September 2014

ADVANCING OPTOMETRY

Diabetic disease Setting our sights on the looming crisis

Optic nerve head drusen Detection and controversial treatment options

CXL for Clinical results and complications

Alzheimer’s disease Towards a non-invasive analysis of ocular biomarkers AU-LIP-2013-19d_A4_v1.pdf 1 7/05/2014 9:18 pm

New Eye Indication* 1

*LIPIDIL is indicated for the reduction in the progression of in patients with Type 2 and existing diabetic retinopathy.

LIPIDIL does not replace appropriate control of blood pressure, blood glucose and blood lipids in reducing the progression of diabetic retinopathy.

See the difference In addition LIPIDIL is indicated as an adjunct 1 ADDing LIPIDIL® to diet in the treatment of: Dyslipidaemia associated with 1 Type 2 diabetes can make Types II, III, IV and V dyslipidaemia

Hypercholesterolaemia

New Retinopathy Indication In Type 2 Diabetes1

See primary advertisement for New Indication details

PBS Information: General Statement for Lipid-Lowering Drugs. Not listed for the treatment of diabetic retinopathy.

Please review the full Product Information (PI) before prescribing. Full PI available on request from Abbott Australasia by calling 1800 225 311 or at: www.medicines.org.au/files/abplipid.pdf Lipidil® (fenofibrate): 145 mg tablets, 30’s; 48 mg tablets, 60’s. Indications: Adjunct to diet in the treatment of hypercholesterolaemia, types II, III, IV and V dyslipidaemia, dyslipidaemia associated with Type 2 diabetes. Reduction in the progression of diabetic retinopathy in patients with Type 2 diabetes.* Does not replace appropriate control of blood pressure, blood glucose and blood lipids. Dosage: Dyslipidaemia and Diabetic Retinopathy: 145 mg tablet to be taken with or without food. Consider dose of 48 mg in patients with renal impairment (CrCl<60ml/min). Contraindications: Children; liver dysfunction; severe renal dysfunction; existing gallbladder disease; coadministration with another fibrate; hypersensitivity to fibrates or ketoprofen; chronic or acute pancreatitis with the exception of acute pancreatitis due to severe hypertriglyceridaemia. Precautions: Attempt diet and lifestyle modifications before initiating therapy for dyslipidaemia; effect on CHD mortality/morbidity not established*; renal impairment; may increase LFT; hepatic impairment, cholelithiasis; pregnancy and lactation; drugs exacerbating hypertriglyceridaemia (oestrogen, b-blocker, thiazides); fructose and/or galactose Before prescribing please review PBS and Product Information available in the primary intolerance (including, Lapp lactase deficiency or galactose malabsorption); lecithin or related product allergy. Interactions: Oral anti-coagulants; HMG-CoA reductase inhibitors (risk of muscle toxicity is increased if used concurrently); other fibrates; cyclosporine (monitor renal function); phenylbutazone; drugs metabolized by cytochrome advertisement in this publication or on request from Abbott Australasia by calling 1800 225 311. P450 isoenzymes CYP2C19, CYP2A6, and CYP2C9. Adverse Effects: GI disorders; skin reactions (including rash and photosensitivity); raised LFT; increase in serum creatinine;

References: 1. Lipidil® Approved Product Information. Lipidil® is a registered trademark of Abbott Australasia, 32–34 Lord St, Botany NSW 2019. pancreatitis; gallstones; thromboembolism; muscle toxicity and rarely rhabdomyolysis. Free call: 1800 225 311. Date prepared: March 2014. AU-LIP-2013-92b *Please note changes in Product Information. References: 1. Lipidil Approved Product Information. Lipidil® is a registered trademark of Abbott Australasia, 32–34 Lord St, Botany NSW 2019. Free call: 1800 225 311. Date prepared: November 2013. AU-LIP-2013-91c

ABBLI0017G_ad_MO_FI_4pp_363x264_[f2].indd 1-2 September 2014

Editor JEFF MEGAHAN 02 12

National Communications New guidelines for diabetic Abstracts Manager sandra shaw retinopathy Dr Laura Downie Jeff Megahan Clinical Editor Associate Professor Mark Roth FAAO 14 Department of Optometry and 05 Optic nerve head drusen Vision Sciences, The University of Multidisciplinary approach Malcolm Gin and Catherine Melbourne to diabetic retinopathy Cheah Cover design Mike Jackson and ­ Goran Nikolic Dr Michael Chilov 16 Optometry Australia Corneal collagen cross- Optometrists Association linking for keratoconus 22 Australia trading as Strategies for severe Dr Elsie Chan Optometry Australia chronic ocular pain ABN 17 004 622 431 Lucas Genereux and 204 Drummond Street 19 Dr Leonid Skorin Jr Carlton VIC 3053 Tel (03) 9668 8500 Alzheimer’s disease and Fax (03) 9663 7478 the eye Dr Christine Nguyen et al [email protected] www.optometrists.asn.au

Copyright © 2014

Comments made in Pharma are of a general nature and intended for guidance only. Optometry Australia and the individual contributors expressly 09 disclaim all liability and responsibility Eye-drop dispensers to any person in respect of, and for the consequences of, anything done or improve patient adherence omitted to be done in reliance wholly or Helen Carter partly on anything in this publication.

Pharma is distributed in Australia and New Zealand. All references to pharmaceutical preparations in Pharma are applicable within Australia. 2 SEPTEMBER 2014

New guidelines for diabetic retinopathy Optometry’s vital role in shared care of patients

Management of Type 2 Diabetes the NHMRC guidelines were soon Jeff Megahan Guidelines. Optometry Australia’s outdated. revised diabetes guidelines were released in June 2014. While drawing heavily on the NHMRC’s guidelines, Optometry Optometry Australia had established Australia’s guidelines for the its own working group* to review its Examination and Management of diabetic retinopathy clinical guidelines Patients with Diabetes recognise Health care organisations in and the 12-month review process technologies such as digital retinal Australia are increasingly advocating a concluded in May 2014. imaging and OCTs, as well as the multidisciplinary approach to diabetes, new treatment modalities for diabetic in which optometrists are expected The National Health & Medical macular oedema, particularly anti- to play a key role in early diagnosis, Research Council (NHMRC) last revised VEGF therapy. monitoring and patient awareness. its Clinical Practice Guidelines for the Management of Diabetic Retinopathy Tacitly acknowledging the changing In April 2014, the Royal Australian in 2008. Developed by the Australian role optometry plays in the diagnosis College of General Practitioners Diabetes Society’s expert panel and and monitoring of mild to moderate updated its General Practice citing literature only up to 2006, non-proliferative diabetic retinopathy,

Retinopathy Findings on Management and stage review/referral timeframe42 No apparent No abnormalities In line with AOA , AAO and JDC, retinopathy OAA recommends annual review Minimal NPDR Microaneurysms (MA) only Review 6-12 months taking into consideration proximity of MA to fovea Mild to moderate More than just MA but less than severe NPDR Refer (see footnote)43 or NPDR This may include: closely monitor • Dot haemorrhages Depending on level of DR present, • Blot haemorrhages 3-6 monthly or annually. • Cotton wool spots • Intraretinal microvascular anomalies (e.g. venous beading) Severe NPDR Any of the following: referral – see • More than 20 intraretinal haemorrhages in each of footnote41 4 quadrants • Definite venous beading in 2+ quadrants • Prominent IRMA in 1+ quadrant AND no signs of proliferative retinopathy PDR One of the following (or unexplained fall in visual acuity): Urgent ophthalmology • Neovascularisation Referral (days–weeks)* • Vitreous/pre-retinal haemorrhage Macula oedema Absent No retinal thickening or hard exudates (HEx) in Follow-up or need to refer should posterior pole be based on the level of NPDR or DR Present Mild – some retinal thickening or HEx in posterior Ophthalmology referral and pole but distant from the macula management Moderate – retinal thickening or HEx approaching (within 4 weeks for HEx within the centre of the macula but not involving the centre 1DD of fovea)* Severe – retinal thickening or HEx involving the fovea

* Optometry Australia recommends that optometrists communicate with ophthalmologists to determine their ­preferred referral timelines to prevent vision loss

Table 1. International Clinical Diabetic Retinopathy and Diabetic Macular Oedema Disease Severity Scale and ­recommended referral patterns SEPTEMBER 2014 3

New guidelines for diabetic retinopathy Optometry’s vital role in shared care of patients

the revised guidelines advocate the The principal optometrist at the Centre and treatment of other risk factors for use of the International Clinical for Eye Health, Paula Katalinic, was diabetic retinopathy such as blood Diabetic Retinopathy and Diabetic a member of the working group that pressure and cholesterol,’ Ms Katalinic Macular Oedema Disease Severity contributed to the revised guidelines. said. ‘It’s important that the results scale (Table 1). The scale simplifies Ms Katalinic, who completed a of the eye exam be communicated to classification of diabetic retinopathy three-year tenure at the renowned the patient’s GP or endocrinologist and is seen as a more clinically useful Joslin Diabetes Center in Boston, following every visit. measure than the Wisconsin scale it says that one of the main points the replaces. working group wanted to stress was ‘Understanding that the level of diabetic the important role of optometry in a retinopathy is predictive of the rate Multidisciplinary approach multidisciplinary diabetes team. of progression to vision-threatening disease is important. It will minimise Optometry Australia’s new guidelines ‘Whether or not a person with diabetes unnecessary referrals to ophthalmologists offer optometrists a concise resource has signs of diabetic retinopathy may for those who could be safely monitored to facilitate consultations and to influence the clinical decision-making by optometrists, and allow more encourage optimum health outcomes of GPs and endocrinologists in terms appropriately-timed referrals,’ Ms for the 1.6 million Australians of the optimal level of glycaemic diagnosed with diabetes mellitus. control for that particular patient, Continued page 4

Procedure Comments Visual acuity (with correction) Distance and Near, monocularly, including pinhole acuity if indicated Pupil reactions Direct/Consensual and Near pupillary responses Ocular motility Extent, fluency and symmetry of ocular movements in all directions of gaze, ruling out eye movement anomalies. Relevant history taking regarding the onset and direction of double vision is necessary. If is manifest, cover test and prism neutralization is also indicated. Visual field screening • Confrontation • Note: visual field screening and baseline testing in the absence of actual or suspected pathology of the visual pathways or brain will not attract a Medicare rebate for item 10940 or 10941. Refraction • On indication • Where patient reports a change in vision or visual function (e.g. increased glare sensitivity) or where a change in habitual visual acuity is measured. Slit lamp biomicroscopy • Recommended at every visit • Examination for iris neovascularisation (NV), diabetic , corneal integrity Tonometry As indicated, recommended pre- and post- pupil dilation Stereoscopic fundus examination • NHMRC guidelines describe pupil dilation using 0.5 to 1.0% tropicamide with pupil dilation as safe (noting dilated ocular fundus examination increases the sensitivity of DR screening) and so consider it mandatory in performing ophthalmoscopy or slit lamp biomicroscopy* unless contraindicated by the presence of potentially occludable anterior chamber angles • 2.5% phenylephrine hydrochloride, unless contraindicated, may help achieve maximum pupillary dilation in patients with DM, particularly those of Aboriginal and Torres Strait Islander descent and patients with heavy iris pigmentation • OAA pupil dilation guidelines can be viewed here • Symptoms of VA reduction or distortion of vision or a significant change of DM control should always prompt dilated pupil examination

Diabetic macular oedema is important to detect, as it is the most frequent cause of visual loss from retinopathy. DMO is best assessed using fundoscopy with slitlamp biomicroscopy (with pupil dilation), grading stereoscopic macular photo- graphs or OCT.

* Guidelines for the Management of Diabetic Retinopathy NHMRC 2008 http://www.nhmrc.gov.au/_files_nhmrc/publications/ attachments/di15.pdf accessed May 2013

Table 2. Recommended examination procedures for examining patients with diabetes 4 SEPTEMBER 2014

New guidelines From page 3

Katalinic said. ‘For instance, a person will be. ‘It really is true that a picture is early diagnosis and treatment to with mild non-proliferative diabetic worth a thousand words when it comes prevent vision loss. As never before, retinopathy has only a minimal risk to the education of a person with optometrists are ideally placed to of progressing to significant levels of diabetes,’ she said. detect previously undiagnosed cases of retinopathy in 12 months and can be diabetic retinopathy. safely monitored by the optometrist if the ‘It’s important for optometrists to build optometrist feels they have the clinical a professional relationship with their By familiarising yourself with the skills and knowledge to do so.’ local ophthalmologist and GP,’ Ms risk factors for developing diabetic Katalinic said. ‘It is worth letting them retinopathy, the severity scales and Table 2 (Page 3) lists recommended know that you want to work with them recommended referral patterns, you examination procedures for examining to best manage the patient’s visual can actively participate in the kind of patients with diabetes. needs. This, in turn, will lead to future multidisciplinary diabetes team that referrals of other patients. is necessary to ensure optimal patient Beyond the vitally important functions care. of diagnosis, monitoring and referral, ‘Practising to the standard of care, optometrists can play a key role dilating all patients with diabetes, Download the full Clinical guidelines in educating diabetic patients and accurately grading the level of diabetic for examining and managing patients encouraging adherence to a diabetes retinopathy and macular oedema, and with diabetes from the Optometry care plan by turning the discussions referring in a timely manner will build Australia website > For Optometrists > about their OCT scans and retinal respect and are likely to enhance the Guidelines. images into opportunities to educate. relationship with your fellow health- For patients with diabetes, seeing the care providers,’ she said. * The working group participants were: early visible clinical manifestations Giuliana Baggoley (convener until December of diabetic retinopathy reinforces the Following the TGA’s approval of 2013); Simon Hanna, Optometry Australia importance of blood glucose control fenofibrate as an indication to slow clinical policy adviser (convener from February 2014); Graham Fist, optometrist; and regular eye examinations. the progression of existing diabetic Eve Hsing, optometrist; Paula Katalinic, retinopathy in people with type 2 Principal Optometrist, Centre for Eye Paula Katalinic suggests saving a few diabetes, timely referral to GPs has Health and professional services manager, Optometry NSW/ACT; Josephine Li, de-identified images of late-stage become critical. As the new guidelines optometrist, Australian College of diabetic retinopathy to show to patients explicitly spell out, everyone with Optometry; Lisa Penrose, optometrist so they can understand that the better diabetes is at risk of developing and observer to the board of Optometry Queensland & Northern Territory; Roman care they take of themselves, the lower diabetic retinopathy, and thorough Serebrianik, Lead Optometrist Primary Care, their risk of vision loss due to diabetes eye examinations are important for Australian College of Optometry.

Diabetes report form

Report to Patient name Date of birth Referral pads Address

This patient with diabetes was examined on With this issue of Pharma Postcode Unaided vision RE LE Aided vision RE

is a complimentary pad of Intraocular pressures at am/pm were REfor ocular health LE assessment. Dilated examination Retinal photographs taken 50 diabetes report forms LE No retinopathy for members of Optometry Non-proliferative diabetic retinopathy Proliferative diabetic retinopathy > Mild Moderate Severe DrivetimeRadio CD Australia. The forms are a quick Diabetic Absent Present and easy way to share the Comments / Recommendations results of your examinations This issue of Pharma with other members of the also includes an audio

Referred to Ophthalmologist No CD with two 10-minute diabetes management team, Yes If Yes, Ophthalmologist: Yours sincerely segments on diabetic

and build your reputation as a Optometrist good communicator. retinopathy and a case study.

Date

Diabetes referral pad - July 2014.indd 1 Copyright © 2014 x8380

23/07/2014 3:34:44 PM SEPTEMBER 2014 5

Multidisciplinary approach to diabetic retinopathy

regularly to keep his licence. He afford to continue the visits. Rather Mike Jackson had not had an for than asking the ophthalmologist what some time and was using ready-made he could do, he simply gave up and BOptom (UNSW) spectacles that he had purchased from stopped attending. GOVOceania.com a petrol station. The changes in his were affecting Visual acuity was 6/12 in each eye and his vision but he managed until he met Dr Michael Chilov refraction did not help. His previous me. When I explained how urgently history included laser treatment and he needed to see an ophthalmologist, MB BS FRANZCO Avastin injections. He said he had not he said he would sell everything he Retina Associates visited his ophthalmologist for two owned so that he could afford to pay years because he could not afford the for specialist care. cost. It was my impression that he had not thought about his since his At this point I contacted Dr Michael previous consultation. Chilov, a retina sub-specialist at the Retina Associates ophthalmic centre A fundus examination revealed that the in Sydney to explain the situation. Dr CASE REPORT 1 patient had a long history of diabetic Chilov asked me to send the patient to retinopathy. (Figures 1 and 2) There were the centre the same day. scars from previous laser treatment, some lipid deposits and a haze around the Ophthalmologist Optometrist discs, which were probably from new vessels. The left eye was marked by a The patient seen by Mr Jackson was The story of this patient was first large pre-retinal haemorrhage reaching examined by me on the same day. He reported in November of 2013 in down and around the macula. had high-risk proliferative diabetic Australian Optometry. A 50-year- retinopathy with a left vitreous/ old male presented for a check-up at Given the magnitude of the situation, preretinal haemorrhage. He had our Sydney optometric practice only the patient and I had a long a 20-year history of diabetes with because he had to complete a form conversation about his situation and suboptimal glycaemic control and he for the Roads and Traffic Authority the severity of his condition. During had not seen an ophthalmologist for (RTA) of NSW. Because of his unstable our discussion, he told me he had almost two years. diabetes, he had been required by been seeing an ophthalmologist but the RTA to have his health assessed stopped going when he could no longer Continued page 6

Figure 1. Case 1. Fundus of right eye reveals laser treatment scars, Figure 2. Case 1. Fundus of left eye shows enormous pre-retinal lipid deposits and a haze around the discs haemorrhage 6 SEPTEMBER 2014

Figure 3. Case 1. Extensive neovacularisation at the right disc Figure 4. Case 1. Preretinal haemorrhage in the left eye (bilateral proliferative diabetic retinopathy)

Multidisciplinary approach From page 5

Figure 5. Case 1. Left eye post-treatment

When I examined him, there was The other aspect to this patient’s number of the challenges in managing bilateral proliferative diabetic treatment was his diabetic control. patients with diabetic retinopathy. All retinopathy, with a preretinal His glycated haemoglobin (HbA1C) optometric practices will have diabetic haemorrhage in the left eye and was 12.3 per cent (the general target patients and will be able to relate this extensive neovascularisation at the is less than seven per cent) suggesting case to patients they may have. right disc. The macula OCT also poor glycaemic control. In an effort to demonstrated macular oedema (Figure address this, I arranged a referral via It is important that optometrists are 3, right eye and Figure 4, left eye). his GP to an endocrinologist. active in the management of their diabetic patients—ensuring regular Prompt treatment was required in the Once the diabetic macular oedema had examination, developing a long- left eye to prevent further bleeding. come under control, I commenced PRP. term relationship with the patients, In patients with both proliferative Unfortunately, he has more recently attending to their vision and refractive retinopathy and macula oedema, developed macular oedema and is needs, educating them, reinforcing Avastin () is often requiring ongoing Avastin injections to need for regular screening to prevent used in the first instance. While manage this. His visual acuity is Right vision loss and organising appropriate panretinal photocoagulation remains 6/7.5 and Left 6/7.5+ (Figure 5, left eye and timely referral when required. the mainstay of proliferative diabetic post-treatment). retinopathy, it does take longer to The screening for diabetic retinopathy have an effect on neovascularisation Ultimately, the patient satisfactorily as part of a comprehensive eye and can worsen diabetic macular completed his RTA health assessment examination is a critical part of oedema. Avastin has the ability and was able to maintain his drivers diabetic management. This assessment to rapidly induce new vessel licence and return to his hobby of four- should be by way of a dilated fundus regression, prevent further bleeding wheel driving. examination. and treat the coexisting macular oedema, and is followed by PRP laser Importance of timely examinations Unfortunately, the circumstances surgery when the macular oedema is surrounding the presentation in this improved. This case amply demonstrates a case report are not uncommon in my SEPTEMBER 2014 7

practice. Whether it is the patient who managing a patient in conjunction multidisciplinary diabetes health-care wakes with acute vision loss from a with an ophthalmologist, the team. Patients who are receiving active vitreous haemorrhage as a result of ophthalmologist should receive a treatment for diabetic retinopathy with proliferative diabetic retinopathy, or diabetes report form with a summary an ophthalmologist should continue to the patient who fails their vision test of findings or concerns the optometrist see their optometrist. Their optometrist for their drivers licence from diabetic may have. can attend to the patient’s ongoing macular oedema, the goal of these refractive needs, monitoring for examinations is to detect early signs of Referral to an ophthalmologist treatment side-effects, such as raised retinopathy to allow early intervention depends on retinopathy grade and intraocular pressure and cataract, and and prevent this from occurring. presence of diabetic macular oedema. provide a valuable educational and All patients with sight threatening support role for these patients. Many cases of sight-threatening retinopathy—diabetic macular oedema retinopathy are not in patients in or proliferative retinopathy, as in this whom the signs were missed, but patient—should be promptly referred rather patients who have slipped to an ophthalmologist. Additionally, CASE REPORT 2 through the gaps. Many patients any patient complaining of reduced with potentially sight-threatening vision or unexplained reduced retinopathy will often be relatively acuity should be referred to an asymptomatic and not understand ophthalmologist for further assessment. Optometrist the need for regular assessment—or simply just forget. Optometry Australia’s newly revised This patient’s visit with me was clinical guidelines for the examination also prompted by the need to complete It is important to educate patients about and management of patients with a form for the RTA of NSW. These the need for ongoing annual reviews, diabetic retinopathy provide some required assessments commonly reveal even if they appear asymptomatic. guidance in this regard. The guidelines serious pathologies in patients who Optometric practices should have recommend the need for follow-up, otherwise would remain untreated. reminder systems in place to ensure referral and appropriate management their patients return for regular review according to retinopathy grade based On examination, we found his vision as per the screening guidelines. on recognised disease severity scales. to be RE 6/12 and LE 6/15. This was (See Page 2) due to his background retinopathy and Importance of timely referrals probably some . His retina The optometrist’s role extends beyond showed signs of drusen and some dot, Optometrists should aim to report assessment to diagnose retinopathy. blot and flame haemorrhages. their findings to the patient’s GP and Optometrists must be key players an endocrinologist (if involved). If and active participants within a Continued page 8

patient, so collaboration and communication of this Dr Anita Sharma information with the GP is vital,’ she said. General practitioner ‘Optometrists are really well-placed to proactively MBBS FRACGP identify diabetic retinopathy and refer these patients to GPs for consideration of fenofibrate and offer tactful Dr Anita Sharma has 24 years of experience as a general reminders about better glycaemic control as part of practitioner, with special training in treating diabetes “whole patient care”.’ and chronic diseases. She says that optometrists are ideally placed to advocate for optimal diabetes and Patients generally turn to the GP for most advice on health management, provided they work as part of a whether to commence a therapy so optometrists should team. leverage off of that,’ she said.

‘Optometrists who familiarise themselves with the Dr Sharma says that the level of glycaemic control, different classifications for diabetic retinopathy and the which is crucial for prevention of worsening diabetic evidence-based review and referral schedules have a huge retinopathy, is an important piece of information that is impact on the quality of patient care,’ she said. too often omitted in the correspondence between diabetes team members. Dr Sharma was keen to point out that even if the patient is being referred on to an ophthalmologist, it is essential to ‘All members of the multi-disciplinary team should be keep the GP informed, as a professional courtesy, for legal aware of the patient’s level of glycaemic control and purposes and to achieve the best health outcomes for the reiterate this point in their correspondence,’ she said. patient. ‘The GP is generally the most frequently-visited ‘This will go a long way in ensuring that action will health-care professional, even by the most non-compliant replace clinical inertia.’ 8 SEPTEMBER 2014

him to see optometrist Mike Jackson plaque is significant to the patient’s Multidisciplinary to monitor his progress six months health and the standard practice is to following his initial consultation with have a carotid Doppler test performed approach me. to check for blockage in the internal carotids. From page 7 I have found that it can often be helpful to alternate reviews with the patient’s Ophthalmologist optometrist and my scheduled reviews. This allows the patient to maintain a During the two-year interval between The patient, who was 67 years old, was relationship with their optometrist, examinations, the patient had being treated for diabetes, attend to any new refractive needs, developed the cholesterol embolus and and cholesterol. His vessels showed provide a further opportunity to his retinopathy had progressed to the crossing changes, consistent with educate the patient about diabetic severe non-proliferative stage. (Figures hypertension. retinopathy and detect any unexpected 6 and 7) changes. Unfortunately, this patient He just narrowly passed the RTA did not follow my recommendations When I reviewed him, I arranged for standard but we referred him to Dr and did not attend follow-up despite a carotid Doppler study to exclude Michael Chilov at Retina Associates for reminders. a carotid source for the embolus. a thorough review of his retinopathy. Because I was also concerned Optometrist about the worsening of his diabetic Dr Chilov wrote back, outlining how he retinopathy, I arranged for him to see had found the patient’s blood pressure About two years later, the patient his GP for review of his glycaemic and sugar level were too high and how returned to our practice with another and cardiovascular risk factor control. he encouraged him to work with his RTA form. His vision had slipped a No active ophthalmic intervention GP for better control to avoid future little to RE 6/12 LE 6/18. He reported was required as there was no diabetic blindness. Dr Chilov told the patient that his blood pressure was better but macular oedema and no proliferative that he wanted to see him again in his limited English made me unsure. I retinopathy. one year and to attend a review at our was unable to determine how his blood optometric practice in six months. sugar levels had been, but I clearly established that he had not been back Ophthalmologist to Dr Chilov.

This patient illustrates many of the His fundus still showed roughly points raised in the first case. When I the same level of retinopathy as his first saw him, he had mild to moderate previous consultation, except for a tiny non-proliferative diabetic retinopathy diamond-like embolus in the right eye, and no macular oedema. I was happy just over the macula, a Hollenhorst to review him in 12 months but wanted plaque. The presence of a Hollenhorst

Figure 6. Case 2. Right fundus photograph at initial presentation Figure 7. Case 2. Right fundus image two years later demonstrates demonstrating microaneurysms, grade one a cholesterol emolus lodged at a vessel bifurcation superior to the (AV nipping, copper wire reflex changes) and multiple hard drusen macula. There is progression of the retinopathy with cotton wool (intermediate and large) spots, retinal haemorrhages and early venous beading. SEPTEMBER 2014 9

Improve patient adherence Eye-drop dispensers assist delivery of IOP medication

a patient’s ability to instil drops tested ‘were able to correctly instil the Helen Carter correctly.1 eye-drop’, that is, squeeze out one drop and instil it into the conjunctival sac Some studies suggest that optometrists without bottle tip contact. should routinely show patients how to instil drops, watch them as they The study, entitled ‘Evaluating eye do it and then assess the patient’s drop instillation technique in patients’, eye-drop regimens ability to instil drops at each follow-up focused on the often overlooked have long been a significant problem consultation. cause of adherence problems—the for some patients but there is a unintentional, improper dosing and growing number of strategies and If patients are asked to demonstrate the instillation of glaucoma medication. devices available to help improve technique, an opportunity for teaching The researchers observed 70 primary their adherence to ocular hypertensive may present itself if the patient is open-angle and primary angle-closure therapy. having difficulty. Demonstrating and glaucoma patients, aged from 35 to 70 teaching proper drop instillation to years, who had been self-administering Among the most common reasons glaucoma patients using artificial glaucoma medications for at least six that patients give for their poor use of tears can be done by an optometrist or months. Those with arthritis, tremors prescribed IOP drops are difficulties another member of the practice staff and other impairments that might instilling eye-drops, inability to master who usually trains patients in contact interfere with their ability to correctly a technique, physical barriers and lens insertion and removal. instil drops were excluded. medication side-effects. Findings Patients were asked to instil one drop Recent studies corroborate these from a bottle of artificial tears into one patient comments, showing that A study published in the Journal of eye using the same technique that they many glaucoma patients are not Glaucoma in March 2012 found that use for glaucoma drops. The number of administering their drops correctly nine out of 10 glaucoma patients drops they squeezed out ranged from and suggesting that education about were not administering their drops one to eight. instillation techniques can improve correctly.2 Only six of 70 patients It is of concern that 31 per cent dropped the eye-drops on their or cheeks, and 75 per cent touched the tip of the bottle to their eye or periocular tissue, while only 28 per cent correctly closed their eyes after instilling drops. Just five per cent occluded their puncta.

In another inquiry into adherence strategies,3 entitled the ‘Eye drop instillation technique in patients with glaucoma’ study, researchers found that there was a significant association between education relating to eye-drop instillation technique and the patient’s ability to instil drops correctly.

Continued page 10

Owen Mumford Autosqueeze Eye Drop Pfizer’s Xal-Ease plastic eye-drop dispens- Dispenser and Owen Mumford Autodrop Eye er and cap opener suitable for use with Xal- Drop Dispenser. Reusable, lightweight plastic atan and Xalacom eye-drops. The dispenser devices that assist with the application of is available from Ophthalmologist FOC and eye-drops. They are available from Diabetes can be ordered in by the patient’s chosen and Medical Supplies. pharmacist from Pfizer. It is complimentary for Xalatan/Xalacom patients. 10 SEPTEMBER 2014

Adherence strategies From page 9

In the study, participants used self-administered topical medication for glaucoma or and were asked to demonstrate how they usually instil eye-drops using a 5 ml bottle of sterile artificial tear solution.

More than half—54.1 per cent or 46 of 85 patients—had a poor drop technique, 11.8 per cent missed the eye, 15.3 per cent touched the tip of the bottle to the bulbar conjunctiva or , and 27.1 per cent touched the or lashes with the bottle tip. Most—81.2 per cent— could not recall being shown how to instil eye-drops but previous instruction regarding drop instillation technique was significantly associated with good technique and increasing age was associated with poor technique.

The study authors recommended that the assessment of a patient’s ability to instil eye-drops correctly should be a routine part of a glaucoma examination.

Strategies

Therapeutically-endorsed Gippsland optometrist Ken Thomas believes the biggest adherence issue is getting elderly, immobile patients to maintain regular contact with either an optometrist or an ophthalmologist.

‘I am concerned that a number of patients, especially in rural areas, simply rely on their GP repeating the glaucoma script, and do not receive appropriate monitoring of intra- ocular pressures, fields and optic nerve head appearance,’ he said. ‘The challenge for our profession is to try and stop One device, these people “falling through the cracks”.’

One drop, Working in a rural area, he often has patients alternate visits between him and their ophthalmologist, or primarily One range. see him and have infrequent trips to their ophthalmologist. ‘This is primarily to minimise their travel. Glaucoma patients generally are in the older age group, they often Xal-Ease is an aid to help ease the administration of Pfizer don’t drive and often have co-morbidities that contribute glaucoma eye drops, dispensing a single drop of medication to mobility issues,’ he said. ‘This can make it difficult directly into the eye. Making daily eye drops easy to instil to get to their specialist. They are often dependent on may help to enhance patient satisfaction with treatment.1 family or friends to take time off work to transport them to Melbourne and they don’t like to impose on them.

Reference: 1. Nordmann JP et al. Eur J Ophthalmol 2009;19(6):949–56. TM Trademark and ® Registered Trademark. © 2014 Pfizer. All rights reserved. Pfizer Australia Pty Limited. ABN 50 008 422 348. 38-42 Wharf Road, West Ryde NSW 2114. Pfizer Medical Information: 1800 675 229. PEPX0011 P8409 1/14.

PEPX0011_XalEase Resize 102x297_FA.indd 1 4/02/2014 11:27 am SEPTEMBER 2014 11

‘Many patients appreciate the fact that field testing and OCT scans have lower cost when performed in an optometric setting compared to an ophthalmological clinic, and we are happy to provide copies of these reports for our patients to present to their glaucoma specialist.’

Thomas says the high use of prostaglandins (nearly 50 per cent of PBS glaucoma prescriptions) and increasing uptake of combination agents (29 per cent of PBS glaucoma scripts) means most patients are on monotherapy and require only one drop per day.

‘This is a huge advantage in ensuring The Opticare eye-drop dispenser fits Autodrop Eyedrop Dispenser. A plastic adherence to the treatment regimen. securely around the eye, prevents touch dispenser, shaped and contoured to fit over a Ensuring that the drop is always taken contamination and ensures that drops go bottle of eye-drops, and around the eye sock- at the same time of day is important for into the eyes and not down the cheek. The et to assist with easy, accurate dispensing compliance, more than for IOP control,’ UK-designed product is sold in Australia by of drops. Available in Australia from Diabetes he said. He suggests to patients that it the Melbourne-based distributor Intelligent and Medical Supplies. might help if they stick a permanent Health Systems. note near their toothbrush, to remind them to have their eye-drops.

‘If patients report difficulty with their drops, I usually instruct them to lie back, close their eyes and apply the but suggested the term ‘non-adherence’ did some work with its Xalatan-bottle drop to the inner canthal region,’ be used. device and found it was a significant Thomas said. ‘Then the eyes are aid for 50 per cent of patients,’ he said. opened and this achieves adequate ‘It’s a very complicated area of study ‘Alcon also did work with its Travatan delivery of the medication. Most with wide variations in the reasons Dosing Aid (TDA) and found a similar patients are surprised to hear that the different patients don’t adhere,’ he figure. One of the challenges is that the eye retains only one-fifth to one-tenth said. ‘Some are personal reasons various bottles are so different. What of an eye-drop.’ including disease “philosophy”, would work for a bottle of Xalatan understanding and education, while won’t work for Cosopt. Thomas doesn’t usually recommend for others there are socio-economic eye-dropper aids but says they work reasons. Some have side-effect induced The national executive officer of well for some patients. reasons and others have physical Glaucoma Australia, Geoff Pollard, said barriers to self-administration— the organisation supplied a limited Side-effects can be another reason for “discompliance”—such as tremor, number of free aids depending on the poor adherence. arthritis, muscle weakness and poor eye-drop manufacturers supplying hand-eye co-ordination. them to the foundation. ‘Alpha agonists have a high rate of allergic reaction, with up to 25 per ‘Some reasons are disease-related cent of patients developing a problem. and while glaucoma is relatively Median time for these follicular or asymptomatic, chronic and incurable, dermatological reactions is 12 months progress is often slow so there is so often the optometrist will be the first no immediate “price” paid by the person to notice this change,’ he said. patient that they notice for omitted ‘Other reactions other than redness are medications. not commonly encountered. It is vital for the optometrist to communicate ‘This truly needs to be individualised 1. Waterman H, Evans JR, Gray TA, with the initiating ophthalmologist if solutions are to be found to help Henson D, Harper R. Interventions before changing any medications.’ each patient, as each is unique and for improving adherence to ocular hypotensive therapy. Cochrane Database what motivates and influences long- Syst Rev 2013; 4: CD006132. doi: Head of the Sydney Eye Hospital term adherence and persistence varies 10.1002/14651858.CD006132.pub3. Glaucoma Unit, Glaucoma Australia enormously and might well change for 2. Gupta R, Patil B, Shah BM et al. Evaluating eye-drop instillation president and Clinical Associate an individual over time,’ Goldberg said. technique in glaucoma patients. J Professor of Ophthalmology, University Glaucoma 2012; 21: 3: 189-189. of Sydney, Professor Ivan Goldberg Professor Goldberg suggested various 3. tatham AJ, Sarodia U, Gatrad F, Awan A. Eye drop instillation technique in said that probably about two-thirds of aids be mentioned so patients can patients with glaucoma. Eye 2013; 27: glaucoma patients were non-compliant consider them when necessary. ‘Pfizer 1293-1298. doi:10.1038/eye.2013.187. 12 SEPTEMBER 2014

the efficacy of topical corticosteroid self-reported rates of cigarette use, Dr Laura Downie treatment with topical non-steroidal any nicotine product use, and serum anti-inflammatory drugs therapy, cotinine levels were used to produce following uncomplicated cataract estimates of potential smoking BOptom PhD(Melb) PGCertOcTher surgery. The main outcome measure deception among adults older than 40 FACO FAAO DipMus(Prac) AMusA was defined as post-operative years with any-level of AMD and those inflammation and pseudophakic at risk of late-stage disease. cystoid macular oedema (PCME), in patients undergoing Any-level AMD was evident in 6.7 per with posterior cent (95% CI, 5.6-7.8 per cent) of this ABSTRACTS chamber intraocular lens implantation cohort. Excluding those with late-stage for age-related cataract. AMD, 9.7 per cent (95% CI, 8.3-11.0 per cent) were at risk of developing A total of 15 randomised clinical trials late-stage disease. Among individuals Association between reproductive were identified from the systematic with any level of AMD, 5.4 per cent factors and AMD in post- literature search. Post-operative (95% CI = 2.1-8.6 per cent) were menopausal women inflammation was reported to be less potential smoking deceivers. A similar in patients randomised to NSAIDs. The rate was seen among those at risk of A population-based, cross-sectional prevalence of PCME was significantly late-stage disease at 5.0 per cent (95% study conducted in Korea has higher in the corticosteroid group than CI = 2.3 per cent to 7.6 per cent). described an association between in the NSAID group (3.8 per cent vs female reproductive factors and the 25.3 per cent; risk ratio: 5.35, 95% CI, The findings suggest that as many as development of late-stage AMD in post- 2.95-9.76). There was no significant 450,000 adults in the USA who are at menopausal women. difference in the number of adverse risk of late-stage AMD misclassify their events between the two treatment smoking status. A nationally-representative dataset groups. that included reproductive and ocular Optom Vis Sci 2014. June 26. Epub ahead of health information for 4,377 post- It was concluded that there was low print. menopausal women (aged ≥ 50 years) to moderate quality of evidence that was analysed from the 2010-2012 topical NSAIDs are more effective How do Müller cells work? Korea National Health and Nutrition in controlling post-operative Examination survey. inflammation after . A paper in the prestigious journal High-quality evidence was found Nature Communications has described Prevalence rates of early and late AMD to support the premise that topical the wavelength-dependent wave were 11.2 per cent (95% confidence NSAIDs are more effective than topical guiding properties of retinal Müller interval [CI], 10.1-12.5) and 0.8 per corticosteroids in preventing PCME. cells. cent (95% CI, 0.5-1.2), respectively. Multivariate logistic regression The authors recommended the Retinal Müller cells separate between analyses revealed that age (OR, 1.12 use of topical NSAIDs to prevent wavelengths to improve day vision per one year), duration of lactation inflammation and PCME after routine with minimal effect on night vision. (OR, 0.91 per six months), and duration cataract surgery. of use of oral contraceptive pills Using computational modelling and (OCP) (OR, 1.10 per six months) were Ophthalmology 2014; June 13. Epub ahead experimental imaging methods, the associated factors for late-stage AMD. of print. authors found that Müller cells, which are the major type of glial cells in the The authors concluded that after Smoking deception and AMD retina, concentrate the green-red part controlling for confounders, a longer of the visible spectrum onto cone duration of lactation appeared to Smoking deception rates for patients photoreceptors, thereby allowing the protect against the development of late with AMD were found to be higher blue-purple part to leak onto nearby rods. AMD. A longer duration of OCP use than generally reported in the US was associated with a higher risk of population. Light propagation by Müller cells late-stage AMD. through the retina was reported to Smoking has been consistently be an integral part of the first step in PLoS One 2014; 9: 7: e.102816. identified as the most important the visual process, increasing photon modifiable risk factor for age-related absorption by cones while minimally Preventing pseudophakic cystoid (AMD). Smoking affecting rod-mediated vision. macular oedema following cataract deception, or failing to self-report as surgery a smoker, is a concern in studies of Nat Commun 2014; 5: 4319. smoking-related disease. A review has found weak evidence A novel ciprofloxacin-releasing for the use of topical non-steroidal Data from the 2005 to 2008 National silicone hydrogel contact lens anti-inflammatory drug (NSAIDs) Health and Nutrition Examination therapy in controlling post-operative Survey were used to produce estimates A novel silicone hydrogel contact inflammation after cataract surgery. of smoking deception among three lens designed for the extended release ethnic groups within the United of ciprofloxacin may be beneficial The systematic review has compared States population. Comparisons of to supplement or augment future SEPTEMBER 2014 13

treatments for microbial . stromal demarcation was 252.9 ± 40.8 patients undergoing cataract surgery μm (range: 208 to 360 μm), with no using a validated questionnaire. Model silicone hydrogel contact lens significant effect on endothelial cell materials were synthesised using a count (p = 0.06). Prior to cataract surgery, approximately molecular imprinting technique to half of patients reported poor sleep. augment ciprofloxacin-release kinetics. The authors concluded that based Cataract removal was found to Various contact lens properties, on the corneal stromal demarcation significantly improve overall sleep including light transmission and line depth and the absence of adverse quality and sleep latency at one surface wettability were determined, corneal outcomes, this technique month post-operatively; this effect was and the in vitro ciprofloxacin-release appeared to be safe and effective in sustained at 12 months. kinetics elucidated using fluorescence performing CXL in relatively thin spectrophotometry. The synthesised . It was concluded that these data materials were then evaluated for demonstrate that implantation of blue- their ability to inhibit Pseudomonas J Refract Surg 2014; 6: 366-372. filtering IOLs do not have a negative aeruginosa growth, both in vitro and in impact upon the sleep-wake cycle, a rabbit model of microbial keratitis. Girls benefit from cheese compared with UV-blocking IOLs.

The synthesised contact lenses were A prospective study conducted in Invest Ophthalmol Vis Sci 2014. June 26. described to have material properties Australian adolescents has found that Epub ahead of print. similar to those of commercial lens the consumption of dairy products, materials and released ciprofloxacin for in particular cheese may have a Corneal sensitivity and tear function more than eight hours. It was reported beneficial effect on blood pressure (BP), in neurodegenerative disease that in vivo, there was no statistically particularly among girls. significant difference between the Neurodegenerative diseases may number of colony forming units The study aimed to prospectively be associated with reduced corneal (CFU) recovered from corneas treated assess whether dairy food sensitivity and abnormal tear function. with ciprofloxacin eye drops (0 CFU/ consumption (milk, cheese, yoghurt) cornea) and those treated with one of was associated with BP and In this study, corneal sensitivity two modified contact lenses (mean: retinal microvascular signs among and tear function were measured 4.3x10^3 CFU/cornea and 2.1x10^3 adolescents. A total of 2353 12-year- in patients with different forms of CFU/cornea). olds and 1216 17-year-olds were neurodegenerative disease and findings examined; longitudinal analyses were compared with age- and sex- Invest Ophthalmol Vis Sci 2014; Jul 15. involved 888 subjects with complete matched controls. Epub ahead of print. baseline and follow-up data. Patients with Alzheimer’s disease Contact lens-assisted collagen After multivariable adjustment, in girls (n = 20), multiple sclerosis (n = cross-linking each serve/day increase in total dairy 20), Parkinson’s disease (n = 30), intake was concurrently associated Friedreich’s ataxia (n = 10) and A report in the Journal of Refractive with 1.04 (p = 0.03) and 1.10 mmHg (p epilepsy (n = 21) were recruited from a Surgery describes a novel method = 0.02) decreases in mean diastolic and tertiary department. Corneal of contact lens-assisted corneal arterial BP respectively; each serve/ sensitivity was measured using the collagen cross-linking (CXL) in eyes day increase in cheese intake over Cochet-Bonnet aesthesiometer. Tear with corneal thicknesses that would five years was concurrently related to function tests included tear-break-up- typically preclude standard CXL. 7.18 (p = 0.001), 5.28 (p = 0.002) and time (TBUT) and Schirmer test without 5.79 mm Hg (p = 0.001) decrease in anaesthesia. Findings from 14 eyes with progressive mean systolic, diastolic and arterial BP, keratoectasia and corneal thicknesses respectively. Compared with control subjects, mean between 350-400 microns, following corneal sensitivity was significantly epithelial debridement, were included Nutr Metab Cardiovasc Dis 2014. June 14. reduced in all of the pre-defined in the case series. After epithelial Epub ahead of print. patient groups with neurodegenerative abrasion, iso-osmolar riboflavin 0.1 per disease (p < 0.05), except for patients cent in dextran was applied every three Cataract surgery improves sleep for with Friedreich’s ataxia (p > 0.05). minutes for 30 minutes. An ultraviolet patients with IOLs Mean TBUT was also significantly (UV) barrier-free soft contact lens shorter in patients with Alzheimer’s soaked in iso-osmolar riboflavin 0.1 per It has been found that a patient’s disease and multiple sclerosis than cent for 30 minutes was placed on the overall sleep quality and sleep latency controls (p < 0.05). Mean Schirmer test cornea. is improved after cataract removal, was relatively lower only in epilepsy irrespective of the type intraocular lens patients (p < 0.05). Once the minimum corneal thickness (IOL) that is implanted. value was confirmed to be greater than These findings suggest the presence 400 microns with the contact lens in This study investigated the level of of varying degrees of abnormality in situ, UVA irradiance was commenced; sleep disturbance in patients both corneal sensitivity and tear function iso-osmolar 0.1 per cent riboflavin before and after cataract surgery, and in different forms of systemic was also instilled in the pre-corneal compared the effect of the implantation neurodegenerative disease. and pre-contact lens region during the of UV-blocking or blue-filtering IOLs. procedure. The mean depth of CXL Quality of sleep was quantified in 961 Curr Eye Res 2014; Jun 23:1-6. 14 SEPTEMBER 2014

Optic nerve head drusen OCT analysis and controversial treatment options

Optic nerve head drusen (ONHD) is not direct pressure on the axons as Malcolm Gin an uncommon finding with a reported well as ischaemia as a result of the BScOptom FVCO prevalence of between 0.4 and 3.7 per compromise to the vascular supply. cent of the population.1 Its inheritance is Literature reports the incidence of considered autosomal dominant linked visual field defects varying from 24 up Catherine Cheah with small ONH and a small optic to 87 per cent,1 typically arcuate and BOptom foramen, and the drusen bodies are not dissimilar to primary glaucoma. calcified acellular deposits. They range in size from five to 1,000 microns and OCT analysis details a thinning are located in the prelaminar portion of of the retinal nerve fibre layer in the optic nerve head. accordance with the loss (Figure 3, and normative data details, Figure 4), ONHD is often buried when young and and the loss can be devastating. All as the glial tissue overlying the retina eye-care practitioners should be aware thins, the drusen become more obvious of the greater risk of ischaemic optic and fluoresce (Figures 1 and 2). Fundus neuropathy with ONHD and caution autofluoresence highlight the drusen patients on sudden unilateral loss of due to the refractile nature of the either field or vision. calcium; however, the definitive test is B scan ultrasonography. Differential Treatment options diagnosis from true papilloedema is essential as the latter signifies raised Treatment for visual field loss with intracranial pressure that can be life ONHD is controversial. Modalities threatening range from no treatment through to medical therapy and on to surgical As the drusen become more visible, options such as ONH decompression visual field defects emerge due to and radial optic neurotomy. Success

1 2

Figures 1 and 2. Fundus autofluoresence highlights the drusen due to the refractile nature of the calcium, but the definitive test is B scan ultrasonography. SEPTEMBER 2014 15

of the modalities seems to be based on anecdotal evidence as in general, the number of cases is small and the changes are slow and occur over a long period.

Grippo and colleagues (2008)2 studied 103 eyes with ONHD and found that in the group of 22 who had coincidental ocular hypertension, 90.9 per cent had visual field loss compared with 66.7 per cent who were normotensive.

It is unclear whether ONHD masks glaucoma or whether ONHD is a risk factor for glaucoma. Certainly, the use of glaucoma medications seems a logical step given this association, and it is intuitive to try to reduce the intraocular pressure and also improve the vascular perfusion of the optic nerve.

Change appears to be the catalyst to begin treatment. Baseline visual fields and OCT is essential, along with careful monitoring of the patient. Loss is generally slow; however, if there Figure 3. OCT analysis shows a thinning of the retinal nerve fibre layer are signs of progression then therapy should be considered. Brimonidine has shown neuroprotective characteristics in the rat model3 but it has a greater incidence of allergy. Current theory suggests hypotension should be avoided to preserve vascular perfusion relegating beta blockers to second- tier treatment. Prostaglandins may therefore be first-line course of action.

Prescribing of glaucoma agents for ONHD is considered an ‘off label’ process, so the cost to the patient is not subsidised by the government. This is an important consideration, given that the use of glaucoma medication is speculative in ONHD and the cost may be prohibitive for some. Careful counselling should be undertaken and patients given informed choices—even though no good scientific studies support the benefit, the rationale is solid and if there is a chance of preserving vision and field with a safe and proven medication, then it should be considered. Figure 4. Normative date details

1. referrers guide to optic nerve head drusen. Centre for Eye Health 2011 www.cfeh.com.au. 2. Grippo T, Shihadeh W, Shargus M et al. Optic nerve head drusen and visual field loss in normotensive and hypertensive eyes. J Glaucoma 2008; 17: 2: 100-104. 3. Galanopoulos A, Goldberg I. Clinical efficacy & neuroprotective effects of brimonidine in the management of glaucoma and ocular hypertension. Clin Ophthalmol 2009; 3: 117-122. 16 SEPTEMBER 2014

Corneal collagen cross-linking for keratoconus

to the anterior 300-350 µm, with improvement in UCVA by 2.85 Snellen 12 Dr Elsie Chan endothelial cell damage occurring lines and BSCVA by 2.03 lines. when the corneal thickness falls below 400 µm.4,8 (Figure 1) One of the only randomised, controlled FRANZCO trials comparing eyes treated with CXL Clinical results and control eyes has been conducted in Melbourne at the Centre for Eye In 2003, Wollensak and colleagues Research Australia and the Royal published the first clinical results of Victorian Eye and Ear Hospital. In this CXL for progressive keratoconus.2 They trial, we found that Kmax flattened reported that progression stopped in all by a mean of -1.03 D after three years treated eyes with a mean improvement in treated eyes, whereas eyes in the Corneal collagen cross-linking of -2.01 D in the maximum keratometry control group steepened by +1.75 D. (CXL) was introduced in 1998 as a value (Kmax) on A similar trend was seen in UCVA.13 treatment that could potentially halt after an average follow-up period of (Figure 2) the progression of keratoconus.1 Since 23 months. Since then, numerous the first clinical study of CXL was case series have been published Studies focusing on the paediatric published in 2003,2 CXL has been supporting these results, with reported population have reported more variable rapidly incorporated into clinical improvements in Kmax ranging from results compared to the adult age practice. A growing number of -0.49 D to -2.66 D.9,10 Changes in group, with changes in Kmax ranging modifications to the treatment protocol uncorrected visual acuity (UCVA) and from an improvement of -1.27 D after are now being explored in an effort to best spectacle-corrected visual acuity two years14 to 55 per cent of eyes increase the efficacy and safety of the (BSCVA) have been more variable, progressing by three years.15 There may treatment. with several studies reporting a modest be a less sustained effect due to a more or no change in UCVA,11 whereas rapidly progressing disease in this Background Caporossi and colleagues reported an younger age group.

CXL is based on the theory that the decreased biomechanical strength in keratoconus is related to a reduction in cross-links within collagen fibres.3 The treatment utilises a photosensitiser, riboflavin (vitamin B2) which is exposed to ultraviolet A (UVA) irradiation to produce an oxygen- dependent chemical reaction, leading to cross-linking. Riboflavin also absorbs UVA to limit the depth of its effect.

The procedure is performed under topical anaesthesia, followed by a nine-millimetre epithelial debridement. This is necessary as riboflavin does not penetrate through an intact epithelial layer. Riboflavin drops are then instilled for 30 minutes followed by UVA irradiation (3mW/cm2) for a further 30 minutes, during which the riboflavin drops are continued.4

Pre-clinical studies have shown that CXL increases the corneal collagen diameter by 12.5 per cent, increases its stiffness by over 300 per cent and increases its stability to enzymatic Figure 1. Intra-operative photograph demonstrating the ultraviolet digestion.5-7 The treatment depth has light source irradiating the cornea, which has been soaked with also been demonstrated to be limited ­riboflavin SEPTEMBER 2014 17

∆Kmax control CXL using UVA at 18mW/cm2 for five 2.5 minutes was unchanged compared ∆Kmax CXL to control eyes.24 A clinical study 2 comparing accelerated (30mW/cm2 for three minutes) and conventional CXL 1.5 found an improvement in Kmax in the conventional group and Kmean (mean 1 keratometry value) in both groups compared to baseline after 12 months.25 0.5 l Treatment of thin corneae 0 ∆ Kmax (D) -0.5 Treatment of corneae less than 400 µm has been shown to lead to endothelial 26 -1 cell damage. Modifications in the treatment protocol are therefore -1.5 necessary before treatment can be 3 6 12 24 36 considered these eyes. One option is the use of hypotonic riboflavin to swell Follow-up (months) the cornea, although there are limited published results using this technique. Figure 2. Bar graph showing the mean change in maximum simulated Two studies suggest stabilisation of ­keratometry value (Kmax) between baseline and 3, 6, 12, 24 and 36 months after keratoconus 12 months following treatment for the control and treatment groups. In the control group, there was a treatment without any damage to significant increase in Kmax compared with continued flattening observed in the the endothelial cells.27,28 Our own treatment group. The columns represent the mean change in Kmax from baseline (DKmax) in dioptres (D) and the error bars represent the standard error. CXL = unpublished data also support the corneal collagen cross-linking.13 safety and efficacy of using hypotonic riboflavin.

l CXL with refractive surgery

Overall, most studies report group. One of the more popular means As CXL gives only modest stabilisation in Kmax in over 80 to enhance penetration of riboflavin improvements in visual acuity, there per cent of treated eyes. Longer across the epithelium has been to use has been much interest in combining term studies suggest stability of the additional agents such as EDTA and CXL with refractive procedures such treatment until at least four to six benzalkonium chloride in combination as intra-corneal ring segments, PRK years.16 with riboflavin. Despite the popularity and phakic intraocular lenses. Results of trans-epithelial CXL, clinical results suggest that refractive procedures Complications have been variable, ranging from combined with CXL can lead to flattening of Kmax by -2.97 22D to significant improvements in visual Complications following CXL have progression by +0.48 D,23 suggesting acuity for at least 12 months.29-31 been reported. While a temporary that this technique may be less Some authors also advocate using stromal haze is seen in almost 90 per effective than conventional treatment. CXL to stabilise the cornea during cent of treated eyes (Figure 3), up to 8.6 refractive procedures for patients at per cent of cases have been reported l Accelerated CXL risk of developing ectasia,32 although to permanently affect visual acuity.17 there remains a lack of clinical data Other complications include treatment Treatment protocols using decreased to support the efficacy of CXL for this failure, sterile infiltrates (up to 7.6 irradiation times are gaining indication. per cent of eyes), scarring,18 infectious popularity. While the conventional keratitis19 and irreversible corneal protocol achieves a total UVA exposure Other indications oedema.20 Rare complications include of 5.4J/cm2 with 30 minutes of UVA corneal melting and perforation.21 at 3mW/cm2, a similar exposure is The efficacy of CXL for keratoconus has possible by increasing the irradiance led to its use in other corneal ectasias Variations in CXL treatment protocol and decreasing the treatment time including post-LASIK ectasia and according to the Bunson-Roscoe law of pellucid marginal degeneration. l Trans-epithelial treatment reciprocity. While devices offering UVA at higher irradiances are commercially Continued page 18 There has been much interest in the available and being used widely, establishment of a technique to enable there remains limited evidence for CXL to be performed without epithelial accelerated CXL in the peer-reviewed debridement. Trans-epithelial or literature. There may also be a limit to ‘epithelium-on’ CXL has the advantage the minimum treatment time, as oxygen of minimising post-operative pain and depletion may occur with higher reducing the risk of infectious keratitis. oxygen usage rates at high irradiances. It may also be useful in the treatment Hammer and colleagues demonstrated of thin corneae and the paediatric age that the in vitro stiffening effect of 18 SEPTEMBER 2014

CXL for keratoconus From page 17

Conclusion

The current recommendations for CXL are in eyes with documented progression of keratoconus where the corneal thickness is above 400 µm at the time of treatment. While results show a modest improvement in corneal topography and visual Figure 3. Slitlamp photograph of post-operative haze one month acuity measurements, stability can following treatment be achieved in over 80 per cent of treated eyes with only a small risk of treatment-related complications. Further clinical studies with extended P, Shah SP. A randomised, prospective crosslinking: bilateral study. J Cataract follow-up are needed to establish study to investigate the efficacy of Refract Surg 2012; 38: 283-291. the safety and efficacy of alternative riboflavin/ultraviolet A (370 nm) 23. Koppen C, Vryghem JC, Gobin L, corneal collagen cross-linkage to halt Tassignon MJ. Keratitis and corneal treatment protocols. the progression of keratoconus. Br J scarring after UVA/riboflavin cross- Ophthalmol 2011; 95: 1519-1524. linking for keratoconus. J Refract Surg 12. Caporossi A, Mazzotta C, Baiocchi 2009; 25: S819-823. S, Caporossi T. Long-term results of 24. Hammer A, Richoz O, Arba Mosquera 1. Spoerl E, Huhle M, Seiler T. Induction riboflavin ultraviolet a corneal collagen S, Tabibian D, Hoogewoud F, Hafezi F. of cross-links in corneal tissue. Exp Eye cross-linking for keratoconus in Corneal biomechanical properties at Res 1998; 66: 97-103. Italy: the Siena eye cross study. Am J different corneal cross-linking (CXL) 2. Wollensak G, Spoerl E, Seiler T. Ophthalmol 2010; 149: 585-593. irradiances. Invest Ophthalmol Vis Sci Riboflavin/ultraviolet-A-induced 13. Wittig-Silva C, Chan E, Islam FM, Wu T, 2014; 55: 2881-2884. collagen crosslinking for the treatment Whiting M, Snibson GR. A randomized, 25. Tomita M, Mita M, Huseynova T. of keratoconus. Am J Ophthalmol 2003; controlled trial of corneal collagen Accelerated versus conventional corneal 135: 620-627. cross-linking in progressive keratoconus: collagen crosslinking. J Cataract Refract 3. andreassen TT, Simonsen AH, Oxlund three-year results. Ophthalmology 2014; Surg 2014; 40: 1013-1020. H. Biomechanical properties of 121: 812-821. 26. Kymionis GD, Portaliou DM, Diakonis keratoconus and normal corneas. Exp 14. Vinciguerra P, Albe E, Frueh BE, Trazza VF, Kounis GA, Panagopoulou SI, Eye Res 1980; 31: 435-441. S, Epstein D. Two-year corneal cross- Grentzelos MA. Corneal collagen cross- 4. Spoerl E, Mrochen M, Sliney D, Trokel linking results in patients younger than linking with riboflavin and ultraviolet-A S, Seiler T. Safety of UVA-riboflavin 18 years with documented progressive irradiation in patients with thin corneas. cross-linking of the cornea. Cornea 2007; keratoconus. Am J Ophthalmol 2012; Am J Ophthalmol 2012; 153: 24-28. 26: 385-389. 154: 520-526. 27. Hafezi F, Mrochen M, Iseli HP, Seiler T. 5. Wollensak G, Wilsch M, Spoerl E, Seiler 15. Chatzis N, Hafezi F. Progression of Collagen crosslinking with ultraviolet-A T. Collagen fiber diameter in the rabbit keratoconus and efficacy of pediatric and hypoosmolar riboflavin solution cornea after collagen crosslinking by [corrected] corneal collagen cross- in thin corneas. J Cataract Refract Surg riboflavin/UVA. Cornea 2004; 23: 503- linking in children and adolescents. J 2009; 35: 621-624. 507. Refract Surg 2012; 28: 753-758. 28. Raiskup F, Spoerl E. Corneal cross- 6. Spoerl E, Wollensak G, Seiler T. 16. O’Brart DP, Kwong TQ, Patel P, linking with hypo-osmolar riboflavin Increased resistance of crosslinked McDonald RJ, O’Brart NA. Long-term solution in thin keratoconic corneas. Am cornea against enzymatic digestion. Curr follow-up of riboflavin/ultraviolet A J Ophthalmol 2011; 152: 28-32 e21. Eye Res 2004; 29: 35-40. (370 nm) corneal collagen cross-linking 29. Yeung SN, Ku JY, Lichtinger A, Low SA, 7. Wollensak G, Spoerl E, Seiler T. to halt the progression of keratoconus. Kim P, Rootman DS. Efficacy of single or Stress-strain measurements of human Br J Ophthalmol 2013; 97: 433-437. paired intrastromal corneal ring segment and porcine corneas after riboflavin- 17. Raiskup F, Hoyer A, Spoerl E. Permanent implantation combined with collagen ultraviolet-A-induced cross-linking. J corneal haze after riboflavin-UVA- crosslinking in keratoconus. J Cataract Cataract Refract Surg 2003; 29: 1780- induced cross-linking in keratoconus. J Refract Surg 2013; 39: 1146-1151. 1785. Refract Surg 2009; 25: S824-828. 30. Coskunseven E, Sharma DP, Jankov MR 8. Wollensak G, Aurich H, Pham DT, 18. Koller T, Mrochen M, Seiler T. 2nd, Kymionis GD, Richoz O, Hafezi Wirbelauer C. Hydration behavior Complication and failure rates after F. Collagen copolymer toric phakic of porcine cornea crosslinked with corneal crosslinking. J Cataract Refract intraocular lens for residual myopic riboflavin and ultraviolet A. J Cataract Surg 2009; 35: 1358-1362. after intrastromal corneal Refract Surg 2007; 33: 516-521. 19. Sharma N, Maharana P, Singh G, Titiyal ring segment implantation and corneal 9. asri D, Touboul D, Fournie P, Malet F, JS. Pseudomonas keratitis after collagen collagen crosslinking in a 3-stage Garra C, Gallois A, Malecaze F, Colin crosslinking for keratoconus: case report procedure for keratoconus. J Cataract J. Corneal collagen crosslinking in and review of literature. J Cataract Refract Surg 2013; 39: 722-729. progressive keratoconus: multicenter Refract Surg 2010; 36: 517-520. 31. Kanellopoulos AJ. Comparison of results from the French National 20. Sharma A, Nottage JM, Mirchia K, sequential vs same-day simultaneous Reference Center for Keratoconus. J Sharma R, Mohan K, Nirankari VS. collagen cross-linking and topography- Cataract Refract Surg 2011; 37: 2137- Persistent corneal edema after collagen guided PRK for treatment of 2143. cross-linking for keratoconus. Am J keratoconus. J Refract Surg 2009; 25: 10. Henriquez MA, Izquierdo L Jr, Ophthalmol 2012; 154: 922-926 e921. S812-818. Bernilla C, Zakrzewski PA, Mannis 21. Labiris G, Kaloghianni E, Koukoula S, 32. Tomita M, Yoshida Y, Yamamoto Y, M. Riboflavin/Ultraviolet A corneal Zissimopoulos A, Kozobolis VP. Corneal Mita M, Waring Gt. In vivo confocal collagen cross-linking for the treatment melting after collagen cross-linking for laser microscopy of morphologic of keratoconus: visual outcomes and keratoconus: a case report. J Med Case changes after simultaneous LASIK and Scheimpflug analysis.Cornea 2011; 30: Rep 2011; 5: 152. accelerated collagen crosslinking for 281-286. 22. Filippello M, Stagni E, O’Brart D. : One-year results. J Cataract 11. O’Brart DP, Chan E, Samaras K, Patel Transepithelial corneal collagen Refract Surg 2014; 40: 981-990. SEPTEMBER 2014 19

Alzheimer’s disease and the eye Group investigates retinal Aß plaques

In addition to , the Australia’s baby-boomer bulge Dr Christine Nguyen eye can also give insight into brain means that in the coming decade, disorders. The eye is an out-pouching a dramatic shift in the demand for of the brain and if parallel changes health care will manifest itself—from BScOptom PhD Melb occur in both of these organs, then the and cancer to retina may provide a unique way to neurodegenerative conditions.6 Jeremiah Lim assess cortical disease. At present, the only definitive BOptom MPhil Melb DipOptom (SP) Retinal imaging may provide a simple diagnosis for Alzheimer’s disease is and inexpensive alternative to cortical post-mortem confirmation of plaques 1 Dr Zheng He imaging, which is limited by the skull. in the brain. Recent clinical findings This barrier prevents simple optical suggest that successful treatment needs imaging of the brain and necessitates to start in the prodromal stages of the BMed China PhD Melb the use of expensive and complex disease, thus making it imperative to cortical imaging techniques such as have an early biomarker. Professor Algis Vingrys PET and MRI. The inability to make definitive BScOptom PGCertOcTher PhD Melb Need for a biomarker early diagnosis and monitor disease FARVO FAAO progression frustrates the development Alzheimer’s disease is a brain disorder of a cure for Alzheimer’s disease. Dr Bang Bui that is in desperate need of a viable Less than one in 10 drugs progresses biomarker. Alzheimer’s is characterised to market,7 in part due to the lack of by a progressive decline in memory effective biomarkers.7 Recent advances BScOptom MOptom PGCertOcTher and executive functions, and its in PET imaging show promise in PhD Melb hallmark is the deposition of cerebral defining biomarkers for Alzheimer’s beta-amyloid (Aß) deposits. There disease;8,9,10 however, the technology remains no effective long-lasting is expensive and its use in everyday treatment for Alzheimer’s and its practice is limited. An inexpensive, annual economic cost globally has been estimated at US$600 billion.5 Continued page 20 The ability to non-invasively visualise neurons and blood vessels is an attribute unique to the eye. This window provides an unparalleled view into general health, as many cardiovascular and brain disorders can have manifestations in the eye.1,2,3 These attributes render the eye and in particular, the neuro-vascular retina an ideal surrogate or ‘biomarker’ for systemic and neural disease.

Optometrists know that using the eye as an indicator of systemic disease is not novel. In current optometric care, assessing the eye for signs of diabetic change is standard practice and can offer perspective of the detection and the progression of the diabetes, as well as the effectiveness of ongoing treatment.

More recently, changes in retinal vessel diameter have been shown to be early predictors of stroke4 and studies are ongoing to make this assessment Figure 1. Retinal vessel analysis when used in conjunction with fundus commonplace among ocular health photography provides further insight into cardiovascular4 and brain professionals. health15 20 SEPTEMBER 2014

Alzheimer’s disease From page 19

specific and quantitative ocular biomarker of Alzheimer’s disease would improve the likelihood of finding a cure.

Eye as a biomarker for Alzheimer’s

While changes in the brain are well recognised in Alzheimer’s Figure 2. PET imaging using Pittsburgh Compound-B6 is a specific biomarker of Alzheimer’s disease, growing evidence shows disease but is expensive as an everyday screening tool that the disease also affects the eye.1 Visual symptoms are frequent early complaints in patients with Alzheimer’s disease, including disease.11,15 The hallmark Aß plaque to analyse them. It is hoped that these deficiencies in colour vision, contrast deposits that occur in the brains of studies will translate to a clinical sensitivity and motion perception.11,12 Alzheimer’s patients have also been tool that can identify the presence of Although the origin of some of these shown to occur in their . Retinal Alzheimer’s disease and monitor its symptoms may occur at the visual Aß plaques have been identified in progression. cortex, other studies have shown that tissue from both human Alzheimer’s changes do occur in the retina. patients10,16 and rodent Alzheimer’s This work is supported by the models.17 A recent study has imaged Melbourne Neuroscience Institute Multiple studies have indicated retinal Aß plaques in vivo in a rodent through an MNI fellowship to Dr that Alzheimer’s patients exhibit model (Figure 1) following injection of Christine Nguyen and a Strategic thinning of retinal nerve fibre layer a contrast agent, curcumin.10 Australian Postgraduate Award and an associated reduction in the (STRAPA) doctoral award to Jeremiah electroretinogram.1,13 Alzheimer’s At the University of Melbourne, our Lim. If successful, future optometrists disease patients exhibit cerebral blood group is investigating vascular, neural may be able to screen their patients flow reduction14 and recent studies and structural developments as ocular for Alzheimer’s disease, thus playing indicate that retinal vascular changes signs of Alzheimer’s disease and a key role in early detection of this can also be seen in Alzheimer’s developing non-invasive techniques devastating illness.

Figure 3. Plaques (numbered 1 to 4) in Alzheimer’s disease can be viewed in vivo in the retina with (green) curcumin staining in rodent eyes10 SEPTEMBER 2014 21

1. Frost S, Martins RN, Kanagasingam Y. Ocular biomarkers for early Breakthrough could end eye injections detection of Alzheimer’s disease. J Alzheimers Dis 2010; 22: 1-16. 2. Patton N, Aslam T, Macgillivray Researchers at the University College London have demonstrated that it is T, Pattie A, Deary IJ, Dhillon B. Retinal vascular image analysis possible to create formulations of tiny nanoparticles loaded with the AMD drug as a potential screening tool for Avastin and deliver significant concentrations to the back of the eye. cerebrovascular disease: a rationale based on homology between cerebral and retinal microvasculatures. J Anat In an article published in the nanotechnology journal Small entitled ‘Topical 2005; 206: 319-348. delivery of Avastin to the posterior segment of the eye in vivo using annexin A5- 3. Greenberg BM, Frohman E. Optical associated liposomes’, the authors explain that they overcame the bypass barriers coherence tomography as a potential readout in clinical trials. Ther Adv within the eye by loading tiny nanoparticles with the drug Avastin and then Neurol Disord 2010; 3: 153-160. suspended those nanoparticles in liquid and used that liquid in the form of eye- 4. Wong TY, Klein R, Couper DJ et al. drops to treat the eyes of rats and rabbits. Retinal microvascular abnormalities and incident stroke: the Atherosclerosis Risk in Communities The results showed that the medication had been as effective as it has already been Study. Lancet 2001; 358: 1134-1140. 5. Wimo A, Prince M. World Alzheimer shown to be via injection. The researchers suggested that, in theory, other drugs Report 2010: The Global Economic such as Lucentis could effectively be delivered by this method. Impact of . Stockholm: Alzheimer’s Disease International 2010: 1-51. ‘The development of eye-drops that can be safely and effectively used in patients 6. economics A. Keeping dementia would be a magic bullet—a huge breakthrough in the treatment of AMD and other front of mind: incidence and debilitating eye disorders,’ lead author Professor Francesca Cordeiro said. prevalence 2009-2050. Canberra: Alzheimer’s Australia; 2009. 7. Kola I, Landis J. Can the Small 2014; 10: 8. doi: 10.1002/smll.201303433 pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 2004; 3: 711-715. 8. Klunk WE, Engler H, Nordberg A et al. Imaging brain amyloid in Alzheimer’s Coffee reduces risk Two players behind disease with Pittsburgh Compound-B. Ann Neurol 2004; 55: 306-319. 9. Villemagne VL, Burnham S, Bourgeat of type 2 diabetes diabetic retinopathy P et al. Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s Increasing coffee consumption by on Chemically reactive molecules disease: a prospective cohort study. average one and half cups per day over must come from both the bone marrow Lancet Neurology 2013; 12: 357-367. a four-year period reduces the risk of as well as the retinal cells themselves 10. Koronyo-Hamaoui M, Koronyo Y, Ljubimov AV et al. Identification type 2 diabetes by 11 per cent. to cause the events that destroy of amyloid plaques in retinas from healthy blood vessels and form leaky Alzheimer’s patients and noninvasive Study authors used observational data new ones and ultimately, ruin vision. in vivo optical imaging of retinal plaques in a mouse model. Neuroimage from three large, prospective, US-based 2011; 54 Suppl 1: S204-217. studies in their analysis. Information According to the study published in 11. Berisha F, Feke GT, Trempe CL, on diet, lifestyle, medical conditions the online publication PLOS ONE, it McMeel JW, Schepens CL. Retinal abnormalities in early Alzheimer’s and other chronic diseases was is a cascade that requires these two disease. Invest Ophthalmol Vis Sci collected every two to four years for players to signal the next event that 2007; 48: 2285-2289. 12. Katz B, Rimmer S. Ophthalmologic more than 20 years. causes the damage. manifestations of Alzheimer’s disease. Surv Ophthalmol 1989; 34: 31-43. The authors found that participants who Excessive glucose in the blood 13. Parnell M, Guo L, Abdi M, Cordeiro MF. Ocular manifestations of increased their coffee consumption by prompts excessive production of Alzheimer’s disease in animal more than one cup/day over a four-year reactive oxygen species (ROS), and the models. Int J Alzheimers Dis 2012; period had an 11 per cent lower risk of light-sensitive retina is particularly 2012: 786494. 14. Nicolakakis N, Hamel E. type 2 diabetes in the subsequent four vulnerable. The research team had Neurovascular function in years compared to those who made no previously documented that ROS from Alzheimer’s disease patients and changes in consumption. Participants white blood cells produced by the experimental models. J Cereb Blood Flow Metab 2011; 31: 1354-1370. who decreased their coffee intake by bone marrow as well as from retinal 15. Cheung CY, Ong YT, Ikram MK et al. one cup a day or more had a 17 per cent cells were the major instigators in Microvascular network alterations higher risk for type 2 diabetes. Changes diabetic retinopathy, but they were not in the retina of patients with Alzheimer’s disease. Alzheimer’s & in tea consumption were not associated sure which mattered most. Dementia 2014; 10: 135-142. with type 2 diabetes risk. 16. Emptage L, Kisilak ML, Wilson They looked at different scenarios, M, Leonenko Z, Campbell M. Sensitivity and specificity of The authors concluded that those with including mice lacking the ability to fluorescence and polarimetry of the highest coffee consumption and who produce ROS by either the retinal or retina in Alzheimer’s disease. Invest maintained that consumption had the white blood cells, and found that if Ophthalmol Vis Sci ARVO E-Abstract Florida, USA; 2014: Abstract 344: lowest risk of type 2 diabetes, 37 per either was lacking, future damage was 3360: C0059. cent lower than those who consumed essentially eliminated. Essentially, one 17. Liu B, Rasool S, Yang Z et al. Amyloid-peptide vaccinations one cup or less per day. alone cannot do it. reduce {beta}-amyloid plaques but exacerbate vascular deposition Diabetologia 2014; March 21. Epub ahead PLOS One 2013; December 17. doi: and inflammation in the retina of Alzheimer’s transgenic mice. Am J of print.Small 2014; 10: 8. doi: 10.1002/ 10.1371/journal.pone.0084357 Pathol 2009; 175: 2099-2110. smll.201303433 22 SEPTEMBER 2014

Strategies for severe chronic ocular pain

Benefits and potential side-effects of retrobulbar injections

Anatomy Her entering visual acuities were Lucas Genereux BS finger counting at three meters in her The sensation of pain from the orbit right eye and 6/6 in her left eye. Initial is carried through branches of the intraocular pressure in her right eye was Dr Leonid Skorin Jr trigeminal nerve, specifically those 60 mmHg as measured with Goldmann of the ophthalmic division. With the applanation tonometry. Slitlamp OD DO MS FAAO FAOCO trigeminal nerve’s broad coverage examination of the right eye revealed throughout the facial region, it is normal lids and lashes, diffuse injection possible that pain experienced in of the bulbar conjunctiva, diffuse the orbit is of a referred origin. The corneal oedema, deep and quiet anterior ophthalmic division of the trigeminal chamber, a stable posterior intraocular nerve contains three of its own major lens, neovascularisation of the iris branches: the frontal, lacrimal and and uveae. Examination of Chronic ocular pain can arise as nasociliary. the left eye yielded normal findings a result of a variety of aetiologies. of all structures. could Pathology such as neovascular These branches decussate posterior not be performed at this time as the glaucoma, end stage glaucoma, to the extraocular muscle cone and corneal oedema would not allow for intraocular tumour, anterior to the trigeminal ganglion. The visualisation of the angle structures. and trauma are all possible causes of frontal branch provides innervation to chronic ocular pain. To alleviate the the upper eyelids, superior orbital rim Dilated fundus examination revealed patient’s pain, one must first determine and scalp areas. The lacrimal branch evidence of widespread blot its cause. The patient’s description of provides innervation to the lacrimal haemorrhages in all quadrants of the the discomfort can help determine the gland, as well as to the conjunctiva and right eye. Detailed examination was cause or causes. the lateral aspect of the upper eyelid. difficult due to corneal oedema, and as The nasociliary nerve innervates the such, no information of the optic nerve Patients who describe their pain as cornea, the lower eyelids and portions health could be attained at this time. superficial are typically suffering from of the skin of the nose.2 The latter pathology of the cornea or conjunctiva.1 distribution is the anatomy behind It was suspected that our patient Superficial pain is often described as Hutchinson’s sign in herpes zoster had recently suffered an ischaemic sharp or shooting. Those who describe ophthalmicus. central retinal vein occlusion in the their pain as deeper in nature are right eye, which the patient had not often suffering from pain that may noticed due to her previously noted also originate from the cornea, but profound acuity reduction in this eye. more likely stems from pathology of CASE REPORT The ischaemic central retinal vein deeper structures such as the sclera, occlusion then resulted in neovascular iris, ciliary body, orbital muscles or glaucoma with significantly increased the sinuses.1 Deeper pain is usually A 94-year-old female presented to intraocular pressure. described by the patient with adjectives our clinic complaining of extreme like ‘dull’,’ constant’ and ‘aching’. ocular pain in her right eye that had Treatment awoken her two nights prior to her If after a thorough ophthalmic visit. She had been self-medicating Pharmacologic attempts to reduce examination—including intraocular with ice packs and extra strength pressure using brimonidine 0.1% were pressure assessment, and anterior acetaminophen, but said that these unsuccessful. Due to the patient’s sulfa and posterior segment evaluation— were no longer effective. allergy, oral acetazolamide tablets the cause of ocular pain is not clear, could not be administered. The patient imaging may be required to elucidate Her ocular history was positive for wet was referred to the emergency room the cause. age-related macular degeneration in to receive an intravenous mannitol her right eye including a prominent solution at a dose of one gram per OCT scans of the orbit may be used disciform scar resulting in severe kilogram of body weight, given over to investigate possible orbital wall vision loss. She was pseudophakic in the course of 45 minutes. Mannitol fracture or foreign body. Magnetic both eyes, and had been followed as a and topical pharmacologic attempts resonance imaging may be used to glaucoma suspect. Her medical history to lower the patient’s intraocular look for soft tissue causes such as was unremarkable aside from an allergy pressure were unable to yield safe and retrobulbar swelling or orbital tumour. to sulfa medications. comfortable pressure levels. SEPTEMBER 2014 23

Strategies for severe chronic ocular pain

Benefits and potential side-effects of retrobulbar injections

Panretinal photocoagulation laser of absolute alcohol. that on a day-to-day basis she had been therapy was performed, but extensive almost pain free, with a reported pain haemorrhaging blocked much of the After the anaesthetic injection, a pause level of one out of 10. retinal tissue, limiting the effectiveness of five minutes was observed to allow of the procedure. After multiple return full anaesthetic effect. During this time, Discussion visits, the patient’s ocular pain had not the syringe containing the anaesthetic subsided and her intraocular pressure was detached, but the needle position A variety of treatment approaches for continued to be in the 50 mmHg range. was not altered (Figure 1). After the chronic severe ocular pain secondary At this point cryotherapy, enucleation, five minute period, a separate syringe to elevated intraocular pressure exist and retrobulbar alcohol injection were containing 2 ml of absolute alcohol (Table 1). The most drastic of these presented as further treatment options. was attached to the previously placed treatment approaches is enucleation, Our patient decided to undergo needle, and the alcohol was injected which is reserved as a final measure; retrobulbar alcohol injection. (Figure 2). Gentle pressure was then however, even this does not ensure applied over the for two minutes, resolution because pain persists in as Retrobulbar alcohol injection to help distribute the medication. many as seven per cent of patients after enucleation.3 A retrobulbar needle was used to On the day of this procedure the administer a 1% lidocaine solution patient had reported that her pain level Less invasive techniques come by way with 1:100,000 epinephrine into the was ‘nine out of 10’. The following day, of retrobulbar injections. The main muscle cone. The injection was done the patient noted that her pain level pharmacologic agents used in these into the lateral third of the lower lid was ‘five out of 10’. Two days after the situations are absolute alcohol 97% and just superior to the inferior orbital injection the pain had subsided to a chlorpromazine at a dose of 25 mg/mL.4,5 rim. To ensure correct application, the reported ‘two out of 10’. At a follow- needle was directed as close to the back up appointment nine weeks after the Oral pain medications are often of the globe as possible. A total of 2 ml injection, the patient reported that not effective. Even when they are of the anaesthetic was initially injected she was happy with the results of the effective, these medications often lose into the retrobulbar space. Anaesthetic retrobulbar injection She reported that their efficacy as the chronicity of the is injected first to prevent the severe about once every week she would have condition drags on. burning sensation that a patient would a flare-up of ocular pain and would otherwise experience from the injection need a dose of acetaminophen, but Continued page 24

Figure 1. Retrobulbar needle in place after anaesthetic injection, Figure 2. Delivery of absolute alcohol to the retrobulbar space prior to absolute alcohol administration 24 SEPTEMBER 2014

Severe ocular Topical and oral glaucoma medications Oral pain medications pain Panretinal photocoagulation laser From page 23 Cyclocryotherapy Retrobulbar absolute alcohol injection Retrobulbar chlorpromazine injection

Table 1. Treatment options for severe chronic ocular pain secondary to neovascular ­glaucoma

Panretinal photocoagulation is a Chlorpromazine is thought to 1. Kumar C, Dowd T, Hawthorne M. first line therapy for neovascular cause anaesthesia by cell lysis Retrobulbar alcohol injection for orbital pain relief under difficult circumstances: glaucoma. The process works by and/or membrane stabilisation.1,4,5 a case report. Annals Academy of destroying retinal tissue with argon Chlorpromazine injection has been Medicine 2006; 35: 260-265. 2. remington LA. Clinical Anatomy and or diode laser. Destruction of tissue proposed to have a efficacy of 80 per Physiology of the Visual System, 3rd Ed. decreases the oxygen requirement cent to 90 per cent and to possess a St. Louis, Missouri: Elsevier Butterworth of the retina, thereby decreasing the longer duration of relief than alcohol Heinemann, 2012: 218-224. 6 3. custer PL, Reistad CE. Enucleation of release of vascular endothelial growth injection. The most notable advantage blind, painful eyes. Ophthalmic Plastic factor, which decreases the amount of chlorpromazine over other treatment and Reconstructive Surgery 2000; 16: 5: of neovascularisation in the anterior methods is in the treatment of seeing 326-329. 4. Skorin L. Treatment for blind and seeing chamber angle. Cyclocryotherapy is eyes. Chlorpromazine has become the painful eyes. Optometry Today 2004; 44: effective at decreasing ocular pressure treatment of choice for treating pain in 1: 34-36. by destroying the ciliary processes, eyes that have useful vision. One study 5. Skorin L. Treatment for blind and seeing painful eyes. Audio-Digest which are responsible for aqueous showed that 50 per cent of patients Ophthalmology 2005; 43: 3. humour production. with seeing eyes that underwent 6. chen TC, Ahn Yuen SJ, Sangalang chlorpromazine injection retained MA, Fernando RE, Leuenberger EU. 6 Retrobulbar chlorpromazine injections Retrobulbar alcohol injections have vision after injection. for the management of blind and seeing been used in the management of pain painful eyes. J Glaucoma 2002; 11: 209- in blind eyes since the early 1900s.4,5 Alcohol and chlorpromazine injections 213. Alcohol achieves analgesia, through have similar potential side-effects. nerve cell destruction via phospholipid Both medications carry the risk of and cholesterol extraction as well eyelid oedema, conjunctival chemosis, as precipitation of mucoprotein and external ophthalmoplegia, cellulitis lipoprotein.1 and blepharoptosis.1,4,5 Retrobulbar alcohol injections also carry the Alcohol does not work by diffusion, risk of neurotrophic keratopathy. which can both help and hinder the Chlorpromazine injections carry outcome. This helps the outcome in additional risk of nausea, vomiting, that it reduces unwanted destruction brief loss of consciousness and fat of neighbouring structures. The lack necrosis.1 It is also possible for patients of diffusion creates a challenge in that receiving chlorpromazine injection to it requires the injection to be given in experience transient loss of vision due close proximity to the targeted nerves to membrane stabilising effects on the for full destruction.1 If the nerves optic nerve.1,4,5 are not sufficiently destroyed, they will regenerate earlier and bring back Conclusion the symptoms of pain.3-5 Successful injections have been shown to provide Retrobulbar injections have made pain relief for up to two years, with the management of both seeing 20-87 per cent lasting for at least three and non-seeing painful eyes less months.3-5 devastating. When a patient presents with this magnitude of misfortune, Retrobulbar injection of the idea of having an eye removed chlorpromazine may be perceived as not a treatment, but as more misfortune. By having Another medication that can these retrobulbar injection options be administered via retrobulbar available for patients, we can set their injection is the phenothiazine anti- minds at ease, and improve their psychotic mediation chlorpromazine. quality of life. AU-LIP-2013-19d_A4_v1.pdf 1 7/05/2014 9:18 pm

New Eye Indication* 1

*LIPIDIL is indicated for the reduction in the progression of diabetic retinopathy in patients with Type 2 diabetes and existing diabetic retinopathy.

LIPIDIL does not replace appropriate control of blood pressure, blood glucose and blood lipids in reducing the progression of diabetic retinopathy.

See the difference In addition LIPIDIL is indicated as an adjunct 1 ADDing LIPIDIL® to diet in the treatment of: Dyslipidaemia associated with 1 Type 2 diabetes can make Types II, III, IV and V dyslipidaemia

Hypercholesterolaemia

New Retinopathy Indication In Type 2 Diabetes1

See primary advertisement for New Indication details

PBS Information: General Statement for Lipid-Lowering Drugs. Not listed for the treatment of diabetic retinopathy.

Please review the full Product Information (PI) before prescribing. Full PI available on request from Abbott Australasia by calling 1800 225 311 or at: www.medicines.org.au/files/abplipid.pdf Lipidil® (fenofibrate): 145 mg tablets, 30’s; 48 mg tablets, 60’s. Indications: Adjunct to diet in the treatment of hypercholesterolaemia, types II, III, IV and V dyslipidaemia, dyslipidaemia associated with Type 2 diabetes. Reduction in the progression of diabetic retinopathy in patients with Type 2 diabetes.* Does not replace appropriate control of blood pressure, blood glucose and blood lipids. Dosage: Dyslipidaemia and Diabetic Retinopathy: 145 mg tablet to be taken with or without food. Consider dose of 48 mg in patients with renal impairment (CrCl<60ml/min). Contraindications: Children; liver dysfunction; severe renal dysfunction; existing gallbladder disease; coadministration with another fibrate; hypersensitivity to fibrates or ketoprofen; chronic or acute pancreatitis with the exception of acute pancreatitis due to severe hypertriglyceridaemia. Precautions: Attempt diet and lifestyle modifications before initiating therapy for dyslipidaemia; effect on CHD mortality/morbidity not established*; renal impairment; may increase LFT; hepatic impairment, cholelithiasis; pregnancy and lactation; drugs exacerbating hypertriglyceridaemia (oestrogen, b-blocker, thiazides); fructose and/or galactose Before prescribing please review PBS and Product Information available in the primary intolerance (including, Lapp lactase deficiency or galactose malabsorption); lecithin or related product allergy. Interactions: Oral anti-coagulants; HMG-CoA reductase inhibitors (risk of muscle toxicity is increased if used concurrently); other fibrates; cyclosporine (monitor renal function); phenylbutazone; drugs metabolized by cytochrome advertisement in this publication or on request from Abbott Australasia by calling 1800 225 311. P450 isoenzymes CYP2C19, CYP2A6, and CYP2C9. Adverse Effects: GI disorders; skin reactions (including rash and photosensitivity); raised LFT; increase in serum creatinine;

References: 1. Lipidil® Approved Product Information. Lipidil® is a registered trademark of Abbott Australasia, 32–34 Lord St, Botany NSW 2019. pancreatitis; gallstones; thromboembolism; muscle toxicity and rarely rhabdomyolysis. Free call: 1800 225 311. Date prepared: March 2014. AU-LIP-2013-92b *Please note changes in Product Information. References: 1. Lipidil Approved Product Information. Lipidil® is a registered trademark of Abbott Australasia, 32–34 Lord St, Botany NSW 2019. Free call: 1800 225 311. Date prepared: November 2013. AU-LIP-2013-91c

ABBLI0017G_ad_MO_FI_4pp_363x264_[f2].indd 1-2 †

FOR wAMD 20 200 O 20 100 NE

20 70 INJECTION

20 50 EVERY TWO

20 40 MONTHS

20 ® † 30 *EYLEA wAMD TREATMENT IS INITIATED

20 WITH ONE INJECTION PER MONTH FOR 25 THREE CONSECUTIVE MONTHS, FOLLOWED 20 20 BY ONE INJECTION EVERY TWO MONTHS1

PBS Information: Authority Required. Refer to PBS Schedule for full Authority Required information for wet AMD. EYLEA is not PBS listed for CRVO. EYLEA® TREATMENT IS INITIATED BEFORE PRESCRIBING,WITH PLEASE ONE REVIEW INJECTION FULL PRODUCT PER MONTH INFORMATION AVAILABLE ON REQUEST FROM BAYER AUSTRALIA LTD, ABN 22 000 138 714, 875 PACIFIC HIGHWAY, PYMBLE, NSWFOR 2073 THREE or go to www.ebs.tga.gov.auCONSECUTIVE MINIMUM PRODUCT INFORMATION EYLEA® [afliberceptMONTH (rch)] INDICATIONS:S, EYLEAFOLLOWED (aflibercept) is indicated in adults BY for the treatment ONE of neovascular (wet) age-related macular degeneration (wet AMD); due to macular oedema secondary to central retinal vein occlusion (CRVO)*. DOSAGE AND ADMINISTRATION: Injection volume1 of 50 μL EYLEA (equivalent to 2 mg aflibercept). For wet AMD: Treatment is initiated with one intravitrealINJECTION injection per month for three consecutive EVERY months, followed TWO by one injection MONTH every two months.S For CRVO*: Treatment is initiated with one per month. After the first three monthly injections, the treatment interval may be extended based on visual and anatomic outcomes. The treatment between doses should not be shorter than one month. Monitoring should be done at the injection visits. During treatment interval extension, the monitoring should be determined by the treating physician based on the individual patient’s response. CONTRAINDICATIONS: Known hypersensitivity to aflibercept or excipients; ocular or periocular infection; active severe intraocular inflammation.PRECAUTIONS: , increase in intraocular pressure; arterial thromboembolic events*; see full PI for effects on fertility, pregnancy, lactation, effects on ability to drive or use machines. ADVERSE EFFECTS: Very common: conjunctival haemorrhage, eye pain. Common: retinal pigment epithelium tear, detachment of retinal pigment epithelium, cataract, cataract nuclear, cataract subcapsular, corneal erosion, corneal abrasion, intraocular pressure increased, vision blurred, vitreous , corneal oedema, vitreous detachment, injection site pain, foreign body sensation in eyes, lacrimation increased, eyelid oedema, injection site haemorrhage, conjunctival hyperaemia, ocular hyperaemia. Others: see full Product Information. Date of most recent amendment: November 2013 *Please note changes in Product Information. Reference: 1. EYLEA Product Information. † wAMD = Wet age-related macular degeneration

EYLEA® is a registered trademark of Bayer AG, Germany. Bayer Australia Limited, ABN 22 000 138 714, 875 Pacific Highway, Pymble, NSW 2073. EYL034 L.AU.SM.12.2013.0263

Eylea_CRVO_Advert_A4_210x297_Final.indd 1 3/12/13 8:57 AM