Ophthalmology

A 28-year-old man with no past ophthalmic history presented with sudden loss of left central vision after dancing vigorously at a night club. On examination, visual acuity in the left eye was 6/60. Fundoscopy revealed a well circumscribed, dense preretinal haemorrhage obscuring his left fovea (Figure A). Optical coherence tomography confirmed the haemorrhage to be located just under the internal limiting membrane (Figure B). Conservative management was applied, and the patient’s vision returned to 6/6 after 3 months. First described by Duane in 1972,1 Valsalva retinopathy is now a well recognised cause of retinal haemorrhage that typically occurs in association with strenuous activity and the Valsalva reflex.

Henri Sueke

A 55-year-old woman who was treated with long-term, high-dose clozapine for schizophrenia presented with bilateral decreased visual acuity. She had pigmentary changes affecting the cornea and the retina, as well as stellate cataract. Chlorpromazine use is known to produce similar changes, but this is the first report to our knowledge of pigmentation associated with clozapine use. (MJA 2009; 190: 210-211) Clinical recordA 55-year-old white woman presented to a tertiary hospital eye clinic with a progressive decline in vision that affected the left eye more than the right. She had a history of schizophrenia, depression, hypothyroidism, gastro-oesophageal reflux and back pain. Her medications were: clozapine 800 mg daily, lithium carbonate 500 mg daily, thyroxine 100 μg daily, and omeprazole 20 mg daily. She had been taking clozapine for 16 years, and her cumulative dose was 4.67 kg. The patient’s best corrected visual acuity was 6/9 in the right eye and 6/60 in the left. Bilateral pigmented deposits were present in the corneal endothelium, and these were most prevalent in the interpalpebral fissure. On dilation, bilateral pigment dusting of the anterior portion of the lens capsule with central stellate opacity was evident (Box, A), and posterior subcapsular and nuclear sclerotic cataract was noted in both eyes. Retinal changes included a right epiretinal membrane and bilateral pigmentary retinopathy. Macular atrophy was present in both eyes and affected fixation on the left. The patient’s skin was brown, particularly in sun-exposed areas including her face, neck and hands. Confocal microscopy of the corneas showed diffuse, highly reflective, irregular honeycomb-shaped deposits on the endothelium (Box, B) and small granular deposits on the posterior stromal layer. Morphology of the endothelium visible between the deposits was normal. Optical coherence tomography confirmed atrophy of the neuroretina, greater in the left eye than the right. Electroretinography showed reduced cone function, indicated by reduced amplitude and latency in the cone response. The patient was diagnosed with presumed clozapine-related ocular and skin pigmentation. In consultation with her psychiatrist, her clozapine dose was reduced to 600 mg daily. On follow-up at 6 months, her vision had not improved, and the deposits had neither reduced nor progressed. DiscussionPigment deposits in the cornea, lens and skin are well documented complications of long-term phenothiazine antipsychotic therapy.1-3 Our patient had ocular changes that were possibly side effects of chronic high-dose clozapine use. The changes were similar to the side effects of phenothiazines, and they were demonstrated by confocal microscopy, optical coherence tomography and electroretinography.1-4 Medication history taken from the patient, as well as a collaborative medication history supplied by the patient’s psychiatric team, revealed no evidence of prior phenothiazine use. Clozapine is a tricyclic dibenzodiazepine derivative with weak D2 and D1 dopamine-receptor blocking activity. It is a relatively new atypical antipsychotic that is used in place of phenothiazines, particularly for refractory schizophrenia. It has noradrenolytic, anticholinergic, antihistaminic and antiserotonergic properties, and its most common side effects are sedation and weight gain. Anticholinergic side effects such as constipation and dry mouth may also occur. Rarely, clozapine can produce potentially lethal agranulocytosis, for which blood count monitoring is required. Myocarditis is another possible lethal side effect. Clozapine therapy is usually commenced at a dose of 25 mg daily, and titrated up to 300–600 mg daily for therapeutic effect. Doses of up to 900 mg can be used for treatment-resistant cases.5 Clozapine is recommended as a substitute for patients who have experienced pigmentation secondary to chlorpromazine use — clinical signs of pigmentation are expected to resolve after a period of chlorpromazine abstinence.6 The aetiology of phenothiazine-related ocular side effects has not been determined. It has been postulated that photosensitisation of tissue proteins occurs in areas with increased sun exposure after accumulation of the drug in these tissues.7 Alternatively, phenothiazines may interact with melanin in the choriocapillaris and retinal pigment in the epithelium, which may induce damage to the photoreceptors. Altered dopaminergic regulation of melatonin is suspected to increase susceptibility of photoreceptors to damage by light.7 In our patient, clozapine may have produced similar side effects to the phenothiazines, as it also acts on dopamine receptors. The dopaminergic system of the retina may respond to accumulation of clozapine and phenothiazines in a similar manner to the nigrostriatal dopaminergic system.8 None of the other medications the patient was taking — namely lithium, omeprazole or thyroxine — are known to cause skin or ocular pigmentation.9,10 Our patient had significant irreversible loss of vision, which may have resulted from chronic, high-dose clozapine use. Anterior and posterior segments of the eye were affected. These changes should be considered as possible side effects of clozapine, particularly if it is given in high doses. If further similar cases become evident, patients on long-term clozapine therapy should be considered for regular ophthalmological review. Phenothiazine-like ocular changes in a patient who was treated with long-term, high-dose clozapine A: Pigmented deposits on the corneal endothelium (arrowhead) and anterior central stellate cataract (arrow). B: Confocal microscopy image of retina showing highly reflective honeycomb-shaped deposits on the endothelial layer (arrow) with an affinity to the cell margin rather than the centre, and endothelial cells with a regular morphology (arrowhead) (original magnification, × 40).

Armand M Borovik MB BS, BSurg · Martina M Bosch MD, FMHOphth · Stephanie L Watson MB BS, FRANZCO, PhD

A 57-year-old overseas tourist presented with confusion and deteriorating vision in her right eye. She had a known history of poorly controlled diabetes and an involuted left eye. No further history was obtainable. Examination of the right eye demonstrated a dislocated crystalline lens, and long-standing tractional retinal detachment. I performed a B-scan ultrasound of the right eye. When doing this investigation, I often tell patients that “It’s like when you are having a baby”, but this time I was surprised by what I saw! The dislocated crystalline lens and funnel tractional detachment formed an amusing but apt image (Figure).

Neil S Sharma

It is with deep sadness that we mourn the passing of Sarah Mitchell after a long battle with breast cancer. Sarah was a Consultant Paediatrician at King Edward Memorial Hospital and Princess Margaret Hospital (KEMH/PMH) in Perth, Western Australia. Sarah was born in England on 15 March 1966. She studied medicine at the University of London, graduating in 1991, and subsequently undertook postgraduate paediatric and neonatal training in London, Sydney and Perth. She developed her interest in neonatal retrievals while working for the Neonatal Emergency Transport Service in New South Wales. She returned to Australia in 2002 as a Senior Registrar in neonatal and paediatric intensive care at KEMH/PMH, where her excellent clinical acumen, compassion and commitment led to her promotion to Consultant status in 2006. Sarah and her husband Steve loved to travel, and visited 35 countries during their 17 years together. It was probably her love of travel and adventure that attracted Sarah to specialise in neonatal retrievals. This ultimately led to her appointment as Director of the WA Neonatal Transport Service, which was perhaps her greatest professional achievement. She had a clear vision for neonatal retrievals in WA, and the innovations she was developing are destined to transform the way the service functions for many years to come. Sarah has always been held in high esteem by all her colleagues. Despite the ever increasing intrusion of her illness and its treatment on her life, she carried on working, always remaining her usual calm, caring, competent and professional self. She also continued to participate in triathlons. She was optimistic despite adversity, and led by example with her dedication and commitment to neonatal practice in WA. Sarah was still working right up until 2 weeks before her death on 22 May 2008, providing support and mentorship to others. Her strength, resilience and determination were an inspiration to her colleagues. Sarah will be remembered as someone who lived life to the full, and was totally committed to life with her husband Steve and to the young patients in her professional care.

Karen N Simmer · Katharine Gardiner

The community of Belmont, Victoria, lost a respected member with the death of Clifford Warmbrunn on 21 June 2008. His life was directed by his two passions: general practice and the Christian church. Cliff was born on 15 November 1933 in Melbourne. He attended Carey Baptist Grammar School and studied medicine at the University of Melbourne, graduating in 1959. In 1963, he joined the Belmont Medical Clinic in Geelong as a general practitioner. For 35 years, Cliff conscientiously cared for patients in the Belmont community. His work as a GP was also an avenue for expressing his Christian faith. As the Belmont practice expanded and took on GP trainees, so did his responsibilities, and he became the senior partner. He also became involved in Clockwork, a service to adolescents established under the auspices of the Geelong Division of General Practice. This enabled him to meet the needs of young people in a more informal setting than structured general practice. During his time at Belmont he served a term as Chairman of the Geelong Subdivision of the Australian Medical Association. After retirement from full-time medical practice in 1998, Cliff continued to do locum work in the district and to be involved with Clockwork. His special interest in retirement was his Chairmanship of Encompass, a support service for people with disabilities — a position he reluctantly relinquished as his health deteriorated. Always a committed Christian, Cliff managed to fit Christian leadership into his busy life. At Belmont Church of Christ, where he took up membership on arrival in Geelong, he was soon a member of the Congregational Council and then Chairman. His broader interests led to him serving on state and national committees of Churches of Christ. In particular, he was Chairman of the Department of Home Missions and Evangelism for a number of years and President of Churches of Christ in Victoria and Tasmania in 1985–1986. Early in 2008, Cliff’s prostatic malignancy escaped control and he was cared for lovingly at home by his wife, Helen. He is survived by Helen, their children John, Anne and Andrew, and six grandchildren.

Trevor A Banks

All topical ophthalmic agents should be considered potentially potent systemically Many Australians are prescribed topical ophthalmic medications for chronic conditions such as glaucoma, ocular inflammation, infection and allergy. Despite their overall safety, these agents have the potential to cause significant systemic side effects and to have serious interactions with oral medications. In many cases, these effects may go unreported by the patient or misdiagnosed by the medical community. There is a need for improved prescribing practices in both the ophthalmic and general medical communities, with increased awareness of the full range of therapeutic agents being taken by the patient. With the recent passage of legislation allowing optometrists prescribing rights under the Pharmaceutical Benefits Scheme (PBS) (National Health Amendment [Pharmaceutical Benefits] Act 2007 [Cwlth]), it is timely to remind all health care practitioners of the potential hazards of topical ophthalmic medications. Pharmacokinetics make ocular drug delivery more akin to intravenous than to oral administration.1 Topically administered medications gain access to the highly vascular nasal mucosa and are variably absorbed, avoiding first-pass hepatic metabolism.2,3 One drop of timolol 0.5% solution in each eye approximates a 10 mg oral dose for treating systemic hypertension or angina.2 All topical agents should be considered as potentially potent systemically. A retrospective analysis of de-identified PBS billing data from Medicare Australia revealed that, between 1999 and 2004, 20 000 Australians per year had been exposed to co-supply of topical and systemic β-blockers.4 This combination has been linked with adverse respiratory and cardiovascular events, as well as reduced topical ocular hypotensive efficacy.5 The scale of this as a Quality Use of Medicines issue is larger than was anticipated. Multiple factors may be responsible: an assumption that topical therapy is systemically “homoeopathic”; the fact that many patients may not mention eye drops when asked about their drug history; and the fact that patients may not remember their full list of medications. Topical medications usually constitute first-line therapy for glaucoma. Parasympathomimetics (pilocarpine derivatives) have been in use for 140 years, topical β-blockers for 30 years, and, more recently, carbonic anhydrase inhibitors, α2-agonists and prostaglandin analogues have emerged. While the overall safety of these agents is recognised, there is a potential for serious side effects in a small proportion of people. As well as their own direct effects systemically, topical agents may have significant additive or interactive effects with systemic medications. Topical β-blockers may precipitate or aggravate bronchospasm, congestive heart failure, bradyarrhythmias, sinus arrest, a variety of central nervous system effects and dyslipidaemias.6-8 In this issue of the Journal, Schweitzer and colleagues (page 406)9 describe a case involving two episodes of melancholic depression in a patient who had been prescribed β-blocker antiglaucoma agents. Taking these medications has been rated as the most significant risk factor for falls in glaucoma patients.10 Parasympathomimetics locally provoke brow ache and/or headache, miosis and myopia, and, with systemic absorption, carry the risk of bradycardia, hypotension, bronchospasm,7 gastrointestinal symptoms and urinary frequency. Topical α2-agonists have been associated with central nervous system depression and with profound hypotension in children.11 Topical carbonic anhydrase inhibitors do not seem to produce the metabolic side effects of their oral counterparts, but may be associated with an idiosyncratic bone marrow suppression and sulphonamide allergy.6 To date, topical prostaglandin analogues have not been associated with cardiovascular or respiratory side effects, adding support to their use as first-line antiglaucoma agents.6 However, their use has been associated with headache, flu-like symptoms and myalgias in up to 10% of patients, with case reports of neurological referral and investigation.11,12 Co-prescription of systemic and topical β-blockers can reduce heart rate in patients with glaucoma.5 Simultaneous administration of topical timolol and systemic verapamil has been associated with severe bradycardia.7 Co-administration of topical α2-agonists with oral monoamine oxidase inhibitors carries a risk of hypertensive crisis and is contraindicated.3 Salicylates have been shown to cause accumulation of systemically administered carbonic anhydrase inhibitors; this is also theoretically possible with topical carbonic anhydrase inhibitors.3 Topical steroid drops are key to the management of ocular allergy and inflammatory disease. While they are well tolerated systemically, their ocular side effects are potentially blinding: potentiation of infection, cataract and glaucoma. Commonly perceived as a “safe” alternative, fluorometholone has been associated with all these ocular side effects, albeit less frequently.13 Topical chloramphenicol is commonly prescribed to treat infective conjunctivitis, and is used perioperatively with ocular surgery. Although bacteriostatic rather than bactericidal in action, its broad spectrum of activity and lack of systemic use make it an ideal first-line ocular topical agent. Its potential to induce life-threatening aplastic anaemia remains controversial: the risk has been estimated to be about 1 in 150 000, at worst,14 but it is likely to be much lower.15 Whether the rare occurrence of this condition is by a dose-dependent or a dose-independent (idiosyncratic) mechanism,14,15 prescribers need to be cautious when prescribing for patients with a personal or family history of blood abnormalities. Concern about this risk has been enough to marginalise the use of chloramphenicol in the United States. Additionally, chloramphenicol should only be prescribed when conjunctivitis is likely to be bacterial in origin and for clinically appropriate time periods.16 We believe prescribing practice can be improved with simple steps: (i) take a full drug history, and specifically ask about eye drops; (ii) physicians must remember to ask whether the patient’s optometrist has prescribed any medication, and should be aware of the newer combination preparations (Combigan [Allergan], Cosopt [Merck, Sharp and Dohme], DuoTrav [Alcon], Xalacom [Pfizer]), all of which contain the β-blocker timolol; (iii) ophthalmologists (and now optometrists) should be aware of a patient’s concurrent systemic health and medication status before commencing any topical agents, particularly β-blockers. The eye is not an isolated organ but may be influenced by systemic diseases and therapies. Further, recent publications1,4,8 highlight the converse — topical therapies for the eye may have significant systemic effects and/or interactions with systemic medications. It is important to be alert to possible systemic side effects and interactions between systemic and topical agents and to investigate and modify treatment regimens appropriately. Limit the use of topical steroids, and use them only with adequate supervision. Remind all patients using topical medications to follow the “double DOT” procedure (Don’t Open eyes Technique and Digital Occlusion of the Tear duct), which involves closing the eyes and applying digital pressure over the lacrimal sac for 1–2 minutes after drop administration (Box 1, Box 2). This reduces systemic absorption by two-thirds, thereby significantly widening the safety margin of all agents.17,18 Recent legislative changes across Australia allow practitioners who are not medically trained to prescribe topical medications, although, at present, legislation varies from state to state. These changes underline the importance of general practitioners and physicians recognising the potential systemic effects of these topical ophthalmic medications and being alert to interactions with other medications. Improved communication between all health care practitioners and ophthalmologists will be vital for patient safety. 1 Lacrimal drainage system 2 The “double DOT” procedure* for reducing systemic absorption of topical ophthalmic medications * Don’t Open eyes Technique and Digital Occlusion of the Tear duct.

Ivan Goldberg MB BS, FRANZCO, FRACS · Gregory Moloney MB BS · Peter McCluskey MB BS, FRANZCO

Patients who notice a red eye or other acute ophthalmic symptoms often present first to their general practitioner, optometrist or local hospital emergency department. Although the most common acute eye diseases in primary practice are the usually benign conditions of viral, bacterial and allergic conjunctivitis, rarer but more serious causes of red eye such as iritis, keratitis and acute glaucoma can lead to permanent loss of vision. The primary health care provider’s initial diagnosis and management can be critical to the patient’s ophthalmic outcome. In one United Kingdom study of 55 patients in which an ophthalmologist had diagnosed a red-eye disorder, only nine had been correctly diagnosed by the referring practitioner.1 To our knowledge, no study of the accuracy of diagnosis of eye conditions by primary health care providers in Australia has yet been published. We audited the hospital records of 1062 new patients presenting to the eye emergency services of the ophthalmology departments of the two major Brisbane hospitals, and analysed the accuracy of the diagnosis and implications of the initial care provided to these patients by their local doctor or optometrist. Lessons from practice Patients with acute eye problems presenting to primary health care providers are often misdiagnosed or mismanaged. Topical antibiotic therapy is overprescribed for acute eye conditions. Particular attention should be paid to sentinel warning symptoms — in particular the presence of one or more of pain, photophobia or blurred vision — as these symptoms almost always indicate serious acute eye disease rather than conjunctivitis. If a patient with a red eye reports pain, photophobia or blurred vision he or she should be given no treatment and referred immediately. Methods Patient records from consecutive presentations to eye emergency services of ophthalmology departments at two hospitals — Princess Alexandra Hospital (PAH) from 18 April to 25 October 2006 and the Royal Brisbane and Women’s Hospital (RBWH) from 1 July to 30 September 2006 — were collected and reviewed. Approval for the project was obtained from the Director of Surgery, Head of Ophthalmology and Ethics Committee of each hospital. Inclusion criteria were initial presentation to a primary health care provider (PHCP) — defined as a GP, optometrist or hospital emergency department doctor — and subsequent referral or patient self-presentation to an eye emergency service for the same complaint. The diagnosis in the ophthalmology department was compared with that by the PHCP, and the accuracy of diagnosis was determined. A preventable adverse outcome was deemed to have occurred if the patient had eye pain, loss of vision, or had been given inappropriate medication that could have been avoided with appropriate initial management or prompt referral. A further subjective assessment of the severity of the adverse outcome was then made. ResultsData were collected for 1062 patients during the designated periods at the two hospitals: 614 (57.8%) from PAH and 448 (42.2%) from RBWH. The referring PHCP was a GP in 50.4%, hospital emergency department doctor in 38.9%, and an optometrist in 10.7% of cases. The 10 most common reasons that PHCPs referred patients to ophthalmology departments are shown in Box 1. Accuracy of primary health care practitoners’ diagnosesA correct initial diagnosis (ie, matching the final ophthalmology department diagnosis) was given for 192 (35.9%) of the 535 patients referred by GPs, 173 (41.9%) of the 413 patients referred by emergency department doctors and 55 (48.2%) of the 114 patients referred by optometrists. Implications of initial inappropriate care by primary health care providersPreventable adverse outcomes: In 123 of the 1062 patients (11.6%), there was an adverse outcome resulting from misdiagnosis or mismanagement by the PHCP. Adverse outcomes in these 123 patients were mild in 63 (51%), moderate in 49 (40%) and severe in 11 (9%). Conditions that were misdiagnosed and subsequently associated with a severe adverse patient outcome are shown in Box 2. In most cases (74%), adverse outcomes were associated with misdiagnosis by PHCPs; in the remainder (26%), there had been a correct initial diagnosis, but subsequent incorrect treatment, or a significant delay in referral. In the 123 patients with preventable adverse outcomes resulting from misdiagnosis or mismanagement, the PHCP was a GP in 78%, an emergency department doctor in 17% and an optometrist in 5% of cases. The 11 most severe preventable adverse outcomes are described in Box 3. Topical antibiotic therapy: Of the total of 1062 patients, 199 (18.7%) had been prescribed topical antibiotic therapy at their initial consultation with their PHCP. Of the 535 patients referred by GPs, 108 (20.2%) had been prescribed antibiotic eye drops before referral. In 54% of these 108 patients, the therapy was judged inappropriate or unnecessary on ophthalmic review, and was ceased. Iritis: There were 59 patients with iritis (acute anterior uveitis), representing 5.6% of the total 1062 patients. Less than a third of patients with iritis (16 of 59; 27%) were diagnosed correctly by the PHCP. Eleven of the 59 patients with iritis (19%) were initially misdiagnosed as having conjunctivitis and treated with topical antibiotic therapy by their GP. Fourteen patients were given no diagnosis and no therapy. Seven patients had their condition misdiagnosed as red eye and were given no therapy. Iritis was misdiagnosed as glaucoma in three patients, hyphaema in two patients, keratitis in two patients, cataract in two patients, and as macular oedema and pain in one patient. The average time to referral or self-presentation to an eye emergency service for patients with iritis was 2.4 days (range, 0–16 days). DiscussionPatients with acute eye problems presenting to PHCPs, especially GPs, are often misdiagnosed or mismanaged. In most cases, this does the patient no harm — for example, misdiagnosing viral conjunctivitis as bacterial conjunctivitis and inappropriately prescribing antibiotic eye drops is unlikely to cause complications, and the patient will spontaneously recover from the infection. However, in some acute eye conditions, the prescription of topical antibiotics can be very harmful indeed — not through any ill effects of the drug, but through the subsequent delay in referral. In the case of serious acute eye conditions like severe iritis or acute glaucoma, a delay of even a few days can result in permanent loss of vision or even blindness. Examples of potentially serious eye diseases that may present to PHCPs are shown in Box 4. In our survey, of 11 patients identified as having had a preventable, severe adverse outcome, 10 had initially presented to their PHCP with a unilateral red eye. All 10 were incorrectly diagnosed as having conjunctivitis and all had been inappropriately prescribed chloramphenicol eye drops as treatment. All had reported ocular pain, photophobia or blurred vision to their PHCP at the initial consultation. The 11th patient had retinal detachment. There is a perception among many ophthalmologists that many GPs “call every red eye conjunctivitis” and that topical antibiotics are overprescribed for acute eye problems. In our review, in more than 50% of cases in which topical antibiotic therapy had been commenced by the PHCP, it was immediately ceased at the first ophthalmology review as being unnecessary or inappropriate. In addition to contributing to a serious delay in patient referral, topical antibiotic use can occasionally cause serious local and rarely systemic complications2 (eg, agranulocytosis from chloramphenicol). There may also be concerns that using antibiotics unnecessarily contributes to increasing antibiotic resistance of organisms.3 How can the situation be improved? A major problem is the lack of equipment, expertise and time available to a GP in a busy practice facing a new patient with an acute eye problem. Many eye conditions (including iritis and acute glaucoma) cannot be diagnosed without a slit lamp microscope and a means of measuring intraocular pressure — equipment that is rarely available to GPs. In addition, many GPs have had little ophthalmological training, and have limited time to spend with each patient. To address these problems, it is suggested that GPs pay careful attention to the symptoms reported by patients with eye complaints, given the difficulty of accurately evaluating their signs. Particular attention should be paid to sentinel warning symptoms — in particular the presence of one or more of pain, photophobia or blurred vision — as these symptoms almost always indicate serious acute eye disease rather than conjunctivitis.4 Patients reporting one or more of these symptoms should be given no treatment, and referred to an ophthalmologist urgently. It should also be recognised by GPs that although unilateral viral conjunctivitis is common, a single red eye should be viewed with more suspicion than bilateral red eyes, which are more likely due to conjunctivitis. 1 The 10 most common reasons that primary health care providers referred patients to ophthalmology department emergency services 2 Conditions originally misdiagnosed by primary health care providers, leading to adverse events for patients 3 Severe adverse outcomes in 11 patients as a result of misdiagnosis or mismanagement by primary health care providers* Patient Age and sex Ophthalmology department diagnosis PHCP diagnosis PHCP treatment Delay in referral Preventable adverse outcome 1 79 M Acute anterior uveitis Red eye Chloramphenicol eye drops 8 days Severe permanent vision loss and severe pain 2 55 F Acute anterior uveitis Conjunctivitis Chloramphenicol eye drops 7 days Moderate permanent vision loss and severe pain 3 77 M Acute anterior uveitis Red eye Chloramphenicol eye drops 10 days Severe pain 4 38 M Acute anterior uveitis Red eye Chloramphenicol eye drops 15 days† Severe pain 5 55 F Acute anterior uveitis Conjunctivitis Chloramphenicol eye drops 9 days Severe pain 6 26 F Bacterial keratitis Conjunctivitis Chloramphenicol eye drops 2 days Severe pain 7 95 F Herpes zoster ophthalmicus Red eye Chloramphenicol eye drops 3 days Mild permanent vision loss, severe pain, delay in commencing antiviral treatment 8 56 M Herpes zoster ophthalmicus Red eye Chloramphenicol eye drops 14 days Severe pain, delay in commencing antiviral treatment 9 77 M Neovascular glaucoma Herpes zoster ophthalmicus Chloramphenicol eye drops 7 days Severe pain 10 26 F Glaucoma and diabetic retinopathy Conjunctivitis Chloramphenicol eye drops 5 days Severe pain 11 29 M Retinal detachment No diagnosis Nil 7 days† Severe permanent vision loss M = male. F = female. PHCP = primary health care provider. * The PHCP was a general practitioner for all patients except Patient 10, who saw a hospital emergency department doctor. † Self-presented. 4 Examples of “red eye” diseases that may present to a primary health care provider

Michael O Statham MB BS(Hons), BAppSci(Optom)(Hons) · Anamika Sharma MB BS(Hons), BMedSci(Hons) · Anthony R Pane MB BS(Hons), MMedSc, FRANZCO

Clinical record A man in his 70s was prescribed DuoTrav eye drops (Alcon Inc; combined prostaglandin analogue [travoprost] and β-blocker [timolol]) for worsening glaucoma. (He had previously been treated with latanoprost.) Within 2–3 days, he felt depressed and described “a black cloud descending over [him]”. His symptoms included tiredness, poor concentration, sleep disturbance, and loss of libido and appetite. Normally fit and active, with a zest for life and a good sense of humour, he struggled to get up in the mornings and lost interest in socialising. His general practitioner prescribed venlafaxine (75 mg, then 150 mg) for the depression. Subsequently, DuoTrav therapy was stopped and a combination of travoprost, brimonidine tartrate and brinzolamide started. A month later, his sleep and appetite were considerably improved and he rated himself as 70% better. Eleven years previously, he had suffered an episode of major depression with melancholic features after his initial diagnosis of glaucoma, for which he was prescribed the β-blocker betaxolol.1 At that time, his symptoms had been worse and of longer standing, requiring hospitalisation and electroconvulsive therapy (ECT). He had recovered slowly, while continuing to experience lethargy and a heavy head. Only several months later, when the episode of depression was linked to the initiation of betaxolol and the β-blocker was stopped, did he fully recover. Within 48 hours of ceasing betaxolol therapy, he felt more energetic, alert and alive. The patient had been treated once before with ECT when he experienced his first depressive episode, at the age of 50 years, associated with severe work-related stress. Both subsequent episodes of depression were seemingly unrelated to stressors or life events. The most common medical treatments for glaucoma in Australia are prostaglandin analogues. However, β-blockers still comprise a substantial proportion of all prescriptions, either alone or in combination. Despite their topical administration, β-blockers are absorbed from the eye through the conjunctival epithelium, lacrimal channels, nasal mucosa and gastrointestinal tract into the systemic circulation. Although only small amounts are absorbed, concentrations may be sufficient to cause systemic β-adrenergic receptor-mediated effects, including slowing of heart rate, lowering of blood pressure and non-response to bronchodilators. Central effects such as depression have also been reported. Lessons from practice Ophthalmic β-blockers are absorbed systemically and may cause central side effects. Depression is an occasional adverse effect of β-blockers, including those used for glaucoma. Ophthalmic β-blockers should be avoided in patients who have a history of clinical depression. When depression evolves soon after commencing β-blocker treatment, serious consideration should be given to changing the medication, as the β-blocker may be the causative agent. The literature investigating a causal relationship between β-blockers and depression is controversial. An evidence-based review concluded that depression was an uncommon side effect of treatment with β-blockers and usually occurred only in the presence of a pre-existing condition.2 Randomised controlled studies of β-blockers in cardiovascular disease found the incidence of depressive symptoms was similar in β-blocker- and placebo-treated groups.3 However, a review of 24 case reports4 showed a temporal relationship between the use of β-blockers and depression in more than half the cases. If there is a close temporal relationship between the commencement of a new treatment and the development of symptoms, the symptoms are considered likely to have been caused by the medication. In the initial case that we reported on this patient,1 depressive symptoms began within days after the diagnosis of glaucoma and commencement of betaxolol treatment. The patient’s symptoms only fully remitted when the drug was stopped, providing further evidence of a causative relationship. The case we report here describes recurrence of depression after the introduction of another β-blocker, timolol, and again cessation of symptoms when treatment was stopped. The recurrence of the syndrome following a re-challenge further strengthens the argument for a causal relationship. (The travoprost component of the medication was unlikely to have been the cause of the depression.) It is possible that the onset of the disorder occurred coincidentally with the introduction of the medication (though such an event is unlikely to have occurred twice) or was caused by the underlying illness for which the new medication was prescribed. In the only study we could find of ophthalmological patients with depression with and without glaucoma, no association was shown between depression and glaucoma.5 Glaucoma is mostly a disease of older people, a group prone to developing depressive illness. Depression is often dismissed in older people as a normal reaction to ageing, loss or chronic illness. However, it is treatable, with a very good prognosis. Older patients are frequently taking multiple medicines and may develop depressive symptoms as a side effect. The purpose of this case presentation is to emphasise that even a drug that is administered topically, such as antiglaucoma eye drops, is absorbed systemically and can potentially cause adverse effects elsewhere, including centrally. There are credible theoretical reasons why β-blockers may cause depression: the number of β1 receptors is increased in the brains of suicide victims and chronically stressed animals, and antidepressants cause down-regulation of β1 receptors. The fact that only a few patients develop depression after taking β-blockers may be due to genetic differences. It is possible that poor metabolisers of the enzyme cytochrome P450 2D6 will be exposed to higher systemic concentrations of β-blockers than those who are normal or fast metabolisers.6,7 To our knowledge, there have been no studies of depression in relation to β-adrenergic receptor gene polymorphisms, although associations have been found between these polymorphisms and haemodynamic effects after administration of betaxolol and timolol.8 Variability between individuals in the time course, affinity and extent of receptor occupation may also be relevant. Vuori and Kaila9 found substantial β1 and β2 blockade in plasma for up to 12 hours after administration of topical timolol. Thus, 12-hour dosage intervals could lead to substantial systemic blockade and could explain the reported systemic side effects. Our report adds to the evidence that depression is an occasional adverse consequence of treatment with β-blockers, including topical antiglaucoma agents. Development of depression is a serious consequence. Discontinuation of a β-blocker may relieve symptoms, but specific antidepressant treatment may also be needed. As there are alternative antiglaucoma medications, it is prudent not to prescribe β-blockers for patients who have a history of depressive illness. If depression develops after commencement of a β-blocker antiglaucoma agent, an alternative medication should be substituted if possible.

Isaac Schweitzer DPM, FRANZCP, MD · Kay Maguire BSc(Hons), MSc, PhD · Chee H Ng MMed, FRANZCP, MD

Trachoma: a blinding scourge from the bronze age to the twenty-first century. Hugh R Taylor. Melbourne: Haddington Press, 2008 (282 pp). ISBN 978 09757695 9 1. Why would a substantial scholarly work devoted solely to trachoma be published in Australia? For two good reasons: firstly, trachoma, a disease of poverty and poor countries, is still found in Australia. Secondly, it is written by a world renowned trachoma expert, the University of Melbourne’s Professor Hugh Taylor. Taylor’s passion is evident in this comprehensive review of trachoma from antiquity to the present, a scientific work of great detail and scope. Copies and extracts of documents, photographs and images, both from the author’s own collection and from sometimes obscure sources, support the text. Many of the photos were taken by Professor Taylor during his extensive field studies in Africa, Mexico and Australia, as well as in his laboratory studies. To this extent, the book provides a record of Taylor’s many years in the field and in the laboratory, his work ranging from vaccine development to simple, practical but effective means of eliminating trachoma in children at risk. Taylor draws our attention to the fact that the establishment in the 19th century of many now-famous ophthalmic hospitals was due to the trachoma epidemic in Europe, and even in Australia. He describes how improved living conditions in Europe and much of Australia at the beginning of the 20th century led to the almost total disappearance of trachoma. There is a clear exposition of why trachoma still exists in some remote areas of Australia, offering evidence of control measures and, importantly, evidence for advocacy to policymakers so that they may make evidence-based decisions on the subject. This book is an invaluable reference work for medical researchers, providing an in-depth knowledge of the subject. For public health planners, sections on the prevalence and natural history of the disease, with proven interventions detailed, will be invaluable. Students will find that this work covers much of what they need to know about a disease all but eliminated, yet which still persists in pockets of disadvantaged areas around the world.

Jill E Keeffe

Born on 8 March 1921 in Melbourne, Ken was educated at St Thomas’ Grammar School and Scotch College and studied medicine at the University of Melbourne, graduating in 1943. In 1947, after gaining a Diploma of Ophthalmology, Ken was appointed Resident Medical Superintendent at the Eye and Ear Hospital in Melbourne. With his appointment, a new era opened for the old Hospital. These were the days when a group of three — the Medical Superintendent, Matron and Manager — ran a public hospital. They were responsible to a semi-autonomous board of management and worked on a shoestring budget. The commander-in-chief was usually the Medical Superintendent, occasionally the Matron, but never the Manager. Ken was very much in charge, and no function of the Hospital was too remote to escape his attention. A small man, dressed informally (sometimes even in overalls), with prominent eyebrows and a penetrating gaze, he was the first contact every new resident doctor had with the Hospital. He was clearly a man of enormous energy and organising ability, dedicated to the revival of the old Hospital and looking for people to help him do it. Ken was a man of few words who loathed pretence and humbug. In the early days, he made it his business to work in the clinics of the Hospital — both the Eye Clinic and the Ear, Nose and Throat Clinic — in order to see proceedings at first hand and to assess the calibre of doctors-in-training. In the inevitable committee work, he did not always side with the majority view, but his formidable intellect, combined with the most thorough preparation, usually ensured that his view prevailed. Over about 20 years, the Hospital was rebuilt and thoroughly modernised, thanks to generous bequests from Peter Howson, Smorgans and others. But Ken’s real obsession was education — postgraduate and undergraduate, medical and nursing. He was pivotal in the establishment of the chairs of Ophthalmology and Otolaryngology at the University of Melbourne, and set up the William Gibson lectures for undergraduates on Saturday mornings, starring Dr John Colvin. Meanwhile, in cooperation with the general hospitals, the steady work of training specialists in both disciplines for fellowships of the Royal Colleges went on. Special clinics, such as those for glaucoma; retinal detachment; orbit, plastic and lacrimal; deafness investigation; and the bionic ear, sprang up and greatly enlivened proceedings. He helped found the Royal Australian College of Ophthalmologists in 1969 and became its President in 1981–82. Ken retired to the Victorian seaside town of Inverloch in 1990 and immersed himself in local affairs and computer activities until his death on 24 May 2008 from mesenteric artery thrombosis. His wife Betty survives him, together with his two sons David and Robert, who are also in the medical profession.

John R Thomson

To the Editor: Trachoma, caused by the bacterium Chlamydia trachomatis, is the leading cause of infectious blindness worldwide.1 In Australia, the burden of disease falls almost exclusively on the Aboriginal population.2 However, there has been little consistent data collection on the prevalence of trachoma in recent years in Australia.3,4 Furthermore, despite Australian Government recommendations for biennial screening of people aged 40–54 years and annual screening of people aged ≥ 55 years in areas where trachoma is or has been endemic,5 very little screening of older people for trachomatous trichiasis has been conducted.2,4 We report on the first large-scale population study in 30 years of the current prevalence of active and cicatricial trachoma in the Northern Territory Aboriginal population. We conducted a standardised clinical screening study of five Aboriginal communities in the Katherine Region of the NT over a 5-week period in 2007. A representative sampling frame of those believed to be currently living in each community was constructed using the medical clinic patient list, the council housing list and the local knowledge of Aboriginal Health Workers seconded from the clinics to assist with the project. All people in each community were invited to undergo a clinical eye examination for trachoma. The parameters of the World Health Organization simplified grading scheme6 were used to determine prevalence of the five signs of trachoma: tarsal conjunctival follicles, intense inflammation, tarsal scarring, trichiasis and corneal opacity. A total of 1316 people (85.2% of the total estimated population), including 415 children aged under 10 years, were screened for trachoma. Across the five communities, active trachoma (assessed as the presence of either follicles or inflammation in one or both eyes) was at an endemic level (> 10%). The prevalences of active trachoma, scarring and trichiasis in different age groups are summarised in the Box. The overall rate of active trachoma in children under 10 years of age was 19.8% (95% CI, 16.0%–23.9%) (n = 82), and two communities had hyperendemic prevalence of trachoma (> 20%) in this age group. The youngest child observed with active trachoma was just over 1 year old. The prevalence of scarring in people aged 20 years and over was 32% (95% CI, 28.3%–35.9%) (n = 193). The youngest person identified with scarring was 7 years old. Six people (2.3% of all people aged 40 years and over) were identified with trichiasis requiring urgent ophthalmological attention. Across the population, this placed the prevalence of unoperated trichiasis at more than four times the acceptable threshold set by the WHO. A seventh person had had trichiasis surgery. That trachoma is still hyperendemic in Aboriginal communities more than 30 years after the National Trachoma and Eye Health Program first identified the extent of trachoma is unconscionable. Urgent and sustained public health and clinical interventions are required, with greater commitment from politicians and health policymakers, if Australia is to join the ranks of other developed nations in eradicating endemic trachoma. The guidelines for trachoma control developed by the Communicable Diseases Network Australia5 need to be resourced appropriately and implemented. Prevalence of active trachoma, scarring and trichiasis in five Aboriginal communities in the Northern Territory in 2007, by age group* TFI = active trachoma (follicles [TF] and/or inflammation [TI]). TS = trachomatous scarring. TT = trachomatous trichiasis. * Vertical bars indicate 95% CIs.

Katrina Roper · Claude-Edouard C Michel · Paul M Kelly · Hugh R Taylor

To the Editor: Microbial keratitis associated with soft contact lens wear is a well recognised, not uncommon, clinical entity and a preventable cause of ocular morbidity.1,2 A 31-year-old woman who occasionally wore soft contact lenses presented to a general practitioner with a 2-day history of bilateral red eye associated with ocular discomfort, photophobia and purulent discharge. She was diagnosed with bilateral conjunctivitis, commenced on chloramphenicol drops and told to return in 5 days. Her symptoms initially improved, but then worsened. Seven days after symptom onset, she presented to hospital for assessment. History revealed that she had worn soft monthly disposable contact lenses twice in the previous month to correct her mild myopia. On examination, the patient’s visual acuity was equivalent to being legally “blind”, being hand movement in the right eye and light perception in the left. On inspection, both eyes appeared grossly abnormal. The right eye had a large central corneal abscess and the left eye had a complete corneal abscess with 360° peripheral corneal thinning (Box, A) — a significant risk for globe perforation. The conjunctiva was markedly injected bilaterally. Corneal scrapes, the contact lenses and the case containing turbid solution were sent for urgent gram stains and microbiological culture. The patient was admitted to hospital and received intensive topical treatment with gentamicin 0.9%, cephalothin 5% and tobramycin ointment. The corneal scrapes revealed Pseudomonas aeruginosa as the causative organism. The patient showed slow improvement with antibiotic therapy. Although the infection cleared, the residual corneal scarring resulted in permanent loss of corneal clarity and hence vision. Four months after treatment was commenced, the patient’s visual acuity had improved to 6/24 in the right eye and 6/36 in the left (Box, B). An Australian review of outcomes after keratitis found that 52% of patients had a final visual acuity of worse than 6/12, the legal visual acuity for driving.3 In this patient, despite saving both eyes and the improvement in her vision, she still has significant functional impairment, being unable to work as a teacher or drive. Corneal transplantation is now her only option for potentially regaining the loss in her functional vision, with a minimum expected recovery time of 2 years. GPs have a difficult job distinguishing between red eye requiring immediate referral and red eye that is not vision-threatening. All contact lens wearers who present with red eye need to be examined for yellow/white corneal infiltrates and, if present, or if the patient cannot be assessed adequately, immediate referral is mandatory. P. aeruginosa is the most common pathogen and one of the most aggressive organisms isolated in contact lens-related microbial keratitis.4 As it is invariably resistant to the bacteriostatic chloramphenicol, the appropriate empirical treatment is either fluoroquinolones or cephalosporins, which ideally should be commenced after corneal scrapes have been performed.5 Left eye at presentation and after 4 months of treatment A: At presentation, there was marked conjunctival injection, 100% epithelial defect (stained with fluorescein [green]) and severe circumferential peripheral corneal thinning (arrow). B: Four months after presentation, there was dense central scarring and peripheral corneal neovascularisation (arrow). Vivek B Pandya, Ophthalmology Resident1Alessandra Martins, Ophthalmology Registrar1,2Shanel Sharma, Ophthalmologist1,21 Department of Ophthalmology, Sydney Eye Hospital, Sydney, NSW. 2 Department of Ophthalmology, Royal Prince Alfred Hospital, Sydney. shanelATunsw.edu.au Green M, Apel A, Stapleton F. A longitudinal study of trends in keratitis in Australia. Cornea 2008; 27: 33-39. <PubMed> Keay L, Edwards K, Naduvilath T, et al. Microbial keratitis predisposing factors and morbidity. Ophthalmology 2006; 113: 109-116. <PubMed> Green MD, Apel AJ, Naduvilath T, Stapleton FJ. Clinical outcomes of keratitis. Clin Experiment Ophthalmol 2007; 35: 421-426. <PubMed> Stapleton F, Keay L, Sanfilippo PG, et al. Relationship between climate, disease severity, and causative organism for contact lens-associated microbial keratitis in Australia. Am J Ophthalmol 2007; 144: 690-698. <PubMed> Constantinou M, Daniell M, Snibson GR, et al. Clinical efficacy of moxifloxacin in the treatment of bacterial keratitis: a randomized clinical trial. Ophthalmology 2007; 114: 1622-1629. <PubMed> (Received 17 Mar 2008, accepted 28 Jul 2008) ©The Medical Journal of Australia 2008 www.mja.com.au PRINT ISSN: 0025-729X ONLINE ISSN: 1326-5377

Vivek B Pandya · Alessandra Martins · Shanel Sharma

To the Editor: A 37-year-old man infected with HIV through exposure to men who have sex with men (MSM) presented with a 6-week history of intermittent fevers, patchy alopecia and a widespread brown/grey macular rash involving his face, trunk, abdomen and all limbs, with scaling of the face, palms and soles. He had no symptoms of meningism or visual disturbance, and had a chronic mild intermittent headache with no recent change in frequency or intensity. His most recent CD4 cell count was 70 cells/μL and his HIV viral load was > 100 000 copies/mL. On admission, a serological test for syphilis was reactive and showed a rapid plasma reagin (RPR) titre of 1 : 64 and a positive enzyme immunoassay for antibody (EIA-Ab), whereas at the onset of the rash 6 weeks previously, a serological test for syphilis was negative. A punch biopsy of the skin lesions showed a perivascular infiltrate with lichenoid inflammation consistent with secondary syphilis. An ophthalmological review showed a bilateral anterior uveitis. Examination of cerebrospinal fluid (CSF) showed a white cell count of 1 × 106/L (100% lymphocytes), a normal glucose level, a mildly elevated protein level of 0.45 g/L and a weakly positive result for a fluorescent treponemal antibody absorbed (FTA-ABS) test. CSF RPR, EIA-Ab and Treponema pallidum particle agglutination (TPPA) test results were all non-reactive. The patient was diagnosed with asymptomatic ocular and neurosyphilis, and treated with intravenous benzylpenicillin (1.8 g 4-hourly for 15 days) and prednisolone eye drops (four times daily for 14 days). The rash faded and the anterior uveitis subsided in the first week of treatment. There is currently a syphilis epidemic among MSM in Victoria, with the number of syphilis notifications increasing 25-fold between 2000 and 2006.1 A strong association between HIV infection and infectious syphilis has been demonstrated in recent years, including in Victoria.2 HIV-infected MSM with early syphilis have a 1.7% risk of having symptomatic early neurosyphilis3 and a 13% risk of having symptomatic ocular syphilis regardless of CD4 cell count.4 There is no pathognomonic finding in ocular syphilis, and the disease may manifest as uveitis, retinitis, optic neuritis, perineuritis, retinal detachment and papillitis. It is recommended that all patients with ocular syphilis undergo CSF examination and be managed as if they had neurosyphilis.5 Current guidelines also recommend CSF examination in HIV-infected patients who have late-latent syphilis, syphilis of unknown duration, any neurological signs or symptoms, or suspected treatment failure.6 The finding of asymptomatic ocular syphilis in our patient suggests there should be a low threshold for eye examination in HIV-infected people with early syphilis, even in the absence of any ocular symptoms, as the diagnosis of ocular syphilis dramatically alters the management of these patients.

Matthew T Kitson · Michelle K Yong · Jennifer F Hoy

Clinical record We report the case of a 54-year-old woman who presented with a painful and swollen left eye 3 days after receiving zoledronate. The patient had been diagnosed with locally advanced breast cancer 3 years earlier. This was managed with four cycles of neoadjuvant chemotherapy (with adriamycin and cyclophosphamide) followed by breast-conserving surgery and axillary dissection. Histological sections from the surgical specimen revealed a 10 mm grade 3 infiltrating ductal carcinoma that was negative for both oestrogen and progesterone receptors. Eight out of 10 axillary lymph nodes were positive for malignancy. The patient went on to receive four cycles of adjuvant chemotherapy (paclitaxel) and postoperative radiotherapy. The patient remained well until a month before presentation, when she developed right hip pain. An x-ray and bone scan showed a suspicious bone lesion within the ischium on the contralateral side to the pain. A computed tomography scan of the chest, abdomen and brain revealed a 1.5 cm right upper lobe lung lesion as well as multiple brain lesions. A biopsy of the lung lesion confirmed the presence of adenocarcinoma consistent with metastatic breast cancer. She commenced oral dexamethasone treatment 4 mg three times daily and, because of the symptoms associated with bone metastases, also received a 4 mg intravenous dose of zoledronate. Three days later, she was reviewed by her local ophthalmologist when she presented with an acutely swollen and painful left eye with associated blurring of vision. On the basis of a moderate cellular infiltrate in the anterior chamber, she was diagnosed with acute iritis and commenced on homatropine 2% three times daily as well as ocular dexamethasone hourly. Two days later, the patient noted increasing pain in the eye, worsening blurring of vision and onset of photophobia. She was reviewed by the ophthalmology department at the hospital where she was undergoing whole brain radiotherapy. She was noted to have reduced visual acuity in the left eye, an injected conjunctiva, a hazy and oedematous cornea, and cells in the anterior chamber. Fundoscopy was unremarkable. A diagnosis of acute anterior uveitis and anterior diffuse scleritis was made. She was continued on homatropine drops but the dexamethasone drops were changed to 2-hourly prednisolone acetate/phenylephrine hydrochloride drops. The patient was reviewed regularly in the ophthalmology clinic over the following 2 weeks. At the time of discharge from the clinic, her visual acuity had improved and the anterior chamber was clear of cells. She had ceased homatropine treatment and was on a weaning dose of ocular steroids. Three months later, she had ceased ocular steroid therapy and her vision had returned to normal. She received no further doses of bisphosphonate after the first administration. Bisphosphonates are indicated for treatment of a number of conditions, including osteoporosis, Paget’s disease, hypercalcaemia associated with malignancy, and bone metastases. Their mechanism of action is via inhibition of osteoclast activity, leading to reduced bone resorption. Common side effects of bisphosphonate treatment are dysphagia, heartburn and oesophagitis. Lessons from practice Bisphosphonates are used to treat a number of clinical conditions, including osteoporosis, Paget’s disease, hypercalcaemia of malignancy, and bone metastases. Various ocular complications of bisphosphonate use have been reported, including conjunctivitis, scleritis, iritis and uveitis. These complications are rare and are readily treatable. Management usually involves cessation of the bisphosphonate and treatment with an ocular topical mydriatic drug and steroids. Since the early 1990s, there have been a number of case reports documenting various ocular complications of bisphosphonate use, including conjunctivitis, scleritis, iritis and uveitis.1-9 In most cases, ocular symptoms began within 72 hours of administration of the bisphosphonate, and symptoms generally improved after local therapy and cessation of the drug. Usually it is the nitrogen-containing bisphosphonates that have been implicated (alendronate, pamidronate, zoledronate, risedronate), but in one report uveitis was associated with a non-nitrogen-containing bisphosphonate (clodronate).5 The mechanism of the inflammation is unclear, but it is known that the nitrogen-containing bisphosphonates cause elevated levels of pro-inflammatory cytokines, including tumour necrosis factor α and interleukin-6.10 The factors that predispose some patients to develop ocular symptoms are not known. Management of patients with ocular complications of bisphosphonate use includes treatment with an ocular topical mydriatic drug and a steroid. In most of the cases described in these case reports, the bisphosphonate treatment was stopped, and, in one case, ocular symptoms recurred on rechallenge with the drug.5 In another case, in which the original bisphosphonate was replaced by a different drug of the same class, eye inflammation was reduced and eventually resolved with continued use, suggesting the development of immunological tolerance.11 Between 1997 and April 2004, there were nearly 6 million Pharmaceutical Benefits Scheme prescriptions filled in Australia for bisphosphonates.12 This figure underestimates overall use, as it does not capture bisphosphonates administered to hospital inpatients. Bisphosphonates are an extremely useful class of drugs, and the point of our case report is not to advocate lesser use, but to highlight the importance of early recognition of potentially sight-threatening ocular conditions, as they are readily treatable.

Melissa M Moore BA, BSc, MB BS(Hons) · Jane M Beith PhD, FRACP

Excessive reliance on intraocular pressure to detect glaucoma leaves many affected patients undiagnosed and untreated; visualisation of the optic disc is a dying art that needs to be revived Intraocular pressure (IOP) is measured by tonometry. In our community, mean IOP is around 15 mmHg, with a normal range (mean ± 2 SD) regarded as 10–21 mmHg. This information is irrelevant to the diagnosis of glaucoma. Misconceptions about the importance of IOP in diagnosing and screening for glaucoma continue to result in unnecessary blindness in Australia from glaucomatous optic neuropathy. An aggressive realignment in our thinking is required. The classic diagnostic triad for glaucoma of raised IOP, arcuate visual field loss and optic nerve head cupping has been inverted. Glaucoma may now be defined as a characteristic, progressive, optic neuropathy showing optic disc cupping as a consequence of neural rim loss. It tends to produce arcuate visual field loss. It is frequently associated with an elevated IOP, but may be diagnosed at any IOP if there is characteristic optic disc and/or visual field damage. This damage indicates susceptibility of that optic nerve to a given IOP. Early work established a population mean IOP, with an about normal distribution.1 It is regrettable that this result came to be interpreted as indicating a “normal” (ie, safe) IOP for an individual patient, particularly as that report recognised that glaucoma could occur despite an IOP of less than 21 mmHg. In the Baltimore Eye Survey, more than 50% of patients with newly diagnosed glaucoma had a “normal” IOP on a single tonometry measurement.2 The term “normal pressure glaucoma” (NPG) has been coined for such eyes, and they may comprise a third to a half of all open-angle glaucoma cases.2,3 Conversely, there is a subset of the population that has IOP elevated above normal, yet does not have glaucoma. This status is labelled ocular hypertension. Detection of elevated IOP remains important at any time. The prevalence of glaucoma at successive levels of IOP greater than 21 mmHg rises exponentially.4 IOP is the single greatest risk factor for glaucoma, and its reduction is the cornerstone of all current treatment. Screening on the basis of IOP alone, however, clearly produces a high rate of potentially disastrous false negatives. Patients continue to undergo “eye-checks” and be reassured that they do not have glaucoma solely on the basis of an IOP measurement. This represents an inadequate standard of care. Visual field loss is no longer a sine qua non of diagnosis. In recognition that up to 40% of axons may be lost from the optic nerve before visual field loss is evident on standard automated perimetry,5 the term “preperimetric glaucoma” connotes this early disease. Rather than being a distinct entity, preperimetric glaucoma really indicates the inadequate sensitivity of this standard psychophysical test in detecting early glaucoma (as compared with its invaluable role in confirming and monitoring established disease). Early detection of disease can thus depend entirely on identifying optic disc cupping, notching or rim loss, and associated retinal nerve fibre layer defects, perhaps in the absence of raised IOP or visual field loss. Newer and more sensitive tests of specific visual processing such as frequency doubling perimetry or short wavelength automated perimetry may detect glaucoma earlier, and may thus shift the boundary in defining preperimetric glaucoma.6 We must also disabuse ourselves of any convenient dichotomy between chronic open-angle glaucoma and acute angle-closure “glaucoma”. (Acute primary angle closure [APAC] causes a painful, unilateral red eye with markedly elevated IOP: patients with APAC may not have optic disc cupping or visual field loss.) It is increasingly evident that a massive and untreated burden of chronic angle-closure glaucoma exists, particularly in Chinese and South-East Asian people,7 and therefore in our immigrant populations and their families. Glaucoma, whether open-angle or closed-angle, is an insidious disease — “the sneak thief of sight”. Its prevalence increases exponentially with age; progression is slow, painless and irreversible; visual acuity is affected only late; and symptoms of peripheral vision loss with mobility difficulties do not occur until gross levels of field constriction have developed. For all these reasons, affected patients tend not to present but instead need to be found. Prevention — or at least slowing — of further vision loss is possible with an effective range of medical, laser or surgical therapies directed at lowering IOP to an individualised target level (which may be considerably lower than 21 mmHg). The limitation to our preventing blindness in Australia is not so much a lack of therapies, but inadequate case detection. Awareness of the newer concepts in glaucoma has been variable among general practitioners, optometrists and even ophthalmologists. Glaucoma has a prevalence of around 3% in the population aged over 50 years, yet 50% of cases of glaucoma in Australia today remain undiagnosed.8 The Melbourne Visual Impairment Project provides a further indictment: of the patients whose glaucoma was detected during the survey and who had seen an eye-care practitioner in the preceding 12 months, nearly half (many of whom had established visual field defects) had not had their glaucoma diagnosed.9 Highly sensitive screening programs of the general population for glaucoma are, however, not cost-effective, producing low case yields and a high number of false positives.10 Despite a panoply of technological wizardry, there remains no device that in a single or screening test can identify early glaucoma with appropriate sensitivity and specificity. Local research is progressing with international collaborators to identify genetic loci responsible for glaucoma,11 but a blood test to identify those genetically at risk is not generally available. What is to be done? Ophthalmologists diagnose and manage glaucoma, but are referral-dependent and thus see a selected sample. The aim that every Australian aged over 40 years have a general eye examination by an eye-care practitioner remains an elusive goal, but such a strategy could detect glaucoma as well as other ocular abnormalities, particularly if glaucoma sufferers could be prompted to reveal their diagnosis to first-degree relatives. “More funding” is a mantra so tired as to engender indifference, but would certainly enable more targeted, resource-intensive testing.12 While the benefit of disease detection seems self-evident, legitimate public health arguments could be mounted that, as progression of glaucoma is slow, diagnosis and treatment of early disease (particularly in older patients with preperimetric glaucoma) is not justifiable. We must also be mindful of the burden of the diagnosis and treatment for the patient.13 Screening protocols would therefore be directed not to detecting early glaucoma per se, but rather to finding those with a greater lifetime risk of loss of functional vision (ie, advanced disease, younger age or higher IOP). In the absence of such a structured program, we are dependent on “opportunistic screening”. In this issue of the Journal, Zegers and colleagues present two clinical vignettes illustrating the importance of a family history of glaucoma,14 which is an excellent starting point in case detection (→ Primary open-angle glaucoma: the importance of family history and role of intraocular pressure). Glaucoma suspects can also be identified by general practitioners and optometrists prepared to examine the optic disc. For the former, ophthalmoscopy is a dying art that needs to be rejuvenated in training programs so that visualisation of the optic disc can resume its place in the routine medical check-up. Optometrists, on the other hand, are technologically equipped and trained to detect and diagnose eye disease, are frequently primary eye-care practitioners, and are numerous. The recent move by a vanguard of optometrists into therapeutics and comanagement remains politically vexed. Nonetheless, medical practitioners must accept and encourage the major contribution to glaucoma detection that many optometrists make. Vision loss from glaucoma is most often preventable. Current therapies are effective if the diagnosis is made early enough. Many treatable patients continue to lose visual field because case-detection strategies are haphazard, incomplete, or suffer from a lingering and inappropriate fixation on elevated IOP as the sole diagnostic criterion. The two simple tasks of asking for a family history of glaucoma and assessing the optic disc (with referral onward of patients with positive findings) represent opportunities to diminish the impact of the commonest preventable cause of irreversible blindness in Australia today. To heighten awareness of glaucoma, the first-ever World Glaucoma Day has been designated for 6 March 2008 (http://www.wgday.net). Glaucoma Australia provides patient and community education and support, and can be contacted at http://www.glaucoma.org.au.

Mark J Walland MB BS, FRANZCO, FRACS

Same time, another place An 8-year-old boy with marasmus presented with poor vision. His right eye had a staphyloma and his left eye a leukoma. He was totally blind in the right eye. His visual acuity in the left eye was only perception of light. Corneal transplantation for his left eye has been planned. The right eye will be enucleated and an ocular prosthesis implanted. Five years earlier, the child was admitted for treatment of kwashiorkor with associated bilateral keratomalacia due to vitamin A deficiency. These ocular sequelae of vitamin A deficiency could have been prevented by its timely supplementation. CommentaryAlthough it is no longer common in Australian Aboriginal communities, malnutrition still occurs in isolated areas. In Australia, keratomalacia of the degree shown here would be exceptional.1 In Africa and parts of south Asia, however, such causes of blindness are not uncommon, particularly among refugees from war and civil strife, where community structure is destroyed, immunisation rates (especially for measles) are low, and malnutrition is common. These circumstances are unfortunately still occurring, exacerbated by climate change, protracted drought and disruption of the normal seasonal cycles of agricultural production. Vitamin A deficiency is common even without kwashiorkor or marasmus, and keratomalacia can be precipitated by an outbreak of measles or acute diarrhoeal disease if vitamin A levels are low. Although blindness in children is far less common than in adults, blind children tend to be blind for longer and have less access to education, and are then less able to contribute to the community and the economy. Such a serious disorder can be avoided entirely by using one of the simplest and most cost-effective public health interventions: vitamin A supplementation. Vision 2020: the Right to Sight (the global initiative of the World Health Organization and the International Agency for the Prevention of Blindness to eliminate avoidable blindness and vision impairment by 2020) prioritises such devastating but needless causes of blindness. This has, through surveillance, advocacy and direct action, led to such sequelae becoming very rare in politically stable countries.

Sunil Karande · Sujit Jagtap · Richard T Le Mesurier

Clinical records Patient 1 In March 2005, a 58-year-old man was referred by his general practitioner for evaluation of a central scotoma with macular sparing in his right eye of 6 weeks’ duration, noticed during reading as a sort of shadow following his point of fixation. He had had no previous ophthalmic complaints and had worn spectacles to correct moderate myopia since the age of 12 years. His health was excellent; he was on no medication and had never had a surgical procedure. Both parents had lost vision from glaucoma. For this reason, his intraocular pressure (IOP) was monitored by his brother, an optician. Over 4 years, repeated IOP measurements of under 22 mmHg had been obtained by non-contact tonometry in both eyes. On examination, visual acuity was 6/6 in both eyes. IOPs of 38 mmHg in the right eye and 30 mmHg in the left eye were obtained by applanation tonometry. A non-contact method yielded pressures of 28 mmHg in the right eye and 22 mmHg in the left eye. Further examination showed open anterior chamber angles and a myopic optic nerve head which was pathologically cupped on the right side and “suspicious looking”, with elongated vertical cupping on the left (Figure A). Later, automated visual field testing showed a large central defect in the right eye, almost reaching the point of fixation (Figure B). The left eye was normal. Therapy with eye drops (timolol/dorzolamide fixed combination, twice daily) was started, which stabilised the pressure at around 10 mmHg in both eyes. The patient’s brother, who had never consulted an ophthalmologist, was advised to do so. He showed no signs of glaucoma. Patient 2 A 69-year-old man presented in June 2005 with slowly deteriorating vision over several years. For the previous 2 months, he complained of bumping into objects in his path. He had never experienced eye pain and had been healthy all his life. His mother, whom he had accompanied to the GP and ophthalmologist for many years, had eventually become blind from glaucoma when very elderly. His sister went blind from glaucoma at the age of 65 years. Twenty-five years earlier, the patient had been seen by an ophthalmologist who saw no signs of glaucoma during a routine examination. The patient claimed that he had never been told to have regular eye checks for glaucoma, and had not done so. On examination, visual acuity was light perception in the right eye and hand movements at 2 m in the left eye. IOPs by applanation tonometry were 53 mmHg for the right eye and 49 mmHg for the left eye. Gonioscopy showed open anterior chamber angles. Both optic nerve heads were completely cupped (Figure C). Visual field examination showed no vision in the right eye and a temporal island of vision in the left eye (Figure D). In an attempt to preserve his remaining vision, medical therapy (timolol/dorzolamide fixed combination, twice daily and latanoprost, daily) was instituted, which stabilised pressures at below 18 mmHg in both eyes. He has noticed no further decline in vision since presentation. The two cases we present here are good examples of how the diagnosis of glaucoma is often missed because of lack of history-taking and/or insufficient clinical examination. Glaucoma is the second leading cause of blindness worldwide;1 nevertheless, knowledge of this disease is poor among the general population as well as among health professionals.2 Primary open-angle glaucoma (POAG) is a chronic and progressive optic neuropathy that causes visual field loss, eventually leading to complete blindness. It can be present for a long time before patients have symptoms. About half of those affected with glaucoma are not aware they have the disease.3 While the most important risk factor for POAG is elevated intraocular pressure (IOP), pressure is only one component of a constellation of findings that define POAG. Glaucoma is a specific optic neuropathy, characterised by optic nerve head cupping and usually associated with (arcuate) visual field loss. Glaucoma may be associated with elevated IOP, but can be diagnosed irrespective of the IOP, so IOP is no longer considered part of the diagnosis. Established risk factors for POAG (besides elevated IOP) are higher age, African ethnicity, a positive family history, thinner corneal thickness, and myopia.1 Diagnostic clues include gonioscopy (visualisation of the drainage angle), characteristic changes in the optic nerve head (cupping — elongation of the optic cup in a vertical direction, as result of, typically inferior, notching of the neuroretinal rim that will be the first sign of POAG), and characteristic (mostly midperipheral) defects on visual field testing. To date, the only effective evidence-based treatment for glaucoma is decreasing IOP;4 any local or systemic risk factors should also be addressed. Lessons from practice All primary care doctors should ask their patients about a family history of primary open-angle glaucoma (POAG), which is an important risk factor for this disease. Patients with POAG should be told to alert their first-degree relatives to the need for an adequate glaucoma screening. “No visual symptoms” does not equal “no POAG”, as visual field defects occur mainly at advanced stages of the disease. Pain is seldom a symptom in POAG (it is associated with acute angle closure glaucoma). About a third of patients with POAG have so-called “normal tension glaucoma”; this will not be detected by measuring intraocular pressure alone. Examining the optic disc is much more important for a correct diagnosis of POAG than measuring intraocular pressure. It is critical to note that symptoms occur late in POAG. If a diagnosis is based only on symptoms, advanced irreversible vision loss is likely. Patients with POAG need to be identified early, which requires a high level of suspicion, adequate screening and prompt referral. In many countries, primary eye care is provided by general practitioners and eye specialists. In others, this role is fulfilled by optometrists. Unfortunately, many health care workers, including (in our experience) even some ophthalmologists, only look at IOP when considering glaucoma as a diagnosis, as in our Patient 1. Over a third of patients with glaucoma have an IOP within the average range (10–21 mmHg).5 They have “normal tension glaucoma” in which, despite an IOP that is not elevated beyond the arbitrary upper limit of 21 mmHg, the optic nerve can show pathological cupping, and the visual field examination can show characteristic defects. These patients will easily be missed if diagnosis is based on IOP. Moreover, some health care workers tend to use non-contact tonometry to measure IOP. Such tonometry tends to underestimate the true pressure, which is more accurately measured with a Goldmann applanation tonometer (Haag–Streit International, Koeniz, Switzerland).6 We emphasise that examination of the optic disc is much more important for a correct diagnosis of POAG than IOP. However, measuring IOP remains important, as our Patient 2 would have been diagnosed by screening IOP alone. We also emphasise that pain is seldom a symptom of POAG. Pain is a feature of acute angle closure glaucoma, in which the IOP reaches very high levels in a very short time because of acute blockage of the drainage angle; this is not a feature of POAG. Family history played an important role in both our patients and should have been investigated during history-taking. First-degree relatives of patients with POAG have a risk about 10 times greater than for people with no family history of glaucoma.7 However, relatives are often unaware of their risk, sometimes even decades after treatment is initiated in their family.8 Patients with primary glaucoma should be advised to alert relatives to the need for adequate glaucoma screening and follow-up. We believe awareness of POAG among the general population (as well as among health care professionals) is poor at best. To increase awareness in the general population, primary care health professionals in particular need a better understanding of this disease. We believe that asking about a family history of glaucoma as a part of an ophthalmic history, or as part of a general medical history, should be routine in all new patients. First-degree relatives of patients with POAG should be advised to be screened by an ophthalmologist or optometrist. Depending on ophthalmic findings, age and other risk factors, first-degree relatives should have a full ocular evaluation on a regular basis (eg, every 2 or 3 years, or more frequently if findings are equivocal). This simple step, and a timely referral can prevent much disability and associated cost for individual patients and the community.

Richard H C Zegers MD · Erik F Reinders MD · Marc D de Smet MD, PhD

Clinical recordA 35-year-old British man was admitted with a 2-week history of abdominal discomfort, fatigue and intermittent high fevers associated with drenching night sweats. He reported having returned to Australia 2 months before presentation from a 12-year around-the-world trip, having travelled extensively for 6 months through South-East Asia and northern Australia. Before that, he had been to Argentina, the Maldives, Egypt, India and Cambodia, where he had worked as a professional kitesurfing instructor. His past medical history was unremarkable and he was not on regular medication. His social history revealed intravenous heroin addiction in his early 20s. He had consumed more than 80 g of alcohol daily for a number of years, with occasional binges, until recently, when drinking alcohol provoked nausea and vomiting. The patient appeared unwell with a tympanic temperature of 40°C. He was fair-skinned and of muscular build. Physical examination showed conjunctival jaundice but no evidence of needle tracks, rashes, finger clubbing, lymphadenopathy or suspicious cutaneous lesions. Tender hepatomegaly was noted, but no ascites or splenomegaly. Findings of cardiac, respiratory and neurological examinations were normal. Abnormal laboratory findings on admission were: albumin concentration, 29 g/L (reference range [RR], 33–47 g/L); alkaline phosphatase titre, 164 U/L (RR, 30–115 U/L); γ-glutamyl transferase titre, 207 U/L (RR, 0–45 U/L); alanine aminotransferase titre, 76 U/L (RR, 0–40 U/L); aspartate aminotransferase titre, 279 U/L (RR, 0–40 U/L); lactate dehydrogenase titre, 4268 U/L (RR, 100–225 U/L); white cell count, 13.4 × 109/L (RR, 4.0–11.0 × 109/L); absolute neutrophil count, 9.7 × 109/L (RR, 1.5–6.0 × 109/L). There was no evidence of thrombocytopenia, renal dysfunction or coagulopathy. Findings on abdominal ultrasonography the day before admission were reported to be normal. Despite there being few clinical features to suggest a source of sepsis apart from the hepatomegaly, because of his travel history and previous history of injecting drug use, a wide variety of infectious diseases, including subacute bacterial endocarditis, typhoid, malaria, and viral hepatitis, were all initially considered in the differential diagnosis. Multiple sets of blood cultures, urine and stool samples were sent for microscopy, culture and sensitivity. Three sets of thick and thin films for malaria as well as a test for Plasmodium falciparum antigen were negative. In view of the clinical hepatomegaly, a computed tomography (CT) scan of the abdomen was performed, which was reported as strongly suggestive of microabscesses (Box). The presumptive diagnosis at this stage was a tropical pyogenic liver abscess, although military tuberculosis and candidiasis were also considered. Intravenous therapy with flucloxacillin, ceftriaxone, ciprofloxacin and metronidazole was initiated. The ceftriaxone was subsequently changed to meropenem, and the ciprofloxacin ceased 5 days after there had been no growth on any cultures. Serological tests for a wide variety of pathogens and diseases were also performed, including: HIV 1 and 2; hepatitis viruses A, B and C; cytomegalovirus; Epstein–Barr virus; Q fever; brucellosis; cryptococcosis; Entamoeba histolytica; Ross River virus; Dengue virus; flavivirus; leptospirosis; schistosomiasis; cysticercosis; and melioidosis. Results for all of these eventually returned negative. Despite the antibiotics and fluids given intravenously, the patient’s condition deteriorated over the course of 6 days and he developed hepatic encephalopathy, ascites, pleural effusions and peripheral oedema. He also continued to spike high temperatures daily, but repeated blood cultures were sterile. A CT scan performed a week after the initial CT scan suggested enlargement of the liver lesions. Although hepatic abscesses were still considered most likely, given the markedly elevated lactate dehydrogenase titre and lack of clinical improvement with broad-spectrum antibiotic therapy, alternative diagnoses, in particular malignancy, were also considered. We therefore performed a core biopsy of the liver under ultrasound guidance. There was no evidence of pus, and the lesional tissue showing strong monoclonal antibody staining against Melan-A and HMB-45 confirmed liver infiltration by a poorly differentiated malignant melanoma. Repeat physical examination included dilated pupil fundoscopy, which showed a brown, dome-shaped subretinal lesion just below the left optic disc, most suggestive of a primary choroidal melanoma. The patient said that he never used sunglasses while kitesurfing. DiscussionExposure of the unprotected eye to sunlight or sunlamps is an important risk factor for the development of intraocular melanoma.1 The incidence of ocular melanoma in dark-eyed individuals is lower, probably because they are less sensitive to solar radiation, or less is transmitted to the choroids.2 Uveal melanoma (affecting the iris, ciliary body, and choroids) is the most common primary intraocular malignancy in the Western world, affecting six to eight adults per million each year. Although fewer than 2% of patients show evidence of metastatic spread at presentation, over 40% will eventually die from widespread disease.3 Most intraocular melanomas are initially asymptomatic. Tumour enlargement may then cause distortion of the pupil (iris melanoma), blurred vision (ciliary body melanoma), or decreased visual acuity caused by either central growth close to the macula or secondary retinal detachment (choroidal melanoma). Because the uveal tract is a vascular structure without lymphatic channels, tumour spread occurs primarily by either local extension or by haematogenous dissemination. The first site of systemic metastases is the liver, although spread to other organs such as lung, bone, and subcutaneous sites have been described.3 Metastasis of melanoma to the liver, although rare, can produce a dramatic initial presentation with fulminant hepatitis, shock, and multisystem organ failure.4 An elevated lactate dehydrogenase titre is one of the most predictive factors for metastatic spread and decreased survival in patients with malignant melanoma, with a sensitivity of 79% and specificity of 92% in detecting disease progression to stage IV melanoma.5 Extraocular extension and metastatic spread are associated with an extremely poor prognosis, and response rates with contemporary single-agent chemotherapy are generally below 10%. A recently published study investigated the use of chemotherapy with intra-arterial hepatic fotemustine.6 Median survival rates were among the longest reported, with an overall response rate of 36%, a median overall survival of 15 months, and a 2-year survival rate of 29%. Our patient was scheduled for three cycles of intravenous fotemustine therapy, but developed significant tumour lysis syndrome with intractable hyperkalaemia. He died shortly after the second cycle, only 28 days after being admitted to hospital. The final diagnosis was hepatic failure secondary to metastatic melanoma from an intraocular primary melanoma. An autopsy was not performed. Coronal reconstruction computed tomography image of the abdomen showing hepatomegaly with numerous low-density lesions scattered throughout both lobes of the liver

Stefan Buchholz MD, MRCP(UK) · George Rudan MB BS, FRACP

Aboriginal and Torres Strait Islander people are three times more likely than non-Indigenous Australians to report vision loss due to cataracts, but are four times less likely to have cataract surgery. To increase access for Aboriginal and Torres Strait Islander people to cataract surgery, we need to identify the barriers to current services and trial strategies to overcome these barriers. Barriers to cataract surgery exist at the health service, community and individual level. Health service factors include infrastructure, cost, and provision of interpreters, escorts and transport. Community factors include social support, perceptions about the success of surgery, and beliefs about the causes of cataracts. Individual factors include ignorance that cataracts can be cured, fear of surgery or poor outcome, and comorbidity. Strategies proven to increase uptake of cataract surgery in other countries could be trialled in remote Australia.

Susan M Wearne

Treatment targeting vascular endothelial growth factor is revolutionising AMD management Age-related macular degeneration (AMD) is the most common cause of blindness and visual disability in the Western world.1,2 In AMD, vision is lost either from a slow atrophic process (dry AMD) or from a much more rapid and destructive process of choroidal neovascularisation (wet AMD). Wet AMD accounts for the vast majority of severe vision loss. Around 15% of people over 50 years of age (approximately 750 000 Australians) have some signs of AMD, which include pigment disturbance and yellow deposits, called drusen, in the macula. These early changes, sometimes referred to as age-related maculopathy or early AMD, do not usually cause symptoms, but they do increase the risk of developing the sight-threatening complications of AMD (or “late” AMD), which result in 1%–2% of people in this age group losing significant vision. The prevalence of these early changes rises exponentially with age, so that nearly two out of three people who reach the age of 90 will have early AMD, with one in four having a significant loss of vision as a result of progressing to late AMD.1 Including both direct and indirect costs of visual impairment, AMD cost Australia $2.6 billion in 2005, and this figure is expected to grow to $6.5 billion over the next 20 years.3 With its enormous impact on quality of life and economic burden to the community, an effective treatment has been keenly sought. Until photodynamic therapy became available in 2000, clinicians treating wet AMD were confined to the use of destructive thermal laser photocoagulation, which destroys the abnormal blood vessels but also the overlying neural retina. While this treatment was better than the condition’s natural history, it was only used in a small group of patients whose blood vessels were well delineated and not located under the centre of the macula (fovea). Photodynamic therapy, on the other hand, employs a low-powered laser that activates a photosensitive dye to achieve preferential destruction of the choroidal neovascularisation, allowing treatment of lesions under the fovea. Although an advance in treatment, few patients who have photodynamic therapy retain reading or driving vision and virtually none improve on their presenting vision. Further advances in treatment have recently been made, following the discovery that vascular endothelial growth factor (VEGF) is a major driver for the abnormal blood vessel growth in wet AMD.4 There are now many drugs that are directed towards blocking VEGF at various sites in its pathway. These drugs have treatment implications in several diseases, particularly cancers, but their impact is now being felt in ophthalmology, due to unprecedented success in treating wet AMD. Recent publications in the New England Journal of Medicine presented results from two large prospective randomised controlled trials investigating the efficacy and safety of ranibizumab as a new treatment for AMD.5,6 Ranibizumab is a humanised antigen-binding fragment of a recombinant monoclonal antibody directed at the VEGF protein. In the two trials, collectively involving over a thousand subjects, ranibizumab was injected into the vitreous humor on a monthly basis for 2 years, and the results compared with sham injections in one study5 and with photodynamic therapy in the other study.6 In both studies, average visual acuity at 12 months had improved by one line on an eye chart in the ranibizumab-treated groups, compared with a reduction in vision in the control groups.5,6 In the study by Rosenfeld et al, 95% of the ranibizumab-treated group maintained relatively stable vision, compared with only 62% of the sham group. Visual acuity improvement of 15 letters (three lines) or more was seen in about a third of the ranibizumab-treated group, compared with 10% of the sham group.5 Similar results were seen in the study comparing ranibizumab treatment with photodynamic therapy.6 The most feared complication of intravitreal injections — bacterial infection inside the eye — occurred in about one in every 2000 injections, or about 1% of the patients in these studies. Potential systemic side effects from anti-VEGF treatments are arterial thromboembolic events, such as stroke and myocardial infarction. There was no statistically significant difference in the risk of arterial thromboembolic events between the anti-VEGF treatment and control groups in these two studies, but the numbers affected were higher in the treated groups.5,6 Further studies are ongoing to monitor for these adverse events. Ranibizumab was approved by the United States Food and Drug Administration for treatment of wet AMD in June 2006, and, although still awaiting registration in Australia, it is available here through a special Therapeutic Goods Administration access scheme. The current cost of ranibizumab is $2000 per injection (with a subsidy scheme in place after three injection payments). Clinical trials are ongoing to evaluate whether less frequent injections of ranibizumab may be equally efficacious. In current clinical practice, many clinicians have adopted a flexible re-treatment regimen, using visual acuity, clinical appearance and optical coherence tomography scanning of the macula to guide the decision to re-treat. How long treatment needs to be continued remains uncertain, as the underlying disease, and hence the stimulus for new blood vessel growth, has not been addressed by these new treatments. Prior to ranibizumab becoming available, clinicians were already using a related drug, bevacizumab (the full length monoclonal antibody to VEGF derived from the same mouse monoclonal antibody as ranibizumab), to treat wet AMD. Bevacizumab is only approved for use in treating metastatic colon cancer. Although there have been no randomised controlled trials evaluating bevacizumab in the treatment of wet AMD, several uncontrolled case series have reported short-term efficacy and safety similar to ranibizumab.7,8 Off-label use of bevacizumab continues around the world, including in Australia, due to its much cheaper cost compared with ranibizumab. No prospective randomised studies comparing ranibizumab and bevacizumab have taken place, although there are plans for such a trial through the US National Eye Institute. Until the results of such a comparative trial are forthcoming, government and the community face a dilemma of whether to approve and subsidise the well studied but expensive drug ranibizumab, or to delay that decision and therefore condone the off-label use of a drug that has not been submitted to the rigours of a randomised clinical trial nor studied to the extent that we expect before a new drug is introduced. Despite these advances in treatment, our knowledge about the underlying mechanisms and pathogenesis of AMD is still lacking. To date, cessation of smoking remains the most important intervention to reduce the risk of AMD and its progression, especially the wet form. There is still no specific treatment for dry AMD, which leads to a slower, but still significant, loss of vision. Also, our ability to predict and prevent progression of early AMD to the visually devastating complications of late AMD is limited. Achieving this would truly represent a major advance in the treatment of AMD. The recent explosion in publications reporting significant gene associations with AMD may prove a major step in helping us achieve this ultimate aim.9,10

Robyn H Guymer MB BS, PhD, FRANZCO

Clinical record A 10-week-old baby presented to a local general practitioner with a 2-day history of discharge from her left eye. This was accompanied by an upper respiratory tract infection. The baby was otherwise healthy, born at term, and had no history of trauma to the eye. Her brother had had conjunctivitis a week earlier, which resolved with chloramphenicol drops within a few days. The treating doctor made the diagnosis of bacterial conjunctivitis and prescribed chloramphenicol ointment to be used four times daily. The discharge became more profuse and purulent, prompting a return to the GP 2 days later. At that consultation, the GP observed lid swelling, and treated a presumed lid infection by adding framycetin eye drops and oral amoxycillin. A further 2 days later, the baby returned with worsening of the lid swelling and green discharge covering the cornea. This prompted the GP to refer the baby to the local hospital, where a corneal abscess was diagnosed. A swab was taken for culture. The child was urgently referred to a paediatric tertiary referral hospital. At the tertiary hospital, the child was found to have copious purulent discharge from the left eye, mild lid swelling, severe conjunctival injection, and a dense opacity in the superior half of the left cornea. There was severe thinning and descemetocele formation over most of the inferior half of the cornea. A corneal scrape was sent for microbiology. A diagnosis of severe bacterial keratitis with impending perforation was made. Topical gentamicin 1.5% eye drops and vancomycin 5% eye drops were given every 30 minutes; and topical ceftazidime 5% was given every hour. Intravenous ceftazidime 50 mg/kg (235 mg) was commenced 6-hourly. Six hours later, the globe had perforated, with widespread iris prolapse through the now necrotic cornea. Pseudomonas aeruginosa was cultured from the conjunctival specimen taken at the referring hospital. The eye was considered unsalvageable (Box 1), so after discussion with the parents, a decision was made to eviscerate the left eye. After evisceration of the ocular contents, the sclera was closed without an implant, and a conformer was placed in the conjunctival fornix. The eye tissue specimen also grew P. aeruginosa, which was sensitive to gentamicin, tobramycin, timentin, ceftazidime and ciprofloxacin. The child was discharged on the third post-operative day with oral ciprofloxacin 10 mg/kg twice a day and topical tobramycin drops 0.3% four times daily. Three months later, an acrylic ball was inserted into the eye cup to restore orbital volume. Infectious conjunctivitis is the most common inflammatory eye condition, comprising 0.7% of all presentations to general practitioners in Australia.1 In contrast, infectious keratitis is rare, but is one of the most visually threatening ocular conditions. Infections initially manifesting as conjunctivitis can spread to involve the cornea. Pseudomonas is one pathogen known for this, as appears to have occurred in this patient. The symptoms of conjunctivitis include irritation, stinging and discharge, whereas severe foreign body sensation, pain, photophobia and blurred vision should raise suspicion of keratitis. Signs differentiating conjunctivitis from keratitis are listed in Box 2. Lessons from practice Examination is of utmost importance in the paediatric population as less information can be gleaned from the history. Keratitis can be mistaken for conjunctivitis in its early stages, especially when an adequate view of the globe is not obtained. Where there is no or limited response to treatment in young infants, the working diagnosis must be reconsidered: a good rule of thumb is if the conjunctivitis does not respond within 72 hours on second-hourly antibiotic drops, either you have the wrong drug or the wrong diagnosis. Make early referral to an ophthalmologist where there is periorbital cellulitis, or when in doubt. Examination findings are most important in young children, because they cannot describe the symptoms. However, examining the eyes of distressed babies and children can be extremely difficult. A few drops of local anaesthetic can make examination easier. Restraining a child or wrapping a baby in a sheet may be necessary. With a baby, a small lid speculum may be necessary to gain an adequate view, and magnification and a bright light source are essential. Progressive ulceration can lead to corneal perforation and endophthalmitis, as in the baby described in this report. Swabs should be considered when there is profuse discharge. Risk factors for keratitis in children include trauma, pre-existing corneal disease, prior corneal surgery, contact lens wear and systemic illness.2,3 Endophthalmitis caused by P. aeruginosa has a particularly poor visual prognosis; a case series of 28 patients reported an evisceration or enucleation rate of 64% and a final visual acuity of 5/200 or better achieved in only 7% of patients.4 In a case series of neonates, septicaemia complicated more than half of all cases of Pseudomonas keratitis, and led to death in 40%.5 The differential diagnosis in our 10-week-old patient is similar to the differential diagnosis of ophthalmia neonatorum, which is defined as severe conjunctivitis arising within 1 month after birth.6 These infections, which include Chlamydia trachomatis and Neisseria gonorrhoea, can be acquired at time of delivery, or from the nasopharyngeal passage and from carers.6 Dacryocystitis can also cause marked lid swelling. This case highlights the importance of considering alternative diagnoses to conjunctivitis, especially where a presumed conjunctivitis does not respond to initial treatment. 1 Keratitis, corneal necrosis and perforation of the globe 2 Clinical signs differentiating conjunctivitis from keratitis Conjunctivitis Keratitis Conjunctiva Inflamed Reactive inflammation is usually present Cornea Clear Opacification (ie, infiltrate ± stromal oedema) An epithelial defect will stain with fluorescein Lid swelling None to mild Adenoviral conjunctivitis can cause moderate lid swelling None to severe Discharge Purulent: generally bacterial Watery: generally viral Little to profuse Usually purulent Anterior chamber Quiet Usually some anterior chamber reaction Can progress to hypopyon

Frances M Kearney BSc(Hons), MB BS · Luke J Maccheron MB BS · Glen A Gole MD, FRANZCO

Photo courtesy of Kathy McClellan, Safe Sight Institute, University of Sydney. Vernal keratoconjunctivitis (VKC) (also known as “spring catarrh”) is an uncommon disorder seen in children and young adults. Patients typically present with redness, intense itch, photophobia and watering in both eyes. VKC is characterised by a “cobblestone” appearance of the conjunctiva, seen on everting the upper eyelid. It is sometimes associated with allergic disorders, including allergic rhinitis, atopic dermatitis and asthma.1,2 It is a chronic disorder with a clinical course of 2–10 years. What treatments are available? Allergen avoidance may be of limited benefit, given the ubiquitous nature of allergens to which patients are sensitive. Symptomatic relief can be obtained by bathing the eyes with cold water or by using icepacks or cold compresses. Topical antihistamines or combined topical antihistamine/mast cell stabilisers (such as olopatadine or lodoxamide trometamol) are the cornerstones of treatment.2 Topical lubricants (preferably preservative-free) are also useful to improve the tear film and to help reduce the allergen load. A short course of topical (or even systemic) steroids may be needed to settle severe symptoms. Other useful therapies include topical non-steroidal anti-inflammatories, oral montelukast, topical cyclosporin (0.05%), subtarsal steroid injection and/or allergen-specific immunotherapy.3-5 Will it get worse? VKC is potentially severe, and may be complicated by corneal ulceration, scarring and neovascularisation, with occasional associated visual impairment. Careful slit-lamp examination, measurement of intraocular pressure and assessment for the presence of keratoconus is required. Patients requiring topical or systemic steroids should be assessed by an ophthalmologist, and an allergy specialist should advise on whether allergen-specific interventions are indicated. What else could it be? VKC should be distinguished from other types of allergic eye disease, including allergic rhinoconjunctivitis (seasonal [hayfever] or perennial) and atopic keratoconjunctivitis, which is more commonly seen in adults than children. Seasonal allergic conjunctivitis is characterised by the acute onset of conjunctival injection and conjunctival oedema, with or without lid oedema, after exposure to allergens. Perennial allergic conjunctivitis is a persistent form of allergic conjunctivitis that occurs throughout the year and is triggered by exposure to allergens such as animal dander, dust mite or mould spores. Atopic keratoconjunctivitis is characterised by eyelid inflammation (with or without complicating staphylococcal blepharitis), together with redness of the eyeball, discharge and photophobia, and sometimes the development of cataracts or keratoconus. Ocular examination is normal between episodes of VKC.1 Fact or fiction — true or false? A negative skin prick test to common aeroallergens excludes vernal keratoconjunctivitis (VKC) (T/F) False. Not all patients with VKC have positive skin prick tests. Non-IgE-mediated inflammatory mechanisms are probably involved in pathogenesis in some cases. Drug hypersensitivity reactions or chemical exposure can produce acute conjunctivitis similar to VKC, but these conditions can be distinguished from VKC by the patient’s history. Giant papillary conjunctivitis is a severe chronic conjunctivitis triggered by exposure to a foreign body such as a suture or a contact lens. Acute uveitis and angle closure glaucoma should be considered in the differential diagnosis for patients presenting with a red eye, but these conditions are usually unilateral, associated with changes in vision, and not itchy. Case scenario* A 15-year-old male presented to his general practitioner with severe ocular itching, irritation, photophobia and excessive watering of the eyes. He had previously been seen for management of his asthma, atopic dermatitis and intermittent allergic rhinitis. His ocular symptoms, present for the previous 9 months, had worsened significantly during the recent spring season. His vision was unchanged, but he had been wearing sunglasses (even sometimes indoors) because of photophobia. Treatment with topical and systemic antihistamines had given only limited relief. Examination revealed bilateral conjunctival injection, without evidence of blepharitis or eczema of the face or eyelids. Eversion of the upper eyelids revealed a rough, cobblestone appearance with a thick, tenacious discharge. The patient was referred to an allergy specialist for further evaluation. Investigation revealed an elevated IgE level of 780 kU/L, with positive skin prick tests to house dust mite and grass pollens. The patient was managed initially with a combination of corticosteroid eye drops, then maintained with topical olopatadine treatment, and dust mite minimisation measures were advised. Regular ophthalmological review failed to show evidence of corneal scarring or visual impairment. Immunotherapy with pollen extract the following year was associated with a dramatic improvement in symptoms, with minimal requirement for additional pharmacological intervention the following spring. * This is a fictional case scenario based on similar real-life cases.

Denis Wakefield MD, FRACP, FRCPA · Peter J McCluskey MD, FRACO, FRACS

Clinical record A 13-year-old girl with no significant medical history was referred to our tertiary hospital for the management of a left corneal abscess. She had borrowed a girlfriend’s coloured plano contact lenses over the preceding weekend. On Monday, the patient presented to her general practitioner with a red and painful left eye and was subsequently assessed by a community ophthalmologist. Topical chloramphenicol was commenced, but after review 24 hours later the patient was referred to us with deteriorating visual acuity, increasing pain, and purulent ocular discharge. On admission, the patient’s left visual acuity was light perception. A large central necrotic corneal abscess and hypopyon were found on slit-lamp examination. Corneal scrapings were taken and the contact lens case submitted for microscopy, Gram stain and bacterial, fungal and viral culture. Intensive (every 15 minutes) fortified gentamicin and cephalothin were commenced in addition to oral ciprofloxacin. Gentamicin- and tobramycin-sensitive Pseudomonas aeruginosa was isolated 48 hours after admission, and the therapy was changed to gentamicin and tobramycin. The patient’s symptoms, hypopyon, and corneal infiltrate size abated, and the residual ulcer after scraping re-epithelialised. She was discharged after 3 weeks with marked corneal thinning and dense residual scarring (Figure), limiting visual acuity to count fingers at 30 cm. Fluorescein staining of a central corneal scar after Pseudomonas keratitis A: View with the naked eye B: Slit-lamp view Keratitis remains a significant risk of wearing contact lenses, despite advances over the past 10 years such as disposable and silicone hydrogel lenses. The incidence of severe keratitis from extended hydrogel lens wear was estimated at 96.4 (95% CI, 37.5–254.2) per 10 000 lens wearers in a British study.1 Even among users of daily disposable hydrogel lenses, the incidence of severe keratitis was 4.9 (95% CI, 2.5–9.6) per 10 000 lens wearers. Contact lens keratitis is precipitated by microtrauma from lens wear, which allows pathogens (Pseudomonas aeruginosa, Acanthamoeba spp., Streptococcus spp., Staphylococcus spp., Serratia spp., Fusarium spp., Aspergillus spp., Curvularia spp., Herpes simplex virus, and others) to invade the damaged cornea. Pseudomonas aeruginosa is one of the most virulent and common pathogenic organisms. It possesses virulence factors that facilitate survival and growth in the human cornea, including bacterial cell surface adherence factors and secreted cytotoxins that destroy corneal epithelium.2 The host immune response further damages the cornea,3 leading to scarring and loss of visual acuity and function. A Pseudomonas corneal ulcer is usually located centrally, and infection develops and progresses rapidly. Among people with contact lens keratitis, Pseudomonas accounts for the largest mean diameter of corneal ulcers, the highest mean nmber of days in hospital, the greatest mean number of outpatient visits, and the poorest visual acuity outcome.4 Lessons from practice Contact lens keratitis is a potentially vision-destroying infection. Pseudomonas keratitis progresses rapidly and often results in significant scarring and visual loss. Lens wearers presenting with a red eye should be referred early for specialist care. Contact lens wearers need to be properly educated regarding contact lens handling and hygiene and made aware of the serious risk of keratitis. Poor contact lens hygiene is a well known risk factor for keratitis.5,6 However, the importance of contact lens hygiene is still poorly appreciated by the community. In a survey of contact lens keratitis in New South Wales, 40% of keratitis patients reported poor hygiene.7 In a study of contact lens users in Auckland, 81% of cosmetic contact lens cases were contaminated with various pathogens.8 Colour and novelty contact lenses are becoming increasingly popular, and can be purchased from outlets such as beauty shops, markets, surf shops and auction websites. This leads to unsafe practices such as wearing lenses overnight, sharing of lenses, and poor lens hygiene. Contact lens care and hygiene play an important part in the prevention of keratitis, and education regarding contact lens hygiene remains an important task for eye care professionals. Medical practitioners and their patients need to be aware of the hazards associated with contact lens wear. Any contact lens wearer presenting with a red eye not relieved by lens removal may have potentially serious keratitis. The patient should be referred to an ophthalmologist for urgent review and prompt treatment, to prevent serious visual loss.

Yi-Chiao Li MSc(Hons), MB BS, PhD · Alina Zeldovich MB BS · Brian J Chua BSc, MB BS, MPH · Neil J Rowe MB BS, MPH, FRANZCO · Frank J Martin MB BS, FRANZCO, FRACS · Kathleen A McClellan PhD, FRANZCO, FRACS

To the Editor: Extended-wear silicone hydrogel contact lenses allow the convenience of 24-hour correction of refractive error and freedom from cleaning solutions and storage containers. However, they are associated with an increase in the risk of microbial keratitis when worn overnight compared with daily wear.1-5 The following cases from a single ophthalmology practice illustrate the risk to contact lens wearers when they use silicone hydrogel contact lenses overnight. A 36-year-old woman presented 11 days after sleeping with her silicone hydrogel contact lenses in overnight. She had increasing right ocular pain and photophobia over the preceding 9 days, which had not resolved with chloramphenicol drops. On examination, visual acuity was 6/18 right and 6/6 left. Corneal cultures grew Acanthamoeba, which responded to polyhexamethylene biguanide and brolene drops hourly. Her final best corrected visual acuity was 6/9 right, 5 weeks later. A 24-year-old woman presented with 2 days of left ocular pain, conjunctival injection, and epiphora following continuous silicone hydrogel contact lens use over the preceding week. On examination, visual acuity was 6/6 right and 6/18 left. A central corneal ulcer with stromal infiltrate and significant anterior chamber activity was present in her left eye (Box). Corneal cultures grew Pseudomonas aeruginosa, which responded to topical gentamicin 1% drops hourly. Her final best corrected visual acuity was 6/5 left, 3 weeks after diagnosis. An 8-year-old girl was seen 2 months after commencing continuous wear of her silicone hydrogel contact lenses for uniocular myopia. She had worn the same lenses for 4 weeks continuously when she presented with a 2-day history of right ocular irritation, photophobia, and conjunctival injection. On examination, visual acuity was 6/36 right and 6/6 left. She was commenced empirically on cephalothin 5% and gentamicin 1% drops hourly. Corneal cultures did not grow any causative organism, and her clinical condition improved significantly over the following 7 days. Her final best corrected visual acuity was 6/9 right. Although microbial keratitis may only affect a small proportion of individuals1,2,5 and our patients did not experience significant reduction in vision following treatment, microbial keratitis is potentially blinding and should not be trivialised. Silicone hydrogel contact lenses have a lower risk of associated microbial keratitis than other lens types, but they do not remove it completely. In view of this, contact lenses should not be worn overnight or for an extended period. Furthermore, a painful red eye in a contact lens wearer should be considered microbial keratitis until proven otherwise, and needs a prompt ophthalmologist referral. Microbial keratitis in a 24-year-old woman

John A Landers · John L Crompton

To the Editor: Uveitis is an intraocular inflammation which potentially leads to permanent loss of vision.1,2 Tuberculosis is considered to be an infrequent infectious cause of uveitis in the developed world. However, its recurrence as a major public health problem raises the possibility that the incidence of tuberculosis-related uveitis in the developed world may rise.3,4 Uveitis in tuberculosis is presumed to result from either direct invasion or a hypersensitivity reaction. At the ophthalmology departments of the Erasmus Medical Center and the Eye Hospital in Rotterdam, The Netherlands, all patients presenting with refractory uveitis undergo investigation for a systemic cause, including tuberculin skin testing. When ocular findings are consistent with intraocular tuberculosis, and the tuberculin skin test is positive, while no other cause of uveitis is suggested by symptoms, signs or ancillary testing, then a diagnosis of presumed intraocular tuberculosis is made. Using these criteria, eight cases of presumed intraocular tuberculosis were identified among 89 people referred with refractory uveitis between January 2002 and January 2004. Characteristics of the eight patients are shown in the Box. One patient (F) withdrew from clinical care, and another (A) later had a positive culture result for tuberculosis on lymph node biopsy. This patient had complete remission of uveitis after tuberculostatic treatment, but was excluded from this study as the aim was to assess whether antituberculosis treatment is warranted based solely on a positive tuberculin skin test. We treated the patients with a complete tuberculostatic regimen (2 months of isoniazid, rifampicin, ethambutol and pyrazinamide, followed by 4 months of isoniazid, rifampicin and ethambutol). All had been previously treated for more than 3 years with immunosuppressive drugs (mainly corticosteroids), either local or systemic, or both, without adequate response. Main outcome measures were visual acuity and degree of intraocular inflammation seen on ophthalmological examination before and on completion of antituberculosis therapy. The predominant clinical finding was blurred vision. Five patients exhibited decreased intraocular inflammation and an increase in visual acuity after antituberculosis treatment, allowing tapering of the corticosteroid treatment. One patient had no response. Improvement as part of the natural history was regarded unlikely. As our department is a tertiary referral centre for patients with uveitis, our patient population is not a representative sample of all patients with uveitis in The Netherlands. Nevertheless, our findings suggest that intraocular tuberculosis should be considered in the differential diagnois of uveitis, even in developed countries. We believe that, given our results, antituberculosis therapy is justified in patients with uveitis even when a positive tuberculin skin test is the only argument for tuberculosis as the cause of the eye disease. An additional argument for antituberculosis treatment is that many patients with uveitis refractory to immunosuppressive therapy can be adequately treated with tumour necrosis factor-α (TNF-α) blocking drugs.5 However, as severe tuberculosis infection has been described after use of these agents, antituberculosis therapy is warranted in any patient with a positive tuberculin skin test who is a candidate for TNF-α blocking therapy. Details of eight patients with presumed intraocular tuberculosis Affected eye Place of birth Visual acuity Uveitis treatment Antituberculosis treatment Patient Sex Age Uveitis Before* After* Response A M 25 Left Anterior Congo NR† NR† NR† NR† NR† B F 40 Both Posterior Cape Verde 1.8/6 (R), 1.2/6 (L) 4.8/6 (both) Local steroids HRZE, HRE Partial response, local steroids continued C F 69 Left Posterior Netherlands‡ 4.8/6 4.8/6 Local steroids HRZE, HRE Complete response, local steroids stopped D M 49 Right Posterior Surinam 0.6/6 0.8/6 Vitrectomy, local steroids HRZE, HRE No response E F 36 Both Anterior Morocco 2.4/6 (R), 3/6 (L) 4.8/6 (R), 6/6 (L) Local steroids HRZE, HRE Complete response, local steroids stopped F F 62 Both Posterior Morocco 0.6/6 (R), 0.6/6 (L) Local steroids — Lost to follow up before treatment G M 54 Right Posterior Surinam 2.4/6 5.5/6 Local and systemic steroids HRZE, HRE Partial response, systemic steroids stopped H F 19 Both Intermediate Netherlands‡ 4.3/6 (R), 1.2/6 (L) 6/6 (R), 6/6 (L) Local steroids HRZE, HRE Complete response, local steroids stopped * Before and after antituberculosis therapy. † NR = no result as patient excluded from the study. ‡ Patient C’s parents were born in The Netherlands, but Patient H’s parents were from Morocco. M = male. F = female. H = isoniazid. R = rifampicin. Z = pyrazinamide. E = ethambutol.

Paul L A van Daele · Marleen Bakker · P Martin van Hagen · G Seerp Baarsma · Robert W A M Kuijpers