Br J Ophthalmol PostScript2 Gragoudas ES, Adamis AP, Cunningham ET Jr, et al. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 2004;351:2805–16. 3 Schwartz

Bevacizumab suppresseschoroidal neovascularisationcaused by pathological myopiaBevacizumab (Avastin, Genentech) is arecombinant humanised, full length, anti-VEGF monoclonal antibody that binds allisoforms of VEGF-A. It has been shown toprolong survival of patients with advancedcolon cancer when combined with 5-fluoro-uracil.1 In this report, we describe the effectof bevacizumab in two patients with chor-oidal neovascularisation (CNV) secondary topathological myopia, which was refractory toother treatment.

Case reportsPatient 1AM is a 36 year old white man who wasdiagnosed with subfoveal CNV caused bypathological myopia (right eye = 211.50 D,left eye = 211.50 D) in his left eye inSeptember 2002 for which he received threephotodynamic therapy (PDT) treatments. Hedeveloped subfoveal CNV in his right eye inJune 2003 and received one PDT treatmentcombined with an intravitreous injection of4 mg of triamcinolone acetonide. In May2004, he presented with recurrent subfovealCNV in his right eye and refused PDT. Off-label use of bevacizumab was discussed andafter informed consent, the patient decided toproceed.Just before treatment in July 2004, best

corrected visual acuity (VA) was 20/40 in theright eye and 20/25 in the left eye. There wasa ring of hyperpigmentation centred on thefovea with a surrounding ring of subretinalblood and substantial subretinal fluid in theright eye (fig 1A). An optical coherencetomography (OCT) scan through the centreof the fovea confirmed the presence of

extensive subretinal fluid (fig 1B, asterisks)with subretinal tissue in the centre of thefovea (arrowheads). An OCT map showedsevere thickening and subretinal fluidthroughout the centre of the macula (fovealthickness 510 mm, macular volume9.29 mm3). In the left eye, there werepigmentary changes and no subretinal bloodor fluid (foveal thickness, 201 mm). In theright eye, the early phase of a fluoresceinangiography (FA) scan showed a central areaof hyperfluorescence surrounded by blockedfluorescence from subretinal blood (fig 2A).Central fluorescence increased in the mid

phase (fig 2B) and in the late phase the areaof hyperfluorescence was larger with indis-tinct borders indicating leakage of dye intosurrounding tissue (fig 2C).The patient received an intravenous infu-

sion of 5 mg/kg of bevacizumab, which hetolerated well. He noted subjective improve-ment in vision in both eyes within 7 days and2 weeks after the infusion, VA was 20/20 inboth eyes and biomicroscopy showed lesssubretinal fluid (fig 1C), confirmed by OCT(fig 1D, asterisk). Compared to the pre-infusion OCT, the retinal thickness mapshowed substantial improvement with adecrease in foveal thickness (330 mm from510 mm) and macular volume (6.89 mm3

from 9.29 mm3). In the early phase of a FAin the right eye (fig 2D), the hyperfluorescentarea was reduced compared to a correspond-ing frame of the baseline FA (fig 2A). Theintensity of hyperfluorescence increasedbetween the early and mid phase (fig 2E)and there was evidence of dye leakage fromthe CNV during the late phase (fig 2F). Thepatient received second and third infusions of5 mg/kg of bevacizumab without any diffi-culty. Six weeks after the first infusion andjust before the fourth infusion, VA was 20/20in each eye and biomicroscopy showed noidentifiable subretinal fluid in the right eyeand resorption of almost all of the subretinalblood (fig 1E). OCT confirmed that there wasno subretinal fluid (fig 1F) and the retinalthickness map showed further improvementcompared to the map after the first infusion.Foveal thickness measured 244 mm andmacular volume was 5.80 mm3. Early phaseof the FA showed further reduction in thearea of hyperfluorescence (fig 2G) comparedto a corresponding frame of the FA done afterthe first infusion (fig 2D). There was only amild increase in brightness of the hyperfluor-escent area in the mid phase of the FA

Figure 1 Fundus appearance and optical coherence tomogram of patient 1 at baseline and afterstarting infusions of bevacizumab.

Figure 2 Fluorescein angiography of patient 1 at baseline and after starting infusions ofbevacizumab.

LETTERS

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(fig 2H) and sharp borders with no furtherincrease in brightness in the late phase(fig 2I). This indicates that there was littlecollection of dye within the CNV and noleakage into surrounding tissue—two favour-able signs. Nine months after the fourthinfusion, the patient was asymptomatic andvisual acuity was 20/20 in each eye. FAshowed no evidence of leakage in either eye.

Patient 2LL is a 52 year old white woman withpathological myopia (refractive error 217.75sphere and 218.75 + 0.756165). The left eyedeveloped subfoveal CNV in February 2002and the patient had six PDT treatments withthe last in January 2004. The right eyedeveloped juxtafoveal CNV and was treatedwith photocoagulation in April 2002.Recurrent CNV occurred beneath the foveaand was treated with PDT on two occasions,the most recent in January 2004.The patient presented in July of 2004

complaining of progressive loss of vision inboth eyes. Visual acuity was 20/100 in theright eye and 20/200 in the left eye. In theright eye, there was a laser scar between thedisc and the nasal border of the fovea. Therewere flecks of subretinal haemorrhage andmild subretinal fluid. In the left eye there washypopigmentation surrounded by a ring ofhyperpigmentation with subretinal fluid,blood, and thickening in the macula(fig 3A). OCT in the left eye showedprominent retinal thickening surrounding asmall central area of retinal atrophy (fig 3B,arrow). The retinal thickness map showedthe thickest region of the retina to be locatedon the inferotemporal side of the fovea.Foveal thickness was 311 mm and macularvolume was 7.30 mm3. In the right eye, OCTshowed retinal thinning in the region of thelaser scar inferonasal to the fovea (fig 3C,arrows), and thickening superotemporal tothe fovea with a pocket of subretinal fluid(asterisk). Foveal thickness was 296 mm andmacular volume was 5.91 mm3. There wassubfoveal CNV in both eyes, and it wasdecided to transit the left eye because there

was more retinal thickening in the left eye.The early phase of the FA showed a centralarea of hyperfluorescence and surroundingblocked fluorescence from subretinal blood(fig 4A). The hyperfluorescence becamemuch brighter during the mid phase of theFA (fig 4B) and leaked during the late phase(fig 4C). The patient refused additional PDTand after careful consideration of potentialrisks and benefits and signing a consentform, the patient was given four intravenousinfusions of 5 mg/kg of bevacizumab atintervals of 2 weeks, which she toleratedwell.Examination before the fourth infusion

showed a VA of 20/64 in the right eye and 20/

200 in the left eye. Biomicroscopy in the lefteye showed reduced subretinal blood com-pared to the baseline examination, butpersistent macular thickening (fig 3D) con-firmed by OCT, which showed a fovealthickness of 304 mm and a macular volumeof 7.37 mm3. In the right eye, there was mildresidual subretinal fluid and a few flecks ofsubretinal blood temporal to the laser scar.OCT in the right eye showed reduced retinalthickening and minimal subretinal fluid withfoveal thickness of 249 mm and a macularvolume of 5.78 mm3 (fig 3F). In the left eye,early phase of a FA (fig 4D) showed a similararea of hyperfluorescence as that seen in theearly phase of the baseline FA (fig 4A), butsubstantially less fluorescence during the mid(fig 4E) and late (fig 4F) phases than thecorresponding phases of the baseline FA,indicating less filling of the CNV with dye.There was still substantial leakage of dye intosurrounding tissue in the late phase (fig 4F).The patient returned 2 months after thefourth infusion noting subjective visualimprovement that had allowed her to resumemany activities that she had previouslystopped. VA was 20/64 in the right eye and20/200 in the left. Contact lens biomicroscopyin the left eye showed no identifiablesubretinal blood or fluid, and macular thick-ness appeared reduced (fig 3G). This wasconfirmed by OCT (fig 3H; foveal thickness253 mm, macular volume 6.40 mm3). In theright eye, there was no identifiable subretinalblood or fluid and OCT showed no changesfrom the scan at week 6. FA in the left eyeshowed reduced hyperfluorescence comparedto previous FAs at all phases, early (fig 4G),mid (fig 4H), and late (fig 4I), and noleakage.

CommentIn two patients, intravenous infusions ofbevacizumab resulted in reduced fluoresceinangiographic evidence of leakage from CNVand decreased retinal thickening and sub-retinal fluid. This anatomical evidence of

Figure 3 Fundus appearance and optical coherence tomogram of patient 2 at baseline and afterstarting infusions of bevacizumab.

Figure 4 Fluorescein angiography of patient 2 at baseline and after starting infusions ofbevacizumab.

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improvement was accompanied by visualimprovement in two of the three eyes inwhich there was active subfoveal CNV atbaseline. The one eye that did not showobjective evidence of visual improvement hadprominent subretinal fibrosis and a centralarea of retinal atrophy at baseline. Althoughspontaneous improvement cannot be ruledout with certainty, the course of these twopatients suggests that antagonism of VEGFwith bevacizumab provided benefit. No ocu-lar or systemic side effects were observed.Recent studies have suggested that VEGF

may be an important stimulus for neovascu-lar age related macular degeneration(AMD).2 3 Despite differences in pathogenesisamong the disease processes, the effect ofbevacizumab in the two patients reportedhere suggests that VEGF may be an impor-tant stimulus for CNV in pathological myopiaas well as AMD. While uncontrolled observa-tions in two patients do not justify wide-spread use of bevacizumab in patients withCNV, additional studies are warranted. Acontrolled clinical trial is needed to determineif bevacizumab is safe and effective inpatients with subfoveal CNV caused bypathological myopia and, if so, to determinethe appropriate frequency of administration.

Q D Nguyen, S Shah, S Tatlipinar, D V Do,E V Anden, P A Campochiaro

Department of Ophthalmology, Johns HopkinsUniversity School of Medicine, 600 North Wolfe

Street, Baltimore, MD, USA

Correspondence to: Peter A Campochiaro, MD,Maumenee 719, Wilmer Eye Institute, Johns Hopkins

University School of Medicine, 600 North WolfeStreet, Baltimore, MD 21287-9277, USA; pcampo@

jhmi.edu

doi: 10.1136/bjo.2005.066431

References

1 Hurwitz H, Fehrenbacher L, Novotny W, et al.Bevacizumab plus irinotecan, fluorouracil, andleucovorin for metastatic colorectal cancer.N Engl J Med 2004;350:2335–42.

2 Gragoudas ES, Adamis AP, Cunningham ET Jr,et al. Pegaptanib for neovascular age-relatedmacular degeneration. N Engl J Med2004;351:2805–16.

3 Schwartz SD, Blumenkranz M, Rosenfeld PJ, et al.Safety of rhuFab V2, an anti-VEGF antibodyfragment, as a single intravitreal injection insubjects with neovascular age-related maculardegeneration. Invest Ophthalmol Vis Sci (suppl)2001;42:S522.

Compliance: clearcommunication’s criticalNon-compliance can be subdivided intovoluntary and involuntary types. Voluntarynon-compliance is patients deciding not touse their medication. Involuntary non-com-pliance refers to situations where medica-tions are used incorrectly, such as eye dropsmissing the conjunctival sac, using incorrectmedication, or following an incorrect regime.The impact of non-compliance is particularlyimportant for patients with chronic diseasessuch as glaucoma.1

We collected data from patients in ourclinic to try to ascertain the frequency andnature of any discrepancies between the dropregimes patients were using and what theirnotes said their current regimes should be.

MethodsOne hundred consecutive patients usingtopical medication to lower intraocular pres-sure attending a UK teaching hospital’sglaucoma service clinics were asked whichdrops they were using and how often theyput them in. Each patient was only enteredinto the study once. If any deviation from thedrop regime described in their notes wasidentified then further questioning was usedto identify the cause of that discrepancy.

ResultsIn total, 30 of the 100 patients were not usingthe antiglaucoma medication as described intheir notes. Eighteen cases were caused byophthalmologists either changing a regimewithout informing the general practitioner ornot giving clear instructions to the patient.Examples include transcription errors by theophthalmologist when dictating the letter tothe general practitioner (four cases), patientsstopping treatments because of side effectswithout contacting clinic (four cases),patients stopping their glaucoma drops aftercataract surgery (three cases), and ambiguitybetween Xalatan and Xalacom (one case).Patient error can be attributed to nine

cases. Examples include patient using dropsless frequently than prescribed (three cases),patient using drops in the wrong eye or oneeye only (two cases), patients changing thedose frequency of their own accord (onecase), and using drops too frequently (onecase).The other three cases were the result of

‘‘unreliable’’ nursing home staff (two cases),and failure to prescribe eye drops on admis-sion to a general medical ward.

CommentOphthalmologists communicating poorlywith patients or with general practitionerscaused nearly one in five patients to use thewrong regime. The responsibility for ensuringthat all communication between the ophthal-mologist and patients or general practitionersis intelligible and unambiguous lies with theophthalmologist.One frequent cause of non-compliance is

newly diagnosed patients thinking that theinitially prescribed bottle is the full course oftreatment, and ceasing treatment when thisbottle expires. This is a well recognisedphenomenon on the literature on persistencywith treatment for glaucoma.2

We were alarmed that 30% of the samplewere using an incorrect drop regime.Involuntary non-compliance merits furtherresearch and poses a considerable threat tothe control of patients’ disease. Furthermore,failure to identify compliance as the cause ofa patient’s apparent lack of response totreatment may result in prescription of moretoxic medication, and increasingly complexdrop regimes, which can lead to furthercompliance problems.3

A J Buller, B Connell, A F SpencerManchester Royal Eye Hospital, Manchester, UK

Correspondence to: A J Buller, Manchester Royal EyeHospital, Oxford Road, Manchester M13 9WH, UK;

[email protected]

doi: 10.1136/bjo.2005.066175

References

1 Schwartz GF. Persistency and tolerability ofocular hypotensive agents: population-basedevidence in the management of glaucoma.Am J Ophthalmol 2004;137(Suppl):S1–S2.

2 Reardon G, Schwartz GF, Mozaffari E. Patientpersistency with topical ocular hypotensivetherapy in a managed care population.Am J Ophthalmol 2004;137(Suppl):S3–S12.

3 MacKean JM, Elkington AR. Compliance withtreatment of patients with chronic open-angleglaucoma. Br J Ophthalmol 1983;67:46–9.

Safety of phacoemulsification ina patient with an implanted deepbrain neurostimulation deviceA 69 year old woman with nuclear scleroticcataracts was examined. She was awaitingneurosurgery for treatment of drug refractorytitubation (head tremor). Before cataract sur-gery, she underwent successful neurosurgery.The implanted Medtronic deep brain stimula-tion device rendered her asymptomatic oftremors. At the cataract preoperative clinicshe showed the device identification card thatstated ‘‘ultrasound diathermy … anywhere onyour body … can result in severe injury ordeath.’’1 Following confirmation fromMedtronic that it was safe to proceed, thepatient had an uneventful left phacoemulsifi-cation performed under general anaesthesiawith the neurostimulator turned ‘‘off.’’ Sevenmonths later she underwent a similar success-ful right phacoemulsification.

CommentDeep brain neurostimulation of the thalamus isthe treatment of choice for drug refractoryessential tremor.2 Indications for its use arewidening and include use in multiple sclerosis,advanced Parkinson’s disease, and movementdisorders such as dystonia.3 The deep brainneurostimulator has three implanted compo-nents. The electrodes are implanted into thesubthalamic nucleus or the globus pallidusinterna,1 2 4 then an insulated lead is placedsubcutaneously from the burr hole to a sealedneurostimulator device beneath the clavicle.The neurostimulator electrical stimulationpulses can be adjusted from external devices.4

There are two recorded fatalities in patientswith implanted deep brain neurostimulation

Accepted for publication 14 January 2005

Accepted for publication 9 January 2005Figure 1 Implanted deep brainneurostimulation device.

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devices who had received short wave dia-thermy ‘‘as used by physiotherapists.’’5

Medtronic also report two similar patientswho were still comatose.1 Another reportdescribed permanent, severe central nervoussystem injury following stimulation of aspinal cord neurostimulator by a radiofre-quency antitheft device.6

Brain damage results from heating of theimplanted electrodes.7 Heat energy releaseddirectly to the body from an external source canbe conducted via the insulated lead of animplanted neurostimulation device, raising thetemperature at the electrode. Furthermore, ifan external source generates an electric currentin the insulated lead, this will result in a rise inthe temperature at the electrode. Ultrasounddiathermy transfers heat directly to the bodywhere short wave diathermy results in aninduced electrical current.8 One study calcu-lated a potential rise of 9.76 C at the deep brainneurostimulator electrode when short wavediathermy was used.7 For phacoemulsificationto be safe in patients with deep brain neuro-stimulators, it must not produce significantheat or generate an electric current.The phacoemulsification hand piece uses

the piezoelectric effect to drive the phacoe-mulsification needle tip in a linear jackham-mer-like movement, physically cutting thelens.9 Acoustic cavitation results from anexplosive collapse of vacuoles formed in fluidaround the swiftly moving phacoemulsifica-tion needle tip.9 A study showed a maximumtemperature rise of 3.5 C in the anteriorchamber during routine phacoemulsifica-tion.10 The risk of this generated heat spread-ing to the implanted electrodes must be low.The phacoemulsification tip does not gener-ate an oscillating magnetic field that mightinduce an electrical current. Theoretically,this should render ultrasound phacoemulsi-fication safe in the presence of implanteddeep brain neurostimulators.With expanding technology, there will

naturally be situations with the potential forinteractions between equipment from differ-ent specialties. Consent should include thepossibility of heat conduction to theimplanted neurostimulation device. The useof local anaesthesia may allow early detectionof discomfort or neurological sequelae. Thesurgeon should make use of all techniques toreduce the heat generated during phaco-emulsification. Medtronic advise turning theneurostimulator off and not placing anycables over the patient’s chest and neck (RCoffey, 3 February 2005, personal commu-nication). There are various neurostimula-tors, including cortical devices, that may haveincreased sensitivity to localised temperatureincreases. Heat formation at the phacoemul-sification needle tip has been analysed;however, further research on the extent ofheat dissipation is required.

C F Parsloe, J M TwomeyMusgrove Park Hospital, Taunton, Somerset

Correspondence to: Mr J M Twomey, Musgrove ParkHospital, Taunton TA1 5DA, Somerset, UK; john.

[email protected]

doi: 10.1136/bjo.2005.066209

References

1 Medtronic. Important safety information.www.medtronic.co.uk/UK/patients/neuro/safety_informationhtml, accessed 4 January, 2005.

2 Gross RE, Lozano AM. Advances inneurostimulation for movement disorders. NeurolRes 2000;22:247–58.

3 Joshua A, Bryant B, et al. The impact of thalamicstimulation on activities of daily living for essentialtremor. Surg Neurol 2003;59:479–85.

4 Medtronic. What is deep brain stimulation?www.medtronic.co.uk/UK/patients/neuro/brain_stimulation.html, accessed 4 January,2005.

5 Medicines and Healthcare Products RegulatoryAgency. Patients with active/powered implants:risk of serious injury from therapeutic diathermytreatment. www.medical-devices.gov.uk/mda/mdawebsitev2.nsf/webvwIndex/3FE48E06AB1F64F200256AB6003F1C6D?OPEN, accessed 4 January, 2005.

6 Eisenberg E, Waisbrod H. Spinal cord stimulatoractivation by an antitheft device. J Neurosurg1997;87:961–2.

7 Ruggera PS, Witters DM, et al. In vitro assessmentof tissue heating near metallic medical implants byexposure to pulsed radio frequency diathermy.Phys Med Biol 2003;48:2919–28.

8 Anderson DM, ed. Dorland’s illustrated medicaldictionary. Philadelphia: WB Saunders, 2000.

9 Dondrea CL, ed. Surgery for cataract. In: Basicand clinical science course. San Francisco:American Academy of Ophthalmology,2004:89–162.

10 Heisler JM, Barmbek AK, et al. In vivomeasurement of the temperature changes duringphacoemulsification. Ophthalmologe2002;99:448–56.

Vertical deviation exacerbatedby convergence andaccommodationWe report a patient with hypertropia causingdiplopia exacerbated by convergence andaccommodation.

Case reportA 36 year old man presented with 8 yearhistory of worsening intermittent doublevision. Visual acuities were 6/5 in each eye.For near there was manifest left hypertropiaand left hyperphoria at distance (fig 1A,table 1). Extraocular movements were fullwith no overactions. No significant differencein vertical deviation in different gaze posi-tions or cyclotropia was found, the deviationincreased on head tilt to the left (table 2).There was no dissociated vertical deviation.1

The angle of deviation varied between 2and 7 prism dioptres at distance and 24and 45 prism dioptres at near on repeatedexaminations. Stereovision was 55 secondsof arc when deviation was prism corrected.The AC/A ratio was normal using gradientmethod. The vertical fusion range was13 prism dioptres at distance (9 prismdioptres base-down and 4 prism dioptresbase-up).The vertical deviation increased on accom-

modation with concave lenses and the devia-tion decreased with 10 dioptre base-in prismsat near (table 1). Eye movement recordingsare shown in figure 1C. Pupil reactions andfundoscopy were unremarkable. Thyroidfunctions, thyroid peroxidase and acetylcho-line receptor antibodies were normal.Tensilon test was negative. Orbicularis oculimuscle single fibre electromyogram wasunremarkable. Neurological examinationand magnetic resonance imaging of the brainand orbits were normal.

CommentKlein-Scharff and Kommerell2 first reportedthree patients with hypotropia and two with

Accepted for publication 21 February 2005

Table 1 Angle of deviation on fixation at distance and near measured with thealternating prism cover test

At 6 metres 5 prism dioptres L/R*At 6 metres with –1D lens 8 prism dioptres L/RAt 6 metres with –2D lens 14 prism dioptres L/RAt 6 metres with –3D lens 25 prism dioptres L/RAt 33 cm 30 prism dioptres L/RAt 33 cm with +3D lens 30 prism dioptres L/RAt 33 cm with 10 prism dioptres base in 15 prism dioptres L/R

*Left over right

Table 2 Harms Wall measurements in nine directions of gaze (upper panel) andhead tilt to the right and left in primary position (lower panel) with left fixation

Left fixation (red filter over left eye)

Elevation+2 14 L/R +1 12 L/R +4 17 L/R0 0 0

+2 17 L/R +4 15 L/R +4 15 L/RLeft 2 Ex 0 2 int Right

+3 15 L/R +5 14 L/R +5 14 L/R2 Ex 0 0

Depression 0

Left fixation

R tilt L tilt+14 9 L/R 27 20 L/R0 0

For each direction of gaze the first number indicated the horizontal deviation (ie, +2 = 2 degreesesotropia), the second measurement indicates the vertical deviation (ie, 14 L/R = 14 degrees left overright) and the number under the horizontal and vertical measurements indicated the cyclodeviation (ie,0 = no cyclodeviation, 2 int = 2 degrees incyclotropia, 2 ex = 2 degrees excyclotropia).

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hypertropia modulated by accommodationand/or convergence. In contrast with ourpatient, +3 dioptre lenses reduced the verticaldeviation at near in at least one case. Theyconcluded that the patient had verticalaccommodative vergence. Four of five of theircases had additional forms of strabismus.Graf and Weinand3 described a case of left

hyperphoria increasing on convergence. Useof convex lenses and concave lenses did notchange the vertical deviation. Similar to ourpatient, this child had an increase in verticaldeviation when the head was tilted to theside of the hyperphoria/tropia. Graf hasrecently attributed this to the unidirectionalfusional vertical vergence tonus that deve-lopes to compensate for the vertical devia-tion.4 Graf5 described three additional caseswith vertical accommodative vergence with

hypotropia. As in our patients concave lensesat distant fixation increased the verticaldeviation. Subsequently, a series of 19patients with differences in the verticaldeviation between near and distance werereviewed.6 Most cases were combined withstrabismus sursoadductorius and strabismusdeorsoadductorius. In 15 of the 19 patientsthe vertical deviation increased and in fourpatients it decreased at near fixation. Weagree that supranuclear or internuclear mis-innervation most likely explains the connec-tion between elevation and accommodationand convergence.2 3 A more peripheral inner-vational abnormality can be excludedbecause there is no elevation of the left eyewhen the patient is looking to the right (noaberrant innervation between the fibres tothe medial rectus and superior rectus).

In our patient it is unclear whether theabnormality was congenital and decompen-sation of hyperphoria increased symptoms, orwhether it was acquired. Increased verticalfusion range argues for a longstandingsquint. The history of most patients in theliterature1 2 was similar, with slow increase ofdiplopia and vertical deviation at near overseveral years. In several patients, combinedamblyopia or other strabismus forms—suchas dissociated vertical deviation—argue foran early onset of the eye motility problem.2 3

Interestingly, one patient5 seemed to havedeveloped the vertical deviation in combina-tion with convergence after trauma. It ispossible that the aberrant re-innervation canbe either congenital or acquired. It would beinteresting to investigate systematically theinfluence on near and distance fixation inpatients with vertical squint.

S Thomas, S J Farooq, F A Proudlock, I GottlobUniversity of Leicester, Robert Kilpatrick Clinical

Sciences Building, Leicester Royal Infirmary, PO Box65, Leicester LE2 7LX, UK

Correspondence to: Professor Irene Gottlob,Department of Ophthalmology, PO Box 65, RKCSB,

University of Leicester, Leicester LE2 7LX, UK;[email protected]

doi: 10.1136/bjo.2005.069351

References

1 Bielschowsky A. Disturbance of the vertical motormuscles of the eye. Arch Ophthalmol1938;20:175–200.

2 Klein-Scharff U, Kommerell G. Verticalaccommodative vergence. Klin MonatsblAugenheilkd 1991;199:344–5.

3 Graf M, Weinand K. Vertical deviation coupled toconvergence. Klin Monatsbl Augenheilkd2000;216:51–3.

4 Graf M, Krzizok T, Kaufmann H. Head-tilt test inunilateral and symmetric bilateral acquiredtrochlear nerve palsy. Klin Monatsbl Augenheilkd2005;222:142–9.

5 Graf M. Drei Falle von vertikaler accomodativerVergenz. Klin Monatsbl Augenheilkd1993;202:136–7.

6 Graf MH, Rost D, Becker R. Influence of viewingdistance on vertical strabismus. Graefes Arch ClinExp Ophthalmol 2004;242:571–5.

Tetracycline induced greenconjunctival pigment depositsThere have been no reports, to our knowl-edge, of a clinical presentation of ocularpigmentation secondary to the use of oraltetracycline only. Tetracycline hydrochlorideis not a well recognised cause of ocularpigmentary changes, but has been reportedto cause pigmentation of teeth and nails.1 Ofall the tetracyclines, minocycline (a secondgeneration drug) is most often associatedwith the adverse effect of pigmentation.1

There have been several case reports ofminocycline induced scleral pigmentation.2–6

Ocular pigmentary changes reportedly causedby tetracycline have been noted in associationwith use of minocycline.7 8 Both patients inthese case reports had had tetracycline/minocycline therapy for more than 10 yearsfor acne vulgaris and had their depositionlocalised within the tarsal conjunctiva.7 It isbelieved that most of the cysts are found atthe inferior border of the lower tarsusbecause of the frequency of pre-existinginvaginations of conjunctival epithelium in

5

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Figure 1 Patient fixating at near with large left over right squint (A) and at distance with nomanifest vertical deviation (B). Eye movement recordings of patient during near and distancefixation demonstrating a slow upward drifting of the left eye, which occurred simultaneously withthe convergence movement (C).

Accepted for publication 13 March 2005

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this location.7 The question was raised thatlong term tetracycline has an effect on thelipid layer of the tear film; noting that thepigmentary deposits were only seen in theconjunctival cysts over the tarsal conjunc-tiva.8 Recently, there has been a case report ofa patient with a 5 year history of minocyclineuse for rheumatoid arthritis who developedfocal palpebral conjunctival pigment depos-its. This patient did not have a reported use oftetracycline.2

Our patient was taking only tetracyclinewithout concomitant or previous minocyclineuse and had bulbar conjunctival lesions. Ourpatient had also been on tetracycline for2K years.

Case reportA 48 year old healthy white asymptomaticman presented for evaluation of ‘‘greencrystals’’ on the conjunctiva of both eyes(fig 1). The patient had noted the onset ofthis pigmentation over the previous severalmonths. The patient was treated for acnevulgaris with tetracycline 500 mg a day forthe past 2K years. He denied the use of anytopical ophthalmic drops. He took Lotensinfor the treatment of hypertension. Pastmedical history was otherwise unremarkable.On examination the patient was noted to

have several dark green granular deposits onthe temporal bulbar conjunctiva of both eyes.The granules appeared discrete, crystalline,and varied in size. Otherwise, the examina-tion was unremarkable. Pigmentation wasnot noted in any other region.

PathologyPathology confirmed the presence of tetra-cycline. The specimen was positive for a non-polarisable foreign material in a submucosaland intraepithelial distribution (fig 2). Thismaterial was calcified and had a faint

brown-yellow tinge. There was no appreci-able inflammatory reaction or giant cellreaction to the material. Pathology wasconsistent with that of previously describedreports of tetracycline.7

CommentTetracyclines of the first generation (tetra-cycline, oxytetracycline, and tetracyclinechloride) are the most commonly prescribedoral antibiotics for acne.9 Tetracycline hasalso been shown to result in improvement ofthe ocular manifestations of rosacea.10 11 Bothconditions are frequent; thus, the ophthal-mologist will encounter many patients beingtreated with tetracycline. Tetracycline fluor-escence has been detected in the conjunctivaof all patients who have taken tetracyclineorally.12 Fluorescence was not generalised butwas restricted to a thin film-like layer on thesurface and to small areas in the surface layerof cells.12

This is the first case report, to our knowl-edge, of clinically visible conjunctival bulbardeposits caused by the use of tetracyclinewithout a history of minocycline use.Pigmentary changes may initially be notedby the ophthalmologist, as in our case report.It is important to recognise signs of

tetracycline pigmentation as it is a commonlyused medication, and cessation of the med-ication may help avoid further pigmentarychanges.

V L Morrison, D O KikkawaUCSD Department of Ophthalmology, UCSD School

of Medicine, La Jolla, CA 92093-0946, USA

B G HerndierUCSD Department of Pathology, UCSD School of

Medicine, La Jolla, CA 92093-0946, USA

D O KikkawaDivision of Ophthalmic Plastic and Reconstructive

Surgery, UCSD Department of Ophthalmology, UCSDSchool of Medicine, La Jolla, CA 92093-0946, USA

Correspondence to: Don O Kikkawa, MD, UCSDDepartment of Ophthalmology, Shiley Eye Center,

9415 Campus Point Drive, La Jolla, CA 92093-0946,USA; [email protected]

doi: 10.1136/bjo.2005.069526

References

1 Eisen D, Hakim MD. Minocycline-inducedpigmentation; incidence, prevention andmanagement. Drug Safety 1998;18:431–40.

2 Bradfield YS, Robertson DM, Salomao DR, et al.Minocycline-induced ocular pigmentation. ArchOphthalmol 2003;121:144–5.

3 Morrow GL, Abbott RL. Minocycline-inducedscleral, dental, and dermal pigmentation.Am J Ophthalmol 1998;125:396–7.

4 Fraunfelder FT, Randall JA. Minocycline-inducedscleral pigmentation. Ophthalmology1997;104:936–8.

5 Sabroe RA, Archer CB, Harlow D, et al.Minocycline-induced discolouration of thesclerae. Br J Dermatol 1996;135:314–16.

6 Angeloni VL, Salasche SJ. Nail, skin, and scleralpigmentation. Cutis 1987;40:229–33.

7 Messmer E, Font RL, Sheldon G, et al. Pigmentedconjunctival cysts following tetracycline/minocycline therapy. histochemical and electronmicroscopic observations. Ophthalmology1983;90:1462–8.

8 Brothers DM, Hidayat AA. Conjunctivalpigmentation associated with tetracyclinemedication. Ophthalmology 1981;88:1212–15.

9 Zouboulis CC, Piquero-Martin J. Update andfuture of systemic acne treatment. Dermatology2003;206:37–53.

10 Del Rosso JQ. A status report on the medicalmanagement of rosacea: focus on topicaltherapies. Cutis 2002;70:271–5.

11 Brown SI, Shahinian L. Diagnosis and treatmentof ocular rosacea. Ophthalmology1978;85:779–86.

12 Dilly PN, Mackie IA. Distribution of tetracycline inthe conjunctiva of patients on long term systemicdoses. Br J Ophthalmol 1985;69:25–8.

Corneal epithelial defects relatedto high postoperativeastigmatismHigh and sometimes irregular astigmatism isnot an infrequent complication followinganterior segment surgery such as suturingof large wounds and corneal transplants.Abnormal corneal topography may affect tearfilm stability adversely. We present the caseof two patients who had persistent post-operative epithelial defects in the lower thirdof the cornea, in the presence of high cornealastigmatism despite aggressive lubrication.Upon addressing their high corneal astigma-tism their epithelial defects resolved.

Case 1An 84 year old man underwent a repeat, HLAmatched, penetrating keratoplasty followinga failed graft for pseudophakic bullouskeratopathy. He had had dry eye symptomswith his primary graft with signs of punctatekeratitis treated with non-preserved lubrica-tion. His repeat graft was uneventful. He wastreated with tacrolimus postoperatively tominimise risk of rejection.Postoperatively, he had persistent dry eye

symptoms for which he was prescribed non-preserved topical lubricants. Six monthspostoperatively sutures in the horizontalmeridian were removed to address ‘‘againstthe rule’’ astigmatism. He presented a monthlater with an epithelial defect in the lowerthird of his graft with an underlying super-ficial stromal melt (fig 1A). Corneal topogra-phy at this time revealed significant ‘‘withthe rule’’ corneal astigmatism of 13 dioptres(fig 1B). Tight sutures were cut and non-preserved lubrication, dexamethasone 0.1%and chloramphenicol 0.5%, was continued.Resolution of the epithelial defect followedrapidly with no further progression of stro-mal melting.

Case 2A 72 year old woman with progressivecataract underwent uncomplicated extracap-sular cataract surgery. She had been diag-nosed with keratoconjunctivitis sicca15 years previously, which at times requiredaggressive topical lubrication to control.Postoperatively, she developed a large centralcorneal defect in the lower third of thecornea. Despite aggressive lubrication theepithelial defect persisted for weeks. Shehad tight superior wound sutures causing11.0 dioptres of astigmatism. It was sus-pected that this could be impeding normalcorneal wetting. Upon their release andcontinued topical lubrication the epithelialdefect resolved.

CommentIt is possible that an irregular corneal surfaceinterferes with normal maintenance of theocular surface tear film. This abnormal teardistribution is likely to be exacerbated by an

Figure 2 Light microscopy of the pathologyspecimen of the conjunctival biopsy showing anon-polarisable foreign material in asubmucosal and intraepithelial distribution.


Figure 1 Clinical photograph of theconjunctival pigmentary deposits.

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underlying dry eye state. If tear deficiencyand degree of astigmatism are extreme,desiccation of the corneal epithelium ispossible, leading to non-healing defects andassociated sequelae.In cases where high or irregular astigma-

tism is associated with postoperative non-healing corneal defects, addressing thedegree of corneal astigmatism may helprestore physiological tear dynamics and reso-lution of the epithelial defect. Corneal suturesmay themselves impede epithelial migration,1

but if this were the only explanation all graftswould be exposed to the same risk.Conversely, not all patients with high astig-matism (non-surgical) have epithelialdefects. This would suggest that more thana single factor is at play in such situations. Toour knowledge high astigmatism as a con-tributory factor to development of persistentepithelial defects post operatively, has notbeen previously considered.

R Singh, T Umapathy, B B Kulkarni, H S DuaUniversity Hospital, Queens Medical Centre,University of Nottingham, Nottingham, UK

Correspondence to: Professor H S Dua, Division ofOphthalmology, University Hospital, Queens MedicalCentre, B Floor, Eye ENT Centre, Nottingham NG7

2UH, UK; [email protected]

doi: 10.1136/bjo.2005.069260

Reference

1 Lemp MA. The surface of the corneal graft: in vivocolour specular microscopic study in the human.Trans Am Ophthalmol Soc 1989;87:619–57.

Non-tuberculous mycobacteriarelated infectious crystallinekeratopathyNon-tuberculous mycobacteria (NTM) oratypical mycobacterial keratitis is an uncom-mon condition causing indolent cornealulceration. The infection mimics herpetic,mycotic, and Nocardia keratitis and diagnosisrequires a high index of suspicion. We reporttwo cases of NTM infection where thepresenting sign was that of crystalline kera-topathy. Both cases were diagnosed bymicrobial culture and successfully treated.

Case 1A 44 year old white female contact lenswearer presented with a 3 week history of

an inflamed eye with a 1.5 mm diameter areaof corneal stromal infiltration. Vision was 6/6in each eye. She was being treated withantivirals and later unsuccessfully with anti-bacterials and steroids. Three active stromalcrystalline infiltrates appeared in the mid-stroma 3 weeks later (fig 1). Culture from acorneal biopsy revealedMycobacterium chelonei.The keratitis responded to topical amikacin

and amphotericin B, which was started onthe suspicion of fungal keratitis, beforemicrobial culture results were available. Thekeratitis resolved over a 4 week period andvision settled at 6/9.

Case 2An 80 year old white woman with pseudo-phakic bullous keratopathy had a penetratingkeratoplasty and was given systemic tacroli-mus. Three months postoperatively she pre-sented with endothelial dusting and a 1 mmmid-stromal abscess with a crystallineappearance (fig 2). A corneal scrape revealedacid fast bacilli for which she was com-menced on topical ciprofloxacin and amika-cin 2.5% but was slow to respond. Cultureconfirmed Mycobaterium chelonei resistant toamikacin. Topical moxifloxacin was addedand oral clarithromycin commenced. Threemonths later, the ulcer healed with a cleargraft but the vision did not improve (count-ing fingers) on account of pre-existingmacular oedema.

CommentNon-tuberculous mycobacteria cause indo-lent corneal ulceration resembling herpesvirus, fungal, or Nocardia keratitis. The vari-able clinical presentations and poor suscept-ibility to conventional antibacterials usuallyresults in a delay in diagnosis.1–3 The twocommon types of NTM causing keratitis are

M chelonei and M fortutium. The clinicalfeatures of NTM include pseudodendriticepithelial defects, subepithelial white fluffyinfiltrates with crystalline satellite lesionsand ulcers with an overhanging necrotic edgeand a grey sloughed base.1 Keratic precipi-tates and endothelial deposits may appear.Early diagnosis is difficult and absence oforganisms in smears and cultures does notexclude the diagnosis of NTM. Repeat scrapesor a corneal biopsy should be considered inall indolent corneal ulcers.Amikacin has been the drug of choice in

Nocardia and atypical mycobacterial infec-tion.1 2 However, approximately 60% ofpatients will not respond to topical amikacin,as with our second case, and use of combina-tion therapy with ciprofloxacin, gatifloxacin,moxifloxacin, and clarithromycin is recom-mended.4–7 Penetrating keratoplasty is per-formed when stromal infiltration isextensive4 but immunosuppression may pre-dispose to recurrent infection. Both ourpatients were treated successfully. The firstpatient had a good visual outcome but thesecond had poor vision due to pre-existingpathology. Successful treatment requires dis-ease awareness, deferring the use of steroidswhen no organism has been isolated and useof effective antibiotics.

T Umapathy, R Singh, H S DuaDivision of Ophthalmology and Visual Sciences,

Queens Medical Centre, University Hospital,Nottingham, UK

F DonaldDepartment of Microbiology, Queens Medical Centre,

University Hospital, Nottingham, UK

Correspondence to: H S Dua, Division ofOphthalmology, B Floor, Eye ENT Centre, UniversityHospital, Queens Medical Centre, Nottingham NG7

2UH, UK; [email protected]

doi: 10.1136/bjo.2005.069856

References

1 Kinota S, Wong KW, Biswas J, et al. Changingpatterns of infectious keratitis: overview of clinicaland histopathologic features of keratitis due toacanthamoeba or atypical mycobacteria, and ofinfectious crystalline keratopathy.Indian J Ophthalmol 1993;41:3–14.

2 Hu FR, Huang WJ, Huang SF. Clinicopathologicstudy of satellite lesions in nontuberculousmycobacterial keratitis. Jpn J Ophthalmol1998;42:115–18.

3 Sridhar MS, Gopinathan U, Garg P, et al. Ocularnocardia infections with special emphasis on thecornea . Surv Ophthalmol 2001;45:361–78.

4 Matoba A. Mycobacterium chelonei keratitis of acorneal graft. Am J Ophthalmol1987;103:595–96.

Figure 1 (A) Diffuse slit lamp photograph of the corneal graft showing an epithelial defect andsuperficial stromal melting in the lower third. (B) Corneal topography showing steep with the ruleastigmatism.


Figure 1 Case 1 showing three active stromalcrystalline infiltrates central to the edge of theulcer.

Figure 2 Case 2 showing a mid-stromalabscess with a crystalline appearance at 5o’clock region of the graft-host junction.


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5 Ford JG, Huang AJW, Pflugfelder SC, et al.Nontuberculous mycobacterial keratitis in southFlorida. Ophthalmology 1998;105:1652–58.

6 Abshire R, Cockrum P, Crider J, et al. Topicalantibacterial therapy for mycobacterial keratitis:potential for surgical prophylaxis and treatment.Clinical Therapeutics 2004;26:191–6.

7 Hyon J-Y, Joo M-J, Hose S, et al. Comparativeefficacy of topical gatifloxacin with ciprofloxacin,amikacin and clarithromycin in the treatment ofexperimental mycobacterium chelonei keratitis.Arch Ophthalmol 2004;122:1166–9.

Xanthogranulomatous disease inthe lacrimal glandWe report three cases of adult lacrimal glandxanthoganulomatous disease that demon-strate the spectrum of this disorder andprovide insight into immune dysfunction.

Case 1A 23 year old asthmatic female had 1 year ofbilateral, painless, lacrimal gland massesfrom polyclonal B cell (CD 20+) infiltration(fig 1A, B) The patient was asymptomatic for18 months after external beam radiation(25 Gy in 10 fractions). While 7 monthspregnant, painless lacrimal gland enlarge-ment recurred, as firm, yellow, nodularmasses (fig 1C). A second biopsy showedfoamy histiocytes, Touton giant cells, andlymphoid infiltrate without necrobiosis(fig 1D). The orbital masses have remainedstable 2 years after corticosteroids and surgi-cal debulking. Systemic involvementincluded breast MALT type lymphoma4 years after presentation.

Case 2A 49 year old Brunei male had 10 years ofbilateral, yellow, mildly steroid responsive,superolateral orbital masses (fig 2A).Previous biopsy showed benign, polyclonallymphocytic proliferation in the lacrimalgland and eyelid xanthoma. Second eyelidand lacrimal gland biopsy demonstratedxanthomatous infiltrate involving obicularisand lymphocytes with some germinal cen-tres, s100 negative, KP1 positive foamyhistiocytes and Touton giant cells, respec-tively (fig 2B–D). Orbital findings improvedwith Solumedrol (3 g over 3 days), ciclo-sporin, and cyclophosphamide. The patientwas lost to follow up after 6 months.Systemic associations included asthma,sinusitis, and polyclonal paraproteinaemia(increased a1 and a2, b globulin, and IgM).

Case 3A 52 year old white female had 2 months ofbilateral, yellow, lacrimal gland masses anddry eye (confirmed by Schirmer’s testing)(see fig 3A–C). Lacrimal gland biopsy demon-strated foamy histiocytes, Touton giant cells,chronic inflammation, bands of fibrosis, andnecrobiosis. The lacrimal gland massesresolved at 2 years after treatment withSolumedrol (3 g over 3 days), methotrexate,pulsed cyclophosphamide, and topical 0.05%ciclosporin (Restasis) (fig 3E–F). She ismaintained on prednisone 40 mg per day,methotrexate 17.5 mg per week, and Restasistwice a day. Systemic associations includedasthma, cervical, axillary, hilar lymphadeno-pathy, iliac, sacral, L4 sclerosis, and xantho-granulomatous disease of the breast forwhich she underwent mastectomy 3 monthsbefore presentation (fig 3D).

CommentAdult xanthogranulomatous disease is a classII histiocytic disorder1 syndromically classi-fied as adult onset xanthogranuloma (AOX),adult onset asthma and periocular xantho-granuloma (AAPOX),2 necrobiotic xantho-granuloma (NBX),3 and Erdheim-Chesterdisease (ECD).4 AOX is a solitary lesion.5 6

AAPOX has B cell mediated findings includ-ing adult onset asthma, lymphadenopathy,and paraproteinaemia.3 Ulcerative skinlesions, paraproteinaemia/myeloma, andsilent internal organ disease characteriseNBX.3 7 8 ECD is typified by lethal, retro-peritoneal and bony sclerosis.4

All our cases had asthma. Case 2 hadelevated serum protein. Case 3 had lympha-denopathy, salivary gland enlargement, andbony sclerosis. Cases 1 and 3 had breastmasses: MALT type lymphoma postdatedorbital disease in case 1; xanthogranuloma-tous disease preceded orbital involvement incase 3. The first two cases could be classifiedas AAPOX. Case 3 had necrobiosis suggestingNBX, but had clinical features of AAPOX and

lacked skin ulcers. These findings demon-strate the adult xanthogranulomatous syn-dromes are not mutually exclusive.Xanthogranuloma histology consists of

non-Langerhans, lipid laden histiocytes,Touton giant cells, and varying degrees oflymphocytic infiltrate, fibrosis, and necrosis(necrobiosis). This infiltration replaced thenormal lacrimal gland architecture causingmass effect and loss of tear production. Thissame process affected the breast in case 3.The immune cascade leading to this histo-

pathological appearance is unknown. Ourprevious work found a predominance ofCD8 (cytotoxic) T cells in areas of fibrosisand lipophage accumulation. We postulatedthat CD8 cells activated histiocytes andfibroblasts. Relevant to this hypothesis, it isfascinating that polyclonal B cell (CD20+)infiltration, without gland destruction orfoamy histiocytes, preceded the developmentof xanthogranuloma in cases 1 and 2 and inone case from the literature6 (fig 1B). Anadditional report was initially diagnosed asSjogren’s syndrome, but lacked histology.9

Figure 1 (A) T1 weighted axial magnetic resonance imaging (MRI) showing bilateral lacrimalgland enlargement. (B) Initial lacrimal gland biopsy showing a dense lymphocytic infiltrate withpreserved ducts (haematoxylin and eosin stain, original magnification 46). (C) Clinical photographof yellow, recurrent mass, right orbit, 2 years after radiation treatment. (D) Second lacrimal glandbiopsy showing Touton giant cells, foamy histiocytes, lymphocytes, and plasma cells (haematoxylinand eosin stain, original magnification 606). (E) Clinical photograph of patient showingimprovement 1 year after treatment.

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Moreover, case 1 developed a monoclonalproliferation of B cells in the breast 1 yearafter the orbital xanthogranuloma.Our cases are unusual because the orbital

xanthogranuloma were limited to the lacri-mal gland, which is devoid of fat. We foundfour similar reports (table 1). Perhapsimmune dysregulation leads to tissuedestruction, and the resultant cell membranefatty acids are scavenged by malfunctioninghistiocytes.The best treatment for xanthogranulo-

matous disease is unknown. Our patientshad some response to steroids, with cases 2and 3 responding to B cell (cyclophospha-mide and methotrexate) and T cell(ciclosporin) suppressors.These cases raise questions regarding the

pathogenesis of non-Langerhans histiocytosisand demonstrate that histopathological andclinical findings must be used for diagnosis in

the spectrum of disorders that is xanthogra-nulomatous disease.

J A Sivak-CallcottDepartment of Ophthalmology, West Virginia

University, Morgantown, WV, USA

W K Lim, L L SeahSingapore National Eye Centre, Singapore

J Oestreicher, D Rossman, N NijhawanDepartment of Ophthalmology, University of Toronto,

Toronto, Ontario, Canada

J RootmanDepartment of Ophthalmology and Visual Sciences,

University of British Colombia, Vancouver, BC,Canada

J Rootman, V WhiteDepartment of Pathology, University of British

Colombia, Vancouver, BC, Canada

H J Williams, W W L ChangDepartment of Pathology, West Virginia University,

Morgantown, WV, USA

A DiBartolomeo*Department of Rheumatology, West Virginia

University, Morgantown, WV, USA

D HowarthDepartment of Pathology, University of Toronto,

Toronto, Ontario, Canada

Correspondence to: Jennifer A Sivak-Callcott, MD,West Virginia University Eye Institute, PO Box 9193,Morgantown, WV 26506, USA; [email protected]

doi: 10.1136/bjo.2004.063578

References

1 Moschella SL. An update of the benignproliferative monocyte-macrophage and dendriticcell disorders. J Dermatol 1996;23:805–15.

2 Jakobiec F, Mills M, Hidayat A, et al. Periocularxanthogranulomas associated with severe adult-onset asthma. Trans Am Ophthalmol Soc1993;91:99–129.

3 Kossard S, Winkelmann RK. Necrobioticxanthogranuloma with paraproteinemia. J AmAcad Dermatol 1980;3:257–70.

4 Veyssier-Belot C, Cacoub P, Caparros-Lefebvre D,et al. Erdheim-Chester disease: clinical andradiologic characteristics of 59 cases. Medicine1996;75:157–69.

5 Mencia-Gutierrez E, Gutierrez-Diaz E, Madero-Garcia S. Juvenile xanthogranuloma of the orbitin an adult.Ophthalmologica 2000;214:437–40.

6 Rouhianen H, Nerdrum K, Puustjarvi T, et al.Xanthogranuloma juvenile—a rare cause oforbital swelling in adulthood. Ophthalmologica1992;204:162–5.

7 Novak P, Robbins T, Winkelmann R. Necrobioticxanthogranuloma with myocardial lesions andnodular transformation of the liver. Hum Pathol1992;23:195–6.

8 Ugurlu S, Bartley GB, Gibson LE. Necrobioticxanthogranuoma: long term outcome of ocularinvolvement. Am J Ophthalmol 2000;129:651–7.

9 Karcioglu ZA, Sharara N, Boles TL, et al. Orbitalxanthogranuloma: clinical and morphologicfeatures in eight patients. Ophthalmic PlastReconstruct Surg 19:372–81.

10 Miszkiel KA, Sohaib SAA, Rose GE, et al.Radiological and clinicopathological features oforbital xanthogranuloma. Br J Ophthalmol2000;84:251–8.

Table 1 Xanthogranulomatous disease presenting in the lacrimal gland

Reference DurationPathologyfirst biopsy

Time to2ndbiopsy

Pathology2nd biopsy

Systemicfindings

Treatment/response Age Sex Diagnosis

Rouhianen6 1 month ‘‘chronicinflam’’

8 months Xantho NR Prednisone, variedcourse

45 F AOX

Miszkiel,10

case 91 year xantho Asthma, eosinophilia,

neutrophiliaSurgery 60 F AAPOX

Tucker11 2–3 months Xantho Paraproteinaemia,polyarticularmigratory arthritis.Later, conjunctivallesions

Prednisone 43 F NBX

Karcioglu9 Xantho Initially ‘‘diagnosedas Sjogren’s’’

23 F Notenoughinfo toclassify

Other cases report dry eye, or lacrimal gland involvement, but not specifically presentation in the lacrimal gland.

Figure 2 (A) Clinical photograph showing bilateral lacrimal gland enlargement and,xanthochromia of the upper eyelids. (B) Second lacrimal gland biopsy demonstrating infiltrationand destruction of the lacrimal gland by lymphorrhages with follicular centres (haematoxylin andeosin stain, original magnification 106). (C) Higher power view of follicular centres and occasionalTouton giant cell (arrows) (haematoxylin and eosin stain, original magnification 206). (D) Toutongiant cells with background of foamy histiocytes, lymphocytes, and plasma cells (haematoxylin andeosin stain, original magnification 606). Photograph reproduced with permission.

Accepted for publication 1 April 2005

None of the authors have any financial interestsregarding this paper.

*Published posthumously.

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11 Tucker N, Discepola M, Blanco G, et al.Necrobiotic xanthogranuloma withoutdermatologic involvement. Can J Ophthalmol1997;32:396–9.

Management of phaeniciaticophthalmomyiasis externaOphthalmomyiasis, maggot or fly larvaeinfestation of the eye, is a rare condition thatcan have variable presentation depending on

the type of fly, the ocular structures involved,and the level of larval infiltration.

Case reportA 60 year old African-American male pre-sented with a chief complaint of a swollen,moderately painful red right eye since 4 amthat day. Ocular history was significant forforeign body lid trauma of unknown aetiol-ogy (presumably a rock or insect) 2 days

earlier while riding his motorcycle withoutprotective goggles.Ocular examination revealed 20/20 vision

in each eye with correction. Pupils, extra-ocular motilities, and confrontation fieldswere normal. Slit lamp evaluation revealedupper and lower lid oedema with milderythema in the right eye. A 1.5 mm roundulcerated lesion was noted on the right outercanthal region that appeared to pulsate as thepatient was examined in the slit lamp (fig 1).The left eye and other ocular structures in theright eye were unremarkable.Upon external digital pressure of the

ulcerated lesion, a foreign organism was seento retreat into the ocular tissue. Manualforceps were used to remove a 1.0 cm longwhite segmented maggot (fig 2). This speci-men was identified by an entomologist undera microscope, as being of the Calliphoridaefamily, Phaenicia lucilia, otherwise known as ascrewworm fly.The patient was given erythromycin oint-

ment for use twice a day over the lesion. After3 days, the patient returned with completeresolution of the lid oedema and erythema(fig 3).

CommentOphthalmomyiasis is generally caused bysheep botflies and flesh flies. The mostcommonly reported organism in the literatureis Oestrus ovis, a botfly highly prevalent insheep herding and farming communities.1 2

These flies typically lay their eggs on decayingorganic material, but are also attracted toopen mucopurulent human sores. Within24 hours, these eggs hatch, producing larvaewhich then feed on human tissue.2 3 This casewas somewhat unusual in that trauma wasthe mechanism by which the fly eggs were

Figure 3 (A, B) Clinical photographs showing bilateral lacrimal gland masses with yellowdiscoloration, parotid/submandibular salivary gland enlargement, and cervical lymphadenopathy.(C) Coronal computed tomography scan showing bilateral lacrimal gland enlargement. (D)Histopathology of mastectomy specimen showing foamy histiocytes, Touton giant cells (arrows),lymphocytes with follicular centres, and necrobiosis (haematoxylin and eosin stain, originalmagnification 106). (E) Clinical photograph 24 months after diagnosis, showing improvement. (F)Coronal computed tomography scan showing resolution of lacrimal gland masses. Photographreproduced with permission.

Figure 2 Manual forceps removal produces a1.0 cm long white segmented maggot.

Figure 1 A 1.5 mm ulcerated lesion thatappears to pulsate.

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deposited. Clinical features of externalophthalmomyiasis can include conjunctivitis,conjunctival hemorrhage, corneal abrasion,and iritis. Internal ophthalmomyiasis canproduce vitreous haemorrhage, tractionalretinal detachment, endophthalmitis, andhypopigmented linear and arcuate subretinaltracks. Some of the cases of presumedinternal ophthalmomyiasis have been basedon hypopigmented subretinal tracks withoutdocumentation of an actual maggot.1

Treatment strategies depend upon the typeof ocular involvement and the level ofdamage. In cases of external ophthalmomyia-sis, manual forceps removal of the larvae isideal. Ophthalmic ointment can be used toblock the larvae’s respiratory pore, therebysuffocating the organism to facilitate manualremoval. Treatment strategies in cases ofinternal ophthalmomyiasis are case specific,ranging from iridectomy, vitrectomy, andretinotomy to laser photocoagulation. This isthe first reported case of ophthalmomyiasisexterna by a screwworm fly, CalliphoridaePhaenicia sp successfully treated with manualforceps removal.

AcknowledgementsThanks to Kipling Will and David Faulkner for theirassistance from the University of California,Berkeley, Entomology Department. Thanks to ABitanga for the photographs. Thanks also toThomas Lietman for his help with the manuscript.

N Huynh, B DolanSan Francisco VA Medical Center, CA, USA

S Lee, J P WhitcherProctor Foundation, CA, USA

J Stanley, J P Whitcher, S LeeUCSF Department of Ophthalmology, CA, USA

Correspondence to: Dr Scott Lee, UCSF Department ofOphthalmology, CA 94122, USA; [email protected]

doi: 10.1136/bjo.2005.071597

References

1 Heyde RR, Seiff SR, Mucia J. Ophthalmomyiasisexterna in California. West J Med1987;144:80–1.

2 Neva FA, Brown HW. Basic clinical parasitology,6th ed. Norwalk, CT: Appleton and Lange,1994:292–4.

3 Sigauke E, Beebe WE, Gander RM, et al. Casereport: ophthalmomyiasis externa in DallasCounty, Texas. Am J Trop Med 2003;68:46–7.

4 Buettner H. Ophthalmomyiasis interna. ArchOphthalmol 2002;120:1598–9.

Vitreous haemorrhage associatedwith Gingko biloba use in apatient with age related maculardiseaseGingko biloba extract is a widely used herbalextract that is readily available as an ‘‘overthe counter’’ product. It is most commonlyused for improving mental alertness andmemory. One of its components, gingkolideB is a potent inhibitor of platelet activatingfactor.1 Long term use has been associatedwith increased bleeding time and it canpotentate the anticoagulant effects of aspirinand warfarin.2

This is a case in which the regular use ofGinkgo biloba was associated with a vitreoushaemorrhage in a woman with a subretinalneovascular membrane, who had no otherrisk factors for haemorrhage.A 78 year old woman, who was otherwise

fit and well, first presented in July 2001to the ophthalmology department inCheltenham General Hospital with a historyof floaters in both eyes. Her visual acuitieswere 6/6 in the right eye and 6/12 correctingto 6/9 in the left eye. Fluorescein angiographyconfirmed exudative age related maculardisease (ARMD) on the left but no treatablediscrete neovascular membrane. She hadfurther loss of vision in the left eye and byOctober 2002 her left eye vision had deterio-rated to 3/60. She experienced a gradualdeterioration of vision in the right eye untilFebruary 2004, when she presented withrapid visual loss in the right eye to 6/24. Anuntreatable occult choroidal neovascularmembrane was demonstrated on fluoresceinangiography. In June 2004 she noted afurther sudden drop in central vision in theleft eye. On examination she had extensivepreretinal and subretinal haemorrhage.Within the next month she developed adense vitreous haemorrhage reducing hervisual acuity to hand movements. A B-scanultrasound confirmed the vitreous haemor-rhage and showed a flat retina with ahaemorrhagic elevation at the posterior poleconsistent with exudative age related macu-lar disease (fig 1). On further questioning sherevealed that she had been taking Gingkobiloba for the past 5 months. She was alsotaking vitamin C 1 g daily, zinc, lutein, Bcomplex, fish oil, Fossamax, and a steroidinhaler for asthma. She was advised to stopthe Gingko biloba and the vitreous haemor-rhage gradually resolved. There has been nofurther bleeding in the follow up period of8 months, but she has been left with exuber-ant macular fibrosis (fig 2).Another case of vitreous haemorrhage

associated with the use of Gingko biloba hasbeen reported in a patient with no other risk

factors for haemorrhage. A 59 year old manunderwent liver transplant for cirrhosiscaused by hepatitis B infection. This wascomplicated postoperatively by a large sub-phrenic haematoma. Three weeks later hedeveloped a right vitreous haemorrhage.3

There are several reports in the literaturelinking the use of Gingko biloba with sponta-neous haemorrhage. These include the reportof a subdural haematoma,4 hyphaema,5 sub-arachnoid haemorrhage,6 and intracerebralhaemorrhage.7

CommentA study evaluating the causes of 653 cases ofspontaneous vitreous haemorrhage foundARMD to be a small yet significant cause.8

A study by el Baba et al showed that in 19% ofreported cases of ARMD complicated bymassive intraocular haemorrhage, thepatients were taking warfarin or aspirin.9

Vitreous haemorrhage is found to have asignificantly higher incidence in patientstaking warfarin or aspirin when the bleedingoccurred.10

This case supplements a series of casereports implicating the use of Gingko bilobain spontaneous haemorrhage. There is adanger in the widely held belief that herbalremedies are benign. Patients often omit totell their doctors of these supplementalmedicines when being asked about their drughistory. Herbal remedies have been exemptfrom scientific scrutiny and product regula-tion and, as a result, we are largely unawareof their full adverse effects profile andpossible drug interactions. It should be maderegular practice to specifically ask patientsabout the use of any herbal remedies orunconventional medicines.

O P MacVie, B A HarneyGloucestershire Eye Unit, Cheltenham, UK

Correspondence to: Olivia P MacVie, GloucestershireEye Unit, Cheltenham General Hospital, Sandford

Road, Cheltenham GL53 7AN, UK;[email protected]

doi: 10.1136/bjo.2005.072454

References

1 Chung KF, Dent G, McKusker M, et al. Effect of aginkolide mixture (BN52063) in antagonising skinand platelet responses to PAF in man. Lancet1987;I:248–51.

2 Fugh-Berman A. Herb-drug interactions. Lancet2000;355:134–8.

3 Hauser D, Gayowski T, Singh N. Bleedingcomplications precipitated by unrecognizedGingko biloba use after liver transplantation.Transplant Int 2002;15:377–9.

Figure 2 B-scan showing vitreoushaemorrhage and haemorrhagic elevation atposterior pole.

Accepted 1 April 2005

Figure 3 Complete resolution of the lidoedema and erythema.

Figure 1 Colour fundus photograph of left eyeshowing extensive macular scar.


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4 Gilbert GJ. Gingko biloba. Neurology1997;48:1137.

5 Rosenblatt M, Mindel J. Spontaneous hyphaemaassociated with ingestion of Gingko bilobaextract. N Engl J Med 1997;336:1108.

6 Vale S. Subarachnoid haemorrhage associatedwith Gingko biloba. Lancet 1998;35:36.

7 Benjamin J, Muir T, Briggs K, et al. A case ofcerebral haemorrhage, can Gingko biloba beimplicated? Postgrad Med J 2001;77:112–13.

8 Butner RW, McPherson AR. Spontaneous vitreoushaemorrhage. Ann Ophthalmol1982;14:268–70.

9 El Baba F, Jarrett WH, Harbin TS, et al. Massivehaemorrhage complicating age-related maculardegeneration. Clinicopathologic correlation androle of anticoagulants. Ophthalmology1986;93:1581–92.

10 Tilanus MA, Vaandrager W, Cuypers MH, et al.Relationship between anticoagulant medicationand massive intraocular haemorrhage in age-related macular degeneration. Graefes Arch ClinExp Ophthalmol 2000;238:482–5.

The legal requirement for drivingin the United Kingdom is metfollowing pupil dilatationDilatation of the pupil (mydriasis) is a corecomponent of a comprehensive ophthalmicexamination and is becoming part of the eyeexamination routine for optometrists in theUnited Kingdom.1 As many patients drive toattend their examinations, concerns havebeen raised regarding the effects of pupillarydilatation on driving and whether or not thevisual standard for driving is met afterdilatation.2–4 Therefore, we investigated theeffect of mydriasis on the visual standard fordriving a private vehicle in the UnitedKingdom.

ReportTwenty adult subjects (mean age 24 years)with normal or corrected to normal visualacuity participated in the study. A selection ofsix different pairs of number plates (black onwhite and black on yellow), which con-formed to the current UK visual standardfor driving (that is, after 1 September 2001),5

was constructed for the study. Monocularand binocular distance logMAR visual acuity

and binocular number plate readings weremade before and after mydriasis (of at least6 mm diameter) with 0.5% tropicamide. Eachsubject performed the number plate testunder standard Driving Standards Agencyconditions (outside) at a fixed test distance of20 metres.6 A pass at the number plate testrequired all numbers and letters to be readcorrectly. Letter by letter scoring was used torecord visual acuity. Data were analysedusing paired t tests (one tailed) as appro-priate. Subjects were also asked for theirviews on the effects of mydriasis using aquestionnaire.3 The study followed the tenetsof the Declaration of Helsinki and approval ofthe protocol was obtained from the institu-tional human research ethics committee.All subjects met the legal requirement for

driving both before and after dilatation,irrespective of the number plate used. Visualacuity decreased (average of three lettersworse) following dilatation (p,0.05 for righteye, left eye and binocular visual acuityresults) (table 1).4 7

Following mydriasis, 13 subjects reportedan increase in glare, 15 felt more sensitive tolight, 14 reported blurry distance vision, fivereported blurry near vision, and one subjectreported no effect of the drops. Most subjectsreported a slight (nine) or moderate (10)effect of the drops; however, the majority(19) felt confident enough to safely drivehome after dilatation.

CommentDespite a loss in visual acuity after dilatation,all subjects passed the number plate test bothbefore and after dilatation and irrespective ofthe background colour of the number plate.Recently, Goel et al found a significantnumber of patients (four of 28) did not passthe number plate test after mydriasis.8

However, subjects in our study were relativelyyoung, wore the appropriate refraction andwere free from signs of ocular disease. Giventhe small effect of mydriasis on visualacuity,4 7 9 it is not surprising that, for oursubjects, mydriasis did not affect the UKvisual standard for driving. Notwithstandingthe relatively small loss in visual acuity, mostsubjects in our study reported a slight or

moderate effect of mydriasis on their vision.Nevertheless, all subjects but one felt con-fident enough to drive home.Wood et al have shown that mydriasis has a

measurable decrease on real life drivingperformance, specifically on the detectionand recognition of low contrast road obsta-cles and the ability to navigate around them.9

These findings, together with our results,suggest that satisfying the UK visual stan-dard for driving does not preclude a decreasein driving performance. Therefore, allpatients should be advised that althoughthe visual standard for driving may be metfollowing mydriasis, caution is advised whendriving after pupillary dilatation.

J Siderov, D Mehta, R VirkAnglia Vision Research, Department of Optometry

and Ophthalmic Dispensing, Anglia PolytechnicUniversity, Cambridge CB1 1PT, UK

Correspondence to: Dr John Siderov, Department ofOptometry and Ophthalmic Dispensing, Anglia

Polytechnic University, Cambridge CB1 1PT, UK;[email protected]

doi: 10.1136/bjo.2005.070722

References

1 Siderov J. Pupillary dilation in primary careoptometry. Part 1. Optician2004;228(5965):18–19.

2 Keightly S. Pupil dilation and driving. Eye2000;14:261–2.

3 Siderov J, Bartlett JR, Madigan CJ. Pupillarydilation: the patient’s perspective. Clin ExperimentOptom 1996;79:62–6.

4 Watts P, O’Duffy D, Riddell C, et al. Can I driveafter those drops, doctor? Eye 1998;12:963–6.

5 DVLA. At a glance guide to the current medicalstandards of fitness to drive. Swansea: DriversMedical Unit, Driver and Vehicle LicensingAuthority, 2003.

6 DSA. Technical Standards Branch, DrivingStandards Agency, UK, personal communication.2005.

7 Montgomery DMI, Macewan CJ. Pupil dilatationwith tropicamide: the effects on acuity,accommodation and refraction. Eye1989;3:845–8.

Table 1 Monocular (RE and LE) and binocular (BE) visual acuity results

Subject Age (years)

Pre-dilatation Post-dilatation

Confident to drive?RE LE BE RE LE BE

1 23 6/623 6/623 6/4.822 6/621 6/622 6/622 Yes2 23 6/6 6/6 6/6+2 6/6 6/7.5+2 6/6+1 Yes3 21 6/6 6/6 6/4.822 6/623 6/623 6/623 Yes4 23 6/6+2 6/6+1 6/6+3 6/7.5+2 6/7.521 6/621 Yes5 24 6/621 6/6+2 6/621 6/621 6/622 6/621 No6 36 6/7.521 6/622 6/621 6/7.521 6/7.522 6/7.5 Yes7 23 6/4.822 6/621 6/4.821 6/621 6/7.521 6/6+2 Yes8 27 6/4.8+3 6/4.821 6/3.823 6/6 6/4.821 6/4.8+1 Yes9 22 6/3.821 6/4.821 6/4.821 6/4.8 6/4.822 6/4.821 Yes10 21 6/6+1 6/6+2 6/6+3 6/621 6/6 6/6 Yes11 20 6/621 6/622 6/4.821 6/6+2 6/621 6/622 Yes12 23 6/4.821 6/622 6/4.821 6/6+2 6/621 6/6+3 Yes13 23 6/621 6/622 6/621 6/7.5+1 6/7.5+2 6/6 Yes14 20 6/4.823 6/622 6/4.822 6/4.822 6/4.822 6/4.822 Yes15 26 6/7.522 6/7.5+3 6/621 6/9.521 6/7.523 6/7.522 Yes16 22 6/4.822 6/7.5 6/4.8 6/4.8 6/621 6/4.822 Yes17 24 6/6+3 6/6+2 6/4.8+1 6/7.5 6/7.5+1 6/6 Yes18 22 6/4.823 6/4.821 6/4.8+1 6/622 6/621 6/6+1 Yes19 22 6/4.821 6/4.8+1 6/4.8+1 6/622 6/621 6/6 Yes20 23 6/6+2 6/6+3 6/4.821 6/7.522 6/7.523 6/7.5 Yes


Competing interests: none declared

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8 Goel S, Maharajan P, Chua C, et al. Drivingability after pupillary dilatation. Eye2003;17:735–8.

9 Wood JM, Garth D, Grounds G, et al. Pupildilatation does affect some aspects of daytimedriving performance. Br J Ophthalmol2003;87:1387–90.

Hydrated scleral buckle: a latecomplication of MAI explantsSeveral long term complications have beenreported with MAI scleral buckles,1–3 asynthetic hydrophilic scleral buckling ele-ment, first introduced in the 1970s.1 Wepresent a case of an extruding, hydratedMAI scleral buckle that presented as anorbital lesion. The magnetic resonance ima-ging (MRI) characteristics of the hydratedMAI buckle are also described.

Case reportAn 81 year old woman was referred to theorbital service for evaluation of a freelymobile non-painful subconjunctival lesionin the left eye present for at least a year.The extraocular movement was full but witha small left exotropia in primary gaze.Anterior segment examination revealed afirm, nodular subconjunctival lesion in thesuperomedial quadrant. The diagnosis ofextruding scleral buckle versus a large orbitalconjunctival inclusion cyst was entertained.She, however, denied a history of retinaldetachment repair.The patient underwent MRI of the orbits

with and without gadolinium infusion whichrevealed a 2.560.7 cm2 elongated, ellipticalmass in the medial intraconal space. Thehyperintensity of the mass on T2 weightedimages, indicative of high water content, ledto the mistaken radiological diagnosis of acystic, fluid filled lesion (fig 1).Introperatively, a swollen intact segmentalbuckle was encountered that disintegratedinto small and large pieces when graspedwith a forceps. Complete meticulous removalof these small fragments was performed(fig 2).

CommentMAI hydrogel explant is made of polymethylacrylate-co-2-hydroxyethyl acrylate crossedlinked with ethylene diacrylate with 15%water2 and was considered an ideal scleralbuckling material since it was as effective assolid silicone rubber buckle and sponge butwith lower incidence of erosion.4 However,long term complications are being morefrequently recognised with the MAI buckle.3

Complications include hydration of the

buckle with erosion and extrusion of theexplant.2 Owing to their hydrophilic nature,buckles tend to swell, become bulky, anddisplace from their intended position. Theseexplants change from an opaque, soft,spongy, whitish appearance to a translucent,gel-like, cream coloured material with hydra-tion.2 They become extremely friable andfragment easily with slight traction uponremoval.1–3 Scanning electron microscopy ofthese hydrated buckles has revealed distor-tion of their micropore architecture.1 2

The presentations of hydrated MAI bucklesare varied. They can become extremely looseand migrate anteriorly, or enlarge in situ andpresent as orbital masses. Since complica-tions do not occur until many years after theorbital surgery, the history of a retinaldetachment repair may not be elicited. Inaddition, these loose buckles usually do notindent the globe and may not be recognisedas being present on indirect ophthalmoscopy.Radiological imaging may be helpful. MRI

T1 weighted images of a hydrated bucklereveal a well defined, hypointense mass,while T2 weighted images reveal a hyper-intense mass as a result of high watercontent. (In contrast, a silicone element willbe black on MRI images.)Removal of hydrated MAI buckles can be

very difficult. Careful sub-Tenon dissectionshould be carried out since any pressure onthe buckle can lead to its fragmentation. Theprocedure is often complicated because of theextremely friable nature of these buckles.Cryoprobe has been used successfully in somecases for removal of the buckles.5 Le Rouic etal demonstrated that removal of MAI buckleswith a cryoprobe is a safe and effectivetechnique with lower fragmentation ratecompared to the use of forceps.5 The cryo-probe allows the water in the swollen explantmaterial to freeze, which helps to reducefragmentation.In conclusion, ophthalmologists should be

aware of the possible complications of theMAI hydrogel buckles. Knowledge of theMRI characteristics of hydrated MAI bucklesmay be helpful in identifying them in theevent they present as a space occupyingorbital mass.

N Bhagat, A Khanna, P D LangerInstitute of Ophthalmology and Visual Science, New

Jersey Medical School, Newark, NJ 07103, USA

Correspondence to: Paul D Langer, MD, Institute ofOphthalmology and Visual Science, New Jersey

Medical School, DOC, Suite 6168, 90 Bergen Street,Newark, NJ 07103, USA; [email protected]

doi: 10.1136/bjo.2005.072280

References

1 Oshitari K, Hida T, Okada AA, et al. Long-termcomplications of hydrogel buckles. Retina2003;23:257–61.

2 Marin JF, Tolentino FI, Refojo MF, et al. Long-termcomplications of the MAI hydrogel intrascleralbuckling implant. Arch Ophthalmol1992;110:86–8.

3 Hwang KI, Lim JI. Hydrogel exoplantfragmentation 10 years after scleral bucklingsurgery. Arch Ophthalmol 1997;115:1205–6.

4 Ho PC, Chan IM, Refojo MF, et al. The MAIhydophilic implant for scleral buckling: a review.Ophthalmic Surg 1984;15:511–15.

5 Le Rouic JF, Bejjani RA, Azan F, et al.Cryoextraction of episcleral Miragel buckleelements: a new technique to reducefragmentation. Ophthalmic Surg Lasers2002;33:237–9.

Complex I respiratory defect inLHON plus dystonia with nomitochondrial DNA mutationLeber hereditary optic neuropathy (LHON)sometimes occurs with dystonia1 in associa-tion with mitochondrial DNA (mtDNA)mutations in complex I.2 We describe apatient with LHON plus dystonia who had asevere complex I respiratory defect with nopathological mtDNA mutation, implying amitochondrial abnormality of nuclear origin.

Case reportThe proband was healthy until age 17 yearswhen she developed progressive right sidedweakness followed 5 years later by a lefthemiparesis with involuntary posturing ofthe left arm and leg. Intelligence was average,and she finished grade 6 at school. Herparents were unrelated, and she had fivehealthy siblings.Neuro-ophthalmological examination at

age 23 documented excellent afferent andefferent visual functioning with no Kaiser-Fleischer ring. Optic discs were hyperaemicand slightly elevated with peripapillary tel-angiectasias in both eyes (fig 1A and B). Shehad modest right sided weakness, diffusehyper-reflexia greater on the right, bilateralBabinski signs, and dystonic posturing on theright while walking.On return 21 months later, she reported

that the vision of both eyes had declined9 months previously. Visual acuity was 20/100 in both eyes with poor colour vision inboth eyes, a mild left afferent pupillarydefect, and bilateral optic atrophy with noresidual hyperaemia or peripapillary telan-giectasias (fig 1C). Gait was somewhat worse,and she was modestly dysarthric. Vision didnot improve during 18 months of follow up.Normal laboratory studies included hae-

mogram, liver and renal function, serumlactate, pyruvate, and 24 hour urine copperexcretion. Cerebral spinal fluid (CSF) lacticacid was slightly elevated (2.8 mm/l withnormal range 0.6–2.2 mm/l), and brain MRIrevealed abnormalities in both basal ganglia(fig 1D).After signing informed consent, the pro-

band, her mother and father, and foursiblings had blood drawn for DNA extraction,polymerase chain reaction amplification, andsequencing of the entire mitochondrial geno-mic coding region as previously described.3

Sequence results were compared to Mitomap(www.mitomap.org/mitomap/mitoseq.html),the human mitochondrial genome database(www.genpat.uu.se/mtDB), GenBank (www.ncbi.nlm.nih.gov/Genbank/index.html), and

Figure 2 Hydrated, friable buckle removed inmultiple small fragments.

Figure 1 T2 weighted MRI image reveals ahyperintense mass exhibiting a mass effect onthe left globe.


Supported by an unrestricted grant from Research toPrevent Blindness.


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a normal control group of 119 people with nomedical problems, who share similar ethni-city with the proband. Mitochondrial respira-tory function in complexes I, III, IV, and Vwas assessed in the proband and oneunaffected sibling using a previouslydescribed flow cytometric functional analysismethod.3 4

The proband, her siblings, and theirmother had one mtDNA sequence variantrecognised as a polymorphism in theJapanese population,5 which was not present

in the 119 normal controls of similar ethni-city. Thirteen previously reported homoplas-mic mtDNA polymorphisms were detected inthe proband, her family, and the controlgroup. The proband, but not her unaffectedbrother, had a severe respiratory defect incomplex I (fig 1E, F, and G).

CommentThis young woman’s initial examination wassignificant for normal vision with hyperaemic

optic discs, pseudopapilloedema, and peripa-pillary telangiectasias. She went on todevelop bilateral optic nerve injury typical ofLHON. She also had progressive basal gang-lion and upper motor neuron disease culmi-nating in bilateral spasticity, a broad basedand unsteady gait, dystonia, and dysarthria.Her clinical course, elevated CSF lactate,normal urinary copper excretion, and severecomplex I respiratory defect imply a mito-chondrial mechanism for optic nerve andbrain injury.Mitochondrial complex I dysfunction in

the absence of a pathological mtDNA muta-tion provides presumptive evidence of amitochondrial abnormality of nuclear origin.Complex I dysfunction has been identified inpatients with sporadic focal dystonia,6 and atleast one familial generalised dystonia syn-drome had a defined nuclear mutationaffecting a mitochondrial protein.7 Otherpatients with LHON plus dystonia have hadcomplex I mtDNA mutation(s), so thispatient broadens the genetic circumstancein which the phenotype may be expected.

K K Abu-AmeroGenetics Department, King Faisal Specialist Hospital

and Research Centre, Riyadh, Saudi Arabia

T M Bosley, S Bohlega, D McLeanNeuroscience Department, King Faisal Specialist

Hospital and Research Centre, Riyadh, Saudi Arabia

Correspondence to: Dr Khaled K Abu-Amero,Department of Genetics, King Faisal SpecialistHospital and Research Center (MBC No 03),PO Box 3354, Riyadh 11211, Saudi Arabia;

[email protected]

doi: 10.1136/bjo.2005.072819

References

1 Nikoskelainen EK, Marttila RJ, Huoponen K, et al.Leber’s ‘‘plus’’: neurological abnormalities inpatients with Leber’s hereditary optic neuropathy.J Neurol Neurosurg Psychiatry 1995;59:160–4.

2 Tarnopolsky MA, Baker SK, Myint T, et al. Clinicalvariability in maternally inherited leber hereditaryoptic neuropathy with the G14459A mutation.Am J Med Genet A 2004;124:372–6.

3 Abu-Amero KK, Bosley TM, Bohlega S, et al.Mitochondrial T9957C mutation in associationwith NAION and seizures but not MELAS.Ophthalmic Genet 2005;26:31–6.

4 Setterfield KWA, Donald J, Thorburn DR, et al.Flow cytometry in the study of mitochondrialrespiratory chain disorders. Mitochondrion2002;1:437–45.

5 Tanaka M, Cabrera VM, Gonzalez AM, et al.Mitochondrial genome variation in eastern Asiaand the peopling of Japan. Genome Res2004;14:1832–50.

6 Schapira AH, Warner T, Gash MT, et al. ComplexI function in familial and sporadic dystonia. AnnNeurol 1997;41:556–9.

7 Binder J, Hofmann S, Kreisel S, et al. Clinical andmolecular findings in a patient with a novelmutation in the deafness-dystonia peptide (DDP1)gene. Brain 2003;126(Pt 8):1814–20.

Retinal haemorrhages in a youngpatient with homocysteinuriaThe most common ocular complication inhomocysteinuria is lens subluxation.1 Wepresent a patient with homocysteinuria whodeveloped subhyaloid haemorrhages duringpars plana vitrectomy/lensectomy for a sub-luxated lens in the right eye. She had alsodeveloped preretinal and intraretinal hae-morrhages in her fellow eye 6 months earlier,

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Figure 1 (A) Fundus photograph of left optic disc showing hyperaemia and peripapillarytelangiectasias. The right disc had a similar appearance. (B) Intravenous fluorescein angiogram ofleft optic disc confirming tortuous vessels with no leakage of fluorescein typical of thepseudopapilloedema of LHON. This photograph was taken at 5:45. The right disc had a similarappearance. (C) Fundus photograph of left optic disc taken 9 months after visual loss showingmodest diffuse pallor of the disc with resolution of disc elevation and peripapillary telangiectasias.The right disc had a similar appearance. (D) Brain magnetic resonance imaging (MRI, Flair TR9502 TE 138/EF) showing bilateral basal ganglion lesions affecting predominantly the putamen,left.right, with parenchymal loss and hyperintense signal implying gliosis without mass effect.Small T2 hyperintense signal abnormalities were also present in the diencephalon, the cerebralpeduncles, and the periaqueductal region. (E), (F), and (G) Overlain histograms showingfluorescence in uninhibited lymphoblasts (dark grey peaks) and in lymphoblasts inhibited withrotenone (light grey peaks) in the patient (E), unaffected sibling (F), and normal control (G). X axis isa logarithmic scale quantifying pulse of fluorescence detected by the flow cytometer; Y axis is alogarithmic scale of number of cells. Dark grey peaks represent fluorescence of cells incubated withdihydroethidium (DHE) only. Light grey peaks represent fluorescence of cells incubated with DHEand rotenone, which inhibits activity of mitochondrial complex I. Fluorescence increased almostthree-fold in control cells (G) and cells of the unaffected sibling (F) after incubation with rotenone(20 mM), while the patient’s cells showed no increase in fluorescence because of pre-existinginhibition, indicating a complex I respiratory defect. This experiment was repeated four times withsimilar results.


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after phacoemulsification of the subluxatedlens. No preoperative or intraoperative antic-oagulation was used for either eye surgeries.

Case reportA 12 year old girl with homocysteinuriapresented with decreased vision in the righteye as a result of an anteriorly luxated lenscausing pupillary block glaucoma with anintraocular pressure (IOP) of 50 mmHg. Theposterior segment was normal. She hadundergone phacoemulsification and anteriorvitrectomy for pupillary block glaucomacaused by subluxated lens in the fellow eye6 months earlier. Retinal examination post-operatively revealed preretinal and intraret-inal haemorrhages in the mid-periphery(fig 1), which cleared spontaneously overthe next 5 months.Since medical therapy was ineffective in

the right eye, she underwent pars planalensectomy and vitrectomy. As the corevitrectomy was initiated, small subhyaloidhaemorrhages were noted to develop in themid-periphery. The vitrectomy settings werechanged to a high cutting speed and lowaspiration but the haemorrhages continuedto form. Induction of the posterior vitreousdetachment was aborted when peripapillaryintraretinal haemorrhages were noted todevelop.On the first postoperative day, a 2 disc

diameter subhyaloid haemorrhage (not seenat the end of the surgery) was noted in themacula (fig 2). All haemorrhages resolvedspontaneously over the next 10 weeks.

CommentThe precise mechanism of action of homo-cysteine on the vascular tree is not wellunderstood. Elevated homocysteine levelscan cause endothelial disruption, structuraldamage by toxic effects on the intima andmedia, increased oxidation of low densitylipoproteins, and alterations of clotting fac-tors leading to a hypercoagulable state.2

Histopathological data derived primarilyfrom animal models demonstrate smoothmuscle cell hypertrophy and hyperplasiaof the arteries.3 Postmortem studies of

hyperhomocysteinaemic patients have shownintimal and medial thickening with disrup-tion of the internal elastic lamina of smalland large vessels.4 Histopathology of smallarteries reveal focal proliferation of connec-tive tissue with increased fibroblasts, col-lagen, and irregular elastic fibres.4 Thesechanges may contribute to the fragility ofsmall arteries and capillaries.Valsalva retinopathy sometimes occurs

with general anaesthesia. We do not believethis patient experienced this mainly becauseValsalva retinopathy is bilateral. The retinalhaemorrhages occurred only in the operatedeye and not the fellow eye each time thepatient underwent surgery.The haemorrhages noted postoperatively in

the left eye may have occurred because ofocular decompression retinopathy. An acutelowering of IOP can decrease the resistance ofthe retinal and choroidal circulation, tem-porarily overwhelming the capacitance of thecapillary bed and resulting in multipleendothelial leaks and intraretinal haemor-rhages.5 Hyperhomocysteinaemia can affectthe autoregulation of small arteries.2 3 Thismay have contributed to the development ofretinal haemorrhages in the left eye. Thesubhyaloid haemorrhages in the right eye,however, were unlikely to be related to oculardecompression retinopathy since no haemor-rhages were seen during pars plana lensect-omy, but these developed soon aftervitrectomy was initiated. Minimal tractiontransmitted to the internal limiting mem-brane and nerve fibre layer by the vitrectomymay have caused the extremely friable super-ficial capillaries to rupture. Indeed, defects inretinal vascular autoregulation due to homo-cysteinuria, may have contributed to thedevelopment of the observed haemorrhages.We hypothesise that individuals with

chronic hyperhomocysteinaemia are at anincreased risk for retinal haemorrhagesbecause of homocysteine mediated destruc-tive changes in small vessel walls and anautoregulatory defect that results in extremecapillary fragility.

R A Shah, M A Zarbin, N BhagatInstitute of Ophthalmology and Visual Science, New

Jersey Medical School, Newark, NJ 07103, USA

Correspondence to: Neelakshi Bhagat, MD, MPH,Institute of Ophthalmology and Visual Science, NewJersey Medical School, Doctor’s Office Center; No6168, 90 Bergen Street, Newark, NJ 07103, USA;

[email protected]

doi: 10.1136/bjo.2005.072330

References

1 Michalski A, Leonard JV, Taylor DS. The eye andinherited metabolic disease: a review. J Roy SocMed 1988;81:286–90.

2 Cook JW, Taylor LM, Orloff SL, et al.Homocysteine and arterial disease. Experimentalmechanisms. Vasc Pharmacol2002;38:293–300.

3 Van Guldener C, Stehouwer CD.Hyperhomocysteinemia, vascular pathology, andendothelial dysfunction. Sem ThrombosisHemostasis 2000;26:281–9.

4 McCully KS. Vascular pathology ofhomocysteinemia: implications for thepathogenesis of arteriosclerosis. Am J Pathol1969;56:111–28.

5 Nah G, Aung T, Yip C. Ocular decompressionretinopathy after resolution of acute primaryangle closure glaucoma. Clin ExperimentOphthalmol 2000;28:319–20.

Internet based ophthalmologyservice: impact assessmentIn 2003, the Department of Health, WesternAustralia, commenced a teleophthalmologyservice between Carnarvon Regional Hospital(CRH) and Lions Eye Institute (LEI) at City ofPerth (at 940 km), pioneering the use ofremote, interactive consultations in ophthal-mology. This assessment (a) reports theimpact of teleophthalmology service onpatient diagnosis, management, outcomes,and satisfaction; and (b) estimates the costsof teleophthalmology service.

Case reportAn internet based system (www.e-icare.com)developed and evaluated at LEI, was used tostore and transmit multimedia data to asecure, central database.1 Practitioners atCRH collected these data, which includedpatients’ demographic details, medical his-tory, and ocular images. A portable slit lampdeveloped at LEI,2 tonometer (Keeler Pulsair3000, Japan), and digital retinal camera(Canon CR4-45NM, Japan) were also used.A questionnaire and interview approachassessed the satisfaction of the patients andpractitioners. Estimation of costs analysedadditional activity data and associated costs.During the 12 month study period, there

were 118 teleophthalmology consultations(42% men, 58% women, mean age 42 years,range 4–73 years). Most patients (53%)became aware of the service through localmedia, while health professionals inCarnarvon referred 36% for teleophthalmol-ogy consultation. Of the 118 cases, 3% of thepatients used teleophthalmology for emer-gency consultation, 94% for testing forglaucoma and diabetic retinopathy; 3% ofthe cases were for expert second opinion andpostoperative follow up.Teleophthalmology proved to have impact

on all the patients, by improving the eye carefacility at CRH itself, instead of the need totravel 940 km to the city. Following telecon-sultation, only 3% of patients were referred toa city hospital. While 55% of patients had noabnormalities detected, 3% of patientsreceived treatment at CRH itself. Theophthalmologist recommended regular fol-low up for 36% of patients seen by tele-medicine.

Figure 2 Fundus photographs of the right eye1 day after pars plana vitrectomy and parsplana lensectomy for an anteriorly subluxatedlens. A 2 disc diameter subhyaloidhaemorrhage is seen in the macula along withone preretinal haemorrhage temporal to themacula. Photographs of other mid-peripheralretinal haemorrhages could not be taken owingto the patient’s non-cooperation.

Figure 1 Fundus photographs of the left eye3 days after undergoing phacoemulsificationand anterior vitrectomy for an anteriorlysubluxated lens. Multiple ovoid subhyaloidpreretinal and intraretinal haemorrhages arenoted in the mid-periphery of the retina.


This work was supported by Research to PreventBlindness Inc, the Lions Eye Research Foundation ofNew Jersey, and the Eye Institute of New Jersey.

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The teleophthalmology consultation costper patient, at current efficiency level, is$279.96 including fixed cost. A cost neutralanalysis estimated, at optimal efficiency of352 patients per annum, cost per patientwould decrease to $107.72. In the remotearea, without teleophthalmology, the cost tothe service provider for a face to faceconsultation with an ophthalmologist is ashigh as $665.44 per patient. The minimumnumber of patients needed to make a costeffective teleophthalmology consultation is126 per annum.The majority of patients (98%) expressed

satisfaction with the internet based consulta-tion and observed it as convenient. Lack ofphysical contact with ophthalmologist wasnot a major concern to many patients (74%).CRH practitioners spoke favourably of usingteleophthalmology, in that they were able toget advice from colleagues and discuss alter-native management strategies. Practitionersat LEI found the experience informative andchallenging.

CommentWhile acknowledging that face to face con-sultations with ophthalmologists are unique,its costs are enormous in remote healthcentres.3–5 The project is a technical andclinical success and one that led to directpotential benefits for patients in terms ofimproved outcomes, as well as considerableeducational experience for the participatingmedical practitioners. However, currentassessment brought to light the importanceof redefining utilisation criteria in order toachieve efficiency. For example, 126 patientsper annum are required for a cost effectiveteleophthalmology service while the currentefficiency rate is 118 per annum (2.2 patientsper week). Better coordination between thelocal healthcare workforce and CRH mayincrease the number of teleophthalmologyconsultations, which in turn will help toachieve breakeven or even establish netsavings. Overall, this assessment indicatesthat the success of teleophthalmology will bebased upon identifying the requirements ofthe service and using appropriate technology.

AcknowledgementsSupported by an IPRS Scholarship and UPA(IS)

Award from University of Western Australia. The

authors thank the Department of Health, Western

Australia, Mr Francisco Chaves (health economist),

and Ms Beth Hudson for her support and assistanceespecially in data collection. The authors also thank

the patients, clinical staff, and administrative

officers in CRH, Carnarvon and at LEI, City of

Perth for their assistance.

S Kumar, M-L Tay-Kearney, I J Constable,K Yogesan

Lions Eye Institute, University of Western Australia,Nedlands, WA 6009, Australia

Correspondence to: Sajeesh Kumar, Lions EyeInstitute, University of Western Australia, 2 VerdunStreet, Nedlands, WA 6009, Australia; sajeesh@

cyllene.uwa.edu.au

References

1 Yogesan K, Constable IJ, et al. Internationaltransmission of tele-ophthalmology images.J Telemed Telecare 2000;5:41–4.

2 Yogesan K, Cuypers M, et al. Tele-ophthalmologyscreening for retinal and anterior segmentdiseases. J Telemed Telecare 2000;5:96–8.

3 Keeffe JE, Weih LM, et al. Utilisation of eye careservices by urban and rural Australians.Br J Ophthalmol 2002;86:24–7.

4 Whitten PS, Mair FS, et al. Systematic review ofcost effectiveness studies of telemedicineinterventions. BMJ 2002;324:1434–7.

5 Sajeesh KR, Mei-Ling TK, Chaves F, et al. Remoteophthalmology services: cost comparison oftelemedicine and alternate scenarios. J TelemedTelecare (in press).

Temperature sensitiveoculocutaneous albinismassociated with missensechanges in the tyrosinase geneOculocutaneous albinism (OCA) describes agroup of autosomal recessive disorders char-acterised by reduced or absent pigmentationof the eye, skin, and hair as a result of acongenital reduction in melanin synthesis.Additional findings in the eye includedecreased visual acuity, nystagmus, iris trans-illumination, hypopigmentation of the uvealtract and retinal pigment epithelium, fovealhypoplasia, and abnormal decussation of theoptic nerve fibres at the optic chiasm leading toa lack of binocular vision.1 2 Type I OCA resultsfrom mutations in the tyrosinase gene andleads to either total absence of tyrosinaseactivity (OCA Ia) associated with absence ofpigmentation (‘‘tyrosinase negative’’), or amarked reduction in tyrosine activity (OCAIb) associated with reduced pigmentation

(‘‘tyrosinase positive’’ or ‘‘yellow albinism’’).We report a new case of the rare varianttemperature sensitive albinism and our identi-fication of missense mutations in the tyrosi-nase gene, not previously found in this form ofalbinism.

Case reportThe patient, a 31 year old woman, wasreferred to us for genetic advice. She hadoriginally presented at 6 weeks old withnystagmus and white hair; her parents bothhave dark hair and olive skin. The diagnosisof oculocutaneous albinism was made at9 months. As she grew older the hair of herhead darkened and, particularly in her teens,the hair on her lower legs and forearmsdarkened. As an adult she has light blondehair, darker eye lashes and eyebrows, whiteaxillary and pubic hair, but strongly pigmen-ted hair on forearms and lower legs (fig 1).When examined in the clinic she had reducedvisual acuity (6/36 bilaterally), marked iristranslucency, and an albinotic retina withfoveal hypolasia bilaterally. Visually evokedpotential revealed crossed asymmetry consis-tent with oculocutaneous albinism. We madea diagnosis of temperature sensitive albinismand searched for mutations in the tyrosinasegene. Blood was taken, with informed con-sent, from the patient and her parents andDNA extracted using standard techniques.Using polymerase chain reaction we ampli-fied each of her tyrosinase gene exons3 andsequenced the entire coding region andintron-exon boundaries. Our patient did nothave the R422Q mutation previously reportedin patients with this phenotype and also didnot have two other mutations known to betemperature sensitive.4 We did identify twomissense mutations: R217Q and A355P, inexons 1 and 3 respectively (fig 2). The exon 1mutation had been inherited from her


Ethical approval was obtained from the University ofWestern Australia Human Ethics Committee and the

Western Australia Aboriginal Health InformationEthics Committee.

doi: 10.1136/bjo.2005.072579

Accepted for publication 12 April 2005Figure 1 Clinical photographs of patient. Note the yellow blonde hair, dark eyebrows, andstrongly pigmented forearm hair. (Photograph reproduced with permission of the patient.)

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mother and the exon 3 mutation from herfather. R217Q has been previously reported inOCA1,5 and A355P in OCA1b in a patientwith ‘‘little apparent pigmentation’’ but withno description of the distribution of thepigmentation.6 Neither has previously beenassociated with a temperature sensitive phe-notype.

CommentTemperature sensitive albinism is a rarevariant, first described in 19911 and subse-quently associated with a particular missensemutation in the tyrosinase gene.1 The muta-tion, R422Q, results in a temperature sensi-tive trafficking defect preventing thetranslocation of the mutant tyrosinase intomelanosomes.4 Thus, at 37 C mutant R422Qtyrosinase is retained in the endoplasmicreticulum and degraded by proteasomes andno pigment is produced. At lower tempera-tures (31 C) the enzyme can be successfullytranslocated into the melanosomes and canproduce pigment. This leads to a phenotypereminiscent of the Siamese cat with nopigment centrally but pigmentation developsin the peripheries (lower legs and forearms).Our patient is heterozygous for missense

mutations in the tyrosinase gene that haveboth previously been reported in OCA1 butneither with a temperature sensitive pheno-type. We are not aware of other patients withthis particular combination of mutations. Ithas been shown that co-expression of wildtype tyrosinase can correct the mutant con-formation in temperature sensitive allelessuch that exit from the endoplasmic reticu-lum and complex carbohydrate processing inthe Golgi is promoted even at the non-permissive temperature.7 It may be that oneof the mutant alleles identified in our patientmodulates the expression of the other,revealing its temperature sensitive naturewhereas coexpression with a different allelemay give no residual activity. Alternatively,this phenotype may be much commoner thanpreviously thought. To date there have beenno studies of function or response to tem-perature variation of these particular mutantforms of tyrosinase. In light of the phenotypewe describe here these studies would bevaluable. Furthermore, it is not unusual for

patients with albinism to report developmentof some pigmentation with age and it wouldbe interesting to review other patients withthese mutations. Unless patients with albin-ism are reviewed later in life this developingphenotype will not be noted.

T Wang, C T Waters, T Jakins, J R W Yates,D Trump

Department of Medical Genetics, Cambridge Institutefor Medical Research, University of Cambridge, UK

K BradshawDepartment of Ophthalmology, Addenbrooke’s

Hospital Trust, Cambridge, UK

A T MooreInstitute of Ophthalmology and Moorfields Eye

Hospital, London, UK

T Wang, D TrumpAcademic Unit of Medical Genetics, St Mary’s

Hospital and Centre for Molecular Medicine, Facultyof Medical and Human Sciences, University of

Manchester, UK

Correspondence to: Professor Dorothy Trump,Academic Unit of Medical Genetics, St Mary’s

Hospital, Hathersage Road, Manchester M13 0JH,UK; [email protected]

doi: 10.1136/bjo.2005.070243

References

1 King RA, Jackson IJ, Oetting WS. Humanalbinism and mouse models. In: Wright AF, Jay B,eds. Molecular genetics of inherited eyedisorders. New York: Harwood AcademicPublishers, 1994;89–122).

2 Abrams LS, Traboulsi E. Albinism. In: Traboulsi E,eds. Genetic diseases of the eye. New York:Oxford University Press, 1998;697–722).

3 Giebel LB, Strunk KM, Spritz RA. Organizationand nucleotide sequences of the human tyrosinasegene and a truncated tyrosinase-related segment.Genomics 1991;9:435–45.

4 Toyofuku K, Wada I, Spritz RA, et al. Themolecular basis of oculocutaneous albinism type 1(OCA1): sorting failure and degradation ofmutant tyrosinases results in a lack ofpigmentation. Biochem J 2001;355(Pt2):259–69.

5 Oetting WS, King RA. Molecular analysis of typeI-A (tyrosinase negative) oculocutaneous albinism.Hum Genet 1992;90:258–62.

6 Spritz RA, Oh J, Fukai K, et al. Novel mutations ofthe tyrosinase (TYR) gene in type I oculocutaneousalbinism (OCA1). Hum Mutat 1997;10:171–4.

7 Halaban R, Cheng E, Hebert DN. Coexpressionof wild-type tyrosinase enhances maturation oftemperature-sensitive tyrosinase mutants. J InvestDermatol 2002;119:481–8.

Choroidal neovascularisationassociated with meningiomaThis report documents the occurrence inthree patients of subretinal choroidal neovas-cular membranes (CNVM) ipsilateral tomeningiomas involving the optic nerve. Wepropose that the association might not becoincidental.

Case 1A 31 year old woman developed a centralscotoma in the left eye that led to thediagnosis of a left sphenoid wing menin-gioma involving the optic canal. The tumourwas resected and her vision returned tonormal. At age 56 a generalised seizure ledto recognition of a recurrence. When therecurrent tumour was resected it proved to bea malignant meningioma. She was thentreated with photon radiation from a 10 MVsource using a three field technique (rightlateral, left lateral, and superior). The totaldose was 45 Gy administered in 25 fractions.Thereafter, on regular follow up eye exam-inations she had normal visual function,pupils, and fundi. At the age of 64 she hada single episode in which for several secondsshe lost all vision in the left eye except for anasal island. There were no residua but herophthalmologist found a new fundusabnormality that prompted referral.Her medical history included migraine and

a cutaneous malignant melanoma. There wasno pertinent family history.The patient’s visual acuities were 20/15 in

each eye. Her colour vision (Ishihara) andpupils were normal. The Goldmann visualfield of her right eye was full but she had arelative inferior altitudinal defect to the I2ewhite stimulus in the left eye. There was3 mm of proptosis of the left eye with normalorbital resiliency. Fundus examination of theleft eye revealed a peripapillary superotem-poral retinal elevation associated with lipid(fig 1, top left). There were no maculardrusen. Echography showed 1.1 mm of ele-vated retina adjacent to the left disc withnormal acoustics. The rest of her neuro-ophthalmological examination was normal.There was hyperfluorescence in the area ofelevation with late leakage of dye on fluor-escein angiography consistent with a peripa-pillary CNVM (fig 1). At that time magneticresonance imaging (MRI) scans showed noevidence of recurrent meningioma.Five years later the vision declined to 20/30

in the left eye. There was neither opticatrophy nor optic disc swelling, but a leftafferent pupillary defect and dyschromatop-sia were observed. MRI showed that thesphenoid meningioma had recurred andinvolved the intracanalicular and posteriororbital segments of the left optic nerve. Therealso was enlargement of the posterior belliesof the left inferior and lateral rectus muscles.

Case 2An 89 year old woman had cataract surgeryon her left eye in December 2000 and herright eye in February 2001. She initially sawwell following surgery; however, in August

Figure 2 Mutations in tyrosinase gene.


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2001 she noted blurring of the vision in herleft eye and a peripapillary CNVM wasdiscovered. Despite two laser applicationsthe patient’s vision continued to worsen.Her medical history included rheumatic

heart disease, hypertension, and hypercho-lesterolaemia. In February 2001 she hadendocarditis complicated by a left hemiplegia.There was no family history of any pertinentdisorder.Her visual acuities were 20/20 in the right

eye and 7/200 in the left. She had dyschro-matopsia of the left eye with 2 mm ofproptosis and a relative afferent pupil defect.Goldmann perimetry revealed a full visualfield in the right eye and only a residual nasalisland in the left. The fundus of the right eyewas normal without drusen. Her left opticdisc was pale and there was nerve fibre layerswelling and haemorrhage adjacent to thenerve. MRI showed a 1.461.261.2 cm homo-geneously enhancing mass along the leftplanum sphenoidale extending into the leftoptic canal consistent with a meningioma.

Case 3A 47 year old woman noticed that she had apainless visual disturbance of her right eye‘‘like looking through a glass of water.’’ Thesymptom persisted, and 2 months later sheawoke with a blind right eye. An MRI scanwas interpreted as normal and her blindness

was ascribed to optic neuritis. She wastreated with a course of corticosteroidsduring which she recovered some vision buther vision failed again after the steroids werediscontinued and thereafter she was unableto see light.She had a history of asthma and obesity.

Her father had age related macular degenera-tion.At the age of 49 she noticed metamor-

phopsia in the left eye, and a large, elevated,extrafoveal CNVM was found. Echographyrevealed 1.3 mm of elevation, which wasacoustically normal. Vision was then 20/20.The right optic disc was atrophic and the leftwas normal. There were no macular drusen.She failed to respond to laser photocoagula-tion and proton beam radiation. Vision failedto 3/200 and the left disc became oedema-tous. MRI scanning showed bilateral opticnerve sheath enlargement and gadoliniumenhancement of the mid and posterior seg-ments of both optic nerves and extension ofthe lesion on the right side over the planumtowards the chiasm. The lesions were inter-preted as primary optic nerve sheath menin-giomas.

CommentChoroidal neovascularisation has been asso-ciated with macular degeneration, histoplas-mosis, pathological myopia, angioid streaks,

optic nerve drusen, optic nerve pits, pseudo-tumour cerebri, chronic inflammation, infec-tion, malignant melanoma, choroidalosteomas, choroidal naevi, photocoagulation,and choroidal rupture. A break in Bruch’smembrane seems to be a common feature inCNV, but the exact pathogenesis remains asubject of debate.1 2

While we cannot eliminate the possibilitythat the association of CNV with meningio-mas and CNV in our patients is merely bychance, several observations suggest other-wise. In each case the fundus of the felloweye was free of drusen, let alone moresubstantive evidence of macular degenera-tion. None of the patients had a disorderknown to predispose to CNV. There has beenone report of CNV after radiation but in thatcase the patient also had significant radiationretinopathy.3 Our irradiated patient (case 1)had no evidence of radiation retinopathy andthe radiation portals spared the eye. One ofour patients was only 49 years old when themembrane was recognised. In two of ourpatients the membrane was peripapillary.Schatz et al published the histopathological

findings in a patient with a primary opticnerve sheath meningioma in which there wasa CNV. However, their patient had chronicdisc oedema and venous collaterals and hadantecedent age related macular degenerationin both eyes.4 Shields et al described aninstance of CNV in a child with an opticnerve glioma. That patient’s disc was alsooedematous.5 Peripapillary CNV has beendescribed with chronic disc oedema of othercauses as well,6 but two of our patients neverhad disc swelling and the third developeddisc oedema only after the CNV was recog-nised.How might a meningioma cause an ipsi-

lateral CNV? The pathophysiological mechan-ism by which these two conditions occurtogether is unclear. It is possible that thetumour tissue could have invaded the eye.CNV has been associated with other tumoursinvolving the choroid.1 2 Ocular invasion wasnot evident on ultrasound (cases 1 and 3) orMRI scans but absence of proof is not proof ofabsence. In the case of Schatz et al there weresmall foci of the meningioma in the peripa-pillary sclera and retrolaminar optic nerve,which were not seen before enucleation.4

Dutton reviewed meningiomas involving theoptic nerve and primary optic nerve sheathmeningiomas. CNV was not mentioned as apresenting sign. None the less, he calculated3.7% of 477 reported cases described intra-ocular invasion by meningiomas.7 Otherauthors have reported histopathological casesof meningioma invading the optic nerve anddisc.8–10

We believe that the association of CNVwith ipsilateral meningiomas in our patientswas not one of chance. The presumedmechanism is invasion of the globe by thetumour sufficient to cause the CNV but belowthreshold for detection by MRI, ultrasound,or ophthalmoscopy.

M S LeeCole Eye Institute, The Cleveland Clinic Foundation,

Cleveland, OH 44195, USA

S LessellNeuro-ophthalmology Unit, Massachusetts Eye and

Ear Infirmary, Harvard Medical School, Boston,MA 02114, USA

Correspondence to: Michael S Lee, MD, Cole EyeInstitute/I-32, The Cleveland Clinic Foundation, 9500

Figure 1 Patient 1. Retinal elevation and lipid exudation superotemporal to the left optic disc (topleft). Venous laminar (top right), arteriovenous transit (bottom left), and late phases (bottom right) ofthe fluorescein angiogram demonstrates peripapillary hyperfluorescent area growing in size andfluorescence consistent choroidal neovascularisation.

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Euclid Avenue, Cleveland, OH 44195, USA;[email protected]

References

1 Green WR, Wilson DJ. Choroidalneovascularization. Ophthalmology1986;93:1169–76.

2 Lopez FP, Green WR. Peripapillary subretinalneovascularization: a review. Retina1992;12:147–71.

3 Spaide RF, Borodoker N, Shah V. Atypicalchoroidal neovascularization in radiationretinopathy. Am J Ophthalmol2002;133:709–11.

4 Schatz H, Green WR, Talamo JH, et al.Clinicopathologic correlation of retinal tochoroidal venous collaterals of the optic nervehead. Ophthalmology 1991;98:1287–93.

5 Shields JA, Shields CL, De Potter P, et al.Choroidal neovascular membrane as a feature ofoptic nerve glioma. Retina 1997;17:349–50.

6 Jamison RR. Subretinal neovascularization andpapilledema associated with pseudotumorcerebri. Am J Ophthalmol 1978;85:78–81.

7 Dutton JJ. Optic nerve sheath meningiomas. SurvOphthalmol 1992;37:167–83.

8 Rodrigues MM, Savino PJ, Schatz NJ. Spheno-orbital meningioma with optociliary veins.Am J Ophthalmol 1976;81:666–70.

9 Coston TO. Primary tumor of the optic nerve: withreport of a case. Arch Ophthalmol1936;15:696–702.

10 Dunn SN, Walsh FB. Meningioma (duralendothelioma) of the optic nerve. ArchOphthalmol 1956;56:702–7.

Intraoperative visual experiencesof cataract patients can be bothpleasant and unpleasantWe read with interest Zia et al’s article, whichhighlights a professional artist’s and a poet’srespective renditions of their visual experi-ences during phacoemulsification and intra-ocular lens implantation under localanaesthesia.1 While it is unclear from thereport whether the artist’s elaborate drawingresembling a ‘‘colourful monkey’’ was asso-ciated with a pleasant or frightening visualexperience, it appears from the poem that thepoet’s visual experience was most probablypleasant and delightful.We have previously reported that the visual

experience during cataract surgery underlocal anaesthesia can be frightening in up to16.2% of patients.2–8 The anxiety that mayresult from the intraoperative visual experi-ence is clinically significant because it maycause patients to become uncooperative dur-ing the procedure and trigger a sympatheticstress response. This may result in hyperten-sion, tachycardia, ischaemic strain on theheart, hyperventilation, and acute panicattacks. These stress responses are particu-larly undesirable in cataract patients who areoften elderly, with systemic co-morbiditiessuch as hypertension and ischaemic heartdisease.2 9 The frightening experience may

also lower patients’ satisfaction with thesurgery.10 11

The poet’s experience reported by Zia et alreminds us that the intraoperative visualexperience during cataract surgery can bepleasant for some patients.1 In fact, ourexperience has shown that the majority ofpatients find their visual experiences pleasantand, in some cases, the visual experienceactually increases their satisfaction with thesurgery. In a recently reported randomisedcontrolled trial conducted in India involving304 patients who underwent phacoemulsifi-cation under either topical anaesthesia (TA)or retrobulbar anaesthesia (RA), the visualexperience was reported by 106 out of 154(68.8%) TA and 102 out of 150 (68%) RApatients to be pleasant and by 47 (30.5%) TAand 46 (30.7%) RA patients to be unplea-sant.12 In a separate unpublished studyconducted in Singapore, eight of 98 patients(8.2%) who had phacoemulsification underTA reported that their satisfaction with thesurgery increased because of their visualexperiences, whereas only two patients(2.0%) experienced a decrease in satisfaction.The remaining 88 patients (89.8%) reportedthat their visual experience did not affecttheir satisfaction with the surgery. Some ofthe patients who found their visual experi-ences pleasant commented on the ‘‘fantasticcolours’’ that they experienced. In anothersimilar study on patients who had cataractsurgery under RA, nine of 152 patients (5.9%)experienced an increase in satisfaction,whereas five patients (3.3%) thought thattheir satisfaction had decreased as a result ofthe visual experiences and the remaining 138patients (90.8%) experienced no change intheir satisfaction.An additional observation is from video-

taped interviews conducted by one of us(CMK) with several leading ophthalmicanaesthesia providers in the United Stateswho had cataract surgery under local anaes-thesia themselves. The video recordings weremade during the annual scientific meeting ofthe Ophthalmic Anaesthesia Society held inChicago in October 2004. The videos clearlyshowed they reported seeing pleasant andbeautiful images during their surgery.In summary, patients may experience

pleasant or unpleasant visual sensationsduring cataract surgery under local anaes-thesia. Further investigation is warranted tohelp ascertain how we can reduce thepossibility of the experience being unpleasantor frightening.

K-G Au EongThe Eye Institute at Alexandra Hospital, National

Healthcare Group, Singapore, The Eye Institute at TanTock Seng Hospital, National Healthcare Group,

Singapore, Department of Ophthalmology, NationalUniveristy of Singapore, Singapore, Singapore Eye

Research Institute, Singapore

C S H Tan, C L Ang, S S G LeeThe Eye Institute at Tan Tock Seng Hospital, National

Healthcare Group, Singapore

R VenkateshAravind Eye Hospitals, Pondicherry, India

R MuralikrishnanLions Aravind Institute of Community Ophthalmology,

Modurai, India

G L FanningHauser-Ross Eye Institute, Sycamore, IL, USA

C M KumarAcademic Department of Anaesthesia, The James

Cook University Hospital, UK

Correspondence to: Dr Kah-Guan Au Eong,Alexandra Hospital 378 Alexandra Road Singapore,Singapore 159964; kah_guan_au_eong@alexhosp.

com.sg

doi: 10.1136/bjo.2005.074823

References

1 Zia R, Schlichtenbrede FC, Greaves B, et al.‘‘Only rarely seen in dreams’’—visualexperiences during cataract surgery.Br J Ophthalmol 2005;89:247–8.

2 Au Eong KG. 6th Yahya Cohen lecture: visualexperience during cataract surgery. Ann AcadMed Singapore 2002;31:666–74.

3 Prasad N, Kumar CM, Patil BB, et al. Subjectivevisual experience during phacoemulsificationcataract surgery under sub-Tenon’s block. Eye2003;17:407–9.

4 Au Eong KG. The Royal College ofOphthalmologists cataract surgery guidelines:what can patients see with their operated eyeduring cataract surgery? Eye 2002;16:109–10.

5 Au Eong KG, Lim TH, Lee HM, et al. Subjectivevisual experience during phacoemulsification andintraocular lens implantation using retrobulbaranaesthesia. J Cataract Refract Surg2000;26:842–6.

6 Au Eong KG, Low CH, Heng WJ, et al. Subjectivevisual experience during phacoemulsification andintraocular lens implantation under topicalanaesthesia. Ophthalmology 2000;107:248–50.

7 Au Eong KG, Lee HM, Lim ATH, et al. Subjectivevisual experience during extracapsular cataractextraction and intraocular lens implantation underretrobulbar anaesthesia. Eye 1999;13:325–8.

8 Tranos PG, Wickremasinghe SS, Sinclair N, et al.Visual perception during phacoemulsificationsurgery under topical and regional anaesthesia.Acta Ophthalmol Scand 2003;81:118–22.

9 Tan CSH, Rengaraj V, Au Eong KG. Visualexperiences of cataract surgery. J CataractRefract Surg 2003;29:1453–4.

10 Leo SW, Au Eong KG. Comments on anaesthesiafor cataract surgery. J Cataract Refract Surg2003;29:633–5.

11 Leo SW, Au Eong KG, Rengaraj V, et al. TheMisericordia Health Centre cataract comfortstudy. Can J Ophthalmol 2003;38:23–4.

12 Rengaraj V, Radhakrishnan M, Au Eong KG, etal. Visual experience during phacoemulsificationunder topical versus retrobulbar anaesthesia:results of a prospective, randomised, controlled,trial. Am J Ophthalmol 2004;138:641–8.

Cigarette pack warning: it cansend you blind!The growing research implicating smoking inage related macular degeneration (AMD)prompted us to write an editorial in 19991

urging the Australian government to warnsmokers of this little appreciated risk.In 2000, the Australian National Quit

campaign ran an advertisement as part of aseries titled ‘‘Every cigarette is doing youdamage,’’ which explicitly addressed AMD. Awebsite describes the campaign here inAustralia (www.quitnow.info.au/script/eye.html) and the television ad may be down-loaded (www.quitnow.info.au/smokescreen/smokescreen.html).In 2006 the Australian government will

require new mandatory pictorial pack warn-ings, one of which will be about AMD. Thiswarning was one of the strongest testedamong smokers in the research conductedfor the government before the announce-ment. The full report and other relatedinformation can be found at tobacco.health.

Presented in part at the North American Neuro-ophthalmology Society annual meeting, Snowbird,

UT, USA, February 2003.

doi: 10.1136/bjo.2005.071696

Accepted for publication 1 May 2005

Supported by the Heed Foundation, Cleveland, OH,USA (MSL).


Accepted for publication 13 May 2005

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usyd .edu .au/ site / supersite / resources /docs/gallery_ packwarnings.htm.

Correspondence to: Professor S Chapman, School ofPublic Health, University of Sydney, Sydney 2006,

Australia; [email protected]

doi: 10.1136/bjo.2005.076562

Reference

1 Mitchell P, Chapman S, Smith W. ‘‘Smoking is amajor cause of blindness’’: a new cigarette packwarning? Med J Aust 1999;171:173–4.

Accepted for publication 9 June 2005

BOOK REVIEWS

The next chapter deals with antimetabolitesin filtration surgery; established antimetabo-lites are covered (5-fluorouracil and mitomycinC), new agents such as antibodies to TGF-b arealso mentioned. The final chapter is ondrainage implants, the Molteno, Baerveldt,and Ahmed implants are discussed. Finallythe actual surgical techniques and the compli-cations are well described.Overall, this is an excellent book, it is

concise, with only 163 pages of illustratedtext, easy to read, and extremely pertinent toclinical practice. A text I thoroughly recom-mend for any trainee ophthalmologist oroptometrist and anyone wanting a brief,contemporary revision text on the diagnosisand management of glaucoma. Although,fortunately or unfortunately, in the end itmay only whet your appetite for informationand leave you wanting more.

N SpencerBristo Eye Hospital, Lower Maudlin Street,

Bristol B S1 2LX UK;[email protected]

Immunology of the lacrimal gland,tear film and ocular surface

Eds Manfred Zierhut, Michael E Stern, David ASullivan. £75, pp 288. London: Taylor andFrancis, 2005, ISBN 184184568X

A short quotation (p 152) summarises thebook: ‘‘These systems are all part of themultiple and redundant and protectivemechanisms…[that] maintain a functioningcornea.’’ Reflecting this complexity, chaptersrange from the pathogenesis of herpetickeratitis to dry eyes, to mucosal immunityand the use of topical ciclosporin, to tear filmand contact lenses and, of course, inflamma-tion. The book includes more unusual chap-ters on ocular surface: these integrate the eyeinto the upper aerodigestive tract. Parallelsbetween lacrimal and salivary glands, whichare not often conducted, focus attention tothe inflammatory and immune processescommon to these mucosae and the diagnosticmarkers they might offer.Some chapters are dense and scholarly:

‘‘Sex, sex steroids and dry eye syndromes’’has no fewer than 232 references, andprovides a ‘‘must read’’ synthesis ofapproaches, results and hypotheses of theresearch undertaken to understand sexrelated differences in lacrimal and meibo-mian gland (dys)function. Other chaptershave a narrower focus: events leading toAcanthamoeba infections and candidates fortherapy are presented in an very clearlyorganised and chapter.Equally elegantly and authoritatively pre-

sented are hypotheses and results showingthat constant parasympathetic input is neces-sary for tear production and thus ocularsurface homeostasis.Though not stated by the editors, this book

contains contributions to a meeting with thesame title, which provided a wonderfulopportunity for discussions. It is rather a pitythat these are not part of the book. Putting upwith different styles is a small price to pay forthis highly informed and expertly abstractedstate of knowledge publication.

M BerryBristol Eye Hospital, Lower Maudlin Street,

Bristol, UK; [email protected]

Glaucoma. 3rd ed.

This excellent text has been in print since 1989and its longevity is testament to its highquality. This is the third edition, with a newco-author John Salmon. Since its previousedition over 8 years ago there have been manyadvances in both the genetics, and the diag-nosis, monitoring and treatment of glaucoma.This text successfully updates the previousedition, and provides a concise, systematic,detailed and well balanced representation ofmodern glaucoma diagnosis and management.This book is aimed at the trainee ophthal-

mologist and optometrist, although it is alsogood basic revision for the practising ophthal-mologist. This is a comprehensive text in thateach type of glaucoma is described in terms ofits main clinical features and management.There are many colour illustrations and photo-graphs, these help the reader to correctlyinterpret clinical signs and diagnostic tests. Italso covers current controversies and newtechniques such as non-penetrating glaucomasurgery. The landmark glaucoma studies andtheir significance are also mentioned. It isperhaps too brief in sections, particularly in thechapters looking at glaucoma diagnosis, peri-metry, and imaging; however, adequate andkey references are provided to allow furtherpursuit of these topics in more depth.The text begins by covering the basic

sciences including the physiology of aqueoussecretion. Then there is a comprehensivedefinition and classification of glaucoma.The different types of glaucoma are describedat length. Tonometry is covered well, includ-ing the range of tonometers, potential errorsin tonometry, and calibration. Gonioscopy isdiscussed including angle structure identifi-cation and the different systems of angleclassification.Retinal nerve fibre and optic nerve head

assessment is described briefly including thenew imaging techniques of scanning lasertomography (Heidelberg retinal tomogramII), ocular coherence tomography (OCT),and scanning laser polarimetry (GDx nervefibre analyser). The images or readoutsproduced by each machine are provided incolour along with a very brief description oftheir interpretation. The various modalities ofperimetry are described, their interpretationis given, and new techniques such as thefrequency doubling contrast test (FDT) andshortwave automated perimetry (SWAP) arediscussed and examples provided.Glaucomamedications are covered very well.

Long standing medication are discussed as wellas new treatment options, including combinedtopical preparations. Neuroprotective agentsare covered with the recent research regardingthese agents. There is a chapter on laser therapywhich covers argon, diode, and selective lasertrabeculoplasty, Nd-YAG laser iridotomy, anddiode laser cycloablation.Trabeculectomy surgery with early and late

complications are discussed comprehensively.There is an excellent and concise chapter onnon-penetrating filtration surgery, coveringthe two most popular techniques—deepsclerectomy and viscocanalostomy.

Eds J Salmon, J Kanski. £46, pp 169.Oxford: Butterworth-Heinemann, 2004, ISBN0750655283.

NOTICES

World Ophthalmology Congress2006 – BrazilThe World Ophthalmology Congress (whichis replacing the International Congress ofOphthalmology) is meeting in February 2006in Brazil.For further information on the congress

and committees, scientific program andcoordinators of different areas are availableat the congress website www.ophthalmolo-gy2006.com.br

Thoughts on Ophthalmology andDevelopmentThe Mathis Eye Foundation is a small,privately financed organisation, established17 years ago by a former international bankerwho began his medical studies at age 40,with the specific intention of working inthird world surgical ophthalmology. TheFoundation’s experiences and lessons learnedare presented in a 26 page bound summaryentitled Thoughts on Poor World OphthalmologyDevelopment, an often critical look at eyesurgery programs in Latin America, Africa,and Haiti. To obtain this report without cost,please contact [email protected].

Vision 2020The latest issue of Community Eye Health (No54) assesses the progress of Vision 2020 atthe district level. For further informationplease contact: Journal of Community EyeHealth, International Resource Centre,International Centre for Eye Health,Department of Infectious and TropicalDiseases, London School of Hygiene andTropical Medicine, Keppel Street, LondonWC1E 7HT, UK (tel: +44 (0)20 7612 7964;email: [email protected]; online edi-tion: www.jceh.co.uk). Annual subscription(4 issues) UK £28/US$45. Free to developingcountry applicants.

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Br J Ophthalmol PostScript2 Gragoudas ES, Adamis AP, Cunningham ET Jr, et al. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 2004;351:2805–16. 3 Schwartz