eyes have a visual acuity worse than 20/200 at six

months.10 The most common causes of visual loss are retinal detachment, chronic vitritis, cataract development, epiretinal membranes, macular ischaemia or oedema, and optic neuropathy.10,17 VZV-induced ARN carries a worse prognosis than those ARN cases caused by HSV.16 Only 32% of VZV-ARN and 67% of HSV-ARN eyes had a final visual acuity of greater than 0.5. VZV-ARN has been shown to have a 2.5 times greater risk to retinal detachments than HSV-ARN. 8,10 Engstrom et al. (1994) were the first to report the devastating nature of PORN in which 67% of cases progressed to no light perception (NLP) vision within four weeks of onset.13 Newer studies using combination systemic antivirals with adjuvant intravitreal injections report less grim outcomes.12,14 Factors affecting final visual acuity are: extent of retinal necrosis and initial visual acuity at the time of starting therapy; development of a retinal detachment; and underlying immune status.12 Overall mortality rates in patients with PORN is high due to their significant underlying immunocompromise. Gore et al. (2012) reported 31% mortality in a South African population.14

Conclusion

The necrotising herpetic retinopathies are rare, potentially devastating ocular conditions. It is prudent to consider ARN as a possible differential in any patient presenting with an anterior uveitis or scleritis and always perform a dilated fundus exam on the first visit. Similarly, PORN should be on the differential when diagnosing retinitis in an immunocompromised patient. PCR-based diagnostic tools are extremely useful and should certainly be used when available. Treatment consists of induction of systemic antiviral medication which can be either oral or intravenous with adjunctive intravitreal injections, followed by long-term maintenance. It is imperative to counsel patients regarding the guarded prognosis carried by these conditions.

References

1. Urayama, AY, Sasaki, T, Nishiyama, Y, et al. Unilateral acute uveitis with periarteritis and detachment. Japan J Ophthalmol. 1971;25:607-19. 2. Culbertson WW, Blumenkranz MS, Haines H, et al. The acute retinal necrosis syndrome. Part 2: histopathology and etiology. Ophthalmology. 1982;89:1317-25. 3. Holland, GN. Standard diagnostic criteria for

Vol 16 | No 1 • Summer 2021 SA Ophthalmology Journal

the acute retinal necrosis syndrome. Am J Ophthalmol. 1994;117(5):663-67. 4. Forster DJ, Dugel PU, Frangieh GT, et al. Rapidly progressive outer retinal necrosis in the acquired immunodeficiency syndrome. Am J Ophthalmol. 1990;110(4):341-48. 5. Margolis, TP, Lowder, CY, Holland, GN, et al. Varicella-zoster virus retinitis in patients with the acquired immunodeficiency syndrome. Am J Ophthalmol. 1991;112(2):119-31. 6. Guex-Crosier, Y, Rochat, C, Herbort, CP. Necrotizing herpetic retinopathies: A spectrum of herpes virus induced diseases determined by the immune state of the host. Ocul Immunol Inflamm. 1997;5(4):259-66. 7. Bonfioli AA, Eller AW. Acute retinal necrosis. In Seminars in ophthalmology 2005 Jan 1 (Vol. 20, No. 3, pp. 155-60). Taylor & Francis. 8. Schoenberger SD, Kim SJ, Thorne JE, et al. Diagnosis and treatment of acute retinal necrosis: a report by the American Academy of Ophthalmology. Ophthalmology. 2017 Mar 1;124(3):382-92. 9. Usui Y, Goto H. Overview and diagnosis of acute retinal necrosis syndrome. In Seminars in ophthalmology 2008 Jan 1 (Vol. 23, No. 4, pp. 275-83). Taylor & Francis. 10. Powell B, Wang D, Llop S, et al. Management strategies of acute retinal necrosis: current perspectives. Clinical Ophthalmology. 2020;14:1931. 11. Young NJ, Bird AC. Bilateral acute retinal necrosis. Br J Ophthalmol. 1978;62(9):581-90. 12. Austin RB. Progressive outer retinal necrosis syndrome: a comprehensive review of its clinical presentation, relationship to immune system status, and management. Clin Eye Vis Care. 2000;12(3-4):119-29. 13. Engstrom RE, Holland GN, Margolis TP, et al. The progressive outer retinal necrosis syndrome. A variant of necrotizing herpetic retinopathy in patients with AIDS. Ophthalmology. 1994;101(9):1488-502. 14. Gore DM, Gore SK, Visser L. Progressive outer retinal necrosis: outcomes in the intravitreal era. Archives of Ophthalmology. 2012;6:700-706. 15. Sugita S, Ogawa M, Shimizu N, et al. Use of a comprehensive polymerase chain reaction system for diagnosis of ocular infectious diseases. Ophthalmology. 2013;9:1761-68. 16. Tran, THC. Polymerase chain reaction analysis of aqueous humour samples in necrotising retinitis. Br J Ophthalmol. 2003;87(1):79-83. 17. Ittner EA, Bhakhri R, Newman T. Necrotising herpetic retinopathies: a review and progressive outer retinal necrosis case report. Clinical and Experimental Optometry. 2016;1:24-29. 

Prevention and treatment of pain and inflammation associated with cataract surgery and reduction in the risk of macular oedema associated with cataract surgery1

NEVANAC® INDICATED FOR: • Prodrug structure delivers relief to key tissues2,3 • 63 % of patients had complete inflammation clearing at Day 14 4 • 83 % of patients were pain-free at Day 14 • Established safety and tolerability with minimal discomfort in clinical trials4,5

SCHEDULING STATUS: S3 NEVANAC Eye drops, suspension Reg. No. 42/15.4/1006. COMPOSITION: 1 ml of suspension contains 1 mg nepafenac. Preservatives: benzalkonium chloride 0.005 % (m/v) and disodium edetate 0.01 % (m/v). PHARMACOLOGICAL CLASSIFICATION: A.15.4 Ophthalmic preparations, Anti-inflammatory agents, non-steroids. INDICATIONS: Prevention and treatment of pain and inflammation associated with cataract surgery and reduction in the risk of macular oedema associated with cataract surgery. DOSAGE AND DIRECTIONS FOR USE: Use in adults: Use the lowest effective dose for the shortest possible duration of treatment. Instill 1 drop of NEVANAC in the conjunctival sac of the affected eye(s) 3 times daily, beginning 1 day prior to cataract surgery, continued on the day of surgery and for the first 2 weeks of the postoperative period. Treatment can be extended to the first 3 weeks of the postoperative period, as directed by the clinician. An additional drop should be administered 30-120 minutes prior to surgery. Treatment can be extended for up to 60 days to reduce the risk of macular oedema associated with cataract surgery. Paediatric patients: The efficacy and safety of NEVANAC in patients below the age of 18 years has not been established. Geriatric patients: No dose adjustment is warranted in these patients as no overall difference in safety and efficacy have been observed in this population. Use in hepatic and renal impairment: NEVANAC has not been studied in patients with hepatic disease or renal impairment. No dose adjustment is warranted in these patients. Shake well before use. If more than one topical ophthalmic medication is being used, the medicines must be administered at least 5 minutes apart. To prevent contamination of the dropper tip and solution, care must be taken not to touch the eyelids, surrounding areas or other surfaces with the dropper tip of the bottle. Keep the bottle tightly closed when not in use. CONTRAINDICATIONS: Hypersensitivity to the active substance, to any of the excipients, or to other non-steroidal anti-inflammatory drugs (NSAIDs) - Heart failure - History of gastrointestinal bleeding or perforation (PUB’s) related to previous NSAIDs. Active or history of recurrent ulcer / haemorrhage / perforations - In patients in whom attacks of asthma, urticaria or acute rhinitis are precipitated by aspirin or other NSAIDs. WARNINGS AND SPECIAL PRECAUTIONS: Use of topical NEVANAC may result in keratitis. Continued use of topical NEVANAC may result in epithelial breakdown, corneal thinning, corneal erosion, corneal ulceration or corneal perforation. These events may be sight threatening. Patients with evidence of corneal epithelial breakdown should immediately discontinue use of NEVANAC and should be monitored closely for corneal health. Topical NEVANAC may slow or delay healing. Topical corticosteroids are also known to slow or delay healing. Concomitant use of NEVANAC and topical steroids may increase the potential for healing problems. Post-marketing experience with topical NSAIDs such as NEVANAC suggests that patients with complicated ocular surgeries, corneal denervation, corneal epithelial defects, diabetes mellitus, ocular surface diseases, rheumatoid arthritis or repeat ocular surgeries within a short period of time may be at increased risk for corneal adverse reactions which may become sight threatening. NEVANAC should be used with caution in these patients. Prolonged use of NEVANAC may increase patient risk for occurrence and severity of corneal adverse reactions. NEVANAC may cause increased bleeding of ocular tissues (including hyphemas) in conjunction with ocular surgery. NEVANAC should be used with caution in patients with known bleeding tendencies or who are receiving other medicines which may prolong bleeding time. NEVANAC contains benzalkonium chloride which may cause irritation and is known to discolour soft contact lenses. Contact lens wear is not recommended during the postoperative period following cataract surgery. Patients should be advised not to wear contact lenses during treatment with NEVANAC. Benzalkonium chloride, used as a preservative in NEVANAC, has been reported to cause punctate keratopathy and/or toxic ulcerative keratopathy. Since NEVANAC contains benzalkonium chloride, close monitoring is required with frequent or prolonged use. An acute ocular infection may be masked by the topical use of NEVANAC. NEVANAC does not have antimicrobial properties. In case of ocular infection, NEVANAC should be used with care with anti- infectives. Caution is required in patients with a history of hypertension and/or heart failure as fluid retention and oedema have been reported in association with NEVANAC therapy. In view of NEVANAC’s inherent potential to cause fluid retention, heart failure may be precipitated in some compromised patients. The elderly have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal (GI) bleeding and perforation (PUBs) which may be fatal. The risk of GI bleeding or perforation is higher with increasing doses of NEVANAC, in patients with a history of ulcers and the elderly. When GI bleeding or ulceration occurs in patients receiving NEVANAC, treatment with NEVANAC should be stopped. NEVANAC should be given with caution to patients with a history of GI disease as the condition may be exacerbated. Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. NEVANAC should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. There is a potential for cross-sensitivity of NEVANAC® to aspirin, phenylacetic acid derivatives, and other NSAIDs. Effects on ability to drive and use machines: If blurred vision occurs at instillation, the patient must wait until the vision clears before driving or using machinery. Pregnancy: NEVANAC should not be used during pregnancy. NEVANAC is contraindicated in the third trimester of pregnancy. Lactation: It is unknown whether NEVANAC is excreted in human milk. NEVANAC should not be used in women breastfeeding their infants. INTERACTIONS: Neither nepafenac nor amfenac inhibit any of the major human cytochrome P450 (CYP1A2, 2C9, 2C19, 2D6, 2E1 and 3A4) metabolic activities in vitro at concentrations up to 300 ng/ml. Therefore, interactions involving CYP-mediated metabolism of concomitantly administered medicines are unlikely. In vitro studies have demonstrated a low potential for interactions. Interactions mediated by protein binding are also unlikely. Use of NEVANAC with another NSAID concomitantly could result in an increase in side effects. SIDE-EFFECTS: NEVANAC: Uncommon: keratitis, allergic conjunctivitis, punctate keratitis, eye pain, foreign body sensation in eyes, eyelid margin crusting. Rare: hypersensitivity, headache, dizziness, blurred vision, eye pruritus, dry eye, eye discharge, photophobia, eye irritation, increased lacrimation, blepharitis, nausea, allergic dermatitis. Frequency unknown: corneal perforation, ulcerative keratitis, corneal thinning, corneal opacity, corneal abrasion, corneal scar, impaired healing (cornea), visual acuity reduced, eye swelling, ocular hyperaemia, vomiting, blood pressure increased. Other NSAIDs: oedema, hypertension and cardiac failure, peptic ulcers, perforation or gastrointestinal bleeding, nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, malaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease, gastritis. Bullous reactions, including Stevens- Johnson syndrome and toxic epidermal necrolysis. Presentation/Pack size: 8 ml round, colourless low density polyethylene bottle and dispensing plug with white polypropylene screw cap containing 5 ml suspension. Note: Before prescribing consult full prescribing information. This BSS is for use on promotional material linked to MCC approved package insert dated 20.03.2018 References: 1. NEVANAC® Eye Drops, Suspension, Approved Package Insert; Novartis South Africa (Pty) Ltd, 20 March 2018 2. Gamache DA, Graff G, Brady MT, Spellman JM, Yanni JM. Nepafenac, a unique nonsteroidal prodrug with potential utility in the treatment of trauma-induced ocular inflammation: I. assessment of anti-inflammatory efficacy. Inflammation. 2000; 24(4):357-370. 3. Ke T-L, Graff G, Spellman JM, Yanni JM. Nepafenac, a unique nonsteroidal prodrug with potential utility in the treatment of trauma-induced ocular inflammation: II. in vitro bioactivation and permeation of external ocular barriers. Inflammation. 2000; 24(4):371-384. 4. Lane SS, Modi SS, Lehmann RP, Holland EJ. Nepafenac ophthalmic suspension 0.1% for the prevention and treatment of ocular inflammation associated with cataract surgery. J Cataract Refract Surg. 2007; 33:53-58. 5. Nardi M, Lobo C, Bereczki A, Cano J, Zagato E, Potts S, et al; International C-04-65 Study Group. Analgesic and anti-inflammatory effectiveness of nepafenac 0.1% for cataract surgery. Clin Ophthalmol. 2007; 1(4):527-533.

Novartis South Africa (Pty) Ltd. Magwa Crescent West, Waterfall City, Jukskei View 2090. Tel. +27 11 347 6600. Co. Reg. No. 1946/020671/07. ZA2102041025. Exp.: 01/2023

40996 02/21

(nepafenac ophthalmic suspension) 1 mg/ml

Or iginal s tud y Common ophthalmic disease in rural SA

Summer 2021 • Vol 16 | No 1 SA Ophthalmology Journal

Common ophthalmic disease presentations at a referral hospital in rural South Africa N Ally MBBCh, MMed, FCOphth(SA) ORCID: 0000-0002-6676-9352 S Ismail MBBCh, DA(SA) HD Alli MBBCh, MMed, FCOphth(SA) ORCID: 0000-0002-8687-0925 Department of Neurosciences, Division of Ophthalmology, University of the Witwatersrand, Johannesburg, South Africa Corresponding author: Dr Naseer Ally, tel: +27823004876; email: naseerally@gmail.com

Abstract Background: The burden of eye disease in rural areas in South Africa has not been well documented. There are studies in South Africa that focus on particular ophthalmic diseases (e.g., cataract) or aspects of eye diseases (e.g., vision-threatening) but none thus far have provided a glimpse into a broader spectrum of disease. Objectives: First, to describe the three most common ophthalmic diseases at a rural hospital in Mpumalanga; second, to assess risk factors for the ophthalmic diseases and compare it to the literature. Methods: A retrospective, descriptive study of all patients attending the Rob Ferreira ophthalmology outpatient clinic between 1 January 2012 and 31 December 2012 was conducted. Results: There were 2 493 patients seen between January and December 2012 at the Rob Ferreira ophthalmology department. Patient records and data were available for 2 143 patients. Most patients seen were black African (89.3%), followed by white (9.1%), and other races (1.5%). Male and female patients accounted for 53.2% (n=1 140) and 46.5% (n=1 003) of patients, respectively. The mean age of patients was 45.69 years.

Introduction

Worldwide, there are significant shortages of healthcare resources in rural areas compared to urban areas. This is globally most pronounced in low-to-middle income countries such as those of SubSaharan Africa.1 Access to healthcare, including eye care, is also underutilised in rural areas due to lower literacy levels, female sex and large distances to a healthcare centre. 2 Less than 10% of research funding is directed towards over 90% of the world’s disease burden according to the Global Forum for Health Research. 3 Research into specific health issues by low-to-middle income countries is also key to their formulating their own health priorities. 3 Most of the ophthalmology literature

Cataracts, ocular trauma, and glaucoma were the three most common eye conditions seen at the hospital. Cataract was significantly associated with age, diabetes mellitus, hypertension and HIV. Glaucoma and ocular trauma were significantly associated with age, sex and black African race. Conclusion: This retrospective audit provides insight into the burden of disease at a tertiary hospital in one of the rural provinces in South Africa. Cataract is the most common diagnosis; glaucoma is underdiagnosed; and trauma places a high burden on ophthalmology services at the hospital. Keywords: ophthalmic disease, glaucoma, cataract, ocular trauma, South Africa Funding: No financial support was received by any of the three authors for performing this research. Conflict of interest: None of the authors have any proprietary interests or conflicts of interest related to this submission.

(>90%) that is published in leading journals is from high-income countries.4 The burden of eye disease in the rural areas of South Africa is not well documented despite many patients with eye diseases residing in rural areas. This consequently creates difficulties for the implementation of any healthcare improvement or intervention strategies.5 The importance of knowing the burden of eye diseases in a particular area is to influence public health policy as well as allocate finances, resources and staff appropriately.6 Rob Ferreira Hospital (RFH) is in Nelspruit, Mpumalanga, a rural South African province. It is one of three hospitals in Mpumalanga that provides ophthalmology services and is the final level of care for many ophthalmology

patients. It serves the patients from Mpumalanga and beyond, with patients seen from as far afield as neighbouring provinces and neighbouring Zimbabwe, Mozambique and eSwatini. The population in Mpumalanga in the 2011 census was 4 million, having increased from 3.3 million in 2001. The population of the province comprises 7.8% of the country’s total population, having increased from 7.5% in 2001.7 This study aims to describe the three most common ophthalmic diseases at the RFH. We also aimed to look for risk factors and compare these to the known literature. This study represents the first known publication on the burden of eye disease at a rural hospital in the province of Mpumalanga, South Africa.

Or iginal s tud y Common ophthalmic disease in rural SA

Methods

A retrospective, descriptive study of all patients attending the RFH ophthalmology department from 1 January 2012 to 31 December 2012 was conducted. Medical records were reviewed. Demographic details such as age, sex and comorbidities were recorded. The ophthalmic diagnoses (e.g., cataract, ocular trauma and glaucoma) were documented. Patients with missing data or illegible diagnoses were excluded. The study was approved by the University of the Witwatersrand Human Research Ethics committee and was conducted in accordance with the tenets of the Declaration of Helsinki. Racial classification was done in accordance with the South African census database.7

Statistical analysis

Statistical analyses were carried out using STATA 16.0 (STATACorp, Texas). Normally distributed continuous variables were expressed as mean (standard deviation) and skewed data as median (interquartile range). Categorical variables were expressed as proportions. A one-sample proportions test was used to check the proportion of males versus females. Univariate and multivariate logistic regression was performed using age, sex, race, diabetes mellitus (DM), hypertension (HPT) and human immunodeficiency virus (HIV) as predictors for cataract and glaucoma. These predictors were chosen based on known risk factors for the diseases. For ocular trauma only age, sex and race were used to generate the multivariate models. To assess the ability of the models to predict their outcome, we used receiver operating characteristic (ROC) curves to calculate the area under the curve (AUC).

Results

The total number of patients attending the hospital during the study period was 2 493. Of these, only 2 143 files were found with adequate data, representing a capture rate of 85.9%. The remaining 350 patient files were either not found, had illegible diagnoses or missing diagnoses. The demographic details, comorbidities and the three most common presenting ophthalmic diseases are described for these 2 143 patients. There were 1 140 males and 1 003 females (p=0.003). The mean (SD) age was 45.7 (23.5) years. Patient demographic data are represented in Table I. The three most common diagnoses that presented to the RFH ophthalmology department were cataract, ocular trauma (both blunt and penetrating) and

Vol 16 | No 1 • Summer 2021 SA Ophthalmology Journal

Table I: Demographic data including sex, comorbidities and race Mean age (SD)

Male n (%)

Female n (%)

p-value*

45.7 (23.5)

1 140 (53.2)

1 003 (46.8)

0.003

Diabetes mellitus (n=287)

60.0 (12.5)

125 (43.6)

162 (56.4)

0.03

Hypertension (n=415)

64.2 (13.0)

171 (40.2)

244 (57.4)

0.0001

HIV (n=187)

41.1 (14.7)

75 (40.1)

112 (59.9)

0.0043

Black African

44.0 (23.3)

1032 (54)

880 (46)

0.0005

White

60.6 (20.5)

93 (47.4)

103 (52.6)

0.48

Other race

54.7 (19.1)

13 (37.1)

22 (62.9)

0.13

Total patients Comorbidity

Race

*One sample proportions test comparing males to females Table II: Demographic characteristics of patients with cataracts, ocular trauma and glaucoma presenting to Rob Ferreira Hospital ophthalmology department Disease

Number

p-value [CI]

Cataract n (%)

831 (38.8%)

[36.7–40.1]

Age (years) mean (SD)

60.0 (20.4)

[44.7–46.7]

Male

409

p=0.969 [−0.21 to 0.20]

Female

422

Sex*

Trauma n (%)

318 (14.8%)

[13.4–16.4]

Age (years) mean (SD)

31.7 (17.4)

[29.8–33.6]

Male

241

p<0.001 [0.71–0.80]

Female

Sex*

Glaucoma n (%)

208 (9.7%)

[8.5–11.0]

Age (years) mean (SD)

62.2 (18.6)

[59.6–64.7]

Male

131

p=0.0002 [0.56–0.70]

Female

Sex*

*One sample proportions test Table III: Multivariate logistic regressions models using cataract, ocular trauma and glaucoma as outcomes Predictor variable

Odds ratio

p-value

Confidence interval (%)

Age

1.06

<0.001

1.04–1.06

1.61

0.002

1.2–2.17

HPT

1.64

<0.001

1.25–2.15

HIV

0.68

0.038

0.47–0.98

Age

0.97

p<0.001

0.97–0.98

Male

2.96

p<0.001

2.24–3.92

Black African

2.05

0.029

1.07–3.90

Age

1.04

p<0.001

1.04–1.05

Male sex

1.86

p<0.001

1.36–2.54

Black African

2.17

p=0.006

1.25–3.77

Hypertension

0.88

p=0.505

0.60–1.29

Diabetes mellitus

0.73

p=0.181

0.46–1.15

Cataracts*

Ocular trauma**

Glaucoma*

*Multivariate logistic regression using age, sex, race, DM, HPT and HIV as predictor variables **Multivariate logistic regression using age, sex, race as predictor variables

Summer 2021 • Vol 16 | No 1 SA Ophthalmology Journal

glaucoma. The demographic data of patients with cataract, ocular trauma and glaucoma are summarised in Table II. After performing a one-sample proportions test, we found a significant crude association between male sex and ocular trauma, as well as male sex and glaucoma. After adjusting for confounders, cataract was significantly associated with age, diabetes mellitus and hypertension (Table III). HIV was also significantly associated with cataract in the multivariate model; however, it was shown to be protective with an odds ratio of 0.67. After accounting for confounders, there was no significant association between sex and the presence of a cataract (p=0.969 [−0.76 to 0.12]). None of the racial groups were significantly

Figure 1. A–C. Receiver operating characteristic (ROC) curves for logistic regression models for cataract (A), ocular trauma (B) and glaucoma (C)

Or iginal s tud y Common ophthalmic disease in rural SA

associated with cataract. Mature cataracts accounted for 27.3% of cataracts. There was a highly significant association between age, sex and black African race with ocular trauma. Significant associations were found between glaucoma and age, male sex and black African race. There was no significant association between glaucoma and other comorbidities. The ROC curves (Figure 1) show that the models for all three diseases perform well at predicting their respective outcomes. The AUC for cataract is 0.80 while ocular trauma and glaucoma both have AUCs of 0.75, respectively.

Discussion

This study provides some insights into the most common ophthalmic diseases seen in a rural province in South Africa. There were more males than females who presented to the hospital during the study period. This is expected and is in keeping with the norms that have been described worldwide. 8,9 Our study also showed that there was a significantly higher proportion of males that were diagnosed with glaucoma and who presented with ocular trauma. This finding was, however, not significant for patients diagnosed with cataract. To our knowledge, this has rarely been shown to be the case as females usually account for the highest burden of cataract while males are more likely to have cataract surgery. 8 This finding should be treated with caution and requires further investigation as it could be accounted for by a number of factors. First, the study design was retrospective, and therefore the diagnosis of cataract may have been made incidentally, when patients presented for other more acute reasons. Cataract was therefore not the primary reason for presentation. Secondly, there could possibly be some local difference in the sex-defined social roles that occur in this region that may account for this difference. 8 This would need further investigation. Thirdly, there may be some socioeconomic factors such as literacy, marital status and socioeconomic status that may have resulted in this.9 The answer may be a combination of the above factors and requires specific research to determine the interplay of various factors. The most common ophthalmic problem seen at the hospital ophthalmology department was cataract. It is well known that cataract is the leading cause of blindness in the world.10 There was a high proportion of mature cataracts accounting for 27.3%. Thus, there is a large proportion of patients who are needlessly blind from a reversible cause. Age is a well-known risk factor and the multivariate analysis in our study confirmed this association.11 As stated above, our study showed no difference between males and females who presented with cataract. Diabetes and hypertension were found to be significantly associated with cataract. This has been found by other population-based studies in South Africa.12 An interesting finding in our study is that HIV seemed protective for the development of cataract even after adjusting for age and other risk factors. This is different from other studies which showed HIV infection to be a risk factor for cataract formation.13 It is thought that increased ageing among HIV patients may affect structures within the eye such as the crystalline lens.14 The finding in our study is contrary to the other published studies. This finding may be due the design of our study and this requires further investigation. Ocular trauma accounted for 14.8% of patients that attended the ophthalmology department, and it places a high burden on hospital services. The mean age of patients in our study presenting with ocular trauma is similar to that of other studies.15,16 We also found a male preponderance of patients with ocular trauma as

Or iginal s tud y Common ophthalmic disease in rural SA

is common in South Africa and other countries.15-18 Our multivariate analysis showed both age and sex as significant predictors of ocular trauma. The upper limit of the 95% CI also tended towards a higher odds ratio when compared to the lower limit, indicating the possibility of a stronger association. Black African race was found to be a significant risk factor for trauma. This may be due to a significant proportion of patients seen at the hospital comprising black Africans, or due to this racial group being of lower socioeconomic standing. Patients from lower socioeconomic groups have been shown to be more at risk of ocular trauma.19 Glaucoma was diagnosed in 208 (9.7%) patients. Glaucoma in black African patients presents earlier, is more severe and progresses more rapidly when compared to Europeans and North Americans. 20 The proportion of glaucoma patients in our study is much lower when compared to a hospital-based study in Saudi Arabia which showed a glaucoma prevalence of 21.5% (we could not find any other South African hospital-based data with which to compare these numbers). 21 A possible reason for this is our patients not presenting to the hospital. If we use a population-based prevalence of 4.5% for glaucoma, as calculated by Rotchford et al. in another area of South Africa, and combine this with census data, this should give us a total prevalence of patients with glaucoma, living in the immediate vicinity of the hospital, and in Mpumalanga, to be 26 495 and 151 450 respectively.7,22 This is in stark contrast to the 208 patients that presented to the RFH ophthalmology department. The full burden of the disease is therefore grossly underestimated with most patients being undiagnosed and subsequently diagnosed too late. Risk factors for glaucoma found in our study included age, male sex and black African race. 20,23 Primary open angle glaucoma, which is the most prevalent subtype in Africa, has also been shown to be more common in males than females. 23 Because glaucoma causes irreversible blindness, the diagnosis and management of glaucoma is an important public health issue in ophthalmology that requires serious attention. The limitations of this study include its hospital-based retrospective design. This means that the proportions represented above are not indicative of the prevalence of disease, but merely indicate the proportions of each disease presenting to the hospital. The results should therefore

be used as hypothesis generating and not hypothesis confirming, especially where it disagrees with established literature. There could be other unmeasured variables accounting for these results. Further prospective, population-based epidemiological studies are required.

Conclusion

Cataract is the leading ophthalmic diagnosis at a rural hospital in Mpumalanga, with a high proportion of patients presenting with mature cataracts. Ocular trauma places a significant burden on ophthalmology resources in this hospital. Glaucoma seems underdiagnosed for the proportion of patients that the hospital serves.

References

1. Strasser R, Kam SM, Regalado SM. Rural health care access and policy in developing countries. Annu Rev Public Health. 2016;37:395-12. 2. Olusanya BA, Ashaye AO, Owoaje ET, Baiyeroju AM, Ajayi BG. Determinants of utilization of eye care services in a rural adult population of a developing country. Middle East Afr J Ophthalmol. 2016 Mar;23(1):96-103. 3. Lee K, Mills A. Strengthening governance for global health research. BMJ. 2000 Sep 30;321(7264):775-76. 4. Mandal K, Benson S, Fraser SG. The contribution to ophthalmic literature from different regions of the world. Int Ophthalmol. 2004 May;25(3):181-84. 5. Lewallen S, Courtright P. Blindness in Africa: present situation and future needs. Br J Ophthalmol. 2001 Aug;85(8):897-903. 6. Flaxman SR, Bourne RRA, Resnikoff S, Ackland P, Braithwaite T, Cicinelli MV, et al. Global causes of blindness and distance vision impairment 1990-2020: a systematic review and meta-analysis. Lancet Glob Health. 2017;5(12):e1221-34. 7. 2011 Census. Statistics South Africa [Internet]. [cited 2016 Jul 12]. Available from: https://www.statssa.gov.za/?page_id=3839 8. Lewallen S, Courtright P. Gender and use of cataract surgical services in developing countries. Bull World Health Organ. 2002;80(4):300-303. 9. Courtright P, Lewallen S. Improving gender equity in eye care: advocating for the needs of women. Community Eye Health. 2007 Dec;20(64):68-69. 10. Resnikoff S, Pascolini D, Etya’ale D, Kocur I, Pararajasegaram R, Pokharel GP, et al. Global data on visual impairment in the year 2002. Bull World Health Organ. 2004 Nov;82(11):844-51.

Vol 16 | No 1 • Summer 2021 SA Ophthalmology Journal

11. Singh S, Pardhan S, Kulothungan V, Swaminathan G, Ravichandran JS, Ganesan S, et al. The prevalence and risk factors for cataract in rural and urban India. Indian J Ophthalmol. 2019 Apr;67(4):477-83. 12. Phaswana-Mafuya N, Peltzer K, Crampin A, Ahame E, Sokhela Z. Prevalence of selfreported diagnosed cataract and associated risk factors among elderly South Africans. Int J Environ Res Public Health. 2017 June;14(12). 13. Schaftenaar E, Khosa NS, Baarsma GS, Meenken C, McIntyre JA, Osterhaus ADME, et al. HIV-infected individuals on longterm antiretroviral therapy are at higher risk for ocular disease. Epidemiol Infect. 2017;145(12):2520-29. 14. Pathai S, Lawn SD, Weiss HA, Cook C, Bekker L-G, Gilbert CE. Increased ocular lens density in HIV-infected individuals with low nadir CD4 counts in South Africa: evidence of accelerated aging. J Acquir Immune Defic Syndr. 2013 Jul 1;63(3):307-14. 15. Cook CD. Perforating eye injuries in KwaZulu. South Afr Med J. 1991 Nov 2;80(9):441-44. 16. Scruggs D, Scruggs R, Stukenborg G, Netland PA, Calland JF. Ocular injuries in trauma patients: an analysis of 28,340 trauma admissions in the 2003-2007 National Trauma Data Bank National Sample Program. J Trauma Acute Care Surg. 2012 Nov;73(5):1308-12. 17. Sahraravand A, Haavisto A-K, Holopainen JM, Leivo T. Ocular traumas in working age adults in Finland–Helsinki Ocular Trauma Study. Acta Ophthalmol (Copenh). 2017 May;95(3):288-94. 18. du Toit N, Mustak H, Levetan C, Cook C. Open globe injuries in patients seen at Groote Schuur Hospital, Cape Town, South Africa. South Afr J Surg. 2013 Jul 31;51(3):97-101. 19. Chua D, Wong W, Lamoureux EL, Aung T, Saw S-M, Wong TY. The prevalence and risk factors of ocular trauma: the Singapore Indian eye study. Ophthalmic Epidemiol. 2011 Dec;18(6):281-87. 20. Cook C. Glaucoma in Africa: Size of the problem and possible solutions. J Glaucoma. 2009 Feb;18(2):124-28. 21. Eid TM, el-Hawary I, el-Menawy W. Prevalence of glaucoma types and legal blindness from glaucoma in the western region of Saudi Arabia: a hospital-based study. Int Ophthalmol. 2009 Dec;29(6):477-83. 22. Rotchford AP, Johnson GJ. Glaucoma in Zulus: a population-based cross-sectional survey in a rural district in South Africa. Arch Ophthalmol. 2002 Apr;120(4):471-78. 23. Jonas JB, Aung T, Bourne RR, Bron AM, Ritch R, Panda-Jonas S. Glaucoma. Lancet. 2017 Nov 11;390(10108):2183-93. 

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Or iginal s tud y Amplitude of accommodation

Vol 16 | No 1 • Summer 2021 SA Ophthalmology Journal

Comparison of amplitude of accommodation in type 1 and type 2 diabetes mellitus PS Makunyane MBChB, MMed(Wits), FC Ophth(SA); Professor and Head: Department of Ophthalmology, Steve Biko Academic Hospital, University of Pretoria, Pretoria, South Africa ORCID: https://orcid.org/0000-0002-9500-4025 SD Mathebula BOptom, MOptom, DPhil (UJ); Professor of Optometry in Visual Optics, Department of Optometry, University of Limpopo, Sovenga, South Africa ORCID: https://orcid.org/0000-0001-8196-2567 Corresponding author: Prof Solani David Mathebula, Department of Optometry, University of Limpopo, Private Bag x1106, Sovenga, 0727, South Africa; tel: 015-268 3222; email: solani.mathebula@ul.ac.za

Abstract Background: The prevalence of diabetes is increasing exponentially due to increasing obesity and reduced physical activity levels. Diabetes affects all structures of the eye; the optics and biometry of the eye are also affected in diabetic patients. Purpose: To compare the amplitude of accommodation (AA) in type 1 and 2 diabetic patients with the age-matched controls. Methods: One hundred individuals under the age of 40 years were examined. There were 22 subjects with type 1, 43 with type 2 diabetes and 35 age-matched controls. The AA was measured using the subjective push-up with the RAF rule (Royal Air Force rule). Descriptive statistics and regression analysis were used to analyse the data. Results: The mean AA was 3.92±0.93, 4.93±1.05 and 7.26±1.30 dioptres (D) in type 1, type 2 and healthy subjects, respectively. There was a significant difference between the mean AA of all

Introduction

Diabetes mellitus (DM) is a complex and heterogeneous group of metabolic diseases characterised by chronic hyperglycaemia resulting from defects in insulin secretion, insulin action or both.1-6 The chronic hyperglycaemia of diabetes is associated with long-term damage,

diabetic patients and the control subjects, p≤0.01. The t-test showed that there was significant difference between the AA measurements in type 1 and type 2, p≤0.01. Conclusion: The results of this study indicate that diabetes mellitus type 1 may have a major impact on the lens biometry and the AA measurements. The differences may indicate a fundamental difference in pathogenesis of reduced AA. Keywords: amplitude of accommodation, beta cells, diabetes, hyperglycaemia, insulin, pancreas Funding: South African Medical Research Council Conflict of interest: The authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this manuscript.

dysfunction and failure of different organs, especially the eyes, kidneys, nerves, heart and blood vessels. DM is classified based on aetiology into four main groups: type 1, type 2, gestational and other types. 2-10 The human crystalline lens continues to grow throughout life.11-17 New cell

fibres continually form and wrap around older cells without any of the cells being discarded. As a result, the lens becomes thicker and more convex with age. The normal increase in convexity of the lens with age could be expected to result in an increase in lens power and thus the tendency towards myopia. However,

Or iginal s tud y Amplitude of accommodation

in healthy eyes no such tendency is observed, but rather, the eyes change in the direction of hyperopia by an average of about 2 dioptres between the ages of 30 and 60 years. This is called the lens paradox.14 This lens paradox is due to a decrease in the refractive index of the lens with age, which compensates for the more convex shape of the lens with age. The amplitude of accommodation (AA) normally decreases with age, leading to presbyopia. From an optical perspective, the optics and biometry of the eye are affected or altered in people with diabetes. The diabetic eye acts like an older normal eye, and with increasing age the changes seem to be exacerbated in diabetes. In patients with diabetes, the optics and biometry of the crystalline lens is disturbed. DM causes an early loss of AA. Several studies have reported a greater reduced AA in people with diabetes when compared with healthy age-matched controls.18-21 The purpose of this study was to investigate the influence of DM type 1 and type 2 on the AA on pre-presbyopic diabetic and control subjects.

and confidentiality was maintained. Inclusion criteria for the diabetic group were individuals aged between 30 and 40 years (as detected by an endocrinologist) with no diabetic retinopathy on fundus examination. Inclusion criteria for the control group were healthy individuals in the same age range without signs or symptoms of diabetes. Exclusion criteria were subjects with cataract, uveitis, glaucoma, prior ocular surgical or previous history of ocular trauma, evidence of diabetic retinopathy, hypertension and other endocrine disorders. Subjects using systemic medications with known accommodative effects were excluded from both groups. Also subjects with manifest presbyopia were excluded. Detailed ocular examination including case history, best corrected visual acuity for distance, intraocular pressure (slit-lamp), biomicroscopy and fundus examinations were performed on both groups. The AA was measured using the RAF rule push-up method.

Procedure

Subjects initially looked at N5 line of the RAF rule at a distance of approximately 40 cm while wearing their habitual prescriptions in the trial frame. 22 Subjects were instructed to look at the target and keep it as clear as possible. Once this was achieved, the target was moved slowly toward the subjects in a smooth manner along the rule and the subject asked to report when it first became blurred. The endpoint was the first slight sustained blur, which was considered to be the point

Methods

This study was carried out in the Department of Ophthalmology, Steve Biko Academic Hospital in Pretoria. The study comprised subjects under 40 years of age. There were 65 subjects with diabetes and 35 age-matched control subjects. Informed consent was obtained in all subjects involved in the study in accordance with the Declaration of Helsinki,

Table I. Descriptive statistics (mean ± standard deviation) for the diabetes and control subjects Variable

Diabetes

Control

p-value

Type 1

Type 2

All

Number of subjects

Age (mean±SD) years

34.23±3.35

35.70±3.31

35.2±3.37

34.69±3.38

0.09

Sex: F/M

13/9

25/18

38/27

22/13

0.91

Corrected visual acuity

6/6

Amplitude of accommodation

3.92±0.93

4.93±1.05

4.95±1.16

7.26±1.30

Mean duration of diabetes in years

15.46±4.48

Capillary blood glucose

8.95±2.08

3.58±2.30 9.81±2.63

7.6±6.6 9.51±2.5

Medication: – Insulin

22/22 (100%) 25/43 (58%) 47/65 (72%)

– Oral agents

– Diet

18/43 (42%) 18/65 (28%) 0

0.00 0.22

when the target could not be cleared after 2 or 3 seconds of blink and attempts to focus. The average speed of the target was 4 cm/s. It took approximately 30 seconds to complete the measurement per subject.

Statistical analysis

Data collected was analysed using the statistical software, IBM Statistical Package for Social Sciences (SPSS), version 24 (SPSS Inc., Chicago, IL). The normality of data was determined using the ShapiroWilk test. Statistical significance was set at p-values < 0.05 for all tests and a 95% confidence interval was used as a measure of precision. An independent sample t-test was applied to determine the difference between two independent means. Correlation between age and AA was established using the Pearson correlation coefficient (r).

Results

The duration of diabetes overall ranged from 1 to 25 years, with a mean of 7.6±6.6 years. There were 38 females and 27 males in the diabetic group while the control group had 22 females and 13 males. Table I shows the demographics of both the diabetic and control groups for AA measurements. The mean AA in the diabetic group was 4.52±1.20 and 4.68±0.99 D for females and males, respectively. In the control group, the mean AA was 7.43±1.34 D for females while it was 6.92±1.18 D for males. Figures 1 to 4 show the box plots for the distribution of the AA measurements in diabetic and control subjects, and in the type of diabetes, respectively. In Figure 1, the diabetic group had a wide distribution of the AA when compared with the controls. However, both measurements Amplitude of accommodation in dioptres

Summer 2021 • Vol 16 | No 1 SA Ophthalmology Journal

9 8 7 6 5 4 3 2

Amplitude of accommodation in diabetes

Amplitude of accommodation in controls

Figure 1. Box plots of measurements of the amplitude of accommodation in diabetic and control subjects. The diabetic subjects had a wider distribution. The average mean difference was −2.23 D.

Or iginal s tud y Amplitude of accommodation

8 7

Amplitude of accommodation in controls

6 5 4 3 2

Female Sex

Male

Figure 2. Box plots showing the distributions of amplitude of accommodation in females and males in both diabetic and control subjects, respectively. The distributions of both females and males in the control group were skewed, one negative and the other positive.

8.00

7.00

6.00

5.00

4.00

3.00

2.00

30.00

7.00 6.00

32.00

34.00 36.00 Age of diabetic subjects in years

38.00

40.00

Figure 5. Change in amplitude of accommodation with age in the diabetic subjects, y=8.13–0.1 (age). As the age increases, the amplitude of accommodation decreases, r=−0.3. There does appear to be some weak negative relationship.

5.00 4.00 3.00 2.00

Type 1

Type 2 Type of diabetes

Figure 3. Box plots of the distributions of the amplitude of accommodation in type 1 and type 2 diabetics. The distribution of the amplitude of accommodation in the type 2 diabetics was wider.

Figure 3 shows the distribution of the measurements of the AA between type 1 and type 2 diabetics. The mean AA in type 1 was 3.92±0.93 D while in type 2 diabetics was 4.93±1.05 D. The Levene’s test for equality of variances showed that there was a significant difference between the measurements of AA in type 1 and type 2 diabetic subjects. The mean difference was −1.00 D with a 95% confidence interval of

between −1.54 and −1.52 D, p<0.05. However, there was no statistically significant difference between the AA measurements in females and males. The means were 4.52±1.20 and 4.68±1.00 D for females and males, respectively (p=0.356). Regression analysis was performed. Figures 5 and 6 show the association between the AA and age in both the study and control groups. There is a

Sex

Amplitude of accommodation in diabetes

8.00

Female Male

7.00

9.00

6.00 5.00 4.00 3.00 2.00

Type 1 Type 2 Type of diabetes

Figure 4. Box plots according to the type of diabetes in female and males were normally distributed when compared to the Gaussian normal distribution curve. The mean difference between subject with diabetes and the controls was −2.30±1.83 D. On average, AA measurements in the control group were 2.23 D higher than the measurements in diabetics.

Amplitude of accommodation in control subjects in dioptres

Amplitude of accommodation in diabetes

Vol 16 | No 1 • Summer 2021 SA Ophthalmology Journal

Amplitude of accommodation in diabetes

Amplitude of accommodation in diabetic subjects in dioptres

Amplitude of accommodation in dioptres

8.00

7.00

6.00

5.00

30.00

32.00

34.00 36.00 Age of control subjects in years

38.00

40.00

Figure 6. Change in amplitude of accommodation with age in the control group, r=−0.7

Or iginal s tud y Amplitude of accommodation

Summer 2021 • Vol 16 | No 1 SA Ophthalmology Journal

weak negative linear relationship (r=−0.3) between AA and age in diabetic group, p=0.00. Some younger diabetic subjects had more reduced AA. There was a significant linear relationship (r=−0.7) between AA and age in the control group, p=0.00. The duration slopes indicate the effect of diabetic duration on the AA.

Discussion

DM is a group of heterogeneous metabolic disorders characterised by chronic hyperglycaemia.1 It has many complications, with premature morbidity and mortality. DM affects the optics and biometry of the eye, and blurriness of vision is often reported as one of the first signs of its presence.16 The results of this study showed that subjects with type 1 DM had AAs that were lower than those with type 2 and control subjects. Many studies have reported reduced AA with diabetes when compared with healthy controls.18-21,23-25 The results of this study showed that type 1 DM is having a profound effect on the AA measurements when compared with type 2 DM subjects. The substantial differences between type 1 and type 2 DM may indicate a fundamental difference in effects on lens optics and biometry related to the aetiology of diabetes. In diabetic patients, the crystalline lens has been reported to become significantly thicker and more convex with age when compared with those of non-diabetic controls. The origin of the profound increase in the dimension of the lens in DM has not yet been explained. Sparrow et al.15,16 found that the increase in lens biometry in patients with DM type 1 is a result of an increase in both the cortex and the nucleus of the lens, which is less apparent in patients with type 2 DM. The causes of thicker and more convex lenses in diabetics could be the increase in cell membrane permeability, deficiency in ionic membrane pump, abnormality in the lens growth, greater cortical thickness or osmotic swelling. 26-32 The cause of the reduced AA measurements noted in this study in type 1 DM remains unclear. It is possible that there is an enhanced production rate of individual lens fibres stimulated by the use of insulin. However, it is also possible that the increased thickening of the diabetic lens is the result of cellular or extracellular over-hydration, which could have been caused by an increase in the osmotic pressure within the lens due to the accumulation of glucose and

its metabolic products within the lens. 20 Insulin has been reported to produce a hypertrophic cellular response in an epithelial tissue, leading to extracellular over-hydration or increased growth of individual lens fibres of the crystalline lens in type 1 diabetics.16,26-32 Type 1 diabetes is an autoimmune disorder characterised by the destruction of the insulin-producing pancreatic beta cells without apparent pathological alterations of other Langerhans cells. 22,26-29 However, the cause is still unknown since it shows heterogeneity in terms of age of onset, severity of autoimmune response and efficacy of therapy. Our study subjects with type 1 diabetes, who are likely to have absolute insulin deficiency, had an average disease duration of 15.5 years. The duration of diabetes is of paramount importance in the reduction of the AA. Individuals at risk of type 2 DM (obese and first-degree relatives) display an initial state of insulin resistance compensated by beta-cell hypersecretion of insulin (hyperinsulinaemia). Over time the pancreatic functional reserve is no longer associated with compensatory hyperinsulinaemia, resulting in an increased blood glucose concentration, called hyperglycaemic hyperinsulinaemia. 26-29 By the time DM is diagnosed, beta cells are no longer able to secrete enough insulin (hyperglycaemic hypoinsulinaemia). However, patients with type 2 DM are not ketosis prone and do not require insulin therapy to prevent ketoacidosis, which is a hallmark feature of type 1 diabetes. 33 The subjects with type 2 diabetes had a disease duration of 3.6 years and thus would be expected to still have residual beta-cell activity due to replacement of insulin. In contrast to type 1 DM, the duration of diabetes had no significant effect on the AA measurements in the type 2 DM. This may be due to the fact that the onset of disease is insidious and hence, the duration of DM in type 2 is often unknown. The duration of type 2 DM is generally underestimated. All patients with type 1 and 58% of type 2 diabetic patients used insulin. The AA measurements did not change with the duration of the diabetes. The effect of the duration of DM on the AA measurements was the same between females and males in both type 1 and type 2 DM.

Conclusion

The human crystalline lens continues to grow throughout life, and it may become

more convex and thicker with age because of the addition of new fibres. In diabetic patients the lens becomes even thicker and more convex with age compared with the lens in healthy subjects. The increase in the dimensions of the diabetic lens may be due to an abnormality in the growth or a swelling of the lens. The results of this study indicate that the group with type 1 diabetes may have a greater impact on the lens biometry, neural factors and changes in curvature of lenticular surfaces and the measurements of AA. This substantial difference may indicate a fundamental difference in pathogenesis. The crystalline lens of the human eye is affected by DM in a number of different and important ways. Hence, eyes of individuals with DM appear to function as more aged than those of age-matched controls without diabetes. Further research is needed to clarify how the AA of thediabetic patient differs from that of a healthy non-diabetic individual of the same age.

Acknowledgement

We thank our colleagues who reviewed and gave valuable comments on the manuscript. We also like to thank the South African Medical Research Council (SAMRC) for support.

References

1. Pretsky L. Principles of Diabetes Mellitus. London: Kluwer Academic Publishers, 2002. 2. Wild S, Reglic G, Green A, Sicree R, King H. Global prevalence of diabetes. Estimates for the year 2000 and projections for 2030. Diabetes Care 2004;27(5):1047-53. 3. Shaw J, Sicree R, Zimmet P. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract 2010;87(1):4-14. 4. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2012;35(Suppl 1):S64-S71. 5. American Diabetes Association. Classification and diagnosis of diabetes. Diabetes Care 2017;40(Suppl 1):S11-S24. 6. Baynest HW. Classification, pathophysiology, diagnosis and management of diabetes mellitus. J Diabetes Metab 2015;6(5):a541. 7. Acharjee S, Ghosh B, Al-Dhubiab BE, Nair AB. Understanding type 1 diabetes: etiology and models. Can J Diabetes 2013;37(4):269-76. 8. Pickett KA. Microvascular complications of diabetes: what’s relevant for practice? J Nurse Practitioners 2016;12(10):683-89. 9. Ashwal E, Hod M. Gestational diabetes mellitus: where are we now? Clin Chim Acta 2015;451(Pt A):14-20. 10. Mack LR, Tomich PG. Gestational diabetes:

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pathogenesis in type 1 diabetes. Immunity

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2010;32:468-78.

11. Bron A, Sparrow J, Brown N, Harding J, Blakytny R. The lens in diabetes. Eye 1993;7(2):260-75. 12. Dubbelman M, Van der Heijde GL. The shape of the aging human lens; curvature,

Type 1 diabetes. Lancet 2014;383:69-82. 27. Ziegler AG, Nepom GT. Prediction and

19. Moss SE, Klein R, Klein BE. Accommodative

28. Fajans SS, Bell GI. MODY: history, genetic,

ability in younger-onset diabetes. Arch

pathophysiology, and clinical decision

Ophthalmol 1987;105(4):508-12. 20. Mathebula SD, Makunyane PS. Amplitude

making. Diabetes Care 2011;34:1878-84. 29. Zaccardi F, Webb DR, Yates T, Davies MJ.

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Pathophysiology of type 1 and type 2

paradox. Vis Res 2001;41(14):1867-77.

presbyopic diabetic patients. JEMDSA

diabetes mellitus: a 90-year perspective.

13. Brown N. The change in lens curvature with age. Exp Eye Res 1974;19:175-183.

2017;22(1):12-16.

Postgrad Med J 2016;92(1):63-69.

21. Braun CI, Benson WE, Remaley NA, Chew EY,

14. Moffar BA, Atchison DA, Pope JM. Explanation

30. Wiemer NGM, Dubbelman M, Kostense

Ferris FL III. Accommodative amplitudes in

PJ, Ringens PJ, Polak BCP. The influence

of the lens paradox. Optom Vis Sci

the early treatment diabetic retinopathy

of diabetes mellitus type 1 and 2 on the

2002;79(2):148-50.

study. Retina 1995;15(4):275-81.

thickness, shape, and equivalent refractive

15. Sparrow JM, Bron AJ, Brown NAP, Neil

22. Sharma IP. RAF near point rule for near point

HAW. Biometry of the crystalline lens in

of convergence – a short review. Ann Eye Sci

early-onset diabetes. Br J Ophthalmol

2017;2(16).a37

1990;74(11):654-60.

Ophthalmology. 2008;115(10):1679-86. 31. Wiemer NGM, Dubbelman M, Hermans

23. Pawelski WJ, Glien H. Studies on

16. Sparrow JM, Bron AJ, Brown NAP, Neil HAW.

index of the human crystalline lens.

EA, Ringens PJ, Polak BCP. Changes in the

accommodation range in diabetics.

internal structure of the human crystalline

Biometry of the crystalline lens in late onset

Ophthalmologica 1971;163(4):216-26.

lens with diabetes mellitus type 1 and type

diabetes: the importance of diabetic type. Br

24. Etezad Razavi M, Sharifi M, Abrishami M,

J Ophthalmol 1992;76:428-33.

Zaker-Abbasi M. Accommodative ability in

17. Atchison DA, Markwell EL, Kasthurirangan S, Pope JM, Smith G, Swann PG. Agerelated changes in optical and biometric characteristics of emmetropic eyes. J Vis 2008;8(4):1-20.

pre-presbyopic diabetic patients. Saf Qual

Pritchard N, Mathur A, Mallen EAH, Atchison

Improv 2015;3(2):203-205.

DA. Biometry of eyes in type 1 diabetes.

25. Mantyjarvi M, Nousiainen I. Refraction and accommodation in diabetic school children. Acta Ophthalmol 1988;66(3):267-71.

18. Adnan, Efron N, Mathur A, Edwards K,

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Or iginal s tud y Potential viral pathogenesis of pterygium

Summer 2021 • Vol 16 | No 1 SA Ophthalmology Journal

Adenovirus and human papillomavirus in the pathogenesis of pterygium EB van der Merwe MBChB(UP), PGDip Dentistry(Oral surgery), MMed(Ophth), FCOphth(SA); Stellenbosch University, Department of Surgical Sciences, Division of Ophthalmology, Cape Town, South Africa ORCID: https://orcid.org/ 0000-0003-0238-7782 J Maritz MBChB, MSc(Med), MMed(Virol Path), FC Path(SA)Viro; Stellenbosch University, Division of Medical Virology, Cape Town, South Africa; PathCare Reference Laboratory, Cape Town, South Africa ORCID: https://orcid.org/0000-0001-5311-9134 KE Delaney BSc(Molecular Biology and Biotechnology), BSc(Hons)(Medical Virology); Stellenbosch University, Division of Medical Virology, Cape Town, South Africa ORCID: https://orcid.org/0000-0001-5845-5778 D Smit MBChB, MMed(Ophth), FCOphth(SA), PhD; Stellenbosch University, Department of Surgical Sciences, Division of Ophthalmology, Cape Town, South Africa ORCID: https://orcid.org/0000-0003-3206-8184 Corresponding author: Dr Ernst Baard van der Merwe, Division of Ophthalmology, Room 5053, Faculty of Medicine and Health Sciences, Stellenbosch University, Francie van Zijl Drive, Parow Valley, 7500, South Africa; tel: +264 81 5503993; email: v_ernst_baard@hotmail.com

Abstract Background: Current understanding of the pathogenesis of pterygium is incomplete. One theory proposes a multi-step model for the pathogenesis of pterygium and suggests that ocular surface viral infections might play an important role. Human papillomavirus (HPV) has been identified as a co-factor in susceptible hosts, and adenovirus (AdV) has also been implicated as a causative organism. This paper describes the frequency with which these two viruses were isolated from excised pterygia in a Namibian population. Methods: In this cross-sectional descriptive study, the primary objective was to determine the prevalence of HPV and AdV isolated from pterygium samples of patients in a Namibian population. Viral nucleic acid extraction and polymerase chain reaction (PCR) were performed on 66 tissue samples from 66 patients. Results: Of the 66 samples, 21 (31.8%) had a positive PCR result of which 15 (22.7%) were HPV positive and six (9.1%) were AdV positive. The mean age of HPV-positive patients was more than eight years lower than that of HPV-negative patients, and the mean age for the AdV-patients was more than seven years higher than that of AdV-negative patients. Of the nine human immunodeficiency virus (HIV)-positive patients included, only

one (11.1%) tested positive for HPV and none tested positive for AdV. Conclusion: The HPV prevalence of this study is in accordance with other similar studies from elsewhere although AdV prevalence is significantly lower than the one other similar study. The significance of the average age differences and the link with HIV requires further investigation. Keywords: adenovirus, human papillomavirus, Namibia, pterygium, virus, viral pathogenesis Funding: Stellenbosch University, Division of Ophthalmology, Departmental research fund – EB van der Merwe Poliomyelitis Research Foundation Bsc (Hons) bursary – J Maritz and KE Delaney National Research Foundation Honours Innovation bursary – J Maritz and KE Delaney Postgraduate merit bursary from Stellenbosch University – EB van der Merwe and KE Delaney Conflict of interest: None of the authors have any conflicts of interest to declare with respect to this study.

Or iginal s tud y Potential viral pathogenesis of pterygium

Introduction

A pterygium is a wing-shaped ocular surface ingrowth of bulbar conjunctiva over the limbus onto the cornea.1 It may compromise vision either by direct obstruction of the visual axis or by causing significant astigmatism.1-3 The limbal tissue was identified in 1983 by Cameron as the site of pathogenesis.4 Most textbooks classify a pterygium as a degenerative lesion.1,2 Recently it has also been described as a proliferative lesion resembling an aberrant woundhealing process with typical histological features. 5,6 Mild inflammatory changes are frequently present 2 and of note is evidence of a reactive fibrovascular stroma with epithelial–mesenchymal transition and neovascularisation, published by Chui in 2011.6 Most authors agree that the pathogenesis of pterygium remains an ophthalmic enigma.6,7 Recent research has focused on anti-apoptotic mechanisms, immunological mechanisms, cytokines, growth factors, extracellular matrix modulators, genetic factors and viral infections as causative factors. 8 The prevalence of pterygium differs significantly according to geographic location.9-11 Ultraviolet radiation exposure and other environmental factors including hot, dry and windy conditions and chronic dust exposure are considered to contribute significantly to the pathogenesis but there is little conclusive evidence to support this.12-15 Inheritance was suggested to play a role as early as 196016 but evidence only suggests a contributory role in some cases.17 All of the above lead to the suggestion of a multi-step model (also called a twohit model) concept for the pathogenesis of pterygium,7 with the suggestion that ocular surface viral infections might play an important role.7 The idea is supported by the discovery of abnormal expression of the p53 tumour suppressor gene in pterygium samples.18-20 Due to the well-known and established link between human papillomavirus (HPV) and cervical cancer due to p53 and HPV protein E6 and E7 association, 21,22 this was the first virus to be implicated and thus researched as a possible co-factor for the pathogenesis of pterygium. With this suggested oncogenic origin and the idea of pterygium as a premalignant lesion,6,23 numerous studies looked at the prevalence of HPV in pterygia and ocular surface squamous neoplasia (OSSN). In a review published by Di Girolamo in

2012, a total of 18 and 16 studies looked at the prevalence of HPV in pterygia and OSSN respectively, and the results were 18.6% for pterygium and 33.8% for OSSN. Even though the range in prevalence of 0–100% for both conditions suggested possible study design differences and virus identification technique problems, it was still concluded that HPV may be a co-factor in susceptible hosts. 24 The other issue arising in most studies is the lack of evidence regarding the mechanism of HPV infection of the ocular surface.7,24 One virus with well-established ocular involvement is adenovirus (AdV). Viral infection is the cause in up to 80% of cases of acute conjunctivitis, and AdV is the identified virus in 65–90% of cases of viral conjunctivitis.1,25 Clinical presentation varies from mild subclinical disease to severe inflammation with significant morbidity and affects immunocompetent as well as immunocompromised patients.1,25-27 Of interest are studies examining the effect of adenovirus E1A protein on p53. 28-30 Another study examined the persistence of adenovirus in the tear film and found evidence of adenovirus DNA in the tear films of patients up to a decade after first presentation with conjunctivitis, thus suggesting the ability of the virus to persist in the conjunctiva or lacrimal apparatus. 31,32 However, in the literature there is only one study that looked at the role of AdV in ophthalmic pterygium ormation. 33 Namibia is a country in south-western Africa. The population according to the last census in 2011 is just over 2.1 million. 34 The Namibian climate is largely arid to semi-arid with high levels of UV exposure which sets the scene for a high incidence and prevalence of both pterygium and OSSN although these have not yet been formally reported.

Methods

The primary objective of the study was to determine the prevalence of HPV and AdV isolated from pterygium samples obtained from patients from all regions in Namibia. The secondary objective was to look at other contributing factors that could be associated with the formation of pterygia. The study was designed as a cross-sectional descriptive study. Ethics approval was obtained by the Health Research Ethics Committee of Stellenbosch University, Cape Town, South Africa (S16/12/242), and permission was obtained from the Department of

Vol 16 | No 1 • Summer 2021 SA Ophthalmology Journal

Ophthalmology at Windhoek Central Hospital to conduct the research there. The research followed the tenets of the Declaration of Helsinki and informed consent was obtained from all participants after the nature and possible consequences of the study were explained to them, making use of an interpreter if required.

Collection

All participants were patients booked for surgical removal of pterygia at Windhoek Central Hospital’s Eye Clinic. This clinic usually does an average of 20 pterygium excisions per week and includes patients from all regions in Namibia. Patients are seen by ophthalmic assistants at eye clinics all over the country and booked for surgery at Windhoek Central Hospital’s Eye Clinic. Patients included in this study were patients presenting for surgery as booked on these routine lists. Only patients older than 18 years of age with a clinical diagnosis of pterygium made by the first authoron the day of surgery were included. We appreciate that there is poor correlation between clinical examination and histological results. The decision to consider a lesion as benign pterygium is based on the absence of features that would be considered atypical or suspicious. Suspicious features include short mean duration since first noticing the lesion, fast and aggressive growth, lesion not situated at the interpalpebral limbus, presence of an obvious feeder vessel, presence of inflammation, presence of leukoplakia or pigmented lesions, nodular or papilliform surface or irregular border. 35 All patients were examined by the first author pre-operatively and the presence of any atypical or suspicious features as well as refusal to participate in the study resulted in exclusion from the study. The first author completed a case report form (Figure 1) for all participants and completed the questions on this form himself. Questions included for the secondary objective were the age of the patients, the sex of the patients, presence of unilateral or bilateral pterygium (for patients with bilateral pterygia only one eye was operated), history of previous eye infections, other eye problems or treatment, smoking status, main source of cooking (open fire, gas or electricity) and working conditions (mainly indoors or mainly outside). Informed consent for the surgery as well as informed consent for inclusion

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Summer 2021 • Vol 16 | No 1 SA Ophthalmology Journal

in the study was obtained from every patient. All pterygium excisions were performed by the same first author and 66 specimens were collected from 66 eyes of 66 patients. Histological examination of clinically unsuspicious samples was not performed due to financial constraints. The tissue for viral testing was labelled and stored in a refrigerator in a 2 ml Eppendorf tube filled with normal saline. The samples were then couriered en bloc

to the Division of Medical Virology at the Faculty of Medicine and Health Sciences of Stellenbosch University in Cape Town, South Africa, for further testing.

PCR testing

Nucleic acid extraction

Viral nucleic acid was extracted from pterygium samples using a commercially available QIAamp® DNA Mini Kit (Qiagen, Hilden, Germany). The manufacturer’s

Patient name____________________________________Age______ Male/Female_____ Study nr

_____________

Ethnicity Ovambo

Kavango

Coloured

Herero

Damara

White

Nama

Lozi

San

Tswana

Other

Region Zambezi Erongo Kunene

Hardap

Ohangwena Omaheke

II Karas

Kavango Kavango east west

Khomas

Omusati

Oshana

Otjizondjupa

Oshikoto

Pterygium Laterality

Unilateral

Bilateral

Side

Right

Left

Orientation

Nasal

Temporal

Primary

Recurrent

Primary or recurrent

History of previous pink eyes?________________________________________________________________________ Other previous eye diagnosis?________________________________________________________________________ Previous eye surgery?___________________________________________________________________________________ Other current eye problems?__________________________________________________________________________

HIV status Positive If positive: CD4 count

Negative

Unknown

___________________________________________________________________________________

Smoking Yes

Source of cooking Fire

Gas

Electricity

Working conditions Mainly outdoors

Mainly indoors

PCR results HPV Positive

Negative

Positive

Negative

Adenovirus Figure 1. Case report form

protocol for DNA purification from tissues was followed and complete tissue lysis was achieved in three hours. The extracted nucleic acid was quantified and assessed using a NanoDrop® ND-1000 Spectrophotometer (Thermo Scientific, Waltham, Massachusetts), and the eluate was stored at −20 °C.

Polymerase chain reaction (PCR)

All extracted samples were subjected to three PCRs using a commercial GeneAmp® PCR System 9700 (Applied Biosystems, Foster City, California). All PCR reactions included appropriate positive and negative controls. A human beta-globin gene PCR served as an internal control for each sample. Amplification of each sample was achieved using 10 µl of DNA eluate together with GoTaq® G2 Flexi DNA Polymerase kit (Promega, Madison, Wisconsin) at the recommended concentration, 1 µl of PCR nucleotide mix (10 mM of each dNTP), 0.5 µl of 5 u/µl GoTaq® G2 Flexi DNA Polymerase and 5 µM of primers GH20 and PC04 in a total volume of 50 µl. 36 Forty cycles of amplification were performed that consisted of an initial denaturation step at 95 °C for 10 minutes followed by cycling through 95 °C for 30 seconds, 55 °C for 30 seconds (annealing step) and 72 °C for 30 seconds (elongation step). HPV PCR was performed using the widely accepted consensus primers, MY09 and MY11. 37 These primers targeted a 450 bp fragment of the HPV genome. PCR was performed using the same concentrations, volumes and PCR conditions as described above but with 50 µM of each primer, in a total volume of 50 µl. Human adenovirus PCR targeted a conserved hexon gene. Primer set AVF and AVR 38 was utilised and successful amplification yielded a 300 bp product. A 50 µl PCR was performed containing 10 µl of DNA template, each primer at a concentration of 10 µM, 2.5 µl of 25 mM MgCl2 was used and the remaining reagents from the GoTaq® G2 Flexi DNA Polymerase kit were used at the supplied concentrations and recommended volumes (Promega, Madison, Wisconsin). The AdV PCR programme consisted of an initial denaturation step at 95 °C for four minutes, followed by 40 cycles, each consisting of cycling through 95 °C for 30 seconds, 59 °C for 30 seconds and 72 °C for 30 seconds. PCR products from all three reactions were stored at 4 °C prior to gel electrophoresis. Products were run in

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Vol 16 | No 1 • Summer 2021 SA Ophthalmology Journal

Table I: Demographic data – HPV Characteristics

Total

Age in years – mean (SD)

46.97 (13.893) 40.73 (10.299) 48.80 (14.357)

HPV-positive HPV-negative

p-value 0.047

Male

27 (40.9)

8 (29.6)

19 (67.8)

0.207

Female

39 (59.1)

7 (17.9)

32 (82.1)

Mixed

8 (12.1)

2 (25)

6 (75)

Black African

58 (87.9)

13 (22.4)

45 (77.6)

Unilateral

20 (30.3)

5 (25)

15 (75)

Bilateral

46 (69.7)

10 (21.7)

36 (78.3)

Indoors

35 (53.0)

8 (22.8)

27 (77.1)

Outdoors

31 (47.0)

7 (22.6)

24 (77.4)

Yes

12 (18.2)

3 (25)

9 (75)

54 (81.8)

12 (22.2)

42 (77.8)

Sex – n (%)

Ethnicity – n (%) 0.587

Laterality – n (%) 0.502

a 1.5% agarose gel submerged in 1X SB buffer and visualised by exposure to ultraviolet-light using an UVIprochemi II D-77LS-26M (Uvitec, Cambridge, United Kingdom). Five microlitres of each PCR product were mixed with 1 µl of Novel Juice (GeneDirex, Taiwan, China) and loaded into an agarose gel well, together with 5 µl of Promega’s 1 kb DNA Ladder (Promega, Madison, California) loaded into the first well of each gel to serve as a reference for determining amplicon size. PCR products were then stored at −20 °C.

Data and analysis

Working conditions – n (%) 0.606

Smoking – n (%) 0.550

Table II: Demographic data – AdV Characteristics

Total

Age in years – mean (SD)

46.97 (13.893) 53.67 (15.603) 46.30 (13.675)

AdV-positive AdV-negative p-value 0.218

Male

27 (40.9)

2 (7.4)

25 (92.6)

0.525

Female

39 (59.1)

4 (10.3)

35 (89.7)

Mixed

8 (12.1)

1 (12.5)

7 (87.5)

Black African

58 (87.9)

5 (8.6)

53 (91.4)

Unilateral

20 (30.3)

2 (10)

18 (90)

Bilateral

46 (69.7)

4 (8.7)

42 (91.3)

Indoors

35 (53.0)

4 (11.4)

31 (88.6)

Outdoors

31 (47.0)

2 (6.5)

29 (93.5)

Yes

12 (18.2)

2 (16.7)

10 (83.3)

54 (81.8)

4 (7.4)

50 (92.6)

Sex – n (%)

Ethnicity – n (%) 0.555

Laterality – n (%) 0.595

Working conditions – n (%) 0.397

Smoking – n (%) 0.298

Table III: HIV association in HPV and AdV HIV association in HPV Total

HPV-positive

HPV-negative

p-value

Positive

9 (13.6)

1 (11.1)

8 (88.9)

0.286

Negative

40 (60.6)

11 (27.5)

29 (72.5)

Unknown

17 (25.8)

3 (17.6)

14 (82.4)

Total

AdV-positive

AdV-negative

p-value

Positive

9 (13.6)

0 (0)

9 (100)

0.345

Negative

40 (60.6)

5 (12.5)

35 (87.5)

Unknown

17 (25.8)

1 (5.9)

16 (94.1)

HIV – n (%)

HIV association in AdV HIV – n (%)

All the results of the PCR tests and questionnaires were entered into an Excel spreadsheet and data was analysed and interpreted with SPSS software (version 25) with guidance and assistance from the Biostatistics Unit at Stellenbosch University’s Faculty of Medicine and Health Sciences. Student t-tests were used for average age calculations while chi-square tests as well as Fisher’s exact test were done on all other parameters. For the results, the Fisher’s exact test results were used.

Results

Of the 66 samples from the 66 patients, 21 (31.8%) had a positive PCR test for one of the two viruses. Fifteen (22.7%) tested positive for HPV, and six (9.1%) tested positive for adenovirus. No sample tested positive for both viruses. Tables I and II show demographic data and the relationship to HPV and AdV status respectively. The mean age of the study population was 46.97±13.89 years. For the HPV-positive patients, the mean age was more than eight years lower than the mean age of the HPV-negative patients (p=0.047). For the AdV-positive patients, the mean age was more than seven years higher than the AdV-negative group. More males (29.6%) than females (17.9%) tested positive for HPV, while more females (10.3%) than males (7.4%) tested positive for AdV. Of the 66 patients included, 30.3% had unilateral disease and 69.7% had bilateral disease (samples were only collected from one eye per patient). Outdoor working conditions (p-values 0.979 and 0.397), cooking mainly with open fires and smoking (p-values 0.835 and 0.298) did not show any relationship with either HPV or AdV status. The HIV status of the patients was also considered (Table III). Seventeen of the

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patients had unknown HIV status and refused voluntary testing after appropriate counselling. Of the 49 patients whose status was known, nine (18.4%) were HIV positive. Of the nine HIV-positive patients, only one (11.1%) tested positive for HPV, and there were 11 HPV-positive patients with a known HIV-negative status. No HIVpositive patient tested positive for AdV, and five patients who tested positive for AdV had a known HIV-negative status.

Discussion

The incidence of pterygium samples that tested HPV positive in our study population (22.7%) is in accordance with the 18.6% published by Di Girolamo in 2012. 24 The incidence of AdV in our study (9.1%) is significantly lower than the 100% in the one other published study. 33 This confirms the accepted correlation between HPV and pterygium but questions the proposed correlation of AdV and pterygium formation. An interesting finding is the lower average age of HPV-positive cases compared to HPV-negative cases as well as the higher average age of AdV-positive cases compared to AdV-negative cases. Although only the HPV results showed statistical significance, both these results might have clinical significance. If these viruses do contribute to pterygium formation, it might be that HPV infection happens at a very young age, and thus once the effect of environmental factors is also added, the clinical presentation of pterygia is earlier. AdV on the other hand is a virus which can occur later in life and thus contribute to the formation of pterygia in patients who would otherwise not have developed pterygia. The difference between the percentage of HPV-positive samples among men and woman might also have clinical significance. The review article from Di Girolamo in 2012 suggests that the global immunisation programme for HPV, which is mainly aimed at young women, might have an effect on pterygium incidence in years to come but this programme only started in 2007 so it is still too early to account for this lower percentage in women. 24 Pterygia have a high prevalence in all regions and among all ethnic groups in Namibia. The idea of including the ethnicity and region to the secondary objective was to determine whether there is a difference in the prevalence of one of the viruses between the different regions and different ethnic groups. In our study, no significant difference was found.

Regarding laterality, the idea was to see if HPV-positive and AdV-positive results were more prevalent in samples from patients with unilateral or bilateral disease. No statistical significance was found. A study where samples from both eyes are tested in patients with bilateral disease will help explore this hypothesis further. Only four patients had a recurrent pterygium and of these only one (25%) tested HPV positive. Therefore, we do not have sufficient data to comment on whether a correlation might exist between recurrence and presence of HPV or AdV. Whether working environment was mainly indoors versus outdoors did not reveal any significant relationship between HPV-positive and HPV-negative as well as AdV-positive or AdV-negative samples. Smoking status also did not reveal any statistical significance. We set out to determine whether there may be a correlation between HIV infection and testing positive for HPV and/or AdV. Of the patients in our study with a known HIV status, 18.1% were positive which is in accordance with the UNAIDS estimated prevalence of 13.8% for Namibia. 39 In our study however, there was no statistical significance found between HIV-positive patients and HPV-positive or AdV-positive samples. The link between HIV and OSSN is well established, with research indicating an added contribution from HPV.40,41 Namibia also has a high incidence of patients presenting with ocular surface neoplasia and further research is needed into the prevalence of HIV as well as HPV and AdV in tissue samples from these patients. An important limitation of our study is the fact that our finding of a significant result may have been due to multiple statistical tests being performed and thereby increasing the family-wise error rate. A larger sample size would also have been preferable if more time had been available.

Conclusions

The HPV prevalence of this study is in accordance with other similar studies. 24 The AdV prevalence is significantly lower than that reported in the only other similar study. 33 The significance and clinical implication of the difference in mean age between patients who tested positive for HPV and AdV will need to be further explored in similar studies from different geographic

locations or by reviewing data from previous studies. The link between HIV with HPV and AdV in pterygia warrants further investigation and more research is needed to determine whether there are other possible links between virus-associated pterygia and the formation of OSSN.

Acknowledgements

The Ministry of Health and Social Services of the Republic of Namibia. The staff of the Ophthalmology Department at Windhoek Central Hospital, especially Sr E Mbandeka, Dr H Ndume and Dr S Obholzer. Pathcare Laboratories in Windhoek, Namibia and at N1 City, Cape Town for the transport of the samples. Mr M McCaul, researcher at Biostatistics Unit, Centre for Evidence-based Health Care, Department of Global Health, Faculty of Medicine and Health Sciences, Stellenbosch University, for his help and guidance with the data analysis.

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papilloma virus with pterygia and ocular-surface squamous neoplasia. Eye. 2012;26(2):202-11. 25. Azari A a, Barney NP. Conjunctivitis:

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32. Horwitz MS. Adenoviruses. In: Fields B (ed). Fields Virology. Philadelphia: Lippincot Williams and Wilkins; 2001: 2301-25 33. Kelishadi M, Kelishadi M, Moradi A, Javid N, Bazouri M, Tabarraei A. Human adenoviruses role in ophthalmic pterygium formation. Jundishapur J Microbiol. 2015;8(4):4-7. 34. Website: Government of Namibia. Accessed 05/07/2020. Census Projected Population. Retrieved from https://www.gov.na/ population 35. Gichuhi S, Macharia E, Kabiru J, et al. Clinical presentation of ocular surface squamous neoplasia in Kenya. JAMA Ophthalmol. 2015;133(11):1305-13. 36. Gravitt PE, Peyton CL, Apple RJ, Wheeler CM. Genotyping of 27 human papillomavirus types by using L1 consensus PCR products

D. Outdoor work and the risk of pterygia:

a systematic review of diagnosis and

by a single-hybridization, reverse line

A case-control study. Int Ophthalmol.

treatment. JAMA. 2013;310(16):1721-29.

blot detection method. J Clin Microbiol.

1998;22(5):293-98. 15. Okoye OI, Umeh RE. Eye health of industrial

26. Erdin BN, Pas SD, Durak I, Schutten M, Sayiner AA. A 5-year study of adenoviruses

1998;36(10):3020-27. 37. Shen-Gunther J, Yu X. HPV molecular assays:

workers in Southeastern Nigeria. West Afr J

causing conjunctivitis in Izmir, Turkey. J Med

Defining analytical and clinical performance

Med. 2002;21(2):132-37.

Virol. 2015;87(3):472-77.

characteristics for cervical cytology

16. Hilgers J. Pterygium: its incidence, heredity and etiology. Am J Ophthalmol. 1960;Oct(50):635-44. 17. Anguria P, Kitinya J, Ntuli S, Carmichael

27. Lion T. Adenovirus infections in

38. Dettmeyer R, Baasner A, Schlamann M, et al.

patients. Clin Microbiol Rev. 2014;27(3):441-62.

Role of virus-induced myocardial affections

28. Steegenga WT, van Laar T, Riteco N, et al.

T. The role of heredity in pterygium

Adenovirus E1A proteins inhibit activation

development. Int J Ophthalmol.

of transcription by p53. Mol Cell Biol.

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18. Dushku N, Hatcher SL, Albert DM, Reid TW.

specimens. Gynecol Oncol. 2011;123(2):263-71.

immunocompetent and immunocompromised

29. Steegenga WT, Shvarts A, Riteco N, Bos

in sudden infant death syndrome: A prospective postmortem study. Pediatr Res. 2004;55(6):947-52. 39. UNAIDS Country Factsheets. http://www. unaids.org/en/regionscountries/countries/

P53 Expression and relation to human

JL, Jochemsen AG. Distinct regulation of

papillomavirus infection in pingueculae,

p53 and p73 activity by adenovirus E1A,

40. C arreira H, Coutinho F, Carrilho C, Lunet

pterygia, and limbal tumors. Arch

E1B, and E4orf6 proteins. Mol Cell Biol.

N. HIV and HPV infections and ocular

Ophthalmol. 1999;117(12):1593-99.

1999;19(5):3885-94.

surface squamous neoplasia: Systematic

19. Tan DT, Lim AS, Goh HS, Smith DR.

30. Chinnadurai G. Opposing oncogenic

Abnormal expression of the p53 tumor

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patients with pterygium. Am J Ophthalmol. 1997;123(3):404-405. 20. Tsai Y, Chang C, Chiang C, et al. HPV infection

2011;19(4):174-83.

namibia.

review and meta-analysis. Br J Cancer. 2013;109(7):1981-88. 41. Nagaiah G, Stotler C, Orem J, Mwanda WO, Remick SC. Ocular surface squamous

31. Kaye SB, Lloyd M, Williams H, et al. Evidence

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film a decade following conjunctivitis. J Med

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Virol. 2005;77(2):227-31.

2010;22(5):437-42. 

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Month 5

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Month 4

Month 5

Month 6

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Month 8

Month 9

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Adapted from LUCENTIS PI 1 and Hosogi M, et al 2 and Prunte C, et al 3

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References: 1. Lucentis Approved Package Insert. Novartis South Africa (Pty) Ltd 23 January 2020. 2. Hosogi M, Shiode Y, Morizane Y, Kimura S, Hosokawa M, Doi S, et al. Two-year Results of Intravitreal Ranibizumab Injections Using a Treat-and-extend Regimen for Macular Edema due to Branch Retinal Vein Occlusion. Acta Med. Okayama 2019; 73(6): 517–522. 3. Prünte C, Fajnkuchen F, Mamood S, et al. Ranibizumab 0.5 mg treat-and-extend regimen for diabetic macular oedema: the RETAIN study. Br J Ophthalmol. 2016; 100: 787–795. 4. Elman MJ, Aiello LP, Beck RW, et al. Randomized Trial Evaluating Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macular Edema. Ophthalmology. 2010; 117(6): 1064-1077. 5. Elman MJ, Bressler NM, Qin H, et al. Expanded 2-year Follow-up of Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macular Edema. Ophthalmology. 2011; 118(4): 609-614. 6. Elman MJ, Ayala A, Bressler NM, et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year randomized trial results. Ophthalmology 2015; 122(2): 375-381. 7. Epstein D, Amrén U. Long-time outcome in patients treated with ranibizumab for diabetic macular edema: a 4-year study. Retina. 2018; 38(1): 183-186. 8. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for Diabetic Macular Edema: Results from 2 Phase III Randomized Trials: RISE and RIDE. Ophthalmology. 2012; 119: 789–801. 9. Lang GE, Berta A, Eldem BM, et al. Two-Year Safety and Efficacy of Ranibizumab 0.5 mg in Diabetic Macular Edema Interim Analysis of the RESTORE Extension Study. Ophthalmology. 2013; 120: 2004-2012. 10. Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE Study: Ranibizumab Monotherapy or Combined with Laser versus Laser Monotherapy for Diabetic Macular Edema. Ophthalmology. 2011;118: 615–625. 11. Patrao NV, Antao S, Egan C, et al. Real-world outcomes of ranibizumab treatment for diabetic macular edema in a United Kingdom national health service setting. Am J Ophthalmol. 2016; 172: 51-57. 12. Massin P, Creuzot-Garcher C, Kodjikian L, et al. Real-World Outcomes with Ranibizumab 0.5 mg in Patients with Visual Impairment due to Diabetic Macular Edema: 12-Month Results from the 36-Month BOREAL-DME Study. Ophthalmic Res. 2019; 62(2): 101-110. 13. Stefanickova J, Cunha-Vas J, Ulbig M, et al. A noninterventional study to monitor patients with diabetic macular oedema starting treatment with ranibizumab (POLARIS). Acta Ophthalmol. 2018; 96(8): e942-e949. 14. Hodzic-Hadzibegovic D, Sander BA, Monberg TJ, et al. Diabetic macular oedema treated with intravitreal anti-vascular endothelial growth factor - 2-4 years follow-up of visual acuity and retinal thickness in 566 patients following Danish national guidelines. Acta Ophthalmol. 2018; 96(3): 267-278. 15. Mitchell P, Sheidow T, Farah M, et al. Effectiveness and safety of ranibizumab 0.5 mg in treatment-naïve patients with diabetic macular edema: Results from the real-world global LUMINOUS study. PLoS ONE 15(6): e0233595. https://doi.org/10.1371/journal.pone.0233595. 16. Hladikova Z, Klofacova E, Kalodova B. Two-year follow-up results of patients with macular edema due to retinal vein occlusion treated with ranibizumab. Czech and Slovak Ophthalmology 2017; 73(2):41–49. 17. Campochiaro P, Heier J, Feiner L, Gray S, Saroj N, Rundle A, et al; for the BRAVO Investigators. Ranibizumab for Macular Edema following Branch Retinal Vein Occlusion Six-Month Primary End Point Results of a Phase III Study. Ophthalmology 2010; 117:1102–1112. 18. Tadayoni R, Waldstein S, Boscia F, Gerding H, Gekkieva M, Barnes E, et al; on behalf of the BRIGHTER Study Group. Sustained Benefits of Ranibizumab with or without Laser in Branch Retinal Vein Occlusion 24-Month Results of the BRIGHTER Study. Ophthalmology 2017; http://dx.doi.org/10.1016/j.ophtha.2017.06.027 19. Spooner K, Hong T, Fraser-Bell S, Chang A. Current Outcomes of Anti-VEGF Therapy in the Treatment of Macular Oedema Secondary to Branch Retinal Vein Occlusions: A Meta-Analysis. Ophthalmologica 2019; DOI: 10.1159/000497492. 21. Pearce I, Clemens A, Brent M, Lu L, Gallego-Pinazo R, et al; on behalf of all the LUMINOUS study investigators. Realworld outcomes with ranibizumab in branch retinal vein occlusion: The prospective, global, LUMINOUS study. PLoS ONE 2020; 15(6):e0234739. 21. Callizo J, Ziemssen F, Bertelmann T, Feltgen N, Vogeler J, Koch M, et al. Real-World Data: Ranibizumab Treatment For Retinal Vein Occlusion In The OCEAN Study. Clin Ophthalmol. 2019; 13:2167–2179. 22. Ng D, Lai T, Cheung C, Ohno-Matsui K. Anti–Vascular Endothelial Growth Factor Therapy for Myopic Choroidal Neovascularization. Asia-Pac J Ophthalmol 2017; 6:554–560. 23. Cheung C, Arnold J, Holz F, Park K, Lai T, Larsen M, et al. Myopic Choroidal Neovascularization Review, Guidance, and Consensus Statement on Management. Ophthalmology 2017; 124:1690–1711. 24. Freitas-da-Costa P, Pinheiro-Costa J, Carvalho B, Falcao M, Brandao E, Falcao-Reis F, et al. Anti-VEGF Therapy in Myopic Choroidal Neovascularization: Long-Term Results. Ophthalmologica 2014; 232:57–63. 25. Hamilton R, Clemens A, Minnella A, Lai T, Dai H, Sakamoto T, et al; on behalf of the LUMINOUS study group. Real-world effectiveness and safety of ranibizumab for the treatment of myopic choroidal neovascularization: Results from the LUMINOUS study. PLoS ONE 2020; 15(1): e0227557. LUCENTIS® 10 mg/mL solution for injection. Composition: Ranibizumab 10 mg per ml. Each vial contains 2,3 mg of ranibizumab in 0,23 ml of which 0,05 ml (equals 0,5 mg) is injected. Vials are for single use only. Indications: LUCENTIS is indicated for the treatment of neovascular (wet) age-related macular degeneration (AMD). The treatment of visual impairment due to diabetic macular oedema (DME) and to retinal vein occlusion (branch RVO or central RVO). The treatment of visual impairment due to choroidal neovascularisation (CNV) secondary to pathologic myopia (PM). Dosage and directions for use: Singleuse vial for intravitreal use only. The recommended dose for LUCENTIS is 0,5 mg given as a single intravitreal injection. This corresponds to an injection volume of 0,05 ml. The interval between two doses injected into the same eye should not be shorter than one month. Treatment of wet AMD, visual impairment due to DME or due to macular oedema secondary to RVO, visual impairment due to CNV secondary PM. Treatment is initiated with one injection per month until maximum visual acuity is achieved. Thereafter, monitoring and treatment intervals should be determined by the medical practitioner and should be based on disease activity as assessed by visual acuity and/or anatomic parameters. Monitoring for disease activity may include clinical examination, functional testing or imaging techniques (e.g. optical coherence tomography or fluorescein angiography). If patients are being treated according to a treat-and-extend regimen, for example, the treatment intervals can be extended stepwise until signs of disease activity or visual impairment recur. The treatment interval should be extended by two weeks at a time for wet AMD and central RVO (CRVO), or by one month at a time for DME and branch RVO (BRVO). If disease activity recurs, the treatment interval should be shortened accordingly. In the treatment of visual impairment due to CNV secondary to PM, many patients may only need one or two injections during the first year, while some patients may need more frequent treatment. LUCENTIS and laser photocoagulation in DME and branch RVO: LUCENTIS has been used concomitantly with laser photocoagulation. When given on the same day, LUCENTIS should be administered at least 30 minutes after laser photocoagulation. LUCENTIS can be administered in patients who have received previous laser photocoagulation. Lucentis must be administered by a qualified ophthalmologist using aseptic techniques. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Patients with active or suspected ocular or periocular infections. Patients with active severe intraocular inflammation. LUCENTIS is contraindicated during pregnancy and lactation. Warnings and special precautions: Intravitreal injections, have been associated with endophthalmitis, intraocular inflammation, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract. Proper aseptic injection techniques must always be used. Patients should be monitored during the week following the injection to permit early treatment if an infection occurs. LUCENTIS has not been studied in patients with active systemic infections or in patients with concurrent eye conditions such as retinal detachment or macular hole. Patients should be instructed to report any symptoms suggestive of endophthalmitis or any of the above mentioned events without delay. Increases in intraocular pressure (IOP) have been seen within 60 minutes of injection of LUCENTIS and may last for a few hours to a few days. Sustained IOP increases have also been reported. Both intraocular pressure and the perfusion of the optic nerve head must be monitored and managed appropriately. Available data do not suggest an increased risk of systemic adverse events with bilateral treatment. There is a potential for immunogenicity with LUCENTIS. There is a potential risk of arterial thromboembolic events following intravitreal use of VEGF inhibitors. A numerically higher stroke rate was observed in patients treated with ranibizumab 0,5 mg compared to ranibizumab 0,3 mg or control, however, the differences were not statistically significant. The difference in stroke rates may be greater in patients with known risk factors for stroke, including history of prior stroke or transient ischemic attack. Therefore, these patients should be carefully evaluated by their medical practitioner as to whether LUCENTIS treatment is appropriate. The LUCENTIS treatment procedure may induce visual disturbances, which may affect the ability to drive or use machines. Patients who experience these signs must not drive or use machines until these temporary visual disturbances subside. Pregnancy and lactation: LUCENTIS is contraindicated in pregnancy. Pregnancy: LUCENTIS should not be used during pregnancy. Women who wish to become pregnant and have been treated with LUCENTIS, should wait at least 3 months after the last dose of ranibizumab. Women of childbearing potential: Women of childbearing potential should use effective contraception during treatment. Lactation: It is not known whether LUCENTIS is excreted in human milk. Mothers on LUCENTIS should not breastfeed their babies. Side effects: Very common: nasopharyngitis, headache, intraocular inflammation, vitritis, vitreous detachment, retinal haemorrhage, visual disturbance, eye pain, vitreous floaters, conjunctival haemorrhage, eye irritation, foreign body sensation in eyes, lacrimation increased, blepharitis, dry eye, ocular hyperaemia, eye pruritus, arthralgia, intraocular pressure increased. Common: influenza, urinary tract infection, anaemia, anxiety, stroke, retinal degeneration, retinal disorder, retinal detachment, retinal tear, detachment of retinal pigment epithelium, retinal pigment epithelium tear, visual acuity reduced, vitreous haemorrhage, vitreous disorder, uveitis, iritis, iridocyclitis, cataract, cataract sub capsular, posterior capsule opacification, punctuate keratitis, corneal abrasion, anterior chamber flare, vision blurred, injection site haemorrhage, eye haemorrhage, conjunctivitis, conjunctivitis allergic, eye discharge, photopsia, photophobia, ocular discomfort, eyelid oedema, eyelid pain, conjunctival hyperaemia, cough, nausea, allergic reactions (rash, urticaria, pruritus, erythema). Uncommon: blindness, endophthalmitis, hypopyon, hyphaema, keratopathy, iris adhesions, corneal deposits, corneal oedema, corneal striae, injection site pain, injection site irritation, abnormal sensation in eye, eyelid irritation. Interactions: No formal interaction studies have been performed. Presentation: 0,23 ml LUCENTIS solution for injection in a glass vial (colourless type I glass) with chlorobutyl rubber stopper. One pack contains one vial, one filter needle. Registration number: 41/15.4 /0860.

40983 02/21

For full prescribing information, please refer to the SAHPRA approved package insert. Novartis South Africa (Pty) Ltd. Magwa Crescent West, Waterfall City, Jukskei View, 2090. Tel +27 11 347 6600. Company Reg No: 1946/020671/07. Kindly report all adverse events and quality complaints occurring with Novartis product within 24hrs. • Email: patientsafety.sacg@novartis.com • Tel: 0861 929 929 • Fax: +27 11 929 2262 • Or report adverse events directly through our website: https://psi.novartis.com/. To report Quality Complaints email: qa.phzais@novartis.com. ZA2102199361 Exp. 02/2023

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C as e rep or t Idiopathic interstitial keratitis in a child

Summer 2021 • Vol 16 | No 1 SA Ophthalmology Journal

Idiopathic interstitial keratitis in a child DA Erasmus MBBCh, MMed, Dip Ophth (SA); Registrar, Department of Neurosciences, Division of Ophthalmology, University of the Witwatersrand, Johannesburg, South Africa ORCID: https://orcid.org/0000-0002-8395-7080 R Höllhumer MBChB, MMed, FC Ophth(SA); Consultant ophthalmologist, Department of Neurosciences, Division of Ophthalmology, University of the Witwatersrand, Johannesburg, South Africa ORCID: https://orcid.org/0000-0002-4375-2224 Corresponding author: Dr DA Erasmus, 40 2nd Avenue, Parktown North, 2193; tel.: +27 76 462 3355; email: daerasmus@icloud.com

Abstract Interstitial keratitis represents inflammation and new vessel formation in the middle layers of the cornea without tissue loss. The most important infective aetiologies include herpes viruses, tuberculosis and syphilis. Non-infectious causes such as Cogan’s syndrome should be considered in those cases with associated neurosensory hearing loss. The pattern and laterality of inflammation together with the presence or absence of systemic features as well as relevant

Introduction

Interstitial keratitis is a non-ulcerative inflammation and subsequent vascularisation of the corneal stroma which does not primarily involve the epithelium or endothelium. The underlying pathophysiology is believed to be a cellular and humoral immune-mediated type IV hypersensitivity response directed towards corneal stromal antigens, infective antigens or a combination of both.1,2 Clinically the infiltration may be diffuse, focal or multifocal and may be located superficially or, more commonly, deep within the stroma. It may be unilateral or bilateral and be further divided into active and inactive forms with the latter defined as a period of no characteristic signs and symptoms in the preceding year. The topographical distribution together with the presence of

investigations can help to establish the underlying cause of interstitial keratitis. Keywords: interstitial, keratitis, inflammation, cornea, stroma Funding: No external funding was received. Conflict of interest: The authors have no conflicts of interest to declare.

systemic features provides a clue to the underlying cause of interstitial keratitis. Interstitial keratitis can be broadly divided into infectious and non-infectious aetiologies. There is a paucity of information regarding interstitial keratitis in Sub-Saharan Africa and in the paediatric population more generally worldwide. The majority of cases that have an infectious aetiology in adults are viral (with herpes simplex virus comprising 35.1%) or treponemal (comprising approximately 18.6% of cases of both congenital and acquired infection); no identifiable cause is found in 32% of cases. Other important viral infections in adults include EpsteinBarr virus (1%), human T-lymphocytic virus type I, mumps and varicella zoster virus (3.1%). Another important mycobacterial cause is tuberculosis (3.1%), although this is expected to have greater relevance in

a tuberculosis (TB) endemic area such as South Africa. Parasitic infections causing interstitial keratitis are very uncommonly encountered in South Africa but imported cases may be due to entities such as leishmaniasis, onchocerciasis (river blindness) and trypanosomiasis. Non-infectious cases include Cogan’s syndrome, sarcoidosis, Hodgkin’s and T-cell lymphoma, Kaposi’s sarcoma, gold and arsenic toxicity, and intraocular sclerosing inflammatory pseudotumour.1-3 We present a case of idiopathic interstitial keratitis in a South African child.

Case presentation

A seven-year-old black African female was bought in by her mother with a one-week history of decreased vision (left eye worse than the right) with associated pain and redness. Furthermore, both of her wrists

C as e rep or t Idiopathic interstitial keratitis in a child

Figure 1a. No abnormal facies, no saddle nose deformity or lowset ears had begun to swell and become stiff approximately two weeks prior. Although the patient denied this was painful, her mother noted that it improved throughout the day and was exacerbated by cold weather. There were no episodes of headaches, nausea, vomiting or tinnitus. Although the patient was HIV-exposed, her birth PCR was confirmed negative. The remaining maternal booking bloods (including RPR) were negative. Immunisation history was inconsistent, with a period of six years elapsing without coverage. Developmentally the patient’s mother reported that she had achieved normal milestones although she gave the history that her hearing was poor from a ‘young age’. Despite this she was coping well academically in Grade 2. At the age of 2 years the patient was diagnosed with juvenile idiopathic arthritis (JIA) following an episode of joint swelling. She was commenced on methotrexate, chloroquine and prednisone for the period 2012 to 2017 during which time she was reportedly well controlled. She was subsequently lost to follow-up and no further symptoms were reported until the most recent presentation. She was otherwise well with no other admissions. There are no known contacts with TB.

Vol 16 | No 1 • Summer 2021 SA Ophthalmology Journal

Figure 1b. Normal dentition

General examination revealed no pallor, jaundice, lymphadenopathy or pitting oedema. Importantly there were no stigmata of congenital syphilis infection including Hutchinson’s teeth, mulberry molars or sabre tibias (Figures 1a and b). The patient was able to walk unaided without difficulty. Her left hand revealed a ‘Z’-shaped deformity with bilaterally swollen and mildly tender proximal interphalangeal joints with associated Boutonniere deformities as seen in Figure 1c. Similarly, both wrists were

Figure 1c. Dorsal view of the hands showing ‘Z’-shaped deformity of the thumbs with swollen interphalangeal joints and wrists

swollen, tender and warm to the touch with clinical effusions as seen in Figure 1d. Both ankles were mildly tender without any gross deformity. Vision was recorded as 6/18 on the right and counting fingers on the left with no improvement on pinhole. Both eyes had ciliary injection with multifocal areas of stromal inflammation and marginal infiltrates that were more prominent on the

Figure 1d. Lateral view of the hands and wrists showing wrist swelling

C as e rep or t Idiopathic interstitial keratitis in a child

Summer 2021 • Vol 16 | No 1 SA Ophthalmology Journal

Figure 2a. Left eye showing multifocal areas of inflammation and deep vascularisation. Note the ‘salmon-patch’ lesion inferiorly left (Figures 2a and b). Three hundred-andsixty degrees of new vessels were noted deep within the stroma. There was a large, deep 3×3.2 mm ‘salmon-coloured’ nodule on the inferior cornea on the left. Decreased corneal sensation and generalised punctate epithelial erosions without larger areas of staining were present bilaterally. The anterior chambers were active with 2+ cells and 1+ flare although iris nodules or transillumination defects were absent. iCare tonometry was 12 and 10 mmHg for the right and left eye respectively. The vitreous was quiet in both eyes. Posterior segment examinations were normal with vertical cup-to-disc ratios of 0.2 bilaterally and no evidence of retinal inflammation. Laboratory testing is shown in Table I which revealed an elevated erythrocyte sedimentation rate (ESR) and serum angiotensin converting enzyme (ACE). Of note was that the mother’s T. pallidum antibodies were negative. The chest X-ray

Figure 2b. Right eye showing multifocal areas of stromal inflammation and vascularisation

film was normal (Figure 3) and a tuberculin skin test was negative (<5 mm) at 48 hours. Auditory testing suggested moderately severe conductive hearing loss in both the right (Figure 4a) and left ear (Figure 4b). Thus, a working diagnosis of idiopathic interstitial keratitis was made and the

Table I: Serological investigations Blood

Value

WCC

5.79

12.4

Platelets

387

ESR

CRP

RVD

Negative

TPHA

Non-reactive (×2)

ANA

Negative

<10

CRP

S-ACE

patient was started on dexamethasone 0.1% QID in both eyes, atropine 1% BD and lanolin ointment at night. The patient was re-referred to paediatric rheumatology and restarted on methotrexate 12.5 mg once weekly, prednisone 20 mg daily and chloroquine 200 mg five times a week for serologically negative JIA. The patient showed significant improvement in symptoms and visual acuity – at her two weeks follow-up her best corrected visual acuity had improved to 6/9 in both eyes, and her corneal inflammation had decreased significantly – specifically the nodule in her left eye had decreased

Figure 4a. Right ear audiogram: moderateto-severe conductive hearing loss

Figure 3. PA and lateral CXR

Figure 4b. Left ear audiogram: moderate-tosevere conductive hearing loss with mixed frequency component @ 500 and 2000 kHz

C as e rep or t Idiopathic interstitial keratitis in a child

Figure 5a. Left eye at two-week follow-up. Note the decreased inflammation and vascularisation. in size and vascularity (Figures 5a and b). Stromal vessels were still present although systemic symptoms had almost completely settled. Over subsequent visits the clinical picture continued to improve, and topical steroids were slowly tapered to once daily maintenance doses.

Discussion

We present a paediatric case of idiopathic interstitial keratitis in a patient known with JIA. The patient responded to topical steroid therapy with full recovery of vision. The differential diagnosis for this presentation includes herpes simplex virus (HSV) or immune stromal interstitial keratitis, syphilitic interstitial keratitis, TB interstitial keratitis as well as Cogan’s syndrome. HSV interstitial keratitis typically presents with a unilateral diffuse or sectoral pattern of inflammation. Importantly the vascularisation is deep and is often associated with an iritis, diminished corneal sensation, iris atrophy and a history of relapsing disease. Although elevated ESR and serum-ACE results are consistent with diffuse inflammation from viral aetiologies, HSV was considered unlikely as they tend to present unilaterally and be associated with iris atrophy or increased pressures. A favourable response to therapy that did not include an antiviral agent is also supportive of a non-viral aetiology. Congenital syphilis forms the majority of syphilitic interstitial keratitis (87%) and is associated with unilateral inflammation that becomes bilateral in 80% of cases. A diffuse pattern with deep and extensive vascularisation with a predilection for the superior cornea is classically described. Vertical transmission from the mother may occur during primary, secondary or latent phases of infection and classically presents

Vol 16 | No 1 • Summer 2021 SA Ophthalmology Journal

Figure 5b. Right eye at two-week follow-up showing improved inflammation and vascularisation

between the ages of five and 20 years with a peak at nine to 11 years.1,2,4 Associated ocular findings include generalised iris atrophy, posterior synechiae and a salt-and-pepper fundus. In some instances a ‘salmon-patch’ is seen which represents a particularly intense area of neovascularisation with or without subsequent extravasation of blood cells.2 Systemic manifestations may include the classical Hutchinson’s triad of sensorineural deafness, anomalous and widely spaced ‘peg-like’ teeth and interstitial keratitis. Other findings may include cognitive impairment, a ‘saddle-shaped’ nose, frontal bossing, overgrowth of the maxilla, mulberry molars and ‘sabre tibias’.1,2 Although our patient has a salmon patch in the left eye, syphilis was actively excluded by negative serology results in both the child and her mother as well as a lack of characteristic stigmata of congenital syphilis infection. Despite a very high incidence and prevalence of systemic disease, ocular TB remains rare. This is further compounded by the challenge in making a diagnosis due to extremely low yield of M. tuberculosis (even with PCR techniques) and difficulty in obtaining ocular tissues for biopsy.5-7 The most common manifestations of ocular TB include granulomatous uveitis and choroiditis; corneal involvement is typically rare (accounting for only 6.8% of all ocular TB cases). A high index of suspicion is thus necessary to make a diagnosis.8,9 Corneal TB may take the form of phlyctenulosis, peripheral ulcerative keratitis and interstitial keratitis, and appears to be a result of an exuberant host-immune response rather than the direct effect of the organism itself. The pattern of interstitial keratitis is usually unilateral and sectoral with a more anterior or mid-stromal vascularisation which may

be associated with sectoral sclerokeratitis.1 TB was excluded in our patient due to lack of contacts, a negative chest X-ray and a negative tuberculin skin test at 48 hours. The bilateral pattern and deep nature of the vessels were also not supportive of TB infection. Cogan’s syndrome is a rare disorder that classically affects young white adults and presents with non-syphilitic interstitial keratitis and sensorineural hearing loss that is similar in nature to Meniere’s disease (sudden onset of tinnitus and vertigo in the setting of chronic hearing loss). The most serious systemic associations include aortitis, aortic dilatation, valvular regurgitation, brain infarction and lower limb ischaemia. Less serious manifestations are protean – including fever, fatigue, weight loss, hepatosplenomegaly, arthralgia and urticaria among others.10 The pathogenesis remains unclear although co-infection with C. pneumoniae has been postulated.11,12 Hayes et al. proposed a classification system in 1980 that divided Cogan’s syndrome into typical and atypical forms. The former retains Cogan’s initial definition of non-syphilitic interstitial keratitis and typical audio-vestibular disease appearing not more than two years after the onset of ocular symptoms. The case definition for atypical Cogan’s syndrome was later significantly broadened to include any ocular inflammation (with or without interstitial keratitis), audiovestibular symptoms (with or without a Meniere’s-type picture) and a delay of more than two years between the onset of ocular and auditory symptoms.10,12-14 The pattern of interstitial keratitis is typically bilateral, occurs rapidly and resolves gradually with topical steroids, with frequent episodes of recurrence.1 Our patient was thoroughly

C as e rep or t Idiopathic interstitial keratitis in a child

Summer 2021 • Vol 16 | No 1 SA Ophthalmology Journal

worked up for Cogan’s syndrome although this is unlikely without classic symptoms of vertigo and tinnitus. Furthermore, audiology testing was consistent with a conductive rather than a sensorineural fallout which likely reflects repeated middle ear infections in adolescence.

Conclusion

Interstitial keratitis represents an exuberant hypersensitivity reaction and vascularisation within the corneal stroma that is often associated with an underlying systemic disease. There is very little information regarding the epidemiology of interstitial keratitis in the paediatric population of Sub-Saharan Africa. The pattern and laterality of interstitial keratitis together with relevant systemic findings and laboratory investigations can give the clinician a clue about the underlying cause. Important diagnoses to consider include HSV, congenital and acquired syphilis, TB and Cogan’s syndrome. In a large proportion of cases the underlying cause is never identified. The non-ulcerative nature of interstitial keratitis means that the visual prognosis is generally favourable when the underlying cause is treated.

References

1. Perez V. Interstitial keratitis. Ocul Immunol Uveitis Found. 2001 Nov;VI. 2. Weisenthal R, Daly MK, de Freitas D, Feder RS, Orlin SE, Tu EY, et al. External disease and cornea. San Francisco, California: American Academy of Ophthalmology; 2019. pp 357-59. (American Academy of Ophthalmology Basic and Clinical Science Course 2019-2020). 3. Schwartz GS, Harrison AR, Holland EJ. Etiology of immune stromal (interstitial) keratitis. Cornea. 1998 May;17(3):278-81. 4. Dahl AA. Interstitial keratitis: Overview, pathophysiology, epidemiology. 2020 May 8 [cited 2020 Aug 18]; Available from: https://emedicine.medscape.com/ article/1194376-overview 5. Bayraktutar BN, Uçakhan-Gündüz Ö. Ocular tuberculosis with progressive unilateral corneal melting. Case Rep Ophthalmol. 2015 Sep 3;6(3):293-97. 6. Sarah B, Batoul MS, Ibtissam H, Ouafa H, Said A, Abdeljalil M. Corneal manifestations of tuberculosis: about 2 cases. Am J Med Case Rep. 2016;4(5):160-64. 7. Alvarez GG, Roth VR, Hodge W. Ocular tuberculosis: diagnostic and treatment challenges. Int J Infect Dis. 2009 Jul;13(4):432-35. 8. Kamal S, Kumar R, Kumar S, Goel R. Bilateral

interstitial keratitis and granulomatous uveitis of tubercular origin. Eye Contact Lens. 2014 Mar;40(2):13-15. 9. Rafiezadeh P, Schmack I, Shajari M, Kohnen T. Autoimmune keratitis in mycobacterium tuberculosis. J Curr Ophthalmol. 2018 May 18;30(4):381-83. 10. Azami A, Maleki N, Kalantar Hormozi M, Tavosi Z. Interstitial keratitis, vertigo, and vasculitis: typical Cogan’s syndrome. Case Rep Med. 2014 Mar 4;2014:1-4. 11. Norton EWD, Cogan DG. Syndrome of nonsyphilitic interstitial keratitis and vestibuloauditory symptoms: a long-term follow-up. AMA Arch Ophthalmol. 1959 May 1;61(5):695-97. 12. Vollertsen RS, McDonald TJ, Younge BR, Banks PM, Stanson AW, Ilstrup DM. Cogan’s syndrome: 18 cases and a review of the literature. Mayo Clin Proc. 1986 May 1;61(5):344-61. 13. Haynes BF, Kaiser-Kupfer MI, Mason P, Fauci AS. Cogan syndrome: studies in thirteen patients, long-term follow-up, and a review of the literature. Medicine (Baltimore). 1980;59(6):426-41. 14. Martínez-Osorio H, Fuentes-Páez G, Calonge M. Severe keratopathy in paediatric Cogan’s syndrome. Rheumatology. 2006 Aug 18;45(12):1576-77. 

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**Prolong corneal contact time with DexaGel1,2 For greater anti-inflammatory effect vs dexamethasone solution1,2 Equivalent efficacy and safety compared to prednisolone1 *Compared to prednisolone. **Compared to dexamethasone solution. References: 1. Struck HG, et al. Comparison of 0.1% dexamethasone phosphate eye gel (Dexagel) and 1% prednisolone acetate eye suspension in the treatment of post-operative inflammation after cataract surgery. Graefes Arch Clin Exp Ophthalmol. 2001 Oct;239(10):737-42. 2. Data on file. Study No. 008 PHA 94; Dr Morgenstern et al.; 1995. Scheduling status: S4 Proprietary name and dosage form: Dexagel (Eye Gel). Composition: Each 1 g contains: 0,985 mg Dexamethasone sodium phosphate. Preservative: Benzododecinium chloride 0,01 % m/m. Pharmacological classification: A 15.2 Ophthalmic preparations with corticosteroids. Registration number: 37/15.2/0275. © 2003 Bausch & Lomb Incorporated. ®/™ donate trademarks of Bausch & Lomb Incorporated. Applicant: Soflens (Pty) Ltd. Reg. No.: 1968/011787/07. 254 Hall Street, Centurion, 0157. Tel: +27 10 025 2100. www.bausch.co.za For full prescribing information, refer to the professional information as approved by the South African Health Products Regulatory Authority (SAHPRA). BL343/18

42 MESSAGE FROM THE PRESIDENT Change

48 OPHTHALMOLOGY AND PHILATELY

L Visser

44 CLIVE’S CORNER

Journal Club C Novis

Famous ophthalmologists Part 2 J Surka

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Vol 16 | No 1 • Summer 2021 SA Ophthalmology Journal

Me s s age f rom t he Pre sident

CHANGE B

enjamin Franklin coined the phrase that ‘change is the only constant in life’ – that remains true but never before has the rate of change been as rapid as now. Pandemics, civil upheavals, natural disasters and our fast-paced modern life is fuelling this rapid change and we must all adapt. Change is innovation and is an absolute necessity in life but sometimes we feel overpowered by the pace and direction of change. Change can be incremental or disruptive. Incremental change or innovation is exactly as it sounds: small, modular change that takes place slowly over time (almost unnoticed), and allows for a gradual development of a product and its workplace. Disruption is a change to the market or workplace that is so powerful and different that it requires others in the field to follow suit or be left behind. To succeed in the face of disruptive change requires established firms/organisations to master three distinct disciplines: ideation (to generate potential new ideas); incubation (to validate these ideas in the market); and scaling (to reallocate the assets and capabilities needed to grow the new idea). My president’s messages over the past two years have, I hope, given some food for thought. I tried to highlight issues that affect all of us, both in our personal and in our professional lives, touching on artificial intelligence, single-use plastics and climate change, genetic engineering, moral injury, the Covid pandemic, fake news and internet fraud. My final message focuses on change. There are changes afoot in healthcare funding

and delivery, and ophthalmologists (and other healthcare providers) must remain at the forefront of disruptive changes in our profession in order not to be swept aside by others who do not have our, or our patients’ interests at heart.

‘

It is not the strongest of the species that survives, nor the most intelligent, it is the one that is most adaptable to change – Charles Darwin

’

The recent establishment of the I Care Network (ICN) by the Ophthalmology Management Group (OMG) might be one such disruptive change that the profession should take ownership of and support, and I would like to congratulate the Board of Directors and CEO of OMG for their ‘ideation’. The period of ‘incubation’ has started and what remains is the ‘scaling’ thereof. It will need the support of the profession. Change will also take place in the OSSA leadership following our AGM in March 2021 with Bayanda Mbambisa filling the presidential hot seat. I wish her all the best for her term – it is a tough position to be in, with many added responsibilities, but I know

that the organisation will be in good hands and that she will be bringing her A-game with her. I for one, am quite happy to step down! In my personal life there will also be major changes come 1 April 2021 when I leave my post as Academic Head of the Department of Ophthalmology at the University of KwaZuluNatal and take up the post as Academic Head of Department of Ophthalmology at Stellenbosch University. This change, for me, brings the exciting prospect of starting afresh, making new friends and acquaintances and hopefully contributing to the moulding of a few new young ophthalmology minds. It also unfortunately means the end of a long relationship with UKZN and the KZN Department of Health and leaving behind dear friends and colleagues. Covid permitting, I will be visiting quite often though! I leave you with a final thought: If you don’t like something, change it. If you can’t change it, change your attitude. 

Dr Linda Visser MBChB, MMed(Ophth), FCOphth(SA)

President: Ophthalmological Society of South Africa

Vol 16 | No 1 • Summer 2021 SA Ophthalmology Journal

Clive’s Cor ner

Journal Club Vojin Djordjevic and Ian Kozlowski

n 2016, I wrote an article entitled ‘Small group learning’ (SA Ophthalmology Journal vol 11 no 1 Summer 2016). This article explained how our Journal Club works. So why am I writing another article about our Journal Club? Because of two letters that I read recently. The first letter was published in a recent OSSA newsletter. It was from a member of OSSA YO (Young Ophthalmologists group). It was a plea by one of our younger colleagues for older colleagues to consider mentoring junior doctors. I was surprised and rather taken aback. One of the best places to get mentoring from older colleagues is at our Journal Club meetings. Yet this young ophthalmologist never

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John Lubuya and Johann Lamprecht, who is explaining the new OSSA app attends our meetings despite having been invited and reminded numerous times. Our meetings are attended by several very senior colleagues. In fact, at several of our meetings a few years ago we had the privilege of the company of the oldest practising ophthalmologist in the country (Dr Harry Gelman, before he retired). We have sub-specialists in almost all fields regularly attending our meetings: retinal surgeons, glaucoma experts, refractive surgeons, optometrists and others. At one stage we even had two orthoptists attending. We have regular guest attendances by experts in all the subspecialities of ophthalmology and specialists from other medical fields. We have also had lawyers, financial advisors and other guests. Recently we have had great talks by local guest experts such as Lara Sandri (retinal oncology), Tony dos Ramos (corneal surgery), Caroline Gooding (thyroid eye disease and oculoplastics), Ed Jervis (retinal pathology and treatment), Sachin Bawa (corneal cross-linking), Muhamed Dawood (retinal issues), Nilesh Dahya (strabismus), Vojin Djordjevic (glaucoma surgery) and Johann Lamprecht (OMG issues). And it’s not like being at a large formal congress. We usually sit around a table or we sit in a semi-circle and talk informally. Obviously, anyone is free to ask questions or give their opinion in an informal atmosphere. Before and after the meeting, one-on-one discussions can often be seen happening. A great deal of mentoring takes place at these meetings. One of our regular attendees has stated that he has learned more at these meetings than in all his time as a registrar. And not just learning about clinical ophthalmology. The business side of being an ophthalmologist in the private sector is not taught to us at all in medical school. At these meetings you can learn business tips from ophthalmologists who own their own practices, who work in large group practices, who own shares in large hospital companies, who own

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their own ASCs or who have shares in these ASCs/day clinics. Now here is what I struggle to understand: most attendees at our meetings are senior ophthalmologists. Why are the juniors so scarce? I have two theories: first, I think that many of the juniors may feel intimidated. They have had many years of being medical students and registrars where their knowledge and skills were constantly being formally observed and tested by seniors. Now that they are qualified, the last thing they want is to be reminded of those bad old days of being constantly judged, tested and criticised. Secondly, I think many of them have young families. They may be struggling to make a living in a new practice. They may be working long hours doing extra shifts at government clinics. When they get home, they want to spend quality time with the family. Most of the seniors are only too happy to be away from their families for a few hours! (One old doc actually thanked me for giving him an excuse to get out of the house. ) The second letter I read was from one of

🙂

Savvas Christodoulou listening to Johann Lamprecht reporting back from OMG

TREAT

before the light goes out at the end of the TUNNEL1,2

Proven intraocular pressure (IOP) lowering up to 38 % from untreated baseline3

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References: 1. Weinreb RN, Khaw PT. Primary open-angle glaucoma. Lancet 2004; 363:1711-20. 2. Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: a review. JAMA 2014; 311(18):1901-1911. 3. Barnebey HS, Orengo-Nania S, Flowers BE, et al. The safety and efficacy of travoprost 0.004 %/timolol 0.5 % fixed combination ophthalmic solution. Am J Ophthalmol. 2005; 140(1):1-7.

SCHEDULING STATUS: S4 DUOTRAV® eye drops, solution. REGISTRATION NUMBER: A40/15.4/0511. COMPOSITION: 1 ml of solution contains 40 μg travoprost and 6,83 mg timolol maleate equivalent to 5 mg timolol, preserved with 0,001 % (m/v) polyquaternium-1 (POLYQUAD®). Excipients: mannitol, propylene glycol, polyoxyethylene hydrogenated castor oil 40, boric acid, sodium chloride, sodium hydroxide and/or hydrochloric acid (to adjust pH) and purified water. PHARMACOLOGICAL CLASSIFICATION: A.15.4 Ophthalmic preparations, other. INDICATIONS: Decrease of elevated intraocular pressure in patients with ocular hypertension or open- angle glaucoma for whom treatment with either travoprost or timolol given alone provides insufficient IOP reduction.CONTRA-INDICATIONS: Hypersensitivity to travoprost, timolol, or to any of the excipients. Patients with bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease, sinus bradycardia, second or third degree atrioventricular block, overt cardiac failure or cardiogenic shock. WARNINGS AND SPECIAL PRECAUTIONS: Systemic effects: DUOTRAV is absorbed systemically. Due to the beta-adrenergic component, timolol, the same types of cardiovascular and pulmonary adverse reactions as seen with systemic beta adrenergic blocking agents may occur. Cardiac failure should be adequately controlled before beginning therapy with timolol. Respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma and, rarely, death in association with cardiac failures, have been reported following administration of timolol maleate. DUOTRAV should be administered with caution in patients subject to spontaneous hypoglycaemia or to diabetic patients as beta adrenergic blocking agents may mask the signs and symptoms of, and the response to hypoglycaemia. It may also mask the signs of hyperthyroidism and cause worsening of Prinzmetal angina, peripheral and central circulatory disorders and hypotension. Anaphylactic reactions: While using DUOTRAV, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be unresponsive to the usual doses of adrenaline used to treat anaphylactic reactions. Concomitant therapy: The effect on intraocular pressure or the known effects of systemic beta-blockade may be potentiated when DUOTRAV is given to patients already receiving an oral beta-blocking agent.The use of two local beta-adrenergic blocking agents or two local prostaglandins is not recommended. Ocular effects: Travoprost may gradually change the eye colour by increasing the number of melanosomes (pigment granules) in melanocytes. Unilateral treatment can result in permanent heterochromia. The long term effects on the melanocytes and any consequences thereof are currently unknown. In controlled clinical trials, periorbital and/or eyelid skin darkening in association with the use of travoprost has been reported. Travoprost may gradually change eyelashes of the treated eye/s. The mechanism of eyelash changes and their long term consequences are currently unknown. Travoprost has been shown to cause slight enlargement of the palpebral fissure in studies in the monkey. However, this effect was not observed during the clinical trials and is considered to be species specific. Caution is recommended when using DUOTRAV in aphakic patients, pseudophakic patients with a torn posterior lens capsule or anterior chamber lenses, or in patients with known risk factors for cystoid macular oedema. In patients with known predisposing risk factors for iritis/uveitis, DUOTRAV can be used with caution. DUOTRAV may cause skin irritation. Patients must remove contact lenses prior to application of DUOTRAV and wait 15 minutes after instillation of DUOTRAV before reinsertion. Effects on ability to drive and use machines: Temporary blurred vision or other visual disturbances may affect the ability to drive or use machines. INTERACTIONS: There is a potential for additive effects resulting in hypotension and/or marked bradycardia when eye drops with timolol are administered concomitantly with oral calcium channel blockers, or beta-blocking agents, antidysrhythmics, digoxin or parasympathomimetics. The hypertensive reaction to sudden withdrawal of clonidine can be potentiated when taking beta-blockers. Beta-blockers such as timolol contained in DUOTRAV may increase the hypoglycaemic effect of antidiabetic agents and may mask the signs and symptoms of hypoglycaemia (see WARNINGS AND SPECIAL PRECAUTIONS). PREGNANCY AND LACTATION: Pregnancy: DUOTRAV should not be used during pregnancy. Women of child-bearing potential: DUOTRAV must not be used in women who may become pregnant unless adequate contraceptive measures are in place. Lactating women: Mother’s breastfeeding their babies should not be treated with DUOTRAV. DOSAGE AND DIRECTIONS FOR USE: For ocular use. Use in adults, including the elderly: The dose is one drop of DUOTRAV® in the conjunctival sac of the affected eye(s) once daily, in the morning or in the evening. DUOTRAV should be used at the same time each day. Nasolacrimal occlusion or gently closing the eyelid after administration is recommended. Use in children and adolescents: The efficacy and safety of DUOTRAV in patients below the age of 18 years have not been established and its use is not recommended in these patients until further data becomes available. Use in hepatic and renal impairment: No dosage adjustment was necessary in these patients. Method of administration: The patient should remove the protective overwrap immediately prior to initial use. To prevent contamination of the dropper tip and solution, care must be taken not to touch the eyelids, surrounding areas or other surfaces with the dropper tip of the bottle. SIDE-EFFECTS: The most frequently reported treatment-related side-effect with DUOTRAV was hyperaemia of the eye (10,8 %), which included ocular or conjunctival hyperaemia. The majority of patients (90 %) who experienced hyperaemia of the eye did not discontinue therapy as a result of this reaction. Common: eye pain, eye irritation, foreign body sensation in eyes, dry eye, eye pruritus, conjunctival hyperaemia, ocular hyperaemia. Uncommon: hypersensitivity, headache, punctate keratitis, photophobia, ocular discomfort, abnormal sensation in eye, blurred vision, keratoconjunctivitis sicca, conjunctivitis, allergic conjunctivitis, meibomianitis, eyelid margin crusting, eyelids pruritus, asthenopia, increased lacrimation, iris hyperpigmentation, growth of eye lashes, dark circles under eyes, bradycardia, hypotension, fatigue, skin discolouration, abnormal hair growth, decreased heart rate. PRESENTATION: White 4 ml bottle, containing a 2,5 ml fill with colourless dispensing plug and white screw cap, all polypropylene. NB. For full prescribing information, please refer to the MCC approved package insert.

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Vol 16 | No 1 • Summer 2021 SA Ophthalmology Journal

Clive’s Cor ner

Jeff Lever and his wife Yael Lever who is an optometrist our younger colleagues posting on the OSSA Whatsapp chat group. He was making a plea to all SA ophthalmologists to stand together. Nothing new about this and of course I fully agree with his sentiments. But what did surprise me is that this young colleague also never attends our Journal Club meetings. Standing together starts with small local groups standing together. Cohesion within a group starts with regular physical meetings. Whatapp groups, email chat forums, and Zoom meetings are fantastic but there is a special bond formed at regular small group physical meetings. Forming bonds and making connections with local colleagues is of obvious benefit to all concerned. It is vital to know who’s who in your area. Gone are the days where an ophthalmologist can be a master of all things ophthalmological. I refer a large percentage of

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William Earl and Themba Ndlovu at a Journal Club meeting. Note the social distancing.

my patients to other ophthalmologists who subspecialise in various fields. I need to know who these experts are and what their capabilities are. This is vital for my patients. My patients also need to know the fees they charge, if they are contracted in with medical aids, if they do WCA cases, etc. And of course, these subspecialists should want to advertise their skills to their colleagues. Another benefit of making friends with your local colleagues is that sooner or later your unhappy patients will land up at them for second opinions! And of course, you will also see patients who have been treated by a local colleague who now comes to you for a second opinion. Younger colleagues should also remember that older colleagues usually retire from surgery before fully retiring from practice. In those last few years, they need to send their surgical cases to someone else. I benefitted enormously from this in my younger days because I made friends with the older colleagues at Journal Club meetings. Each Journal Club meeting provides each attendee with three CPD points. So, you can get all your CPD points just by attending these meetings. And now even ethics points. Recently our CPD accreditor, SAMA, has agreed that we may have an annual ethics meeting provided that they pre-approve the topics or guest speaker as the case may be. At the start of our last annual ethics meeting, we all stood up and recited the Hippocratic oath! Most of us had not recited this oath since graduating as medical doctors, so it was quite an occasion! We then discussed various ethical, legal and financial issues concerning current ophthalmology practice in SA including a few court cases and a few cases that were heard by the HPCSA disciplinary committee. Talking about ethics, ‘gossip’ is a word that is frowned upon in polite circles. But actually gossip has always played an important part in communities and social groups. Not all gossip is necessarily nasty. It’s just another way of spreading local news which may be of importance to the health and well-being of

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the society. There is much gossip to be heard at our meetings! The Optiklin Journal Club (also known as the East Rand Ophthalmology Journal Club) has been around for a long time. In January we will be celebrating our 25th anniversary. We meet once a month and had never missed a meeting in all these years until April 2020 during hard lockdown. We only cancelled that one April meeting. After that we carried on meeting with the usual Covid precautions in place. One of the doctors requested Zoom meetings but a quick survey done among our regular attendees was strongly against virtual meetings. When we started in 1996, we used to subscribe to about a dozen journals including Survey of Ophthalmology, Review of Ophthalmology, Eye, Ophthalmology (the ‘blue journal’), Cataract and Refractive Surgery, Retina, Glaucoma, AJO (American Journal of Ophthalmology), BJO (British Journal of Ophthalmology), Archives, and others. Gradually over the years, thanks to the internet, we have reduced this costly business and now most of our articles are taken from online sources. Optiklin has now been closed down and so our meetings are no longer held there in Benoni. At the moment we hold our meetings at Ian Kozlowski’s practice in Bedfordview (east of Joburg). If you would like to attend a meeting or present something you feel will be of value to colleagues, please feel free to email me at clivenovis@mweb.co.za 

Dr Clive Novis Dip Optom, MBBCh(Wits), MMed(Wits), FCS(Ophth)

clivenovis@mweb.co.za

Vol 16 | No 1 • Summer 2021 SA Ophthalmology Journal

Opht halmolog y and philately

Famous ophthalmologists Part 2 J

uzer Surka is an ophthalmologist and enthusiastic philatelist, who first started collecting stamps and commemorative envelopes at a young age. In subsequent years he has focused his collection and research on medically themed stamps, and more specifically, on those relating to the field of Ophthalmology, where he has collected to date in the region of around 60 original stamps. In 2005, as a member of the National Committee for the Prevention of Blindness, he was instrumental in getting the South African Postal Service to release a stamp to raise awareness around the prevention of blindness – an elegant, plain white stamp with the word ‘Hello’ written in Braille. It was a first of its kind in the history of South African philately. Philately is the study and collection of postage stamps. As stamp collecting gained in popularity over the years and around the world, collectors became more specialised in their areas of interests and collections; medical philately being no exception. Many countries have produced stamps on a wide range of medical topics, from health promotion and disease prevention to medical advances and notable clinicians. Ophthalmology has its fair share of stamps, and discovering them can be a fun and interesting way to learn about some of the history and heritage of the specialty. In this series, we intend to look at various ophthalmology-related stamps, starting with famous clinicians and scientists. We hope the reader finds this to be informative and fun.

Vladimir Filatov Vladimir Petrovich Filatov (1875–1956) was a Russian ophthalmologist credited with the first successful corneal transplant. He was born in Milkailovka, south of Moscow, and obtained his medical degree in 1897 from the University of Moscow. He became a lecturer and later Professor of Ophthalmology in Odessa. He introduced the tube flap grafting method, corneal transplantation, and preservation of grafts from cadaver eyes. He founded the Institute of Eye Diseases & Tissue Therapy in Odessa, Soviet Union (today Ukraine). He performed his first unsuccessful corneal transplant in 1912. After numerous attempts, he achieved the first successful transplant in 1931, where he used a donor eye stored in a moist chamber at 2–4 °C and popularised the technique. His main claim to fame is the creation of the first eye bank in 1931. He died in Odessa in 1956 at the age of 81 years. After Filatov died in 1956, his apprentice Nadezhda Vladimir Filatov Puchkovskaya led Stamp issued by the Soviet the Institute of Union (Russia) in 1962

Eye Diseases & Tissue Therapy in Odessa, which was renamed in honour of Filatov as The Filatov Institute of Eye Diseases & Tissue Therapy.

Ignacio Barraquer Ignacio Barraquer (1884–1965) came from the famous ophthalmology family of Barraquer in Spain and is associated with many inventions in ophthalmic surgery. He was born in Barcelona, where he studied Medicine, obtaining his doctorate in 1908. He attended special courses on mechanics, moulding and plastic art at the School of Arts and Trades; physics and chemistry at the Instituto General; and comparative anatomy, botany, bacteriology and applied chemistry at the Universidad de Madrid. At the universities of Paris and Montpellier, he studied histology, ophthalmology, embryology and parasitology. When his father retired, he was appointed Acting Professor of Ophthalmology at the

Ignacio Barraquer Stamp issued by Spain on 20 June 1984

School of Medicine from 1919 until 1923. He conceived the idea of extracting cataracts using a delicate and subtle application of a suction cup without damaging the tissues of the eye upon observing a leech capture a little stone in an aquarium. He invented many surgical instruments and procedures involving cataract surgery, many of which are named after him. He was also famous for his incredible car collection. He grew his collection to include some of the most sought-after classic cars in the world, including the highly desirable MercedesBenz 300 S Coupe.

Harold Ridley Sir Harold Lloyd Ridley (1906–2001) was an ophthalmic consultant at the Royal London Ophthalmic Hospital at Moorfields. Dr Ridley treated Royal Air Force pilots who suffered from eye injuries, many of which included fragments of airplane canopies made of the then new material, polymethyl methacrylate (PMMA). PMMA or ‘Perspex’ was used in the canopies of two planes in the Royal Air Force. He noted the inertness of those pieces in the eye. Only after the war in 1940, while in operating theatre, a remark by a resident that it was a pity not to be able to replace the removed lens made him think about an intraocular lens. Almost a decade later in 1949, he performed the first intraocular lens implant. The British medical community rejected the procedure as too risky, so in 1949 Ridley

Summer 2021 • Vol 16 | No 1 SA Ophthalmology Journal

Harold Ridley Stamps released by Great Britain in 2003 and 2010

Opht halmolog y and philately obtained his greatest reputation internationally for his treatment of glaucoma, which was first published in 1924. He referred to this operation initially as electro-cautery puncture and later simply as Preziosi’s operation. The procedure was considered an advance over the other available filtering operations such as trephination, sclerectomy and iridencleisis. It was further developed by Harold G Scheie in 1957. Preziosi’s operation for glaucoma remained in use for many years until the development of trabeculectomy.

Fred Hollows Stamps released by Australia (1995 and 2012 ) and Eritrea (2003)

Henry Gidney Henry Gidney practised ophthalmology in India during the British Raj. He was born in India on 9 June 1873, and was schooled in Bombay and Edinburgh. At the age of 16, he joined Calcutta Medical School. He returned to Britain to take a Diploma in Public Health (DPH) at Cambridge University plus a further Diploma in Ophthalmology (DO) at Oxford University. He remained at Oxford as a Research Fellow, lecturing in ophthalmology, and his surgical skill in this field gained a great reputation. At 36 years old, he was already an FRCS and MRCP. After he retired from the Indian Army in 1919, he set up his private eye hospital in Bombay. In 1926, Gidney founded the All India AngloIndian Association. He died in India in 1942. The Gidney House of The Frank Anthony Public School, Bangalore, is named after Sir Henry Gidney.

conducted his first implant operation in secret. Despite some initial problems with complications, by the 1970s improved instrumentation and microsurgical techniques had made the procedure the most common treatment for cataracts.

Professor of Ophthalmology at the University of New South Wales in Sydney. From 1965– 1992 he chaired the ophthalmology division, overseeing the teaching departments at the University of New South Wales, and the Prince of Wales and Prince Henry hospitals. His visits to Nepal in 1985, Eritrea in 1987 and Vietnam in 1991 resulted in training programmes to train local technicians to perform eye surgery. These experiences motivated him to find a way to reduce the cost of eye care and treatment in developing countries. Hollows organised intraocular lens laboratories in Eritrea and Nepal to manufacture and provide lenses at cost, which was about A$10 (approximately US$7.50) each. Both laboratories started production after his death in 1993. Today, the factories have produced millions of lenses and are a continuing reminder of his enduring impact.

Bibliography

Luigi Preziosi Sir Luigi Preziosi (1888–1965) was a Maltese politician and a doctor who specialised in ophthalmology. He was mostly known for devising an original operation for the treatment of glaucoma in 1924, which remained in use for many decades. In 1924 he was appointed Professor of Ophthalmology at the University of Malta. He was unusually interested in trachoma diseases, which were prevalent in Malta at the time. Luigi Preziosi In his early years, Stamp released by Malta in 1988 however, he

Henry Gidney (1873–1942) Stamp released by India in 1973

Frederick Cossom Hollows Fred Hollows (1929–1993) was a New Zealand– Australian ophthalmologist who became known for his work in restoring eyesight to thousands of people in Australia and many other countries. It is estimated that more than one million people in the world can see today because of initiatives instigated by Hollows, the most notable example being The Fred Hollows Foundation. In 1961, he went to Moorfields Eye Hospital in England to study ophthalmology. He then did post-graduate work in Wales before moving to Australia in 1965, where he became Associate

https://en.wikipedia.org/wiki/ Fred_Hollows#cite_note-10 https://en.wikipedia.org/wiki/ Henry_Gidney#cite_note-Times1942May6-4 Obituary Count Sir Luigi Preziosi (pdf). London: The British Journal of Ophthalmology (BJO). Retrieved 24 January 2016. 

Prof J Surka MBBS, DOMS, MS(Ophth), FCS(Ophth)SA

Email: jsurka@gmail.com

Vol 16 | No 1 • Summer 2021 SA Ophthalmology Journal

B o ok re vie w

Big Pharma and Eco Activists Author: David Bristow Publisher: Jacana Media (South Africa) Year of publication: 2020 Number of pages: 223 Reviewer: Clive Novis (clivenovis@mweb.co.za)

was browsing around Exclusive Books (my favourite shop) and saw this book at the ‘General Science’ section. I decided to buy it because it was a South African book by a South African author and it seemed relevant for doctors. I was not disappointed. David Bristow has been around. He is a journalist, a writer, and an eco-activist. He has written over 20 books, this being his latest work. I enjoy reading books written by professional writers for obvious reasons: their writing is easy to read and interesting (as it has to be if they want to make a living). These books are not always well researched and so an open, sceptical mind is always needed. This book, however, seems to be well researched. The book is divided into 20 chapters, each telling a different story about environmental affairs in this country. Chapter 1: The story about Alexander von Humboldt, the father of ecology. He was born in 1769 in Germany. We all owe a huge debt of gratitude to this man. Chapter 2: How big pharma can sometimes con the public and the medical profession. I have reviewed several whole books on this subject but this chapter gives us a nice little summary with a South African flavour. Chapter 3: Big Business, especially the oil and tobacco companies, are the evil protagonists of this chapter. Bristow accuses the big oil companies of fuelling the climatechange-denial lobby. Chapter 4: Rhino poaching is the topic of

discussion here. Did you know that one single rhino horn can be worth R4 million!? Chapter 5: Food and food additives are the issue here. Bristow defends MSG saying that it does not deserve its harmful reputation. Did you know that arsenic used to be used to treat syphilis? Chapter 6: This chapter is about ‘Big Farma’. Some of the large farming and agricultural supply companies are bullying the smaller farmers. Some people have even been killed for standing up to these bullies! Chapter 7: Power and energy. Coal, nuclear, natural gas, solar, wind. Each has its advantages and disadvantages for this country but Bristow thinks that nuclear is probably the best solution. Chapter 8: Cleaning up oil slicks, and the companies we must thank for this important work. Chapter 9: Genetically modified crops, pesticides, etc. Bristow quotes from Harari’s book Sapiens saying that industrial farming has been one of the greatest crimes visited on Earth. Chapter 10: Organic farming. Soil is 90% of farming. There are more living organisms in a handful of good soil than people on Earth! Chapter 11: All about bees and how essential they are. It takes about 1 200 bees to gather nectar from about 2 million flowers to make one jar of honey! Most honey sold is concocted sugar water, and lots of honey comes from bees fed on a diet of sugar water.

Chapter 12: The sad state of South African rivers. Chapter 13: Plastic waste is one of the leading causes of environmental pollution. The plastic waste produced by PPE for Covid is enormous. The lockdown resulted in the closure of waste-recycling plants. Chapter 14: Climate change. Bristow says that we have only a very small window of opportunity to reverse the causes of climate change. The effects of climate change may well make the Covid pandemic look like a drop in the ocean. Chapter 15: Gideon Groenewald and other activists’ important contribution to the SA ecosystem. Chapter 16: The importance of trees. Chapter 17: Geological and environmental health were issues discussed as long ago as the time of Hippocrates. The number one killer of mineworkers is silicosis. Chapter 18: Green living and dying. ‘Every time you choose a food, you are selecting a farmer, either a destructive one or a regenerative one’. A tree should be planted on all graves. Chapter 19: How to get off the grid and simplify your life. Easier said than done. Chapter 20: Expropriation of farms is not just a ruse to get ANC cadres’ hands on white-owned farms. It’s about the much more extensive tribal lands and who controls them. Congratulations to David Bristow for writing such an informative book for South Africans. 

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