familial pseudotumoral sclerochoroidal calcification associated with chondrocalcinosis

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Orbital varices and orbital walldefectsOrbital varices are a vascular hamartomatypified by a plexus of low pressure, low flow,thin walled and distensible vessels thatintermingle with the normal orbital ves-sels.1–4 If freely communicating with theorbital circulation, engorgement of varicescan occur by increasing venous pressurethrough the Valsalva manoeuvre,5 bendingposture,6 coughing or straining and these, inturn, lead to the clinical characteristics ofvariable proptosis, intermittent pain, andorbital haemorrhage.7 8

Observation is usually warranted for smalllesions, but surgical intervention may benecessary in advanced cases: indications forsurgical intervention include non-resolvingepisodes of thrombosis, severe disfiguringproptosis or displacement of the globe, andoptic nerve compression.1–3 Surgery can beextremely difficult, as varices are very friableand intimately intermixed with normal orbi-tal structures; there is also a significant riskof visual loss as a result of haemorrhage oroptic nerve damage, the latter being generallycaused by vascular compromise.9 10 The asso-ciation of orbital venous anomalies withorbital wall defects provides a further sourceof surgical difficulty because of the closeproximity of intracranial structures and thecontinuity with extraorbital or intracranialvenous anomalies.

Case seriesThe orbital database, at Moorfields EyeHospital, was used to identify patients witha clinical diagnosis of low pressure orbitalvarices and their orbital imaging (computedtomography and/or magnetic resonanceimage) was reviewed. Images were examinedfor evidence of orbital expansion, osseousdefects of the orbit, nose or sinuses, andanomalies of the frontal lobes. Patients whohad either orbital or intracranial surgerybefore the date of imaging were excludedfrom the investigation.The clinical diagnosis of orbital varices was

identified in 310 patients, and imaging wasavailable for 223 patients (72%). Six patientswith previous orbital or intracranial surgerywere excluded and nine cases (4%) had

associated anomalies of the neighbouringorbital walls (table 1).Four cases (patients 1–4) were associated

with ‘‘pitting’’ of the orbital wall secondary toorbital varices (fig 1A). Another three cases(patients 6–8) were associated with enlarged

superior orbital fissure and two cases(patients 5 and 9) with multiple orbital roof‘‘defects’’ (fig 1B). Orbital varices were pre-sent up to the dural space in two cases (pati-ents 4 and 5), and involved the frontal lobeparenchyma in one case (patient 6; fig 1C, D).

Figure 1 (A) (Patient 1) Extensive left orbital varices (white arrows) causing orbital expansion,globe displacement, and ‘‘pitting’’ of the orbital roof and lamina papyracea (black arrows). (B)(Patient 5) Bilateral orbital varices associated with multiple defects, rather than pitting, of the orbitalwalls. (C) (Patient 6) Right orbital varices, with phleboliths, extending through the orbital apex intothe middle cranial fossa (white arrows) and (D) associated with intracranial bone ‘‘pitting’’ and‘‘defects’’ (black arrows). (E) Coronal and (F) axial CT scans of patient 2 with superonasal varices(white arrows) of right orbit in 1981. (G–J) Repeat coronal and axial CT scans in 2001 showsignificant enlargement of the bone defect with complete loss of mineralisation, and expansion ofthe frontal lobe meninges into the orbital wall defect (black arrow).

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One patient (case 2) had thinning of thesuperonasal quadrant of the orbital wall,nasal orbital wall pitting, and a low ipsilateralcribriform plate, when first seen at age 21 in1981 (fig 1E, F). On repeat imaging 20 yearslater (2001), this patient was noted to havedeveloped proptosis, a defect in the super-onasal wall of the orbit, and a new mid-linenasal encephalocele (fig 1I, J).

CommentFine cut (3 mm) orbital CT scans easilydelineate varices and diagnostic phleboliths,which occur from thrombus formation,7 andprovide an excellent natural contrast betweenbrain, bone, and varix. The typical findingsfor varices include an ill defined multilocu-lated mass, with some patchy contrastenhancement, in communication with theneighbouring orbital circulation4–7; diffuseexpansion of the orbital walls is well recog-nised in some cases, especially in childhoodlesions.Several factors may have biased the study

population: many are symptomatic patients,having been referred from other ophthalmicunits in consideration for surgical interven-tion. The apparent incidence of orbital walldefects (4%) in our series may, therefore, be aslight overestimate. In a minority of patients,orbital varices may be associated with orbitalwall defects, and such defects may, even-tually, lead to an encephalocele formation.Clinicians should be aware of these, appar-ently unreported, associations beforeembarking on surgical intervention for orbitalvarices.

N Islam, K Mireskandari, G E RoseMoorfields Eye Hospital, London EC1V 2PD, UK

Correspondence to: Mr G E Rose, Orbital Service,Moorfields Eye Hospital, City Road, London EC1V

2PD, UK;

doi: 10.1136/bjo.2003.024547

Accepted for publication 10 July 2003

References

1 Rootman J. Diseases of the orbit. Amultidisciplinary approach, 2nd ed. Philadelphia:Lippincott Williams and Wilkins, 2002:517–22.

2 Beyer R, Levine MR, Sternberg I. Orbital varices:a surgical approach. Ophthal Plast Reconstr Surg1985;1:205–10.

3 Wright JE, Sullivan TJ, Garner A, et al. Orbitalvenous anomalies. Ophthalmology1997;104:905–13.

4 Rubin PAD, Remulla HD. Orbital venousanomalies demonstrated by spiral computedtomography. Ophthalmology1997;104:1463–70.

5 Shields JA, Dolinskas C, Augsburger JJ, et al.Demonstration of orbital varix with computedtomography and Valsalva manoeuvre.Am J Ophthalmol 1984;97:108–10.

6 Cohen JA, Char DH, Norman D. Bilateral orbitalvarices associated with habitual bending. ArchOphthalmol 1995;113:1360–2.

7 Bullock JD, Goldberg SH, Connelly PJ. Orbitalvarix thrombosis. Ophthalmology1990;97:251–6.

8 Foroozan R, Shields CL, Shields JA, et al.Congenital orbital varices causing extremeneonatal proptosis. Am J Ophthalmol2000;129:693–4.

9 Harris GJ, Sakol PJ, Bonavolonta G, et al. Ananalysis of thirty cases of orbital lymphangioma.Pathophysiologic considerations andmanagement recommendations. Ophthalmology1990;97:1583–92.

10 Weill A, Cognard C, Castaings L, et al.Embolization of an orbital varix after surgicalexposure. Am J Neuroradiol 1998;19:921–3.

Exenteration of invasiveconjunctival squamous cellcarcinomaOcular surface squamous neoplasia (OSSN)includes conjunctival intraepithelial neopla-sia with dysplasia, carcinoma in situ andconjunctival squamous cell carcinoma (SCC).Beside ultraviolet B irradiation identified asan risk factor, OSSN is associated withhuman papillomavirus type 16 and 18(HPV-16, HPV-18).1–5 The exact role andpossible prognostic value of p53 overexpres-sion is unclear and little is known about itsexpression during the development of con-junctival SCC.

Case reports

Patient 1A 75 year old man was referred with a10 year history of a conjunctival mass of theleft eye with visual acuity of hand movement.

Previous biopsies had revealed conjunctivaldysplasia. On examination, the tumour ofthe ocular and tarsal conjunctiva of thelower lid covered the entire corneal surface(fig 1A).

Patient 2A 90 year old patient presented with a 2 yearhistory of an extensive conjunctival papillo-matous tumour of the left eye covering threequarters of the cornea with visual acuity oflight perception. A full thickness biopsy wasperformed.Both patients underwent orbital exentera-

tion including removal of the eyelids.Histopathologically the focal invasive, com-pletely removed tumour of patient 1 grew in apapillomatous manner. The tumour cells ofthe conjunctival neoplasm showed stronglyenlarged nuclei with prominent nucleoli, andformed cohesive units with intercellularbridges (fig 1B).The exophytic tumour of patient 2 was

predominantly intraepithelial with foci ofsubepithelial invasion. Focal tumour anapla-sia was observed in the otherwise moderatelydifferentiated tumour with squamous celldifferentiation.Immunostaining of both specimens

revealed strong p53 (monoclonal mouse-anti-human p53-protein DO-7, Dako) over-expression (.26% of epithelium cells) andlow expression of p21 (,6% of epitheliumcells) of the invasive region of the tumourindicating an inactivating p53 mutation(fig 1C). While in patient 1 expression forp53 was found in all epithelial layers, inpatient 2 it was expressed suprabasally. Incontrast, both p53 and p21 showed moderatereactivity in the dysplastic region up to themiddle layer of the tumour (fig 1D). In theapical layer epithelium cells were occasionallyp21 positive.Immunostaining for HPV (HPV screening

antibody, Virofem Diagnostica, Germany)was positive in patient 1.

CommentThe high recurrence rate of OSSN of 9–64%after resection seems to depend on thehistopathological grade and status of surgicalmargins.5 HPV-16 and HPV-18 are considered

Table 1 Characteristics of nine patients with orbital wall defects in association with orbital varices

No SideAge (years)at referral Sex

Main location of orbitalvarix

Expansionof orbit Absent walls Ethmoid Cribriform Frontal

1 Left 6 M Medial and extensivesuperomedial

Present Small roof defect Pitted bone andsmaller ethmoid

L-low R-normal

Dips low atcribriform

2 Right 21 F Extraconal–medial Present Tiny thin area SNQ Pitted bone andsmaller ethmoid

R-low L-mild Low frontal lobeover cribriform

3 Left 62 M Superomedial Present Pitted roof and smalldefects of veins

Compressed Normal Hint of varix butotherwise normal

4 Right 58 F Panorbit intraconal andextraconal

Present Post superior wall andpitted bone

Normal Normal Varices up tofrontal lobe andintraconal

5 Right 47 M Panorbit intraconal andextraconal

Absent Posterior orbital roof Normal Normal Varices up todural space

6 Right 14 F Posterior intraconal,superior extraconal

Present Enlarged SOF Normal Normal Varices intofrontal lobe

7 Left 40 F Posterior intraconal Present Enlarged SOF andsmall lateral wall

Slightly smaller Unknown Normal

8 Left 37 F Posterior intraconal andextraconal

Present Very enlarged SOF,patchy SNQ defectsposteriorly

Normal Normal Normal

9 Left 66 M Extraconal–superior(large)

Present Posterior orbital roof Slightly smaller Normal Normal

SNQ = superonasal quadrant; SOF = superior orbital fissure.

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to be possible cofactors involved in initiationand early progression of OSSN.1–4 7 Thoughboth of the presented tumours were clinicallypapillomatous, immunostaining for HPV waspositive only in patient 1.The tumour suppressor gene p53 has been

found to be inactivated in over 50% of humancancers. In OSSN, overexpression of p53 hasbeen previously reported in some SCC ofconjunctiva.6 7 In the SCC of our patients, p53overexpression indicating inactivating p53mutations were observed only in the invasivepart of the tumour, but not in the carcinomain situ. While Dushku and coworkersassumed that p53 mutations could be anearly event in tumour development consis-tent with ultraviolet radiation, our findingsclearly indicate that mutations of p53 are alate event that occur with disease progres-sion, as observed with other solid tumours.7 8

Karcioglu and associates found a correlationbetween p53 overexpression and unfavour-able clinical course.9 In contrast, Aoki andcolleagues found no expression for p53 inSCC but positive staining in dysplasia.10

Our results of two exenterated advancedstages of SCC emphasise the necessity toremove dysplastic OSSN completely to pre-vent progression to invasive carcinomas.Identification of inactivating p53 mutationsmay indicate an increased risk for invasive-ness. Therefore immunohistochemical analy-sis of biopsy specimen may help in themanagement of these tumours.

R Guthoff, W E LiebDepartment of Ophthalmology, Julius Maximilians

University Wurzburg, Germany

P Strobel, A ZettlInstitute of Pathology, Julius Maximilians University

Wurzburg, Germany

Correspondence to: Dr R Guthoff, Universitats-Augenklinik, Josef-Schneider-Strasse 11, 97080

Wurzburg, Germany; [email protected]

doi: 10.1136/bjo.2003.038588

Accepted for publication 7 December 2003

References

1 McDonnell JM, Mayr AJ, Martin WJ. DNA ofhuman papillomavirus type 16 in dysplastic andmalignant lesions of the conjunctiva and cornea.N Engl J Med 1989;320:1442–6.

2 McDonnell JM, McDonnell PJ, Sun YY. Humanpapillomavirus DNA in tissues and ocular surfaceswabs of patients with conjunctival epithelialneoplasia. Invest Ophthalmol Vis Sci1992;33:184–9.

3 Nakamura Y, Mashima Y, Kameyama K, et al.Detection of human papillomavirus infection insquamous tumours of the conjunctiva and lacrimalsac by immunohistochemistry, in situhybridisation, and polymerase chain reaction.Br J Ophthalmol 1997;81:308–13.

4 Karcioglu ZA, Issa TM. Human papilloma virusin neoplastic and non-neoplastic conditions ofthe external eye. Br J Ophthalmol1997;81:595–8.

5 Lee GA, Hirst LW. Ocular surface squamousneoplasia. (Review) Surv Ophthalmol1995;39:429–50.

6 Toth J, Karcioglu ZA, Moshfeghi AA, et al. Therelationship between human papillomavirus andp53 gene in conjunctival squamous cellcarcinoma. Cornea 2000;19:159–62.

7 Dushku N, Hatcher SL, Albert DM, et al. p53expression and relation to human papillomavirusinfection in pingueculae, pterygia, and limbaltumors. Arch Ophthalmol 1999;117:1593–9.

8 Gryfe R, Swallow C, Bapat B, et al. Molecularbiology of colorectal cancer. Curr Probl Cancer1997;21:233–300.

9 Karcioglu ZA, Toth J. Relation between p53overexpression and clinical behavior of ocular/orbital invasion of conjunctival squamous cellcarcinoma. Ophthal Plast Reconstr Surg2000;16:443–9.

10 Aoki S, Kubo E, Nakamura S, et al. Possibleprognostic markers in conjunctival dysplasia andsquamous cell carcinoma. Jpn J Ophthalmol1998;42:256–61.

Familial pseudotumoralsclerochoroidal calcificationassociated withchondrocalcinosisSclerochoroidal calcification is the depositionof calcium at the level of the sclera andchoroid. Two entities have been described:metastatic calcifications resulting fromdeposition of calcium in normal tissuescaused by phosphocalcic metabolismabnormality such as primary and secondaryhyperparathyroidism,1 pseudohypoparathyr-oidism, hypervitaminose D, vitamin D intox-ication, hypophosphataemia, sarcoidosis,Bartter syndrome, and Gitelman syndrome23;and dystrophic calcifications caused by sec-ondary deposition of calcium in abnormaltissues despite normal serum levels of cal-cium and phosphate.Sclerochoroidal calcifications can also be

idiopathic.4 We describe the first case ofhereditary form of sclerochoroidal calcifica-tions associated with familial articular chon-drocalcinosis.

Case reportA 69 year old man was admitted to thedepartment of ophthalmology in November1999 with gradual deterioration of vision inboth eyes. He had a medical history ofarticular chondrocalcinosis. His father,brother, and son were treated for the samedisease.On examination, best corrected visual

acuity was 20/120 in the right eye and fingercounting in the left eye. Slit lamp examina-tion and ocular tension were normal. Thefunduscopy revealed multiple bilateral pseu-dotumoral white choroidal masses in botheyes (fig 1). Ultrasound examination of theeyes confirmed the calcific nature of thelesions.On fluorescein angiography in March 1979

the pseudotumoral lesions were smaller anddid not involve the macular area in left eye(fig 1, left).He had an extensive metabolic evaluation

in the Broussais department of physiologythat was normal. The systemic diagnosis wasfamilial articular chondrocalcinosis.We decided to examine the whole family to

search for ophthalmic abnormalities linkedwith familial chondrocalcinosis.The 74 year old brother and the 40 year old

son also suffered from chronic articularchondrocalcinosis. Their best visual acuitywas 20/20 in both eyes.

Figure 1 Patient 1. (A) Extensive papillomatous tumour, subtotally covering the corneal surface ofthe left eye. Nodular thickening of the lower eyelid indicates eyelid involvement. (B) Histologicalappearance. Papillomatous pattern of the large epithelial lesion with focal invasion above thecornea. Subepithelially, inflammatory cells and some dilated vessels (haematoxylin and eosin,original magnification,62.5). (C) p53, showing strong diffuse reactivity in invasive regionindicating an inactivating p53 mutation (original magnification,610). (D) p53, showing moderateexpression predominantly in the suprabasal layers in dysplastic conjunctiva of the same specimen(original magnification,610).

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The brother’s funduscopy revealed multiplebilateral, extrafoveal pseudotumoral whitechoroidal masses (fig 2, top). The son’sfunduscopy revealed plaque-like and onlyslightly elevated lesions seen in the mid-periphery (fig 2, bottom). Ultrasonogramsconfirmed the calcific nature of these lesions.

CommentIn 1997, Shields et al5 described a case ofsclerochoroidal calcifications in a normocal-caemic patient who had chondrocalcinosis.We first describe a familial case of scler-

ochoroidal calcifications associated with cal-cium pyrophosphate dihydrate (CPPD). Inthis family, autosomal dominant inheritanceis highly likely because there are affectedindividuals in each generation, there is maleto male transmission, and every affectedmember has an affected parent.Inheritance in sclerochoroidal calcifica-

tions has never been described; however,hereditary forms of chondrocalcinosis havealready been described.

In our report, a patient had a 24 yearfollow up showing a progressive involvementof the macular area, suggesting a growth ofthe calcifications. Two types of calcificationshave been described previously, the plaque-like and the pseudotumoral type.To our knowledge, it has never been

determined if the plaque-like lesions evolveinto tumour-like lesions. In 1992, Schachatand associates6 reported 10 cases with followup ranging from 7 months to 10 years, forwhom no change in the lesion was seen. Thisis the first observation with 24 years of followup suggesting a possible evolution of plaque-like lesions to pseudotumoral lesions.We suggest that every patient affected by

familial chondrocalcinosis should have anophthalmic examination to detect sclerochor-oidal calcification. These lesions seem to beevolving in time with possible involvement ofthe macula. Choroidal neovascularisation isalso a vision threatening complication ofsclerochoroidal calcifications.7 Our case sug-gest the need to perform ophthalmological

examination in patients and family membersof patients affected by chondrocalcinosis.

S Boutboul, T Bourcier, J-P Heligon, P Houiller,M Ullern, M Abitbol, V Borderie, L Laroche

CHNO des XV-XX, 28, Rue de Charenton 75571 ParisCedex 12 Paris, France

Correspondence to: Dr Sandrine Boutboul, CHNO desXV-XX, 28, Rue de Charenton 75571 Paris Cedex 12

Paris, France; [email protected]

doi: 10.1136/bjo.2003.039925

Accepted for publication 15 December 2003

References

1 Suzuki JI, Takeda M, Sekine N, et al. Bilateralmetastatic sclerochoroidal calcification in apatient with hyperparathyroidism.Ophthalmologica 1992;205:10–14.

2 Bourcier T, Blain P, Massin P, et al.Sclerochoroidal calcification associated withGitelman syndrome. Am J Ophthalmol1999;128:767–8.

3 Vezzoli G, Soldati L, Jansen A, et al. Choroidalcalcifications in patients with Gitelman’ssyndrome. Am J Kidney Dis 2000;6:855.

4 Lim JI, Goldberg MF. Idiopathic sclerochoroidalcalcification. Arch Ophthalmol1989;107:1122–3.

5 Shields JA. Sclerochoroidalcalcification incalcium pyrophosphate dihydrate depositiondisease (pseudogout). Arch Ophthalmol1997;115:1077–9.

6 Schachat AP, Robertson DM, Mieler WF, et al.Sclerochoroidal calcification. Arch Ophthalmol1992;110:196–9.

7 Cohen SY, Guyot-Sionnest M, Puech M.Choroidal neovascularization as a latecomplication of hyperparathyroidism.Am J Ophthalmol 1998;126:320–2.

Whole body PET/CT imaging fordetection of metastatic choroidalmelanomaMetastatic choroidal melanoma typically pre-sents in the liver. Therefore, liver enzymeassays are the most common haematologicalevaluation performed after treatment.1

In 1985, The Collaborative OcularMelanoma Study required periodic medicalevaluations including a physical examina-tion, liver functions studies, a complete bloodcount, and a chest x ray. If liver enzymesexceeded 1.5 times normal, computed tomo-graphy (CT) of the abdomen was required. Iflow attenuation hepatic nodules suggestedmetastatic disease, fine needle aspirationbiopsy of the liver tumours provided cyto-pathological confirmation.1

Positron emission tomography (PET) is amolecular imaging technique that uses radi-olabelled molecules to image metabolic activ-ity in vivo.2 3 When whole body PET wascombined with computed radiographic tomo-graphy (CT), PET/CT put anatomy and func-tion on the same page making practical a newera of physiological imaging.2–6

This study examines the ability of positronemission tomography combined with com-puted tomography (PET/CT) to allow fordetection of previously occult metastaticmelanoma.

Case reportA 77 year old woman presented with a15.4615 mm width and 13.2 mm high collarbutton shaped choroidal melanoma with alarge secondary retinal detachment in her righteye. Her preoperative medical evaluation

Figure 1 Fluorescein angiography of the 69 year old patient in 1979 (left) and 2000 (right)showing evolution of the sclerochoroidal calcifications with time.

Figure 2 Funduscopy of the patient’s brother (top) and son (bottom) revealing tumour-like andplaque-like calcifications.

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(including CT imaging of the abdomen)proved negative. She was treated by enu-cleation.

Two years later a follow up medicalevaluation revealed elevated liver functionstudies (table 1) and a chest x ray showed a

pleural effusion. CT of the abdomen withcontrast revealed multiple low attenuationhepatic foci consistent with metastatic mel-anoma.A PET/CT was requested. Fifty minutes

after intravenous administration of 15.2 mCiof fluordeoxyglucose, whole body PET/CTimaging revealed enlarged para-aortic lymphnodes and a subcutaneous nodule in theabdominal wall (fig 1). The CT portion of thePET/CT also revealed two 3 mm nodules inthe upper lobe of the right lung (too small tobe visualised by PET imaging). PET imagingwas able to reveal multiple bony metastasisthat were not seen on the CT portion (fig 1).Both CT and PET showed a large livermetastasis, but CT was better at definingtumour size. Since it is a physiological assay,PET also demonstrated the metabolic activityof the metastatic tumours (fig 1).

CommentIn this case, whole body PET/CT was found tobe capable of uncovering metastases not seenwith abdominal CT alone. This led us awayfrom considering regional perfusion of theliver, hepatic resection, and towards systemictreatment.7 8 Therefore, when PET/CT identi-fies extrahepatic involvement, it can have asignificant impact on the management ofpatients with metastatic choroidal mela-noma.PET/CT could also be used for initial

staging. Early detection of occult metastases

Figure 1 On the left, the CT demonstrates the anatomy; on the right the PET shows areas ofhypermetabolism (glucose uptake); in the middle the two images are fused. PET/CT revealedenlarged para-aortic lymph nodes and a subcutaneous nodule in the anterior abdominal wall. ThePET imaging portion of the PET/CT was able to reveal multiple bony metastases that were not seenon the CT portion of the examination. Both CT and PET showed a large liver metastasis.

Table 1 Patient characteristics

Physical Examination Blood examination X rayCT scan abdomenwith contrast

Whole body PET/CT

CT PET

General IcterusSubcutaneous tissue 2 nodules in the

anterior abdominalwall

No lesions noted 1.4 cm subcutaneousnodule in the anteriorabdominal wall

Hypermetabolic focus inthe subcutaneous tissueof the anterior abdominalwall

Nodes None No lesions noted Enlarged para aorticlymph nodes on theleft side

Hypermetabolic focus inthe upper abdomen

Lungs No abnormalitiesnoted

Pleuraleffusion ofright lungbase.No nodules

Pleural effusion rightlung base andcalcified hilar nodes

Two small 3 mmnodules in the rightupper lobe.Right pleural effusion

No foci noted

Liver Enlarged High bilirubin, AST,ALT, alkalinephosphatase, GGT

Enlarged. 2 areas oflow attenuation inthe anterior aspectof the right lobe

Low attenuation lesion.20 cm in greatestdiameter in the rightlobe with calcificationseen posteriorly.Numerous lowattenuation lesionsthroughout both lobesof the liver

Enlarged. Largehypermetabolic focus inthe right lobe with masseffect. Numeroushypermetabolic focithroughout remainder ofliver.

Kidney 8 mm cyst midpoleand 2 cm cyst upperpole of left kidney

Large right renal cyst.Additional smallercysts

Photopenic defect due tolarge right renal cyst

Bone No lesions noted No lesions noted Hypermetabolic foci inthe right skull base, leftscapula, left humerus,sternum, multiplebilateral ribs, thoracicand lumbosacral spine,pelvis, and bilateralfemurs

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offers the potential to avoid ineffective andexpensive enucleations, radioactive plaques,proton irradiation, eye wall resections, orlaser treatment.9 10 Local therapies would beabandoned in favour of systemic treatments.Another issue related to PET/CT is cost. Up

to five times more than CT of the abdomen,PET/CT is only covered (Medicare) for mela-noma staging/restaging when the stage of thecancer remains in doubt after completion ofconventional imaging (or if the clinicalmanagement would differ depending on thePET findings). Since PET/CT revealed extra-hepatic foci in this case, it changed ourclinical approach. There is little doubt aboutthe improved ability of PET/CT to detectlesions; the real issue is cost and if the resultswill change outcomes.This study goes one step further than CT,

MRI, or PET alone. By combining whole bodyPET and CT, this examination joins anatomyand function in one examination (fig 1). Therelative efficacy of PET/CT to locate metas-tases should be evaluated within the frame-work of a prospective study.

P T Finger, M KurliThe New York Eye Cancer Center, New York, USA

P T Finger, M Kurli, P Wesley, L TenaThe New York Eye and Ear Infirmary, New York, USA

P T Finger, L TenaSt Vincent’s Comprehensive Cancer Center, New

York, USA

P T Finger, K R KerrBeth Israel Medical Center

P T Finger, A PavlickNew York University School of Medicine, New York,

USA

Correspondence to: Paul T Finger, MD, The New YorkEye Cancer Center, 115 East 61st Street, New York,

NY 10021, USA; [email protected]

doi: 10.1136/bjo.2003.039289

Accepted for publication 1 January 2004

References

1 Diener-West M, Hawkins BS, Markowitz JA, et al.A review of mortality from choroidal melanoma. IIA meta-analysis of 5-year mortality ratesfollowing enucleation, 1966 through 1988. ArchOphthalmol 1992;110:245–50.

2 Townsend DW, Cherry SR. Combined anatomyand function: the path to true image fusion. EurRadiol 2001;11:1968–74.

3 Mijnhout GS, Hoekstra OS, van Tulder MW, et al.Systematic review of the diagnostic accuracy of18F-fluorodeoxyglucose positron emissiontomography in melanoma patients. Cancer2001;91:1530–42.

4 Stas M, Stroobants S, Dupont P, et al. 18-FDGPET scan in the staging of recurrent melanoma:additional value and therapeutic impact.Melanoma Res 2002;12:479–90.

5 Swetter SM, Carroll LA, Johnson DL, et al.Positron emission tomography is superior tocomputed tomography for metastatic detection inmelanoma patients. Ann Surg Oncol2002;9:646–53.

6 Finger PT, Czechonska G, D’Arienzo P, et al.Positron emission tomography of choroidalmelanoma. Probl Med Nukl 1996;10:235–9.

7 Mavligit GM, Charnsangavej C, Carrasco CH, etal. Regression of ocular melanoma metastatic tothe liver after hepatic arterial chemoembolization

with cisplatin and polyvinyl sponge. JAMA1988;260:974–6.

8 Albert DM, Niffenegger AS, Willson JK.Treatment of metastatic uveal melanoma: reviewand recommendations. Surv Ophthalmol1992;36:429–38.

9 Moshfeghi DM, Moshfeghi AA, Finger PT.Enucleation. Surv Ophthalmol2000;44:277–301.

10 Finger PT. Radiation therapy for choroidalmelanoma. Surv Ophthalmol 1997;42:215–32.

Trans-Tenon’s retrobulbartriamcinolone infusion for smallchoroidal neovascularisationIntravitreal and sub-Tenon’s corticosteroidsare being evaluated for the treatment ofchoroidal neovascularisation (CNV).1–3 Wereported on the efficacy of triamcinoloneacetonide administered as a trans-Tenon’sretrobulbar infusion (triamcinolone infusion)in reducing inflammation in uveitic eyes.4

Here we evaluated the same treatment ineyes with small subfoveal CNV.

Case reportsTriamcinolone infusion was performed in 22eyes of 22 patients with subfoveal CNV ofgreatest diameter less than or equal to 1 discdiameter (DD). The diagnoses were agerelated macular degeneration (AMD) in 14eyes, idiopathic CNV in four eyes, polypoidalchoroidal vasculopathy (PCV) in three eyes,and punctate inner choroidopathy (PIC) inone eye. One AMD eye had undergoneablative argon laser photocoagulation forCNV previously, but no other eyes hadreceived previous treatment. The medianpost-triamcinolone infusion follow up was7.5 months (range 4–27 months).Pretreatment fluorescein angiography (FA)

revealed predominantly classic CNV in 12eyes and predominantly occult CNV in 10eyes. Records were reviewed retrospectivelyand did not require institutional review boardapproval. Informed consent was obtainedbefore each procedure.The patient’s eye was prepared with

povidone-iodine and sterile drapes applied.After topical anaesthesia, conjunctiva andTenon’s capsule were incised in the infero-temporal quadrant. A 23 gauge curved bluntcannula approximately 2.1 cm in length(#HS-2764, Handaya Co, Ltd, Tokyo, Japan)was inserted to the hub into sub-Tenon’sspace and 20 mg (0.5 ml) triamcinoloneacetonide (Bristol Pharmaceutical, KK,Tokyo, Japan) was infused. The wound wasleft unsutured and 0.5% levofloxacin wasinstilled topically three times a day for1 week.Onset of CNV fibrosis was observed in 14

eyes (64%) by 3 months post-triamcinoloneinfusion (fig 1). Rates of fibrosis were 50%(7/14 eyes) for AMD, 100% (4/4 eyes) foridiopathic CNV, 67% (2/3 eyes) for PCV, and100% (1/1 eye) for PIC. Fibrosis did notcorrelate with CNV size or lesion composi-tion. FA performed at 3 months showeddecreased lesion leakage in 12 eyes (55%),no change in five eyes (23%), and increasedleakage in five eyes (23%). Best correctedvisual acuity (VA) at 3 months for all eyesimproved by >0.2 logarithm of the minimumangle of resolution (logMAR) in four eyes(18%), remained unchanged in 13 eyes(59%), and worsened by >0.2 logMAR infive eyes (23%). The median decimal VA forall eyes was 0.30 before treatment (range0.08–1.0) and 0.24 at 3 months after treat-ment (range 0.05–1.2). Of the 14 eyes withAMD, the VA at 3 months improved by >0.2logMAR in one eye (7%), remained

Figure 1 Colour fundus photographs and fluorescein angiography late images of an eye in a65 year old patient with age related macular degeneration and small subfoveal choroidalneovascularisation before (A, B; best corrected visual acuity 0.3) and 3 months after triamcinoloneinfusion (C, D; best corrected visual acuity 0.7).

This work was supported by The EyeCare Foundationand Research to Prevent Blindness, New York, USA.

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unchanged in 10 eyes (71%), and worsenedby>0.2 logMAR in three eyes (21%). In theseAMD eyes, the median decimal VA was 0.30before treatment (range 0.08–1.0) and 0.20 at3 months after treatment (range 0.05–0.7).Complications such as intraocular pressureelevation, infection, or cataract progressionwere not noted in any eyes.

CommentThis interventional case series shows thattrans-Tenon’s retrobulbar infusion of triam-cinolone acetonide resulted in lesion fibrosisin the majority of eyes with small CNV,efficacy being best for idiopathic CNV or CNVrelated to PIC. The mechanism of action oftriamcinolone acetonide in inhibiting CNVgrowth probably involves several pathways.The effect of corticosteroids in inhibitinginflammatory cells that participate in theneovascular response probably has a promi-nent role.5 6 Triamcinolone acetonide hasspecifically been shown to inhibit basicfibroblast growth factor induced migrationand tube formation of choroidal microvascu-lar endothelial cells.7 Furthermore, triamci-nolone acetonide inhibits choroidalneovascularisation induced by laser traumain a rat model.8 Finally, triamcinolone acet-onide may decrease vascular permeability,thereby decreasing influx of serum proteinsthat may contribute to an angiogenic micro-environment.9 Longer follow up and greaternumbers of cases in a randomised clinicaltrial are needed to confirm these results.

A A Okada, T Wakabayashi, E Kojima,Y Asano, T Hida

Kyorin Eye Center, Kyorin University School ofMedicine, 6–20–2 Shinkawa, Mitaka, Tokyo, Japan

Correspondence to: A A Okada, MD, Department ofOphthalmology, Kyorin University School of

Medicine, 6–20–2, Shinkawa, Mitaka, Tokyo 181–8611 Japan; [email protected]

doi: 10.1136/bjo.2003.039719


References

1 Challa JK, Gillies MC, Penfold PL, et al. Exudativemacular degeneration and intravitrealtriamcinolone: 18 month follow-up. AustNZ J Ophthalmol 1998;26:277–81.

2 Danis RP, Ciulla TA, Pratt LM, et al. Intravitrealtriamcinolone acetonide in exudative age-relatedmacular degeneration. Retina 2000;20:244–50.

3 Gillies MC, Simpson JM, Luo W, et al. Arandomized clinical trial of a single dose ofintravitreal triamcinolone acetonide forneovascular age-related macular degeneration:one year results. Arch Ophthalmol2003;121:667–73.

4 Okada AA, Wakabayashi T, Morimura Y, et al.Trans-Tenon’s retrobulbar triamcinolone infusionfor the treatment of uveitis. Br J Ophthalmol2003;87:968–71.

5 Proia A, Hirakata A, McInnes J, et al. The effect ofangiostatic steroids and B-cyclodextrintetradecasulfate on corneal neovascularization inthe rat. Exp Eye Res 1993;57:693–8.

6 Oh H, Takagi H, Takagi C, et al. The potentialangiogenic role of macrophages in the formationof choroidal neovascular membranes. InvestOphthalmol Vis Sci 1999;40:1891–8.

7 Wang Y, Friedrichs U, Eichler W, et al. Inhibitoryeffects of triamcinolone acetonide on bFGF-induced migration and tube formation inchoroidal microvascular endothelial cells. GraefesArch Clin Exp Ophthalmol 2002;240:42–8.

8 Ciulla TA, Criswell MH, Danis RP, et al.Intravitreal traimcinolone acetonide inhibits

choroidal neovascularization in a laser-treated ratmodel. Arch Ophthalmol 2001;119:399–404.

9 Carnuccio R, Di Rosa M, Guerrasio B, et al.Vasocortin: a novel gluococorticoid-induced anti-inflammatory protein. Br J Pharmacol1987;90:443–5.

Retinoblastoma in a childconceived by in vitro fertilisationAs the number of infants born through invitro fertilisation (IVF) grows, there isincreased interest regarding the long termeffects of IVF and other assisted reproductiontechniques on such offspring. Recent reportshave noted cancer in children born after IVFor fertility drug use (table 1).1

In 2001, retinoblastoma was reported tooccur in a child born through IVF in Israel.2

Since then, an additional report documentedfour cases from the Netherlands.3 Here weadd a sixth case and the first from the UnitedStates. Of these children four had unilateralretinoblastoma and two bilateral disease(table 2).During 2002, a 16 month old child was

referred to The New York Eye Cancer Centerwith no known family history of eye disease.She had a blind painful right eye withneovascular glaucoma. Intraocular pressureswere 35 mm Hg in the right eye, and 14 inthe left. Examination of the anterior chamberof the right eye revealed cells on the cornealendothelium and iris neovascularisation.While ophthalmoscopic examination of theright eye was not possible because of opaquemedia, ultrasonography revealed a denselycalcified mass in the posterior pole (fig 1).Computed radiographic tomography demon-strated tumour calcification with no evidenceof extrascleral or optic nerve extension.4 Post-enucleation histopathology confirmed thediagnosis of retinoblastoma.5 The parentsdid not approve genetic studies of the child.Further history revealed that this child was

born through IVF with a donor egg and thefather’s sperm. In order to carry the child, thepostmenopausal mother received oestrogenand progesterone before and during gesta-tion.

CommentSeveral theories of IVF related carcinogenesisexist. Prenatal exposure to fertility drugs mayinitiate cancer in the embryo or parentalgerm cells. However, an evidence basedassociation between IVF treatments and

cancer development (in the women takingthe drugs) has not been established.6

Another possible mechanism has beenassociated with the culture medium used inthe IVF test tube. Experiments on micesuggest that subtle changes in the ingredientsof the culture media may alter the activity ofimprinted genes.7 Like fertility drugs, itremains to be seen whether altered geneimprinting can lead to cancers such asretinoblastoma.A third possible mechanism of carcinogen-

esis includes inheritance of genetic defectsfrom gametes and embryo trauma performedduring routine intracytoplasmic sperm injec-tion (ICSI) type IVF.The most likely explanation for an

increased risk of secondary carcinogenesis isthat the population of patients seeking IVF isdissimilar to the general population. Patientsseeking IVF are older or have medicalproblems that interfere with fertility. Thisposes a problem with any study other than arandomised prospective trial that comparesbabies from untreated infertility patients whobecome pregnant versus babies from infertilepatients who become pregnant using IVF. Todate all studies published are observations ofclusters of disease with the suggestion thatthere is a cause and effect relation.8

Table 1 Anomalies and cancersreported in offspring of IVF

Condition Reference

Neuroectodermaltumours

White et al10

Kobayashi et al11

Neuroblastoma(Note: associatedwith the use offertility drugs only.)

Kramer et al12

Michalek et al13

Retinoblastoma Moll et al3

Cruysberg et al14

Anteby et al2

Hepatoblastoma Melamed et al15

Toren et al16

Clear cell kidneysarcoma

Toren et al16

Lymphoma Kobayashi et al11

Transposition of thegreat arteries

Lancaster17

Berg et al18

Neural tube defects Lancaster17

Several types of congenital anomalies andcancers have been reported in the literature,primarily in the form of case reports. Therelation between IVF and these conditions isnot definitively established.

Table 2 Retinoblastoma in children born through IVF

Reference

Sex and ageat diagnosis(months) Eye

Cause ofsubfertility

DNA 13q14analysis

Assisted reproductivetechnique

Anteby et al2 NR, 30 Unilateral NR NR IVF with donor spermMoll et al3 F, 38 Both Unexplained Exon 8

mutatedIVF with 6 courses ofclomid

Moll et al3 M, 15 Left Maternal cause Normal IVFMoll et al3 F, 34 Right Unexplained Normal IVFMoll et al3 M, 8.5 Both Unexplained Intron 3

mutatedIVF with 8 AI attempts

Moll et al3 F, 32 Left Paternal cause Normal IVF with ICSIThis report F, 16 Right Maternal cause NR IVF

NR, not reported; AI, artificial insemination; ICSI, intracytoplasmic sperm injection.Current literature on retinoblastoma in children born through IVF includes three case reports thatdescribe a total of six cases of retinoblastoma in these children. The characteristics of these patients andthe patient discussed in this report are listed below.

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Retinoblastoma is the most commonintraocular cancer of childhood and affectsapproximately 300 children each year in theUnited States. Retinoblastoma is a manifes-tation of a de novo deletion or mutation ofthe q14 band of chromosome 13, occurring asa ‘‘second hit’’ during embryogenesis or theresult of two hit deletions in retinal cells. Inthat it could be the result of chromosomalbreakage and deletions in IVF born children,surveillance of retinoblastoma incidence inchildren born through IVF is warranted.7–9

With the advent of assisted reproductivetechnology (ART) in 1977, American coupleshave increasingly turned to such treatmentsto overcome fertility problems. Nationwide,99 629 procedures were performed in 2000 byART. In that year, fertility treatments inwhich the egg and sperm are handled in thelaboratory resulted in 25 228 live births and35 025 infants. This report expands informa-tion on geography and determinants of bothART success and multiple birth risks (beyondthat which appears in the 2000 AssistedReproductive Technology Success Rates19).Therefore, it seems reasonable to maintain aregistry of post-IVF children, to support largeepidemiological studies with long term followup, and prospective randomised studies ofinfertile couples in order to determine if thereis a relation between IVF and cancers such asretinoblastoma.

I Lee, P T FingerThe New York Eye Cancer Center, New York City, NY,

USA

I Lee, P T Finger, J A Grifo, A R Rausen,A Rebarber

New York University School of Medicine, New YorkCity, NY, USA

D H BaradAlbert Einstein College of Medicine, New York City,

New York, USA

Correspondence to: P T Finger, The New York EyeCancer Center, 115 East 61st Street, New York City,

NY 10021, USA; [email protected]

doi: 10.1136/bjo.2003.041160


References

1 Klip H, Burger CW, deKraker J, et al. Risk ofcancer in the offspring of women who underwentovarian stimulation for IVF. Hum Reprod2001;16:2451–8.

2 Anteby I, Cohen E, Anteby E, et al. Ocularmanifestations in children born after in vitrofertilization. Arch Ophthalmol2001;119:1525–9.

3 Moll AC, Imhof SM, Cruysberg JR, et al. Incidenceof retinoblastoma in children born after in-vitrofertilisation. Lancet 2003;361:309–10.

4 Finger PT, Harbour JW, Karcioglu Z. Risk factorsfor metastasis in retinoblastoma. Surv Ophthalmol2002;47:1–16.

5 Moshfeghi DM, Moshfeghi AA, Finger PT.Enucleation. Surv Ophthalmol2000;44:277–301.

6 Lerner-Geva L, Geva E, Lessing JB, et al. Thepossible association between in vitro fertilizationtreatments and cancer development. Int J GynecolCancer 2003;13:23–7.

7 Doherty AS, Mann MR, Tremblay KD, et al.Differential effects of culture on imprinted H19expression in the preimplantation mouse embryo.Biol Reprod 2000;62:1526–35.

8 Bruinsma F, Venn A, Lancaster P, et al. Incidenceof cancer in children born after in-vitrofertilization. Human Reprod 2000;15:604–7.

9 Lerner-Geva L, Toren A, Chetrit A, et al. The riskfor cancer among children of women whounderwent in vitro fertilization. Cancer2000;88:2845–7.

10 White L, Giri N, Vowels MR, et al.Neuroectodermal tumours in children born afterassisted conception. Lancet 1990;336:1577.

11 Kobayashi N, Matsui I, Tanimura M, et al.Childhood neuroectodermal tumours andmalignant lymphoma after maternal ovulationinduction. Lancet 1991;338:955.

12 Kramer S, Ward E, Meadows AT, et al. Medicaland drug risk factors associated withneuroblastoma: a case-control study. J NatlCancer Inst 1987;78:797–804.

13 Michalek AM, Buck GM, Nasca PC, et al. Gravidhealth status, medication use, and risk ofneuroblastoma. Am J Epidemiol1996;143:996–1001.

14 Cruysberg JR, Moll AC, Imhof SM. Bilateralsporadic retinoblastoma in a child born after invitro fertilization. Arch Ophthalmol2002;120:1773, author reply 1773–4.

15 Melamed O, Bujanover Y, Hammer J, et al.Hepatoblastoma in an infant born to a motherafter hormonal treatment for sterility.N Engl J Med1982;307:820.

16 Toren A, Sharon N, Mandel M, et al. Twoembryonal cancers after in vitro fertilization.Cancer 1995;76:2372–4.

17 Lancaster PA. Congenital malformations after invitro fertilization. Lancet 1987;2:1392–3.

18 Berg T, Ericson A, Hillensjo T, et al. Deliveries andchildren born after in-vitro fertilization in Sweden

1982–95: a retrospective cohort study. Lancet1999;354:1579–85.

19 National Summary and Fertility Clinic Report.Assisted reproductive technology success rates.MMWR 2000;52:No SS-9.

Angle closure glaucoma afterlaser photocoagulation forretinopathy of prematurityInfantile angle closure glaucoma (ACG) is arare consequence of retinopathy of prema-turity (ROP) and usually occurs a few yearsafter laser treatment for ROP.1–3 A Medlinesearch for ACG following laser photocoagula-tion extracted only one case. In the case, ACGoccurred in 2 weeks after laser photocoagula-tion and although occurrence of iris bombe inboth eyes was described, the mechanism forthe ACG was not fully clarified.4

We present a case of bilateral ACG thatoccurred within a several weeks after thelaser photocoagulation for ROP. We shalldiscuss the importance of ultrasound biomi-croscopy (UBM) in the diagnosis.

Case reportA baby girl, born at 25 weeks gestationweighing 796 g, was diagnosed with stage 2plus, zone 2 ROP bilaterally at 33 weeks.Diode laser photocoagulation, 986 applica-tions right eye and 629 left eye, with 200–240 mW, 0.4 second duration, was performedby a paediatric ophthalmologist. On thefollowing day, severe hyphaema wasobserved bilaterally but there was no evi-dence of choroidal detachment by B-modeultrasound sonography. Topical atropine andcorticosteroid were started and she was

Figure 1 B-scan ultrasonography. (A) Alongitudinal view of the right eye demonstratesa tumour posterior to a closed funnel retinaldetachment. (B) A transverse view of the eyedemonstrates a rounded, densely calcifiedtumour. R, retina; S, shadow in orbit; C,calcification; T, tumour; ON, optic nerve.

Supported by The EyeCare Foundation, Inc andResearch to Prevent Blindness, New York City, USA.

The authors have no proprietary interest in anymaterial mentioned in this study.

Figure 1 Photographs of the anterior segmentof left eye (A) and right eye (B) obtained with anoperative microscope after peripheraliridectomy. The photographs show shallowanterior chambers and persistent pupillarymembranes and iridohyaloid vessels (A), andcorneal opacity (B).

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followed up conservatively. During the followup period, total posterior synechia wasformed in the both eyes and the anteriorchamber became shallow.At 39 weeks, the corneal diameter had

increased, and the anterior chamber wasextremely shallow bilaterally. The intraocularpressure (IOP) in the right eye was elevatedto 28 mm Hg, and she was referred to ourhospital.Our examination showed that the corneal

diameter was increased to 11 mm bilaterally.Slit lamp examination showed cornealoedema and shallow anterior chamber depthbilaterally, especially in the right eye. Thecorneal oedema made the funduscopy diffi-cult bilaterally. The IOP under the generalanaesthesia was 33 mm Hg right eye and17 mm Hg left eye. Persistent pupillary mem-branes and iridohyaloid vessels wereobserved but rubeosis iridis was not observed(fig 1).UBM images of anterior segments demon-

strated iris bombe bilaterally, and the entireright iris surface was adherent to the cornealendothelium. As a result, the anterior capsule

of the lens was also attached to the cornealendothelium (fig 2). Choroidal detachmentand a retrolental mass were not observed byB-mode ultrasound sonography (fig 2).Peripheral iridectomy was performed bilat-

erally (fig 1). Postoperatively, her peripheralanterior chamber deepened bilaterallyalthough the lens in the right eye was stilladherent to the corneal endothelium. Indirectophthalmoscopy revealed normal cup to discratio. The IOP fell to normal levels bilaterally.

CommentShallow anterior chambers in ROP patientsare known to be caused by various factors—for example, choroidal detachment afterexcessive photocoagulation, development ofretrolental mass, or relative increment in lensthickness,5 but usually the cause of shallowanterior chamber cannot be determined. Inour case, the development of hyphaema afterphotocoagulation induced posterior synechia,and the iris bombe followed. The displace-ment of the anterior chamber structures wasinduced by the forward movement of the iris-lens diaphragm in the right eye, and theocular fragility in premature baby mayexplain this deformity.Vitreous haemorrhage is known to occur in

7.9% of ROP cases after photocoagulation.6 Inour case, there is a possibility that thehyphaema was derived from vitreous hae-morrhage. Another possibility is an acciden-tal photocoagulation of persistent pupillarymembranes and/or iridocorneal vesselscaused the hyphaema. We are not aware ofsuch morphological changes after photocoa-gulation for ROP.ACG that occurs immediately after retinal

photocoagulation in ROP patients is rare, butis still an important complication. In ROPpatients, the lens and its ligament are weak,and therefore not only ACG but also lensdisplacement occurred. It is important thatwe be aware of the possible development ofACG following retinal photocoagulation forROP.

A Uehara, T Kurokawa, N Gotoh,N Yoshimura

Department of Ophthalmology, Shinshu UniversitySchool of Medicine, Matsumoto, Japan

T TokushimaDepartment of Ophthalmology, Nagano Children’s

Hospital, Nagano, Japan

Correspondence to: N Yoshimura, MD, PhD,Department of Ophthalmology and Visual Sciences

Kyoto University Graduate School of Medicine, Kyoto606-8507, Japan; [email protected]

doi: 10.1136/bjo.2003.037994


References

1 Bloidi FC. Retrolental fibroplasias (retinopathy ofprematurity). Trans Am Acad OphthalmolOtolaryngol 1955;59:35–8.

2 McCormic AQ, Pratt-Johnson JA. Angle closureglaucoma in infancy. Ophthalmic Surg1971;2:91–3.

3 Smith J, Shivitz I. Angle-closure glaucoma in adultwith cicatrical retinopathy of prematurity. ArchOphthalmol 1984;102:371–2.

4 Lee AL, Lee LR, Gole GA. Angle-closure glaucomaafter laser treatment for retinopathy ofprematurity. J AAPOS 1998;2:383–4.

5 Hibino Y, Takahashi M, Majima A. Studies onocular functions of cicatrical retinopathy of

prematurity. Managements of refractive elements.Jpn J Clin Ophthalmol 1978;32:655–62.

6 Fallaha N, Lynn MJ, Aaberg TM Jr, et al. Clinicaloutcome of confluent laser photoablation forretinopathy of prematurity. J AAPOS2002;6:81–5.

Sequential treatment of centralretinal vein occlusion withintravitreal tissue plasminogenactivator and intravitrealtriamcinoloneTreatment for central retinal vein occlusion(CRVO) remains disappointing despiterecently proposed intraocular surgical tech-niques.1 2 We previously introduced the use ofintravitreal tissue plasminogen activator(TPA) for acute central retinal vein occlusionin 1999.3 Numerous investigators have con-firmed its safety and suggested that it mayhave a beneficial role in the treatment ofacute central retinal vein occlusion.4–7

Although some studies in rabbits suggestthe rabbit retina is not permeable to TPA,

Figure 2 Composite images of the anteriorsegment scanned with UBM (top) and schematicrepresentations (bottom). (A) Left eye. Posteriorsynechia and iris bombe can be seen. C,cornea; L, lens; AC, anterior chamber; S,posterior synechia; PC, posterior chamber. (B)Right eye. The high echo lines (arrowheads)along the corneal endothelium represent the irisadherent to the corneal endothelium and the irisbombe. The lens is displaced into the anteriorchamber and the anterior chamber iscompletely obliterated. The arrow representsthe posterior capsule of the lens. Note that thecornea is distended and is thin as a result of thehigh intraocular pressure. The thickness of thecornea at the centre is 394 mm, and 613 mm inthe left eye as measured with a caliper installedin the UBM model 840 Humphrey.

Figure 1 (A) Fundus photograph shows anacute CRVO with dilated retinal veins, retinalhaemorrhages, and retinal oedema. (B) Fundusappearance 1 month after intravitreal injectionof tissue plasminogen activator. (C) Photographof the same eye 5 months later.

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investigators found the porcine retina was, infact, permeable to TPA.8 9 Our clinical experi-ence with intravitreal TPA in humans withCRVO and large submacular haemorrhagesstrongly suggests that intravitreal TPA doescross the human retina. Greenberg et al werethe first to report the possible beneficial effectof intravitreal steroids on patients withchronic CRVO.10 This report describes asequential treatment strategy for patientswith CRVO who present early in the courseof their disease and can be performed in theoffice while avoiding the risks of vitrectomy.It utilises intravitreal TPA in the acute phaseof the vein occlusion to attempt clot lysis, andthen treats any remaining vascular leakagewith intravitreal triamcinolone.

Case reportA 59 year old obese, hypertensive flightinstructor presented with a sudden decreasein vision for 7 days in the right eye. Visionwas 20/400 right eye and 20/20 left eye . Thepatient was diagnosed with an acute CRVO inthe right eye (fig 1A). The left eye wasnormal. After being advised of the risks andbenefits, the patient elected to undergointravitreal injection of TPA (75 mg).Thirteen days later, the patient noted markedimprovement in vision with 20/60 vision.Thirty four days after the injection, thepatient’s vision was 20/30 (Fig 1B).Six months after intravitreal TPA injection,

the vision remained 20/30, but the patientstill complained of metamorphopsia andblurry vision despite resolution of otherfindings of CRVO (fig 1C). Fluoresceinangiogram (FA) revealed persistent macularoedema (fig 2A). Optical coherence tomogra-phy (OCT) showed the foveal thickness to be331 m with mild intraretinal oedema. After

being advised of the risks and the benefits,the patient then underwent injection ofintravitreal triamcinolone (4 mg).Six weeks after the intravitreal triamcino-

lone, the FA returned to normal and OCTshowed decreased foveal thickness from331 mm to 291 mm. The patient reported asignificant improvement in vision withdecreased metamorphopsia. Vision was 20/25 with no late leakage on the fluoresceinangiogram (fig 2B).

CommentTo our knowledge, this represents the firstpublished case of CRVO treated sequentiallywith intravitreal TPA for the acute phase andintravitreal triamcinolone for the chronicphase. TPA is a drug that must be used earlyin the course of thrombus formation to beeffective. We do not recommend its use forpatients with chronic symptoms. Intravitrealsteroids appear to decrease the blood-retinalbarrier breakdown and macular oedema, butrecurrent oedema may occur since the ster-oids do not appear to affect the thrombusitself.

J M L, J J K, M C CheungOphthalmology, University of California at San

Francisco, San Francisco, CA, USA

J M Lahey, J J KOphthalmology, Kaiser Permanente, Hayward, CA,

USA

Correspondence to: J M Lahey, MD, Ophthalmology(Retina), Kaiser Permanente Medical Center, 27400Hesperian Boulevard, Hayward, CA 94545-4299,

USA; [email protected]

doi: 10.1136/bjo.2004.043406

Accepted for publication 3 February 2004

References

1 Opremcak EM, Bruce RA, Lomeo MD, et al.Radial optic neurotomy for central retinal veinocclusion: a retrospective pilot study of 11consecutive cases. Retina 2001;21:408–15.

2 Weiss JN, Byone LA. Injection of tissueplasminogen activator into a branch retinal vein ineyes with central retinal vein occlusion.Ophthalmology 2001;108:2249–57.

3 Lahey JM, Fong DS, Kearney J. Intravitreal tissueplasminogen activator for acute central retinalvein occlusion. Ophthalmic Surg Lasers1999;30:427–34.

4 Weizer JS, Fekrat S. Intravitreal tissueplasminogen activator for the treatment of centralretinal vein occlusion. Ophthalmic Surg LasersImaging 2003;34:350–2.

5 Glacet-Bernard A, Kuhn D, Vine AK, et al.Treatment of recent onset central retinal veinocclusion with intravitreal tissue plasminogenactivator: a pilot study. Br J Ophthalmol2000;84:609–13.

6 Ghazi NG, Noureddine B, Haddad RS, et al.Intravitreal tissue plasminogen activator in themanagement of central retinal vein occlusion.Retina 2003;23:780–4.

7 Elman MJ, Raden RZ, Carrigan A. Intravitrealinjection of tissue plasminogen activator forcentral retinal vein occlusion. Trans AmOphthalmol Soc. 2001;99: 219–21; discussion222–3).

8 Kamei M, Misono K, Lewis H. A study of theability of tissue plasminogen activator to diffuseinto the subretinal space after intravitrealinjection in rabbits. Am J Ophthalmol1999;128:739–46.

9 Mahmoud TH, Peng Y-W, Proia A, et al.Intravitreal tissue plasminogen activatorpenetrates the retinal veins in a porcine model ofvascular occlusion. Invest Ophthalmol Vis Sci.

2002;43: E-abstract 3533, Presented at ARVO,2002.

10 Greenberg PB, Martidis A, Rogers AH, et al.Intravitreal triamcinolone acetonide for macularoedema due to central retinal vein occlusion.Br J Ophthalmol 2002;86:247–8.

Severe post-laser suprachoroidalhaemorrhaging in a diabeticpatient receiving anticoagulantsAlthough the aetiology is not well under-stood, expulsive suprachoroidal haemorrha-ging (ESH) is the most severe complicationassociated with intraocular surgery.Anticoagulants are considered a risk factorfor spontaneous suprachoroidal haemorrha-ging in cases with high myopia, age relatedmacular degeneration, and diabetic retino-pathy.1–5 However, ESH post photocoagula-tion is extremely rare regardless ofanticoagulant therapy. We have experienceda severe case of post-laser ESH correlatedwith anticoagulant therapy, which resulted inirreversible visual disturbance.

Case reportA 70 year old woman was diagnosed withpre-proliferative diabetic retinopathy basedon fluorescein angiographic examinations.Two months before diagnosis, she had righteye cataract surgery. During the past 6 years,the patient received warfarin (4 mg/day) andaspirin (81 mg/day) because of atrial fibrilla-tion after myocardial infarction. Laser photo-coagulation was performed in her right eyewith a Nidek MC-7000, yellow-green laser.Operating conditions were 200–280 burns persession with a spot size 200 mm, exposure0.2 seconds, power 100–120 mW using aQuadraSpheric contact lens (Volk, Tokyo,Japan). Treatment was separated into threepartitions with a minimum 2 week intervalbetween sessions. Three days after finalphotocoagulation, the patient had a suddenvisual loss to hand movements. In slit lampexaminations, the retina seemed to beattached to the posterior surface of theimplanted intraocular lens. Severe choroidaldetachment was found by fundus examina-tion (fig 1). The B-mode ultrasonographyshowed massive haemorrhaging in the chor-oidal space (fig 2). In systemic examinations,multiple purple spots were observed in bothher arms. Microhaematuria was also found.Blood examination revealed blood sugar167 mg/dl; platelet number 179 000 6106/l;PT% 19% (control 70–120); PTs 28.7 seconds;PT INR 4.72 (control 1); APTT 80.2 seconds(control 24.0–38.0); and bleeding time5 minutes. Although surgery was planned toproceed as soon as the anticoagulant waswashed out, her right eye lost all lightperception before treatment.

CommentWe have described a case of ESH after laserphotocoagulation in a patient receiving anti-coagulant therapy. Laser photocoagulation isknown as an effective treatment for variousocular diseases and is a widely used, non-incision surgical procedure. However, a num-ber of complications have been reported, withsome citing an irreversible visual distur-bance.6 On the other hand, anticoagulanttherapy is prevalent after cardiac/braininfarctions, which necessitate long termcoagulation system management. In thepresent case, the PT INR was extremelyprolonged (a respected value of 2–3 is

Figure 2 (A) Fluorescein angiogram revealspersistent macular oedema andhyperfluorescence 6 months after intravitrealTPA injection. (B) Late frames show resolution ofmacular oedema 6 weeks after intravitrealtriamcinolone.

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appropriate for post-cardiac infarction).Presumably, choroidal microbleedinginitiated by photocoagulation persistedbecause of an overly suppressed coagulationsystem; blood pooled in the choroidal space,which assumed an ESH. To our knowledgethere is only one other similar case reportedby Khairallah et al that showed post-laserchoroidal haematoma in a diabetic patienttreated with anticoagulant.7 Even thoughESH incidence is low, extreme caution mustbe exercised when performing laser therapyin patients using anticoagulants, because ofpotentially serious outcomes. An age of65 years or more, history of stroke, historyof gastrointenstinal bleeding, a serious mor-bid condition (recent myocardial infarction,renal insufficiency, or severe anaemia), andatrial fibrillation are five high risk factors formajor bleeding in outpatients treated withwarfarin.8 If possible, preoperative coagula-tion system examinations are recommendedfor high risk patients receiving anticoagulanttreatments.

A Mikawa, S Honda, I Sugita, N Okamoto,H Toda

Department of Ophthalmology, Kitano Hospital,Tazukekofukai Medical Research Institute, Osaka,

Japan

Correspondence to: A Mikawa, Department ofOphthalmology, Kitano Hospital, TazukekofukaiMedical Research Institute, 2-4-20 Ougimachi,

Kita-ku, Osaka 530-8480, Japan;[email protected]

doi: 10.1136/bjo.2004.043489

Accepted for publication 14 February 2004

References

1 Chak M, Williamson TH. Spontaneoussuprachoroidal haemorrhage associatedwith high myopia and aspirin. Eye2003;17:525–7.

2 Fadi EB, William H, Jarrett H, et al. Massivehemorrhage complicating age-related maculardegeneration. Ophthalmology1986;93:1581–92.

3 Edwards P. Massive choroidal hemorrhage inage-related macular degeneration: acomplication of anticoagulant therapy. J AmOptom Assoc 1996;67:223–6.

4 Yang SS, Arthur D, McDonald R. Massivespontaneous choroidal hemorrhage. Retina2003;23:139–44.

5 Raj A, Sekhri R, Salam A, et al.Massive subretinalbleed in a patient with background diabeticretinopathy and on treatment with warfarin. Eye2003;17:649–652.

6 Zweng HC, Little HL, Hammond AH.Complications of argon laser photocoagulation.Trans Am Acad Ophthalmol Otolaryngol1974;78:OP195–204.

7 Khairallah M, Chachia N. Post-laser choroidalhematoma in a diabetic patient treated with anoral anticoagulant. J Fr Ophtalmol1994;17:138–140.

8 Landefeld CS, Goldman L. Major bleeding inoutpatients treated with warfarin: incidence andprediction by factors known at the start ofoutpatient therapy. Am J Med 1989;87:144–52.

Authors’ replyWe appreciate the interest and many com-ments we have received regarding our recentarticle.1 In reply to the comments by DrVedantham, we acknowledge the paucity ofexperimental data to prove that accurateplacement of corticosteroids into the sub-Tenon’s space provides good drug penetrationinto the eye. However, the studies to thecontrary cited by Vedantham have all usedneedles to make such ‘‘accurate placement,’’including the study by Jennings et al,2 whichutilised the technique described by Tessler.3

Use of needles represents not only a potentialhazard to the eye in terms of accidental globepenetration, but also makes it much moredifficult to place any sub-Tenon’s injectionunder the posterior Tenon’s capsule near themacula and/or around the optic nerve. It hasbeen shown that many injections intendedfor the sub-Tenon’s space merely end upsomewhere in the orbit outside of Tenon’scapsule.4 We believe that our method using a23 gauge blunt, curved, long cannula (theone we used was No HS-2764 by Handaya Co,Ltd, Tokyo, Japan) assures accurate place-ment into the target space, thereby increasingtherapeutic efficacy and obviating the needfor globe invasive procedures such as intravi-treal injection of corticosteroids, corticoster-oid intravitreal implants, and/or therapeuticvitrectomy.However, we are in agreement with

Vedantham, in that ultimately corticosteroidplaced outside of the eye may be no match forthe efficacy that may be obtained by corti-costeroid placed inside the eye. Yet we havefound such a high efficacy rate for the trans-Tenon’s retrobulbar infusion of triamcinolonein uveitis that we can conceive of no reasonwhy this treatment should not be tried beforeprocedures such as intravitreal injections thatcarry risks of severe complications are con-sidered. For example, as also pointed out byVedantham, the risks of intravitreal cortico-steroid injections even include developmentof a rare form of mycobacterial endophthal-mitis.5 Therefore, the risk to the eye ofintravitreal procedures, especially wheninvolving corticosteroid administration, can-not be taken lightly. Furthermore, we believethat the reason why sub-Tenon’s injections ofcorticosteroids have not become popularamong retina specialists who for exampletreat diabetic macular oedema, is more likelyrelated to the lower efficacy rate when usingneedles as opposed to the technique using aninfusion cannula that we advocate. Lastly,obtaining the infusion cannula seems like asmall inconvenience (and an even smallercost) to the physician compared to the risk ofdoing intravitreal injections of corticosteroidsas a treatment of first choice as advocated byVedantham. We strongly encourage all uvei-tis and retina specialists who have up untilnow been disappointed with the efficacy oftheir sub-Tenon’s corticosteroid injections, tomake the effort to obtain an appropriatecannula and revise their technique beforejumping to intravitreal procedures.In reply to the first comment by Dr Mehta,6

we acknowledge the current WHO guidelines,revised for 2003, that include recommenda-tions for extrapulmonary tuberculosis.7

However, we would also like to amendMehta’s comment, in that the WHO admitsin those guidelines that there are many

Figure 2 The findings of B-mode ultrasoundexamination. A massive haemorrhage in thechoroids is present.

Figure 1 A fundus photograph of the patient after laser photocoagulation. A severe choroidaldetachment associated with secondary retinal detachment was found.

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regimens with reported efficacy including a6 month regimen of rifampicin (with strep-tomycin also given in the initial phase only)for meningeal tuberculosis. Furthermore, theWHO recommendations are for active extra-pulmonary tuberculosis that has been diag-nosed by specimen examination or strongclinical evidence, and give no recommenda-tions for latent infection. As we have pre-viously reported in a series on intraoculartuberculosis, systemic examination failed toidentify a focus of active tuberculosis in themajority of our patients,8 and we have cometo suspect that the uveitis we observed maybe an immune response to latent tuberculosisantigen sequestered elsewhere. Therefore, thepatients we described were given a diagnosisof ‘‘presumed intraocular tuberculosis,’’ thatis with uveitis presumed to be related to theMycobacterium tuberculosis organism.Furthermore, we would like to clarify thatin the cases of presumed ocular tuberculosisthat received trans-Tenon’s retrobulbartriamcinolone infusion,1 this treatment wasjudged to be effective in two of three eyes.Regardless, since the focus of active or latenttuberculosis was never identified in ourpatients, a two drug regimen of isoniazidand rifampicin was used as a therapeutic trialfor antituberculosis therapy. A similar ther-apeutic trial for ocular tuberculosis, albeitwith isoniazid alone, has been previouslyadvocated in Japan by Ishihara and Ohno.9

With regard to the second comment,among the 16 patients who were receivingsome form of systemic immunosuppressivetherapy, we did not notice any difference inoutcome when compared to patients whowere not on immunosuppressive therapy. Inother words, the efficacy of trans-Tenon’sretrobulbar triamcinolone infusion was thesame. However, we suspect that the recur-rence rate after triamcinolone infusion maybe different, and we are currently investigat-ing this possibility.

A A Okada, T WakabayashiKyorin Eye Center, Kyroin University School of

Medicine, Tokyo, Japan

Correspondence to: Annabelle A Okada, Kyorin EyeCenter, Kyroin University School of Medicine, Tokyo,

Japan; [email protected]

doi: 10.1136/bjo.2003.038851

Accepted for publication 20 November 2003

References

1 Okada AA, Wakabayashi T, Morimura Y, et al.Trans-Tenon’s retrobulbar triamcinolone infusionfor the treatment of uveitis. Br J Ophthalmol2003;87:968–71.

2 Jennings T, Rusin MM, Tessler HH, et al. Posteriorsub-Tenon’s injections of corticosteroids in uveitispatients with cystoid macular edema.Jpn J Ophthalmol 1988;32:385–91.

3 Tessler H. Uveitis. In: Peyman GA, Sanders DR,Goldberg MF, eds. Principles and practice ofophthalmology, Vol 2.1st ed. Philadelphia:Saunders, 1980:1554–629.

4 Freeman WR, Green RL, Smith RE. Echographiclocalization of corticosteroids after periocularinjection. Am J Ophthalmol 1987;103:281–8.

5 Benz MS, Murray TG, Dubovy SR, et al.Endophthalmitis caused by Mycobacteriumchelonae abscessus after intravitreal injection oftriamcinolone. Arch Ophthalmol2003;121:271–3.

6 Mehta SA. Trans-Tenon’s triamcinolone andpretreatment. Br J Ophthalmol 2003.www.bjophthalmol.com/cgi/eletters/87/8/968#183, 1 Aug 2003.

7 World Health Organization. Case definitions (p24) and standardised treatment regimens (p 35–36). In: Treatment of tuberculosis: guidelines fornational programmes, 3rd ed. (WHO/CDS/TB/2003.313). Geneva: WHO, 2003 (accessed on13 October 2003).

8 Morimura Y, Okada AA, Kawahara S, et al.Tuberculin skin testing in uveitis patients andtreatment of presumed intraocular tuberculosis inJapan. Ophthalmology 2002;109:851–7.

9 Ishihara M, Ohno S. [Ocular tuberculosis].Nippon Rinsho 1998;56:3157–61.

Owls’ eyes move‘‘Double crossed,’’ the cover illustration andarticle by Schwab on the barn owl refers tothe alleged immobility of the owl’s eyes.1 Thisis a myth which should not be perpetuated inthe BJO. The owl’s eyes do in fact move, andwhile the amount is not large, it is justenough for two papers on the subject2 3 Thephrase ‘‘nearly immobile’’ is preferable.

M J Steinbach

Correspondence to: Professor Martin J Steinbach,University of Toronto, Department of Ophthalmologyand Vision Sciences, Toronto Western Hospital, 399

Bathurst Street, Toronto M5T 2S8, Canada;[email protected]

doi: 10.1136/bjo.2004.042291


References

1 Schwab IR. Double crossed. Br J Ophthalmol2003;87:1442.

2 Steinbach MJ, Money KE. Eye movements of theowl. Vis Res 1973;13:889–91.

3 Steinbach MJ, Angus RG, Money KE. Torsionaleye movements of the owl. Vis Res1974;14:745–6.

Tropical 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.

Elimination of avoidable blindnessThe 56th World Health Assembly (WHA)considered the report on the elimination ofavoidable blindness (doc A56/26) and urgedMember States to: (1) Commit themselves tosupporting the Global Initiative for theElimination of Avoidable Blindness by settingup a national Vision 2020 plan by 2005; (2)Establish a national coordinating committeefor Vision 2020, or a national blindnessprevention committee to help implementthe plan; (3) Implement the plan by 2007;(4) Include effective monitoring and evalua-tion of the plan with the aim of showing areduction in the magnitude of avoidableblindness by 2010; (5) To support themobilisation of resources for eliminatingavoidable blindness. The WHA also urgedthe Director-General to maintain and streng-then WHO’s collaboration with MemberStates and the partners of the GlobalInitiative for the Elimination of AvoidableBlindness as well as aid in the coordinationand support of national capability.

4th International Congress onAutoimmunityThe 4th International Congress onAutoimmunity will take place 3–7November 2004 in Budapest, Hungary. Thedeadline for the receipt of abstracts is 20 June2004. Further details: Kenes InternationalGlobal Congress Organisers and AssociationManagement Services, 17 Rue du Cendrier,PO Box 1726, CH-1211 Geneva 1, Switzerland(tel: +41 22 908 0488; fax: +41 22 732 2850;email: [email protected]; website:www.kenes.com/autoim2004).

XVI International Congress for EyeResearchThe XVI International Congress for EyeResearch will be held on 29 August – 3September 2004 in Sydney, Australia. Forfurther information, please contact:[email protected] (website: www.tourhosts.com.au/icer2004).

Glaucoma Society Silver JubileeMeeting 2004The Silver Jubilee Meeting and Dinner for theGlaucoma Society will be held on 3 December2004 at the Royal College of Physicians inRegents Park, London. The meeting will takeplace between 8.30am and 5pm and thedinner will be held between 6.30pm and10pm. For further information, please con-tact: Janet Flowers, Administrator, 29 QuarryHill, Grays, Essex, RM17 5BT (tel: 01375383172; e-mail: [email protected]).

NOTICES

Low vision careThe latest issue of Community Eye Health (No49) deals with the problems and manage-ment of low vision. 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 and

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doi: 10.1136/bjo.2003.039925 2004 88: 1094-1095Br J Ophthalmol

S Boutboul, T Bourcier, J-P Heligon, et al. chondrocalcinosiscalcification associated with Familial pseudotumoral sclerochoroidal

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