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increaseof the doseto 2.5 mgbevacizumab. Obviously, primary

non-responders do not show an enhanced reaction to more

intensive treatment in RVOa pattern that has already been

demonstrated in patients treated with anti-angiogenic therapy

of diabetic macular oedema.18 A recent paper suggests a

potential rebound phenomenon due to an upregulation of

VEGF receptors following intravitreal bevacizumab administra-

tion in patients with RVO of chronic nature.19 Recent studies

also showed the close correlation between aqueous VEGF levels

and the severity of macular oedema in patients with RVO.20 21

Therefore it may be hypothesised that a more prolonged VEGF

blockademay benecessary in patients with high and prolonged

VEGF levels.

Despite the clear limitation of the study due to the small

number of patients in the CRVO group (n= 6), subgroup

analysis indicated a better response to bevacizumab treatment

in patients with macular oedema secondary to BRVO. Patients

with CRVO showed a comparable reduction in CRT , butfunctional effects were not statistically significant. Therefore,

our data do not provide evidence for recommending the use of

intravitreal bevacizumab in patients with macular oedema

secondary to CRVO.

It has been suggested that anti-VEGF therapy at an early

stage of ischaemic CRVO may be more beneficial.22 However,

we only included patients with no neovascularisation and a

persistent (. 3 months) macular oedema to allow for sponta-

neous improvement and to reduce a potential negative effect of

anti-VEGF therapy on early collateral vessel formation.

Even if anti-VEGF treatment is only a symptomatic method

for patientswith CM O secondary to RVO, it showed promising

results after 1 year of follow-up. The main drawback of this

new treatment modality seemsto bethe short durability of the

therapeutic effect with the need for frequent retreatments.

Large randomised controlled clinical trials should be conducted

to compare both entities and to evaluate the long-term efficacy

and safety after repeated bevacizumab treatment in patients

with CM O secondary to RVO according to their ischaemicstatus and intraocular VEGF levels.

Figure 4 A 66-year old patient with cystoid macular oedema secondary to branch retinal vein occulusion. The patient received four injections atbaseline, month 1, month 2 and at month 3. CRT, central retinal thickness; Tx, treatments; VA, visual acuity.

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Acknowledgements:The authors thank M Amschl, C Hirn and G Stock forperforming fluoresceinangiograms.

Competinginterests: None declared.

Ethics approval: Obtained

Patient consent: Obtained

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in anolder population: the Blue Mountains EyeStudy.Arch Ophthalmol2006;124:72632.

2. Hayreh SS, ZimmermanB, McCarthyMJ , et al. Systemic diseases associatedwithvarious types of retinal vein occlusion.AmJ Ophthalmol 2001;131:6177.

3. Blondel J ,Glacet-Bernard A, Bayani N, et al. Retinal veinocclussion andhyperhomocysteinemia.J Fr Ophthalmol 2003;26:24953.

4. Rath EZ,Frank RN, Shin DH, et al. Riskfactors for retinal vein occlusion. A casecontrol study. Ophthalmology1992;99:50914.

5. Koizumi H,Ferrara DC, Brue C, et al. Central veinocclusioncasecontrol study.AmJ Ophthalmol 2007;144:85863.

6. Aiello LP, AveryRL, ArriggPG, etal. Vascularendothelial growthfactorinocularfluidof patients withdiabetic retinopathyand other retinal disorders.N Engl J Med1994;331:14807.

7. Branch Vein Occlusion Study Group. Argonlaser photocoagulationfor macularedema in branch vein occlusion. AmJ Ophthalmol 1984;98:27182.

8. The Central Vein Occlusion Study Group. Evaluationof grid patternphotocoagulationfor macular edema in central vein occlusion. The Central Vein

OcclusionStudy Group M. Ophthalmology1995;102:142533.9. Avitabile T,Longo A, Reibaldi A. Intravitreal triamcinolone comparedwith macularlaser grid photocoagulation for thetreatment of cystoidmacular edema.AmJ Ophthalmol 2005;140:695702.

10. Karacorlu M, KaracorluSA, Ozdemir H,etal. Intravitrealtriamcinoloneacetonidefortreatment of serous macular detachment in central vein occlusion. Retina2007;27:102630.

11. Gregori NZ,Rosenfeld PJ, PuliafitoCA, et al. One-year safetyand efficacy ofintravitrealtriamcinoloneacetonideforthemanagement ofmacularedemasecondaryto central vein occlusion. Retina 2006;26:88995.

12. RosenfeldPJ , FungAE,PuliafitoCA.Optical coherencetomographyfindings afteranintravitreal injectionof bevacizumab(avastin) for macular edema fromcentral veinocclusion. Ophthalmic Surg Lasers Imaging 2005;36:3369.

13. Iturralde D,SpaideRF, Meyerle CB, et al. Intravitreal bevacizumab(Avastin)treatment of macular edema in central retinal veinocclusion: a short-termstudy.Retina 2006;26:27984.

14. Hsu J ,Kaiser RS, SivalingamA, et al. Intravitreal bevacizumab(avastin) in centralvein occlusion. Retina 2007;27:10139.

15. RabenaMD, PieramiciDJ , CastellarinAA, etal. Intravitrealbevacizumab(Avastin)inthetreatment of macular edema secondary to branch retinal vein occlusion. Retina2007;27:41925.

16. KriechbaumK,Michels S, Prager F, et al. Intravitreal avastinfor macular oedemasecondary to retinal vein occlusiona prospectivestudy. Br J Ophthalmol2008;92:51822.

17. Fung AE, RosenfeldPJ , Reichel E. The International Intravitreal BevacizumabSafetySurvey: usingthe internet to assess drugsafetyworldwide. Br J Ophthalmol2006;90:13449.

18. Diabetic RetinopathyClinical Research Network, Scott IU,EdwardsAR, etal. AphaseII randomizedclinical trial of intravitreal bevacizumabfor diabetic macularedema.Ophthalmology 2007;114:18607.

19. Matsumoto Y,FreundKB, Peiretti E, et al. Rebound macular edema followingbevacizumab(Avastin) therapy for retinal venous oclusivedisease. Retina2007;27:42631.

20. Noma H,Funatsu H, Yamasaki M, et al. Aqueous humour levels of cytokines arecorrelatedto vitreous levels and severityof macular oedema in branchretinal vein

occlusion. Eye 2008;22:428.21. Noma H,MinamotoA, Funatsu H, et al. Intravitreal levels of vascular endothelialgrowthfactor and interleukin-6 arecorrelatedwith macular edema in branchretinalvein occlusion. Graefes Arch Exp Ophthalmol 2006;244:30915.

22. Boyd SR,Zachary I, Chakravarthy U, et al. Correlationof increasedvascularendothelial growthfactorwithneovascularizationandpermeabilityinischemic centralvein occlusion. Arch Ophthalmol 2002;120:164450.

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doi:10.1136/bjo.2008.1384792009;93;457-462; originally published online 25 Nov 2008;Br. J. Ophthalmol.

M Georgopoulos, K Polak, F Prager, C Prnte and U Schmidt-Erfurth

(Avastin)following intravitreal injection of bevacizumabCharacteristics of severe intraocular inflammation

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Characteristics of severe intraocular inflammationfollowing intravitreal injection of bevacizumab(Avastin)

M Georgopoulos, K Polak, F Prager, C Prunte, U Schmidt-Erfurth

Department of Ophthalmology,Medical University of Vienna,Vienna, Austria

Correspondence to:Professor U Schmidt-Erfurth,Department of Ophthalmology,Medical University of, Vienna,Spitalgasse 23, A-1090 Vienna,Austria; [email protected]

Accepted 30 September 2008Published Online First25 November 2008

ABSTRACT

Background/aims: To report a series of severe

intraocular inflammatory events following intravitreal

injections of bevacizumab (Avastin). This procedure is

performed on a rapidly increasing number worldwide, and

rare complications such as intraocular inflammation,

endophthalmitis or intraocular haemorrhage are gaining in

importance in clinical routine.

Methods: This is a single-centre retrospective interven-

tional case series of eight patients with severe intraocular

inflammation after intravitreal injection of bevacizumab at

one referral centre consecutively seen out of approxi-

mately a total of 2500 injections performed in that timeperiod. Patients who developed severe intraocular

inflammation after intravitreal injection were evaluated

clinically, including slit-lamp examination, best-corrected

Snellen visual acuity (VA), slit-lamp photography, optical

coherence tomography and fluorescein angiography prior

to the event and during follow-up.

Results: Patients noticed a painless drop in VA up to

2 days following the injection. All patients had a marked

anterior chamber reaction with increased flare and cells,

but no hypopyon. Typical posterior segment findings

included vitreous cellular infiltrates of pseudogranuloma-

tous aspect. Due to their initial clinical aspect suspicious

of an endophthalmitis, three cases were treated withsystemic antibiotics, but the final diagnosis was uveitis.

Five cases showed a characteristic pseudogranulomatous

vitreous infiltration as seen in vitritis and were treated

only topically.

Conclusions: Characteristic features of an inflammation

induced by bevacizumab injection include an early onset

with painless loss in VA mostly without conjunctival or

ciliary injection. Patients respond to systemic or topical

cortisone treatment with slow recovery but without

permanent damage. Vitreous haemorrhage and infectious

endophthalmitis might be differentiated by time course

and symptoms.

Treatment of neovascular age-related maculardegeneration (AMD) with intravitreal applicationof vascular endothelial growth factor (VEGF)inhibitors is a novel therapeutic option.13 Since

VEGF inhibition is a symptomatic treatment witha transient biological effect, anti-VEGF substanceshave to be injected intravitreally repeatedly and atrelatively short intervals of 4 to 6 weeks. Due tothe high incidence of AMD and exudative retinalvascular diseases, the broad spectrum of othertherapeutic indications and the need for repeated

administrations, enormous numbers of intraocularinjections are being performed worldwide.

Therefore, the safety and tolerability of thetherapy have become an important issue.

Ranibizumab offers an excellent safety profile,and the incidence of side effects as documented inthe clinical trials with monthly injections over2 years was extremely low.4 5 Because ranibizumabwas not approved in the beginning of theantiangiogenetic era, the off-label use of bevacizu-mab (Avastin, Genentech), a full-length antibody,became widely spread based on initial reports on itseffectiveness.

Bevacizumab contains the Fab and Fc portions of

a regular antibody, with a molecular weight of148 kDa and binds to the identical epitope on

VEGF molecules like ranibizumab. Despite obviousdifferences in the bioavailability, affinity and half-life of the drug,6 a similar effect on ocularvasculature should be expected and was demon-strated by multiple interventional case series andsmall clinical studies.7 8 The current clinical experi-ence indicates that bevacizumab may offer atherapeutic benefit similar to ranibizumab, includ-ing antipermeability and antiproliferative effects.However, as with all antiangiogenic compounds,intravitreal injections have to be repeated fre-quently for as long as the disease process is active,leading to high rates of repeat injections.

Eventual complications of this off-label applica-tion present a special medical and legal problems.6

Recently, Fung et alhave published a summary ofreported complications covering more than 7000injections in 12 countries.9 From their results, theyconclude that the treatment appears to be safe. Wehave recently published a study on inflammatoryactivity after intravitreal administration of bevaci-zumab which showed no increased uveiticresponse in 61 consecutive patients.10

This article presents a series of eight consecutivecases of severe non-septic intraocular inflammation

following intravitreal injection of bevacizumab.The characteristic features of this complication anddifferential diagnosis to endophthalmitis are iden-tified in detail.

METHODSThis is a single-centre retrospective interventionalcase series of eight patients with severe intraocularinflammation after intravitreal injection of bevaci-zumab at one referral centre consecutively seen outof approximately a total of 2500 injections appliedin that time peroiod at our retinal service depart-ment. We always discuss the off-label use of

bevacizumab and its potential risks and benefitswith our patients, and they have to sign a

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comprehensive consent form before administration of the drug.Bevacizumab (Avastin 25 mg/ml) is dispensed in a tuberculinesyringe by our pharmacy using an aseptic technique. Patientsare prepared with topical anaesthetic (tetracaine-phenylephrine)and 5% povidone/iodine eye-drops. All intravitreal injections arethen performed in a minor operating room. Under sterileconditions, a topical anaesthetic (oxybuprocain) and povidone/iodine eye-drops are used again before placement of a sterile

eyelid speculum. At the superior or inferior temporal quadrant,1.25 mg (0.05 ml) or 2.5 mg (0.1 ml) of bevacizumab is injectedintravitreally through the pars plana 3.5 mm from the limbususing a 30-gauge needle directed to the centre of the globe. Afterthe injection, intraocular pressure and retinal artery perfusionare checked, and povidone/iodine eye-drops and antibiotic/cortisone ointment (gentamycin/dexamethasone) are applied.Patients are instructed to use topical antibiotics (gentamycin)three times a day for 3 days. They are routinely examined at1 week by an ophthalmologist, and all patients return to ourretinal service department 1 month after each injection.Patients are instructed to return immediately to our departmentin any event of pain, redness of the eye or decreased visualacuity (VA).

The history of those patients who developed severe intrao-cular inflammation after intravitreal injection are evaluated indetail. Main outcome measures include presence of pain,decreased VA, slit-lamp examination of the anterior segmentwith special regard to conjunctival hyperaemia, cornealendothelial precipitates, anterior chamber reaction (flare/cells)and hypopyon, intraocular pressure measurement and dilatedfundus examination with special attention for the presence ofvitreous cells and a posterior pseudogranulomatous reaction.Furthermore, the onset and duration of symptoms as well asrecovery time are recorded. For analysis, all findings aresummarised in tables 1, 2.

CLINICAL PRESENTATION AND SYMPTOMS

Report of case 1A 62-year-old female patient presented with decreased vision inthe left eye over 2 weeks, with an onset 2 days after intravitrealinjection of Avastin (2.5 mg/0.1 ml) due to choroidal neovascu-larisation (CNV).

At the time of presentation, VA of the left eye had dropped tohand movements with hyperaemia of the conjunctival vessels,endothelial precipitates of the cornea and anterior chamberreaction (2+ cells and 2+ flare). The posterior segment flarecould not be examined in detail. The patient was treated withtopical antibiotics and cortisone every hour, and systemicantibiotics for 5 days (see table 1). Six months later, no cells or

flare were present in the anterior chamber or vitreous, and theVA was 0.05 Snellen (20/400).

Report of case 2A 74-year-old male patient presented with increasing pain,conjunctival hyperaemia, epiphora and decreased vision in theleft eye.

Therapy of CNV was switched from photodynamic therapy(PDT) to intravitreal injections of bevacizumab with an initialinjection 12 months earlier. A third injection (2.5 mg/0.1 ml)was performed 2 weeks before.

At the time of presentation, symptoms already persisted formore than 10 days, and VA had decreased from 0.5 Snellen (20/

40) to 0.3 Snellen (20/63). Slit-lamp examination disclosedsevere hyperaemia of the conjunctival vessels, endothelial

precipitates, 3+ cells (frozen water), 2+ flare and fibrin inthe lower portion of the anterior chamber, but no hypopyon(fig 1). The posterior segment showed 1+ flare in the vitreousbody.

Endophthalmitis was diagnosed, an anterior chamber tap wastaken and intravitreal vancomycin (1 mg/0.1 ml) and ceftazi-dime (2.25 mg/0.1 ml) were applied. Gram staining onlyshowed granulocytes, but no micro-organisms. The patient

was treated with topical antibiotics every hour, and systemicantibiotic treatment was performed (see table 1) for 10 days.

VA decreased to 0.05 Snellen (10/200). However, inflammatorysymptoms resolved after adding topical cortisone every hour onday 8. Best-corrected VA finally improved to 0.1 Snellen (20/200) with minimal residual anterior chamber reaction (cells 1+,flare 1+) 2 weeks after treatment initiation. One month later,

VA had increased to 0.6 Snellen (20/32).

Report of case 3An 85-year-old female patient presented with decreased visionin the left eye without pain, 4 days after her fourth intravitrealinjection of bevacizumab.

At the time of presentation, her VA was 0.2 Snellen (20/100).Slit-lamp examination disclosed normal conjunctival appear-ance, 1+ cells and 1+ flare in the anterior chamber. Posteriorsegment showed 2+ cells of pseudogranulomatous appearance,that is large roundish cellular aggregates and 1+ flare in thevitreous body (fig 2). She was admitted with the diagnosis ofpseudogranulomatous iridocyclitis following intravitreal injec-tion of bevacizumab and treated with topical antibiotics andcortisone every hour and systemic treatment with cortisone.During therapy, VA increased to 0.4 Snellen (20/50), andanterior chamber reaction as well as the posterior chamber cellsresolved.

Report of case 4The history of this patient comprised eight intravitrealinjections of bevacizumab (1.25 mg/0.04 ml) during the last15 months due to branch retinal vein occlusion with persistingmacular oedema in the left eye and VA of 0.8 Snellen (20/25)before the event.

One day after her eighth intravitreal injection of bevacizu-mab, the patient presented with decreased vision in her righteye. VA had dropped to hand movements, without pain orconjunctival injection. Slit-lamp examination revealed ananterior chamber reaction with 2+ cells and 1+ flare and 3+vitreous infiltrates with a pseudogranulomatous aspect (fig 3).Due to the clinical appearance vancomycin (1 mg/0.1 ml),ceftazidime (2.25 mg/0.1 ml) and dexamethasone (4 mg/

0.1 ml) were given intravitreally. Systemic antibiotic treatmentand topical cortisone eye-drops were given every hour for7 days. Eight days later, VA had increased to 0.8 Snellen (20/25)with normal anterior segment findings.

Report of case 5This 74-year-old female patient was treated earlier for neovas-cular AMD with submacular haemorrhage four times withbevacizumab. One day after her fourth intravitreal injection ofbevacizumab (2.5 mg/0.1 ml), she noticed a drop in VA from0.1 Snellen (20/200) to 1/40 (20/800). She presented withendothelial precipitations, 1+ flare and 2+ cells of the anteriorchamber and 3+ vitreous infiltrates. After 4 days with hourly

topical cortisone, slit-lamp findings improved, and after1 month VA improved to initial values of 0.1 Snellen (20/200).

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Table1

Patientcharacteristics:diagnosis,

the

rapy,

timecourseandimpactonvisualacuity(VA)(Snellen/decimal)

Case

no

Age

Diagnosis

Culturemicrobiology

Therapy(primary/final)

VA

before

VA

atpresentation

VA

final

Onsetof

symptomsatday

Durationoftherapy:

systemicintravenous/

topical(days)

Recoveryafter

days

Case

1

62

NeovascularAMD

Notdone

SA/SC

0.4

(20/50)

HM

0.05(20/400)

2

5/45

60

Case

2

74

NeovascularAMD

Negative

SA/SC

0.4

(20/50)

0.0

5(10/200)

0.6(20/32)

2

10/45

45

Case

3

85

NeovascularAMD

Notdone

SC+

TC

0.5

(20/40)

0.2

(20/100)

0.3(20/63)

0

0/60

30

Case

4

71

Branchretinalvein

occlusion

Notdone

SA/SC

0.8

(20/25)

HM

0.8(20/25)

1

7/30

15

Case

5

74

NeovascularAMD

Notdone

TC

0.1

(20/200)

1/40(20/800)

0.1(20/200)

1

0/3

4

Case

6

82

NeovascularAMD

Negative

TC

0.0

4(20/500)

1/20(20/400)

0.1(20/200)

1

0/14

30

Case

7

29

Gyrateatrophy

Negative

TC

0.5

(20/40)

CF

0.4(20/50)

1

0/30

30

Case

8

69

Centralretinalvein

occlusion

Negative

TA+

TC

0.6

(20/32)

1/30(20/600)

0.4(20/50)

1

0/30

30

AMD

,age-relatedmaculardegeneration;CF,countingfin

gers;HM,

handmotion;SA,systemicantibiotics:vancomycin261gandceftazidime361gintravenous

ly;SC,systemiccortisone:prednisolone(100mgap

rednisolonbymouth);TA,

topical

antib

iotics:tobramycin(Tobrex)andlomefloxacin(Okazin)eye-dropsortobramycin(Tobrex)andofloxacin

(Floxal)eye-drops;TC,

topicalcortisone:prednisolo

ne(Ultracortenol)eye-drops.

Table2

Characteristicsymptomsandslit-lam

pfindings

Case

no

Pain

Conjunctivalhyperaemia

Cornealendothelialprecipitates

Anteriorchamberreaction(flare/cells)

Hypopyon

IOP

Vitreouscells

PPR

Case

1

No

Yes

Yes

2+/2+

No

15

1+

No

Case

2

Yes

Yes

Yes

2+/3+

No

16

2+

No

Case

3

No

No

No

1+/1+

No

11

2+

Yes

Case

4

No

No

Yes

1+/2+

No

10

3+

Yes

Case

5

No

No

Yes

1+/2+

No

10

3+

Yes

Case

6

No

No

No

1+/2+

No

9

2+

Yes

Case

7

No

No

Yes

1+/2+

No

10

3+

Yes

Case

8

No

No

Yes

1+/3+

No

12

3+

Yes

IOP,

intraocularpressure;PPR,posteriorpseudogranulomatousreaction.

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Report of case 6

An 82-year-old female patient with neovascular AMD presented2 days after her second intravitreal injection of bevacizumab(2.5 mg/0.1 ml) with decreased VA since 1 day from0.04 Snellen (20/500) to 1/20 (20/400). Slit-lamp findingsincluded 1+ flare and 2+ cells of the anterior chamber andvitreous cells 1+ with a pseudogranulomatous appearance.Topical therapy with antibiotic and cortisone eye-drops wasgiven for 2 weeks. One month after the initial presentation, slit-lamp findings were normal, and VA returned to 0.1 (20/200).

Report of case 7

A 29-year-old male patient received his first intravitrealinjection of bevacizumab (2.5 mg/0.1 ml) 1 day before presen-tation because of gyrate atrophy with active cystoid macularoedema. A drop in VA from 0.5 Snellen (20/40) to counting

fingers was noticed. Slit-lamp findings included endothelialprecipitates, 1+ flare and 2+ cells in the anterior chamber, thevitreous cells (2+) mostly in terms of large pseudogranuloma-tous aggregates. Topical therapy with antibiotics and cortisonewas applied for 1 month, and VA returned to 0.4 Snellen (20/50) with normal biomicroscopic findings.

Report of case 8

A 69-year-old male patient with central retinal vein occlusion inhis left eye had an intravitreal injection of triamcinolone 1 yearago, but VA remained at 0.5 Snellen (20/40). Due to persistingcystoid macular oedema, he then received five bevacizumabinjections during the last year, and VA remained stable at

0.6 Snellen (20/32). He noticed a significant drop in VA the dayafter the sixth intravitreal injection of bevacizumab (2.5 mg/0.1 ml) from 0.6 (20/32) to 1/30 (20/600), without pain orredness of the eye. Slit-lamp findings included endothelialprecipitations (fig 4), 1+ flare and 3+ cells of the anteriorchamber. The posterior segment could not be examined indetail. An anterior chamber tap was taken which showed nogrowth of micro-organisms. Topical therapy with antibioticsand cortisone was applied for 1 month and led to completeresolution of the symptoms.

RESULTS

Time course

Patients became symptomatic between several hours (cases 3 to8) to 2 days (case 1 and 2).

Acute symptomsSymptoms consisted of a painless drop in VA (except for case 2).

All patients had marked anterior chamber reaction withincreased flare and cells, but no hypopyon (fig 1).Conjunctival hyperaemia was only found in cases 1 and 2. Sixof the cases presented with corneal endothelial precipitates

(fig 4). All cases also demonstrated vitreous cell infiltration, incases 3 to 8 as large cellular aggregates labelled pseudogranu-lomatous (table 2; figs 2, 3).

DIAGNOSISIn three cases (1, 2, 4) an endophthalmitis was suspectedinitiallyin two of those due to morphology and symptoms (1,2), and in one (4) mainly because of massive drop in VA. In allthree cases the primary diagnosis was revised to uveitis due tothe clinical course (no change after systemic and topicalantibiotics, but fast recovery after cortisone). An anteriorchamber tap was performed in cases 2, 5, 6, 7 and 8, butculture was negative for micro-organisms. In cases 2 and 8,

Gram staining only showed granulocytes. Despite negativeculture, some uncertainty concerning the final diagnosisremains. Cases 3 and 57 had an initial diagnosis of vitritisdue to the pseudogranulomatous aspect of the vitreousinfiltration (figs 2, 3). Case 8 was admitted with anterioruveitis because of reduced visibility of the vitreous appearance.

Response to treatmentIn cases 1, 2 and 4, systemic intravenous antibiotic treatmentwas performed using vancomycin and ceftazidin for 7 to

Figure 1 Slit-lamp photography 2 weeks after intravitreal injection ofbevacizumab: hyperaemia of the conjunctival vessels, endothelialprecipitations and anterior chamber 2+flare and 3+ cells (indicated byarrow), but no hypopyon (case 2).

Figure 2 Slit-lamp photography of intravitreal cells(pseudogranulomatous infiltrates) (case 3).

Figure 3 Slit-lamp photography of the pseudogranulomatous

appearance of the vitreous inflammation with high magnification(case 4).

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10 days with little effect. Case 3 received systemic treatmentwith 100 mg of prednisolone by mouth (Aprednisolon), reducedto 50 mg after 5 days. The other four cases (58) received onlytopical therapy leading to a prolonged resolution of the cellularresponce. Cases 2 and 4 received additional intravitreal

vancomycin (1 mg/0.1 ml) and ceftazidin (2.25 mg/0.1 ml)without resolution. Topical treatment was performed in alleight cases. We started with antibiotic eye-drops (tobramycin(Tobrex), lomefloxacin (Okazin) or ofloxacin (Floxal)) incombination with prednisolone (Ultracortenol) every hour.

RecoveryOnly case 5 (which was mild at initial presentation) recoveredafter 4 days; the others had a recovery time from 2 weeks to2 months.

In all but one case, the massive drop in VA after the injectionrecovered (see table 1).

Differential diagnosisWith respect to the time course, cases 3 to 8 are similar to ourpatients with vitreous haemorrhage occurring in the samepopulation (seven cases, not presented) who usually havesymptoms starting from the first day on. These patients showeda cellular infiltration of the vitreous body with a morehomogenous aspect. In contrast, cases 3 to 7 demonstratedwith a typical pseudogranulomatous aspect with large vitreousinfiltrates indicating vitritis (figs 2, 3).

The majority of cases had an early massive drop in VAwithout any orbital or periorbital pain, which is in contrast toinfectious endophthalmitis. They also recovered immediatelyafter therapy with cortisone. Nevertheless, in cases 1, 2 and 4, apresumed infectious endophthalmitis was the primary diagnosis

and cannot be excluded with certainty.

DISCUSSIONA massive immunological response following intravitreal injec-tion of bevacizumab is a possible event and may occur evenafter preceding uneventful interventions. The reaction presentsprimarily as an intensive inflammation of the posterior segmentassociated with a significant loss of VA. The differentialdiagnosis includes infectious endophthalmitis or vitreoushaemorrhage, which may also occur after intravitreal injections.

Inflammation induced by bevacizumab is characteristically ofan early onset associated with a painless drop in VA mostlywithout conjunctival hyperaemia. Patients present with a

marked anterior chamber reaction, but regularly withouthypopyon. The vitreous condition includes large cellular

aggregates of pseudogranulomatous aspect, but microbiologicalfindings were always negative. Systemic treatment withantibiotics (if performed) shows no benefit, but patientsrespond to systemic or topical cortisone treatment with a slowbut persistent recovery. There was no permanent retinaldamage. Intraocular haemorrhage and infectious endophthalmi-tis might be differentiated by time course and symptoms.

At our department, more than 2500 intravitreal injections

with bevacizumab were performed in 2006 and the first6 months of 2007. Only minor complications like subconjunc-tival haemorrhage and corneal abrasion were noted, which areprobably related to the procedure rather than to the medication.It is important to perform intravitreal injections under sterileconditions using povidone-iodine drops applied several times inadvance and a sterile speculum.1113 The injections are performedat our department by different injectors using the sametechnique. Patients are advised to take antibiotic drops for3 days and in case of symptoms present immediately.

Three cases of severe inflammation leading to hospitaladmission occurred which were treated with systemic anti-biotics due to their initial presentation simulating infectiousendophthalmitis. In a population of more than 2500 individualinjections, this rate represents an incidence of about 0.3% in oursetting. To date we have not observed a single culture positiveendophthalmitis after intravitreal injections of bevacizumab,which might be the consequence of a tight perioperativeregimen regarding the procedure as mentioned above.

In a publication on bevacizumab-related complications,inflammation occurred in 0.14% and started 2 to 7 days afterinjection but lasted no longer than 1 week, whereas oneinfectious endophthalmitis was recorded (0.01%), whichoccurred as late as 5 days after injection.9 A case report ofanterior uveitis after bevacizumab use showed onset ofsymptoms 3 weeks following injection.14

In a recent report of two culture-positive cases of endophthal-

mitis (coag. neg. staphylococci) after bevacizumab injection, theonset of symptoms was documented 2 days after injection, andthe main symptom was reduced VA. The authors state thatclassic signs of endophthalmitis might be lacking in case ofpreceding intravitreal injection of bevacizumab.15

In a study of 53 eyes with a maximum number of fourconsecutive injections, no cases of endophthalmitis occurredduring 3 months. The authors therefore concluded that in theirexperience, bevacizumab is less likely to induce inflammationthan ranibizumab.16 Recently, bevacizumab was used success-fully for CME in uveitis patients without any side effects.17

A retrospective short-term study on bevacizumab including81 eyes identified no cases of uveitis or endophthalmitis, but theauthors state that these adverse events would be identified onlyif they occurred in more than 4% of cases. 7 A large retrospectivestudy on bevacizumab including 266 eyes showed a low rate ofintraocular inflammation with no endophthalmitis after3 months of follow-up, and the authors hypothesise that theproportion of patients developing intraocular inflammation ishigher with other compounds such as pegaptanib and ranibi-zumab.18

Intraocular inflammation has been reported with intravitrealinjection of ranibizumab in a large prospective clinical trial in1.3% of the patients.2 Of the five cases of presumedendophthalmitis, no culture was obtained in one eye. Theremaining four cases were culture-negative, and the authorsstate that it is difficult to distinguish a culture negative

endophthalmitis from sterile uveitis in patients treated withintravitreal antibiotics. From these clinical trials, one may

Figure 4 Slit-lamp photography of corneal endothelial precipitates3 days after intravitreal injection of bevacizumab (case 8).

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deduce that even Fab-fragments are able to induce animmunological response, even considering the low concentra-tion occurring in the systemic circulation. There is thehypothesis that inflammation may occur more readily in eyesof individuals with a more immunoreactive disposition, such assubclinical inflammation or specific HLA subtypes.

In principle, it is more likely that the larger protein load ofbevacizumab with an additional Fc fragment may induce an

immunogenic response. Furthermore, bevacizumab is harvestedfrom cultures of mammalian ovarian cancer cells, that is thecellular production pathway, which includes glycosylation ofthe proteins with a higher immunogenic potential than the non-glycosylated pure proteins produced by a bacterial pathway inranibizumab. Also, bevacizumab is produced for intravenousinfusion and therefore undergoes a less tight purificationprocedure than drugs formulated for intraocular use. It isassumed that bevacizumab solutions contain about 70% of non-humanised material.

Another issue that has to be addressed is the legal problemresulting from complications occurring with off-label therapy.Bevacizumab is not approved by legal authorities for intraocularuse. At present, we already have medications which have beeninvestigated in large controlled trials and therefore are approvedfor intravitreal use. These trials show exact data on possiblecomplications and their incidence. For bevacizumab it wasanticipated that these might be similar. However, analysis ofthe nature of the inflammatory response of ranibizumab offers aslightly different profile than that of bevacizumab.Inflammation after intravitreal injection of ranibizumab occursmainly 0 to 5 days after injection (in our series we had a medianof 1 day, which is comparable). The clinical presentation mayequally present as iritis (only anterior chamber flare/cells,anterior uveitis19), vitritis (only vitreous cells, intermediateuveitis19) or both (anterior chamber and vitreous involved,iridocyclitis). Most importantly, the response affects the

anterior segment with hypopyon as a major symptom (wehad no case with hypopyon, and all our cases were in theiridocyclitis group). Only one case of granulomatous vitritis wasreported after intravitreal ranibizumab (data on file, Novartis).It remains to be determined whether the frequency and natureof the intraocular response seen in patients after intravitrealinjection of bevacizumab or ranibizumab differ.

Postoperative inflammation is a rare, but serious, complica-tion because progression to endophthalmitis might result inirreversible vision loss. Differentiating cases of uveitic intrao-cular inflammation from infectious endophthalmitis is difficult,as shown in our first two cases, because endophthalmitis isfrequently culture-negative. In case 2, the impressive improve-ment following topical corticoid therapy supported the exclu-

sion of infectious endophthalmitis. For the differentiation ofvitreous haemorrhage with anterior segment involvement frominfectious endophthalmitis or uveitis, the clinical course is ofimportance. Intravitreal bleeding is usually seen immediately

after the injection, and VA improves rapidly without furthertherapy. Six out of eight cases showed a typical pseudogranu-lomatous vitreous inflammation, which is in contrast to themore homogenous appearance of a vitreous haemorrhage. Aftertherapy with cortisone, all but one case had a good final VAoutcome.

In conclusion, we reported a series of eight patients whoreceived intravitreal bevacizumab and experienced a drop in VA

at a median of 1 day after injection. A typical severe acuteintraocular inflammatory response with pseudogranuloma-tous appearance of vitreous infiltration which resolvedfollowing systemic or topical cortisone treatment was typicalfor our cases.

Competing interests:None.

REFERENCES1. Heier JS,Antoszyk AN, Pavan PR, et al. Ranibizumab for treatment of neovascular

age-related macular degeneration: a phase I/II multicenter, controlled, multidosestudy. Ophthalmology2006;113:642e14.

2. Rosenfeld PJ,Brown DM, Heier JS, et al. Ranibizumab for neovascular age-relatedmacular degeneration. N Engl J Med2006;355:141931.

3. Adamis AP, Altaweel M, Bressler NM, et al. Changes in retinal neovascularization

after pegaptanib (Macugen) therapy in diabetic individuals.Ophthalmology2006;113:238.

4. Pieramici DJ, Avery RL. Ranibizumab: treatment in patients with neovascular age-related macular degeneration. Expert Opin Biol Ther2006;6:123745.

5. Rosenfeld PJ,Rich RM, Lalwani GA. Ranibizumab: Phase III clinical trial results.Ophthalmol Clin North Am 2006;19:36172.

6. Gillies MC. What we dont know about avastin might hurt us. Arch Ophthalmol2006;124:14789.

7. Avery RL, Pieramici DJ, Rabena MD, et al. Intravitreal bevacizumab (Avastin) forneovascular age-related macular degeneration. Ophthalmology2006;113:36372e5.

8. Arevalo JF, Fromow-Guerra J, Quiroz-Mercado H, et al. Primary intravitrealbevacizumab (Avastin) for diabetic macular edema: results from the Pan-AmericanCollaborative Retina Study Group at 6-month follow-up.Ophthalmology2007;114:74350.

9. Fung AE, Rosenfeld PJ, Reichel E. The International Intravitreal Bevacizumab SafetySurvey: using the internet to assess drug safety worldwide. Br J Ophthalmol2006;90:13449.

10. Kiss C,Michels S, Prager F, et al. Evaluation of anterior chamber inflammatoryactivity in eyes treated with intravitreal bevacizumab.Retina 2006;26:87781.

11. Aiello LP,Brucker AJ, Chang S,et al. Evolving guidelines for intravitreous injections.Retina2004;24(5 Suppl):319S.

12. Ta CN. Minimizing the risk of endophthalmitis following intravitreous injections.Retina2004;24:699705.

13. Jager RD,Aiello LP, Patel SC, et al. Risks of intravitreous injection: a comprehensivereview. Retina 2004;24:67698.

14. Pieramici DJ, Avery RL, Castellarin AA, et al. Case of anterior uveitis afterintravitreal injection of bevacizumab. Retina 2006;26:8412.

15. Aggio FB,Farah ME, de Melo GB, et al. Acute endophthalmitis following intravitrealbevacizumab (Avastin) injection. Eye 2007;21:4089.

16. Rich RM,Rosenfeld PJ, Puliafito CA, et al. Short-term safety and efficacy ofintravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration.

Retina2006;26:495511.17. Cordero Coma M,Sobrin L, Onal S,et al. Intravitreal bevacizumab for treatment of

uveitic macular edema. Ophthalmology2007;114:15749e1.

18. Spaide RF, Laud K, Fine HF, et al. Intravitreal bevacizumab treatment of choroidal

neovascularization secondary to age-related macular degeneration. Retina2006;26:38390.

19. Jabs DA,Nussenblatt RB, Rosenbaum JT. Standardization of uveitis nomenclaturefor reporting clinical data. Results of the First International Workshop. Am J Ophthalmol2005;140:50916.

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doi:10.1136/bjo.2008.138453

2009;93;463-467; originally published online 29 Aug 2008;Br. J. Ophthalmol.J W Kim, V Kathpalia, I J Dunkel, R K Wong, E Riedel and D H Abramson

enucleationOrbital recurrence of retinoblastoma following


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References

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Orbital recurrence of retinoblastoma followingenucleation

J W Kim,1 V Kathpalia,1 I J Dunkel,2 R K Wong,1 E Riedel,3 D H Abramson1

1 Ophthalmic Oncology Service,Memorial Sloan-KetteringCancer Center, New York, USA;2 Department of Pediatrics,Memorial Sloan-KetteringCancer Center, New York, USA;3 Department of Epidemiologyand Biostatistics, MemorialSloan-Kettering Cancer Center,New York, USA

Correspondence to:Dr J W Kim, OphthalmicOncology Service, MemorialSloan-Kettering Cancer Center,1275 York Ave, New York, NY10021, USA;

[email protected]

Presented at the InternationalSociety of Ocular Oncology, 27June 2007, Siena, Italy andAmerican Academy ofOphthalmology Annual Meeting12 November 2007, NewOrleans, LA, USA.

Accepted 6 August 2008Published Online First29 August 2008

ABSTRACT

Background/aims: To determine the incidence, clinical

presentation and histopathological profile of patientsdeveloping orbital recurrence following enucleation for

retinoblastoma.

Methods: A cohort of 1674 consecutive patients

undergoing enucleations between 1914 and 2006 wasretrospectively reviewed to identify cases of orbital

recurrence. A detailed chart review of all identifiedpatients with orbital recurrence following enucleation was

performed. The main outcome measures were histo-

pathological features of the enucleated globe, clinicalpresentation, status of metastatic disease and clinical

outcomes of treatment at last follow-up.

Results: There were 71 cases of orbital recurrenceidentified in the study, for an incidence of 4.2% (71 of1674 cases). The diagnosis of orbital recurrence was

made between 1 and 24 months after enucleation (mean6 months), with 69 of the 71 patients (97%) being

diagnosed within the first 12 months. Over a follow-upperiod of 3208 months (mean 34.8 months), 60 of 71

patients developed metastatic disease (85%), and 53 of

71 patients died from metastatic retinoblastoma (75%).For the subgroup of cases diagnosed as having orbital

recurrences after 1984, 10 of 11 patients (91%) are aliveand well.

Conclusions: All patients undergoing enucleation for

retinoblastoma need to be followed carefully for the first2 years after surgery for the possibility of orbital relapse.The majority of retinoblastoma patients with orbital tumour

recurrence develop systemic metastatic disease, althoughmortalities appear to be improving in the modern era.

Retinoblastoma is the most common primaryintraocular cancer in the paediatric population.Survival rates for retinoblastoma patients varywidely between modernised and developingnations, with figures as high as 9098% in theUnited States and Europe and as low as 24% insome African countries.16 The reported disparitybetween survival rates has been attributed to theadvanced stage of diagnosis in less industrialisednations, often in the form of orbital retinoblas-toma. Whereas orbital disease may be observed inup to 50% of newly diagnosed cases in poornations,5 7 orbital retinoblastoma is not as com-monly encountered in developed countries, withan incidence of 5.09.5% reported from severallarge referral centres.810 Patients with orbitalretinoblastoma are thought to have a poorsystemic prognosis, with mortalities reaching 90100% of biopsy-confirmed cases.1012 Such discoura-ging survival rates are comparable with the high

death figures for retinoblastoma patients reportedby Hirschberg in 1869,13 suggesting that little

progress has been made in managing patients withthe orbital form of the disease.As pointed out by Ellsworth in 1974, orbital

retinoblastoma may be diagnosed when a patientpresents with extraocular disease or as a form oflocal recurrence following enucleation.10 When apatient presents with intraocular retinoblastoma,primary enucleation is thought to offer cure ratesof 9095%.14 15 Orbital tumour recurrence follow-ing enucleation is considered a relatively rarecomplication, although its true incidence has onlybeen estimated.8 16 There have also been efforts todemonstrate an association between certain histo-pathological features of enucleated eyes and the

risk for local and systemic relapse, although aconsensus on these putative risk factors is lack-ing.9 1519 Other than isolated case reports, fewstudies have described the clinical profiles ofpatients who present with an orbital tumourrecurrence after an uncomplicated enucleation.20 21

The aim of our study was to systemically analysethe clinical and histopathological features ofpatients developing orbital relapse following enu-cleation for retinoblastoma. To examine this groupof patients, we reviewed the clinical, radiographicand pathological data of orbital recurrence casesidentified from a large series of retinoblastomapatients undergoing enucleations at our institu-tion.

MATERIALS AND METHODS

We examined the records of enucleated cases fromthe registry of retinoblastoma patients at theMemorial Sloan-Kettering Cancer Center to iden-tify cases of orbital tumour recurrence. Thedatabase is also maintained by the NationalCancer Institute (NCI) and includes all casesenucleated by our service from 1914 to 2006. Allcases with extraocular disease diagnosed at pre-sentation by clinical examination or radiographiccharacteristics were excluded. The enucleationtechnique utilised by our service has been describedpreviously.22 23 Approval for this retrospectivestudy was obtained from the InstitutionalReview Board at the Memorial Sloan-KetteringCancer Center.

Once the cases were identified, both demo-graphic and pathological data were collected froma retrospective chart review. Results of thesystemic metastatic work-up (at the time of orbitalrecurrence diagnosis) were classified as follows: (1)metastatic disease (any evidence of retinoblastomaoutside the orbit), (2) bone disease (evidence ofretinoblastoma involving the bone or bone marrow

and (3) central nervous system (CNS) disease(evidence of retinoblastoma in the intracranial

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cavity or spinal column). For each patient, the predominantsymptom(s) or sign(s) that led to the diagnosis of orbitalrecurrence was recorded in the following categories: (1) localorbital or socket signs or symptoms (ie, proptosis, eyelidswelling, or problems with the prosthesis), (2) orbital or socketmass noted on routine examination by the physician, (3) eyelidecchymosis or bleeding from the socket, (4) non-localisingsymptoms such as lethargic behaviour, fever or other constitu-

tional complaints and (5) contralateral orbit/ocular signs orsymptoms. In bilateral enucleation cases, both surgical dateswere recorded, and the side of orbital recurrence was noted.

RESULTSThere were 71 biopsy-confirmed cases of orbital recurrenceidentified in the study. The overall incidence of orbitalrecurrence following enucleation for retinoblastoma was 4.2%(71 cases/1674 enucleated patients) (table 1). A subgroupanalysis revealed that the incidence of orbital recurrence before1960 was 5.0%, whereas the incidence after 1960 was 4.0%,suggesting a possible decrease in the incidence of orbitalrecurrence in the modern era. However, when the incidence

was calculated for approximate 20-year periods, the rate variedbetween 3.7 and 5.1% (table 1), without any apparent down-ward trend in incidence over time.

The clinical profiles of the orbital recurrence cases arepresented in table 2. The age of retinoblastoma diagnosis forthe 71 cases ranged between 1 and 78 months (mean23.1 months); there were 34 bilateral retinoblastoma cases and37 unilateral retinoblastoma cases. Among the 71 identifiedpatients with orbital recurrences, there were 93 enucleatedglobes (22 bilateral enucleations), and histopathological datawere available for 77 globes (both partial and complete). Whenthe pathological report was absent or there was no specificcomment regarding a risk category (optic nerve invasion,choroidal invasion, sclera invasion), the globe was marked as

data not available for that histopathological feature. A reviewof the histopathological data of the enucleated eyes showed thefollowing: 35 specimens had confirmed evidence of optic nerveinvasion past the lamina cribrosa (negative in 35 globes, datanot available in 23 globes), and seven of these eyes had a positiveoptic nerve margin. Two globes had confirmed evidence oftumour erosion into or through the sclera (negative in 73 globes,data not available in 18 globes), and 32 globes demonstratedchoroidal invasion (negative in 34 globes, data not available in27 globes). There were 11 cases of orbital recurrence (with dataavailable in all three categories) that demonstrated no evidenceof optic nerve invasion, choroidal invasion or scleral invasion.

Table 3 demonstrates the clinical outcomes of the 71retinoblastoma patients with orbital tumour recurrences. Thediagnosis of orbital recurrence was made between 1 and24 months after enucleation (average 6 months), with 69 ofthe 71 patients being diagnosed within the first 12 months. The

patient that had the longest time period between the enuclea-tion and orbital recurrence was case 29; this was a bilateral case,with the ipsilateral side being enucleated 24 months prior to theorbital recurrence and the contralateral side being enucleated3 months before the orbital recurrence. Overall, metastaticwork-up performed at the time of orbital recurrence diagnosisrevealed that 44 of 71 cases had evidence of systemic disease(62%); at the end of the follow-up period, 60 of 71 cases had

developed metastatic disease (85%). The total length of follow-up was determined from the date of diagnosis to the lastexamination in the chart or the date of death due to metastaticdisease; the range of follow-up in this group of patients was 3208 months (average 34.8 months). During the period offollow-up, 61 of the 71 cases died (86%). However, there wereeight cases in this group of 61 patients who survived more than2 years (after orbital recurrence diagnosis), and four of the eightcases were confirmed to have mortality related to secondcancers. Assuming that a survival of.24 months is equivalentto a cure, the adjusted metastatic death rate was determined tobe 53 of 71 cases (75%). For the subgroup of patients diagnosedas having orbital recurrences after 1984, 10 of 11 cases are aliveand well (as of the last follow-up date).

Table 4 displays the clinical presentations of patientsdiagnosed as having orbital recurrences. For the group of 71patients, the most common presentation was a local symptomor sign related to a mass lesion in the orbit, such as eyelidswelling, an ill-fitting prosthesis, visible mass or proptosis (33cases). The second most common category was a diagnosismade on routine examination during a scheduled follow-upappointment; typically an asymptomatic mass was visualised orpalpated in the socket after removal of the prosthesis (23 cases).Other patients were diagnosed during a work-up of non-localising, constitutional symptoms such as lethargy, somno-lence, fever, anorexia or headache, prompting a clinicalexamination of the socket or a neuroimaging study which led

to the diagnosis (seven cases). Other patients presented withbleeding from the socket or eyelid ecchymosis (five cases) (figs 1,2). Finally, three patients presented with proptosis or eyelidswelling involving the contralateral orbit.

DISCUSSIONIn 1974, Ellsworth reported the largest series of patients withorbital retinoblastoma, when he described 110 cases with orbitaldisease identified from the database of patients treated at theEdward S. Harkness Eye Institute in New York.10 In thatlandmark paper, 110 patients were identified from a total seriesof 1160 cases of retinoblastoma, for an overall incidence of 9.5%.Published under the rubric of orbital retinoblastoma,

Ellsworth included patients who presented with obvious orbitaldisease on clinical examination or on radiographic imaging,cases with an extraocular mass encountered at the time ofenucleation, orbital extension diagnosed only on histopathologyand finally patients with orbital relapse following enucleationfor intraocular disease. Because this latter group of patients hastraditionally been categorised with cases presenting withextraocular disease, the exact incidence of orbital recurrencefollowing enucleation has been difficult to estimate. In 1987,Hungerford e t al reported an incidence of 5% for orbitalretinoblastoma in a group of 317 children referred forretinoblastoma, although they acknowledged that some ofthese cases already had extraocular disease at presentation.8

Khelfaoui et al reported a slightly higher incidence of 7.6% in

172 enucleated eyes, although again, some of these cases werereferred for extraocular disease and had evidence of metastasis

Table 1 Incidence of orbital recurrence following enucleation

Time Enucleated patients Recurrences Incidence (%)

19101929 27 1 3.7

19301949 157 8 5.1

19501969 717 32 4.5

19701989 551 19 3.4

19902006 222 11 4.9

Before 1960 462 23 5.0

1960 and after 1212 48 4.0

Totals 1674 71 4.2

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at presentation.9 The analysis of 1674 patients enucleated byour service from 1914 to 2006 showed an orbital relapse rate of4.2%, which may be more accurate than previous reports due tothe large number of patients in our series and the inclusion ofonly biopsy-confirmed cases of orbital recurrence followingenucleation. However, it should be acknowledged that ourstudy may have included cases with subclinical orbital disease atthe time of enucleation, since there were seven cases with a

positive optic nerve margin and two cases with scleral invasion.A subgroup analysis did not reveal a downward trend inincidence over time (for 20-year periods), suggesting that therate of orbital recurrence has remained relatively constant in ourdatabase of patients undergoing enucleations. Interestingly,several groups have published smaller series of enucleatedpatients treated with prophylactic chemotherapy with muchlower rates of orbital recurrence, suggesting that adjuvanttherapy of patients with high-risk histopathological featuresfollowing enucleation may decrease this type of tumourrelapse.15 19 Our retrospective study was not designed to analysethe issue of prophylactic chemotherapy and whether adjuvanttreatment decreases the incidence of orbital relapse, animportant issue which can only be addressed with a prospective,

randomised study.In our group of 71 cases, the timing of the orbital tumour

recurrence following enucleation was always within the first2 years after surgery, with approximately 97% of patientspresenting within the initial 12 months (69 of 71). The shortinterval for the development of this complication was alsodescribed by Ellsworth10, and Hungerford et al found that themean interval from enucleation to orbital recurrence in theirseries was 6.7 months.8 The most common presentation was aclinical complaint such as eyelid swelling or chemosis, suggest-ing that clinicians should not attribute periocular or orbitalsymptoms during the first year after enucleation as a sign of abenign conjunctivitis or preseptal cellulitis. A problem with the

ocular prosthesis was also a frequent mode of presentation inthese patients, and extrusion or displacement of a previouslysatisfactory prosthesis should be considered a suspicious sign forpossible tumour recurrence. In the socket, the characteristic

lesion was a subconjunctival mass with a purplish hue, due tothe prominent vascularity of the tumour mass.24 The vascularitymay also explain the finding of periocular ecchymosis or frankbleeding from the socket in five patients. A significant numberof patients were also diagnosed on routine examinations, andthe practice of removing the prosthesis in asymptomaticpatients during follow-up evaluations seems justified, particu-larly within the first 2 years after enucleation. There were seven

patients with non-localising signs that eventually led to thediagnosis of orbital tumour recurrence, and several patientspresented with a mass lesion in the contralateral orbit,reinforcing the importance of being vigilant for unusualsymptoms in patients with a history of retinoblastoma.

Our study confirms the findings of Ellsworth and Hungerfordet althat retinoblastoma patients with tumour recurrence in theorbit are likely to have other sites of extraocular relapse.8 10 Inour series, 75% of patients with orbital recurrence eventuallydied from systemic metastatic disease. Ellsworth reported anoverall survival rate of only 9.4% for patients with biopsy-confirmed orbital retinoblastoma, although this figure includedpatients who presented initially with extraocular disease.10 InHungerfords series of orbital recurrence cases diagnosed

between 1970 and 1984, only one of 16 patients survived(6%).8 In our series, 91% of patients diagnosed as having anorbital tumour recurrence after 1984 are alive and well. Theimproved survival data for patients with orbital retinoblastomain the last two decades can be attributed to the aggressivesystemic approach implemented by our group in the 1980s.Ellsworth was the first to recognise the value of systemicchemotherapy in improving the survival of patients with orbitalretinoblastoma.10 In Hungerfordet als series of 16 patients withorbital recurrences, the only patient to survive was one of thefour cases that received chemotherapy.8 Our treatment strategyfor extraocular retinoblastoma has evolved into a multimodalapproach for all patients with orbital tumour recurrence.24 25

When a patient is confirmed to have orbital disease followingenucleation, our current protocol is to perform a metastaticevaluation with a brain MRI, abdominal CT scan, lumbarpuncture, bone scan and bone-marrow aspirate and biopsy.

Table 2 Clinical and histopathological data

Total orbitalrecurrencecases

Unilateral/bilateralRB

Age ofretinoblastomadiagnosis (months) Optic-nerve invasion Choroidal invasion Scleral invasion

Patients = 71 Unilateral = 37 112 months = 17 Yes = 35 Yes = 32 Yes = 2

Enucleatedglobes= 93

Bilateral = 34 1324 months = 25 No = 35 No = 34 No = 73

2536 months= 23 Margin+= 7 Data NA =27 Data NA =18

3748 months= 5 Data NA= 23.4 8 = 1

Mean = 23.1

NA, not available.

Table 3 Clinical outcomes of 71 orbital recurrence cases

Enucleation to OR(months)

Metastatic diseaseat presentation Bone dis ease CNS dis ease Outcome Follow-up (months)

03 = 15 Yes = 44 Yes = 28 Yes = 12 Deceased = 61 012 = 28

46 = 31 No = 22 No = 32 No = 48 Alive = 10 1324 = 26

712 = 23 Data NA = 5 Data NA = 11 Data NA = 11 2536 = 1

3748=1

.1 2 = 2 .49= 15

Mean = 6 Mean = 34.8NA, data not available; OR, orbital recurrence.

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Because of the high risk of metastatic disease, patients found tohave only local disease in the orbit receive systemic multiagentchemotherapy as well as orbital radiotherapy. Patients withdisseminated disease such as bone-marrow involvement receivehigh-dose multiagent chemotherapy with stem-cell rescue,while those with CNS disease may also receive intrathecalradioimmunotherapy.

Several histopathological features of enucleated eyes havebeen recognised as risk factors for extraocular relapse inretinoblastoma patients. There appears to be universal agree-ment that optic-nerve invasion with tumour involvement of the

resection margin and extrascleral spread are highly predictivemarkers for extraocular relapse.26 27 The prognostic value ofother extraretinal features, such as choroidal invasion andretrolaminar optic-nerve invasion (with a negative margin), hasbeen debated, although there is general agreement that thesefeatures increase the risk for systemic disease.9 18 In our series oforbital recurrence cases, 35 of the 70 globes (with data available)demonstrated evidence of optic nerve invasion, and 32 of 66globes (with data available) had choroidal invasion, indicating ahigher risk of metastatic disease in this cohort of patients thanother published series of retinoblastoma patients undergoingenucleations.15 16 26 Interestingly, only seven enucleated globeswere identified as having a positive optic nerve margin, and two

globes had evidence of scleral invasion in this group of 71 orbitalrecurrence cases. Additionally, there were 11 cases without anyhistopathological risk factors (ie, choroidal invasion, scleralinvasion or optic nerve invasion). One explanation is thatmicroscopic invasion through the sclera or optic nerve bytumour cells may have been missed when the globe wasexamined histopathologically. However, the finding of threecases of contralateral orbital recurrence in our series suggeststhat non-contiguous tumour spread may be an under-recog-nised mechanism for orbital relapse in some of these cases.Haematogenous metastasis to the ipsilateral or contralateral

orbit has been reported as a mechanism for orbital recurrence,particularly to the orbital bones28 29

Patients developing orbital tumour recurrence followingenucleation for advanced intraocular disease represent a uniquesubset of patients, and they should be distinguished frompatients who present with extraocular retinoblastoma. Orbitalrecurrence following enucleation represents a type of tumourrelapse that occurs from either local or non-contiguous spread tothe orbit, often in the setting of systemic metastatic disease.The incidence of orbital tumour recurrence in our study of 1674patients undergoing enucleations was 4.2%, and patients andtheir families should be warned about the possibility of tumourrelapse during the preoperative discussion. Based on these data,histopathological risk factors are not always reliable in predict-ing which patients will ultimately develop orbital tumourrecurrence. Therefore, all patients undergoing enucleations forintraocular retinoblastoma require careful follow-up during thefirst 2 years after surgery, and clinicians should be aware thatpatients may be asymptomatic or present with subtle, non-localising or even contralateral symptoms. The majority ofpatients diagnosed as having orbital recurrence followingenucleation eventually develop metastatic disease, emphasisingthe need for a careful systemic work-up of these cases once theyhave been identified. With intensive systemic treatment, theprognosis for retinoblastoma patients with orbital tumour

recurrence appears to be improving in the modern era.

Competing interests:None.

Ethics approval: Ethics approval was provided by the Institutional Review Board atthe Memorial Sloan-Kettering Cancer Center.

Patient consent: Obtained.

REFERENCES1. de Sutter E,Havers W, Hopping W, et al. The prognosis of retinoblastoma in terms of

survival. A computer assisted study. Part II.Ophthalmic Paediatr Genet1987;8:858.

2. Ajaiyeoba IA,Akang EE, Campbell OB, et al. Retinoblastomas in Ibadan: treatmentand prognosis. West Afr J Med1993;12:2237.

3. Abramson DH, Niksarli K, Ellsworth RM, et al. Changing trends in the managementof retinoblastoma: 19511965 vs 19661980. J Pediatr Ophthalmol Strabismus1994;31:327.

4. Tamboli A, Podgor MJ, Horm JW. The incidence of retinoblastoma in the UnitedStates: 1974 through 1985. Arch Ophthalmol1990;108:12832.

Table 4 Clinical presentation of orbital recurrence cases

No of patients (%) Clinical presentation

33 (46) Local orbital symptoms/problems with prosthesis

23 (32) Routine examination

7 (10) Non-local ising/consti tutional symptoms

5 (7) Eyelid ecchy mos is /bleeding from socket

3 (4) Contralateral orbit/socket

71 total

Figure 1 Clinical photograph showing chemosis and eyelid ecchymosisin a patient with an orbital tumour recurrence following enucleation.

Figure 2 Coronal magnetic resonance imaging study (T1 withgadolinium) of the same patient in fig 1 demonstrating a subperiostealtumour recurrence to the marrow space of the orbital floor.

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5. Bowman RJ,Mafwiri M, Luthert P, et al. Outcome of retinoblastoma in east Africa.Pediatr Blood Cancer2008;50:1602.

6. Gatta G, Capocaccia R, Stiller C,et al. Childhood cancer survival trends in Europe: aEUROCARE Working Group study.J Clin Oncol2005;23:374251.

7. Abramson DH,McCormick B.Neoplasms of the eye. 4th edn. Baltimore: Williams &Wilkins, 1997.

8. Hungerford J, Kingston J, Plowman N. Orbital recurrence of retinoblastoma.Ophthalmic Paediatr Genet1987;8:638.

9. Khelfaoui F, Validire P, Auperin A, et al. Histopathologic risk factors inretinoblastoma: a retrospective study of 172 patients treated in a single institution.Cancer1996;77:120613.

10. Ellsworth RM. Orbital retinoblastoma. Trans Am Ophthalmol Soc 1974;72:7988.11. Hopping W, Waubke TN, Sack H. Orbital involvement in retinoblastoma. Mod Probl

Ophthalmol1975;14:3827.12. Rootman J, Ellsworth RM, Hofbauer J, et al. Orbital extension of retinoblastoma: a

clinicopathological study. Can J Ophthalmol1978;13:7280.13. Hirschberg J. Anatomisch untersuchungen. Ueber glioma retinae. Arch Ophthalmol

1868;14:30.14. Howarth C,Meyer D, Hustu HO,et al. Stage-related combined modality treatment of

retinoblastoma. Results of a prospective study. Cancer1980;45:8518.15. Honavar SG,Singh AD, Shields CL, et al. Postenucleation adjuvant therapy in high-

risk retinoblastoma. Arch Ophthalmol2002;120:92331.16. Chantada GL,Dunkel IJ, de Davila MT,et al. Retinoblastoma patients with high risk

ocular pathological features: who needs adjuvant therapy? Br J Ophthalmol2004;88:106973.

17. Kopelman JE,McLean IW, Rosenberg SH. Multivariate analysis of risk factors formetastasis in retinoblastoma treated by enucleation.Ophthalmology1987;94:3717.

18. Stannard C, Lipper S, Sealy R, et al. Retinoblastoma: correlation of invasion of theoptic nerve and choroid with prognosis and metastases. Br J Ophthalmol1979;63:56070.

19. Uusitalo MS, Van Quill KR, Scott IU, et al. Evaluation of chemoprophylaxis inpatients with unilateral retinoblastoma with high-risk features on histopathologicexamination. Arch Ophthalmol2001;119:418.

20. Karcioglu ZA, Mullaney PB, Millar LC. Extrusion of porous polyethyleneorbital implant in recurrent retinoblastoma. Ophthal Plast Reconstr Surg1998;14:3744.

21. Stevenson KE,Hungerford J, Garner A. Local extraocular extensionof retinoblastoma following intraocular surgery. Br J Ophthalmol

1989;73:73942.22. Abramson DH, Ellsworth RM. The surgical management of retinoblastoma.

Ophthalmic Surg 1980;11:5968.23. Abramson DH, Schefler AC. Update on retinoblastoma.Retina 2004;24:82848.24. Grabowski EF, Abramson DH. Intraocular and extraocular retinoblastoma. Hematol

Oncol Clin North Am 1987;1:72135.25. Dunkel IJ, Aledo A, Kernan NA, et al. Successful treatment of metastatic

retinoblastoma. Cancer2000;89:211721.26. Magramm I, Abramson DH, Ellsworth RM. Optic nerve involvement in

retinoblastoma. Ophthalmology1989;96:21722.27. Shields CL, Shields JA, Baez KA, et al. Choroidal invasion of retinoblastoma:

metastatic potential and clinical risk factors.Br J Ophthalmol1993;77:5448.28. Mohan K,Gupta A, Saini JS, et al. Retinoblastoma metastatic to the contralateral

orbit. Br J Ophthalmol1990;74:31112.29. MacKay CJ, Abramson DH, Ellsworth RM. Metastatic patterns of retinoblastoma.

Arch Ophthalmol1984;102:3916.

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doi:10.1136/bjo.2008.1413662009;93;468-473; originally published online 15 Dec 2008;Br. J. Ophthalmol.

Pearce, M C Briggs, H Heimann and S P HardingS Murjaneh, M Garca-Fiana, S Mahmood, P M Lenfestey, S A Taylor, I A

neovascular age-related macular degenerationverteporfin photodynamic therapy in patients witheffectiveness in routine clinical practice ofObservational prospective study of the


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Observational prospective study of the effectivenessin routine clinical practice of verteporfinphotodynamic therapy in patients with neovascularage-related macular degeneration

S Murjaneh,1 M Garc a-Finana,2 S Mahmood,1 P M Lenfestey,1 S A Taylor,1 I A Pearce,1

M C Briggs,1 H Heimann,1 S P Harding1

1 St Pauls Eye Unit, RoyalLiverpool University Hospital,Liverpool, UK; 2 Centre forMedical Statistics and HealthEvaluation, University ofLiverpool, Liverpool, UK

Correspondence to:Professor S P Harding,Consultant Ophthalmic Surgeon,St Pauls Eye Unit, Royal

Liverpool University Hospital,Prescot Street, Liverpool L7 8XP,UK; [email protected]

Accepted 28 August 2008Published Online First15 December 2008

ABSTRACT

Aims: To investigate effectiveness in routine clinicalpractice of verteporfin photodynamic therapy (PDT) forneovascular age-related macular degeneration (nAMD).

Patients and methods: Patients commencing PDT for

nAMD in a single UK centre entered a prospectiveobservational 7-year study and were followed for 2 years.Best-corrected visual acuity (BCVA) and contrast sensi-

tivity (CS) were measured at each visit by accreditedtechnicians after full protocol refraction on standardisedcharts. Reasons for failure to complete the course oftherapy were documented.

Results:1008 patients entered the study between 1999and 2006. 81% and 52% completed 12 and 24 monthsfollow-up respectively (excluding administrative censor-ing). Results at 12 and 24 months respectively were:

maintenance of BCVA 62%, 63%; drop in mean BCVA(letters) 10.1, 9.4; numbers of treatments 2.9, 3.5. Themean CS remained stable. No correlation of change inBCVA outcome between first and second treated eyes in

82 bilateral cases was detected. Loss to follow-up wassignificantly associated with age, CS and distance from

the treating centre.Conclusions:PDT delivered in clinical practice is at least

as effective as that reported in randomised clinical trialsand uses fewer treatments.

Subfoveal choroidal neovascularisation (CNV)causing exudative age-related macular degenera-tion (AMD) is the leading cause of severe visualimpairment in the developed world in patients over50 years of age.13 Verteporfin photodynamic ther-apy (PDT) has been shown to be effective inrandomised controlled clinical trials (RCTs) atreducing the likelihood of further visual loss whenCNV is characterised on fluorescein angiography asclassic/no occult or predominantly classic.4 5

Recent studies have demonstrated the efficacy ofboth pegaptanib and ranibizumab in the treatmentof AMD with 70% and 92% maintenance of visionrespectively.68

The evidence of effectiveness of PDT in routineclinical practice is limited. When new therapies areintroduced into clinical practice this evidence isessential for clinicians and funding bodies to allowthe measurement of the generalisability of resultsfrom RCTs in which patients are carefully selected.

In this paper, we present 7 years of clinical

experience of PDT for AMD in a regional medicalretina referral centre. We analysed changes in

visual function over a 2-year follow-up periodand report the outcome of a smaller number ofpatients who were followed for a longer period oftime. We identified a subgroup of patients whoreceived bilateral treatment and investigatedwhether the change in visual acuity of the secondeye treated is associated with treatment outcomeof the first eye.

PATIENTS AND METHODSThe study was conducted at St Pauls Eye Unit,Royal Liverpool University Hospital. Patients withsuspected treatable CNV were referred fromophthalmologists throughout the UK and Eire.

The baseline screening visit comprised a fullassessment similar to Treatment for Age-relatedMacular Degeneration with PhotodynamicTherapy (TAP) published procedures.4 Patientsdeemed eligible for treatment were consented fordata collection and analysis, and recruited into alongitudinal prospective observational study. Theywere followed 3-monthly for 2 years, reduced to 6-

monthly in the second year if the lesion wasassessed to be inactive.

BCVA was measured at each visit and CS atalternate visits using full refraction protocol andstandardised illumination by externally accreditedoptometrists. BCVA and CS were recorded asletters read at 1 m on an Early TreatmentDiabetic Retinopathy Study (ETDRS) chart andPelliRobson chart respectively.

Inclusion criteria at baseline were extendedbeyond those used in the TAP study followingexpert workshops in Liverpool to include BCVA>30 ETDRS letters, CNV within 200 mm of the

foveal centre and lesion size(

7000m

m. Patientswith retinal angiomatous proliferation (RAP) andpolypoidal choroidal vasculopathy (PCV) wereincluded. Eyes outside these criteria were treatedonly in exceptional circumstances.

At 24 months, patients who had inactive lesionshad the option to be discharged or referred back totheir local unit; many who lived locally elected tocontinue further follow-up within this study.Follow-up was also continued in those patientswho had active lesions, who developed recurrencesor developed AMD requiring treatment in theother eye.

Treatment was

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