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

increase of the dose to 2.5 mg bevacizumab. 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 administration 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
blockade may be necessary 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, but
functional effects were not statistically significant. Therefore,
Br J Ophthalmol 2009;93:452456. doi:10.1136/bjo.2008.141085

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 spontaneous 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 patients with CMO secondary to RVO, it showed promising
results after 1 year of follow-up. The main drawback of this
new treatment modality seems to be the 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 CMO secondary to RVO according to their ischaemic
status and intraocular VEGF levels.
455

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Clinical science
Acknowledgements: The authors thank M Amschl, C Hirn and G Stock for
performing fluorescein angiograms.
Competing interests: None declared.

11.
12.

Ethics approval: Obtained


Patient consent: Obtained

13.

REFERENCES

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Hayreh SS, Zimmerman B, McCarthy MJ, et al. Systemic diseases associated with
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Blondel J, Glacet-Bernard A, Bayani N, et al. Retinal vein occlussion and
hyperhomocysteinemia. J Fr Ophthalmol 2003;26:24953.
Rath EZ, Frank RN, Shin DH, et al. Risk factors for retinal vein occlusion. A case
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Koizumi H, Ferrara DC, Brue` C, et al. Central vein occlusion casecontrol study.
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Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid
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Branch Vein Occlusion Study Group. Argon laser photocoagulation for macular
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Occlusion Study Group M. Ophthalmology 1995;102:142533.
Avitabile T, Longo A, Reibaldi A. Intravitreal triamcinolone compared with macular
laser grid photocoagulation for the treatment of cystoid macular edema.
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Karacorlu M, Karacorlu SA, Ozdemir H, et al. Intravitreal triamcinolone acetonide for
treatment of serous macular detachment in central vein occlusion. Retina
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Gregori NZ, Rosenfeld PJ, Puliafito CA, et al. One-year safety and efficacy of
intravitreal triamcinolone acetonide for the management of macular edema secondary
to central vein occlusion. Retina 2006;26:88995.
Rosenfeld PJ, Fung AE, Puliafito CA. Optical coherence tomography findings after an
intravitreal injection of bevacizumab (avastin) for macular edema from central vein
occlusion. Ophthalmic Surg Lasers Imaging 2005;36:3369.
Iturralde D, Spaide RF, Meyerle CB, et al. Intravitreal bevacizumab (Avastin)
treatment of macular edema in central retinal vein occlusion: a short-term study.
Retina 2006;26:27984.
Hsu J, Kaiser RS, Sivalingam A, et al. Intravitreal bevacizumab (avastin) in central
vein occlusion. Retina 2007;27:10139.
Rabena MD, Pieramici DJ, Castellarin AA, et al. Intravitreal bevacizumab (Avastin) in
the treatment of macular edema secondary to branch retinal vein occlusion. Retina
2007;27:41925.
Kriechbaum K, Michels S, Prager F, et al. Intravitreal avastin for macular oedema
secondary to retinal vein occlusiona prospective study. Br J Ophthalmol
2008;92:51822.
Fung AE, Rosenfeld PJ, Reichel E. The International Intravitreal Bevacizumab Safety
Survey: using the internet to assess drug safety worldwide. Br J Ophthalmol
2006;90:13449.
Diabetic Retinopathy Clinical Research Network, Scott IU, Edwards AR, et al. A
phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular
edema. Ophthalmology 2007;114:18607.
Matsumoto Y, Freund KB, Peiretti E, et al. Rebound macular edema following
bevacizumab (Avastin) therapy for retinal venous oclusive disease. Retina
2007;27:42631.
Noma H, Funatsu H, Yamasaki M, et al. Aqueous humour levels of cytokines are
correlated to vitreous levels and severity of macular oedema in branch retinal vein
occlusion. Eye 2008;22:428.
Noma H, Minamoto A, Funatsu H, et al. Intravitreal levels of vascular endothelial
growth factor and interleukin-6 are correlated with macular edema in branch retinal
vein occlusion. Graefes Arch Exp Ophthalmol 2006;244:30915.
Boyd SR, Zachary I, Chakravarthy U, et al. Correlation of increased vascular
endothelial growth factor with neovascularization and permeability in ischemic central
vein occlusion. Arch Ophthalmol 2002;120:164450.

Br J Ophthalmol 2009;93:452456. doi:10.1136/bjo.2008.141085

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Characteristics of severe intraocular inflammation


following intravitreal injection of bevacizumab
(Avastin)
M Georgopoulos, K Polak, F Prager, C Prnte and U Schmidt-Erfurth
Br. J. Ophthalmol. 2009;93;457-462; originally published online 25 Nov 2008;
doi:10.1136/bjo.2008.138479

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Characteristics of severe intraocular inflammation


following 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; ursula.schmidterfurth@meduniwien.ac.at
Accepted 30 September 2008
Published Online First
25 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 interventional case series of eight patients with severe intraocular
inflammation after intravitreal injection of bevacizumab at
one referral centre consecutively seen out of approximately a total of 2500 injections performed in that time
period. 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 pseudogranulomatous aspect. Due to their initial clinical aspect suspicious
of an endophthalmitis, three cases were treated with
systemic 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 macular


degeneration (AMD) with intravitreal application
of vascular endothelial growth factor (VEGF)
inhibitors is a novel therapeutic option.13 Since
VEGF inhibition is a symptomatic treatment with
a transient biological effect, anti-VEGF substances
have to be injected intravitreally repeatedly and at
relatively short intervals of 4 to 6 weeks. Due to
the high incidence of AMD and exudative retinal
vascular diseases, the broad spectrum of other
therapeutic indications and the need for repeated
administrations, enormous numbers of intraocular
injections are being performed worldwide.
Br J Ophthalmol 2009;93:457462. doi:10.1136/bjo.2008.138479

Therefore, the safety and tolerability of the


therapy have become an important issue.
Ranibizumab offers an excellent safety profile,
and the incidence of side effects as documented in
the clinical trials with monthly injections over
2 years was extremely low.4 5 Because ranibizumab
was not approved in the beginning of the
antiangiogenetic era, the off-label use of bevacizumab (Avastin, Genentech), a full-length antibody,
became widely spread based on initial reports on its
effectiveness.
Bevacizumab contains the Fab and Fc portions of
a regular antibody, with a molecular weight of
148 kDa and binds to the identical epitope on
VEGF molecules like ranibizumab. Despite obvious
differences in the bioavailability, affinity and halflife of the drug,6 a similar effect on ocular
vasculature should be expected and was demonstrated by multiple interventional case series and
small clinical studies.7 8 The current clinical experience indicates that bevacizumab may offer a
therapeutic benefit similar to ranibizumab, including antipermeability and antiproliferative effects.
However, as with all antiangiogenic compounds,
intravitreal injections have to be repeated frequently for as long as the disease process is active,
leading to high rates of repeat injections.
Eventual complications of this off-label application present a special medical and legal problems.6
Recently, Fung et al have published a summary of
reported complications covering more than 7000
injections in 12 countries.9 From their results, they
conclude that the treatment appears to be safe. We
have recently published a study on inflammatory
activity after intravitreal administration of bevacizumab which showed no increased uveitic
response in 61 consecutive patients.10
This article presents a series of eight consecutive
cases of severe non-septic intraocular inflammation
following intravitreal injection of bevacizumab.
The characteristic features of this complication and
differential diagnosis to endophthalmitis are identified in detail.

METHODS
This is a single-centre retrospective interventional
case series of eight patients with severe intraocular
inflammation after intravitreal injection of bevacizumab at one referral centre consecutively seen out
of approximately a total of 2500 injections applied
in that time peroiod at our retinal service department. We always discuss the off-label use of
bevacizumab and its potential risks and benefits
with our patients, and they have to sign a
457

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Clinical science
comprehensive consent form before administration of the drug.
Bevacizumab (Avastin 25 mg/ml) is dispensed in a tuberculine
syringe by our pharmacy using an aseptic technique. Patients
are prepared with topical anaesthetic (tetracaine-phenylephrine)
and 5% povidone/iodine eye-drops. All intravitreal injections are
then performed in a minor operating room. Under sterile
conditions, 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 injected
intravitreally through the pars plana 3.5 mm from the limbus
using a 30-gauge needle directed to the centre of the globe. After
the injection, intraocular pressure and retinal artery perfusion
are 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 at
1 week by an ophthalmologist, and all patients return to our
retinal service department 1 month after each injection.
Patients are instructed to return immediately to our department
in any event of pain, redness of the eye or decreased visual
acuity (VA).
The history of those patients who developed severe intraocular inflammation after intravitreal injection are evaluated in
detail. Main outcome measures include presence of pain,
decreased VA, slit-lamp examination of the anterior segment
with special regard to conjunctival hyperaemia, corneal
endothelial precipitates, anterior chamber reaction (flare/cells)
and hypopyon, intraocular pressure measurement and dilated
fundus examination with special attention for the presence of
vitreous cells and a posterior pseudogranulomatous reaction.
Furthermore, the onset and duration of symptoms as well as
recovery time are recorded. For analysis, all findings are
summarised in tables 1, 2.

CLINICAL PRESENTATION AND SYMPTOMS


Report of case 1
A 62-year-old female patient presented with decreased vision in
the left eye over 2 weeks, with an onset 2 days after intravitreal
injection of Avastin (2.5 mg/0.1 ml) due to choroidal neovascularisation (CNV).
At the time of presentation, VA of the left eye had dropped to
hand movements with hyperaemia of the conjunctival vessels,
endothelial precipitates of the cornea and anterior chamber
reaction (2+ cells and 2+ flare). The posterior segment flare
could not be examined in detail. The patient was treated with
topical antibiotics and cortisone every hour, and systemic
antibiotics for 5 days (see table 1). Six months later, no cells or
flare were present in the anterior chamber or vitreous, and the
VA was 0.05 Snellen (20/400).

Report of case 2
A 74-year-old male patient presented with increasing pain,
conjunctival hyperaemia, epiphora and decreased vision in the
left eye.
Therapy of CNV was switched from photodynamic therapy
(PDT) to intravitreal injections of bevacizumab with an initial
injection 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 for
more than 10 days, and VA had decreased from 0.5 Snellen (20/
40) to 0.3 Snellen (20/63). Slit-lamp examination disclosed
severe hyperaemia of the conjunctival vessels, endothelial
458

precipitates, 3+ cells (frozen water), 2+ flare and fibrin in


the lower portion of the anterior chamber, but no hypopyon
(fig 1). The posterior segment showed 1+ flare in the vitreous
body.
Endophthalmitis was diagnosed, an anterior chamber tap was
taken and intravitreal vancomycin (1 mg/0.1 ml) and ceftazidime (2.25 mg/0.1 ml) were applied. Gram staining only
showed granulocytes, but no micro-organisms. The patient
was treated with topical antibiotics every hour, and systemic
antibiotic treatment was performed (see table 1) for 10 days.
VA decreased to 0.05 Snellen (10/200). However, inflammatory
symptoms resolved after adding topical cortisone every hour on
day 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 3
An 85-year-old female patient presented with decreased vision
in the left eye without pain, 4 days after her fourth intravitreal
injection of bevacizumab.
At the time of presentation, her VA was 0.2 Snellen (20/100).
Slit-lamp examination disclosed normal conjunctival appearance, 1+ cells and 1+ flare in the anterior chamber. Posterior
segment showed 2+ cells of pseudogranulomatous appearance,
that is large roundish cellular aggregates and 1+ flare in the
vitreous body (fig 2). She was admitted with the diagnosis of
pseudogranulomatous iridocyclitis following intravitreal injection of bevacizumab and treated with topical antibiotics and
cortisone every hour and systemic treatment with cortisone.
During therapy, VA increased to 0.4 Snellen (20/50), and
anterior chamber reaction as well as the posterior chamber cells
resolved.

Report of case 4
The history of this patient comprised eight intravitreal
injections of bevacizumab (1.25 mg/0.04 ml) during the last
15 months due to branch retinal vein occlusion with persisting
macular oedema in the left eye and VA of 0.8 Snellen (20/25)
before the event.
One day after her eighth intravitreal injection of bevacizumab, the patient presented with decreased vision in her right
eye. VA had dropped to hand movements, without pain or
conjunctival injection. Slit-lamp examination revealed an
anterior 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 treatment
and topical cortisone eye-drops were given every hour for
7 days. Eight days later, VA had increased to 0.8 Snellen (20/25)
with normal anterior segment findings.

Report of case 5
This 74-year-old female patient was treated earlier for neovascular AMD with submacular haemorrhage four times with
bevacizumab. One day after her fourth intravitreal injection of
bevacizumab (2.5 mg/0.1 ml), she noticed a drop in VA from
0.1 Snellen (20/200) to 1/40 (20/800). She presented with
endothelial precipitations, 1+ flare and 2+ cells of the anterior
chamber and 3+ vitreous infiltrates. After 4 days with hourly
topical cortisone, slit-lamp findings improved, and after
1 month VA improved to initial values of 0.1 Snellen (20/200).
Br J Ophthalmol 2009;93:457462. doi:10.1136/bjo.2008.138479

62
74
85
71

1
2
3
4

5
6
7
8

Case
Case
Case
Case

Case
Case
Case
Case

Neovascular AMD
Neovascular AMD
Neovascular AMD
Branch retinal vein
occlusion
Neovascular AMD
Neovascular AMD
Gyrate atrophy
Central retinal vein
occlusion

Diagnosis

Not done
Negative
Negative
Negative

Not done
Negative
Not done
Not done

Culture microbiology

TC
TC
TC
TA + TC

SA/SC
SA/SC
SC + TC
SA/SC

Therapy (primary/final)
(20/50)
(20/50)
(20/40)
(20/25)

0.1 (20/200)
0.04 (20/500)
0.5 (20/40)
0.6 (20/32)

0.4
0.4
0.5
0.8

VA before

1/40 (20/800)
1/20 (20/400)
CF
1/30 (20/600)

HM
0.05 (10/200)
0.2 (20/100)
HM

VA at presentation

0.1
0.1
0.4
0.4

(20/200)
(20/200)
(20/50)
(20/50)

0.05 (20/400)
0.6 (20/32)
0.3 (20/63)
0.8 (20/25)

VA final

1
1
1
1

2
2
0
1
0/3
0/14
0/30
0/30

5/45
10/45
0/60
7/30

Duration of therapy:
systemic intravenous/
Onset of
symptoms at day topical (days)

4
30
30
30

60
45
30
15

Recovery after
days

Br J Ophthalmol 2009;93:457462. doi:10.1136/bjo.2008.138479

No
Yes
No
No
No
No
No
No

Case
Case
Case
Case
Case
Case
Case
Case

Yes
Yes
No
No
No
No
No
No

Conjunctival hyperaemia

IOP, intraocular pressure; PPR, posterior pseudogranulomatous reaction.

1
2
3
4
5
6
7
8

Pain

Characteristic symptoms and slit-lamp findings

Case no

Table 2
Yes
Yes
No
Yes
Yes
No
Yes
Yes

Corneal endothelial precipitates


2+/2+
2+/3+
1+/1+
1+/2+
1+/2+
1+/2+
1+/2+
1+/3+

Anterior chamber reaction (flare/cells)

No
No
No
No
No
No
No
No

Hypopyon

15
16
11
10
10
9
10
12

IOP

1+
2+
2+
3+
3+
2+
3+
3+

Vitreous cells

No
No
Yes
Yes
Yes
Yes
Yes
Yes

PPR

AMD, age-related macular degeneration; CF, counting fingers; HM, hand motion; SA, systemic antibiotics: vancomycin 261 g and ceftazidime 361 g intravenously; SC, systemic cortisone: prednisolone (100 mg aprednisolon by mouth); TA, topical
antibiotics: tobramycin (Tobrex) and lomefloxacin (Okazin) eye-drops or tobramycin (Tobrex) and ofloxacin (Floxal) eye-drops; TC, topical cortisone: prednisolone (Ultracortenol) eye-drops.

74
82
29
69

Age

Patient characteristics: diagnosis, therapy, time course and impact on visual acuity (VA) (Snellen/decimal)

Case no

Table 1

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Figure 1 Slit-lamp photography 2 weeks after intravitreal injection of


bevacizumab: hyperaemia of the conjunctival vessels, endothelial
precipitations and anterior chamber 2+ flare and 3+ cells (indicated by
arrow), but no hypopyon (case 2).

Report of case 6
An 82-year-old female patient with neovascular AMD presented
2 days after her second intravitreal injection of bevacizumab
(2.5 mg/0.1 ml) with decreased VA since 1 day from
0.04 Snellen (20/500) to 1/20 (20/400). Slit-lamp findings
included 1+ flare and 2+ cells of the anterior chamber and
vitreous cells 1+ with a pseudogranulomatous appearance.
Topical therapy with antibiotic and cortisone eye-drops was
given for 2 weeks. One month after the initial presentation, slitlamp findings were normal, and VA returned to 0.1 (20/200).

Figure 2 Slit-lamp photography of intravitreal cells


(pseudogranulomatous infiltrates) (case 3).

Acute symptoms
Symptoms consisted of a painless drop in VA (except for case 2).
All patients had marked anterior chamber reaction with
increased flare and cells, but no hypopyon (fig 1).
Conjunctival hyperaemia was only found in cases 1 and 2. Six
of the cases presented with corneal endothelial precipitates
(fig 4). All cases also demonstrated vitreous cell infiltration, in
cases 3 to 8 as large cellular aggregates labelled pseudogranulomatous (table 2; figs 2, 3).

DIAGNOSIS

A 29-year-old male patient received his first intravitreal


injection of bevacizumab (2.5 mg/0.1 ml) 1 day before presentation because of gyrate atrophy with active cystoid macular
oedema. A drop in VA from 0.5 Snellen (20/40) to counting
fingers was noticed. Slit-lamp findings included endothelial
precipitates, 1+ flare and 2+ cells in the anterior chamber, the
vitreous cells (2+) mostly in terms of large pseudogranulomatous aggregates. Topical therapy with antibiotics and cortisone
was applied for 1 month, and VA returned to 0.4 Snellen (20/
50) with normal biomicroscopic findings.

In three cases (1, 2, 4) an endophthalmitis was suspected


initiallyin two of those due to morphology and symptoms (1,
2), and in one (4) mainly because of massive drop in VA. In all
three cases the primary diagnosis was revised to uveitis due to
the clinical course (no change after systemic and topical
antibiotics, but fast recovery after cortisone). An anterior
chamber tap was performed in cases 2, 5, 6, 7 and 8, but
culture was negative for micro-organisms. In cases 2 and 8,
Gram staining only showed granulocytes. Despite negative
culture, some uncertainty concerning the final diagnosis
remains. Cases 3 and 57 had an initial diagnosis of vitritis
due to the pseudogranulomatous aspect of the vitreous
infiltration (figs 2, 3). Case 8 was admitted with anterior
uveitis because of reduced visibility of the vitreous appearance.

Report of case 8

Response to treatment

A 69-year-old male patient with central retinal vein occlusion in


his left eye had an intravitreal injection of triamcinolone 1 year
ago, but VA remained at 0.5 Snellen (20/40). Due to persisting
cystoid macular oedema, he then received five bevacizumab
injections during the last year, and VA remained stable at
0.6 Snellen (20/32). He noticed a significant drop in VA the day
after the sixth intravitreal injection of bevacizumab (2.5 mg/
0.1 ml) from 0.6 (20/32) to 1/30 (20/600), without pain or
redness of the eye. Slit-lamp findings included endothelial
precipitations (fig 4), 1+ flare and 3+ cells of the anterior
chamber. The posterior segment could not be examined in
detail. An anterior chamber tap was taken which showed no
growth of micro-organisms. Topical therapy with antibiotics
and cortisone was applied for 1 month and led to complete
resolution of the symptoms.

In cases 1, 2 and 4, systemic intravenous antibiotic treatment


was performed using vancomycin and ceftazidin for 7 to

Report of case 7

RESULTS
Time course
Patients became symptomatic between several hours (cases 3 to
8) to 2 days (case 1 and 2).
460

Figure 3 Slit-lamp photography of the pseudogranulomatous


appearance of the vitreous inflammation with high magnification
(case 4).
Br J Ophthalmol 2009;93:457462. doi:10.1136/bjo.2008.138479

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Clinical science

Figure 4 Slit-lamp photography of corneal endothelial precipitates


3 days after intravitreal injection of bevacizumab (case 8).
10 days with little effect. Case 3 received systemic treatment
with 100 mg of prednisolone by mouth (Aprednisolon), reduced
to 50 mg after 5 days. The other four cases (58) received only
topical therapy leading to a prolonged resolution of the cellular
responce. 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 all
eight cases. We started with antibiotic eye-drops (tobramycin
(Tobrex), lomefloxacin (Okazin) or ofloxacin (Floxal)) in
combination with prednisolone (Ultracortenol) every hour.

Recovery
Only case 5 (which was mild at initial presentation) recovered
after 4 days; the others had a recovery time from 2 weeks to
2 months.
In all but one case, the massive drop in VA after the injection
recovered (see table 1).

Differential diagnosis
With respect to the time course, cases 3 to 8 are similar to our
patients with vitreous haemorrhage occurring in the same
population (seven cases, not presented) who usually have
symptoms starting from the first day on. These patients showed
a cellular infiltration of the vitreous body with a more
homogenous aspect. In contrast, cases 3 to 7 demonstrated
with a typical pseudogranulomatous aspect with large vitreous
infiltrates indicating vitritis (figs 2, 3).
The majority of cases had an early massive drop in VA
without any orbital or periorbital pain, which is in contrast to
infectious endophthalmitis. They also recovered immediately
after therapy with cortisone. Nevertheless, in cases 1, 2 and 4, a
presumed infectious endophthalmitis was the primary diagnosis
and cannot be excluded with certainty.

DISCUSSION
A massive immunological response following intravitreal injection of bevacizumab is a possible event and may occur even
after preceding uneventful interventions. The reaction presents
primarily as an intensive inflammation of the posterior segment
associated with a significant loss of VA. The differential
diagnosis includes infectious endophthalmitis or vitreous
haemorrhage, which may also occur after intravitreal injections.
Inflammation induced by bevacizumab is characteristically of
an early onset associated with a painless drop in VA mostly
without conjunctival hyperaemia. Patients present with a
marked anterior chamber reaction, but regularly without
hypopyon. The vitreous condition includes large cellular
Br J Ophthalmol 2009;93:457462. doi:10.1136/bjo.2008.138479

aggregates of pseudogranulomatous aspect, but microbiological


findings were always negative. Systemic treatment with
antibiotics (if performed) shows no benefit, but patients
respond to systemic or topical cortisone treatment with a slow
but persistent recovery. There was no permanent retinal
damage. Intraocular haemorrhage and infectious endophthalmitis might be differentiated by time course and symptoms.
At our department, more than 2500 intravitreal injections
with bevacizumab were performed in 2006 and the first
6 months of 2007. Only minor complications like subconjunctival haemorrhage and corneal abrasion were noted, which are
probably related to the procedure rather than to the medication.
It is important to perform intravitreal injections under sterile
conditions using povidone-iodine drops applied several times in
advance and a sterile speculum.1113 The injections are performed
at our department by different injectors using the same
technique. Patients are advised to take antibiotic drops for
3 days and in case of symptoms present immediately.
Three cases of severe inflammation leading to hospital
admission occurred which were treated with systemic antibiotics due to their initial presentation simulating infectious
endophthalmitis. In a population of more than 2500 individual
injections, this rate represents an incidence of about 0.3% in our
setting. To date we have not observed a single culture positive
endophthalmitis after intravitreal injections of bevacizumab,
which might be the consequence of a tight perioperative
regimen regarding the procedure as mentioned above.
In a publication on bevacizumab-related complications,
inflammation occurred in 0.14% and started 2 to 7 days after
injection but lasted no longer than 1 week, whereas one
infectious endophthalmitis was recorded (0.01%), which
occurred as late as 5 days after injection.9 A case report of
anterior uveitis after bevacizumab use showed onset of
symptoms 3 weeks following injection.14
In a recent report of two culture-positive cases of endophthalmitis (coag. neg. staphylococci) after bevacizumab injection, the
onset of symptoms was documented 2 days after injection, and
the main symptom was reduced VA. The authors state that
classic signs of endophthalmitis might be lacking in case of
preceding intravitreal injection of bevacizumab.15
In a study of 53 eyes with a maximum number of four
consecutive injections, no cases of endophthalmitis occurred
during 3 months. The authors therefore concluded that in their
experience, bevacizumab is less likely to induce inflammation
than ranibizumab.16 Recently, bevacizumab was used successfully for CME in uveitis patients without any side effects.17
A retrospective short-term study on bevacizumab including
81 eyes identified no cases of uveitis or endophthalmitis, but the
authors state that these adverse events would be identified only
if they occurred in more than 4% of cases.7 A large retrospective
study on bevacizumab including 266 eyes showed a low rate of
intraocular inflammation with no endophthalmitis after
3 months of follow-up, and the authors hypothesise that the
proportion of patients developing intraocular inflammation is
higher with other compounds such as pegaptanib and ranibizumab.18
Intraocular inflammation has been reported with intravitreal
injection of ranibizumab in a large prospective clinical trial in
1.3% of the patients.2 Of the five cases of presumed
endophthalmitis, no culture was obtained in one eye. The
remaining four cases were culture-negative, and the authors
state that it is difficult to distinguish a culture negative
endophthalmitis from sterile uveitis in patients treated with
intravitreal antibiotics. From these clinical trials, one may
461

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Clinical science
deduce that even Fab-fragments are able to induce an
immunological response, even considering the low concentration occurring in the systemic circulation. There is the
hypothesis that inflammation may occur more readily in eyes
of individuals with a more immunoreactive disposition, such as
subclinical inflammation or specific HLA subtypes.
In principle, it is more likely that the larger protein load of
bevacizumab with an additional Fc fragment may induce an
immunogenic response. Furthermore, bevacizumab is harvested
from cultures of mammalian ovarian cancer cells, that is the
cellular production pathway, which includes glycosylation of
the proteins with a higher immunogenic potential than the nonglycosylated pure proteins produced by a bacterial pathway in
ranibizumab. Also, bevacizumab is produced for intravenous
infusion and therefore undergoes a less tight purification
procedure than drugs formulated for intraocular use. It is
assumed that bevacizumab solutions contain about 70% of nonhumanised material.
Another issue that has to be addressed is the legal problem
resulting from complications occurring with off-label therapy.
Bevacizumab is not approved by legal authorities for intraocular
use. At present, we already have medications which have been
investigated in large controlled trials and therefore are approved
for intravitreal use. These trials show exact data on possible
complications and their incidence. For bevacizumab it was
anticipated that these might be similar. However, analysis of
the nature of the inflammatory response of ranibizumab offers a
slightly different profile than that of bevacizumab.
Inflammation after intravitreal injection of ranibizumab occurs
mainly 0 to 5 days after injection (in our series we had a median
of 1 day, which is comparable). The clinical presentation may
equally present as iritis (only anterior chamber flare/cells,
anterior uveitis19), vitritis (only vitreous cells, intermediate
uveitis19) or both (anterior chamber and vitreous involved,
iridocyclitis). Most importantly, the response affects the
anterior segment with hypopyon as a major symptom (we
had no case with hypopyon, and all our cases were in the
iridocyclitis group). Only one case of granulomatous vitritis was
reported after intravitreal ranibizumab (data on file, Novartis).
It remains to be determined whether the frequency and nature
of the intraocular response seen in patients after intravitreal
injection of bevacizumab or ranibizumab differ.
Postoperative inflammation is a rare, but serious, complication because progression to endophthalmitis might result in
irreversible vision loss. Differentiating cases of uveitic intraocular inflammation from infectious endophthalmitis is difficult,
as shown in our first two cases, because endophthalmitis is
frequently culture-negative. In case 2, the impressive improvement following topical corticoid therapy supported the exclusion of infectious endophthalmitis. For the differentiation of
vitreous haemorrhage with anterior segment involvement from
infectious endophthalmitis or uveitis, the clinical course is of
importance. Intravitreal bleeding is usually seen immediately

462

after the injection, and VA improves rapidly without further


therapy. Six out of eight cases showed a typical pseudogranulomatous vitreous inflammation, which is in contrast to the
more homogenous appearance of a vitreous haemorrhage. After
therapy with cortisone, all but one case had a good final VA
outcome.
In conclusion, we reported a series of eight patients who
received intravitreal bevacizumab and experienced a drop in VA
at a median of 1 day after injection. A typical severe acute
intraocular inflammatory response with pseudogranulomatous appearance of vitreous infiltration which resolved
following systemic or topical cortisone treatment was typical
for our cases.
Competing interests: None.

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review. Retina 2004;24:67698.
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bevacizumab (Avastin) injection. Eye 2007;21:4089.
Rich RM, Rosenfeld PJ, Puliafito CA, et al. Short-term safety and efficacy of
intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration.
Retina 2006;26:495511.
Cordero Coma M, Sobrin L, Onal S, et al. Intravitreal bevacizumab for treatment of
uveitic macular edema. Ophthalmology 2007;114:15749e1.
Spaide RF, Laud K, Fine HF, et al. Intravitreal bevacizumab treatment of choroidal
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Orbital recurrence of retinoblastoma following


enucleation
J W Kim, V Kathpalia, I J Dunkel, R K Wong, E Riedel and D H Abramson
Br. J. Ophthalmol. 2009;93;463-467; originally published online 29 Aug 2008;
doi:10.1136/bjo.2008.138453

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Clinical science

Orbital recurrence of retinoblastoma following


enucleation
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-Kettering
Cancer Center, New York, USA;
2
Department of Pediatrics,
Memorial Sloan-Kettering
Cancer Center, New York, USA;
3
Department of Epidemiology
and Biostatistics, Memorial
Sloan-Kettering Cancer Center,
New York, USA
Correspondence to:
Dr J W Kim, Ophthalmic
Oncology Service, Memorial
Sloan-Kettering Cancer Center,
1275 York Ave, New York, NY
10021, USA;
jwkim0103@yahoo.com
Presented at the International
Society of Ocular Oncology, 27
June 2007, Siena, Italy and
American Academy of
Ophthalmology Annual Meeting
12 November 2007, New
Orleans, LA, USA.
Accepted 6 August 2008
Published Online First
29 August 2008

ABSTRACT
Background/aims: To determine the incidence, clinical
presentation and histopathological profile of patients
developing orbital recurrence following enucleation for
retinoblastoma.
Methods: A cohort of 1674 consecutive patients
undergoing enucleations between 1914 and 2006 was
retrospectively reviewed to identify cases of orbital
recurrence. A detailed chart review of all identified
patients with orbital recurrence following enucleation was
performed. The main outcome measures were histopathological features of the enucleated globe, clinical
presentation, status of metastatic disease and clinical
outcomes of treatment at last follow-up.
Results: There were 71 cases of orbital recurrence
identified in the study, for an incidence of 4.2% (71 of
1674 cases). The diagnosis of orbital recurrence was
made between 1 and 24 months after enucleation (mean
6 months), with 69 of the 71 patients (97%) being
diagnosed within the first 12 months. Over a follow-up
period 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 alive
and well.
Conclusions: All patients undergoing enucleation for
retinoblastoma need to be followed carefully for the first
2 years after surgery for the possibility of orbital relapse.
The majority of retinoblastoma patients with orbital tumour
recurrence develop systemic metastatic disease, although
mortalities appear to be improving in the modern era.

Retinoblastoma is the most common primary


intraocular cancer in the paediatric population.
Survival rates for retinoblastoma patients vary
widely between modernised and developing
nations, with figures as high as 9098% in the
United States and Europe and as low as 24% in
some African countries.16 The reported disparity
between survival rates has been attributed to the
advanced stage of diagnosis in less industrialised
nations, often in the form of orbital retinoblastoma. Whereas orbital disease may be observed in
up to 50% of newly diagnosed cases in poor
nations,5 7 orbital retinoblastoma is not as commonly encountered in developed countries, with
an incidence of 5.09.5% reported from several
large referral centres.810 Patients with orbital
retinoblastoma are thought to have a poor
systemic prognosis, with mortalities reaching 90
100% of biopsy-confirmed cases.1012 Such discouraging survival rates are comparable with the high
death figures for retinoblastoma patients reported
by Hirschberg in 1869,13 suggesting that little
Br J Ophthalmol 2009;93:463467. doi:10.1136/bjo.2008.138453

progress has been made in managing patients with


the orbital form of the disease.
As pointed out by Ellsworth in 1974, orbital
retinoblastoma may be diagnosed when a patient
presents with extraocular disease or as a form of
local recurrence following enucleation.10 When a
patient presents with intraocular retinoblastoma,
primary enucleation is thought to offer cure rates
of 9095%.14 15 Orbital tumour recurrence following enucleation is considered a relatively rare
complication, although its true incidence has only
been estimated.8 16 There have also been efforts to
demonstrate an association between certain histopathological features of enucleated eyes and the
risk for local and systemic relapse, although a
consensus on these putative risk factors is lacking.9 1519 Other than isolated case reports, few
studies have described the clinical profiles of
patients who present with an orbital tumour
recurrence after an uncomplicated enucleation.20 21
The aim of our study was to systemically analyse
the clinical and histopathological features of
patients developing orbital relapse following enucleation for retinoblastoma. To examine this group
of patients, we reviewed the clinical, radiographic
and pathological data of orbital recurrence cases
identified from a large series of retinoblastoma
patients undergoing enucleations at our institution.

MATERIALS AND METHODS


We examined the records of enucleated cases from
the registry of retinoblastoma patients at the
Memorial Sloan-Kettering Cancer Center to identify cases of orbital tumour recurrence. The
database is also maintained by the National
Cancer Institute (NCI) and includes all cases
enucleated by our service from 1914 to 2006. All
cases with extraocular disease diagnosed at presentation by clinical examination or radiographic
characteristics were excluded. The enucleation
technique utilised by our service has been described
previously.22 23 Approval for this retrospective
study was obtained from the Institutional
Review Board at the Memorial Sloan-Kettering
Cancer Center.
Once the cases were identified, both demographic and pathological data were collected from
a retrospective chart review. Results of the
systemic metastatic work-up (at the time of orbital
recurrence diagnosis) were classified as follows: (1)
metastatic disease (any evidence of retinoblastoma
outside the orbit), (2) bone disease (evidence of
retinoblastoma involving the bone or bone marrow
and (3) central nervous system (CNS) disease
(evidence of retinoblastoma in the intracranial
463

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Clinical science
cavity or spinal column). For each patient, the predominant
symptom(s) or sign(s) that led to the diagnosis of orbital
recurrence was recorded in the following categories: (1) local
orbital or socket signs or symptoms (ie, proptosis, eyelid
swelling, or problems with the prosthesis), (2) orbital or socket
mass noted on routine examination by the physician, (3) eyelid
ecchymosis or bleeding from the socket, (4) non-localising
symptoms such as lethargic behaviour, fever or other constitutional complaints and (5) contralateral orbit/ocular signs or
symptoms. In bilateral enucleation cases, both surgical dates
were recorded, and the side of orbital recurrence was noted.

RESULTS
There were 71 biopsy-confirmed cases of orbital recurrence
identified in the study. The overall incidence of orbital
recurrence following enucleation for retinoblastoma was 4.2%
(71 cases/1674 enucleated patients) (table 1). A subgroup
analysis revealed that the incidence of orbital recurrence before
1960 was 5.0%, whereas the incidence after 1960 was 4.0%,
suggesting a possible decrease in the incidence of orbital
recurrence in the modern era. However, when the incidence
was calculated for approximate 20-year periods, the rate varied
between 3.7 and 5.1% (table 1), without any apparent downward trend in incidence over time.
The clinical profiles of the orbital recurrence cases are
presented in table 2. The age of retinoblastoma diagnosis for
the 71 cases ranged between 1 and 78 months (mean
23.1 months); there were 34 bilateral retinoblastoma cases and
37 unilateral retinoblastoma cases. Among the 71 identified
patients with orbital recurrences, there were 93 enucleated
globes (22 bilateral enucleations), and histopathological data
were available for 77 globes (both partial and complete). When
the pathological report was absent or there was no specific
comment regarding a risk category (optic nerve invasion,
choroidal invasion, sclera invasion), the globe was marked as
data not available for that histopathological feature. A review
of the histopathological data of the enucleated eyes showed the
following: 35 specimens had confirmed evidence of optic nerve
invasion past the lamina cribrosa (negative in 35 globes, data
not available in 23 globes), and seven of these eyes had a positive
optic nerve margin. Two globes had confirmed evidence of
tumour erosion into or through the sclera (negative in 73 globes,
data not available in 18 globes), and 32 globes demonstrated
choroidal invasion (negative in 34 globes, data not available in
27 globes). There were 11 cases of orbital recurrence (with data
available in all three categories) that demonstrated no evidence
of optic nerve invasion, choroidal invasion or scleral invasion.
Table 3 demonstrates the clinical outcomes of the 71
retinoblastoma patients with orbital tumour recurrences. The
diagnosis of orbital recurrence was made between 1 and
24 months after enucleation (average 6 months), with 69 of
the 71 patients being diagnosed within the first 12 months. The
Table 1 Incidence of orbital recurrence following enucleation
Time

Enucleated patients

Recurrences

Incidence (%)

19101929
19301949
19501969
19701989
19902006
Before 1960
1960 and after
Totals

27
157
717
551
222
462
1212
1674

1
8
32
19
11
23
48
71

3.7
5.1
4.5
3.4
4.9
5.0
4.0
4.2

464

patient that had the longest time period between the enucleation and orbital recurrence was case 29; this was a bilateral case,
with the ipsilateral side being enucleated 24 months prior to the
orbital recurrence and the contralateral side being enucleated
3 months before the orbital recurrence. Overall, metastatic
work-up performed at the time of orbital recurrence diagnosis
revealed 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 followup was determined from the date of diagnosis to the last
examination in the chart or the date of death due to metastatic
disease; the range of follow-up in this group of patients was 3
208 months (average 34.8 months). During the period of
follow-up, 61 of the 71 cases died (86%). However, there were
eight cases in this group of 61 patients who survived more than
2 years (after orbital recurrence diagnosis), and four of the eight
cases were confirmed to have mortality related to second
cancers. Assuming that a survival of .24 months is equivalent
to a cure, the adjusted metastatic death rate was determined to
be 53 of 71 cases (75%). For the subgroup of patients diagnosed
as having orbital recurrences after 1984, 10 of 11 cases are alive
and well (as of the last follow-up date).
Table 4 displays the clinical presentations of patients
diagnosed as having orbital recurrences. For the group of 71
patients, the most common presentation was a local symptom
or sign related to a mass lesion in the orbit, such as eyelid
swelling, an ill-fitting prosthesis, visible mass or proptosis (33
cases). The second most common category was a diagnosis
made on routine examination during a scheduled follow-up
appointment; typically an asymptomatic mass was visualised or
palpated in the socket after removal of the prosthesis (23 cases).
Other patients were diagnosed during a work-up of nonlocalising, constitutional symptoms such as lethargy, somnolence, fever, anorexia or headache, prompting a clinical
examination of the socket or a neuroimaging study which led
to the diagnosis (seven cases). Other patients presented with
bleeding from the socket or eyelid ecchymosis (five cases) (figs 1,
2). Finally, three patients presented with proptosis or eyelid
swelling involving the contralateral orbit.

DISCUSSION
In 1974, Ellsworth reported the largest series of patients with
orbital retinoblastoma, when he described 110 cases with orbital
disease identified from the database of patients treated at the
Edward S. Harkness Eye Institute in New York.10 In that
landmark paper, 110 patients were identified from a total series
of 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 orbital
disease on clinical examination or on radiographic imaging,
cases with an extraocular mass encountered at the time of
enucleation, orbital extension diagnosed only on histopathology
and finally patients with orbital relapse following enucleation
for intraocular disease. Because this latter group of patients has
traditionally been categorised with cases presenting with
extraocular disease, the exact incidence of orbital recurrence
following enucleation has been difficult to estimate. In 1987,
Hungerford et al reported an incidence of 5% for orbital
retinoblastoma in a group of 317 children referred for
retinoblastoma, although they acknowledged that some of
these 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 were
referred for extraocular disease and had evidence of metastasis
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Clinical science
Table 2 Clinical and histopathological data
Total orbital
recurrence
cases
Patients = 71
Enucleated
globes = 93

Unilateral/bilateral
RB

Age of
retinoblastoma
diagnosis (months) Optic-nerve invasion

Choroidal invasion

Scleral invasion

Unilateral = 37
Bilateral = 34

112 months = 17 Yes = 35


1324 months = 25 No = 35

Yes = 32
No = 34

Yes = 2
No = 73

2536 months = 23 Margin+ = 7


3748 months = 5 Data NA = 23
.48 = 1
Mean = 23.1

Data NA = 27

Data NA = 18

NA, not available.

at presentation.9 The analysis of 1674 patients enucleated by


our service from 1914 to 2006 showed an orbital relapse rate of
4.2%, which may be more accurate than previous reports due to
the large number of patients in our series and the inclusion of
only biopsy-confirmed cases of orbital recurrence following
enucleation. However, it should be acknowledged that our
study may have included cases with subclinical orbital disease at
the 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 in
incidence over time (for 20-year periods), suggesting that the
rate of orbital recurrence has remained relatively constant in our
database of patients undergoing enucleations. Interestingly,
several groups have published smaller series of enucleated
patients treated with prophylactic chemotherapy with much
lower rates of orbital recurrence, suggesting that adjuvant
therapy of patients with high-risk histopathological features
following enucleation may decrease this type of tumour
relapse.15 19 Our retrospective study was not designed to analyse
the issue of prophylactic chemotherapy and whether adjuvant
treatment decreases the incidence of orbital relapse, an
important 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 first
2 years after surgery, with approximately 97% of patients
presenting within the initial 12 months (69 of 71). The short
interval for the development of this complication was also
described by Ellsworth10, and Hungerford et al found that the
mean interval from enucleation to orbital recurrence in their
series was 6.7 months.8 The most common presentation was a
clinical complaint such as eyelid swelling or chemosis, suggesting that clinicians should not attribute periocular or orbital
symptoms during the first year after enucleation as a sign of a
benign conjunctivitis or preseptal cellulitis. A problem with the
ocular prosthesis was also a frequent mode of presentation in
these patients, and extrusion or displacement of a previously
satisfactory prosthesis should be considered a suspicious sign for
possible tumour recurrence. In the socket, the characteristic

lesion was a subconjunctival mass with a purplish hue, due to


the prominent vascularity of the tumour mass.24 The vascularity
may also explain the finding of periocular ecchymosis or frank
bleeding from the socket in five patients. A significant number
of patients were also diagnosed on routine examinations, and
the practice of removing the prosthesis in asymptomatic
patients during follow-up evaluations seems justified, particularly within the first 2 years after enucleation. There were seven
patients with non-localising signs that eventually led to the
diagnosis of orbital tumour recurrence, and several patients
presented with a mass lesion in the contralateral orbit,
reinforcing the importance of being vigilant for unusual
symptoms in patients with a history of retinoblastoma.
Our study confirms the findings of Ellsworth and Hungerford
et al that retinoblastoma patients with tumour recurrence in the
orbit are likely to have other sites of extraocular relapse.8 10 In
our series, 75% of patients with orbital recurrence eventually
died from systemic metastatic disease. Ellsworth reported an
overall survival rate of only 9.4% for patients with biopsyconfirmed orbital retinoblastoma, although this figure included
patients who presented initially with extraocular disease.10 In
Hungerfords 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 an
orbital tumour recurrence after 1984 are alive and well. The
improved survival data for patients with orbital retinoblastoma
in the last two decades can be attributed to the aggressive
systemic approach implemented by our group in the 1980s.
Ellsworth was the first to recognise the value of systemic
chemotherapy in improving the survival of patients with orbital
retinoblastoma.10 In Hungerford et als series of 16 patients with
orbital recurrences, the only patient to survive was one of the
four cases that received chemotherapy.8 Our treatment strategy
for extraocular retinoblastoma has evolved into a multimodal
approach for all patients with orbital tumour recurrence.24 25
When a patient is confirmed to have orbital disease following
enucleation, our current protocol is to perform a metastatic
evaluation with a brain MRI, abdominal CT scan, lumbar
puncture, bone scan and bone-marrow aspirate and biopsy.

Table 3 Clinical outcomes of 71 orbital recurrence cases


Enucleation to OR
(months)

Metastatic disease
at presentation
Bone disease

CNS disease

Outcome

Follow-up (months)

03 = 15
46 = 31
712 = 23

Yes = 44
No = 22
Data NA = 5

Yes = 12
No = 48
Data NA = 11

Deceased = 61
Alive = 10

012 = 28
1324 = 26
2536 = 1
3748 = 1
.49 = 15
Mean = 34.8

Yes = 28
No = 32
Data NA = 11

.12 = 2
Mean = 6
NA, data not available; OR, orbital recurrence.

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Clinical science
Table 4 Clinical presentation of orbital recurrence cases
No of patients (%)

Clinical presentation

33 (46)
23 (32)
7 (10)
5 (7)
3 (4)
71 total

Local orbital symptoms/problems with prosthesis


Routine examination
Non-localising/constitutional symptoms
Eyelid ecchymosis/bleeding from socket
Contralateral orbit/socket

Because of the high risk of metastatic disease, patients found to


have only local disease in the orbit receive systemic multiagent
chemotherapy as well as orbital radiotherapy. Patients with
disseminated disease such as bone-marrow involvement receive
high-dose multiagent chemotherapy with stem-cell rescue,
while those with CNS disease may also receive intrathecal
radioimmunotherapy.
Several histopathological features of enucleated eyes have
been recognised as risk factors for extraocular relapse in
retinoblastoma patients. There appears to be universal agreement that optic-nerve invasion with tumour involvement of the
resection margin and extrascleral spread are highly predictive
markers for extraocular relapse.26 27 The prognostic value of
other extraretinal features, such as choroidal invasion and
retrolaminar optic-nerve invasion (with a negative margin), has
been debated, although there is general agreement that these
features increase the risk for systemic disease.9 18 In our series of
orbital recurrence cases, 35 of the 70 globes (with data available)
demonstrated evidence of optic nerve invasion, and 32 of 66
globes (with data available) had choroidal invasion, indicating a
higher risk of metastatic disease in this cohort of patients than
other published series of retinoblastoma patients undergoing
enucleations.15 16 26 Interestingly, only seven enucleated globes
were identified as having a positive optic nerve margin, and two
globes had evidence of scleral invasion in this group of 71 orbital
recurrence cases. Additionally, there were 11 cases without any
histopathological risk factors (ie, choroidal invasion, scleral
invasion or optic nerve invasion). One explanation is that
microscopic invasion through the sclera or optic nerve by
tumour cells may have been missed when the globe was
examined histopathologically. However, the finding of three
cases of contralateral orbital recurrence in our series suggests
that non-contiguous tumour spread may be an under-recognised mechanism for orbital relapse in some of these cases.
Haematogenous metastasis to the ipsilateral or contralateral

Figure 2 Coronal magnetic resonance imaging study (T1 with


gadolinium) of the same patient in fig 1 demonstrating a subperiosteal
tumour recurrence to the marrow space of the orbital floor.
orbit has been reported as a mechanism for orbital recurrence,
particularly to the orbital bones28 29
Patients developing orbital tumour recurrence following
enucleation for advanced intraocular disease represent a unique
subset of patients, and they should be distinguished from
patients who present with extraocular retinoblastoma. Orbital
recurrence following enucleation represents a type of tumour
relapse that occurs from either local or non-contiguous spread to
the orbit, often in the setting of systemic metastatic disease.
The incidence of orbital tumour recurrence in our study of 1674
patients undergoing enucleations was 4.2%, and patients and
their families should be warned about the possibility of tumour
relapse during the preoperative discussion. Based on these data,
histopathological risk factors are not always reliable in predicting which patients will ultimately develop orbital tumour
recurrence. Therefore, all patients undergoing enucleations for
intraocular retinoblastoma require careful follow-up during the
first 2 years after surgery, and clinicians should be aware that
patients may be asymptomatic or present with subtle, nonlocalising or even contralateral symptoms. The majority of
patients diagnosed as having orbital recurrence following
enucleation eventually develop metastatic disease, emphasising
the need for a careful systemic work-up of these cases once they
have been identified. With intensive systemic treatment, the
prognosis 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 at
the Memorial Sloan-Kettering Cancer Center.
Patient consent: Obtained.

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Figure 1 Clinical photograph showing chemosis and eyelid ecchymosis


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Howarth C, Meyer D, Hustu HO, et al. Stage-related combined modality treatment of
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ocular pathological features: who needs adjuvant therapy? Br J Ophthalmol
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Uusitalo MS, Van Quill KR, Scott IU, et al. Evaluation of chemoprophylaxis in
patients with unilateral retinoblastoma with high-risk features on histopathologic
examination. Arch Ophthalmol 2001;119:418.
Karcioglu ZA, Mullaney PB, Millar LC. Extrusion of porous polyethylene
orbital implant in recurrent retinoblastoma. Ophthal Plast Reconstr Surg
1998;14:3744.
Stevenson KE, Hungerford J, Garner A. Local extraocular extension
of retinoblastoma following intraocular surgery. Br J Ophthalmol
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Observational prospective study of the


effectiveness in routine clinical practice of
verteporfin photodynamic therapy in patients with
neovascular age-related macular degeneration
S Murjaneh, M Garca-Fiana, S Mahmood, P M Lenfestey, S A Taylor, I A
Pearce, M C Briggs, H Heimann and S P Harding
Br. J. Ophthalmol. 2009;93;468-473; originally published online 15 Dec 2008;
doi:10.1136/bjo.2008.141366

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Observational prospective study of the effectiveness


in routine clinical practice of verteporfin
photodynamic therapy in patients with neovascular
age-related macular degeneration
S Murjaneh,1 M Garca-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, Royal


Liverpool University Hospital,
Liverpool, UK; 2 Centre for
Medical Statistics and Health
Evaluation, University of
Liverpool, 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; s.p.harding@liverpool.ac.uk
Accepted 28 August 2008
Published Online First
15 December 2008

ABSTRACT
Aims: To investigate effectiveness in routine clinical
practice of verteporfin photodynamic therapy (PDT) for
neovascular age-related macular degeneration (nAMD).
Patients and methods: Patients commencing PDT for
nAMD in a single UK centre entered a prospective
observational 7-year study and were followed for 2 years.
Best-corrected visual acuity (BCVA) and contrast sensitivity (CS) were measured at each visit by accredited
technicians after full protocol refraction on standardised
charts. Reasons for failure to complete the course of
therapy were documented.
Results: 1008 patients entered the study between 1999
and 2006. 81% and 52% completed 12 and 24 months
follow-up respectively (excluding administrative censoring). 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. The
mean CS remained stable. No correlation of change in
BCVA outcome between first and second treated eyes in
82 bilateral cases was detected. Loss to follow-up was
significantly 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 trials
and uses fewer treatments.

Subfoveal choroidal neovascularisation (CNV)


causing exudative age-related macular degeneration (AMD) is the leading cause of severe visual
impairment in the developed world in patients over
50 years of age.13 Verteporfin photodynamic therapy (PDT) has been shown to be effective in
randomised controlled clinical trials (RCTs) at
reducing the likelihood of further visual loss when
CNV is characterised on fluorescein angiography as
classic/no occult or predominantly classic.4 5
Recent studies have demonstrated the efficacy of
both pegaptanib and ranibizumab in the treatment
of AMD with 70% and 92% maintenance of vision
respectively.68
The evidence of effectiveness of PDT in routine
clinical practice is limited. When new therapies are
introduced into clinical practice this evidence is
essential for clinicians and funding bodies to allow
the measurement of the generalisability of results
from RCTs in which patients are carefully selected.
In this paper, we present 7 years of clinical
experience of PDT for AMD in a regional medical
retina referral centre. We analysed changes in
468

visual function over a 2-year follow-up period


and report the outcome of a smaller number of
patients who were followed for a longer period of
time. We identified a subgroup of patients who
received bilateral treatment and investigated
whether the change in visual acuity of the second
eye treated is associated with treatment outcome
of the first eye.

PATIENTS AND METHODS


The study was conducted at St Pauls Eye Unit,
Royal Liverpool University Hospital. Patients with
suspected treatable CNV were referred from
ophthalmologists throughout the UK and Eire.
The baseline screening visit comprised a full
assessment similar to Treatment for Age-related
Macular Degeneration with Photodynamic
Therapy (TAP) published procedures.4 Patients
deemed eligible for treatment were consented for
data collection and analysis, and recruited into a
longitudinal prospective observational study. They
were followed 3-monthly for 2 years, reduced to 6monthly in the second year if the lesion was
assessed to be inactive.
BCVA was measured at each visit and CS at
alternate visits using full refraction protocol and
standardised illumination by externally accredited
optometrists. BCVA and CS were recorded as
letters read at 1 m on an Early Treatment
Diabetic Retinopathy Study (ETDRS) chart and
PelliRobson chart respectively.
Inclusion criteria at baseline were extended
beyond those used in the TAP study following
expert workshops in Liverpool to include BCVA
>30 ETDRS letters, CNV within 200 mm of the
foveal centre and lesion size (7000 mm. Patients
with retinal angiomatous proliferation (RAP) and
polypoidal choroidal vasculopathy (PCV) were
included. Eyes outside these criteria were treated
only in exceptional circumstances.
At 24 months, patients who had inactive lesions
had the option to be discharged or referred back to
their local unit; many who lived locally elected to
continue further follow-up within this study.
Follow-up was also continued in those patients
who had active lesions, who developed recurrences
or developed AMD requiring treatment in the
other eye.
Treatment was administered according to the
TAP protocol.4 The laser power output was
measured at the beginning of each treatment
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Clinical science
session and was considered acceptable if within 10% of nominal
level. If patients needed bilateral treatment at baseline, one eye
was treated initially and the other after 2 weeks. Simultaneous
bilateral treatment was performed if retreatment in both eyes
was required at subsequent visits. Retreatment was undertaken
if the angiographic and clinical features suggested continued
CNV activity, and this was guided by a locally produced
protocol9 (see table 1).
In cases of bilateral treatment, the first treated eye was
deemed the study eye. The second eye was defined as the
second eye to receive treatment when treated within 12 months
of the first. The fellow eye was defined as the eye which did
not receive PDT treatment.

Statistical analysis
Descriptive and statistical analyses were performed using
Microsoft Excel and Access and the statistical package R version
2.5.0.
The change in visual outcome was classified as (a) moderate
visual improvement (>15 letters gained or equivalent to halving
the visual angle); (b) mild visual improvement (.5 and ,15
letters gained); (c) no change ((5 letters change); (d) mild
visual loss (.5 letters and ,15 letters lost); (e) moderate visual
loss (>15 letters and ,30 letters or equivalent to doubling the
visual angle10 11); and (f) severe visual loss (>30 letters lost).
Two-way analysis of variance was used to test whether, in
patients with bilateral treatment, change in BCVA of the second
eye was significantly associated with change in BCVA of the
first eye treated.
Reasons for loss to follow-up were recorded: planned early
discharge, referral back to a local unit, unable to attend due to
illness, failure to attend for no reason and referral to another
treatment modality. Distance travelled to reach the treatment
centre was taken as the distance from the referring primary care
trust (PCT) head office and analysed in three groups: local,
regional and national. Logistic regression analysis was applied to
test whether loss to follow-up was influenced by visual
outcome, distance from treatment centre, age and gender.
This analysis was performed with continuous variables converted into binary based on the mean values from the data

sample. The interaction term CS*BCVA was initially considered


but then excluded, since it did not contribute to a better fit of
the model.

RESULTS
Between November 1999 and October 2006, 1438 patients
referred with CNV were screened and assessed for possible
treatment. A total of 1008 AMD patients met the eligibility
criteria, were recruited for the study and commenced their
course of PDT. Of these 1008 patients, 139 received their first
treatment within 12 months prior to the end of the study and
were still being followed up at the end of the study
(administrative censoring), and 163 were lost to follow-up
during the first year. From the remaining 706 patients who
completed 12 months follow-up, 128 patients had received
their first treatment within 24 months prior to the end of the
study and were still being followed up at the end of the study,
while 192 were lost to follow-up during the second year of
study. A CONSORT style distribution of patients is shown in
fig 1.
At baseline the majority of patients had classic no occult (735
(72.9%)) or predominantly classic CNV (218 (21.6%)), with a
small number of cases of RAP (38 (3.8%)), PCV (6), minimally
classic (3), occult/no classic (4) and other (4). At baseline, the
mean age was 77.2 years (range 47 to 102, SD 7.5), and 540
(54%) were female. The mean GLD at baseline was 3247 mm
(range 322 to 7380, SD 1492). The mean total number of
treatments was 2.91 in year 1 and 0.54 in year 2.

Table 1 Clinical guidelines in retreatment with photodynamic therapy


Fluorescein
angiogram
Visual acuity
(subjective and/or
objective)

Subretinal fluid
Choroidal
neovascularisation

Haemorrhage/
exudate
Fibrosis
Visit
Retinal pigment
epithelium

Consider retreatment

Consider no retreatment

Leakage

No leakage

Dropping

Stable

,20 letters
Severe loss within 14 days of
treatment
Persistent
Cleared
Subfoveal
Not under foveal centre
Extension or recurrence Inactive

New

3 months

Development of chorioretinal
anastomosis
Cleared
.75%
9+ months
Large serous detachment
Tear

Br J Ophthalmol 2009;93:468473. doi:10.1136/bjo.2008.141366

Figure 1 Flow chart showing demography of study population. AMD,


age-related macular degeneration.
469

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Clinical science

Figure 2 Illustration of the results given in table 4 (low panel) showing the classification of patients based on their change in best-corrected visual
acuity at 12 and 24 months from baseline.

Visual function

Bilateral treatment

Visual function outcomes over the 2 years of the study are


shown in tables 2, 3 and figs 2, 3. Additional outcome data from
years 3 to 5 are shown in tables 2, 3. The mean BCVA fell in the
first 6 months, followed by a further slight drop between 6 and
12 months with stabilisation thereafter. The mean CS remained
stable throughout the course of therapy (fig 3).

One hundred and two patients were treated bilaterally, of


whom 20 had missing data from one eye at 12 months.
Twenty-seven of the remaining 82 lost >15 letters in their first
(or study) eye (failed group), while 55 maintained their BCVA
(no-failed group). The BCVA of the second eye at baseline and
12 months is plotted in fig 4 for both groups. Two-way analysis

Figure 3 Evolution of best-corrected visual acuity (VA; first row) and contrast sensitivity (CS; second row) over time. The mean values at each time
point are represented by the black squares. Spline interpolation was applied to illustrate the continuous change over time (red line) and the
corresponding 95% confidence interval (blue lines). The three lines added in the right panels show the course of best-corrected visual acuity (upper
panel) and contrast sensitivity (lower panel) over time for three randomly selected patients who completed follow-up at 24 months.
470

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Clinical science
Table 2 Mean best-corrected visual acuity and contrast sensitivity at specified time points
Month

Baseline

12

Data label range (month)


0
1.5 to 4.5
4.5 to 7.5
7.5 to 10.5
Visual acuity (letters) (SD)
48.4 (11.1) 42.9 (16.0) 40.1 (16.8) 39.9 (16.9)
Change from previous visit (letters)
25.5
22.8
20.2
Sample size for specific time points 1008
911
815
650
Contrast sensitivity (letters)
21.5 (6.8)
21.2 (7.7)
21.0 (8.0)
21.6 (7.6)
Change from previous visit (letters)
20.3
20.2
+0.6
Sample size for specific time points 905
490
739
380

18

24

10.5 to 15
15 to 21
21 to 33
38.3 (17.9) 39.9 (18.1) 39.0 (18.0)
21.6
+1.6
20.9
681
449
384
21.5 (8.1)
22.6 (8.0)
22.3 (8.3)
20.1
+1.1
20.3
614
413
342

36

48

60

33 to 45
39.8 (18.4)
+0.8
90
24.3 (7.0)
+2.0
81

45 to 57
43.8 (20.7)
+4.0
26
24.8 (6.3)
+0.5
22

57 to 63
44.6 (17.1)
+0.8
5
27.2 (3.6)
+2.4
5

Table 3 Frequency distribution of change in best-corrected visual acuity (Early Treatment Diabetic Retinopathy Study letters read) classified as
moderate and mild increase, stable, mild, moderate and severe loss and maintenance of vision
Month

Baseline

Data label range (month)


Sample size at specified time
Moderate increase (>15 gained (%))
Mild increase (.5 to ,15 gained (%))
Stable ((5 letters change (%))
Mild loss (.5 to ,15 lost (%))
Moderate loss (>15 to ,30 lost (%))
Severe loss (>30 lost (%))
Maintenance (,15 lost (%))

0
1008

1.5 to 4.5
4.5 to 7.5
7.5 to 10.5
911
815
650
4.4
4.7
5.2
10.6
9.0
9.4
40.3
31.3
28.3
24.0
23.4
23.1
15.5
22.4
23.7
5.2
9.2
10.3
79.3
68.4
66.0

of variance showed no statistically significant difference in


BCVA at treatment onset in the second eye in patients from the
failed group (49 letters) when compared with the no-failed
group (51 letters) (p = 0.47). Patients in the failed group lost less
vision in their second eye (mean eight letters lost) when
compared with the no-failed group (mean 14 letters lost), but
the difference was not statistically significant (p = 0.17).

12

18

24

36

48

60

10.5 to 15
681
4.9
9.5
25.0
22.6
24.8
13.2
62.0

15 to 21
449
6.2
12.7
24.5
19.6
24.5
12.5
63.0

21 to 33
384
5.2
10.4
25.3
22.4
23.2
13.5
63.3

33 to 45
90
5.6
13.3
21.1
15.5
27.8
16.7
55.5

45 to 57
26
11.5
7.7
19.2
23.1
27.0
11.5
61.5

57 to 63
5
0
40.0
0.0
20.0
40.0
0.0
60.0

Loss to follow-up
Reasons for loss to follow-up are shown in table 4. The
distribution of distances travelled to the treatment centre for
the 1008 patients was: local (,20 miles) 357 (37%), regional (20
to 60 miles) 307 (31%), national .60 miles 310 (32%).
Frequency of loss to follow-up within each group was: local
39.8%, regional 40.8% and national 57.3%.
Logistic regression analysis revealed that the probability of
being lost to follow-up in patients who are older than 77 years,
have CS (21 letters at baseline or who travel more than
60 miles to the treatment centre is greater when compared with
patients without these characteristics (table 5). The odds of
dropping out from the study increased by at least 52% in
patients who lived more than 60 miles from the treatment unit,
increased by at least 14% in older patients (.77 years when
compared with (77 years) and decreased by at least 5% and
18% in patients whose CS at baseline was greater than 21 and
17 letters respectively. On the other hand, females and patients
with a better BCVA at baseline showed a lower probability of
being lost to follow-up, although the results were not
statistically significant.

DISCUSSION

Figure 4 Best-corrected visual acuity (BCVA) of the second eye at


times 0 and 12 months for 82 patients with bilateral treatment (second
eye commenced treatment within 12 months of the first eye). The left
column shows the individual values of BCVA for 27 patients who lost
>15 letters at 12 months for the first eye (failed group). The right
column shows the BCVA of 55 patients who maintained their visual
acuity of the first eye (no-failed group). The horizontal segments
represent the mean values of BCVA for each group and time point. The
mean BCVA decreased six and 14 letters after 1 year of treatment for the
failed and no-failed group, respectively.
Br J Ophthalmol 2009;93:468473. doi:10.1136/bjo.2008.141366

In this large prospective series from a single treatment centre,


BCVA as defined in the TAP study was maintained in 62% and
63% of treated patients at 12 and 24 months, respectively.
These findings are similar to those seen in the treatment arm of
TAP (59% at 24 months) and are consistent with our previously
reported short-term outcomes.9 Relatively small but important
numbers of patients experienced improvement of vision of more
than five letters (14.4% at 12 months, 15.6% at 24 months)
with larger numbers experiencing stabilisation defined as a
change of ,5 letters (25.0% at 12 months, 25.3% at
24 months). Conversely, a group of patients did lose more than
30 letters (13.2% at 12 months, 13.5% at 24 months).
As seen in the treatment arm of TAP, the mean BCVA
dropped in the first 6 months of follow-up and was then
maintained (fig 3). However, it is important to recognise that
471

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Clinical science
Table 4 Reasons for failure to complete follow-up at 12 and 24 months from baseline
Period (months)

012

Initial sample size


1008
Administrative censoring
139*
Relevant sample size
869
Completed follow-up
706
Lost to follow-up
163
Reasons for failure to complete planned follow-up
Planned discharge{
20
Referred to local unit for further follow-up{
28
DNA no reason{
25
Discharge by patientill1
29
Deceased"
27
Administrative error1
27
Referred for other therapy{
7

1224

81.2
18.8

706
128{
578
386
192

2.3
3.2
2.9
3.3
3.1
3.1
0.8%

49
32
23
14
35
31
8

024

66.8
33.2

1008
267*{
741
386
355

52.1
47.9

8.5
5.5
4.0
2.4
6.1
6.1
1.4%

69
60
48
43
62
58
15

9.3
8.1
6.5
5.8
8.4
7.8
2.0%

Administrative censoring = patients still attending who had not reached the deemed follow-up point.
*Patients recruited within 12 months before the end of the study period and who were still attending clinic appointments at the
time the study ended.
{Patients recruited within 24 months before the end of the study period and who were still attending clinic appointments at the
time the study ended.
{Possibly related to treatment outcome.
1Not related to treatment outcome.
"Causes not documented.

there is a wide variation in individual response to therapy as


illustrated in the right-hand panels of fig 3, with variation in
patterns of response at all stages of the course of therapy.
Contrast sensitivity is an important measure of visual
function, especially in patients with AMD.12 However, CS is
not commonly utilised by clinicians or clinical trials in the
management of patients with exudative AMD. CS was not
studied in the RCTs of pegaptanib or ranibizumab, and reports
from TAP were limited. Our results showed maintenance of CS
with mean change of 0.0 and +0.8 letters at 12 and 24 months,
respectively, and are comparable with TAP, which reported loss
of 1.3 letters in the treatment group by 24 months. Similar to
BCVA, there is variation in individual courses of CS, although
this variation is less wide.
Our results on maintenance and improvement of vision at 12
and 24 months were achieved with fewer clinic visits and fewer
treatments than TAP. We consider our units protocol of
retreatment based on clinician decision-making (table 1) rather
than just the presence of angiographic leakage as in TAP9 is the
main factor in reducing the required number of treatments.
Compared with TAP, our patients had larger lesions at
baseline up to 7380 mm (TAP(5400 mm). Our subgroup of
patients who were followed beyond 3 years provide new longterm data on PDT. The TAP extension study is the only other
study to date that has reported results of PDT beyond
24 months.13 In the TAP extension, patients were reselected at
24 months, while our patients were retained in the study for

different reasons, including bilateral disease, recurrence and


whether they lived locally. Mean changes in BCVA and CS
improved after the 24-month visit in our patients compared
with a mean five letters lost by year 3 in TAP. Mean numbers of
treatments were also less at 0.32, 0.17 and 0.14 in year 3, 4 and
5, respectively (1.3 in year 3 in TAP). Our results need to be
interpreted with caution due to the selection bias and relatively
small numbers. However, they do indicate that PDT can
continue to have a beneficial effect beyond 24 months and also
that retreatment is required in a small group of patients.
Smith et al studied the cost-effectiveness of PDT for AMD in
the UK when PDT was applied to predominantly classic
subfoveal CNV in the better seeing eye, basing their outcomes
on TAP protocol (3 monthly visits with retreatment treatment
if leakage was present on FA) and its main outcome of
maintenance of VA.14 They suggested that a reduction in the
number of treatments per patient would improve the costeffectiveness of PDT for AMD in the UK, assuming that similar
outcomes to TAP are maintained. Our outcomes may indicate
better cost-effectiveness, as we had fewer treatments, less
frequent visits, stability of CS throughout the course of therapy
and improvement in BCVA in 15.6% of our patients. Further
studies are required to investigate the cost-effectiveness of
different protocols of PDT in alternative settings.
Our results show that there are multiple difficulties facing
both clinicians and researchers treating elderly patients requiring multiple visits over a long period of time. This is a problem

Table 5 Results of logistic regression analysis of loss to follow-up


Covariate
Distance
(reference = local)
Age
Contrast sensitivity
baseline
Visual acuity baseline
Gender

Model coefficient (b) SE (b)

OR

95% CI for the OR

p Value

Regional
National
.77 years
.21 letters

0.13
0.83
0.46
20.38

0.22
0.21
0.17
0.17

1.13
2.29
1.59
0.68

0.74
1.52
1.14
0.49

0.56
,0.001
,0.01
0.02

.48 letters
Female

20.18
20.14

0.17
0.17

0.83
0.87

0.60 to 1.16
0.63 to 1.20

to
to
to
to

1.74
3.44
2.21
0.95

0.29
0.40

Variables: distance (local, regional and national, defined in text), age (binary variable: ( and .77 years), contrast sensitivity at
baseline (binary variable: ( and .21 letters), best-corrected visual acuity at baseline (binary variable: ( and .48 letters),
gender.

472

Br J Ophthalmol 2009;93:468473. doi:10.1136/bjo.2008.141366

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Clinical science
not faced by RCTs which select patients who are likely to
attend. The frequency of patients completing 24-month followup was high at 87% in TAP in which 3-monthly attendances
were required and remained high at 8090% in the RCTs of
pegaptanib and ranibizumab with attendances required at 6and 4-weekly respectively.68 In contrast we had greater loss to
follow-up increasing over time from 18.8% at 12 months to
47.9% by 24 months, and this is a potential source of bias in our
results. We did not exclude any patient on the basis of their
general health, social circumstances or the likelihood of
attending for 2 years. Our results confirm that travelling
distance for elderly patients is a significant factor in nonattendance outside RCTs. However, excluding justified reasons
for loss to follow-up which are associated with this elderly
population (planned early discharge, referral back to a local unit,
self discharge due to illness and patient death, referral to other
therapies), our follow-up rates were good at 93.9% and 85.7% at
12 and 24 months, respectively.
The logistic regression analysis of baseline characteristics as
predictors of compliance to therapy included age, gender,
BCVA, CS and the distance travelled to the treatment centre.
This showed that patients who are younger than 77 have CS
.21 letters and travel ,60 miles to the treatment centre are
more likely to complete the therapy course. Patients with a
better BCVA at baseline (.48 letters) were more likely to
complete their follow-up, but this difference was not statistically significant.
There is a perceived impression that patients respond in a
similar way to PDT in their second treated eye as in their first
treated eye. We were unable to demonstrate a correlation and in
fact found a trend that patients who responded poorly in their
first eye tended to respond better in their second eye.
In conclusion, this study suggests that PDT for AMD in
routine clinical practice is at least as effective as that reported in
RCTs and requires fewer visits, investigations and treatments.
Maintenance of CS reflects another aspect of visual function
outcome of this therapy. Visual outcomes can be sustained over
a prolonged period of follow-up. BCVA outcome in the second
treated eye does not appear to correlate with BCVA outcome in

Br J Ophthalmol 2009;93:468473. doi:10.1136/bjo.2008.141366

the first. Compliance with follow-up in patients with AMD is


more challenging than is suggested by RCTs. However, younger
patients with higher CS and BCVA at baseline and who travel a
shorter distance to the treatment centre are more likely to have
better compliance.
Competing interests: St Pauls Eye Unit has received departmental commercial
funding as a clinical centre in the TAP and VIP studies. SAT, IAP, MCB, HH and SPH
have received support for travel and conference attendance.
Patient consent: Obtained.

REFERENCES
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Bressler NM, Bressler SB, Fine SL. Age-related macular degeneration. Surv
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TAP study group. Photodynamic therapy of subfoveal choroidal neovascularisation in
age-related macular degeneration with verteporfin: one-year results of 2 randomised
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TAP study group. Photodynamic therapy of subfoveal choroidal neovascularisation in
age-related macular degeneration with verteporfin: two-year results of 2 randomised
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Rosenfeld PJ, Brown DM, Heier JS, et al.Ranibizumab for neovascular age-related
macular degeneration. N Engl J Med 2006;355:141931.
Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for
neovascular age-related macular degeneration. N Engl J Med 2006;355:143244.
Gragoudas ES, Adamis AP, Cunningham ET Jr, et al. Pegaptanib for neovascular
age-related macular degeneration. N Engl J Med 2004;351:280516.
Barnes RM, Gee L, Taylor S, et al. Outcomes in verteporfin photodynamic therapy
for choroidal neovascularisationbeyond the TAP study. Eye 2004;18:80913.
Early Treatment Diabetic Retinopathy Study Research Group. Early Treatment
Diabetic Retinopathy Study design and baseline patient characteristics: ETDRS Report
Number 7. Ophthalmology 1991;98:74156.
Macular Photocoagulation Study. Argon laser photocoagulation for senile macular
degeneration. Results of a randomized clinical trial. Arch Ophthamol 1982;100:91218.
McClure ME, Hart PM, Jackson AJ, et al. Macular degeneration: do conventional
measurements of impaired vision equate with visual disability? Br J Ophthalmol
2000;84:24450.
TAP Study Group. Verteporfin therapy for subfoveal choroidal neovascularization in
age-related macular degeneration: three-year results of an open-label extension of 2
randomized clinical trialsTAP Report no. 5. Arch Ophthalmol 2002;120:130714.
Smith DH, Fenn P, Drummond M. Cost effectiveness of photodynamic therapy with
verteporfin for age related macular degeneration: the UK case. Br J Ophthalmol
2004;88:110712.

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Periocular basal cell carcinoma: 5-year outcome


following Slow Mohs surgery with formalin-fixed
paraffin-embedded sections and delayed closure
D S Morris, E Elzaridi, L Clarke, A J Dickinson and C M Lawrence
Br. J. Ophthalmol. 2009;93;474-476; originally published online 5 Dec 2008;
doi:10.1136/bjo.2008.141325

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Clinical science

Periocular basal cell carcinoma: 5-year outcome


following Slow Mohs surgery with formalin-fixed
paraffin-embedded sections and delayed closure
D S Morris,1 E Elzaridi,1 L Clarke,1 A J Dickinson,1 C M Lawrence2
1

Department of Ophthalmology,
Royal Victoria Infirmary,
Newcastle upon Tyne, UK;
2
Department of Dermatology,
Royal Victoria Infirmary,
Newcastle upon Tyne, UK
Correspondence to:
Dr D Morris, Department of
Ophthalmology, Royal Victoria
Infirmary, Newcastle upon Tyne
NE1 4LP, UK; dsm@doctors.
org.uk
Accepted 12 November 2008
Published Online First
5 December 2008

ABSTRACT
Aim: The aim of the study was to determine the 5-year
outcome of periocular basal cell carcinoma (BCC)
managed by Mohs surgery using formalin-fixed, paraffinembedded sections (Slow Mohs).
Methods: This was a prospective, non-comparative,
interventional case series of all patients with periocular
BCC treated by Slow Mohs in Newcastle upon Tyne, UK,
between 1985 and 1999. Data collected included
demographic information, indication for Slow Mohs,
tumour site, histology, recurrence rate after 5 years and
cosmetic outcome.
Results: Of 287 BCCs in 278 patients, 5-year follow-up
data were available for 173 (60.2%). Recurrence following
Slow Mohs occurred in one patient: 0.34% of total and
0.58% of those with 5-year follow-up. The main indication
for Slow Mohs was most frequently due to the tumour
site. Cosmetic outcome was deemed excellent in 56%,
good in 18%, adequate in 8%, unknown in 14% and
revision advised in only 4%.
Conclusion: The low 5-year recurrence rate (0.58%)
reported in this prospective series confirms the importance of margin-controlled removal of recurrent, poorly
defined or critically sited BCCs, and illustrates that Slow
Mohs is equivalent to standard Mohs. While delayed
closure does not appear to compromise cosmetic
outcome, this technique offers a histologically superior
and cheaper alternative to frozen-section Mohs surgery.

Basal cell carcinoma (BCC) is the most common


malignant tumour managed by ophthalmologists;
indeed BCC accounts for 90% of malignant eyelid
tumours in the USA.1 BCC is more common in
elderly, fair-skinned patients, often with a history
of chronic exposure to the sun.2
Although rarely metastatic, BCC invades locally,
and recurrent or more aggressive histological
subtypes can still prove fatal with a mortality rate
of 211% for eyelid tumours.3 4 This emphasises
the importance of curative primary surgery.
Conventional histology following standard surgical
excision examines only 12% of the tumour
margin, and is curative in approximately 90% of
patients.57 Mohs original fixed tissue technique8
was developed to enable the entire excision margin
to be examined histologically. The method has
been modified over the years and is now generally
performed using frozen sections.9 This technique,
called Mohs micrographic surgery (MMS), enables
microscopic examination of the entire excision
margin thus ensuring tumour removal but with
preservation of as much healthy tissue as possible.
Current literature suggests an overall cure rate of
474

99100% after MMS for primary BCC and 9496%


for recurrent BCC.7 10 11 Hence MMS is ideal for
periocular BCC where recurrence is much more
difficult to manage and preservation of the eyelids
is vital so as not to affect the function of the eyes
and cosmesis of the face.12
Although MMS is most often performed with
frozen sections, the same technique for 100%
margin control can also be performed by processing
tissue through formalin fixation and paraffinembedded sections. This process takes 2448 h
and is generally called Slow Mohs. It is widely
acknowledged that the resulting sections are
histologically superior to frozen sections, and
may therefore be easier to interpret. This is the
first prospective series to report the 5-year outcomes of periocular BCC managed by Slow Mohs
using formalin-fixed, paraffin-embedded tissue
rather than frozen sections.

MATERIALS AND METHODS


A prospective, non-comparative, interventional
case series was conducted and data were collected
on all patients with periocular BCC treated by
Slow Mohs in Newcastle upon Tyne from 1985 to
1999. All medial canthal and recurrent tumours
were selected for Slow Mohs, as well as BCCs that
could not be confidently fully excised with a 4 mm
margin without significantly compromising the
cosmesis or function of the final outcome.
The site of the BCC was noted as upper eyelid,
lower eyelid or medial canthus. In keeping with
other studies, tumours at the lateral canthus were
described as upper or lower eyelid.13 Tumours
outside this region were excluded from the study.
Other details collected included age and sex,
original indication for Slow Mohs, prior recurrence,
histology, number of stages taken, recurrence rates
within 5 years, cosmetic outcome and follow-up.
All patients were treated by a trained Mohs
surgeon (CML) and paraffin-fixed sections were
used. The tumour was first debulked, usually by
excision and sometimes by curettage, defined as
removal of all visible tumour tissue. This was not
counted as the first Mohs stage. Then the first
12 mm stage was excised around the debulked
excision margin of the tumour. A map of the
excision site was drawn. The excised tissue was
divided into pieces, usually less than 1 cm maximum
diameter, and their position drawn on the map and
marked on the patient with sutures. The removed
tissue was orientated using tissue dyes marked at the
edge of each piece. The tissue was then prepared for
examination as previously described.14
Br J Ophthalmol 2009;93:474476. doi:10.1136/bjo.2008.141325

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Clinical science

Figure 1

The main indications for Slow Mohs surgery in this series.

If tumour was identified in the sections after microscopic


examination of the first stage, further layers were excised from
that site and examined as before. This process was continued
until no further tumour was identified in the excised tissue. The
defect was then closed by an ophthalmologist and, since 1994,
by a trained oculoplastic surgeon (AJD). Cosmesis was assessed
at 1 m with the naked eye in the clinic room setting. Outcome
was judged as excellent if there were no functional problems
(such as epiphora) and when observation at 1 m revealed no
evidence of any abnormality or visible scar; outcome was good if
the lid positions were normal with no functional problems and
the patient was completely satisfied but the scars were visible at
1 m; outcome was adequate when the reconstruction was
apparent, but deemed as good as could be achieved; outcome
was poor when either the function or cosmesis of the
reconstruction warranted further surgery.

RESULTS
Two-hundred and eighty-seven BCCs were treated in 278
patients, of whom 141 (51%) were female and 137 (49%) were
male, with an average age of 65.5 (range 2589) years. Five-year
follow-up data were available for 173 (60.2%) of these cases. Of
the remaining 114 cases (39.8%), 67 had died and 47 either
declined review or were lost to follow-up for other reasons.
There were no deaths related to BCC or their surgical
treatment.
The main indications for Slow Mohs (fig 1) were critical site
(42%), ill-defined margins (29%), prior recurrence (19%), large
tumour size (defined as greater than 15 mm) (7%) and
previously incompletely excised tumour (3%). Fifty per cent of
tumours affected the lower lid, 41% the medial canthus and 9%
the upper lid. The number of Mohs stages required for clearance
is illustrated in fig 2, with the average being 1.47 stages and the
maximum being 7 stages. Tumour histology was as follows:
76% common solid; 4% morphoeic; 3% superficial; 17%
unknown.
Subsequent reconstruction employed various techniques,
including rotational or advancement flap (42%), direct closure
(22%), full thickness graft (14%), healing by secondary intention
(16%), partial closure and partial secondary intention (2%) and
others (4%) (fig 3). Cosmetic outcome was deemed excellent in
56%, good in 18%, adequate in 8% and unknown in 14%.
Revision of the surgical site was advised in only 4% (fig 4).
Recurrence following Slow Mohs occurred in only one patient:
0.34% of total and 0.58% of those with 5-year follow-up.
Br J Ophthalmol 2009;93:474476. doi:10.1136/bjo.2008.141325

Figure 2 The number of Mohs stages required for histological


clearance of tumour in this series.

DISCUSSION
To the best of our knowledge, this prospective series of
periocular BCCs managed by Slow Mohs is the first report of
5-year outcomes using formalin-fixed and paraffin-embedded
sections rather than frozen sections. The series included a large
number of high risk tumours with a significant risk of
recurrence, namely critically sited BCC at the medial canthus,
large tumours, those with indistinct margins and recurrences
from previous conventional excision, which comprised almost
20% of the cohort. This was therefore a group with the
potential to have a significant rate of recurrence during 5-year
follow up.
The results show an excellent 5-year recurrence rate of 0.58%,
significantly lower than simple excision57 and equivalent to or
lower than previously published results of MMS using frozen
sections.7 10 11 Although 5-year follow-up data were only
available in 173 patients, the data are unique in coming from
formalin-fixed and paraffin-embedded sections, and still represent more than 60% of the cohort.
In an extensive review of all studies that examined recurrence
rates in the treatment of primary BCC, Rowe et al found that
the 5-year recurrence rate for MMS was 1%; surgical excision,
10.1%; curettage and electrodessication, 7.7%; radiation therapy, 8.7%; and cryosurgery 7.5%.7 In a large study from the
Cleveland Clinic, Roenigk et al reported 4-year cure rates for
primary BCC of 98.6% for MMS, although these tumours were
not just confined to the periocular region.15 Malhotra et al
reported 5-year recurrence rates of 0% and 7.8% for primary and
recurrent tumours, respectively, in the Australian Mohs
database.11 However, only 42% of patients completed the
follow-up.
Although periocular BCCs are most common in the lower
eyelid,16 a disproportionate number of tumours at the medial
canthus are reported in this and other MMS studies11 because
the medial canthus is deemed to be a critical site where tumours
are difficult to excise completely. In addition, recurrence
frequently leads to orbital and/or bony invasion and the risk
of then requiring exenteration. This makes Mohs surgery the
technique of choice for primary and recurrent medial canthal
tumours.
It is important to appreciate the difference between intraoperative selective frozen section biopsy examination of
suspicious areas and Mohs surgery. The former examines only
small areas that are clinically suspicious whereas Mohs surgery
475

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Clinical science

Figure 3 Types of closure and healing techniques used following


removal of basal cell carcinoma by Slow Mohs surgery in this series.
enables the entire excision margin to be examined, allowing
clinically invisible tumour extension to be identified.
MMS utilising frozen sections has the obvious advantage that
the result is available within 12 h and in many cases the
excision and closure stages can be completed on the same day.
However, frozen sections have inferior structural preservation
compared with formalin-fixed material, making interpretation
more difficult. In our hospital the formalin-fixed sections were
examined by both the pathologist and the Mohs surgeon,
ensuring expert interpretation of the slides. The disadvantage of
paraffin-embedded sections versus frozen sections is that there
is a delay of at least 24 h before the results become available and
it is known whether further excision is required. This means
that the patient has the inconvenience of attending hospital on
several occasions. However, in our hands there was minimal
surgical risk, the wounds were not generally painful, and the
cosmetic outcome was not compromised by a delay of less than
5 days, with 84% of patients having good or excellent outcomes.
In addition patients were very accepting of the extra visits to
hospital. Defects in the upper eyelid also present no problem,
provided the eye is covered with ointment and a non-contact
occlusive dressing to ensure that corneal desiccation is avoided.
Any technique such as MMS or Slow Mohs that helps to
prevent aggressive recurrence of BCC whilst preserving as much
healthy tissue as possible should be encouraged, especially
because most studies suggest that successful long-term cure is
considerably reduced following recurrence.13 The quality of
histological material is vital in determining the tumour margin,
and paraffin-based sections offer the best possible preservation
of the tissue sample.
This series shows that Slow Mohs surgery with paraffinembedded sections offers a similar cure rate to standard MMS
with frozen section for periocular BCCs. It therefore offers the
opportunity of developing a Mohs service with less committed
technician time. In addition Slow Mohs has the advantage of
being the procedure of choice for some pigmented tumours that
are difficult to diagnose on frozen section and therefore require
a superior histological technique. However the compromise is
multiple visits for the patient and delayed wound repair.
We report the first series using Slow Mohs for periocular BCC
with 60.2% 5-year follow-up and 0.58% recurrence. These data

476

Figure 4

Post-operative cosmetic outcome in this series.

confirm the optimal place of Mohs surgery in the management


of eyelid BCC and emphasise the value of multidisciplinary
management. Slow Mohs surgery with paraffin sections should
be considered as an alternative for institutions where standard
Mohs surgery with frozen section is not a viable option.
Competing interests: None declared.
Ethics approval: The study was started before ethical approval was required in the
region.

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Intermediate uveitis: long-term course and visual


outcome
N Vidovic-Valentincic, A Kraut, M Hawlina, S Stunf and A Rothova
Br. J. Ophthalmol. 2009;93;477-480; originally published online 9 Dec 2008;
doi:10.1136/bjo.2008.149039

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Clinical science

Intermediate uveitis: long-term course and visual


outcome
N Vidovic-Valentincic,1 A Kraut,1 M Hawlina,1
S
Stunf,1 A Rothova2
1

Eye Clinic, University Clinical


Centre, Ljubljana, Slovenia;
2
Department of Ophthalmology,
University Medical Center
Utrecht, the Netherlands
Correspondence to:
Dr N. Vidovic Valentincic, Eye
Clinic, University Clinical Centre,
Grabloviceva 46, Ljubljana,
Slovenia; vid.val@t-2.net
Accepted 9 November 2008
Published Online First
9 December 2008

ABSTRACT
Aim: In this retrospective cohort study we investigated
the long-term course and visual outcomes of intermediate
uveitis (IU).
Methods: We performed an institutional study of
patients with IU with a follow-up of at least 10 years,
followed at a tertiary referral centre.
Results: We studied 29 patients with unilateral or
bilateral IU. The average age at onset of IU was 31 (range
864) years. At onset, three patients (10%) had
associated systemic disease (two with sarcoidosis and
one with multiple sclerosis) and one patient had
granuloma annulare. During the follow-up period, one
additional patient was diagnosed with sarcoidosis and one
with multiple sclerosis. The percentage of eyes with legal
blindness and visual impairment gradually increased over
time (from 9/53 (17%) at onset to 15/53 (28%) at 10-year
follow-up), with macular oedema, cataract and vitreous
opacities being the most common causes of vision loss.
The presence of associated anterior uveitis was more
frequently noted in patients younger than 20 years at
onset. Remissions of intraocular inflammation of at least
1 year were noted in 10/29 (34%) of patients. The mean
time-to-remission was 8.6 years; patients who had
remissions were younger at the onset of IU than those
with ongoing active IU (p = 0.036). Remissions of IU
showed borderline association with the absence of
systemic disease (p = 0.046).
Conclusions: One-third of IU patients achieved a
remission of their intraocular inflammation for longer than
1 year and had a mean time-to-remission of 8.6 years.
Patients who were younger at onset of IU were more
likely to achieve remission than those who were older at
onset.

Intermediate uveitis (IU) is a chronic intraocular


inflammatory disorder in which the vitreous
represents the major site of inflammation.1 IU
predominantly affects patients under the age of 40
years and comprises approximately 10% of the
general uveitis population.2 The exact aetiology of
IU is not known, although it is often associated
with systemic illnesses such as sarcoidosis, multiple sclerosis (MS) and several infectious diseases.36
IU is frequently associated with peripheral
retinal phlebitis and is characterised by a high
prevalence of cystoid macular oedema (CMO).7
Although CMO develops in about 60% of patients,
the visual prognosis of IU patients is usually
favourable.7 8 Remissions of the disease have been
occasionally reported, but the incidence of remission over time is not yet known.810 In this study,
we investigated the clinical manifestations of IU in
29 patients with a follow-up of at least 10 years,
Br J Ophthalmol 2009;93:477480. doi:10.1136/bjo.2008.149039

and determined the course of the disease and its


outcome.

METHODS
Twenty-nine patients with IU and a follow-up
longer than 10 years were followed at University
Ophthalmologic Hospital in Ljubljana, Slovenia.
Slovenia is a small country (2 million inhabitants)
located in the south of Europe; there are 110
ophthalmologists and the tertiary care of patients
with uveitis is located in our institution. From the
original series of 29 patients with onset of IU
between 1985 and 1995, no patient was lost to
follow-up. We also followed patients with remissions regularly, usually once per year.
The diagnosis of IU was made according to the
diagnostic criteria of the Standardization of Uveitis
Nomenclature (SUN) Working Group.1 Pars planitis was defined as the idiopathic IU associated with
the presence of snow-banking and/or snowballs.1
All patients underwent repeated medical and
laboratory examinations for their uveitis including
erythrocyte sedimentation rate, complete blood
counts, serum angiotensin-converting enzyme
level, syphilis serology, chest radiography and
Mantoux testing. Borrelia serology was not systematically tested: results were available in 9/29
patients, and were negative in all nine. Legal
blindness was defined as a best-corrected visual
acuity (VA) of 20/200 or less for the better eye, and
visual impairment was defined as a best-corrected
VA of 20/60 or less but better than 20/200.11
Diagnosis of MS was always made by a
neurologist and was based on disseminated plaques
of demyelisation on MRI with oligoclonal bands in
cerebrospinal fluid.12 The diagnosis of sarcoidosis
was considered in cases proven either by bronchoalveolar lavage or by tissue analysis. Diagnosis of
CMO was always documented either by fluorescein angiography (FA) or ocular coherence tomography (OCT)
According to the SUN Working Group, remission of uveitis is defined as inactive disease for at
least 3 months.1 In the present series of patients
with longstanding IU, however, we defined the
remission of IU as the absence of intraocular
inflammation for at least 12 months without any
systemic treatment and/or topical treatment. The
presence of sporadic cells in the vitreous was
allowed.
Systemic treatment was applied in cases with
CMO resistant to local treatment and/or in cases
with decreased VA due to vitreous opacities. In
cases with unilateral or asymmetric involvement,
the periocular steroid injections were applied first,
and systemic treatment was initiated only in cases
477

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Clinical science
Table 1 Clinical characteristics of 29 patients with intermediate uveitis
and a follow-up of at least 10 years

Table 2 Complications and remissions in 29 patients with intermediate


uveitis during the 10-year follow-up

Follow-up time (years)

Follow-up time (years)

Characteristic

Onset

10

Characteristic

Onset

Bilateral involvement
Snow-banking
Number of patients who had ever
received systemic treatment
Number of patients on systemic
treatment
Definitive diagnosis of multiple
sclerosis
Definitive diagnosis of sarcoidosis
Other systemic disorders*

20 (69)
7 (24)
9 (31)

23 (79)
8 (28)
10 (34)

23 (79)
9 (31)
11 (38)

24 (83)
9 (31)
11 (38)

Cystoid macular oedema


Cataract
Retinal detachment
Secondary glaucoma
Other complications{
Surgical interventions
Remissions

6
12
0
0
1
0
0

11
19
1
2
3
3
0

10

1 (3)

2 (7)

2 (7)

2 (7)

2 (7)

3 (10)

3 (10)

3 (10)

Value are n (%).


Remissions longer than 12 months developed in 10/29 of the patients within 10 years
after the onset of intermediate uveitis (table 2).
*Including granuloma annulare, atopic dermatitis, systemic hypertension and
seronegative arthritis (n = 1 for each).

with insufficient effect and/or intolerance to this treatment


modality.
Statistical analysis was performed using chi square or Fishers
exact test whenever appropriate, and p,0.05 was considered
significant. To assess the development of cataract, CMO and
remission over time, we performed KaplanMeier analyses.

RESULTS
The mean age at the first ophthalmologic consultation was
31 years. Bilateral involvement increased over time, resulting in
53/58 (91%) affected eyes. The general characteristics of the
patients are given in table 1.
Mean time-to-remission was 8.6 (SE 0.5, 95% CI 7.6 to 9.5)
years (fig 1). Six out of ten patients with remissions (60%) had
an onset of IU when younger than 20 years, in contrast to 4/19
(21%) of patients from the non-remission group (p = 0.036).
The remaining 19 patients had an ongoing inflammatory
activity of IU; however, the number of patients on systemic
treatment decreased over time (p = 0.05).
Clinical characteristics at onset of IU in patients with and
without remission did not differ (for snow-banking, CMO and
cataract: p = 0.1, p = 0.45 and p = 0.14, respectively) nor did the
visual outcome (VA better than 20/60 was observed in 14/20
(70%) eyes in the remission group and 24/33 (72%) eyes in the
non-remission group). All cases associated with systemic disease
were in the non-remission group (p = 0.04). One patient with
granuloma annulare achieved remission.
Remissions longer than 3 months but shorter than
12 months developed in an additional five patients. However,
all of these patients resumed active intraocular inflammation
later and only one of them achieved a subsequent remission
longer than 1 year.
At the first ophthalmologic consultation, three patients had
systemic disease (two with sarcoidosis and one with MS).
Within the first 2 years of follow-up, a systemic disease
manifested in two additional patients (table 1). Concurrent
anterior uveitis was more frequent in the patients younger than
20 years at first ophthalmologic consultation (5/10 (50%) versus
0/19 (0%); p,0.001). Posterior synechiae were present in three
patients, who were all younger than 13 years at first
ophthalmologic presentation (p = 0.01). Prominent periphlebitis
was present in 7/29 patients: four of them had systemic disease
(two had MS and two had sarcoidosis (p = 0.02)).
478

(21)
(41)
(0)
(0)
(3)
(0)

5
(38)
(66)
(3)
(7)
(10)
(10)
(0)

12
23
2
3
3
4
4

10
(41)
(79)
(7)
(10)
(10)
(14)
(14)

13* (45)
24 (83)
3 (10)
4 (14)
3 (10)
15 (51)
10 (34)

Values are n (%).


*Over time, seven patients with cystoid macular oedema developed atrophic macular
scars.
{Includes central retinal vein occlusion, severe dry eye syndrome and keratopathy.

Complications are shown in table 2. Over time, 7/13 patients


with CMO developed atrophic changes in the macula. Six of these
seven patients developed CMO during the first 2 years of followup. No further associations predisposing to the development of
atrophic macular changes could be identified. Peripheral retinal
neovascularisations were not observed. Three patients developed
retinal detachment and all had snow banks previously (p = 0.006).
The causes of retinal detachments (RD) included: vitreous
haemorrhage and subsequent traction in one patient; rhegmatogenous RD after uneventful cataract surgery in one patient; and in
the remaining patient the retinal tear developed in the inner layer
of the peripheral retinoschisis. Vitrectomy was performed in all
eyes with RD. All three patients with RDs achieved remission.
Secondary glaucoma developed in four patients (two due to
peripheral anterior synechiae, one due to secluded pupil and one
case of glaucoma was induced by periocular steroid injection.
KaplanMeier plots of the development of two major complications of cataract and CMO with time are shown in figs 2 and 3.
The percentage of eyes with legal blindness and visual
impairment gradually increased over time (from 9/53 (17%) at
onset to 15/53 (28%) at 10-year follow-up). Bilateral legal
blindness developed in one female patient with sarcoidosis.
When the patients were subdivided according to their visual
outcome, no differences were found in age (p = 0.47) or in the
number of patients with remissions (p = 0.08). In contrast, poor
visual outcome was associated with systemic treatment
(p = 0.002; selection bias) and the presence of CMO
(p = 0.003). VA at the 10-year follow-up in patients with and
without snow-banking did not differ (p = 0.92).
Systemic treatment over time was required in 11/29 (38%) of
patients: nine patients received corticosteroids, one of whom
was treated in combination with cyclosporine and three in
combination with methotrexate. One patient received monotherapy regimen with methotrexate and one with mycofenolate
mofetil. Periocular steroid injections were used in conjunction
with systemic treatment in four patients and were given in five
additional patients as the only treatment.

DISCUSSION
Our study demonstrates that approximately one-third (10/29
(34%)) of patients with IU achieved a remission of their ocular
disease for longer than 12 months within 10 years of follow-up.
In the remainder of patients, the inflammatory activity became
gradually less severe, as can be observed from the decreasing
number of patients using systemic medications.
We were unable to find previous data on the remission rates
of IU in long-term follow-up, the exception being a study of
Br J Ophthalmol 2009;93:477480. doi:10.1136/bjo.2008.149039

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Clinical science

Figure 1 KaplanMeier analysis of time-to-remission in patients with


intermediate uveitis. The function also presents the descending share of
patients with ongoing disease.
cyclitis from 1973 where Smith et al9 found a remission rate of
5% in patients with a follow-up time varying from 4 to 26 years.
In children with IU, de Boer et al8 observed that remission of IU
longer than 12 months occurred in 47% of the children in whom
IU manifested before the age of 16 years, which is in agreement
with our results.
The SUN Working Group has recently put forward a
definition of remission as inactive disease at least 3 months
after discontinuing all treatment.1 If the SUN definition was
used in our study, the remission rate would be even higher,
specifically 48%. However, all patients with remissions longer
than 3 months, but shorter than 12 months, resumed an active
inflammation later on. In contrast, none of patients with a
remission longer than 12 months developed active IU during the
follow-up. Obviously, we cannot entirely exclude the possibility
of future active IU after our follow-up ended. However, it is
probable that a more prolonged period of inactivity than
3 months is needed to study remissions in chronic uveitis
entities characterised by variable periods of active and inactive
inflammatory process. Although remissions occurred in onethird of patients by 10 years, none occurred by 2 years and less
than one-half of remissions had occurred by 5 years. All patients
were followed at our tertiary centre and a possible bias to
selecting a more severely affected population of IU patients
cannot be entirely excluded.
Our study underlines the fact that the presence of anterior
uveitis, eventually complicated by posterior synechiae, was
significantly more frequent in patients aged less than 20 years at
onset, which is in concordance with earlier findings.3 8 13
Previously, about 15 to 33% of IU patients have been found to
have an associated systemic disease.4 10 1316 We found a
significant association between periphlebitis and associated
systemic disease (p = 0.019). According to the literature, not
only periphlebitis, but also snow-banking might be present in
MS and sarcoidosis.46 1719 We did not observe an association
between snow-banking and systemic disease, possibly due to
the limited number of patients with snow-banking included in
the study. The relationship observed earlier between granuloma
annulare and IU was also observed in our series.16
Br J Ophthalmol 2009;93:477480. doi:10.1136/bjo.2008.149039

Figure 2 KaplanMeier analysis of time-to-cataract development in


patients with intermediate uveitis. The mean time-to-cataract
development was estimated at 3.2 (SE 0.7, 95% CI 1.9 to 4.7) years for
the total population of 29 patients.
Complications typical for IU are well described, although
long-term follow-up data in the literature are scarce. In our
study, cataract and CMO were the most frequent complications: cataract was the main cause of (temporary) visual loss at
presentation and CMO was the main cause of permanent visual
loss at 10 years.8 10 2022 These findings address the importance of
early treatment of CMO in patients with IU.
Our study demonstrates a favourable visual prognosis in IU
patients, and is in accordance with the findings of other
authors.10 13 20 Donaldson et al reported that 18/24 (75%) eyes of
patients with pars planitis maintained a VA of 20/40 or better
after 10 years.15 The visual prognosis at 10 years was similar for

Figure 3 KaplanMeier analysis of time-to-cystoid macular oedema


(CMO) development in patients with intermediate uveitis. The mean time
to CMO development was estimated at 6.3 (SE 0.8, 95% CI 4.8 to 7.9)
years for the total population of 29 patients.
479

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Clinical science
IU patients in the remission and non-remission group. Since the
average time-to-remission was 8.6 years, it is probable that a
longer follow-up is needed to assess the eventual differences in
visual outcomes between these IU groups.
In conclusion, we have reported on the occurrence of
remissions longer than 12 months in 34% of patients with IU,
with an average time-to-remission of 8.6 years. In addition, we
found an association between the periphlebitis in IU and the
presence of systemic disease. Our findings are of value for all
ophthalmologists who treat and counsel patients with IU.
Funding: This study was supported by the National Medical Research Council Grants
No. 0796/2003, 0863/2004 and CSI/0002/2005, and Biomedical Research Council
Grant No. 501/1/25-5, with additional support from the Singapore Tissue Network and
the Ministry of Health, Singapore.
Competing interests: None declared.
Ethics approval: This study followed the principles of the Helsinki Declaration and
was approved by a local ethics committee.
Patient consent: Obtained.

REFERENCES
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Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of Uveitis Nomenclature


SUN Working Group. Standardization of uveitis nomenclature for reporting
clinical data. Results of the First International Workshop. Am J Ophthalmol
2005;140:50916.
Guex-Crosier Y. Epidemiology of uveitis. Rev Prat 1999;49:198994.
Whitcup SM. Intermediate uveitis. In: Nussenblatt RB, Whitcup SM, eds. Uveitis,
fundamentals and clinical practice, 3rd edn. Philadelphia, PA: Mosby, 2004:291300.
Malinowski SM, Pulido JS, Folk JC. Long-term visual outcome and complications
associated with pars planitis. Ophthalmology 1993;100:81825.
Capone A Jr, Aaberg TM. Intermediate uveitis. In: Albert DM, Jacobiec FA, eds.
Principles and Practice of Ophthalmology: Clinical Practice. Philadelphia, PA:
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Breeveld J, Rothova A, Kuiper H. Intermediate uveitis and Lyme borreliosis.


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Lardenoye CW, van Kooij B, Rothova A. Impact of macular edema on visual acuity in
uveitis. Ophthalmology 2006;113:14469.
de Boer J, Berendshot TTJM, van der Does P, et al. Long term follow-up of
intermediate uveitis in children. Am J Ophthalmol 2006;141:61621.
Smith RE, Godfrey WA, Kimura SJ. Chronic cyclitis. I. Course and visual prognosis.
Trans Am Acad Ophthalmol Otolaryngol 1973;77:7608.
Palimeris G, Marcomichelakis N, Konstantinidou V, et al. Intermediate uveitis: what
is the natural course of the disease and its relationship with other systemic diseases?
Eur J Ophthalmol 1994;4:2237.
Kraut JA, McCabe CP. The problem of low vision. Definition and common problems.
In: Albert DM, Jacobiec FA eds. Principles and Practice of Ophthalmology: Clinical
Practice. Philadelphia, PA: WB Saunders, 1994:36646.
Compston A, Coles A. Multiple sclerosis. Lancet 2002;359:122131.
Murphy CC, Hughes EH, Frost NA, et al. Quality of life and visual function in patients
with intermediate uveitis. Br J Ophthalmol 2005;89:11615.
Boskovich SA, Lowder CY, Meisler DM, et al. Systemic diseases associated with
intermediate uveitis. Cleve Clin J Med 1993;60:4605.
Donaldson MJ, Pulido JS, Herman DC, et al. Pars planitis: a 20-year study of
incidence, clinical features, and outcomes. Am J Ophthalmol 2007;144:8127.
van Kooij B, van Dijk MC, de Boer J, et al. Is granuloma annulare related to
intermediate uveitis with retinal vasculitis? Br J Ophthalmol 2003;87:7636.
Quentin CD, Altenhoff M, Schipper HI, et al. Retinal periphlebitis and multiple
sclerosis. Incidence, cerebrospinal fluid and results of visual evoked potentials.
Fortschr Ophthalmol 1990;87:35961.
Zierhut M, Foster CS. Multiple sclerosis, sarcoidosis and other diseases in patients
with pars planitis. Dev Ophthalmol 1992;23:417.
Chen L, Gordon LK. Ocular manifestations of multiple sclerosis. Curr Opin Ophthalmol
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Rothova A, Suttorp-van Schulten MS, et al. Causes and frequency of
blindness in patients with intraocular inflammatory disease. Br J Ophthalmol
1996;80:3326.
Durrani OM, Tehrani NN, Marr JE, et al. Degree, duration, and causes of visual loss
in uveitis. Br J Ophthalmol 2004;88:115962.
Bodaghi B, Cassoux N, Wechsler BHD, et al. Chronic severe uveitis (etiology and
visual outcome in 927 patients from a single center). Medicine (Baltimore)
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Br J Ophthalmol 2009;93:477480. doi:10.1136/bjo.2008.149039

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Twenty-four-hour intraocular pressure control


with the travoprost/timolol maleate fixed
combination compared with travoprost when both
are dosed in the evening in primary open-angle
glaucoma
A G P Konstas, D Mikropoulos, A-B Haidich, K S Ntampos and W C Stewart
Br. J. Ophthalmol. 2009;93;481-485; originally published online 19 Nov 2008;
doi:10.1136/bjo.2008.147322

Updated information and services can be found at:


http://bjo.bmj.com/cgi/content/full/93/4/481

These include:

References

This article cites 19 articles, 5 of which can be accessed free at:


http://bjo.bmj.com/cgi/content/full/93/4/481#BIBL

Rapid responses

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Clinical science

Twenty-four-hour intraocular pressure control with


the travoprost/timolol maleate fixed combination
compared with travoprost when both are dosed in
the evening in primary open-angle glaucoma
A G P Konstas,1 D Mikropoulos,1 A-B Haidich,2 K S Ntampos,1 W C Stewart3,4
1

Glaucoma Unit, 1st University,


Department of Ophthalmology,
Thessaloniki, Greece;
2
Department of Hygiene,
Aristotle University of
Thessaloniki, Greece; 3 PRN
Pharmaceutical Research
Network, LLC, Dallas, Texas,
USA; 4 Carolina Eye Institute,
University of South Carolina,
Columbia, South Carolina, USA
Correspondence to:
Dr W C Stewart, PRN
Pharmaceutical Research
Network, LLC, 5001 LBJ
Freeway, Suite 700, Dallas, TX
75244, USA; info@prnorb.com
Accepted 15 October 2008
Published Online First
19 November 2008

ABSTRACT
Objective: To evaluate the 24 h efficacy and safety of
the travoprost/timolol maleate fixed combination (TTFC)
versus travoprost when both are dosed in the evening in
primary open-angle glaucoma patients.
Methods: Prospective, double-masked, crossover, activecontrolled, randomised 24 h comparison. After a 6 week
medicine-free period, patients were randomised to either
TTFC or travoprost for 8 weeks and were then switched
to the opposite treatment for another 8 weeks. At the
end of the washout and treatment periods, a 24 h
pressure curve was performed.
Results: Thirty-two patients completed the study. The
TTFC group demonstrated a lower absolute intraocular
pressure level (2.4 mm Hg) for the 24 h curve and at all
time points, compared with travoprost (p(0.047). The
pressure reduction from untreated baseline was significantly different between treatments for all time points
(p = 0.018). The mean 24 h pressure fluctuation was
lower with TTFC (3.0 mm Hg) compared with travoprost
(4.0 mm Hg, p = 0.001). No statistical difference existed
between the two treatment groups for any adverse event
(p.0.05).
Conclusions: This study suggests that when both drugs
are dosed in the evening the TTFC provides improved
intraocular pressure reduction, compared with travoprost,
over the 24 h curve and for each individual time point in
primary open-angle glaucoma patients.

Recently the travoprost 0.004%/timolol maleate


0.5% fixed combination (DuoTrav, Alcon
Laboratories, Fort Worth, Texas, US) gained
regulatory approval in the European Union. This
new fixed combination is indicated for the treatment of patients with open-angle glaucoma or
ocular hypertension needing further intraocular
pressure reduction from a beta-blocker or prostaglandin analogue.
Barnebey and associates showed, in a multicentre, parallel, regulatory trial, that patients
treated with morning dosed travoprost/timolol
fixed combination had a further reduction in
intraocular pressure from a baseline of 0.9 to
2.4 mm Hg more than evening dosed travoprost
alone.1 Consequently, a morning dosed travoprost/
timolol fixed combination should provide incrementally better intraocular pressure control than
prior prostaglandin analogue monotherapy.
However, previous information by Konstas and
associates, evaluating the latanoprost-based fixed
combination (Xalacom, Pfizer, New York), has
Br J Ophthalmol 2009;93:481485. doi:10.1136/bjo.2008.147322

shown that evening dosing provides better intraocular pressure control compared with latanoprost
alone (1.1 vs 2.5 mm Hg).2 3 However, little similar
information exists for the other prostaglandinbased fixed combination preparations available
commercially.
The purpose of this current study was to
evaluate the 24 h intraocular pressure efficacy
and safety between evening dosed travoprost/
timolol fixed combination and evening dosed
travoprost in primary open-angle glaucoma
patients. We wished to evaluate the potential
greater ocular hypotensive benefit over 24 h of
dosing both the fixed combination and the
prostaglandin in the evening compared with prior
studies that dosed the fixed combination in the
morning.

METHODS
Patients
Patients were recruited for this prospective, doublemasked study from the Glaucoma Unit of the 1st
University Department of Ophthalmology,
AHEPA Hospital, Thessaloniki, Greece (Clinical
Trial Number: NCT00444184). All patients who
agreed to participate in the study and met the
inclusion and exclusion criteria were enrolled. We
included primary open-angle glaucoma patients of
either gender, older than 29 years of age, who
demonstrated: willingness to comply with the
investigators and protocols instructions; willingness to sign the Institutional Review Board
approved informed consent document; a clinical
diagnosis of primary open-angle glaucoma in at
least one eye (study eye); at screening an intraocular pressure considered to be at a level in both
eyes, in such a way as to ensure clinical stability of
vision and the optic nerve throughout the trial; at
baseline an untreated intraocular pressure of 24 to
37 mm Hg inclusive at two separate 10:00 (SD 1) h
measurements. Primary open-angle glaucoma was
defined as those patients with open, normalappearing anterior chamber angles per gonioscopy
and with typical glaucomatous optic atrophy
(neural rim thinning, notching, saucerisation or
nerve fibre layer disc haemorrhage) with typical
glaucomatous visual-field damage (arcuate, Seidel
or paracentral scotoma or nasal step).
We excluded patients who received therapy if
they had a previous history of unresponsiveness
(deemed to be a morning intraocular pressure
reduction of less than 10%) to any antiglaucoma
481

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Clinical science
medication, including travoprost or timolol, or if there was any
history of non-compliance. Patients were also excluded from
this study if they demonstrated: unreliable applanation
tonometry; inadequate visualisation of the ocular fundus or
anterior chamber; a concurrent infectious/non-infectious conjunctivitis, keratitis or uveitis; a history of hypersensitivity to
any components of the preparations used in this trial; woman of
childbearing potential or not using reliable birth control;
pregnancy or lactation; a clinically severe medical or psychiatric
condition; participation (or current participation) in any
investigational drug or device trial within the previous
3 months prior to the screening visit; an intraocular conventional surgery or laser surgery in the participating eye; risk of
visual-field or visual-acuity worsening as a consequence of
participation in the trial, a cup-to-disc ratio of 0.8 or worse or a
mean deviation of worse than 14 dB on visual-field testing (not
attributable to cataract); an inability to give informed consent;
anticipated change in systemic hypotensive therapy during the
active treatment portion of the trial (Visits 26); progressive
retinal or optic nerve disease apart from glaucoma; unwillingness to accept the risk of iris colour or eyelash changes; risk for
uveitis or cystoid macular oedema in this trial; or history of
ocular herpes simplex, reactive airway disease, second- or thirddegree heart block, poorly compensated congestive heart failure
or concomitant use of systemic beta-blockers.

Methods
All patients signed an informed consent agreement approved by
an institutional review board before any procedures were
performed. The Treaty of Helsinki was followed for this study.
At Visit 1, subjects had an ophthalmic and systemic history
taken and had dilated funduscopy and automated full threshold
perimetry performed (Humphrey 242 test, SITA standard). At
this visit, as well as at all other visits, the intraocular pressure
(two measurements at 10:00 (1) h were averaged) was
measured, and Snellen visual acuity and slit-lamp biomicroscopy were performed. This time was chosen as the peak
pressure in Greece based on prior data.4 5 Qualified patients were
then washed out of their glaucoma medications and asked to
return in 6 weeks for the baseline visit (Visit 2).
At Visit 2, and at all other 24 h monitoring visits (Visits 4 and
6), patients had intraocular pressure measurements at 06:00,
10:00, 14:00, 18:00, 22:00 and 02:00 h. Patients who met the
intraocular pressure inclusion requirements were randomly
assigned, by a computer-generated randomised number list, to
receive either the travoprost/timolol maleate fixed combination
or travoprost for the first 8-week treatment period to be
instilled one drop to the study eye(s) at 20:00. No washout
period was used between groups. The study was designed to
complete washout over the 8-week treatment period before the
efficacy visit.6
A safety evaluation was performed after 2 weeks of treatment
(Visit 3). At the end of Period 1, a 24 h curve was again
performed (Visit 4). Patients were then switched to the second
study medicine for Period 2. A safety visit was again performed
after 2 weeks of treatment (Visit 5), and a final 24 h curve was
performed at the end of the second 8-week treatment period
(Visit 6).
Only the same investigators (DM, KSN) at the clinical site
measured the intraocular pressure and used the same calibrated
instrument (Goldmann applanation tonometer) to perform the
24 h monitoring of the intraocular pressure. During the study
the investigators, staff and patients were masked to the
treatment regimen. The two drugs used were provided in
482

identical bottles (gift by Alcon Laboratories, Fort Worth, Texas).


A dosing coordinator allocated the medications to the patients
according to a code and did not participate in this trial in any
other way. Patients were only aware of the dosing of the study
treatment.
Patients were admitted to the hospital in the morning, and
measurements were recorded at 10:00, 14:00, 18:00, 22:00, 02:00
and 06:00 h. At the 22:00 h measurement, patients were awake
at bed rest. The 02:00 and 06:00 h intraocular pressure
measurements were performed immediately after wakening
and at the slit lamp. Patients were encouraged to carry out a
normal life as much as possible within the hospital boundaries.
Patients were instructed regarding correct medication instillation and compliance. In this study, all patients were instructed
to perform nasolacrimal occlusion for 1 min after instillation of
each study eye-drop. At each visit, local and systemic side
effects that occurred during the treatment period were recorded.
Side effects were evaluated by asking patients a general query
about their state of health. Patients also were asked about their
compliance with the study medicine using a general query.

Statistics
All reported p values were two-tailed, with p,0.05 considered
as significant. This study had an 80% power to identify a
1.5 mm Hg difference between individual time points and
between mean 24 h intraocular pressures assuming a standard
deviation of 2.8 mm Hg between treatments. In patients with
bilateral glaucoma, one eye was randomly chosen at the time of
study enrolment.
Statistical analyses comparing the primary efficacy variable,
24 h intraocular pressure (average intraocular pressure for the
six time points evaluated), was performed using a repeated
measures of analysis because of the contiguous nature of the
data. Furthermore, because of the crossover design, a Matched
Pairs platform was used to test period and carryover effects.7
For secondary efficacy variables, the individual time points
were evaluated with a paired t test within the ANOVA. The
Bonferroni-adjusted p values were calculated to adjust for
multiple comparisons for all individual time points. The mean
24 h intraocular pressure fluctuation (average of the highest
pressure reading minus the lowest pressure reading within the
24 h curve for each patient) and the mean maximum and
minimum intraocular pressure values were analysed with a
paired t test. The number of patients who experienced adverse
events between treatment groups was evaluated with a
McNemar test.8

RESULTS
Patients
All enrolled patients (n = 34) had primary open-angle glaucoma.
The mean age of study patients was 63.9 (9.4) years. Fifteen
patients (44%) were male, and 19 (56%) were female. All were
of Greek ethnic origin. The average central corneal thickness
was 553.7 (27.3) mm, and the average Snellen visual acuity was
0.9 (0.2) (range 0.2 to 1.0). The average cup-to-disc ratio was 0.6
(0.1) (range 0.4 to 0.7), and the average mean deviation was 6.8
(3.0) dB. Four patients (12%) were previously untreated, and 30
(88%) were using previous antiglaucoma therapy, with the most
common therapy being the dorzolamide/timolol fixed combination (n = 10) and the latanoprost/timolol fixed combination
(n = 5).
Thirty-two patients completed the study. Two patients were
discontinued from study medicine prior to 24 h intraocular
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Clinical science
the mean maximum and minimum pressures were significantly
lower with the travoprost/timolol fixed combination therapy
(p,0.001, for both comparisons). No carryover (p = 0.31) or
period effects (p = 0.89) were detected in the present study.

Adverse events
There was no statistical difference between the two treatment
groups for any adverse event (table 3). The most common
adverse event detected was conjunctival hyperaemia, which was
found in 24% (n = 8) of patients treated with travoprost
monotherapy compared with 15% (n = 5) when patients were
treated with the travoprost/timolol fixed combination
(p = 0.25). In all, 24 adverse events were detected in the
travoprost monotherapy group, and 22 were noted in the fixed
combination therapy.

DISCUSSION

Figure 1 Mean 24 h intraocular pressure (IOP) (95% CI) at baseline


(grey line), on travoprost treatment (dotted black line) and on the
travoprost/timolol fixed combination treatment (solid black line).
pressure assessment; one was taking travoprost/timolol fixed
combination and experienced ocular intolerance, and the other
was taking travoprost and was discontinued due to headaches
and gastrointestinal disturbance.

Intraocular pressure
The mean intraocular pressure and the pressure reductions from
baseline are shown in tables 1, 2 as well as fig 1. The intraocular
pressure was significantly reduced from untreated baseline at
each individual time point and for the mean 24 h pressure for
both treatment groups (p,0.001).
When treatments were compared directly, the travoprost/
timolol fixed combination demonstrated lower absolute intraocular pressure levels for the 24 h curve and at all time points
(table 1). When the pressure reduction from untreated baseline
was compared between treatment groups (table 2), the findings
mirrored those of the absolute intraocular pressure.
The mean 24 h intraocular pressure fluctuation was also
significantly lower with the travoprost/timolol fixed combination therapy (3.0, 95% CI 2.6 to 3.4) compared with travoprost
monotherapy (4.0, 95% CI 3.5 to 4.5, p = 0.001). Additionally,

In multicentre, parallel, well-controlled studies, Barnebey and


associates showed that patients treated with the travoprost/
timolol fixed combination dosed in the morning had a further
reduction in intraocular pressure from a baseline of 0.9 to
2.4 mm Hg more than travoprost alone.1 Further, Schuman and
coworkers demonstrated that the mean intraocular pressure
ranged from 16.2 to 17.4 mm Hg with the travoprost/timolol
fixed combination dosed in the morning compared with 15.4 to
16.8 mm Hg in the concomitant travoprost and timolol group.9
In a similar study, Hughes and associates noted the mean
intraocular pressure was from 15.2 to 16.5 mm Hg in the
patients using the travoprost/timolol fixed combination compared with 14.7 to 16.1 mm Hg in the concomitant therapy
group.10
More recently, Denis and coworkers evaluated morning
versus evening dosing of the travoprost/timolol fixed combination in a small, parallel, six-week study and showed there was
no daytime difference with morning (16.516.7 mm Hg) versus
evening dosing (16.117.2 mm Hg).11 In addition, Topouzis and
coworkers in a parallel, multicentre comparison between the
travoprost and latanoprost-based fixed combinations with
morning dosing demonstrated similar daytime efficacy between
the two fixed combinations. Only at the end of the dosing cycle
at the 09:00 measurement across all visits was the travoprostbased fixed combination statistically more effective than the
latanoprost fixed combination.12
The purpose of this crossover trial was to evaluate the 24 h
efficacy and safety of the travoprost/timolol maleate fixed
combination versus travoprost alone, both evening dosed, in
patients with primary open-angle glaucoma.

Table 1 Absolute intraocular pressure (IOP) levels (mm Hg)


Time points

Baseline mean (95% CI)

Travoprost mean (95% CI)

Travoprost/timolol mean (95% CI)

p Value*

06:00
10:00
14:00
18:00
22:00
02:00
24 h IOP
Maximum
Minimum
Fluctuation

27.7
28.9
26.9
26.7
24.9
24.3
26.6
29.8
23.7
6.1

20.0
20.3
19.8
19.8
18.8
18.7
19.6
21.7
17.7
4.0

17.3
17.7
17.2
17.1
16.7
17.1
17.2
18.7
15.7
3.0

0.001{
0.002{
0.002{
0.001{
0.008{
0.047{
,0.001
,0.001
,0.001
0.001

(26.7 to 28.8)
(27.8 to 30.0)
(25.8 to 28.0)
(25.5 to 28.0)
(24.1 to 25.8)
(23.2 to 25.5)
(25.6 to 27.6)
(28.6 to 30.9)
(22.7 to 24.6)
(5.2 to 7.0)

(18.9 to 21.1)
(19.2 to 21.4)
(18.7 to 20.9)
(18.7 to 20.9)
(17.7 to 19.9)
(17.6 to 19.8)
(18.5 to 20.6)
(20.6 to 22.7)
(16.6 to 18.8)
(3.5 to 4.5)

(16.2 to 18.4)
(16.6 to 18.8)
(16.1 to 18.4)
(16.0 to 18.2)
(15.5 to 17.8)
(16.0 to 18.2)
(16.2 to 18,2)
(17.7 to 19.7)
(14.6 to 16.7)
(2.6 to 3.4)

*Between treatments.
{Bonferroni-adjusted p values.

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Clinical science
Table 2 Intraocular pressure (IOP) reduction from baseline (mm Hg)
Time points

Travoprost mean (95% CI)

Travoprost/timolol mean (95% CI)

p Value

06:00
10:00
14:00
18:00
22:00
02:00
Mean 24 h IOP

7.7
8.7
7.2
7.0
6.2
5.7
7.1

10.4
11.3
9.7
9.7
8.3
7.3
9.4

,0.001*
,0.001*
,0.001*
,0.001*
0.002*
0.018*
,0.001

(6.8
(7.8
(6.2
(6.1
(5.2
(4.8
(6.3

to
to
to
to
to
to
to

8.6)
9.7)
8.1)
7.9)
7.1)
6.6)
7.8)

(9.4 to 11.3)
(10.3 to 12.2)
(8.8 to 10.6)
(8.8 to 10.6)
(7.4 to 9.2)
(6.3 to 8.2)
(8.7 to 10.2)

*Bonferroni-adjusted p values; IOP, intraocular pressure; CI, confidence interval.

In this study, the fixed combination provided a lower


intraocular pressure (2.4 mm Hg) over the 24 h curve compared
with travoprost alone. In addition, the intraocular pressure
decrease from untreated baseline was greater with the fixed
combination compared with travoprost alone for the 24 h
diurnal curve (2.3 mm Hg) and for each individual time point.
Overall, for the daytime when generally untreated pressure is
higher, the average pressure difference between the fixed
combination and travoprost therapy alone was between 2.4
and 2.6 mm Hg.
This information is important clinically because it shows
that, compared with morning dosing (last visit diurnal
average:1.7 mm Hg in Barnebey et al1), evening dosed travoprost/timolol fixed combination has the potential to provide
greater separation in pressure, during the daytime, compared
with evening dosed travoprost alone. These results also reflect
previous evidence by Konstas and associates, who demonstrated
that evening dosed latanoprost/timolol fixed combination
provided a greater separation (2.5 mm Hg) from latanoprost
therapy than morning dosing.13
The reason why evening dosing provided a greater separation
from prostaglandin monotherapy in this study is not entirely
clear from our results. Previous research has shown that evening
dosing of a prostaglandin analogue provides better daytime
pressures.13 14 These findings demonstrate that ocular prostaglandins may have a peak effect 12 to 24 h after dosing. When
this peak effect is applied to daytime pressures, which are
generally higher than evening pressures,13 14 by dosing in the
evening, it probably more effectively controls the 24 h mean
pressure.
In the present study the mean 24 h pressure reduction from
baseline for travoprost (26%) was consistent with prior studies

evaluating 24 h efficacy of prostaglandin analogues.15 The 35%


24 h pressure reduction with the travoprost/timolol fixed
combination is higher than what has been observed in several
prior studies with morning dosing for this type of therapy.15
This could be attributed to the higher baseline pressure or the
evening dosing of the fixed combination. Further, previous
studies have noted that travoprost may demonstrate a lower
pressure in the late afternoon compared with latanoprost as
well as a lower 24 h fluctuation.1517 These two potentially
greater clinical effects on intraocular pressure may have
contributed to the enhanced 24 h reduction from baseline for
the travoprost-based fixed combination in this study than
normally observed with other fixed combinations.
Furthermore, the fixed combination manifested significantly
less fluctuation of 24 h pressure versus travoprost monotherapy
when both were dosed in the evening. Prior studies with the
latanoprost/timolol fixed combination had not shown a further
reduction in the 24 h fluctuation compared with latanoprost
alone.13 In contrast, the mean level of 24 h fluctuation of
3.0 mm Hg is the lowest observed among 24 h pressure studies,
described in the prior work by Konstas, Stewart and associates,
of any of pharmaceutical treatment for glaucoma.2 46 13 15 16 18
Some evidence suggests that greater fluctuation in 24 h pressure
may be an independent risk factor, apart from mean pressure, in
progression of glaucoma.19 20 However, the relationship of 24 h
pressure fluctuation to progression as an independent risk factor
remains to be elucidated.
The primary importance of the development of fixed
combinations for glaucoma is that by improving patient
adherence, they may also improve long-term prognosis.
However, the relationship between fixed combinations and
enhanced adherence, or improved prognosis has yet to be

Table 3 Adverse events


Travoprost (n = 34)

Travoprost/timolol (n = 34)

Adverse event*

n (%)

n (%)

p Value

Conjunctival hyperaemia
Foreign-body sensation
Ocular discomfort
Stinging
Itchiness
Hypertrichosis
Headache
Watering
Dry-eye sensation
Superficial punctate epitheliopathy
Systemic hypotension
Gastrointestinal syndrome disturbance
Ocular intolerance
Leg ache

8
0
3
5
2
1
1
1
1
0
0
1
0
1

5
3
2
4
1
1
0
1
1
2
1
0
1
0

0.25
0.25
1
1
1
1
1
1
1
0.5
1
1
1
1

(23.5)
(0)
(8.8)
(14.7)
(5.9)
(2.9)
(2.9)
(2.9)
(2.9)
(0)
(0)
(2.9)
(0)
(2.9)

(14.7)
(8.8)
(5.9)
(11.8)
(2.9)
(2.9)
(0)
(2.9)
(2.9)
(5.9)
(2.9)
(0)
(2.9)
(0)

*Some patients experienced multiple side effects.

484

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Clinical science
demonstrated in a controlled study. Certainly, fixed combinations improve the convenience of glaucoma therapy by reducing
the number of eye-drops, as well as potentially decreasing the
cost of therapy.21
To date, regulatory approvals worldwide and published
literature are based on efficacy and safety comparisons between
fixed combinations and the individual components, or the
concomitant use of both constituents. This approach, however,
does not take into account other important clinical benefits
such as enhanced adherence, improved convenience and reduced
cost to patients.
No differences in side effects between treatment groups were
observed in this trial. However, the study was powered to
detect differences in intraocular pressure and not for safety.
Therefore, greater numbers of patients would probably be
needed to adequately evaluate potential safety differences
between these products.
This study suggests that the evening dosing of travoprost/
timolol fixed combination compared with travoprost alone
provides a further statistical and clinically meaningful intraocular pressure reduction over 24 h in primary open-angle
glaucoma patients.
This study did not evaluate the long-term 24 h efficacy of the
travoprost/timolol fixed combination compared with travoprost alone nor investigated differences in the long-term visual
outcomes between the two medications. In addition, we did not
evaluate directly a morning dosed fixed combination arm in this
study. Further research is needed to elucidate the efficacy of the
morning versus evening travoprost/timolol fixed combination
as well as to other fixed and unfixed therapies.
Funding: The clinical site was supported in part by an unrestricted grant from Alcon.
The administrative site, Pharmaceutical Research Network, LLC, received no financial
support for this study.
Competing interests: None.

3.

4.
5.

6.
7.
8.
9.

10.

11.

12.

13.

14.

15.
16.

17.

18.

Ethics approval: Ethics approval was provided by the Bioethics Committee of the
Medical School of Aristotle University of Thessaloniki.
Patient consent: Obtained.

19.

REFERENCES

20.

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Barnebey HS, Orengo-Nania S, Flowers BE, et al. The safety and efficacy of
travoprost 0.004%/timolol 0.5% fixed combination ophthalmic solution.
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Konstas AG, Lake S, Economou AI, et al. 24-Hour control with a latanoprost-timolol
fixed combination vs timolol alone. Arch Ophthalmol 2006;124:15537.

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Higginbotham EJ, Diestelhorst M, Pfeiffer N, et al. The efficacy and safety of


unfixed and fixed combinations of latanoprost and other antiglaucoma medications.
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exfoliation and primary open-angle glaucoma. Arch Ophthalmol 1997;115:1825.
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latanoprost 0.005%. Am J Ophthalmol 2001;131:7989.
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glaucoma or ocular hypertension. Am J Ophthalmol 2005;140:24250.
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of a combination travoprost 0.004%/timolol 0.5% ophthalmic solution.
Eur J Ophthalmol 2006;16:40715.
Topouzis F, Melamed S, Danesh-Meyer H, et al. A 1-year study to compare the
efficacy and safety of once-daily travoprost 0.004%/timolol 0.5% to once-daily
latanoprost 0.005%/timolol 0.5% in patients with open-angle glaucoma or ocular
hypertension. Eur J Ophthalmol 2007;17:18390.
Konstas AGP, Maltezos AC, Gandi S, et al. Comparison of the 24 hour intraocular
pressure reduction with two dosing regimes of latanoprost and timolol in patients
with open-angle glaucoma. Am J Ophthalmol 1999;128:1520.
Alm A, Stjernschantz J, the Scandinavian Latanoprost Study Group. Effects on
intraocular pressure and side effects of 0.005% latanoprost applied once daily,
evening or morning: a comparison with timolol. Ophthalmology 1995;102:174352.
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Diurnal fluctuation of ocular blood flow


parameters in patients with primary open-angle
glaucoma and healthy subjects
B Pemp, M Georgopoulos, C Vass, G Fuchsjger-Mayrl, A Luksch, G Rainer and
L Schmetterer
Br. J. Ophthalmol. 2009;93;486-491; originally published online 24 Nov 2008;
doi:10.1136/bjo.2008.148676

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Clinical science

Diurnal fluctuation of ocular blood flow parameters in


patients with primary open-angle glaucoma and
healthy subjects
B Pemp,1 M Georgopoulos,2 C Vass,2 G Fuchsjager-Mayrl,2 A Luksch,2 G Rainer,2
L Schmetterer1,3
1

Department of Clinical
Pharmacology, Medical
University of Vienna, Austria;
2
Department of Ophthalmology,
Medical University of Vienna,
Austria; 3 Center for Biomedical
Engineering and Physics,
Medical University of Vienna,
Austria
Correspondence to:
Professor L Schmetterer,
Department of Clinical
Pharmacology, Medical
University of Vienna, Wahringer
Gurtel 1820, 1090 Vienna,
Austria;
leopold.schmetterer@
meduniwien.ac.at
Accepted 3 November 2008
Published Online First
24 November 2008

ABSTRACT
Background/aims: To investigate the fluctuations of
ocular blood flow parameters over 13 h in patients with
primary open-angle glaucoma (POAG) and in healthy eyes,
and to relate these fluctuations with variations in
intraocular pressure (IOP) and mean ocular perfusion
pressure (OPP).
Methods: 15 patients with POAG and 15 control subjects
were included. Measurements of systemic blood pressure
(SBP), fundus pulsation amplitude (FPA), choroidal blood
flow (CHBF), optic nerve head blood flow (ONHBF) and
IOP were performed at 08:00, 12:00, 17:00 and 21:00.
OPP was calculated from IOP and SBP. The coefficient of
variation (CV) was calculated for all individual parameters
to assess their variability.
Results: The time response of the ocular haemodynamic
variables was not different between the groups. Most of
the outcome variables showed significantly larger
fluctuations in patients with POAG compared with healthy
controls (CV: FPA: 0.085 (SD 0.033) vs 0.054 (0.029),
p = 0.012; CHBF: 0.082 (0.030) vs 0.052 (0.023),
p = 0.005; ONHBF: 0.086 (0.044) vs 0.059 (0.032),
p = 0.063). These changes were not associated with OPP
or IOP. Changes over time correlated among the different
ocular haemodynamic outcome measures in patients with
POAG (r = 0.678, r = 0.557, r = 0.545; p,0.04) but not
in the control subjects (r = 0.336, r = 20.227,
r = 20.130; p.0.22).
Conclusion: Patients with POAG show a larger diurnal
fluctuation of ocular blood flow parameters. These
fluctuations appear not to be related to a higher statistical
error of the applied measurement techniques in POAG
patients. These data support the hypothesis that POAG is
associated with vascular dysregulation.

Primary open-angle glaucoma (POAG) is characterised by damage of nerve fibres in the optic nerve
head and ganglion cell loss in the retina leading to
progressive visual-field loss. The pathophysiological mechanisms underlying this disease remain
unclear. For a long time elevated intraocular
pressure (IOP) was considered the only important
factor in the development of glaucoma and to this
day remains the main therapeutic target.
Nevertheless, glaucomatous damage can occur at
normal IOP levels. Additional pathogenetic concepts of POAG were introduced, including abnormal ocular perfusion.1 Building on this theory, it
has been assessed that POAG is associated with
vascular dysregulation of optic nerve head, retina
and choroid, leading to damage by ischaemia/
reperfusion phenomena.2
486

Several studies have evaluated the role of IOP


variation during the day as a risk factor for
glaucoma progression,3 4 and considerable interest
has been directed towards this topic in the recent
years.57 Circadian fluctuation in ocular perfusion
pressure (OPP) also appears to be an independent
risk factor for POAG and normal tension glaucoma.810
The present study aimed to investigate whether
ocular blood flow is subject to larger diurnal
variation in patients with POAG compared with
age-matched control subjects. We performed an
unmasked comparative trial investigating fluctuations of different ocular blood flow parameters
over 13 h during the day and evaluated the
correlation between diurnal variations of three
different ocular blood flow parameters among each
other and with IOP, blood pressure and OPP.

MATERIALS AND METHODS


Subjects
The study was approved by the Ethics Committee
of the Medical University of Vienna and was
performed in conformity with the tenets of the
Declaration of Helsinki. We included 15 patients
with POAG and 15 control subjects with healthy
eyes in this study after informed written consent
was signed. Each subject was examined in a
prestudy screening, which included physical examination and medical history, measurement of blood
pressure and pulse rate, and an ophthalmic
examination including visual acuity testing, measurement of IOP and slit-lamp biomicroscopy and
funduscopy. Glaucoma patients were included if
they featured a POAG with a medical history of
IOP over 22 mm Hg, a cup/disc (C/D) ratio
between 0.4 and 0.9, and mild glaucomatous
defects in three recent visual field tests
(Humphrey Field Analyzer, 30-2 program; Carl
Zeiss Meditech, Dublin, California) with a mean
deviation ,10. An abnormal visual field was
defined as having a glaucoma hemifield test result
outside normal limits and/or a corrected pattern
standard deviation with p,0.05. Patients with
trabeculectomy, laser trabeculoplasty or other
types of glaucoma surgery in their medical history
or with signs of any other ophthalmic disease with
possible vascular involvement such as diabetic
retinopathy, age-related macular degeneration or
retinal vein or artery occlusion were excluded. All
of the patients used topical antiglaucoma therapy
and had actual IOP levels below 22 mm Hg. Ten of
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Clinical science
the POAG patients also took systemic concomitant medication
(table 1).
Inclusion criteria for the age-matched control subjects were
overall normal medical and physical findings, and definite
normal ophthalmic findings. The subjects were matched with
the POAG patients with regard to their IOP levels. Nine of the
15 control subjects took systemic concomitant medication
(table 1). Participants with treated systemic hypertension were
not excluded from the study because of the high prevalence of
this condition in elderly people. Individuals with diabetes
mellitus or uncontrolled severe systemic hypertension with
values above 170 mm Hg systolic blood pressure (SBP) or
100 mm Hg diastolic blood pressure (DBP) were excluded from
both groups. All subjects had to have ametropia of less than
3 dioptres and were asked to refrain from alcohol and caffeine
for at least 24 h before the study day.
All measurements were performed on the same eye at 08:00,
12:00, 17:00 and 21:00 in a darkened room in a seated position
after a resting time of at least 10 min to stabilise haemodynamic
conditions. Stabilisation was verified with repeated blood
pressure measurements.

Measurement of fundus pulsation amplitude by laser interferometry


Ocular fundus pulsation amplitude (FPA) was measured by laser
interferometry. This technique, which enables estimation of the
pulsatile component of choroidal blood flow (CHBF), has been
described by Schmetterer et al.11 Briefly, the eye is illuminated
along the optical axis by a coherent laser beam with a
wavelength of 783 nm. The laser light is reflected at the front
surfaces of the cornea and the retina. The resulting two reemitted light waves produce concentric interference fringes,
which change their pattern synchronously with pulsation. From
the detected interferogram distance changes between corneal
Table 1 Medication and number of glaucoma patients and control
subjects with healthy eyes taking these drugs

Topical medication
Timolol
Timolol+latanoprost
Timolol+dorzolamide
Carbonic anhydrase inhibitors (dorzolamide,
brinzolamide)
Prostaglandin analogues (bimatoprost,
travoprost)
Systemic medication
Beta receptor blockers
Angiotensin-converting enzyme inhibitors
Angiotensin II receptor antagonists
Thiazid diuretics
Sulfonamide diuretics
Calcium-channel blockers
Statins
Levothyroxine
Low-dose acetylsalicylic acid
Phenprocoumon
Molsidomine
Metildigoxin
Betahistine
Nedocromil
Fenoterol
Codergocrine mesylate
Piracetam

Glaucoma
(n = 15)

Healthy
(n = 15)

15
6
3
1
2

10
1
2
1
1

2
4
1
1
1
1
1
1
1

9
1
2
1

2
2
1

2
1

Br J Ophthalmol 2009;93:486491. doi:10.1136/bjo.2008.148676

and retinal surface during the cardiac cycle can be calculated.


The maximum change in corneoretinal distance during one
cardiac cycle is called FPA. In the present study FPA was
measured in the fovea by asking the subjects to fixate the laser
point directly.

Measurement of choroidal and optic nerve head blood flow


We used laser Doppler flowmetry (LDF) to measure CHBF and
optic nerve head blood flow (ONHBF). The principles of LDF
have been described in detail by Bonner and Nossal.12 In brief,
vascularised tissue is illuminated by a beam of coherent laser
light. Scattering on moving red blood cells (RBCs) in tissue
capillaries leads to a frequency shift of the scattered light,
according to the optical Doppler effect. In contrast static
scatterers in tissue do not change light frequency but lead to a
randomisation of light directions impinging on erythrocytes.
This light diffusion in tissue leads to a broadening and shifting
of the spectrum of scattered light, from which the parameters
mean RBC velocity, mean blood volume and mean blood flow
can be calculated in relative units. In the present study we used
a fundus camera-based LDF system (LDV-5000, Oculix, Arbaz,
Switzerland), which has been described in detail previously.13 14
Coherent light with a wavelength of 670 nm was directed to the
fovea to assess subfoveal CHBF and to the intact neuroretinal
rim of the optic nerve to assess ONHBF. In all four
measurements the same spots were investigated for 2 min on
average, depending on the individual fixation skills.

Measurement of IOP and systemic haemodynamics


IOP was measured with a slit-lamp mounted Goldmann
applanation tonometer (Haag-Streit, Bern, Switzerland) after
instillation of two drops of oxybuprocainhydrochloride combined with sodium fluorescein. SBP, DBP and mean arterial
blood pressure (MAP) were measured on the upper arm by an
automated oscillometric device (HP-CMS patient monitor,
Hewlett Packard, Palo Alto, California). Pulse rate was automatically recorded by the same unit from a finger pulse
oxymetric device. The mean OPP was calculated as 2/
36MAPIOP.

Data analysis
The sample size calculation was based on our previously
obtained data.15 16 Using a two-sided alpha error of 5% and a
power of 80%, differences in variability of 25% were detectable
between groups using the present sample size. For the
assessment of variability of all individual parameters, the
coefficients of variation (CV) were calculated using the four
consecutive measurements. In addition, a mixed effects model
was used, including both fixed and random effects (intercept).
Finally, correlations between the changes over baseline of ocular
haemodynamic outcome measures were analysed with linear
regression by the use of univariate modelling. All statistical
analyses were done with the Statistica software package
(Release 4.5, StatSoft, Tulsa, Oklahoma). Data are presented
as means (SD). A two-tailed p,0.05 was considered the level of
significance.

RESULTS
The baseline characteristics of both groups are presented in
table 2.
There were no significant differences between the groups
except for horizontal and vertical C/D ratios which were
significantly higher in the glaucoma patients (ANOVA). The
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Clinical science
Table 2 Subject groups demographics and baseline parameters of
patients with primary open-angle glaucoma and control subjects with
healthy eyes
Glaucoma (n = 15) Healthy (n = 15)
Age
65.4 (10.3)
Gender (male/female)
8/7
Systolic blood pressure (mm Hg)
143.3 (9.6)
Diastolic blood pressure (mm Hg)
72.9 (10.2)
Pulse rate (min21)
75.5 (12.6)
Intraocular pressure (mm Hg)
16.7 (2.1)
Ocular perfusion pressure (mm Hg)
47.9 (7.5)
Optic disc size (mm2)
2.2 (0.5)
Horizontal cup/disc ratio
0.70 (0.10)*
Vertical cup/disc ratio
0.73 (0.09)*
Mean deviation (Humphrey 30-2 visual field) 23.7 (2.9)

64.4 (8.6)
10/5
139.1 (15.2)
77.2 (10.0)
80.6 (7.9)
15.8 (2.5)
51.9 (7.9)
2.3 (0.5)
0.58 (0.10)*
0.59 (0.09)*

Averaged data are presented as means (SD).


*One-way ANOVA was performed to detect differences between the groups, p,0.05.

averaged diurnal measurements of both groups are shown in


fig 1. None of the measured parameters showed any significant
changes in either of the study groups during the period of

observation. Comparison of the two groups failed to show any


differences in the mean values of all outcome parameters,
although haemodynamic parameters were slightly lower in
glaucoma patients (p value range: 0.1010.351). The mean IOP
was between 16.6 and 16.9 mm Hg in POAG patients and
between 15.7 and 15.9 mm Hg in control subjects.
After calculation of the CVs from the four measurements, we
found a significantly larger diurnal variability of the ocular
blood flow parameters FPA (0.085 (SD 0.033) vs 0.054 (0.029),
p = 0.012 between groups) and CHBF (0.082 (0.030) vs 0.052
(0.023), p = 0.005) in patients with POAG as compared with
healthy controls (fig 2). Variations of ONHBF (0.086 (0.044) vs
0.059 (0.032), p = 0.063) and IOP (0.079 (0.032) vs 0.061 (0.021),
p = 0,083) tended to be higher in the glaucoma patients. The CV
for OPP (0.043 (0.017) vs 0.057 (0.029), p = 0.103) was not
significantly different between groups. There was a difference in
MAP variation with a higher variability in healthy controls
(0.025 (0.009) vs 0.040 (0.023), p = 0.023).
Additionally we performed a correlation analysis between the
changes over time of measured and calculated parameters. Here
we present data for the relative changes at 17:00 over 08:00.

Figure 1 Diurnal fluctuation of


measurements from 08:00, 12:00, 17:00
and 21:00. Group mean values (SD),
glaucoma patients represented by black
squares, healthy controls by empty
squares. There is no significant change of
parameters and no significant difference
between groups.

488

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Clinical science

Figure 2 Coefficient of variation (CV) of intraocular pressure (IOP),


mean arterial pressure (MAP), ocular perfusion pressure (OPP), fundus
pulsation amplitude (FPA), optic nerve head blood flow (ONHBF) and
choroidal blood flow (CHBF) calculated from four measurements over the
study period. Data are presented as means (SD). *A mixed effects model
was used to detect significant differences between the groups, p,0.05.

Data for the other times are comparable (data not shown). This
analysis reveals that the changes of all measured ocular blood
flow parameters in both groups were not associated with
fluctuations of IOP (POAG: r,0.055, healthy: r,0.356) or OPP
(POAG: r,20.048, healthy: r,0.119). In patients with POAG
we found consistent and significant correlations between the
changes over time of CHBF and FPA (r = 0.678, p = 0.006),
between ONHBF and FPA (r = 0.557, p = 0.031) and between
CHBF and ONHBF (r = 0.545, p = 0.036) (fig 3). These
correlations were not found in healthy controls.

DISCUSSION
The results of four measurements in 13 h indicate a larger
variability of ocular blood flow parameters in patients with
POAG compared with control subjects. In addition, the
variations of three different measurement techniques for ocular
blood flow correlated only in glaucoma patients but not in
controls. In principle a larger fluctuation of ocular blood flow
parameters in patients with glaucoma may arise from two
different phenomena. On the one hand it may be a result of
reduced reproducibility due to problems like target fixation. On
the other hand a larger fluctuation may arise from a truly larger
variability of ocular blood flow as a consequence of instable
perfusion. Our correlation analysis supports the latter hypothesis. Considering that we did not observe larger fluctuations of
IOP, MAP or OPP in glaucoma, we cannot determine the reason
for this larger variability.
Diurnal changes of ocular blood flow in healthy and
glaucomatous eyes have been assessed in few studies only. In
a previous study we assessed the 12 h reproducibility of CHBF
parameters in healthy subjects including FPA and LDF.15 The
CVs were in the same order as in the current report. In keeping
with our present findings, Claridge and Smith did not find any
significant diurnal variation of pulsatile ocular blood flow
(POBF) in patients with POAG, patients with ocular hypertension and normotensive control subjects during 21 h.17 Harris et al
also did not observe any changes of ophthalmic arterial
Br J Ophthalmol 2009;93:486491. doi:10.1136/bjo.2008.148676

haemodynamics in four colour Doppler imaging measurements


during the night.18 Interestingly enough, Okuno et al found a
significant decrease in optic nerve head perfusion but not of
choroid-retina perfusion at 21:00 versus 09:00 in patients with
normal tension glaucoma using laser speckle measurements.19
Although we did not find any significant reduction in ONHBF
over time, their conclusion of a larger variability of optic nerve
head perfusion in glaucoma patients fits well with the results of
our present study. Comparing the results of these studies the
differences in study populations need, however, to be taken into
account.
As mentioned before, circadian fluctuation in OPP has been
identified as a risk factor for glaucoma.810 We could not find any
significant difference in absolute OPP or OPP fluctuation
between glaucoma patients and healthy controls. However,
the present study indicates that even with comparable IOP and
OPP there is still a difference in the stability of ocular perfusion
between healthy and glaucomatous eyes.
Several studies have presented data of reduced blood flow in
the optic nerve head of glaucoma patients using LDF20 or
scanning LDF.21 22 This could not be observed in the present
study, although all blood flow parameters tended to be lower in
glaucoma patients. A larger sample size may have been required
to find such a difference, but our sample size calculation was
not based on this aim. Also, LDF has some limitations in
assessing ONHBF which have been discussed previously.23
Another limitation of this study is the large number of
participants who used systemic medication. However, the
pharmacological agents taken by the participants in this trial
stem from many different classes, and the few vasoactive
substances may have little implication on the results of this
study.24 The use of topical antiglaucomatous therapy represents
another factor that could have an influence on the findings of
our study. Several studies have investigated the influence of
different topical glaucoma therapy on ocular blood flow, but the
effects are generally considered small.24 Only two treatment
regimen included dorzolamide, which may indeed affect ocular
perfusion.25 However, we cannot completely rule out possible
effects of medication used by the participants, particularly on
diurnal blood flow variability. On the other hand, the fact that
the study groups were well matched for IOP and OPP by the use
of medication allows for a comparison of the variation of blood
flow parameters independent from elevated IOP values in
POAG.
We did not measure blood flow parameters during the night,
because such measurements cannot be done without awakening
the patient. During the night hours, variability in ocular blood
flow may well be higher than during the day, and the
differences between glaucoma patients and healthy controls
may exceed the relatively subtle differences observed in the
present study. In addition, we have only chosen four fixed time
points in the present study, because the measurements were
exhausting for older participants.
In conclusion, the results from this study indicate that
patients with POAG have a larger diurnal fluctuation of ocular
blood flow. Since we observed correlations between these
fluctuations as assessed with different methods, this does not
appear to be related to higher statistical errors in patients. Our
results are therefore compatible with the idea that glaucoma has
characteristics of a low-grade ischaemic disease with dysfunctional regulation of ocular microcirculation. Both circadian IOP
fluctuation and larger ocular blood flow fluctuation may well
contribute to the disease process, although these hypotheses
need to be confirmed in large-scale clinical outcome trials.
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Clinical science

Figure 3 Linear correlations between the changes over time of choroidal blood flow (CHBF) and fundus pulsation amplitude (FPA), of optic nerve head
blood flow (ONHBF) and FPA and of CHBF and ONHBF in glaucoma patients (AC) and control subjects (DF). Relative changes over baseline 17:00
versus 08:00. Solid lines: linear correlations, dashed lines: 95% CI. *Significant correlations.

490

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Clinical science
Competing interests: None.

11.

Ethics approval: Ethics approval was provided by the Ethics Committee of the
Medical University of Vienna.

12.

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Claridge KG, Smith SE. Diurnal variation in pulsatile ocular blood flow in normal and
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Glaucoma detection: the content of optometric


eye examinations for a presbyopic patient of
African racial descent
R Shah, D F Edgar, P G Spry, R A Harper, A Kotecha, S Rughani and B J W
Evans
Br. J. Ophthalmol. 2009;93;492-496; originally published online 5 Dec 2008;
doi:10.1136/bjo.2008.145623

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Clinical science

Glaucoma detection: the content of optometric eye


examinations for a presbyopic patient of African
racial descent
R Shah,1,2 D F Edgar,2 P G Spry,3 R A Harper,4 A Kotecha,2 S Rughani,1 B J W Evans1,2
1

The Neville Chappell Research


Clinic, The Institute of
Optometry, 5662 Newington
Causeway, London, UK; 2 Henry
Wellcome Laboratories for
Vision Sciences, Department of
Optometry and Visual Science,
City University, Northampton
Square, London, UK; 3 Bristol
Eye Hospital, Lower Maudlin
Street, Bristol, UK; 4 Academic
Department of Ophthalmology,
Manchester Royal Eye Hospital,
Oxford Road, Manchester, UK
Correspondence to:
Dr R Shah, The Neville Chappell
Research Clinic, The Institute of
Optometry, 5662 Newington
Causeway, London SE1 6DS,
UK; rakhee19@gmail.com
Accepted 12 November 2008
Published Online First
5 December 2008

ABSTRACT
Aims: Standardised patient (SP) methodology is the gold
standard for evaluating clinical practice. We investigated
the content of optometric eyecare for an early presbyopic
SP of African racial descent, an at-risk patient group for
primary open-angle glaucoma (POAG).
Methods: A trained actor presented unannounced as a
44-year-old patient of African racial descent, complaining
of recent near vision difficulties, to 100 community
optometrists for an audio-recorded eye examination. The
eye examinations were subsequently assessed via a
checklist based on evidence-based POAG reviews, clinical
guidelines and expert panel opinion.
Results: Ninety-five per cent of optometrists carried out
optic disc assessment and tonometry, which conforms to
the UK College of Optometrists advice that those patients
aged .40 years should receive at least two of the
following tests: tonometry, optic disc assessment, visual
field testing. Thirty-five per cent of optometrists carried
out all of these tests and 6% advised the SP of increased
POAG risk in those of African racial descent.
Conclusion: SP encounters are an effective measure of
optometric clinical practice. As in other healthcare
disciplines, there are substantial differences between
optometrists in the depth of their clinical investigations,
challenging the concept of a standard sight test. There
is a need for continuing professional development (CPD) in
glaucoma screening, in which the increased risk of POAG
in those of African racial descent should be emphasised.

The prevalence of primary open-angle glaucoma


(POAG) in the UK population aged .40 years is
estimated to be 2.0%, with 542 000 people
estimated to have the disease and up to 65% of
cases undetected.1 Prevalence is higher in people
described as Afro-Caribbean and West African,
with onset at a younger age compared with people
described as Caucasian.2 Late presentation with
advanced disease is a risk for blindness from
glaucoma.3 Late detection may result from patients
not engaging with community eyecare, from a
failure of health professionals to identify the
disease at an early stage or from unusually rapid
disease progression.
Population screening for glaucoma is not performed in the UK, hence POAG patients are
typically detected through case finding.4 To aid
early detection of glaucoma, the College of
Optometrists (CoO) in the UK advises patients
to have an eye examination every 2 years, and
more frequently if there is a family history of the
condition.5 The CoO advises the public that those
aged .40 years should receive a combination of at
492

least two of the following three tests: optic disc


assessment, tonometry, visual field assessment.6
The Association of Optometrists in the UK takes
the view that for at-risk groups basic field
screening and tonometry are one of the core
units of the Regulation Eye Examination.7
In the UK, most cases of suspected glaucoma are
referred to the hospital eye service by general
practitioners,1 although more than 90% of these
referrals are initiated by optometrists.8 Bowling et
al reported that nearly one-half (45.8%) of all
patients referred to glaucoma clinics were discharged at first visit.8 Detection rates for POAG are
likely to vary across the optometric profession,
because criteria for using screening tests and for
referral of suspected cases have been shown to vary
widely between optometrists.9
There are approximately 10 500 optometrists in
the UK10 and about 95% work as primary care
optometrists in community optical practices.11
These community optometrists are the major
providers of primary eyecare services in the UK.
To investigate the content of typical optometric
community eyecare in England we used a methodology (standardised patients (SPs)) which,
although novel in eyecare, is the gold standard
methodology for the evaluation of clinical practice.12 This paper aims to provide data on the
content of typical optometric eye care in England
for a patient in an at-risk group for POAG
presenting with recent deterioration in her near
vision.
The SP is trained to give consistent verbal and
behavioural responses to the examiner13 in order to
portray a specific complaint accurately.14 In order
to measure everyday clinical practice, it is important for the SPs visit to be unannounced: the
practitioner must not believe that the SP is there to
assess their clinical practice.
The primary research objective of the present
study was to determine whether the eye examination performed by optometrists in England is
appropriate for the detection of POAG. A panel
of glaucoma experts advised on the questions and
tests appropriate for an optometrist examining a
presbyopic patient of African racial origin in this
age group presenting with near vision problems
(tables 1 and 3). It must be stressed that the views
of the panel of experts are not intended to define
good practice, but rather to list possibly relevant
investigations and questions to be assessed in our
research.
Guidance on what an eye examination may
include is published in the CoOs code of ethics and
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Clinical science
guidance for professional conduct. For the routine eye examination this states:15
The optometrist has a duty to carry out whatever tests are
necessary to determine the patients needs for vision care as to
both sight and health. The exact format and content will be
determined by both the practitioners professional judgement
and the minimum legal requirements.

The legal requirements are defined in the Sight Testing


(Examination and Prescription) (No 2) Regulations issued in
1989, following measures contained in the Health and
Medicines Act 1989. The section relevant to the eye examination states:
(1) When a doctor or optician tests the sight of another person it
shall be his duty
(a) to perform for the purpose of detecting signs of injury,
disease or abnormality in the eye or elsewhere
(i) an examination of the external surface of the eye and its
immediate vicinity
(ii) an intraocular examination, either by means of an
ophthalmoscope or by such other means as the doctor or
optician considers appropriate
(iii) such additional examinations as appear to the doctor or
optician to be clinically necessary.

accurate completion of the checklist for those practitioners


(70%) who gave consent for this option.
Quality control of the actors performance was essential. Each
audio-recording was played back by the researcher to ensure
that the checklists were accurately completed. The actor was
monitored every 2025 visits by attending the Institute of
Optometry (London, UK) for an eye examination with a staff
clinician. This eye examination was video-recorded and the
actor completed a checklist in the usual way. The checklist was
compared with the video-recording for inaccuracies, so that any
further instruction could be given if required.
The actor presented as a 44-year-old patient of African racial
origin attending for an eye examination, requesting new reading
spectacles. She was instructed to report no personal or family
history of glaucoma, and did not mention (or indicate any
knowledge of) the increased risk of glaucoma in people of
African origin. The patient had not had an eye examination for
about 2 years. Although patients .40 years old with a close
family history of glaucoma are automatically eligible for NHSfunded community eye care, those of African racial origin are
not. The examination was private as there was no family
history of glaucoma. The script (presenting symptoms and
standardised answers to questions) is summarised in box 1.

RESULTS
METHODS
In research of this type the clinician is the research subject. In
accordance with the tenets of the Declaration of Helsinki,16
research participants should have the right to safeguard their
integrity and should have the right to abstain from participation. Therefore, the informed consent of the participants was a
prerequisite for the study, which is common practice in other SP
research.17
A random selection of 100 optometrists was recruited as
detailed in a previous publication.18 Although the optometrists
were expecting visits from SPs, steps were taken to ensure that
the SP remained undetected. Participating optometrists were
not given any information about the characteristics of the SP,
nor were they aware that their ability to investigate appropriately a patient in a high-risk group for glaucoma was being
assessed. No SP visits took place within 1 month of the
optometrist recruitment. The SP was a professional actor and,
prior to visiting consenting optometrists, she underwent
intensive one-to-one training on the different aspects of an
eye examination.19 This involved use of a document entitled
The journey through an eye examination, which describes an
eye examination in lay terms. The actor observed and received
several eye examinations (some whilst being observed) from
different clinicians at the Institute of Optometry. The actor was
trained to remember and record details of the clinical encounter.
Some eye examinations were video-recorded during the training
to allow for quality control later in the study when it was felt
that it would be helpful to remind the SP of certain tests. The
SP was also given a copy of a video of one of their training eye
examinations on a compact disc. At the end of the training the
actor signed a confidentiality agreement stating that any
information gathered during the eye examinations was confidential and would be used solely for the completion of the
checklist provided.
A pre-designed checklist was completed by the SP immediately after each consultation. The checklist consisted of
questions and tests that the optometrist may or may not have
carried out. The actor used a digital audio-recorder to facilitate
Br J Ophthalmol 2009;93:492496. doi:10.1136/bjo.2008.145623

The participation rate, expressed as the proportion of optometrists who could be contacted and who agreed to participate,
was 27%. Thirty-five per cent of optometrists carried out all
three tests typically used to detect POAG (ophthalmoscopic
assessment of optic discs, tonometry, visual field testing) and
95% carried out both optic disc assessment and tonometry.
Only one optometrist who carried out a visual field assessment

Box 1 A summary of the standardised patient symptoms


and answers to questions asked during an eye
examination
c

Your last eye examination was 2 years ago when you needed
new reading glasses. If asked, you dont think that any other
problems were detected.
Your distance vision appears to be good, but you have recently
been experiencing difficulty whilst reading using your current
spectacles. If asked, you have noticed the deterioration over
the last couple of months and it is worse if you are reading in
poor lighting and when you are tired. You have not
experienced any other visual symptoms (eg floaters, flashes,
double vision).
You are in good health (no diabetes, no high blood pressure),
but you have an underactive thyroid for which you take
thyroxine daily. You dont take any other prescribed
medication. If asked, you attended an eye hospital as a child
because you think you have a lazy eye (left eye). If asked, you
remember having to wear a patch but are not aware of any
surgery or injuries to your eyes. If asked, you dont suffer from
glaucoma. Your father was diabetic (tablet- and dietcontrolled) and has had cataract operations on both eyes.
There is no other family history of any other ocular or medical
condition.
You do drive but did not drive in today. You are a project
manager and spend most of your day using a computer. Your
hobbies are going to the gym and reading.

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Clinical science
and ophthalmoscopy did not carry out tonometry. The results
are summarised in table 1.
Most optometrists (83%) advised a re-examination interval.
Seventy-six per cent advised 2 years, 22% advised 1 year and
two optometrists advised 18 months. At the end of each eye
examination the SP asked the optometrist if she was at a greater
risk of any eye conditions. Ninety optometrists responded to
this question, and responses are listed in table 2.
Table 3 compares the percentages of optometrists working in
independent, small and large multiple optical practices who
performed the tests/procedures suggested by the expert panel as
being appropriate for this patient. The randomisation process
for practitioner selection resulted in the SP visiting 50
independent practices, 34 large multiple pratices and 16 small
multiple practices as defined by Shah et al in 2008.18 On average,
optometrists performed six of the eight tests/procedures
(minimum four, maximum seven).

DISCUSSION
In answer to the primary research question, 35 optometrists out
of the 100 sampled carried out all three of the tests stated by the
CoO as relevant for the accurate detection of POAG. Although
it is encouraging that 95 of the optometrists carried out at least
two of the key tests (ophthalmoscopy and tonometry), it is of
some concern that one optometrist did not carry out any form
of fundus examination and four optometrists did not carry out
tonometry.
An alternative method to the SP approach to gain insight into
optometric clinical activities is through questionnaires,20 notably those administered by the CoO.11 Although useful, these are
subject to sampling bias since conscientious practitioners are
more likely to respond. In addition, there is a further source of
bias, with human nature resulting in replies that indicate higher
standards of practise than may actually pertain. We have
compared our SP-generated data with those from a recent CoO
Table 1 The proportion of optometrists visited by the standardised
patient that asked questions and/or performed tests listed on the
checklist completed by the standardised patient at the end of each
examination

Tests and questions from the checklist

Optometrists that asked


the question/performed
a test (%)

Date of last eye examination


Reason for visit
Have you experienced any pain/discomfort of the eyes?
Previous ocular historyDo you have glaucoma?
Is there a family history of glaucoma?
Anterior segment examination using a slit lamp
Gonioscopy
Fundus examination
Using direct ophthalmoscopy
Using slit lamp biomicroscopy
Using head-mounted indirect ophthalmoscopy
Using a fundus camera
No fundus examination
Tonometry
Using contact tonometry
Using non-contact tonometry
Visual fields
Using full threshold testing
Using supra-threshold testing

94
100
75
30
95
37
0
99
86
22
2
8
1
96
12
84
36
4
32

The proportions shown are based on the entire sample (n = 100). For fundus
examination several optometrists used more than one method.

494

clinical practice survey of UK optometrists (n = 2751). This


wide-ranging survey included questions on tests that would be
performed on a .40-year-old black African-Caribbean adult
with no family history of glaucoma. The survey included
hospital optometrists (3%), who were excluded from our
research, plus optometrists from Scotland (9%) and Wales
(2%), who benefit from expanded scope of practice for NHS
primary eyecare.
The usage of glaucoma screening tests, and the criteria
chosen for referral, varies widely across the optometric
profession.21 Although the SP did not have a family history of
glaucoma, raised intraocular pressure (IOP) or suspiciouslooking discs, it is still disappointing that only 36% of
optometrists carried out a visual field assessment. In the CoO
survey, a comparable 43% of respondents would always carry
out perimetry on a similar patient, although 51% would
perform perimetry sometimes.22
Although most new generation perimeters contain suprathreshold screening programmes, it is interesting to note that
four optometrists carried out full threshold testing, despite the
increased test duration. Advanced visual field loss has been
found in 20% of patients newly diagnosed with POAG. This
could be due to late presentation of patients, failure of
optometrists to carry out visual field tests, inappropriate
interpretation of visual fields or unusually rapid disease
progression. Examinations in small and large multiple practices
were more likely to include visual field screening (50% and 47%)
than in independent practices (24%, chi square = 2.99, p = 0.08).
However, independent practices were more likely than multiples to include full threshold visual field testing in their
examination (chi square = 2.83, p = 0.09). This can be attributed to our finding that a greater proportion of multiple
practices delegate screening tests to trained lay personnel
compared with independent practices.18
The CoO survey (2008) established that at least 80% of
optometrists have access to a non-contact tonometer and 54%
to a Goldmann/Perkins tonometer.22 Optometrists in the
current study demonstrated a preference for non-contact
tonometry (84%) rather than contact tonometry (12%). While
96% of practitioners undertook tonometry, it is of concern that
four optometrists failed to measure IOP in a patient in this age
group and of African racial origin, although all four examined
the fundus and one carried out supra-threshold visual field
screening.
Measurement of IOP alone is not effective for glaucoma
screening.23 Harper and Reeves4 concluded that the diagnostic
accuracy of disc assessment in isolation is inadequate for
screening. Hence, a combined strategy of IOP measurement,
optic disc and visual field assessment is necessary.4 9 23 Visual
field screening should be used routinely, but the challenge is to
design a protocol that can be implemented without imposing
substantial further demands and costs on primary eye care
practitioners.4 Vernon found an increased use of visual field
screeners by optometrists between 1988 and 1993 led to an
increase in the proportion of false positive referrals.24 This
suggests that the use of visual field tests per se does not
necessarily increase the accuracy of referrals for suspect POAG.
However, if a defect is noted during visual field testing,
repeating the visual field testing has been found to reduce false
positive referrals.9 25 Similarly, when raised IOPs were recorded
using non-contact tonometry, repeating tonometry using a
contact tonometer rather than a non-contact tonometer
resulted in an improvement in the accuracy of referrals.26
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Clinical science
Table 2 Responses to the question Am I at a greater risk of any
particular conditions?
Advice given to the standardised patient regarding her risk of
developing any conditions
Optometrists (%)
Not at risk of any conditions
Not at risk of any conditions and advised not to worry
At a low risk of glaucoma as no immediate family history
(relevance of family history as a risk factor explained by
optometrist)
Would only be at a greater risk of developing glaucoma if there
was a family history
Ruled out risks of any conditions after the eye examination
At an increased risk of glaucoma as patient of African racial
descent
Increased risk of glaucoma with age
Regular eye examinations are important for early diagnosis of
any conditions
Important to have regular blood tests to keep a check on
diabetes due to family history of diabetes
Important to keep a regular check on the underactive thyroid

27
12
16

44
14
6
5
2
11
3

The proportions shown are based on the entire sample (n = 100). The values do not
add up to 90 (the number who addressed this question), because several optometrists
recommended more than one option

A benefit resulting from the recent changes to the General


Ophthalmic Services in Scotland was to encourage the use of
dilation, contact applanation tonometry and full threshold field
testing on patients, with the aim of reducing inappropriate
hospital referrals. Optometrists are able to repeat tests and
procedures when necessary by performing a supplementary
examination.27 Ang et al 28 investigated the influence of the new
NHS contract on glaucoma referrals in Scotland. After the
introduction of the new general ophthalmic services (GOS)
contract, there was a statistically significant increase in truepositive referrals (from 18.0% to 31.7%; p = 0.006) and a
decrease in false-positive referrals (from 36.6% to 31.7%;
p = 0.006). In addition, there were increases in the number of
referrals containing information from applanation tonometry
(from 11.8% to 50.0%; p = 0.000), from dilated fundal examination (from 2.2% to 24.2%; p = 0.000) and from repeat visual
fields (from 14.8% to 28.3%; p = 0.004) compared with the
6-month period before the introduction of the new contract.28
Although gonioscopy is one of the tests required for a
complete baseline examination to characterise the glaucoma

type, it is not a core competence which UK optometrists are


expected to possess at registration and is not routinely carried
out in optometric practice. Optometrists may learn the
technique during postgraduate training and 6% have access to
a gonioscope lens.22 However, none of the optometrists visited
carried out anterior chamber angle assessment using gonioscopy. More than 90% of optometrists have access to a slit lamp
bio-microscope,22 but only one-third of optometrists visited
carried out an anterior segment examination. A variety of
approaches to fundus examination was apparent, with 9%
examining the fundus by both monocular direct and binocular
indirect ophthalmoscopy, and 8% taking fundus photographs. It
is encouraging that 22% of optometrists used slit-lamp
binocular indirect ophthalmoscopy on this patient, which is
likely in part to reflect continuing professional development
(CPD) in this area in recent years.
If not already discussed by the optometrist, the SP asked at
the end of the examination if she was at greater risk of any eye
conditions. Only 6% of optometrists discussed the link between
race and glaucoma, which may reflect either lack of knowledge
or a reluctance to alarm the patient. Furthermore, only 5%
discussed the increased risk of glaucoma with age, while 16%
advised the SP that she was at a low risk as there was no
immediate family history, and 44% informed the SP that she
would be at greater risk if there was a family history. All this
suggests there is a need for CPD on the risk factors for
glaucoma, particularly on the link between POAG and race.
There were differences between practitioners in the duration
and depth of their clinical investigations. This is not surprising,
since practitioners are individuals with different levels of
experience, and variations in approach are inevitable. This
highlights that not all eye examinations are identical, suggesting
that a standard sight test does not exist. Overall, the
differences between different types of practice were not
statistically significant, indicating that for a patient of this
type the thoroughness of eyecare cannot be predicted reliably
from the type of practice.
Optometrists who consent to participate in a study of this
nature may be more confident of their skills and may perform
better than those who declined participation.29 Hence, our
results may overestimate performance, although we took
several measures to minimise this risk.18 A potential limitation
is the possibility of practitioners detecting the SP actor during

Table 3 The percentage of optometrists working in independent, small multiple practices and large multiple
practices who carried out tests/procedures felt to be appropriate for this patient by the expert panel
Expert panel recommended tests

Independent
(n = 50) (%)

Small multiple
(n = 16) (%)

Large multiple
(n = 34) (%)

Total sample
(n = 100) (%)

Ask about a family history of glaucoma


Gonioscopy
Fundus examination
Using direct ophthalmoscopy
Using slit lamp biomicroscopy
Using a fundus camera
Tonometry
Using contact tonometry
Using non-contact tonometry
Visual fields
Using full threshold testing
Using supra-threshold testing
Objective assessment of refractive error
Subjective refraction

90
0
98
84
22
14
94
18
76
24
8
16
80
100

100
0
100
88
38
6
100
19
81
50
0
50
75
100

100
0
100
88
15
0
97
0
97
47
0
47
91
100

95
0
99
86
22
8
96
12
84
36
4
32
83
100

The proportions shown are based on the entire sample (n = 100). For fundus examination several optometrists used more than one
method.

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Clinical science
their visit. Participating optometrists were asked to inform the
researchers if they detected the SP. None reported identifying
this SP and nothing that took place during the eye examinations
led the SP to suspect that she had been detected.
Another limitation is that our research only involved
optometrists working within 1.5 h of travel from central
London. We excluded optometrists working in the City of
London, since their practices are likely to have an atypical
patient demographic (eg relatively few children and older
people). It should be noted that improved funding arrangements
and expanded scope of practice for NHS primary eyecare in
Scotland and Wales27 mean that our data are unlikely to reflect
the situation in these regions.
This study has further demonstrated that SP encounters are
an effective way of measuring clinical practice within optometry and should be considered for further comparative measurements of quality of care. As in research using SPs in other
healthcare disciplines,13 14 our research has highlighted a notable
variation in the standards of different practitioners. We suggest
that future CPD could usefully focus on specific criteria and
methods for glaucoma screening, such as indirect ophthalmoscopy and contact tonometry, and specific referral criteria. Most
importantly, we feel that future CPD should emphasise
predisposing factors for POAG, and in particular the increased
risk of glaucoma in people of African racial descent.
Funding: The present work was funded in part by EyeNET, the Association of
Optometrists, the Royal National Institute of Blind People (RNIB), the Central (LOC)
Fund, the American Academy of Optometry (British Chapter) and the College of
Optometrists.
Competing interests: None declared. The views expressed in this publication are
those of the authors and not necessarily those of any of the funding organisations. The
funding sources had no role in the design, conduct, or reporting of the study or in the
decision to submit the manuscript for publication. The researchers had open and full
access to all the data files for the study and had full control over the data.
Ethics approval: Obtained.
Patient consent: Obtained.
RS, DFE and BJWE are members of EyeNET, the primary care eye research network
supported by the Department of Health.

4.
5.

6.

7.
8.
9.
10.
11.
12.
13.
14.

15.

16.
17.

18.
19.

20.
21.
22.
23.
24.
25.
26.

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Intraocular pressure control and fluctuation: the


effect of treatment with selective laser
trabeculoplasty
M Nagar, E Luhishi and N Shah
Br. J. Ophthalmol. 2009;93;497-501; originally published online 23 Dec 2008;
doi:10.1136/bjo.2008.148510

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Clinical science

Intraocular pressure control and fluctuation: the


effect of treatment with selective laser
trabeculoplasty
M Nagar, E Luhishi, N Shah
Clayton Hospital, The Mid
Yorkshire Hospitals NHS Trust,
Northgate, Wakefield, UK
Correspondence to:
Ms M Nagar, Clayton Hospital,
The Mid Yorkshire Hospitals
NHS Trust, 1 Woodthorpe Park
Drive, Sandal, Northgate,
Wakefield WF2 6HY, UK;
madhunagar@hotmail.com
Accepted 28 November 2008
Published Online First
23 December 2008

ABSTRACT
Aims: To evaluate the effect of selective laser
trabeculoplasty (SLT) on intraocular pressure (IOP) control
and diurnal tension curves of patients with open-angle
glaucoma (OAG) and ocular hypertension (OHT), and to
compare this effect with that of latanoprost.
Methods: Forty patients were randomised to receive
either SLT or latanoprost. IOP control was evaluated by
comparing pretreatment values with post-treatment
measurements on day 3, week 1, month 1 and 4
6 months; success was defined as 20% decrease in IOP.
Tension curves were plotted prior to treatment and 4
6 months afterwards; success was 50% reduction in
fluctuation.
Results: SLT decreased pressure by 4.7 mm Hg on
average (95% CI 3.6 to 5.7 mm Hg; p,0.01). The
reduction was similar for latanoprost at all follow-ups
except month 1; 75% of SLT patients and 73% of
latanoprost patients achieved success in IOP control
(p = 0.4). SLT significantly reduced IOP fluctuation, but
latanoprost was more effective (3.6 mm Hg, 95% CI 3.2
to 3.9 mm Hg vs 2.5 mm Hg, 95% CI 2.2 to 2.9 mm Hg
for SLT; p = 0.04). Success in fluctuation reduction was
50% for SLT and 83% for latanoprost (p = 0.045).
Conclusions: Both SLT and latanoprost had a significant
impact on IOP control and fluctuation. While latanoprost
may be more likely to reduce IOP fluctuation, SLT has the
benefit of being a one-time intervention not requiring
ongoing patient compliance.

Intraocular pressure (IOP) is no longer part of the


formal definition of glaucoma but pressure still
matters. Elevated IOP is the major risk factor for
the development and progression of glaucoma, and
it is the only modifiable risk factor. We also know
that IOP is a variable variable, as it fluctuates
with time. A single IOP measurement, especially if
done in the first hours of the afternoon, is not
sufficient to evaluate correctly the IOP-related risk
in glaucoma patients.1 Asrani et al found a strong
relationship between large diurnal fluctuations of
IOP and glaucoma progression, and proposed
diurnal intraocular pressure as an independent risk
factor for the progression of glaucoma.2 It is still
not clear what is more damaging to the retinal
ganglion cells and optic nervespeak IOP, mean
IOP or fluctuating IOPbut the aim of management is to achieve a target IOP with minimal
diurnal fluctuation. Measuring these fluctuations,
however, is a challenging task that must take into
account the circadian cycle of IOP, the effect of
posture and the varying effects of pharmacological
or surgical intervention.
Br J Ophthalmol 2009;93:497501. doi:10.1136/bjo.2008.148510

Prostaglandin analogues are known to reduce


diurnal IOP fluctuation,35 but failure to take
medication correctly and missed appointments
present major barriers to successful treatment
outcomes. Even simple medication regimens may
not be complied with, since, until late in the
disease, the only symptoms may be the side effects
of the medication. Patients are sometimes unaware
of poor compliance or they are hindered by
physical inability and therefore unable to use eyedrops adequately. Such problems are compounded
because the physician often is unable to determine
whether and to what extent a patient is not
complying with therapy.6
Surgery is an alternative approach for the
reduction in IOP and flattening of the diurnal
curve. Argon laser trabeculopasty (ALT) and
selective laser trabeculopasty (SLT) have both been
used in glaucoma management. Medeiros and
colleagues observed significantly less IOP fluctuation following trabeculectomy as compared with
medical treatment.7 Unlike ALT, SLT facilitates
aqueous flow through the trabecular meshwork
without causing any significant damage to it.8 Its
ability to reduce IOP has been demonstrated.911
There has been one previous published investigation showing a decrease in IOP fluctuations
following SLT,12 but this was a small pilot study.
The aim of this study was to evaluate the effect
of SLT on IOP control and diurnal tension curves
of patients with OAG and OHT. This treatment
effect was compared with that of the prostaglandin analogue, latanoprost.

MATERIALS AND METHODS


The study was designed as a prospective, randomised, masked trial. It was conducted at the
Clayton Eye Centre, Wakefield, West Yorkshire,
UK, and Medical Ethics Committee approval was
obtained. Fifty-three consecutive patients with
newly diagnosed OHT or primary OAG were
assessed. Of these, 13 were excluded, as they did
not meet the inclusion/exclusion criteria (table 1);
40 patients did meet the criteria and were
recruited. Before entry into the study, informed
consent was obtained. Patients underwent a
detailed examination including a full ocular and
medical
history,
visual-field
assessment
(Humphrey 242 perimetry), slit-lamp biomicroscopy, gonioscopy, pachymetry, mydriatic funduscopy and Goldmann tonometry at different time
points throughout the day. A diurnal tension curve
was plotted using IOPs recorded at 08:00, 11:00,
14:00 and 18:00. The difference between the peak
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Clinical science
Table 1 Patient recruitment inclusion and exclusion criteria
Inclusion criteria
Patients with open-angle glaucoma
Aged 4080 years
Newly diagnosed as having open-angle glaucoma
Diurnal intraocular pressure fluctuation more than 3 mm Hg
A classification of outside normal limit involving same visual-field area at two initial prescreening visits using glaucoma hemifield test
Borderline classification was acceptable only if obvious glaucomatous optic disc cupping was present in an area corresponding to the visual-field defect
Willing to undergo selective laser trabeculopasty versus latanoprost treatment trial
Patients with ocular hypertension
Aged 4080 years
Newly diagnosed as having ocular hypertension
Diurnal intraocular pressure fluctuation of more than 3 mm Hg
Intraocular pressure between 24 and 32 mm Hg in one eye and 21 and 32 mm Hg in the other (determined on two visits)
Normal optic disc
Normal visual field using Humphrey visual field on two separate screening visits
No evidence of glaucomatous damage
Willing to undergo selective laser trabeculopasty versus latanoprost treatment trial
Exclusion criteria
Diurnal intraocular pressure fluctuation of less than 3 mm Hg
Diagnoses other than open-angle glaucoma and ocular hypertension (eg, patients with narrow angles, congenital glaucoma)
Advanced glaucoma
Normal tension glaucoma
Previous laser or surgical glaucoma invention or any previous anterior segment surgery
Pregnancy
Ocular condition precluding visualisation of trabecular meshwork
Impairment preventing adequate understanding to sign an informed consent or cooperate during study procedures
Potential need for other ocular surgery within the 46-month follow-up period
Unable to comply with intended follow-up visits

and trough IOP recorded in the diurnal curve was noted as the
diurnal fluctuation.
Following this examination, patients were randomised into
one of the two treatment groups: SLT or latanoprost.
Randomisation was performed using a sealed, shuffled envelope
system. Cards were placed into identical sealed envelopes,
which were shuffled several times and sequentially numbered.
No patient identifiers were used and none of the individuals
involved in generating the randomisation took any further part
in the study. The envelopes were kept in a locked drawer, which
was accessed just prior to treatment when the next numbered
envelope was opened and the patient allocated to the group
according to the modality written on the card. If indicated, both
eyes of each patient received identical treatments on the basis of
randomisation. However, only one eye of each patient was
entered into the study. It was not possible to mask the treating
ophthalmologist (MN) or the patient due to the nature of
interventions, but the two observers responsible for follow-up,
data collection and analysis (NS and EL) were masked to the
patients group allocation.

SLT treatment group


The laser used was the Ellex Tango ophthalmic laser system
(Ellex, Adelaide, Australia), a frequency doubled, q-switched
Nd:YAG laser emitting at 532 nm, with a pulse duration of
3 ns, a spot size of 400 mm and pulse energies ranging from 0.2
to 1.4 mJ, coupled to a slit-lamp delivery system with a HeNe
aiming system. One surgeon (MN) performed the laser
procedures. Immediately prior to treatment, an application of
amethocaine 1% was instilled into the eye. The patient was
seated at the slit lamp, a single mirror goniolens was used, and
the laser was focused on the trabecular meshwork. Using a
400 mm spot the entire width of the trabecular meshwork was
irradiated with each pulse. The laser energy was initially set at
498

0.8 mJ, and a single pulse was delivered at the 12 oclock


position. If cavitation bubbles appeared, the energy was reduced
by 0.1 mJ increments until no bubble formation or fine
champagne bubbles were observed and treatment continued at
this energy level. If no cavitation bubbles occurred, the energy
was increased by increments of 0.1 mJ until bubble formation
and then decreased as described above. The entire meshwork
was treated with 100 (SD 5) non-overlapping spots. The total
number of pulses and the energy delivered were recorded.
Postoperatively, non-steroidal anti-inflammatory drops (ketorolac tromethamine), were prescribed four times a day for
5 days.

Latanoprost treatment group


Patients allocated to this group were instructed to instil one
drop of latanoprost 0.005% into the eye every night.
Compliance was stressed, and any questions that the patients
had were addressed during the teaching session.
All patients in both treatment groups were evaluated by one
of the two masked observers at day 3, week 1, month 1 and at
final follow-up which occurred between months 4 and 6. IOP
control was evaluated by comparing the baseline measurement
with the value obtained at each follow-up. On each occasion,
Table 2 Intraocular pressure reduction at each follow-up
visit adjusted for baseline intraocular pressure (SE)
Follow-up

Selective laser
trabeculoplasty

Latanoprost

Day 3
Week 1
Month 1*
Months 46

5.7
3.6
3.2
6.2

5.7
5.3
7.0
7.8

(0.7)
(0.7)
(0.8)
(0.8)

(0.7)
(0.8)
(0.7)
(0.8)

*Significantly different by Tukey HSD test at p,0.05.

Br J Ophthalmol 2009;93:497501. doi:10.1136/bjo.2008.148510

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Clinical science
Table 3 Percentage of patients with successfully controlled intraocular pressure in study eye
Follow-up

Selective laser trabeculoplasty (%)

Latanoprost (%)

Odds ratio* (95% CI)

p Value

Day 3
Week 1
Month 1
Months 46

63
45
41
75

37
56
67
73

0.81
2.20
6.21
1.65

0.6
0.08
0.003
0.4

(0.35
(0.92
(1.72
(0.52

to
to
to
to

1.92)
6.22)
51.10)
6.07)

*Odds ratio for success with latanoprost versus selective laser trabeculoplasty, adjusted for baseline intraocular pressure.

this measurement was taken in the morning within the same


2 h period. The observers were instructed not to ask questions
regarding mode of treatment, and patients were advised not to
discuss their treatment with these doctors. Instead, patients
were provided with the chief investigators (MN) contact
details, and if there were any questions or concerns, these were
dealt with separately to the study follow-ups.
At the final follow-up visit (between 4 and 6 months
postintervention) Goldmann tonometry was performed to
assess IOP control, and the measurement was repeated at
08:00, 11:00, 14:00 and 18:00 to create a diurnal tension curve.
Treatment success for IOP control was defined as at least a 20%
reduction from baseline measurement. For IOP fluctuation,
success was defined as at least a 50% reduction in the
fluctuation. At the end of the study, eyes that had not achieved
adequate IOP control were treated with laser or latanoprost at
the discretion of the chief investigator.

Statistical analysis
A power analysis statement was calculated by the statistician
based on 0.9 power to detect a significant difference in
fluctuation of IOP between the groups (p = 0.05, two-sided),
and assuming an SD of 2 mm Hg, it was estimated that 16 eyes
were required for each study group. We deemed this number
suitable for a feasibility study. If both eyes were treated, only
one eye was chosen for analysis using a random number
generator. Independent-samples t tests were used to compare
the two treatment groups at baseline and to compare those
with partial versus complete follow-up. The difference between
IOP prior to treatment and at each follow-up visit was
calculated. These difference scores were analysed with linear
mixed models to determine whether there were any differences
in IOP control between treatment groups at each follow-up.
Logistic regression was used to evaluate whether there were any
differences in success of IOP control between treatment groups.
All models were adjusted for baseline IOP to reduce the
influence of regression to the mean effects. The statistical
analyses included baseline IOP or baseline IOP fluctuation as
covariates in the models. IOP fluctuation was defined as the
maximum minus the minimum of the diurnal tension curves.
The difference in IOP fluctuation (peak minus trough) between
the baseline tension curve and the post-treatment tension curve
was calculated, and an analysis of covariance was used to
determine whether the IOP fluctuation difference varied with
treatment. Logistic regression was used to assess the difference
in successful control of IOP fluctuation between treatment
groups. All IOP fluctuation analyses were adjusted for baseline
fluctuation. Statistical analyses were performed with SAS JMP
(V7.01, SAS Institute, Cary, North Carolina).

RESULTS
Of the 40 patients, 21 (52%) were male, 19 (48%) female, and all
were Caucasians (100%). The mean age was 66.4 years (range
Br J Ophthalmol 2009;93:497501. doi:10.1136/bjo.2008.148510

43 to 88). Seventeen patients (43%) had the diagnosis OAG, and


23 (57%) were OHT.
Twenty patients were randomised to the latanoprost treatment group and 20 patients to the SLT group. There were no
significant differences between the two treatment groups in
terms of age, sex, race, aetiology of raised IOP or follow-up.
However, there was a difference between the groups for
baseline IOP (p = 0.017). Of the 40 patients, 30 attended all
appointments. Analysis of those with complete (n = 30) versus
incomplete (n = 10) follow-up showed there to be no significant
difference in age, sex, treatment assigned or baseline IOP (all
p.0.4). Incomplete follow-up occurred mainly because of the
short interval between the standard clinic appointment and the
study appointment to monitor diurnal fluctuation.

IOP control
For the SLT group, the mean IOP prior to treatment was 26.1
(4.0) mm Hg. In the latanoprost group, the mean baseline IOP
was significantly lower at 22.8 (4.5) mm Hg (p = 0.017). SLT
lowered the IOP significantly (mean reduction across all followup visits 4.7 mm Hg; 95% CI 3.6 to 5.7; p,0.01), and the
treatment effect was similar for both groups at all follow-ups
except the 1-month assessment. At this appointment, there was
a greater treatment effect with the latanoprost group, that is, a
mean reduction of 7.0 mm Hg versus 3.2 mm Hg (p,0.05).
However, in the longer term, at the 46-month follow-up, the
treatment effect was not significantly different: the absolute
reduction was 6.2 mm Hg with SLT as compared with a
7.8 mm Hg reduction in the latanoprost group. The treatment
effects at each follow-up visit are given in table 2 and illustrated
in fig 1.
In terms of success in IOP control, the percentage of patients
in the treatment groups achieving control at each follow-up is
shown in table 3. The odds of success were the same for the two

Figure 1 Mean intraocular pressure reduction (IOP) at each follow-up


visit, adjusted for baseline intraocular pressure. Error bars indicate SEM.
SLT, selective laser trabeculoplasty.
499

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Clinical science
treatments except the month 1 follow-up when latanoprost
provided a greater success (odds ratio 6.25; CI 1.72 to 51.10;
p = 0.003). At the final follow-up, 75% of patients in the SLT
group and 73% in the latanoprost group achieved success in IOP
control (p = 0.4).

IOP fluctuation
Diurnal tension curves measured prior to treatment and at final
follow-up showed that SLT had a significant impact on IOP
fluctuation. The mean IOP fluctuation (peak minus trough) for
this treatment group was 5.5 (2.7) mm Hg and a reduction of
2.3 (2.4) mm Hg, that is, 41% reduction in IOP fluctuation was
achieved after treatment (p = 0.0007). In comparison, the
latanoprost group had a mean IOP fluctuation of 5.7
(2.1) mm Hg, which decreased by 3.7 (2.8) mm Hg
(p,0.0001), that is, 64% reduction in IOP fluctuation was
achieved after treatment. After adjustment for baseline IOP
fluctuation, there was a significant difference between treatments, with the latanoprost group having a greater reduction in
fluctuation (3.6 vs 2.5 mm Hg; p = 0.0444). The mean IOP
fluctuation is shown before and after treatment for both SLT
and latanoprost in fig 2.
Treatment with SLT was successful in lowering IOP
fluctuation in 50% of patients, whereas latanoprost showed
success in 83% of cases. After adjustment for baseline IOP
fluctuation, success was more likely for latanoprost than for
SLT (odds ratio 2.25; CI 1.01 to 5.67; p = 0.049).

DISCUSSION
The importance of IOP fluctuation was identified by the
pointwise, linear regression analysis of the AGIS patients
reported by Nouri-Mahdavi et al.13 IOP fluctuation remained a
significant predictor of visual field (VF) worsening despite
inclusion of mean IOP and the number of glaucoma interventions as an independent covariate in the regression models.
When multivariate logistic regression was repeated, excluding
IOP fluctuation, the mean IOP reached statistical significance
(p = 0.045) along with age, number of surgical interventions and
male gender. The low correlation between IOP fluctuation and
mean IOP during follow-up and the less significant p value for
the latter after exclusion of IOP fluctuation from the multivariate analysis suggest that IOP fluctuation is an independent
and stronger predictor than mean IOP for VF progression. It was
also found that each 1 mm Hg increase in IOP fluctuation

equated to an approximately 30% increase in the risk of VF


progression. In summary, the two parameters in AGIS
consistently associated with VF progression were greater IOP
fluctuation and older age at first glaucoma intervention. In our
study, both treatment modalities had a significant impact on
IOP fluctuation, with SLT successfully lowering IOP fluctuation
in 50% of patients and latanoprost in 83% of patients. The
response rate and IOP reduction in this present study were
comparable with those reported in published literature in which
the success rate varies from 64% to 89%.1416
The crossover study of Orzalesi et al comparing three
prostaglandin analogues found no significant difference
between these agents in their ability to lower IOP during the
24 h circadian cycle.4 Other studies have reported conflicting
findings, however.17 18 Although it is unclear if one of the
prostaglandin analogues is superior to others in its ability to
damp IOP fluctuation, the prostaglandin analogues, as a class,
appear to provide significant IOP reduction throughout the 24 h
circadian cycle. Our study clearly supports the concept that
latanoprost damps IOP fluctuation, and it demonstrates the
ability of SLT to have a significant effect, too. This study has
also confirmed the well-established benefit of SLT in controlling
the mean IOP, which was comparable with that of the
prostaglandin analogues.19 However, SLT has the advantage of
not being dependent on patient compliance. This fact alone
may influence long-term success in some patients.
We recognise that our study is limited by the number of
patients and the difference between the treatment groups
baseline IOPs. A study with increased patient recruitment and,
ideally, 24 h IOP monitoring would be helpful. Higher peak
pressures can occur during sleep at night, but these are difficult
to diagnose. Such elevated night-time pressures might be at
least a partial explanation why seemingly well-controlled
patients show glaucomatous progression.2023
An observation worthy of comment was the presence of some
slow/late responders in the SLT group. In a large number of
instances, the response was predominantly immediate (IOP
reduction noted on week 1), but there were a few late
responders (1015%) who showed an IOP reduction between
4 and 12 weeks post-treatment, hence the difference in IOP
reduction at months 1 and 4 (table 2).
More research is needed to determine the best treatment
indications and stepwise therapies, particularly in relation to
long-term compliance by the patient. SLT is a realistic firstoption choice in some cases, even in those with significant IOP
fluctuation, although further research will help to establish the
optimum role for SLT.
Competing interests: None.
Ethics approval: Ethics approval was provided by the Research and Ethics
Committee, Pinderfields & Pontefract NHS trust.

REFERENCES
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Figure 2 Mean intraocular pressure (IOP) fluctuation before and after


treatment for selective laser trabeculoplasty (SLT) and latanoprost. Error
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Asrani S, Zeimer R, Wilensky J, et al. Large diurnal fluctuations in intraocular
pressure are an independent risk factor in patients with glaucoma. J Glaucoma
2000;9:13442.
David R, Zangwill L, Briscoe D et al. Diurnal intraocular pressure variations: an
analysis of 690 diurnal curves. Br J Ophthalmol 1992;76:2803.
Orzalesi N, Rossetti L, Bottoli A, et al. Comparison of the effects of latanoprost,
travoprost and bimatoprost on circadian intraocular pressure in patients with
glaucoma or ocular hypertension. Ophthalmology 2006;113:23946.
Dubiner HB, Sircy MD, Landry T, et al. Comparison of the diurnal ocular hypotensive
efficacy of travoprost and latanoprost over a 44 hour period in patients with elevated
intraocular pressure. Clin Ther 2004;26:8491.

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Realini T. Selective laser trabeculoplasty: a review. J Glaucoma 2008;17:497502.
Latina MA, Sibayan SA, Shin DH, et al. Q-switched 532-nm Nd:YAG laser
trabeculoplasty (selective laser trabeculoplasty). Ophthalmology 1998;105:208290.
Gracner T, Pahor D, Gracner B. Efficacy of selective laser trabeculoplasty in the
treatment of primary open angle glaucoma. Klin Monatsbl Augenheilkd
2003;220:84852.
Hollo G, Kothy P, Toth M. Influence of selective laser trabeculoplasty on the 24-hour
diurnal intraocular pressure fluctuation in primary open-angle glaucoma: a pilot study.
Invest Ophthalmol Vis Sci 2007;48:E-Abstract 3979.
Nouri-Mahdavi K, Hoffman D, Coleman A, et al. Predictive factors for glaucomatous
visual field progression in the Advanced Glaucoma Intervention Study. Ophthalmology
2004;111:162735.
Melamed S, Ben Simon GL, Levkovitch-Verbin H. Selective laser trabeculoplasty as
primary treatment for open-angle glaucoma: a prospective, non-randomized pilot
study. Arch Ophthalmol 2003;121:95760.
Kano K, Kuwayama Y, Mizoue S, et al. Clinical results of selective laser
trabeculoplasty. Nippon Ganka Gakkai Zasshi 1999;103:61216.

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Noecker RS, Dirks MS, Choplin NT, et al. A six-month randomized clinical trial
comparing the intraocular pressure-lowering efficacy of bimatoprost and latanoprost
in patients with glaucoma and ocular hypertension. Am J Ophthalmol 2003;135:55
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Denis P, Launois R, Devaux M, et al. Comparison of diurnal intraocular pressure
control by latanoprost versus travoprost: results of an observational survey. Clin Drug
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Nagar M, Ogunyomade A, OBrart DPS, et al. A randomized prospective study
comparing selective laser trabeculoplasty with latanoprost for the control of
intraocular pressure in ocular hypertension and open angle glaucoma. Br J Ophthalmol
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501

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Comparison of A-scan and MRI for the


measurement of axial length in silicone oil-filled
eyes
G Bencic, Z Vatavuk, M Marotti, V L Loncar, I Petric, B Andrijevic-Derk, J Skunca
and Z Mandic
Br. J. Ophthalmol. 2009;93;502-505; originally published online 15 Dec 2008;
doi:10.1136/bjo.2008.147868

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Clinical science

Comparison of A-scan and MRI for the measurement


of axial length in silicone oil-filled eyes
G Bencic,1 Z Vatavuk,1 M Marotti,2 V L Loncar,1 I Petric,1 B Andrijevic-Derk,1 J Skunca,1
Z Mandic1
1

University Department of
Ophthalmology, University
Hospital Sestre milosrdnice,
Zagreb, Croatia; 2 University
Department of Radiology,
University Hospital Sestre
milosrdnice, Zagreb, Croatia
Correspondence to:
Dr G Bencic, University
Department of Ophthalmology,
University Hospital Sestre
milosrdnice, Vinogradska 29,
Zagreb, Croatia; goranbencic@
hotmail.com
Accepted 9 November 2008
Published Online First
15 December 2008

ABSTRACT
Aims: The aim of the study was to compare the accuracy
of A-scan biometry and MRI for the measurement of axial
length in silicone oil-filled eyes.
Methods: This was a prospective randomised study of
70 patients. Biometry was performed using MRI in 33
patients (MRI group) and A-scan echography in 37
patients (A-scan group). The difference between predicted and final refraction was measured and evaluated
statistically.
Results: In patients with axial length >26 mm, the mean
deviation of the final from predicted refraction was 21.23
(SD 0.67) D in the MRI group and 22.3 (SD 2.02) D in the
A-scan group. The difference between these two groups
was statistically significant (p = 0.02). In patients with
axial length ,26 mm, the mean deviation of the final
from predicted refraction was 20.12 (SD 1.29) D in the
MRI group and 20.33 (SD 1.39) D in the A-scan group.
There was no statistical significance between the two
groups (p = 0.629).
Conclusion: For highly myopic patients MRI biometry
was a more accurate measurement of axial length in
silicone oil-filled eyes. A-scan and MRI biometry were
comparably accurate in measuring axial length in patients
with axial length ,26 mm.

Silicone oil endotamponade has been used in


vitreoretinal surgery for complex cases of retinal
detachment for almost 50 years.1 The most
frequent indications for pars plana vitrectomy
followed by intravitreal silicone oil injection are:
retinal detachment complicated with proliferative
vitreoretinopathy, retinal redetachment, severe
proliferative diabetic retinopathy and trauma.24
Cataract is the most common complication after
intravitreal injection of the silicone oil. Silicone oil
removal can then be combined with cataract
extraction to avoid further surgery.57 This surgical
procedure demands accurate axial length measurement and precise calculation of intraocular lens
(IOL) power.
Biometry of silicone oil-filled eyes is difficult to
perform and measurements may not always be
obtainable. Using ultrasonographic biometry in
silicone oil-filled eyes has several disadvantages.810
Silicone oil slows down the speed of sound, making
the axial length appear to be longer. The absorption of sound waves in silicone oil results in poor
penetration, thus further impairing the measurement. Finally, multiple fluid interfaces can also be
a source of error in axial length measurements.
Optical biometry has recently been introduced
as an alternative method for IOL calculation.11 The
main drawback of this method is the inability to
502

perform the measurement in patients with dense


cataracts and poor fixation, with a reported rate of
measurement failure of 438%.1215 X-ray computed
tomography measurement of axial length in
silicone oil-filled eyes has also been reported.16
To the best of our knowledge, the use of MRI for
axial measurement in silicone oil-filled eyes has not
been previously described in literature. The aim of
this study was to compare the accuracy of A-scan
and MRI biometry for measuring axial length in
silicone oil-filled eyes.

MATERIALS AND METHODS


For this randomised prospective study we recruited
81 patients in the University Department of
Ophthalmology, University Hospital Sestre
milosrdnice, Zagreb, Croatia, from September
2004 to June 2006. Patients undergoing phacoemulsification and silicone oil removal were
enrolled. All patients had previous pars plana
vitrectomy with scleral buckle and silicone oil
endotamponade due to rhegmatogenous retinal
detachment, or vitrectomy with silicone oil endotamponade in cases where scleral buckle surgery
had failed. Exclusion criteria were: more than two
previous surgeries, presence of tractional retinal
detachment or retinal detachment resulting from
penetrating eye injury. The study was approved by
the hospital ethical committee and was consistent
with the principles of the Declaration of Helsinki.
All patients signed an informed consent before
entering the study.
A-scan and MRI biometry were performed in all
patients for the purpose of the study. A-scan
biometry was carried out using an ALCON
Ultrascan (Alcon Laboratories, Fort Worth, TX,
USA) with patients sitting upright. In this position
the silicone oil is in contact with the macula,
reducing the possibility of false measurement. In
order to eliminate the axial length magnification
caused by the silicone oil, the velocity of the sound
in a silicone oil-filled eye was changed to 987 m/s.
MRI biometry was performed using a SIEMENS
Magnetom Harmony 1.5 T (Siemens AG, Munich,
Germany). Average axial eye length was obtained
from six separate MRI biometry measurements.
Every measurement was carried out using the
computer terminal of the MRI device to take the
best cross-section through the eyeball. The best
cross-section was where both lateral eye muscles
were visible, or where the lens and/or optical nerve
cross-section were the thickest. The distance
between corneal apex and fovea centralis was
considered to be the axial distance (fig. 1).
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Clinical science
RESULTS
Eighty-one patients were recruited. Seventy patients completed
the 6-month follow-up (table 1). Eleven patients were excluded
from final analysis because of retinal re-detachment (n = 10)
and loss to follow-up (n = 1). There was no statistically
significant difference in age (p = 0.856), sex (p = 0.153), number
of previous procedures (p = 0.378), duration of silicone oil
endotamponade (p = 0.213), incidence of silicone oil complications (p = 0.849) and intraocular pressure (p = 0.341) between
the MRI and A-scan groups. However, statistically significant
differences between preoperative and postoperative visual
acuity were noted on each follow-up visit in the MRI
(p = 0.009) and A-scan (p = 0.007) groups.

Comparison of refractive error for the MRI and A-scan groups

Figure 1 MRI axial length measurement in a silicone oil-filled eye. Note


the slight indentation of the globe caused by scleral buckle. The optic
nerve, lens and both lateral eye muscles are visible in this cross-section.
The SRK/T formula was used for IOL power calculations in
all eyes. Every patient included in the study had two
calculations of IOL power: one obtained using ultrasound
biometry and the other using MRI biometry. At random, only
one of these values was taken, dividing patients into two
groups: MRI group (IOL power calculated from MRI biometry)
and A-scan group (IOL power calculated from ultrasound
biometry). The sample size for this study was determined by
the Altman nomogram for calculating sample size,17 with at
least 33 participants in each group.
Combined phacoemulsification with silicone oil evacuation
and IOL implantation was carried out in all patients. Follow-up
visits were arranged on the 7th, 30th, 90th and 180th
postoperative day. At every follow-up visit visual acuity was
assessed using Snellen optotype, intraocular pressure was
measured using applanation tonometry and the anterior eye
segment was examined on a slit lamp. Eye fundus examination
was performed using a 90 D non-contact Volk Superfield lens
(Volk Optical Inc., Mentor, Ohio, USA). Automated refractometry during cycloplegic mydriasis was performed using a
Topcon KR-8800 Auto Refractor (Topcon Europe Medical B.V.,
Capelle a/d Ijssel, the Netherlands).
Predicted refractive error was defined before operation, based
on preoperative refractive error and medical history.
Postoperative refractive error was obtained using automated
refractometry and it was expressed as a spherical equivalent.
The total postoperative refractive error was obtained by
automated refractometry, while the final postoperative refractive error was calculated by subtracting total postoperative
refractive error from predicted refractive error.
For statistical analysis the Wilcoxon matched pair test was
used to test values within each group. A separate analysis of
subgroups within each group was also performed (patients with
axial length >26 mm and axial length ,26 mm). The Mann
Whitney test was used to test the values between the MRI and
A-scan groups. A p value of ,0.05 was considered to show a
statistically significant difference.
Br J Ophthalmol 2009;93:502505. doi:10.1136/bjo.2008.147868

The mean deviation of the final from the predicted refractive


error was 20.36 (SD 1.26, 95% CI 21 to 0.56) D for the MRI
group and 20.76 (SD 1.73, 95% CI 21.33 to 20.18) D for the Ascan group. The difference between predicted and final postoperative refractive error was not statistically significant for the
MRI group (p = 0.125). However, there was a statistically
significant difference between these variables within the A-scan
group (p = 0.021). These results prompted us to perform
additional statistical analysis within each subgroup of patients
(axial length >26 mm; axial length ,26 mm) in both the MRI
and A-scan groups.
In patients with axial length >26 mm the mean deviation of
the final from the predicted refractive error was 21.23 (SD 0.7,
95% CI 22.36 to 20.25) D for the MRI group and 22.3 (SD
2.02, 95% CI 23.98 to 20.60) D for the A-scan group. The
difference between predicted and final postoperative error was
statistically significant in the MRI (p = 0.018) and A-scan
(p = 0.035) groups.
In patients with axial length ,26 mm the mean deviation of
the final from the predicted refractive error was 20.12 (SD 1.29,
95% CI 20.64 to 0.39) D for the MRI group and 20.33 (SD 1.39,
95% CI 20.86 to 0.20) D for the A-scan group. There was no
statistically significant difference between predicted and final
postoperative refractive error in either the MRI (p = 0.749) or in
the A-scan (p = 0.242) group.

Comparison of refractive error between the MRI and A-scan


groups
In order to compare final postoperative refractive error between
MRI and A-scan groups further statistical analysis was carried
out:
1. The difference in final postoperative refractive error
between MRI and A-scan groups was not statistically
significant (p = 0.184).
2. In patients with axial length >26 mm the difference in final
postoperative refractive error between MRI and A-scan
groups was statistically significant (p = 0.02) (table 2).
3. In patients with axial length ,26 mm there was no
statistically significant difference in final postoperative
refractive error between the MRI and A-scan groups
(p = 0.629).

DISCUSSION
Historically, different techniques have been proposed to solve
the problem of axial length measurement in silicone oil-filled
eyes. These include preoperative axial length measurement,18
intraoperative biometry22 or measurement of the contralateral
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Clinical science
Table 1 Baseline characteristics of the 70 patients in the study
Characteristic

MRI group

A-scan group

p Value

Patients (n)
Patients with axial length ,26 mm (n)
Patients with axial length >26 mm (n)
Age (years)*
Silicone oil endotamponade duration (months)*
Previous procedures (n)*

33
26
7
62 (8)
12.36 (5.04)
1.1 (0.38)

37
29
8
59 (12)
10.72 (3.56)
1.175 (0.31)

0.719
0.787
1.000
0.856
0.213
0.378

*Values are mean (SD).

eye.21 All these methods have practical (anisometropia, scleral


buckle, monocular patients) or technical limitations.1820 22
Ultrasonographic biometry in silicone oil-filled eyes is a very
demanding procedure. It requires an upright patient position
and the measurement is often impaired by the absorption of
sound waves. This is especially so in highly myopic eyes,
particularly those with posterior staphyloma, which further
exaggerates measurement error.
At present, there are few studies on refractive outcome after
combined cataract and silicone oil removal. Murray et al
performed combined cataract extraction and silicone oil removal
in seven patients.24 Axial length was measured with A-scan. The
average deviation between postoperative and final refraction
was 0.74 (SD 0.5, range 01.83) D. The highest deviation from
final refraction (3.16 D) was noticed in a highly myopic patient
with an axial length of 28.75 mm. Ghoraba et al published the
results of combined cataract and silicone oil removal in 29
patients.8 Axial length measurement was performed using Ascan biometry. They reported that 74% of eyes were within 2 D
of predicted refraction. The highest deviation was noticed in
highly myopic eyes (3.04 (SD 2.68) D). The authors pointed out
that in some highly myopic patients axial length could not be
measured using A-scan biometry. We had the same difficulty in
one patient with MRI axial length of 29.4 mm and posterior
staphyloma.
To resolve the problem of measuring axial length in silicone
oil-filled eyes Takei et al proposed using computed tomography.16 They studied 12 eyes, nine of which had a deviation of
postoperative refraction ,2 D. Patients with a higher deviation
had an axial length of >27 mm. According to the authors, the
source of error was mainly due to the 3 mm slice thickness.
Obtaining better resolution with thinner slices would expose
patients to a larger amount of irradiation.
In our study, we compared the accuracy of A-scan and MRI
axial length measurement in silicone oil-filled eyes. The
accuracy was estimated by comparing predicted refraction with
final postoperative refraction in the MRI and A-scan groups.
Two subgroups within each of the two groups were also
analysed: patients with axial length >26 mm and patients with
axial length ,26 mm.

The deviation of the final postoperative refraction from the


predicted refraction was statistically significant in the A-scan
group (p = 0.021), while it was not statistically significant in the
MRI group (p = 0.125).
The analysis of highly myopic patients (axial length
>26 mm) showed a much higher deviation of the final
postoperative refraction, especially in patients measured by Ascan biometry (p = 0.035). To our surprise, there was also a
statistically significant difference between predicted and final
postoperative refraction in the MRI group (p = 0.018).
However, when we compared final postoperative refraction
between the MRI and A-scan groups, we found a statistically
significant difference in a subset of patients with axial length
>26 mm (p = 0.02). These results suggest that MRI biometry is
more accurate in measuring the axial eye length of highly
myopic patients because of a smaller deviation in the final
postoperative refraction.
In patients with axial length ,26 mm the difference between
final and predicted refraction was not statistically significant
either in the MRI (p = 0.749) or in the A-scan (p = 0.242) group.
MRI and A-scan biometry appear to be equally accurate in
silicone oil-filled eyes with axial length ,26 mm.
There are two main reasons for inaccurate MRI measurements in our study. The first is the section thickness and
subsequent position of the MRI slice. In this study we used a
3 mm section thickness. Using those settings, it is very
important to position of MRI slices accurately in relation to
the orbit and eyeballs. If the slices are not positioned
carefully, the measured axis of the eye might not correspond
with a true axis, resulting in an inaccurate measurement. The
second reason lies in inaccurate patient positioning, or unsteady
patients who move their heads during the imaging. The use of
surface coils and new generation MRI devices, which were
unavailable at the beginning of this study, could have addressed
these problems more effectively.
In the last few years, optical biometry has been increasingly
used instead of ultrasound biometry for IOL measurement.11 23
This technique has also been advocated in complex cases of
silicone oil-filled eyes. Habibababi et al analysed the refractive
outcome in 13 silicone oil-filled eyes.25 The mean deviation of

Table 2 Comparison of final postoperative refractive error in the subset of patients in the MRI and A-scan
groups with axial length >26 mm on every follow-up
Patients (n)

FPR7
FPR30
FPR90
FPR180

FPR*

Range{

MRI group

A-scan group

MRI group

7
7
7
7

8
8
8
8

21.27
21.37
21.26
21.23

(0.63)
(0.78)
(0.77)
(0.67)

A-scan group
22.72
22.54
22.49
22.42

(2.01)
(1.87)
(1.62)
(1.76)

MRI group

A-scan group

22.12,
22.62,
22.62,
22.37,

25.67,
25.00,
24.50,
24.50,

20.5
20.5
20.25
20.25

0.75
0.50
0.50
0.50

p Value
0.0128
0.0487
0.0149
0.0200

*Values are means (SD).


{Values are minimum, maximum.
FPR, final postoperative refractive error.

504

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Clinical science
the final refraction was 20.3 (SD 0.91, range 21.87 to 1.3) D.
However, the study enrolled only patients with an axial length
,26 mm.
Nepp et al evaluated biometry and refractive outcome in 117
silicone oil-filled eyes by using standardised ultrasound echography and partial coherence interferometry.15 The deviation
between precalculated and final refraction was less than 1 D in
85% of cases. The authors noted that partial coherence
interferometry could not be performed in 38% of patients,
either because of a dense cataract or because of technical
problems. This incidence is much higher than previously
reported.1214 In addition, the authors did not analyse refractive
outcome separately in highly myopic patients, and to date there
are no data about refractive outcome in highly myopic eyes
measured by laser interferometry.
A-scan and MRI biometry are comparably accurate in
measuring axial length in silicone oil-filled eyes in patients
with axial length ,26 mm. In highly myopic patients, ie in
those with axial length >26 mm, MRI biometry might be a
better choice because of the smaller deviation from the predicted
refraction.

6.
7.

8.
9.
10.
11.

12.
13.
14.

15.

16.

17.

Funding: None.
Competing interests: None declared.

18.

Ethics approval: Obtained.

19.

Patient consent: Obtained.

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Baer RM, Aylward WG, Leaver PK. Cataract extraction following vitrectomy and
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Rajan MS, Keilhorn I, Bell JA. Partial coherence laser interferometry vs. conventional
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Hitzenberger CK, Drexler W, Dolezal C, et al. Measurement of the axial length of
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Graefes Arch Clin Exp Ophthalmol 2005;243:96772.
Takei K, Sekine Y, Okamoto F, et al. Measurement of axial length of eyes with
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tomography. Br J Ophthalmol 2002;86:4750.
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Smiddy WE, Loupe DN, Michels RG, et al. Refractive changes after scleral buckling
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Malukiewicz A, Wismewska G, Stafiej J. Changes in axial length after retinal
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Frau E, Lautier-Frau M, Labetoulle M, et al. Phacoemulsification combined with silicone
oil removal through posterior capsulorhexis. Br J Ophthalmol 1999;83:14067.
El-Baha SM, El-Samadoni A, Idris HF, et al. Intraoperative biometry for intraocular
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Laser-scanning in vivo confocal microscopy


reveals two morphologically distinct populations
of stromal nerves in normal human corneas
N Visser, C N J McGhee and D V Patel
Br. J. Ophthalmol. 2009;93;506-509; originally published online 5 Dec 2008;
doi:10.1136/bjo.2008.150599

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Clinical science

Laser-scanning in vivo confocal microscopy reveals


two morphologically distinct populations of stromal
nerves in normal human corneas
N Visser,1,2 C N J McGhee,1 D V Patel1
1

Department of Ophthalmology,
Faculty of Medical and Health
Sciences, University of
Auckland, Auckland, New
Zealand; 2 School of Medical
Sciences, University Medical
Centre Utrecht, the Netherlands
Correspondence to:
Dr D V Patel, Department of
Ophthalmology, Private Bag
92019, University of Auckland,
Auckland, New Zealand; dipika.
patel@auckland.ac.nz
Accepted 12 November 2008
Published Online First
5 December 2008

ABSTRACT
Background: The purpose of this study was to use laser
scanning in vivo confocal microscopy to elucidate the
location and morphology of stromal nerves in the normal
human central cornea.
Methods: Analysis was performed via an established
database of laser-scanning in vivo confocal microscopy on
images of the central cornea of normal subjects. The
depth and morphology of the stromal nerves were
determined.
Results: The population of this study consisted of 99
eyes of 99 healthy subjects (38 male, 61 female). The
mean age of the group was 34.7 (SD 13.3, range 1384)
years. Two morphologically different populations of
stromal nerves were observed: (1) straight, dichotomous
branching nerves; and (2) tortuous nerves with a beaded
appearance. The mean recorded depth of straight stromal
nerves (186 (SD 66) mm) was significantly deeper than
the mean depth of the tortuous stromal nerves (140 (SD
87) mm) (p,0.001).
Conclusions: The current study identified two morphologically distinct stromal nerve populations in the normal
human cornea. We hypothesise that the two morphological nerve populations described here may represent
functionally heterogeneous nerves. Further research is
required to determine if these in fact represent different
types of sensory nerves.

In vivo confocal microscopy is a non-invasive


method used to analyse the human living cornea.
This technique has led to a greater understanding
of the architecture of corneal nerves.13
A number of reports have described the presence
of tortuous, aberrant nerve trunks in the
anterior and mid corneal stroma in diseases such
as Schnyders crystalline dystrophy,4 type 2 diabetes mellitus,5 leprosy,6 and amiodarone-induced
keratopathy,7 and following photorefractive keratectomy.8
Only a few studies have examined stromal
nerves in the normal healthy population.
Indeed, most of these studies have been performed
on post mortem tissue911 and only one published
study has used in vivo confocal microscopy to
analyse stromal nerve architecture in the normal
cornea.2 The recent development of laser-scanning
in vivo confocal microscopy (LSCM) has led to
improved imaging of the epithelium, sub-basal
nerve plexus and stroma, producing images with
greater contrast than those generated by white
light in vivo confocal microscopes.12
506

The purpose of this study was to use LSCM to


elucidate the location and morphology of stromal
nerves in the normal human central cornea.

MATERIAL AND METHODS


The analysis was performed using a large database
of LSCM images obtained from normal human
subjects assessed between March 2005 and
September 2007. LSCM had been performed on
the central cornea of all subjects using the
Heidelberg Retina Tomograph II Rostock Corneal
Module
(RCM;
Heidelberg
Engineering,
Heidelberg, Germany) at the Department of
Ophthalmology, University of Auckland, as
described previously.14
The exclusion criteria were previous contact lens
wear, ocular surgery or ocular trauma, the presence
of other ocular diseases, and the presence of
systemic diseases that might affect the cornea.
Images from one cornea of each patient were
selected for analysis and the eye to be examined
was selected randomly.
For each subject, demographic data were
recorded and all images containing stromal nerves
were included. The location depth (mm), as
established by the in vivo confocal microscope,
was recorded for each image that contained
stromal nerves. All images selected were subsequently randomised by a single observer (DVP) and
then a qualitative description of the nerves was
established by an independent observer (NV).

RESULTS
The population of this study consisted of 99 eyes
of 99 healthy subjects (38 male, 61 female). The
mean age of the group was 34.7 (SD 13.3, range
1384) years. There were no visible stromal nerves
in 14 corneas from 14 subjects. From the remaining
subjects, 462 images exhibited stromal nerves and
were selected for further analysis.
Within the corneal stroma two distinct nerve
populations could be distinguished: (1) straight
nerves, often with dichotomous branching (fig. 1A,
B); and (2) tortuous nerves with a beaded
appearance (fig. 1C, D).
Straight nerves were present in 80 subjects,
while tortuous nerves were present in 43 subjects.
Tortuous nerves were most often observed in the
anterior stroma and mid stroma. Occasionally, these
nerves were noted alongside straight nerves (fig. 1E).
Interestingly, some stromal nerves were occasionally in apparent contact with keratocytes
(fig. 1F). No nerves were visible in the posterior
corneal stroma.
Br J Ophthalmol 2009;93:506509. doi:10.1136/bjo.2008.150599

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Clinical science
Figure 1 Laser-scanning in vivo
confocal microscopy images of corneal
stromal nerves in normal subjects. (A)
Straight dichotomous branching (arrow)
nerve in the anterior part of the stroma
(depth 130 mm). (B) Thick straight nerve
in the mid stroma (depth 350 mm). (C)
Tortuous nerves (arrows) in the anterior
part of the stroma (depth 70 mm). (D)
Tortuous nerves (arrows) in the mid
stroma (depth 210 mm). (E) Straight
nerve (arrow) and tortuous nerve
(arrowhead) (depth 160 mm). (F)
Keratocyte (arrow) apparently in contact
with a stromal nerve (depth 290 mm).

The mean recorded depth of straight stromal nerves (186 (SD


66) mm) was significantly deeper than the mean depth of the
tortuous stromal nerves (140 (SD 87) mm) (p,0.001, Mann
Whitney U test).

DISCUSSION
The current study identified two morphologically different
corneal stromal nerve populations. The observation of thick,
straight, stromal nerves, often with a dichotomous branching
pattern, is in accordance with data from previous research.2 14 15
However, a second morphologically distinct nerve population,
Br J Ophthalmol 2009;93:506509. doi:10.1136/bjo.2008.150599

consisting of thinner, tortuous nerves with a beaded appearance, was observed in the corneal stroma and these have not
been described in the literature before.
In the classic anatomical description of human corneal nerve
architecture, thick nerve bundles originating from the ophthalmic division of the trigeminal nerve enter the peripheral stroma
in a radial fashion and run anteriorly towards the central
cornea. Di- or trichotomous branching occurs to give rise to
smaller branches that innervate the anterior and mid stroma.2
The sub-epithelial plexus is formed immediately beneath
Bowmans layer and has been described as being limited to
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Clinical science
the peripheral cornea and possibly absent from the central
cornea.14 Oliveira-Soto and Efron were able to image the subepithelial nerve plexus in the central cornea using slit-scanning
in vivo confocal microscopy (SSCM): they reported that these
nerves showed great variability in tortuosity and noted that
50% of these nerves exhibited beading.2 Although this suggests
that the tortuous nerve population described in the current
study may represent the sub-epithelial plexus, this plexus has
been described as only being present in a single plane in the
anterior stroma immediately posterior to Bowmans layer,2 16
whereas tortuous beaded nerves were detected in locations as
deep as the mid stroma in the current study.
Although there are no published data validating corneal depth
measurements using the RCM, the errors produced by the
combination of involuntary anteriorposterior movement of the
subject and the requirement of manual adjustment of the focal
plane mean that this method is unlikely to have the degree of
accuracy and repeatability of confocal microscopy through
focusing (CMTF)17 or the ConfoScan with the Z-ring adapter.18
However, despite this significant limitation, the depth measurements in this study were generally in accordance with the
corneal depth associated with preceding, and subsequent scans
and subjective examination of the acquired images clearly
confirms the presence of tortuous beaded nerves in the anterior
and mid-stromal regions (fig. 1).
There were no visible stromal nerve images in 14% of central
corneas in this study. Because all subjects in the study were
considered to have normal corneas on history and examination,
it can be presumed that stromal nerves were present in all
corneas but had not been detected in some. This is probably due
to a combination of the relatively low density of stromal nerves
in the central cornea2 and the inconsistency in the total number
of images acquired for each subject in this study.
One hypothesis regarding the two morphological nerve
populations described here is that they may represent functionally
heterogeneous nerves. It is known that the human cornea
contains different functional types of corneal sensory fibres:
mechano-nociceptors that fire in response to indentation of the
corneal surface, polymodal-nociceptors that are activated by
mechanical stimuli, heat and chemical irritants, and cold-sensitive
receptors.19 Elegant three-dimensional reconstructions by Guthoff
et al16 have shown that Ad and C fibres penetrate Bowmans layer
orthogonally and separately and both types of nerve fibres are
reported to arise from the sub-epithelial nerve plexus. An
alternative theory is that the observations described in the current
study are the result of a single population of nerve fibre bundles
that become morphologically different to facilitate nerve passage
through the more anterior stromal layers. A possible reason for
more beading near the anterior cornea is that the extended
tortuous length of the nerves in the anterior stroma requires
periodic power stations (dense accumulations of mitochondria
and other organelles) to facilitate efficient nerve conduction.
In the current study, keratocytes were occasionally noted to be
in apparent contact with stromal nerves (straight or tortuous) or
vice versa. Interestingly, in a detailed electron microscopic analysis
of nerve fibres in the human cornea, keratocytes have been shown
to occasionally invaginate nerve fibres.15 Contact between
keratocytes and nerves is also observed more often in patients
with keratoconus than in control subjects,20 and it has been
suggested that corneal nervekeratocyte interactions in keratoconus may lead to remodelling of the extracellular matrix.21
The majority of previous in vivo confocal microscopy studies
describing nerve morphologies used either a tandem-scanning
confocal microscope or an SSCM, while in this study an LSCM
508

was used. The LSCM has been shown to generate higher quality
images of the sub-basal nerve plexus and the corneal stroma
than the SSCM. The images produced by a LSCM have
significantly greater contrast than those produced by SSCM;
the contrast in LSCM images remains high up to all edges of
each image while the contrast decreases remarkably towards the
lateral edges of each SSCM image.12 The improved resolution
and contrast of the LSCM in this study may thus have enabled
the visualisation of this second population of thinner, tortuous,
beaded nerves in the corneal stroma.
Stromal nerve diameter and density were not measured in
this study. Stromal nerve diameter measurements would be
inaccurate since these nerves commonly traverse obliquely,
relative to the en face section of the images. The cross-section is
therefore not always through the centre of the nerve, and so offcentre cross-sections will make the nerve appear falsely thinner.
Stromal nerve orientation is also an important factor when
considering nerve density analysis, unlike analysis of sub-basal
plexus nerve density.1 Visible nerve length per frame area will
vary with the path of the nerve through the field, but it does
not necessarily relate to nerve density in the stroma.
In conclusion, the current study identified two apparently
morphologically distinct stromal nerve populations in the
normal adult human cornea. Further research is obviously
required to determine if these in fact represent different types of
sensory nerves. Furthermore, a prospective study including
corneal aesthesiometry and measurements of the central corneal
thickness (to enable localisation of the stromal nerves to
anterior, mid or posterior stromal locations) would be useful
in providing further insight into the effects of corneal disease on
morphology and function of corneal nerves.
Competing interests: None declared.
Ethics approval: Obtained.
Patient consent: Obtained.

REFERENCES
1.

2.
3.

4.

5.
6.
7.
8.
9.
10.
11.
12.

13.

14.

Patel DV, McGhee CNJ. Mapping of the normal human corneal sub-basal nerve
plexus by in vivo laser scanning confocal microscopy. Invest Ophthalmol Vis Sci
2005;46:44858.
Oliveira-Soto L, Efron N. Morphology of corneal nerves using confocal microscopy.
Cornea 2001;20:37484.
Patel DV, McGhee CN. In vivo laser scanning confocal microscopy confirms that the
human corneal sub-basal nerve plexus is a highly dynamic structure. Invest
Ophthalmol Vis Sci 2008;49:340912.
Ciancaglini M, Carpineto P, Doronzo E, et al. Morphological evaluation of Schnyders
central crystalline dystrophy by confocal microscopy before and after
phototherapeutic keratectomy. J Cataract Refract Surg 2001;27:18925.
Mocan MC, Durukan I, Irkec M, et al. Morphologic alterations of both the stromal and
subbasal nerves in the corneas of patients with diabetes. Cornea 2006;25:76973.
Zhao C, Lu S, Tajouri N, et al. In vivo confocal laser scanning microscopy of corneal
nerves in leprosy. Arch Ophthalmol 2008;126:2824.
Ciancaglini M, Carpineto P, Zuppardi E, et al. In vivo confocal microscopy of patients
with amiodarone-induced keratopathy. Cornea 2001;20:36873.
Erie JC, Patel SV, McLaren JW, et al. Keratocyte density in the human cornea after
photorefractive keratectomy. Arch Ophthalmol 2003;121:7706.
Muller LJ, Marfurt CF, Kruse F, et al. Corneal nerves: structure, contents and
function. Exp Eye Res 2003;76:52142.
Muller LJ, Pels L, Vrensen GF. Ultrastructural organization of human corneal nerves.
Invest Ophthalmol Vis Sci 1996;37:47688.
Muller LJ, Vrensen GF, Pels L, et al. Architecture of human corneal nerves. Invest
Ophthalmol Vis Sci 1997;38:98594.
Patel DV. In vivo confocal microscopy of the cornea in health and disease. PhD
disseration. Department of Ophthalmology, University of Auckland, New Zealand,
2005.
Niederer RL, Perumal D, Sherwin T, et al. Age-related differences in the normal
human cornea: a laser scanning in vivo confocal microscopy study. Br J Ophthalmol
2007;91:11659.
Auran JD, Koester CJ, Kleiman NJ, et al. Scanning slit confocal microscopic
observation of cell morphology and movement within the normal human anterior
cornea. Ophthalmology 1995;102:3341.

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Clinical science
15.
16.
17.

Muller LJ, Pels L, Vrensen GF. Ultrastructural organization of human corneal nerves.
Invest Ophthalmol Vis Sci 1996;37:47688.
Guthoff RF, Wienss H, Hahnel C, et al. Epithelial innervation of human cornea: a
three-dimensional study using confocal laser scanning fluorescence microscopy.
Cornea 2005;24:60813.
McLaren JW, Nau CB, Erie JC, et al. Corneal thickness measurement by confocal
microscopy, ultrasound, and scanning slit methods. Am J Ophthalmol
2004;137:101120.

18.
19.
20.
21.

McLaren JW, Nau CB, Kitzmann AS, et al. Keratocyte density: comparison of two
confocal microscopes. Eye Contact Lens 2005;31:2833.
Belmonte C, Acosta MC, Gallar J. Neural basis of sensation in intact and injured
corneas. Exp Eye Res 2004;78:51325.
Muller LJ, Marfurt CF, Kruse F, et al. Corneal nerves: structure, contents and
function. Exp Eye Res 2003;76:52142.
Brookes NH, Loh IP, Clover GM, et al. Involvement of corneal nerves in the
progression of keratoconus. Exp Eye Res 2003;77:51524.

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Knowledge of visual experience during cataract


surgery under local anaesthesia: a nationwide
survey of UK ophthalmologists
A Laude, K G Au Eong and K B Mills
Br. J. Ophthalmol. 2009;93;510-512; originally published online 2 Aug 2006;
doi:10.1136/bjo.2006.097030

Updated information and services can be found at:


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References

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Clinical science

Knowledge of visual experience during cataract


surgery under local anaesthesia: a nationwide survey
of UK ophthalmologists
A Laude,1,2 K G Au Eong,1,3,4,5 K B Mills2
1

The Eye Institute at Tan Tock


Seng Hospital, National
Healthcare Group, Singapore;
2
Manchester Royal Eye
Hospital, National Health Service
Trust, UK; 3 The Eye Institute at
Alexandra Hospital, National
Healthcare Group, Singapore;
4
Department of Ophthalmology,
Yong Loo Lin School of
Medicine, National University of
Singapore, Singapore;
5
Singapore Eye Research
Institute, Singapore
Correspondence to:
Dr K G Au Eong, Singapore
International Eye Cataract Retina
Centre, 3 Mount Elizabeth
Medical Centre, Singapore
228510, Singapore;
kah_guan_au_eong@alexhosp.
com.sg
Accepted 8 June 2006
Published Online First
2 August 2006

ABSTRACT
Aim: To evaluate the knowledge and practices of UK
ophthalmologists regarding patients subjective visual
experience during cataract surgery under local anaesthesia.
Methods: A nationwide postal survey was conducted on
UK ophthalmologists using a standardised questionnaire.
Results: The proportion of surgeons who operated under
regional anaesthesia who thought that patients could
experience the following visual sensations were: no light
perception (54%); light perception (95%); one or more
colours (93%); flashes of light (81%); movement (87%);
instruments (61%); surgeons hands or fingers (53%);
surgeon (43%); and changes in light brightness (88%).
Fifty-eight per cent of them thought that patients might
be frightened by this, and 77% thought that preoperative
counselling could help alleviate this fear. The proportion of
surgeons who operated under topical anaesthesia who
thought that patients could experience the following visual
sensations were: no light perception (10%); light
perception (94%); one or more colours (97%); flashes of
light (86%); movement (96%); instruments (81%);
surgeons hands or fingers (65%); surgeon (51%);
changes in light brightness (95%). Fifty-nine per cent of
them thought that patients might be frightened by this,
and 80% thought that preoperative counselling could help
alleviate this fear.
Conclusion: Most UK surgeons believed that during
cataract surgery under local anaesthesia, patients might
experience various visual sensations which could cause
fear and that such fear could be alleviated by preoperative
counselling.

Previously reported case series have shown that


only a minority of cataract patients operated on
using local anaesthesia experience no light perception during the surgery.17 The majority of patients
retain sufficient visual function to experience a
variety of visual sensations in the operated eye
during cataract surgery, whether it is done under
topical or regional anaesthesia.38 Some of these
visual sensations include perception of light, movements, flashes, one or more colours, surgical
instruments, the surgeons hands or fingers, the
surgeon and changes in light brightness.9 A
minority of patients experience no light perception
either transiently or throughout the operation.3 4
Since cataract surgery is the most commonly
performed major eye operation, and most of these
procedures are performed under topical anaesthesia
or regional anaesthesia using the retrobulbar,
peribulbar or sub-Tenon injection route,10 it is
important to understand the knowledge and
510

practice of ophthalmologists with regards to this


phenomenon of retained vision during cataract
surgery. The subject of what patients may see
during cataract surgery is not discussed in any
major ophthalmic textbooks and has not been well
studied until recently.9 We therefore conducted a
nationwide survey of practising ophthalmologists
in the UK to determine their knowledge and
practices in relation to the visual experiences of
patients undergoing cataract surgery under topical
or regional anaesthesia.

MATERIALS AND METHODS


A list of UK ophthalmologists with specialist
accreditation and registered with the Royal
College of Ophthalmologists in London was
obtained with permission. A standardised, selfadministered questionnaire and an accompanying
cover letter were mailed to each of the ophthalmologists in the list. A self-addressed, stamped
envelope was also included for returning the
questionnaire, although the options of returning
the answered questionnaire through facsimile or
electronic mail were also given.
The surgeons were questioned on the anaesthetic method employed for their surgery. The onepage questionnaire contained two sets of similar
questions, one for those who performed cataract
surgery under topical anaesthesia and another for
those performed under regional anaesthesia (see
table 1). Only ophthalmologists who had performed at least one cataract surgery under either
topical or regional anaesthesia within the last
1 year were included in the analysis.
In the questionnaire, surgeons were asked
whether they thought that the patients could
experience a range of visual sensations during the
surgery, which included: no perception of light,
and perception of light, colours, flashes of light,
movements, instruments, surgeons hands or fingers, surgeon and changes in brightness of light. In
addition, they were asked whether they thought
that their patients could be frightened by them,
and whether they believed that preoperative
counselling might help alleviate this fear. Finally,
they were also asked if they had received feedback
from their patients about their visual experiences
during surgery.

RESULTS
Out of 643 questionnaires that were sent out to
the ophthalmologists, a total of 423 (67%) completed responses were received. Thirty-three of the
respondents reported to have not performed any
Br J Ophthalmol 2009;93:510512. doi:10.1136/bjo.2006.097030

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Clinical science
Table 1 Sample copy of the survey form: Central Manchester and Manchester Childrens University Hospitals
Visual Experience During Cataract Surgery Questionnaire
Name:________________________
Grade: Consultant/Specialist Registrar/Senior House Officers/Others: ___________ (please specify)
Section A: Regional Anaesthesia (RA) Please circle your answer
1. Do you perform cataract surgery under regional anaesthesia (RA) (If yes, please specify: peribulbar/
retrobulbar/subtenon/others _________)? (Defined as having performed one or more cataract surgery in the
1 year before interview)
2. Do you think patients can perceive the following during cataract surgery under RA?
a. No light perception
b. Light perception
c. Colours (one or more)
d. Flashes of light
e. Movements
f. Instruments
g. Surgeons hands/fingers
h. Surgeon
i. Change in brightness of light
3. Do you think patients may be frightened by their visual experience during cataract surgery under RA?
4. Do you routinely counsel your patients preoperatively about possible visual experience during cataract
surgery under RA?
5. Do you think preoperative counselling about possible visual experience during cataract surgery under RA can
reduce the fear patients may have from their visual experience?
6. Have any of your patients ever told you that he/she could see during cataract surgery under RA?
7. Have any of your patients ever told you that he/she was frightened by the visual experience during cataract
surgery under RA?
Section B: Topical Anaesthesia (TA)
1. Do you perform cataract surgery under topical anaesthesia (TA) (If yes, please specify: with/without
intracameral anaesthesia)? (Defined as having performed one or more cataract surgery in the 1 year before
interview)
2. Do you think patients can perceive the following during cataract surgery under TA?
a. No light perception
b. Light perception
c. Colours (one or more)
d. Flashes of light
e. Movements
f. Instruments
g. Surgeons hands/fingers
h. Surgeon
i. Change in brightness of light
3. Do you think patients may be frightened by their visual experience during cataract surgery under TA?
4. Do you routinely counsel your patients preoperatively about possible visual experience during cataract surgery
under TA?
5. Do you think preoperative counselling about possible visual experience during cataract surgery under TA can
reduce the fear patients may have from their visual experience?
6. Have any of your patients ever told you that he/she could see during cataract surgery under TA?
7. Have any of your patients ever told you that he/she was frightened by the visual experience during cataract
surgery under TA?

cataract surgery in the last 1 year. The results of the remaining


390 (61%) respondents were analysed.

Yes

No (proceed to section B)

Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes

No
No
No
No
No
No
No
No
No
No
No

Yes

No

Yes
Yes

No
No

Yes

No (end of
interview)

Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes

No
No
No
No
No
No
No
No
No
No
No

Yes

No

Yes
Yes

No
No

Sometimes

Sometimes

not. Forty-seven per cent of surgeons did not indicate whether


or not they used any supplementary intracameral anaesthesia.

Surgeons knowledge of patients visual experience


Types of anaesthesia
For ophthalmologists who had performed surgery under local
anaesthesia during the past 1 year, 215 (55%) respondents
operated under regional anaesthesia alone, 31 (8%) operated
under topical anaesthesia alone, while 144 (37%) operated under
both regional and topical anaesthesia.
The choice of regional anaesthesia employed included subTenon anaesthesia only (30%), peribulbar anaesthesia only
(19%) or retrobulbar anaesthesia only (4%). Some surgeons used
more than one type of regional anaesthesia (31%) to perform
their surgeries. About 16% of surgeons did not indicate what
type of regional anaesthesia they used.
For surgeons who operated under topical anaesthesia, about
30% reported using intracameral anaesthesia, while 23% did
Br J Ophthalmol 2009;93:510512. doi:10.1136/bjo.2006.097030

More than half (54%) of the surgeons who operated under


regional anaesthesia thought that the patients might experience
no perception of light during the surgery, while only about 10%
of those who operated under topical anaesthesia thought so.
When asked about the visual sensations that the patients
might experience during surgery, the percentage of surgeons
operating under regional anaesthesia who thought that the
patients could perceive were: light perception (95%); one or
more colours (93%); flashes of light (81%); movement (87%);
instruments (61%); surgeons hands or fingers (53%); surgeon
(43%); and changes in light brightness (88%).
For surgeons who operated under topical anaesthesia, the
percentage who thought that the patients could perceive visual
sensations were: light perception (94%); one or more colours
511

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Clinical science
(97%); flashes of light (86%); movement (96%); instruments
(81%); surgeons hands or fingers (65%); surgeon (51%); and
changes in light brightness (95%).

Fear from intraoperative visual experience


When questioned about whether the patients might be
frightened by their visual experience during surgery, 58% of
surgeons who operated under regional anaesthesia thought so.
Thirty-nine per cent did not think that the patients would be
frightened by their visual experience, and 3% did not indicate in
their response. For surgeons who operated under topical
anaesthesia, 59% thought that patients would be frightened
by their visual experience, while 41% did not think so.
The majority of surgeons in both groups (regional anaesthesia
group 77%, topical anaesthesia group 80%) thought that
preoperative counselling could help alleviate the fear of patients
from their visual experiences. In addition, 64% of the regional
anaesthesia group counselled their patients preoperatively,
either routinely (35%) or occasionally (29%), and 78% of the
topical anaesthesia group counselled their patients preoperatively, either routinely (57%) or occasionally (21%), about
potential visual experience during cataract surgery.

Patients experience
Most of the surgeons have had their patients report to them
that they could see during the surgery (88% in the regional
anaesthesia group and 90% in the topical anaesthesia group). A
small number of surgeons, 11% in the regional anaesthesia
group and 16% in the topical anaesthesia group, have had
patients report to them that they were frightened by their visual
experience.

the surgeons performed the surgery under regional or topical


anaesthesia. Published studies have shown that the visual
experience of patients undergoing cataract surgery can be
frightening in 316% of patients.3 58
It is interesting to note that the majority of surgeons thought
that preoperative counselling could help alleviate fear from the
patients visual experience. The value of preoperative counselling on the reduction of fear from visual experience of patients
has been shown in a multicentre randomised clinical trial.13 It is
reassuring to find out that most surgeons counselled their
patients preoperatively about potential visual sensations either
routinely or occasionally.
In summary, the results of this survey show that most UK
ophthalmologists were aware of the visual sensations that
patients might encounter during cataract surgery under regional
and topical anaesthesia. While opinions differ about whether
the visual experience might cause fear or not, many already
practised preoperative counselling for their patients.
Acknowledgements: We would like to thank the Royal College of Ophthalmologists,
London, UK, for providing the list of specialist accredited ophthalmologists in the UK
registered with the college.
Competing interests: None.
Presented in part at the National Healthcare Group Annual Scientific Congress 2004,
Singapore, 910 October 2004.

REFERENCES
1.
2.
3.

4.

DISCUSSION
More than half of the surgeons who responded believed that
patients might experience no light perception during surgery
under regional anaesthesia, while about 10% believed the same
for patients who underwent surgery under topical anaesthesia.
Studies have shown that some patients (up to 20%) do
experience no perception of light either transiently or throughout the surgery under regional or topical anaesthesia.1 3 11 12 It is
therefore important for surgeons to be aware of this fact so that
they can reassure patients who have no light perception during
the operation that their loss of vision is normal.
Most surgeons surveyed were aware of the various types of
visual sensations which patients might perceive during the
surgery. This was also supported by the finding that the
majority of surgeons have had patients report to them that they
could see during the surgery. However, opinions about whether
these visual sensations might frighten patients were divided,
with just over half of surgeons surveyed thinking that patients
might be frightened by them. The finding was similar whether

512

5.
6.

7.

8.

9.
10.
11.
12.
13.

Levin ML, OConnor PS. Visual acuity after retrobulbar anaesthesia. Ann Ophthalmol
1989;11:3379.
Murdoch IE, Sze P. Visual experience during cataract surgery. Eye 1994;8:6667.
Au Eong KG, Lim TH, Lee HM, et al. Subjective visual experience during
phacoemulsification and intraocular lens implantation using retrobulbar anaesthesia.
J Cataract Refract Surg 2000;26:8426.
Newman DK. Visual experience during phacoemulsification cataract surgery under
topical anaesthesia. Br J Ophthalmol 2000;84:1315.
Prasad N, Kumar CM, Patil BB, et al. Subjective visual experience during
phacoemulsification cataract surgery under sub-Tenons block. Eye 2003;17:4079.
Tranos PG, Wickremasinghe SS, Sinclair N, et al. Visual perception during
phacoemulsification cataract surgery under topical and regional anaesthesia. Acta
Ophthalmol Scan 2003;81:11822.
Wickremasinghe SS, Tranos PG, Sinclair N, et al. Visual perception during
phacoemulsification cataract surgery under subtenons anaesthesia. Eye
2003;17:5015.
Au Eong KG, Low CH, Heng WJ, et al. Subjective visual experience during
phacoemulsification and intraocular lens implantation under topical anaesthesia.
Ophthalmology 2000;107:24850.
Au Eong KG. Sixth Yahya Cohen lecture: visual experience during cataract surgery.
Ann Acad Med Singapore 2002;31:66674.
Leaming DV. Practice styles and preferences of ASCRS members2002 survey.
J Cataract Refract Surg 2003;29:141220.
Scott RA, Acharya PA, Jake Man CM, et al. Peribulbar anaesthesia. Br J Ophthalmol
1994;78:592.
Talks SJ, Chong NHV, Gibson JM, et al. Visual acuity and papillary reactions after
peribulbar anaesthesia. Br J Ophthalmol 1994;78:413.
Voon LW, Au Eong KG, Saw SM, et al. Does preoperative counselling reduce the fear
of patients from visual experience during phacoemulsification under topical
anaesthesia? Results of a multicenter randomised clinical trial. J Cataract Refract
Surg 2005;10:19669.

Br J Ophthalmol 2009;93:510512. doi:10.1136/bjo.2006.097030

Downloaded from bjo.bmj.com on 31 March 2009

Conjunctival cytology in floppy eyelid syndrome:


objective assessment of the outcome of surgery
R Medel, T Alonso, J I Vela, M Calatayud, L Bisbe and J Garca-Arum
Br. J. Ophthalmol. 2009;93;513-517; originally published online 5 Dec 2008;
doi:10.1136/bjo.2008.144287

Updated information and services can be found at:


http://bjo.bmj.com/cgi/content/full/93/4/513

These include:

References

This article cites 23 articles, 6 of which can be accessed free at:


http://bjo.bmj.com/cgi/content/full/93/4/513#BIBL

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Clinical science

Conjunctival cytology in floppy eyelid syndrome:


objective assessment of the outcome of surgery
R Medel,1,2 T Alonso,1 J I Vela,3 M Calatayud,1 L Bisbe,1 J Garca-Arum1,2
1

Hospital Universitari Vall


DHebron, Barcelona, Spain;
2
Instituto de Microciruga Ocular
(IMO), Barcelona, Spain;
3
Hospital de la Santa Creu y
Sant Pau, Barcelona, Spain
Correspondence to:
Dr T Alonso, Department of
Ophthalmology, Universitari
Hospital Vall DHebron, pg Vall
DHebron 119-129, 08035
Barcelona, Spain; 35916taa@
comb.es
Accepted 12 November 2008
Published Online First
5 December 2008

ABSTRACT
Aims: Upper eyelid shortening is the main surgical
procedure in floppy eyelid syndrome (FES). The efficacy of
surgery is assessed by improvements in the symptoms,
since objective evaluation is difficult. Conjunctival
impression cytology was assessed as an objective
method for the evaluation of the effectiveness of surgery
for FES.
Method: The study was a prospective interventional
study in 16 patients (26 eyelids) with FES, who were
enrolled over a period of 8 months. Patients were
examined 14 weeks before surgery and 16 weeks after
surgery. Cases were classified into three groups
according to the severity of symptoms and papillary
reaction. A full-thickness pentagonal wedge resection
was performed in the upper eyelid. Impression cytology
was performed in all patients at 14 weeks before
surgery and 16 weeks after surgery.
Results: Postoperative improvements in cellular morphology and goblet cell count were found in 20 of 22
eyelids (91%) and this led to a decrease of least one
grade in Nelsons classification. In two cases (9%) the
Nelson grade remained stable. Postoperative improvement on cytology was statistically significant with the
Wilcoxon signed ranks test (p,0.001).
Conclusion: Conjunctival cytology provides an objective
method for the evaluation of the efficacy of surgical
techniques proposed for the treatment of eyelid laxity
syndromes.

Floppy eyelid syndrome (FES) was first described in


19811 2 by Culbertson and Ostler in overweight
male patients who experienced nocturnal eyelid
eversion caused by severe eyelid laxity. The
patients presented with chronic papillary conjunctivitis and ocular symptoms, including irritation,
tearing and a foreign body sensation. Other typical
findings in this condition are eyelash ptosis,
superficial punctate keratopathy and, less commonly, keratoconus.35 Although the syndrome
was first observed in middle-aged obese men,1 2 6
it has also been described in young patients7 8 and
women.9 10
The pathogenesis of FES is not well understood.
It has been related to an ischaemic mechanism11
and to dysfunction of the tear and Meibomian
glands.12 13 Given the common association between
this syndrome and obstructive sleep apnoea and
obesity, this ischaemia has been explained by
hypoxia caused by hypoventilation. Another theory is that ischaemia is caused by pressure exerted
on the eyelid while sleeping face downwards,
which would result in lateralisation of symptoms
towards the side of the decubitus.1 6 Ocular
irritation leads to rubbing the eyes, which, in turn,
Br J Ophthalmol 2009;93:513517. doi:10.1136/bjo.2008.144287

increases ocular inflammation, thereby worsening


the situation and creating a vicious circle. Both
ischaemia and chronic inflammation can cause
changes in the elastic fibres and produce severe
eyelid laxity. The ocular inflammation could be
secondary to the eyelid laxity, be a consequence of
the same factors that cause the eyelid alteration, or
be due to other factors, such as tear film
abnormality with a deficiency of lipids, which
leads to excessively rapid tear evaporation.
The first steps in the treatment of FES are
administration of lubricating eye drops, providing
eyelid shields and giving advice to try not to sleep
on the more involved side. When these measures
are not enough, surgical shortening of the upper
eyelid can be used to avoid nocturnal eversion.
Assessment of surgical efficacy for this condition is
usually based on improvements in the symptoms,
since objective evaluation is difficult. We propose
conjunctival impression cytology as an objective
method to evaluate the effectiveness of FES
surgery.
Impression cytology is a non-invasive technique
that allows determination of the morphology,
density and grade of metaplasia of the most
superficial cell layers of the conjunctival epithelium. Since its first description in 1977 by Egbert et
al,14 it has been used to assess the ocular surface in
patients with cicatricial pemphigoid15 16 and keratoconjunctivitis sicca. It has also proved useful in
vitamin A deficiency and mucopolysaccharidosis.17
Although squamous metaplasia is uncommon in
patients with floppy eyelid, they do develop
cellular changes in the conjunctival epithelium
due to chronic irritation.
If the changes in ocular surface cellularity are
secondary to eyelid laxity, conjunctival impression
cytology could be a useful objective test to evaluate
the degree of success of any surgical procedure used
to correct eyelid laxity.

MATERIAL AND METHODS


A prospective interventional study was performed
in 16 patients (26 eyelids) with FES, who were
enrolled over a period of 8 months. Data collected
on each patient included age, sex, follow-up time,
bilaterality, and associated systemic and ocular
diseases.
Given the relationship between FES and obesity,1 2 6 the body mass index (BMI) for each
patient was calculated according to the formula
BMI = weight (kg)/height squared (m2). Patients
were classified into four grades according to the
BMI, as described by Garrow18.
Patients were examined 14 weeks before surgery
and were re-examined 16 weeks postoperatively.
513

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Clinical science

Figure 1 Group F0: patients with sporadic symptoms and minimal


papillary reaction (P1).

Figure 3 Group F2: patients with constant symptoms and a


considerable papillary reaction (P3).

Ocular symptoms were documented, including tearing, foreign


body sensation, nocturnal eversion and photophobia. Slit-lamp
examination was done to determine the existence and grade of
bulbar conjunctival injection, tarsal papillary reaction and superficial punctate keratopathy. Severity of eyelid laxity was
measured in the four lids by the distraction and snapback tests.
Ease of eversion of the upper lid was also evaluated.
During the preoperative examination period, we realised that
there was a direct relationship between the frequency of
symptoms (foreign body sensation, tearing, irritation, photophobia) and the tarsal papillary reaction. Patients with no
papillary reaction (P0) or papillae smaller than 0.3 mm (P1)
were asymptomatic or presented few symptoms. Patients with
a papillary reaction between 0.3 and 1 mm (P2) experienced
frequent (although not constant) symptoms (several episodes
per month). Last, patients with papillae larger than 1 mm (P3)
presented persistent symptoms, with severe superficial punctate
keratitis in two cases and a corneal ulcer in one.
The cases were classified according to the severity of
symptoms and the papillary reaction in the tarsal conjunctiva.
Group F0 (eight eyelids) contained patients with no symptoms
or sporadic symptoms and minimal papillary reaction (fig. 1).
Group F1 (ten eyelids) included patients with frequent
symptoms, P2 papillary reaction and occasional keratitis, which
were easily controlled with topical humectant treatment (fig. 2).
Group F2 (eight eyelids) included patients with constant
symptoms and a considerable papillary reaction (P3) (fig. 3).
This last group presented severe corneal disease refractory to
medical treatment (one case of corneal ulcer, two cases of
keratoconus) (table 1).

Impression cytology was performed in all patients using a


Millipore (Billerica, Massachusetts, USA) mixed cellulose ester
(MCE) filter to peel one to three layers of superficial epithelial
cells. Following instillation of topical anaesthesia, filters were
placed over the superior bulbar and tarsal conjunctiva. A
pathologist classified the specimens according to Nelsons
grading system19 (table 2, figs 46).
All eyelid-shortening procedures were performed by the same
surgeon under local anaesthesia using 0.5% bupivacain with
adrenaline and sedation. A full-thickness pentagonal wedge
resection was performed in the upper eyelid at 57 mm of the
external cantus. The amount of eyelid resected was determined
by the surgeon during the procedure by superposition of the
surgical flaps. Sutures were removed on day 7. The specimen of
eyelid tissue obtained was analysed by a pathologist.

RESULTS
The study included 14 men and two women, aged 3578 (mean
58.8) years. Symptoms were bilateral in ten patients and
unilateral in six. Among 26 eyelids analysed, 15 were on the
right and 11 on the left.
Among the 16 patients studied, two were overweight, 11
obese and three morbidly obese. Although all patients had a
BMI above normal, there was no correlation between BMI and
the severity of the syndrome (ANOVA, p = 0.076).

Table 1

Classification of floppy eyelid syndrome

Group

Symptoms

Papilla

Cornea

F0
F1
F2

Sporadic
Frequent
Constant

P0P1
P2
P3

Normal
Occasional SPK
Severe SPK, ulcer

SPK, superficial punctate keratitis.

Table 2

Figure 2 Group F1: patients with frequent symptoms, P2 papillary


reaction and occasional keratitis.
514

Nelsons grading system

Findings

Grade 0

Grade 1

Grade 2

Grade 3

Cell size
Cytoplasm
Nucleus
Nuclear:cytoplasmic
ratio
Goblet cells
Goblet cells cytoplasm

Smaller
Eosinophil
Large
1:2

Small
Eosinophil
Small
1:3

Large
Variable
Small
1:41:5

Large
Basophil
Picnotic/absent
1:6

.500
PAS+++

350500
PAS+++

100350
PAS++

,100
PAS2

PAS, periodic acidSchiff reagent.

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Clinical science

Figure 4

Conjunctival cytology: Nelson grade 1.

In four cases (two in F1 and two in F2) preoperative status


could not be evaluated by the pathologist because the specimens
lacked cellularity. Thus, cytology study could only be carried
out in 22 eyelids. After surgery, improvements in cellular
morphology and the number of goblet cells were documented in
20 of 22 eyelids (91%), with decreases of at least one grade on
Nelsons classification. In two cases (9%) the Nelson grade
remained stable, with no changes relative to preoperative status.
None of the cases had poorer postoperative than preoperative
cytology results. The two cases with no improvement on
postoperative cytology were from group F0; in both F1 and F2,
100% of cases showed improvement. Postoperative improvement on cytology was statistically significant with Wilcoxon
signed ranks test (F0, p,0.02; F1, p,0.007; F2, p,0.02; all
groups p,0.001). See table 3 for a summary of the results.

DISCUSSION

Figure 5

Conjunctival cytology: Nelson grade 2.

Figure 6

Conjunctival cytology: Nelson grade 3.

Mean eyelid shortening was 9.7 (range 813) mm in group F1


and 7.88 (range 610) mm in group F0. Group F2 needed the
greatest shortening, with a mean of 14.88 (range 1028) mm.
Pathological study of the eyelid tissue removed showed a
preserved tarsal structure with rupture and loss of elastic fibres
in all cases. In 22 cases, a non-specific chronic inflammatory
infiltrate was found in the conjunctival epithelium and
perifollicular area, with foreign body inflammatory reaction,
glandular duct dilatation and mucin extravasation.
The conjunctival papillary reaction decreased after surgery.
Improvement was 100% in groups F1 and F2, and only 14% in
group F0. All patients reported subjective improvement in
symptoms following surgery; none experienced worsening.
With regard to impression cytology findings, mean preoperative Nelson grades obtained by the groups were: F0, 1.25; F1,
1.37; and F2, 2. The postoperative Nelson grades were: F0, 0.37;
F1, 0.25; and F2, 0.6 (fig. 7).
Br J Ophthalmol 2009;93:513517. doi:10.1136/bjo.2008.144287

Floppy eyelid syndrome mainly affected men (87.5%) with a


high BMI (100%) in our series, as was described in the first
report of this syndrome.1 In obese patients, systemic hypoventilation resulting in ischaemia was one of the first hypotheses
proposed to explain eyelid laxity. This may have been the main
mechanism in our series, in which 87.5% of the patients were
obese. In patients with neither obesity nor obstructive sleep
apnoea syndrome, other causal factors should be considered to
explain ischaemia, such as a mechanical factor related to the
position while sleeping, with compression of the eyelids.
Compulsive rubbing of the eyes creates a vicious circle and
may be another associated mechanical factor. Rubbing the eyes
irritates them and this results in more rubbing. Mechanical
factors have been gaining importance since the description of
lax eyelid syndrome by Van Den Bosch and Lemij,20 in which
a wider concept of upper eyelid laxity syndrome, unrelated to
age, sex or obesity, was proposed. Burkat and Lemke use the
term acquired lax eyelid syndrome for patients with eyelid
laxity, but no obesity or sleep disorder.21 These authors reported
only 18.6% of obesity in a series of 70 patients, and 41.4% had a
normal BMI.
It is likely that these differences in aetiological factors among
the various series are due to dissimilar inclusion criteria, mainly
in the degree of laxity and symptoms. In the most severe cases,
it should be easier to simultaneously encounter obesity,
obstructive sleep apnoea syndrome and an eyelid-compressive
sleeping position.

Figure 7

Preoperative and postoperative Nelson grade.


515

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Clinical science
Table 3 Summary of results
BMI (kg/m2)

Shortening
(mm)

P-pre

P-post

Nelson-pre

Nelson-post

1
2
3
4
5
6
7
8
Mean

31.91
38.56
33.53
33.53
44.95
30.1
28.72
30.5
33.97

6
7
7
7
10
8
9
9
7.88

1
1
1
1
1
1
1
1
1

1
1
1
0
1
1
1
0
0.75

2
1
1
2
2
1
0
1
1.25

0
0
1
1
1
0
0
0
0.37

9
10
11
12
13
14
15
16
17
18
Mean

31.91
38.56
31.88
31.88
40.26
44.95
36.5
28.72
39.68
34.2
32.98

8
8
11
11
10
13
10
8
10
8
9.7

2
2
2
2
2
2
2
2
2
2
2

0
1
1
1
1
1
1
1
1
0
0.8

2
1
1
1
1
2
2

1
1.37

0
0
0
0
0
1
1

0
0.25

19
20
21
22
23
24
25
26
Mean

58.43
28.4
28.4
36.5
35.15
35.15
34.2
38.7
36.86

28
10
18
16
10
12
12
13
14.88

3
3
3
3
3
3
3
3
3

2
1
0
1
1
1
1
1
1

3
3
2
2

1
1
2

2
1
0
1

0
0
0.6

Nelson grade
F0

F1

F2

BMI, body mass index; Nelson-post, postoperative Nelson grade; Nelson-pre, preoperative Nelson grade; P-post, postoperative
papillary reaction; P-pre, preoperative papillary reaction.

The most widely used surgical technique for this condition is


horizontal shortening. We performed pentagonal resection of
the upper eyelid in all cases because it allows exact measurement of the amount of eyelid resected and examination of the
differences in millimetres of resection.22 Other techniques with a
better aesthetic result, such as lateral tarsal strip with or
without periostial flap, have been described. Surgical shortening
of the four eyelids has also been described.21 23
Histological study of the specimens was consistent with the
findings of Netland et al:24 a decrease in elastic fibres (on
modified Verhoeff stain), glandular duct dilatation, conjunctival
inflammation and granuloma formation instead of normal
collagen fibrils1 3 14 1618 22 In other studies, the use of immunohistochemistry has demonstrated an increase in immunoreactivity for elastolytic proteases in areas with no elastin.
Upregulation of elastolytic enzymes induced by various stimuli
would be the direct cause of degradation of the elastic fibres and
the resulting tarsal laxity and lash ptosis.25
We classified FES into three groups according to the severity of
symptoms and the degree of papillary reaction. No relationship
was found between FES severity and the BMI. There was,
however, a relationship between the severity of the syndrome and
severity of the Nelson grade. Therefore, chronic inflammation of
the ocular surface associated with eyelid laxity may promote
changes in conjunctival epithelium cells. The considerable
difference in Nelson grade between group F2 and the remaining
516

groups, and the slight difference between groups F0 and F1 (0.125)


are notable. Because cases with considerable keratitis were
included in group F2, we conclude that the above-cited difference
may indicate the existence of a cytological grade threshold
beyond which severe keratitis would develop. This cytological
threshold could be between Nelson grade 1.375 and 2.
The improvement in postoperative cytology, observed mainly
in groups F1 and F2, demonstrates that surgical shortening of
the eyelid can improve the ocular surface problems these
patients experience, by inverting the process of conjunctival
epithelium keratinisation and favouring the development of a
normal epithelium.
In some cases, after performing conjunctival cytology, the
pathologist could not properly assess the specimen because of a
lack of cellularity. This occurred in four cases, which all were
excluded from the study of conjunctival cytology results.
An important decrease, but not complete disappearance, of
the papillary reaction was observed in all cases. This decrease in
papillary size may be related to the fact that nocturnal eversion
of the eyelid was resolved by surgery; thus, chronic inflammation decreased and the symptoms abated. The improvement in
symptoms resolves eye-rubbing by the patient, and this, in turn,
eliminates a mechanical stimulus for ocular irritation, breaking
the vicious circle.
Among the mildest cases (F0), the improvement in cytology
results and symptoms was minimal, a finding that questions
Br J Ophthalmol 2009;93:513517. doi:10.1136/bjo.2008.144287

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Clinical science
surgical treatment for these patients. Classification of patients
with eyelid laxity according to the severity of symptoms, the
degree of papillary reaction and the conjunctival cytology
allows us to predict the outcome of surgical treatment better
and provides an improved basis for indicating surgery.
Eyelid laxity in patients with chronic ocular surface inflammation and tearing may be coincidental. This clinical entity can
have several causes, some of which are frequent, such as allergic
conjunctivitis. Although many studies have shown an improvement in symptoms with eyelid surgery, they do not provide
objective findings to support the hypothesis that eyelid laxity is
a cause of chronic ocular irritation. In the present study, a
relationship was found between the degree of eyelid laxity and
objective findings, such as the degree of papillary reaction and
Nelson grade on conjunctival cytology, and the improvements
in both these variables after surgical shortening of the eyelid.
Therefore, there is evidence that excessive eyelid laxity causes a
clinical condition involving chronic conjunctival inflammation
and non-specific symptoms of ocular irritation which, in many
cases, can be corrected by eyelid surgery.

REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.

CONCLUSION
Eyelid laxity is a cause of chronic conjunctival inflammation
with non-specific symptoms of ocular irritation. Examination of
the ocular surface with conjunctival cytology shows cellularity
changes that correlate with the severity of symptoms. Eyelidshortening surgery has been effective in correcting these
alterations. Even though conjunctival cytology of the ocular
surface is not used routinely in clinical practice, it provides an
objective method to evaluate the efficacy of surgical techniques
in clinical trials for the treatment of eyelid laxity syndromes.
Further studies with a larger number of cases are needed to
confirm these results.
Competing interests: None declared.
Patient consent: Obtained

Br J Ophthalmol 2009;93:513517. doi:10.1136/bjo.2008.144287

16.
17.
18.
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20.
21.
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Parunovic A, Ilic B. Floppy eyelid syndrome with keratoconus. Br J Ophthalmol
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Culbertson WW, Tseng SC. Corneal disorders in floppy eyelid syndrome. Cornea
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Schwartz LK, Gelender H, Forster RK. Chronic conjunctivitis associated with floppy
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Gross RH, Mannis MJ. Floppy eyelid syndrome in a child with chronic unilateral
conjunctivitis. Am J Ophthalmol 1997:10910.
Paciuc M, Mier ME. A woman with the floppy eyelid syndrome [letter].
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Easterbrook M. Floppy eyelid syndrome. Can J Ophthalmol 1985;20:2645.
Sussman MS, Bulckley GB. Oxygen-derived free radicals in reperfusion injury.
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Gonnering RS, Sonneland PR. Meibomian gland dysfunction in floppy eyelid
syndrome. Ophthal Plast Reconstr Surg 1987;3:99103.
Liu DT, Di Pascuale MA, Sawai J, et al. Tear film dynamics in floppy eyelid syndrome.
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Egbert PR, Lauber S, Maurice DM. A simple conjunctival biopsy. Am J Ophthalmol
1977;84:798801.
Adams AD. The morphology of human conjunctival mucus. Arch Ophthalmol
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Hatchell DL, Sommer A. Detection of ocular surface abnormalities in experimental
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Garrow JS. Treat obesity seriously. Edinburgh: Churchill Livingstone, 1981:3.
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Van den Bosch WA, Lemij HG. The lax eyelid syndrome. Br J Ophthalmol
1994;74:6668.
Burkat CN, Lemke BN. Acquired lax eyelid syndrome: an unrecognized cause of the
chronically irritated eye. Ophthal Plast Reconstr Surg 200521:528.
Dutton JJ. Surgical management of floppy eyelid syndrome. Am J Ophthalmol
1985;99:55760.
Periman LM, Sires BS. Floppy eyelid syndrome: a modified surgical technique.
Ophthal Plast Reconstr Surg 200218:3702.
Netland PA, Sugrue SP, Albert DM, et al. Histopathologic features of the floppy
eyelid syndrome. Involvement of tarsal elastin. Ophtalmology 1994;101:17481.
Schlotzer-Schrehardt U, Stojkovic M, Hofmann-Rummelt C, et al. The pathogenesis
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Fundus autofluorescence and Fourier-domain


optical coherence tomography imaging of 10 and
20 millisecond Pascal retinal photocoagulation
treatment
M M K Muqit, J C B Gray, G R Marcellino, D B Henson, L B Young, S J Charles,
G S Turner and P E Stanga
Br. J. Ophthalmol. 2009;93;518-525; originally published online 15 Dec 2008;
doi:10.1136/bjo.2008.148833

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Clinical science

Fundus autofluorescence and Fourier-domain optical


coherence tomography imaging of 10 and
20 millisecond Pascal retinal photocoagulation
treatment
M M K Muqit,1 J C B Gray,1 G R Marcellino,2 D B Henson,1 L B Young,1 S J Charles,1
G S Turner,1 P E Stanga1
1

Manchester Royal Eye


Hospital, Oxford Road,
Manchester, UK; 2 OptiMedica
Corporation, Santa Clara,
California, USA
Correspondence to:
Mr P E Stanga, Consultant
Ophthalmologist and
Vitreoretinal Surgeon,
Manchester Royal Eye Hospital,
Oxford Road, Manchester
M13 9WH, UK;
retinaspecialist@btinternet.com
Accepted 22 November 2008
Published Online First
15 December 2008

ABSTRACT
Aim: To report the evolution of pattern scanning laser
(Pascal) photocoagulation burns in the treatment of
diabetic retinopathy, using Fourier-domain optical coherence tomography (FD-OCT) and fundus autofluorescence
(AF), and to evaluate these characteristics with clinically
visible alterations in outer retina (OR) and retinal pigment
epithelium (RPE).
Methods: Standard red-free and colour fundus photography (FP), FD-OCT, and fundus camera-based AF were
performed in 17 eyes of 11 patients following macular and
panretinal photocoagulation (PRP).
Results: One hour following Pascal application, visibility
of threshold burns on FP was incomplete. AF enabled
visualisation of complete treatment arrays at 1 h, with
hypoautofluorescence at sites of each laser burn. AF
signals accurately correlated with localised increased
optical reflectivity within the outer retina on FD-OCT. AF
signals became hyperautofluorescent at 1 week, and
corresponded on FD-OCT to defects at the junction of the
inner and outer segments of the photoreceptors (JI/OSP)
and upper surface of RPE. A 10 ms macular laser pulse
produced a localised defect at the level of JI/OSP and
RPE. Macular and 20 ms PRP burns did not enlarge at
1 years and 18 months follow-up respectively.
Conclusions: We report the in vivo spatial localisation and
clinical correlation of medium-pulse Pascal photocoagulation
burns within outer retina and RPE, using high-resolution FDOCT and AF. Ophthalmoscopically invisible and threshold
Pascal burns may be accurately localised and mapped by AF
and FD-OCT, with monitoring over time.

Laser photocoagulation remains the gold standard


treatment for diabetic macular oedema (DMO) and
proliferative diabetic retinopathy (PDR). The Early
Treatment Diabetic Retinopathy Study (ETDRS)
recommends visible end point (VEP) laser photocoagulation, although subthreshold and modified
laser strategies are being frequently reported.14 The
original ETDRS used long pulse duration, 100
200 ms, burns for macular and panretinal photocoagulation (MP, PRP). It is well recognised that
conventional (long pulse) laser scar expansion may
be associated with photoreceptor loss, retinal
pigment epithelium (RPE) hypertrophy, subfoveal
fibrosis and paracentral scotomas.5
Recently, selective retina therapy (SRT) demonstrates therapeutic effects using short pulse durations.3 Micropulse and non-VEP photocoagulation
have been reported to produce visual outcomes
518

that are equally effective or better than modified


VEP laser.4 6 However, ophthalmologists have
found laser titration difficult in the absence of
visible laser uptake, with risks of overlapping
retreatment burns.
For new laser technology, the goal of retinal
photocoagulation is to target the RPE with
minimal photoreceptor damage and RPE cell loss,
and perhaps barely visible scar formation.
The Pascal (pattern scanning laser) photocoagulator is a new laser delivery system introduced in
2005.7 It semiautomates the procedure and can
deliver single applications of multiple laser burns to
the retina. Pascal uses medium-pulse duration, 10
30 ms, burns for either PRP or MP. Importantly,
this results in less destruction within the outer
retina than with conventional burns, presumably
due to less thermal diffusion to the choroid.8
Despite recent knowledge of Pascal therapeutic
parameters,9 Pascal uptake may be difficult to
quantify in clinical practice. Assessment of laser
burns may be even more challenging in the
presence of retinal thickening of varied topography, or poorly pigmented RPE with low contrast.
It is important to determine the in vivo effects on
tissue across a range of therapeutic parameters, for
laser application to be safe and well tolerated by
patients.
In this article, we describe a pilot study of in vivo
retinal imaging of medium-pulse Pascal burns using
Fourier-domain optical coherence tomography
(FD-OCT) and fundus autofluorescence (AF) in a
cohort of patients with diabetes. The main aim of
our study was to assess the visibility and morphology of Pascal lesions within outer retina and RPE
and better understand the lasertissue interaction.
Our secondary aims were to investigate the effects
of different Pascal thresholds on retinal autofluorescence and to evaluate the evolution of Pascal
burns over time.

MATERIALS AND METHODS


Subjects
A consecutive series of patients with diabetes
undergoing routine unilateral or bilateral Pascal
for macular oedema and PDR were studied. Ocular
comorbidity included high myopia, cystoid macular oedema secondary to branch vein occlusion and
diffuse DMO.
All patients gave informed consent, and all
investigations were performed as part of routine
Br J Ophthalmol 2009;93:518525. doi:10.1136/bjo.2008.148833

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Clinical science
Pascal photocoagulation system

Table 1 Pascal photocoagulation parameters

Case

Energy
Pascal type (mW)

Spot size
Duration (ms) (mm)

Spot
spacing
(spots)

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17

HSG
FG
FA
HSG
FA
HSG
FG
FG
TG
TG
FA
HSG
FA
FA
HSG
PRP
PRP

10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
20
20

1.5
1.5
1.5
1.5
1.5
1.5
1.5
2.0
1.5
1.5
1.5
2.0
1.5
1.5
1.5
2.0
1.5

100
125
100
150
150
125
150
200
150
150
150
150
125
125
100
300
400

100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
400
400

CRT, central retinal thickness; FA, focal array; FG, full grid; HSG, horseshoe grid; PRP,
panretinal photocoagulation; TG, temporal grid.

care at Manchester Royal Eye Hospital, UK. FD-OCT and AF


were performed before laser treatment, and 1 h, 1 week,
2 weeks, 1 month and 1 year after MP. In the PRP group, AF
was performed after 1 h, 1 month, 3 months and 18 months.
However, it was not possible for all patients to undergo all tests
at the previously mentioned time-points.

This is a frequency-doubled neodymium-doped yttrium aluminium garnet (Nd: YAG) solid-state laser with a wavelength of
532 nm, using a 630650 nm diode laser aiming beam.7
Photocoagulation is applied in a rapid raster sequence with a
pattern array. In order to achieve this, the pulse duration of each
burn is reduced to 1020 ms. Squares are available in adjustable
262, 363, 464 and 565 arrays. The 565 array was used for PRP
in two patients.
In full grid treatment, the A plus B pattern consisted of four
concentric rings with 112 spots encircling the fovea. Each octant
of the array contains 14 spots, and focal macular MP may
comprise single or multiple octants. Photocoagulation of the
papillomacular bundle may have the potential to produce
centrocaecal scotomas over time. The papillomacular bundle
may be spared by using a horseshoe-shaped grid (HSG) array.
To configure an HSG, the superonasal and inferonasal octants
were excluded to give a total array of 84 spots. The diameter of
the innermost ring is 2000 mm (safety zone), and this inner
ring of 12 spots is delivered in 132 ms, which is theoretically
below a patients reaction time. The 100 mm spots were placed
one and a half burn widths apart.

Ocular imaging
Fundus autofluorescence
AF intensity is determined by the quantity and distribution of
lipofuscin.10 We used a fundus flash-camera system (Topcon
TRC-50DX, type IA) with an imaging field of 50u. The AF
exciter filter has a 30 nm bandwidth and central wavelength of
580 nm, with 60% transmission. The barrier filter has a 40 nm

Table 2 Ocular imaging classifications

Case

Diagnosis

1
2

CSMO
Diffuse
DMO
CSMO
Diffuse
DMO
CSMO
Diffuse
DMO
Diffuse
DMO
Diffuse
DMO
Diffuse
DMO
Diffuse
DMO
CSMO
Diffuse
DMO
CSMO
BVO+
CMO
Diffuse
DMO
PDR
PDR

3
4
5
6
7
8
9
10
11
12
13
14
15
16
17

Optical coherence
tomography
macular oedema
Snellen visual acuity patterns

Clinical visibility of laser


uptake at 2 weeks

Laser masking
features

6/5
6/5

Sponge-like
Sponge-like

Y
N

SRNFLR
SRNFLR

6/18
6/9

Sponge-like
Sponge-like

Y
N

Choroidal folds
Myopic RPE attenuation

6/9
6/36

Sponge-like
Sponge-like

N
N

Myopic RPE attenuation


SRNFLR

6/24

Sponge-like

SRNFLR

6/60

Exudates

6/5
6/6

Cystoid+
Sponge-like
Cystoid+
Sponge-like
Cystoid+
Sponge-like
Sponge-like
Sponge-like

6/9
6/18

Sponge-like
Chronic cystoid

N
N

6/12

Cystoid+
Sponge-like
NA
NA

Diffuse retinal
thickening
Diffuse retinal
thickening
Nil
Diffuse retinal
thickening
Exudates
Hypoxic
RPE attenuation
Diffuse retinal
thickening
NA
NA

6/12
6/9

6/6
6/6

N
Y
N

Y
Y

BVO, branch vein occlusion; CMO, chronic macular oedema; CSMO, clinically significant macular oedema; DMO, diabetic macular
oedema; PDR, proliferative diabetic retinopathy; RPE, retinal pigment epithelium; SRNFLR, superficial retinal nerve fibre layer reflexes.

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Figure 1 (A, B, C) Colour and red-free fundus photographs (CFP, RFFP), and late frame fluorescein angiography of patient 1 before laser. (D) Diffuse
macular oedema and fundus autofluorescence (AF) showing an increased signal at the fovea. (E, F) One hour after horseshoe-shaped grid (HSG) Pascal
(100 mm spot size, 10 ms), grey-white burns visible with blurred edges on CF and RFFP. (G) Complete array of burns appearing well demarcated as
hypoautofluorescent spots on AF. (H) Horizontal Fourier-domain optical coherence tomography (FD-OCT) scan at 1 h through the fovea, showing three
vertical bands of increased optical reflectivity within the outer plexiform layer (OPL), extending through the thin band of high reflectivity immediately
internal to the outer highly reflective layer and into the upper surface of retinal pigment epithelium (RPE). (I, J) Two weeks after Pascal, superficial nerve
fibre layer reflexes masking the complete array of laser burns on CF and RFFP at the macula. (K) AF at 2 weeks demonstrating an increased signal at
the site of each laser burn within the HSG array. (L) At 2 weeks, FD-OCT (horizontal, 3 mm 3D scan) demonstrating reduced optical reflectivity within
the OPL with an accompanying defect at the level of the junction between the inner and outer segments of the photoreceptors (JI/OSP) and upper
surface of RPE. The laser burn measures 83 mm in diameter. (M) At 4 weeks postlaser, the FD-OCT (overlapping horizontal 6 mm line scan)
demonstrating the localised defects at the JI/OSP in high resolution corresponding to laser burns with sparing of photoreceptors and RPE adjacent to
either side of each burn.
bandwidth and central wavelength of 695 nm. AF images show
the spatial distribution of signal intensities for each pixel in grey
values. Dark signals correspond to low pixel values and blocked
autofluorescence, and bright signals correlate with high pixel
values and increased autofluorescence due to a window-type
effect.11

is believed to correspond to the junction between the inner and


outer segments of the photoreceptors (JI/OSP), and the outer
HRL has been reported to represent the melanin in RPE.1315 We
used three acquisition modes, namely 6 mm/6 mm size retina
and choroidal 3D-scans, overlapping line scans with averages
taken of five high-resolution images and retina 3D scans with a
3 mm/3 mm acquisition area.

Fourier domain optical coherence tomography


FD-OCT (Topcon, 3D OCT-1000) allows non-contact, in vivo
visualisation of the retina. Image detection is based on retrieval
of an optical A-scan from interferometric signals as a function of
spectral fringe patterns.12 High acquisition speeds (25 000 Ascan/s) permit visualisation of retinal morphology up to an axial
resolution of 5 mm. Important reflective signals within the outer
retina include the outer highly reflective layer (HRL). The thin
band of high reflectivity immediately internal to the outer HRL
520

RESULTS
Seventeen eyes of 11 patients with diabetes (mean age 54 years
(median 54, range 2676); 15 (88%) males; 15 (88%) Caucasian
and two (12%) Asian) were treated. Fifteen eyes received MP,
and two eyes underwent PRP (table 1). Within the MP group,
five patients received a HSG, four had full grid, four eyes
received a focal macular pattern, and the remaining two eyes
underwent temporal grid. Visual acuity was 6/5 to 6/9 in 10
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Figure 2 Photograph showing diffuse exudative diabetic macular oedema that was treated with conventional (long pulse) temporal macular laser
3 months previously, and with a single intravitreal bezacizumab injection given 2 weeks prior to Pascal treatment. (A, B) Colour and red-free fundus
photographs (CFP, RFFP) of patient 8, 1 h after full grid (FG) Pascal. Laser burns are visible superior to the fovea and not visible elsewhere within the FG
array. (C) Horizontal Fourier-domain optical coherence tomography (FD-OCT) 3D scan performed 1 h prior to Pascal FG (10 mm spot size, 100 ms)
showing sponge-like intraretinal oedema with a cystoid space. (D) FD-OCT at 1 h showing six vertical bands of increased optical reflectivity within the
outer plexiform layer (OPL), extending through the thin band of high reflectivity immediately internal to the outer highly reflective layer and into the
upper surface of retinal pigment epithelium (RPE). (E, F) Laser burns masked by the diffuse retinal thickening and not clearly visible on CFP and RFFP,
4 weeks after FG treatment. (G) Fundus autofluorescence (AF) performed at 4 weeks after laser showing hyperautofluorescent spots, corresponding to
the complete FG array with a Pascal foveal exclusion zone of 2000 mm. The conventional laser burns are visible as mixed high and low signal spots
superotemporal and inferotemporal to the Pascal FG array. (H) FD-OCT (horizontal, 6 mm 3D scan) demonstrating reduced optical reflectivity within the
outer plexiform layer with accompanying defects at the level of the junction between the inner and outer segments of the photoreceptors and upper
surface of RPE.

(59%) eyes, 6/12 to 6/24 in five (29%) eyes and worse than 6/36
to 6/60 in two (12%).

Postoperative laser parameters


Laser spot arrays were more easily visible after 1 h on
ophthalmoscopy and colour fundus photography (CFP). With
red-free photography (RFP), burn edges were blurred, and overall
spot sizes were smaller than expected (fig 1). In the presence of
choroidal folds, high myopia, and exudative DMO, the visibility
of burns was difficult at 1 h, becoming even more difficult after
1 week (fig 2). Young patients with diabetes have bright
superficial RNFL reflexes, and this appearance may mask the
underlying lasertissue interaction signs. The laser spots became
less visible on CFP and RFP in four eyes (fig 1) 4 weeks after laser.
Br J Ophthalmol 2009;93:518525. doi:10.1136/bjo.2008.148833

AF imaging demonstrated hypoautofluorescence at 1 h


postlaser in the 15 MP eyes studied. The size and shape of each
Pascal spot and hypoautofluorescent signal were altogether
similar within the designated treatment array. HSG and full grid
configurations, and also titration spots were clearly delineated
with hypoautofluorescent spots (fig 1).
In a single patient, all burns appeared hyperautofluorescent at
1 week, and it is possible that AF signals increased with higher
laser power used from 100 mW up to 200 mW observed within
the titration scale (fig 3).
The CFP and RFP visibility of complete Pascal arrays was
incomplete in 12 eyes after 2 weeks, but increased AF signals
accurately mapped laser burns in 15 eyes over 4 weeks (figs 1, 2).
A single patient in the MP group had 1 years follow-up, and the
macular lesions were hypoautofluorescsent. In comparison with
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Clinical science

Figure 3 Photograph showing patient 11 who received a single octant of Pascal (100 mm spot size, 10 ms) for clinically significant macular oedema.
(A, B) Colour and red-free fundus photographs (CFP, RFFP) at 1 h after laser showing grey-white laser burns temporal to the fovea. (C) Fundus
autofluorescence (AF) demonstrating the complete octant of burns as hypoautofluorescent spots. The two rows of titration burns are partially visible on
CFP, with increasing visibility on RFFP. (C) AF clearly demonstrating the titration burns, with the power intensity varying from temporal to nasal
hypoautofluorescent spots (100 mW, 125 mW, 150 mW, 175 mW, 200 mW). A power of 150 mW was used as the threshold level for the octant
treatment array. (D) Horizontal Fourier-domain optical coherence tomography (FD-OCT) scan performed through the fovea before laser. (E) FD-OCT 1 h
after laser demonstrating three vertical bands of increased optical reflectivity within the outer plexiform layer (OPL). (F) A horizontal FD-OCT scan
through the titration zone demonstrating five vertical bands of increased optical reflectivity. Each band shows increasing reflectivity within the OPL and
greater disruption of the outer highly reflective layer (HRL) as the burns move from temporal to nasal retina, and this corresponds to stepwise increases
in the titration powers. (G, H) One week after laser, the grey-white burns are visible on CFP and RFFP. (I) AF demonstrating the complete octant of
burns as hypoautofluorescent spots temporal to the fovea, with increased signal demonstrated with all titration burns. FD-OCT of the treatment (J)
octant (horizontal, 6 mm 3D scan) and of the titration zone (horizontal 3 mm 3D scan (K), high definition overlapping horizontal 6 mm line scan (L)
demonstrating reduced optical reflectivity within the OPL with an accompanying defect at the level of the junction between the inner and outer
segments of the photoreceptors and upper surface of RPE. (K, L) On the titration scans, there is increasing disruption of the outer HRL with increasing
power intensity. The laser burn measures 88 mm in diameter (J).
100 ms conventional MP scars, Pascal burns appeared uniform in
shape with no coalescence of scars at 1 years follow-up.
Macular oedema was classified using OCT before laser
intervention16 (table 2): sponge-like (10/15 eyes), sponge-like
and cystoid (4/15 eyes) and chronic cystoid (1/15 eye).
At 1 h, vertical bands of moderate and high reflectivity
(VBMHR) were observed within the outer nuclear layer (ONL),
with extension from the inner HRL through the outer plexiform
layer (OPL). These VBMHR corresponded to Pascal burns (figs 1,
2). The OPL showed slight thickening, and the inner retinal
architecture remained intact. The basal border of the outer HRL
showed no signs of disruption.
At 1 week, there were localised areas of hyporeflectivity at the
level of JI/OSP and apical RPE that corresponded to laser burns.
The VBMHR showed reduced hyper-reflectivity within the OPL.
522

At 2 weeks, different stages of Pascal burn development were


represented. Patients with an underlying thin outer HRL (fig 2)
developed visible pigmentation and hypertrophy, observed as a
tiny cleft of hyper-reflectivity at the centre of the burn protruding
into the OPL. In other cases, the VBMHR had resolved to varying
degrees with an intact OPL layer that corresponded to nonpigmented lesions. Overlapping FD-OCT may demonstrate JI/
OSP and outer HRL defects in high definition (fig 3).
We observed that 10 ms burns remained highly localised,
with no significant reflectivity changes in adjacent RPE or
neuroretina. Although the laser spot size delivered was 100 mm,
the burns were measured on FD-OCT in three patients at 79 mm
(patient 1), 83 mm (patient 3) and 88 mm (patient 11).
At 1 year, macula burns appeared as square-edged foci of
hyporeflectivity within the JI/OSP and apical RPE. On 3D
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Clinical science

Figure 4 (A, B) Colour and red-free fundus photographs (CFP, RFFP) of patient 15, 1 year following horseshoe-shaped grid (HSG) Pascal for diabetic
macular oedema. Focal spots of hypopigmentation in the parafoveal macular region are visible. (C) Fundus autofluorescence (AF) demonstrating
hypoautofluorescence within the macular treatment array. The burns appear round and uniform in size and shape, with no coalescence of burns. In the
temporal macula, previous conventional laser burns are visible as larger hypoautofluorescence lesions with varying shapes of burns and coalescence of
burns. (D, E) FD-OCT (horizontal, 6 mm 3D scan) of a single burn demonstrating sparing of the inner neuroretina and an accompanying defect at the
level of the junction between the inner and outer segments of the photoreceptors and upper surface of retinal pigment epithelium (RPE). The outer highly
reflective layer on either side of the Pascal burn demonstrates normal reflectivity.
mapping with FD-OCT, fresh Pascal burns appeared columnar
in shape (fig 4). The outer HRL remained intact on either side of
each burn, together with basal aspects of outer HRL.
For the two cases of PRP, AF showed hypoautofluorescence at
1 h postlaser, with hyperautofluorescence at 4 and 12 weeks
follow-up. Regarding laser-burn evolution, a patient treated
with Pascal PRP in November 2006 was investigated (fig 5). The
patient had 2 weeks previously undergone conventional 50 ms
PRP. Over 18 months follow-up, both conventional laser and
Pascal burns appeared as hypoautofluorescent spots. However,
on comparison of serial CFP and AF imaging, Pascal burns
remained non-pigmented and unchanged in size and shape over
this period. Conventional 100 ms laser burns appeared variable
in size, shape and pigmentation.

DISCUSSION
In this study, we aimed to investigate AF and FD-OCT
appearances of medium-pulse Pascal photocoagulation.
Controversy exists in clinical practice as to whether Pascal
burns within PRP or macular arrays are uniform in uptake,
based on clinical biomicroscopy. The higher power intensity of
VEP burns originally described by the ETDRS in DMO may
increase the risk of paracentral scotomas, choroidal rupture and
choroidal neovascularisation. However, these risks are now
more rarely associated with modified ETDRS MP regimens.2
Br J Ophthalmol 2009;93:518525. doi:10.1136/bjo.2008.148833

In order to understand the evolution of Pascal MP burns, we


investigated a range of patients with diabetes with variable
retinal morphology. Laser photocoagulation in diffuse DMO
may result in excessive laser power due to masking of burns by
retinal thickening and exudates. It is possible that increasing
pulse durations may lead to suprathreshold burns that evolve
over time to produce zonal photoreceptor loss and macular
capillary loss.
In experimental work with rabbit retina, medium pulse
demonstrated localised homogenous burns.17 In rabbit eyes, the
power required to produce ophthalmoscopically visible spots
was shown to decrease with increasing pulse duration, but the
cumulative pulse energy increased with pulse duration.8 We
observed no complications within the outer retina at 10 ms and
20 ms.9
AF is a non-invasive tool to investigate the in vivo effects of
laser photocoagulation on RPE metabolism. Framme has
reported AF signals following SRT to remain hyperautofluorescent for up to 3 years.18 Framme and coworkers described
difficulty in visualisation of AF signal changes with the
Heidelbergh angiograph (confocal scanning laser ophthalmoscopy system) in DMO patients treated by SRT.18 Immediate
hypoautofluorescence was not observed in these patients, and
laser burns could not be visualised over time.
In contrast, we found AF to be a reliable method of detecting
the totality of Pascal burns at all time points, whether
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Figure 5 Photograph showing patient 17 who received conventional (50 ms pulse) panretinal photocoagulation (PRP) to the retinal periphery 2 weeks
prior to Pascal. (A, B) Colour and red-free fundus photographs (CFP, RFFP) of the superonasal retinal quadrant 1 h after Pascal PRP (565 spot array,
400 mm spot size, 20 ms). (C) Pigmented, conventional PRP burns in the retinal periphery, and Pascal PRP burns within the treatment arrays. The
conventional PRP burns show hyperpigmentation and coalescence of laser burns in the periphery. (D, E) After 18 months, Pascal PRP burns unchanged
in size and shape on CFP and RFFP. Fundus autofluorescence (AF) demonstrates hypoautofluorescence within the PRP array, and there is no significant
expansion of the Pascal burns in comparison with initial fundus photography (A, B).
ophthalmoscopically visible, barely visible or invisible. None of
our patients required a retreatment with Pascal for subtherapeutic laser uptake. In the presence of exudative, cystoid and
sponge-like DMO, we were able to accurately locate laser burns
with AF. We used alterations in AF and changes in reflectivity
on FD-OCT to verify then monitor burns over time. PRP lesions
were visualised successfully in our two patients.
In DMO, we started titration at 100 mW, and a barely visible
burn was designated as threshold. Interestingly, the totality of
titration burns used in our patients showed hypoautofluorescence after 1 h. In one case, five laser spots of increasing
intensity were required to establish threshold. The selected
threshold was 150 mW; however all burns from 100 mW
(invisible) up to 200 mW (white grey burn, suprathreshold)
produced hypoautofluorescence at 1 h, followed by hyperautofluorescence. In the MP group, all titration spots showed
increased AF signal over 2 to 4 weeks.
In the last decade, Toth et al have demonstrated argon bluegreen laser lesions in Macaca mulatta retina using time-domain
OCT.19 With FD-OCT, we can evaluate alterations in retinal
architecture in greater detail. After 1 h, each Pascal burn
produced a VBMHR that corresponded spatially with blockage
of background signal on AF. Disruption of the JI/OSP suggests
that each VBMHR may consist of coagulated photoreceptor
elements and Muller cells within the OPL. VBMHR appeared
surrounded by vacuoles of hyporeflectivity, and this suggests
oedema within the OPL. We observed localised proliferation
within the apical RPE with no morphological alterations within
inner retina, and this correlates with reported histopathological
work.7
524

The observed hyperautofluorescence was associated with a


window defect and increased lipofuscin production at sites of
photocoagulation. This phenomenon occurred at both invisible
and barely visible Pascal intensities. The 100 mm burns produced
at 10 ms duration appear to result in a burn size smaller than
the original laser spot size by approximately 15%.
In the long term, FD-OCT evaluation of macular scars
showed hyporeflective defects at the JI/OSP and apical RPE.
Scars appeared barely visible, with no full-thickness extension
through outer HRL, or any significant expansion.19 20 The
adjacent HRL was unaffected on both sides of the Pascal scar.
In Pascal 20 ms PRP, initial hyperautofluorescence appears to
fade by 6 months, and hypoautofluorescence remained up to
18 months in one patient with no significant laser scar
enlargement.
Laser-induced alterations in RPE function and morphology
are linked to progressive photoreceptor apoptosis. The initial
acumulation of lipofuscin may be the by-product of therapeutic
metabolic effects within outer retina. However, evolution of AF
signals over time suggests that an increased load of lipofuscin
may result from the coagulated photoreceptors and/or RPE cells.
We have demonstrated with AF and FD-OCT that 1020 ms
Pascal produces well-circumscribed and highly localised burns.
Individual spots of Pascal arrays result in uniform laser uptake
within the outer retina.. Threshold (barely visible) Pascal burns
may always result in RPE alterations, even if the complete array is
not immediately clinically visible. AF may be used as a monitoring
tool after laser photocoagulation, either to confirm successful
placement of burns or to target future retreatments especially
when using ophthalmoscopically invisible or threshold burns.
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Clinical science
Funding: This study was sponsored/funded by OptiMedica Corporation.
Competing interests: GRM is employed by the OptiMedica Corporation and has a
proprietary interest in the Pascal Photocoagulator.

9.

10.

Patient consent: Obtained.

REFERENCES
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Fong DS, Strauber SF, et al. Comparison of the modified early treatment diabetic
retinopathy study and mild macular grid laser photcoagulation strategies for diabetic
macular edema. Arch Ophthalmol 2007;125:46980.
Framme C, Schuele G, Roider J, et al. Influence of pulse duration and pulse number
in selective RPE laser treatment. Lasers Surg Med 2004;34:20615.
Luttrul JK, Musch DC, Mainster MA. Subthreshold diode micropulse
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Hudson C, Flanagan JG, Turner GS, et al. Influence of laser photocoagulation for
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Moorman CM, Hamilton AM. Clinical applications of the micropulse diode laser. Eye
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Blumenkranz MS, Yellachich D, Anderson DE, et al. New instrument:
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Jain A, Blumenkranz MS, Paulus Y, et al. Effect of pulse duration on size and
character of the lesion in retinal photocoagulation. Arch Ophthalmol 2008;126:7885.

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Schmitz-Valckenberg S, Holz FG, Bird AC, et al. Fundus autofluorescence
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Leitgeb R, Hitzenberger CK, Fercher AF. Performance of Fourier domain vs. time
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Costa RA, Skaf M, Melo LA Jr, et al. Retinal assessment using optical coherence
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Stanga PE, Kychenthal A, Fitzke FW, et al. Retinal pigment epithelium translocation
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Ophthalmology 2002;109:14928.
Chauhan DS, Marshall J. The interpretation of optical coherence images of the
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Otani T, Kishi S, Maruyama Y. Patterns of diabetic macular edema with optical
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Krauss JM, Puliafito CA, Lin WZ, et al. Interferometric technique for investigation of
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Framme C, Brinkmann R, Birngruber R, et al. Autofluorescence after selective RPE
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Abnormal optic disc and retinal vessels in


children with surgically treated hydrocephalus
S Andersson and A Hellstrm
Br. J. Ophthalmol. 2009;93;526-530; originally published online 23 Dec 2008;
doi:10.1136/bjo.2008.142315

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Clinical science

Abnormal optic disc and retinal vessels in children


with surgically treated hydrocephalus
S Andersson,1 A Hellstrom1,2
1

Department of Ophthalmology,
Institute of Clinical Neuroscience
and Physiology, Goteborg,
Sweden; 2 International
Paediatric Growth Research
Centre, Department of
Paediatrics, Institute of the
Health of Women and Children,
The Sahlgrenska Academy of
Goteborg University, Goteborg,
Sweden
Correspondence to:
Dr S Andersson, Department of
Ophthalmology, The Queen Silvia
Childrens Hospital, Sahlgrenska
stra, 416
University Hospital/O
85 Goteborg, Sweden;
susann.andersson@oft.gu.se
Accepted 26 November 2008
Published Online First
23 December 2008

ABSTRACT
Aims: To investigate the morphology of the optic disc and
retinal vessels in children with surgically treated hydrocephalus.
Methods: A prospective, population-based study was
performed in 69 children (median age 9.6 years) with
early surgically treated hydrocephalus. All children were
examined by ophthalmoscopy. Additionally, optic disc and
retinal vessel morphology was evaluated in 55 children by
digital image analysis of ocular fundus photographs.
Results: Optic atrophy was found in 10 of 69 children
(14%). In comparison with a reference group, the median
optic-disc area was significantly smaller (p = 0.013) in
the children with hydrocephalus. There was no corresponding difference in cup area, so the rim area was
significantly smaller in the hydrocephalic children
(p = 0.002). Children with hydrocephalus had an abnormal retinal vascular pattern, with significantly straighter
retinal arteries and fewer central vessel branching points
compared with controls (p,0.001 and p,0.001,
respectively).
Conclusion: Hydrocephalus is associated with subnormal
optic disc and rim areas and an abnormal vascular
pattern, indicating a pre/perinatal disturbance of the
development of these structures. A promising finding is
that the frequency of optic atrophy in the present study
was lower than previously reported, most likely reflecting
improved perinatal care and better regulation of the
intracranial pressure.

Hydrocephalus is a disorder in which reduced


outflow or absorption of cerebrospinal fluid causes
increased intraventricular and intracranial pressure
with distension of the ventricles. Hydrocephalus
may develop prenatally, perinatally or postnatally.
The definition of infantile hydrocephalus, as used
in this study, is hydrocephalus present at birth or
developing within the first year of life. Surgical
treatment with ventriculoperitoneal shunting or
ventriculostomy may restore the pressure to
normal levels.1 2
Both anterior and posterior visual pathways may
be affected in children with hydrocephalus.
Papilloedema is very rare in infants and young
children, and despite the high intracranial pressure,
papilloedema is also absent in a majority of infants
with hydrocephalus.3 This is probably due to the
fact that open sutures permit the head to enlarge in
response to the increased pressure. However, large
or rapid elevations in intracranial pressure may
exceed this response, causing papilloedema.4
Optic atrophy (OA) is a well-known complication of raised intracranial pressure. In children, OA
may or may not have been preceded by papilloedema. A number of different mechanisms for OA
526

in children with hydrocephalus have been


described, including optic nerve ischaemia, optic
nerve or chiasmal traction, chiasmal compression
and trans-synaptic neuronal degeneration.5 Optic
nerve hypoplasia (ONH) is typically described as a
small optic nerve head, pale in colour and sometimes surrounded by a double ring.6 7 The growth
of the normal optic disc and nerve is only partly
completed at birth, and growth continues until
adulthood.8 9
During the last few decades, there have only
been a few studies performed on children with
hydrocephalus regarding ocular and fundus appearance. These studies have described optic disc
oedema and/or atrophy (17% and 29%), detected
using ophthalmoscopy.3 10
To our knowledge, no population-based morphometric study has been performed on the ocular
fundus of children with surgically treated hydrocephalus. In the present study, therefore, we set
out to describe optic disc and retinal vessel
morphology, using both ophthalmoscopy and
digital-image analysis of fundus photographs in
children with hydrocephalus.

MATERIALS AND METHODS


The inclusion criteria for the study were a head
circumference .2 standard deviation scores (SDS)
greater than body-length SDS and enlarged ventricles present at birth, or developing during the
first year of life, requiring surgical treatment.11 The
inclusion criterion that the hydrocephalus should
have necessitated neurosurgical treatment was
used to delineate a homogenous group. There are
a few children with transient hydrocephalus
constituting less than 10% of all. One subgroup is
the very preterm infants with posthaemorrhagic
enlargement of the ventricles that may resolve
within a few weeks when the blood is reabsorbed,
some children with time limited disturbance of the
CSF circulation after an infection and a group with
external hydrocephalus during the first year of
life due to a maturity-dependent imbalance
between CSF production and reabsorbtion.
Between 1989 and 1993, 103 children born in a
well-defined area in south-western Sweden (the
counties of Vastra Go
taland, Halland and
Varmland) met the inclusion criteria. Six children
died shortly after surgery, and five children who
had been surgically treated outside the region were
excluded from this ophthalmological follow-up
study. Of the remaining 92 children, 15 did not
agree to participate, and two were excluded as they
had moved out of the region. Six children did not
want to take part of the ocular fundus examination. Hence, 69 children were available for the
Br J Ophthalmol 2009;93:526530. doi:10.1136/bjo.2008.142315

Downloaded from bjo.bmj.com on 31 March 2009

Clinical science
study, 32 girls and 37 boys, 7.2 to 12.8 years of age (median age
9.6 years), with a median GA at birth of 39 weeks (range 27 to
42 weeks) and a median birth weight SDS of +0.5 (range 24 to
+4) (see table 1). All children underwent an eye examination,
including ocular fundus photography; 84% had some kind of
visual deficit, such as subnormal visual acuity, strabismus,
impaired stereo vision, refractive errors and/or visuoperceptual
problems. Nine children (13%) were visually impaired according
to the definition of the World Health Organization (WHO
1997), and 64% had significant refractive errors.12
Only correctly focused photographs with the optic disc
centred were accepted for analysis; 55 of the children (27 girls
and 28 boys) fulfilled this criterion. Of the remaining 14
children, all agreed to ophthalmoscopy.

Reference group
A total of 99 healthy Swedish children (56 boys and 43 girls)
born at term, with an age range of 3 to 19 years (mean age
10.1 years) constituted a reference group for the evaluation of
ocular fundus morphology by the digital image analysis
system.13 No association between studied variables and sex
and age could be found in these children. The visual acuities of
the reference group ranged from 0.0 (logMAR) to 0.1 (logMAR)
(median 0.0 logMAR).
The study was approved by the Committee for Ethics at the
Medical Faculty, Go
teborg University.

Digital image analysis of fundus photographs


The ocular fundus photographs were obtained, by film
photography, through dilated pupils and analysed quantitatively, using a specifically designed computer-assisted digital
mapping system.14
The area of the optic disc was measured by marking the
outlines with a cursor. The optic disc was defined by the inner
border surrounding the nerve tissue; care was taken not to
include the white peripapillary scleral ring. The cup was defined
by its contour, and its definition was facilitated by the course of
the vessels and by its pallor. The neuroretinal rim area was
obtained by subtraction of the cup area from the disc area. The
indices of tortuosity for arteries and veins were defined as the
path length of the vessel divided by the linear distance from the
vessel origin to a reference circle 3 mm from the centre of the
optic disc. Vessels were also marked from their branching point
to the reference circle, and within this area the total number of
branching points (arteries and veins), that is, the number of
retinal vessels, was calculated. The same method of digital
analysis was used for both the hydrocephalic children and the
reference group, and all measurements were performed by the
same person.

Retrospective review of medical files


The aetiology of hydrocephalus varied. Hydrocephalus was
associated with myelomeningocele (MMC) in 26 children, with

intraventricular haemorrhage in 17 children, with malformations in 18 children, and with infections in four children. In four
cases, the aetiology was unknown. Thirteen children were born
preterm.
The time of the mothers last menstrual period was recorded,
and GA was estimated by fetal ultrasonography, performed at
week 17 of gestation (postmenstruation). The fetal ultrasonographic data were used to determine the GA at birth. The
perinatal data and associated diagnoses are presented in table 1.

Statistical methods
The ocular fundus variables for each child were calculated from
the mean of the two eye measurements. The median and 95%
CI for the median were calculated for the areas of the optic disc,
cup and rim, the tortuosity of arteries and veins, and the
number of vascular branching points. The WilcoxonMann
Whitney test was used to compare the medians in the group of
hydrocephalic children with the medians in the reference group.

RESULTS
Optic nerve morphology
Optic disc variables for children with hydrocephalus and
controls are shown in table 2.
The children with hydrocephalus had a smaller median opticdisc area than the reference group of healthy children (2.21 and
2.42 mm2 respectively, p = 0.01). No difference was found in the
median cup area (0.31 vs 0.34 mm2). Thus, the children with
hydrocephalus had a significantly smaller median rim area than
the reference group (1.79 and 2.07 mm2 respectively, p = 0.002)
(figs 1, 2).
Nine children (16%) had an optic-disc area below the 5th
centile (table 3).
Examination by indirect ophthalmoscopy showed OA in 10
out of 69 children (14%); six had fundus photographs of
acceptable quality for digital analysis. Three of these had an
optic disc and rim area below the 5th centile for controls, two
had large optic cups in normal sized discs, and one child had a
normal disc appearance on the photographs.

Optic-nerve morphology and clinical findings


Visual acuity among the 55 children ranged from ability to
fixate a penlight to 20.1 logMAR (median 0.1). Refraction
ranged from 21 to +6 dioptres (spherical equivalent).
Strabismus was noted in 39 of 54 children (72%).
Five of the 10 children with optic atrophy had a VA of
(0.3(logMAR).
Among the children with VA>0.5(logMAR), two out of three
children had optic discs and neuroretinal rim areas smaller than
the 5th centile for controls.
Strabismus was noted in seven out of nine children with optic
atrophy.

Table 1 Aetiology, gestational age, birth weight and associated diagnoses in children with hydrocephalus (n = 69) in relation to a comparison group
of 140 healthy children
Aetiology

Gestational age (weeks)


Md (range)

Birth weight SDS


Md (range)

Hydrocephalus with myelomeningocele (n = 26)


Hydrocephalus without myelomeningocele (n = 43)
Reference (n = 140)

39 (33 to 42)
38 (27 to 41)
40 (35 to 42)

+0.5 (22.5 to +4)


+0.5 (24 to +4)
+0.2 (24 to +5.5)

Associated diagnoses
Cerebral paresis

Epilepsy

IQ,70

0/26
12/43 (28%)
0

2/26 (8%)
15/43 (35%)
0

4/21 (19%)
17/40 (43%)
0

Md, median.

Br J Ophthalmol 2009;93:526530. doi:10.1136/bjo.2008.142315

527

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Clinical science
Table 2 Areas of the optic disc, cup and neuroretinal rim of children with hydrocephalus (n = 55) in relation
to a reference group (n = 99)
Variables
2

Optic-disc area (mm )


Cup area (mm2)
Rim area (mm2)
Tortuosity index for arteries
No of vascular branching points

Hydrocephalus

Controls

Median (95% CI)

Median (95% CI)

p Value

2.21 (1.31 to 3.20)


0.31 (0 to 0.96)
1.79 (0.87 to 2.92)
1.07 (1.02 to 1.13)
23 (17 to 31)

2.42 (1.44 to 3.46)


0.34 (0 to 0.84)
2.07 (1.27 to 2.90)
1.09 (1.03 to 1.17)
28 (20 to 35)

0.01
NS
0.002
,0.001
,0.001

Strabismus was present in 39 of the 54 children who also had


an ocular fundus evaluation; nine of these 39 (23%) had a rim
area below the 5th centile (p = 0.003).

Retinal vessel morphology


Of the 55 children who had fundus photographs taken, 51
childrens retinal vessel morphology could be analysed. Children
with hydrocephalus had an abnormal retinal vascular pattern,
with significantly straighter retinal arteries and fewer central
vessel branching points compared with controls (p,0.001 and
p,0.001, respectively).
A reduced number of vascular branching points below the 5th
centile for controls was found in seven of 51 children (14%)
with hydrocephalus (p = 0.037) (figs 1, 3).
The two groups did not differ significantly in vein tortuosity.
There was no significant relationship between retinal vessel
morphology and either visual acuity or strabismus.

rim areas, as well as an abnormal retinal vascular pattern with


less tortuous arteries and a reduced number of central vascular
branching points.
Children with hydrocephalus born preterm had a significantly
smaller rim area compared with those born at term. These
findings are well in accordance with the results of Hellstro
m et
al, who found a small rim area in non-hydrocephalic children
born at a GA of less than 29 weeks.15 Also, when excluding the
children born preterm, the group of children with hydrocephalus had smaller rim areas compared with controls.
Histologically, ONH is characterised by a reduction in both
the number of axons and the optic nerve diameter. Optic
atrophy is characterised by a similar histopathology, except that
the diameter of the optic nerve may be diminished in some cases
but preserved in others.4 7 It is possible that ONH could be
regarded as a non-progressive optic atrophy acquired at any

Aetiology and gestational age


In comparison with those born at term, children born preterm
were found to have a smaller rim area as well as increased
tortuosity of the central retinal vessels (p = 0.015 and p = 0.004,
respectively). There was no other correlation between aetiology
and ocular fundus variables.

DISCUSSION
Independently of aetiology, children with hydrocephalus were
found to have subtle abnormal optic nerve morphology in
comparison with controls, illustrated by smaller optic disc and

Figure 1 Fundus photography of a girl with hydrocephalus showing an


example of a small optic-disc area, a small neuroretinal rim area and a
decreased number of retinal vascular branching points.
528

Figure 2 Areas of the optic disc, cup and neuroretinal rim of children
with hydrocephalus in relation to a reference group. The yellow area
depicts the 5th to the 95th centile range, and the dotted line indicates the
median for the control group.
Br J Ophthalmol 2009;93:526530. doi:10.1136/bjo.2008.142315

Scoring of immunoreactivity for heat shock protein (HSP) 27 and -crystallins in human retinoblastoma cells with or without history of
preoperative chemotherapy. The score of HSP27 immunoreactivity is significantly higher in the chemotherapy-treated (chemo+) group (n = 6) than in
the no chemotherapy (chemo) group (n = 12) (p 0.0001, left side). In contrast, the immunoreactivity score of A-crystallin reveals significantly
higher expression in the chemo group than that in the chemo+ group (p 0.01, middle side). Immunoreactivity for B-crystallin shows no significant
statistical correlation despite treatment with chemotherapy (p 0.05, right side).

Proposed mechanism of the apoptotic pathway for


chemotherapeutic agent-induced apoptosis, and the presumed protective
mechanisms of heat shock protein (HSP) 27 and B-crystallin affected
by chemoreduction in retinoblastoma cells. Anticancer drugs can induce
upregulation of Bak and translocation of Bax and Bcl-Xs and the release
of cytochrome c from the mitochondria. Procaspase-9 is activated by
cytochrome c release, which causes activation of procaspase-3 and
eventually execution of the apoptotic programme. HSP27 inhibits the
activation of procaspase-9 and procaspase-3. -Crystallin blocks
upregulation of Bak and translocation of Bax and Bcl-Xs, and suppresses
the procaspase-3 directly, thereby inhibiting the activation of
downstream apoptotic events.
Br J Ophthalmol

Clinicopathological profiles in retinoblastoma cases examined in this study


a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18

0.5
1
4
2
1
3
2
1
1
1
3
2
0.5
2
1
3
1
2

F
F
M
F
F
F
F
F
M
F
M
M
F
F
F
M
F
M

R
R
R
R
R
R
L
L
L
R
R
L
L
L
R
L
L
R

+
+
+
+
+
+

Un
Well
Un
Well
Un
Un
Un
Well
Un
Un
Un
Un
Well
Un
Un
Un
Well
Well

50
90
40
70
80
10
10
50
10
30
10
10
10
10
10
10
10
20

+
+

+
+

+
+
+

10
10
10
10
20
10
30
70
20
80
10
20
20
90
70
40
30
60

50
70
30
50
70
10
70
60
20
80
10
50
10
30
90
10
30
30

Diff, differentiation; ON, optic nerve; Un, undifferentiated; Well, well differentiated.
et al
J Biol Chem
et al
Invest Ophthalmol Vis Sci
et al
Cancer
et al
Breast Cancer Res Treat
et al
J Clin Invest
et al
Laryngoscope
et al
Cell Stress Chaperones
et al
BMC Cancer
Br J Oral Maxillofac Surg
et al

Ophthalmol

Clin North Am
et al
Arch Ophthalmol
et al
Cancer
Res
et al
Cancer Res
et al
J Biol Chem
et al
et al

Cell Death Differ

FEBS Lett

et al
Exp Eye Res

J Biol Chem

Prog Retin Eye Res

Apoptosis

et al
et al

FASEB J
et al

J Biol Chem

Mol Cell Biol


J Biol Chem

Clin Cancer Res

Br J Ophthalmol

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Education
Br. J. Ophthalmol. 2009;93;545
doi:10.1136/bjo.2008.144303a

Updated information and services can be found at:


http://bjo.bmj.com/cgi/content/full/93/4/545

These include:

References

This article cites 10 articles, 2 of which can be accessed free at:


http://bjo.bmj.com/cgi/content/full/93/4/545#BIBL

Rapid responses

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Education

ANSWERS
From questions on page 423

1. Describe the slit-lamp findings (fig 1A,B) and in vivo confocal


microscopy findings (fig 2A,B) of the pigment line
Examination reveals paracentral golden brown pigment lines
arranged in a semicircular fashion around the base of the cones.
The pigment line is not homogenous but made of tiny
particulate deposits which extend in to the adjacent cornea on
either side. Towards their ends, the lines show many finer
branches converging towards the main deposit centrally (fig
1A,B). IVCM reveals 35 mm bright dot-like deposits within the
epithelial layers and superficial stroma of cornea sparing the
basement membrane (fig 2A,B) but closely associated with the
subbasal nerve plexus (fig 2C).
In comparison, IVCM of a Fleischer ring also reveals bright
dots, which probably represent haemosiderin/ferritin (fig 2D).
These range in size from 3 to 10 mm and are mainly situated in
the suprabasal and basal epithelial layers with none visible in
the stroma. Moreover, the bright dots in a Fleischer ring are very
scanty compared with those seen in amiodarone keratopathy,
and in up to 30% of cases of Fleischer ring they may not be seen
at all.1

2. What is the differential diagnosis of golden brown lines on the


cornea?
Golden brown lines are presumably iron lines. These occur as
Hudson and Stahli lines in 25% of otherwise normal eyes; in
keratoconus as Fleischer ring at the base of the cone; as Stocker
lines anterior to the heads of pterygia; and as Ferry lines in
anterior to filtering blebs.5 Iron lines also occur in association
with corneal scars and Salzmann nodular degeneration. Iron
deposits in the basal corneal epithelium have been reported after
a variety of refractive and other corneal procedures, including
penetrating keratoplasty, epikeratophakia, keratophakia, keratomileusis, radial keratotomy, excimer photorefractive keratectomy, intrastromal corneal rings and LASIK.6 Amiodarone
keratopathy should perhaps be added to this list of differential
diagnosis.

3. How does amiodarone affect the eye?


The most common ocular side effect of amiodarone is corneal
verticillata. Other potential problems include lens opacities and
anterior ischaemic optic neuropathy. Ocular symptoms are
uncommon. Coloured haloes around lights due to diffraction of
light by the epithelial deposits are the most frequent symptoms.
Other reported symptoms include blurred vision, glare, dry eyes
and irritation.2
Four grades of amiodarone keratopathy are recognised.3 Grade
1 is where small brown punctate epithelial opacities coalesce to
form a horizontal line in the inferior third of the cornea. In
Grade 2, the line has a number of branches. Grade 3 shows an
increase in the number of branches to form a whorl-like pattern.
There is no staining with fluorescein. Grade 4 was added later to
include irregular brown clumps of pigment accompanying the
branching pattern.4

Br J Ophthalmol April 2009 Vol 93 No 4

DISCUSSION
Our case emphasises the need for adequate history in conjunction with careful slit-lamp evaluation in the work up of
keratoconus.
The Fleischer ring is a brownish pigmentation in the basal
epithelium at the base of the cone. It is usually incomplete and
seen in at least 5070% of patients with keratoconus.7 Initial
slit-lamp examination in our case revealed paracentral golden
brown pigment deposits arranged in a semicircular fashion at
the base of the cone. These resembled a Fleischer ring but on
closer inspection revealed fine branching lines at the ends. These
lines were not typical of a vortex keratopathy being more
tightly arranged. In addition, illumination through a cobalt blue
filter did not highlight the ring as it would do a Fleischer ring.
It is difficult to differentiate amiodarone from ferritin on
IVCM, as both appear to be bright white dots. Images of ferritin
deposits tend to be slightly larger than amiodarone deposits.
Ferritin in a Fleischer ring is usually confined to the epithelial
layer,1 while amiodarone deposits can be observed in the stroma
and along the subepithelial nerve plexus.8
Amiodarone keratopathy is not likely to affect vision,9 and
our patients deterioration is more likely to be related to his
keratoconus. Amiodarone-related optic neuropathy has been
documented2 and may account for transient blurring of vision.
In our case, visual field tests and visual-evoked potential were
normal.
The pathogenesis of corneal iron deposits remains unclear and
has been the subject of considerable debate implicating tear-film
dynamics, epithelial cell migration, desquamation and homeostasis. Reports of corneal iron deposition associated with
various refractive surgical procedures have described intracellular ferritin in the basal epithelial layer.10 Our observation is
that ferritin and perhaps other deposits tend to occur or
concentrate along points of abrupt change in corneal steepness.
This has also been commented on in another study.6

Final diagnosis
Amiodarone keratopathy masquerading as Fleischer ring in a
patient with keratoconus.
Br J Ophthalmol 2009;93:545. doi:10.1136/bjo.2008.144303a

REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.

O
, Kanpolat A, Ylmaz N, et al. In vivo confocal microscopy findings in
Ucakhan O
keratoconus. Eye Contact Lens Sci Clin Pract 2006;32:18391.
Mantyjarvi M, Tuppurainen K, Ikaheimo K. Ocular side effects of amiodarone. Surv
Ophthalmol 1998;42:3606.
Locke LC, Blesch K. Vortex keratopathy. Clin Eye Vision Care 1989;1:14356.
Orlando RG, Dangel ME, Schaal SF. Clinical experience and grading of amiodarone
keratopathy. Ophthalmology 1984;91:11847.
Ferry AP. A new iron line of the superficial cornea; occurrence in patients with
filtering blebs. Arch Ophthalmol 1968;79:1425.
Vongthongsri A, Chuck RS, Jay S, et al. Corneal iron deposits after laser in situ
keratomileusis. Am J Ophthalmol 1999;127:856.
Bron AJ. Keratoconus. Cornea 1988;7:1639.
O
, Kanpolat A, Ylmaz N, et al. Amiodarone keratopathy. An in vivo
Ucakhan O
confocal microscopy study. Eye Contact lens 2005;31:14857.
Reasor MJ, Kacew S. Drug-induced phospholipidosis: Are there functional
consequences? Exp Biol Med (Maywood) 2001;226:82530.
Rose GE, Lavin MJ. The HudsonStahli line III: observations on morphology, a critical
review of aetiology and a unified theory for the formation of iron lines of the corneal
epithelium. Eye 1987;1:4759.

545

Downloaded from bjo.bmj.com on 31 March 2009

Rituximab for treatment of ocular inflammatory


disease: a series of four cases
P A Kurz, E B Suhler, D Choi and J T Rosenbaum
Br. J. Ophthalmol. 2009;93;546-548
doi:10.1136/bjo.2007.133173

Updated information and services can be found at:


http://bjo.bmj.com/cgi/content/full/93/4/546

These include:

References

This article cites 9 articles, 4 of which can be accessed free at:


http://bjo.bmj.com/cgi/content/full/93/4/546#BIBL

Rapid responses

You can respond to this article at:


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Innovations

Rituximab for treatment of ocular inflammatory


disease: a series of four cases
P A Kurz,1,2,3 E B Suhler,1 D Choi,1 J T Rosenbaum1
1

Casey Eye Institute/Oregon


Health & Science University,
Portland, Oregon, USA; 2 Dayton
VA Medical Center, Dayton,
Ohio, USA; 3 Ohio State
University Department of
Ophthalmology, Columbus, Ohio,
USA
Correspondence to:
Dr J T Rosenbaum, Mail Code
L467AD, 3181 SW Sam Jackson
Park Road, Portland, OR 97239,
USA; rosenbaj@ohsu.edu
Accepted 31 October 2008

ABSTRACT
Rituximab may be effective in the treatment of ocular
inflammatory disease. Dosing is less frequent than many
medications currently available. Four cases are reported,
each of which appeared to have responded well to
treatment with rituximab, although patient 2 was able to
remain on a low dose of prednisone for only 2 months.
The ongoing pilot study will hopefully provide additional
insight into the benefit of rituximab for treatment of
scleritis and idiopathic orbital inflammatory disease.

Rituximab (Rituxan), a genetically engineered,


chimeric, monoclonal antibody that recognises
CD20 on mature B lymphocytes, has demonstrated
efficacy in the treatment of rheumatoid arthritis
(RA), systemic lupus erythematosus (SLE), thyroid-associated ophthalmopathy and Wegener granulomatosis (WG).18 One report also suggests
benefit in refractory anterior uveitis.9 Rituximab
is proposed to deplete CD20+ B cells by three
mechanisms: antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity and
apoptosis. Treatment with rituximab intravenously results in profound reduction in peripheral
blood B lymphocytes for approximately 6 to
12 months, although longer periods of depletion
can occur.10

PATIENT 2
A 27-year-old female with diabetes, RA and
bilateral anterior scleritis failed treatment with
anakinra, methotrexate, hydroxychloroquine, etanercept, adalimumab, minocycline and leflunomide. Treatment with rituximab allowed her to
taper prednisone to 30 mg every other day while
continuing methotrexate 20 mg/week.
Five months after receiving rituximab, she
required retreatment for recurrent joint and eye
symptoms. With continued methotrexate therapy,
she tapered prednisone to 5 mg/day and remained
quiet on this dose for 2 months before flaring
following a hospital admission for hyperglycaemia.

PATIENT 3
A 29-year-old female with severe idiopathic orbital
inflammation failed methotrexate, MMF and
combination therapy with methotrexate and
ciclosporin. She had only transient benefit with
cyclophosphamide 1000 mg intravenous Q
3 weeks for 4 months before it was stopped after
she had a rash with the last two infusions. Three to
4 months after treatment with rituximab, she
stopped methotrexate due to nausea. She remained
quiet off all medications for 1 year before having
recurrent orbital inflammation which responded to
reinstitution of oral methotrexate 15 mg/week.

INNOVATION
Patients with WG may develop orbital inflammation. Scleritis can be associated with RA, SLE and
WG. Although the use of rituximab for ocular
inflammatory disease has not been extensively
studied, it seems reasonable to consider rituximab
to treat these ocular inflammatory conditions. We
report two cases of refractory scleritis and two
cases of non-infectious orbital inflammation in
which treatment with rituximab appeared beneficial.

PATIENT 1
A 57-year-old white male with a history of nodular
scleritis failed treatment with non-steroidal antiinflammatory drugs, azathioprine and mycophenolate mofetil (MMF) monotherapy. After treatment with rituximab, he tapered off prednisone.
He remained quiet on MMF 1000 mg twice daily
for 11 months before having a mild, unilateral flare
that was promptly controlled with low-dose
prednisone.
Seventeen months following the rituximab infusions, he had a bilateral flare requiring prednisone
40 mg/day. Repeat treatment with rituximab
induced remission and allowed prednisone tapering.
546

PATIENT 4
A 30 year-old female with limited WG failed
treatment with azathioprine, methotrexate and
oral cyclophosphamide. She gained 23 kg on
prednisone and had required treatment with
intravenous methylprednisolone. The orbital disease continued to worsen despite prednisone
50 mg/day.
Following rituximab, both sinus and orbital
disease improved. With continued subcutaneous
methotrexate therapy at 25 mg/week, prednisone
was tapered to 6 mg/day.
Four months following treatment with rituximab, she had increased nasal crusting requiring a
small pulse of prednisone 20 mg/day which was
tapered to 10 mg/day over 2 weeks and subsequently back to 6 mg/day.

SIDE EFFECTS
The most common side effects with rituximab are
infusion-related symptoms, which usually occur
with the first infusion, may vary in severity and
are usually reversible with medical intervention.
These symptoms may include a flu-like illness,
fever, chills/rigors, urticaria, nausea, headache,
Br J Ophthalmol 2009;93:546548. doi:10.1136/bjo.2007.133173

Downloaded from bjo.bmj.com on 31 March 2009

Innovations
Table 1 Four patients responses
Total duration of
follow-up
(months)

Patient

Sex

Age (years)

Disease

No of months
before 2nd
infusion required

57

Scleritis

17

11

27

Rheumatoid
arthritis and
scleritis

13 mg QD
40 mg QD
40 mg QD

29

No 2nd infusion

7
12

30 mg QOD
0

5 mg QD
0

30

30

Idiopathic orbital
inflammation
Limited Wegener
and orbital
inflammation

4 (sinus not
orbit)

50 mg QD

6 mg QD

Mean
31.6 mg QD
SD 16.5

Mean
5.8 mg QD
SD 5.6
Effect
225.8 mg
SE 7.8
p value = 0.017

No 2nd infusion

No of months Prednisone dose prior


before flare
to rituximab therapy

Lowest prednisone dose


after rituximab therapy
0
3 mg QD
30 mg QOD

26
22

QD, taken daily; QOD, taken every other day.

bronchospasm, hypotension and angio-oedema. More severe


manifestations which can even lead to death rarely include
hypoxia, pulmonary infiltrates, myocardial infarction, ventricular fibrillation or other cardiac arrhythmias, cardiogenic
shock, acute respiratory distress syndrome, acute renal failure
requiring dialysis (in the setting of tumour lysis syndrome),
severe mucocutaneous skin reactions, hepatitis B reactivation,
progressive multifocal leucoencepalopathy, other opportunistic
infections, abdominal pain, and bowel obstruction or perforation (when used in combination with chemotherapy in patients
with diffuse large B cell lymphoma).
All patients in our case series were pretreated with
diphenhydramine 2550 mg intravenous, acetaminophen and
methylprednisolone 100 mg intravenous just before the infusion. Patients 1 and 2 noted itching with infusion. Patient 1 also
noted anxiety with the infusion (perhaps related to the
methylprednisolone). Patient 4 had nausea that was controlled
with promethazine and rigors that responded to lorazepam and
meperidine.

POTENTIAL APPLICATION
Rituximab may have a role in treatment of ocular inflammatory
disease, including refractory scleritis and non-infectious orbital
inflammatory disease. Continued investigation will help define
this role.

SUMMARY
Rituximab may be effective in the treatment of ocular
inflammatory disease. Dosing is less frequent than many
medications currently available. We have reported four cases
here, each of which appeared to have responded well to
treatment with rituximab, although patient 2 was able to
remain on a low dose of prednisone for only 2 months. Our
ongoing pilot study will hopefully provide additional insight
into the benefit of rituximab for treatment of scleritis and
idiopathic orbital inflammatory disease.
Funding: We are grateful for financial support from the Stan and Madelle Rosenfeld
Family Trust.
Competing interests: JTR, EBS and PAK disclose a relationship with Genentech, in
that Genentech is sponsoring the follow-up Phase I/II prospective study.

CASE SERIES
For patients 13, a treatment with rituximab consisted of 1 g
intravenous twice, with a 2-week interval between doses
(table 1). Patient 4 received 375 mg/m2 weekly for 4 weeks. A
mixed-effects model was used to test the statistical significance
of the difference in prednisone dose levels before and after
rituximab therapy while accounting for potential correlations
among repeated measures within a person.

Ethics approval: Ethics approval was provided by the Institutional Review Board,
Oregon Health & Science University.
Patient consent: Obtained.

REFERENCES
1.

2.

LIMITATION
The obvious limitation of this case series is the small sample
size. However, as these inflammatory conditions are relatively
uncommon, it is difficult to develop large randomised clinical
trials dealing with inflammatory eye disease. Patients 13
received rituximab in a different dosing regimen than Patient 4.
With a small sample size, it is unclear whether one dosing
regimen is preferred over the other. We do not have data
quantifying the B-lymphocyte count before and after treatment
in these cases.
Br J Ophthalmol 2009;93:546548. doi:10.1136/bjo.2007.133173

3.

4.

5.

6.

Looney RJ, Anolik JH, Campbell D, et al. B cell depletion as a novel treatment for
systemic lupus erythematosus: a phase I/II dose-escalation trial of rituximab. Arthritis
Rheum 2004;50:25809.
Keogh KA, Wylam ME, Stone JH, et al. Induction of remission by B lymphocyte
depletion in eleven patients with refractory antineutrophil cytoplasmic antibodyassociated vasculitis. Arthritis Rheum 2005;52:2628.
Edwards JC, Szczepanski L, Szechinski J, et al. Efficacy of B-cell-targeted therapy
with rituximab in patients with rheumatoid arthritis. New England J of Medicine
2004;350:257281.
Keogh KA, Ytterberg SR, Fervenza FC, et al. Rituximab for refractory Wegeners
granulomatosis report of a prospective, open-label pilot trial. Am J Respir Crit Care
Med 2006;173:1807.
El Fassi D, Neilsen CH, Bonnema SJ, et al. B lymphocyte depletion with the
monoclonal antibody rituximab in Graves disease: a controlled pilot study. J Clin
Endocrinol Metab 2007;92:16202.
El Fassi D, Nielsen CH, Hasselbalch HC, et al. Treatment-resistant severe, active
Graves ophthalmopathy successfully treated with B lymphocyte depletion. Thyroid
2006;16:70910.

547

Downloaded from bjo.bmj.com on 31 March 2009

Innovations
7.

8.

Salvi M, Vannucchi G, Campi I, et al. Efficacy of rituximab treatment for thyroidassociated ophthalmopathy as a result of intraorbital B-cell depletion in one
patient unresponsive to steroid immunosuppression. Eur J Endocrinol
2006;154:51117.
Vannucchi G, Campi I, Curro N, et al. Rituximab treatment of Graves disease and
thyroid-associated ophthalmopathy: effects on thyroid autoimmunity and thyroid

9.
10.

morphology at ultrasound. In Proceedings of the 31st Annual Meeting of the European


Thyroid Association, Naples, Italy, 2006:20 (Abstract).
Tappeiner C, Heinz C, Specker C, et al. Rituximab as a treatment option for
refractory endogenous anterior uveitis. Ophthalmic Res 2007;39:1846.
Popa C, Leandro MJ, Cambridge G, et al. Repeated B lymphocyte depletion with
rituximab in rheumatoid arthritis over 7 years. Rheumatology 2007;46:62630.

Education
ANSWERS
From questions on page 422

1. Describe the non-ocular findings


Figure 1B,C demonstrates cutaneous blistering on the plantar
aspect of the foot and penis respectively, which were preceded
by urticarial eruptions. The case demonstrates the importance
of a full systemic examination of patients presenting with
ocular manifestations, whereupon the diagnosis was only made
from a penile biopsy. A decision not to perform a conjunctival
biopsy was made to prevent any potential worsening of scarring
and/or course of disease,2 although some reports suggest that
bulbar conjunctival biopsies are safe and well tolerated in
patients with MMP.3

2. What is the diagnosis based on the penile biopsy?


This is the direct immunofluorescence image. The semithin
biopsy section demonstrates IgG deposition at the basement
membrane, consistent with a diagnosis of MMP. It should be
noted that a diagnosis of MMP should not be on biopsy alone,
as direct immunofluorescence techniques are not 100% sensitive. Immunoglobulin deposition at the basement membrane
may also occur in other pathological conditions such as linear
IgA disease, paraneoplastic pemphigus, bullous pemphigoid and
epidermolysis bullosa aquisita, and thus biopsy results must
always be interpreted in conjunction with the clinical findings.
Biopsy results may fluctuate from positive to negative within
the course of the disease and may not be related to disease
activity or treatment.4 Treatment should not be denied to
young patients with a clinical picture of severe presumed ocular
MMP and negative biopsies.

prevalence of opportunistic infections resulting in fatal outcome, our patient to date has tolerated therapy well. Rituximab
is a treatment that should be reserved only for severe refractory
cases of ocular MMP, where other more standard immunosuppressants have failed. Other alternatives include intravenous
immunoglobulin therapy, which has been shown to be a safe
and a potential treatment of patients with non-responsive and
progressive MMP.7
DISCUSSION
MMP with ocular involvement is a severe bilateral autoimmune
disease characterised by progressive conjunctival cicatrisation
and corneal vascularisation with scarring. Fifty per cent of
patients have systemic features, specifically oesophageal,
oropharyngeal lesions and cutaneous blisters. MMP typically
occurs in patients over 55 but should be considered in younger
patients with chronic conjunctival inflammation, as this group
may acquire severe and rapidly progressive ocular disease.8 The
majority of patients will require immunosuppression in an
attempt to limit disease progression.9 10
With the increasing understanding of the immunopathology
of blinding ocular autommune conditions alongside the available increasing armitarium of biological therapies, we are now
able to tailor therapies to treatment-refractory cases, such as
biological therapy in uveitis.11 12
Br J Ophthalmol 2009;93:548. doi:10.1136/bjo.2007.129510a

REFERENCES
1.
2.
3.

3. What is rituximab, and how does it work?


Rituximab is a humanised monoclonal antibody against CD20
antigen expressed by B lymphocytes and treatment induces
depletion of CD20+ B lymphocytes. The rationale of use was
based on the diagnosis of autoimmune MMP, a disorder
mediated by B cells leading to pathological antibody and
complement deposition, while treatment may also suppress
the antigen-presenting cell capacity of B cells.
Rituximab is approved for the treatment of non-Hodgkins
lymphoma and rheumatoid arthritis, and is increasingly being
utilised for the treatment of other autoimmune diseases. For
example, rituximab has successfully treated refractory bullous
autoimmune disorders such as bullous pemphigoid and pemphigus vulgaris5 as well as scleritis associated with Wegener
granulomatosis.6 Although complications of rituximab therapy
include fever, nausea, renal toxicity, cardiac arrhythmias
decreased immunoglobulins, neutropenia and thus increased
548

4.
5.
6.
7.
8.
9.
10.
11.
12.

Tauber J, Jabbur N, Foster S. Improved detection of disease progression in ocular


cicatricial pemphigoid. Cornea 1992;11:44651.
Frith PA, Venning VA, Wojnarowska F, et al. Conjunctival involvement in cicatricial
and bullous pemphigoid: A clinical and immunopathological study. Br J Ophthamol
1989;73:526.
Mondino BJ, Brown SI. Immunosupressive therapy in ocular cicatricial pemphigoid.
Am J Ophthamol 1983;96:4539.
Fern AI, Jay JL, Young H, et al. Dapsone therapy for the acute inflammatory phase of
ocular pemphigoid. Br J Ophthalmol 1992;76:3325.
Schmidt E, Seitz CS, Benoit S, et al. Rituximab in autoimmune bullous diseases:
mixed responses and adverse effects. Br J Dermatol 2007;156:3526.
Cheung CMG, Murray PI, Savage COS. Successful treatment of Wegeners
granulomatosis associated scleritis with rituximab. Br J Ophthalmol 2005;89:1542.
Sami N, Bhol KC, Razzaque AA. Intravenous immunoglobulin therapy in patients with
multiple mucosal involvement in mucous membrane pemphigoid. Clin Immunol
2002;102:5967.
Rauz S, Maddison RGN, Dart JKG. Evaluation of mucous membrane pemphigoid with
ocular involvement in young patients. Ophthalmology 2005;112:126874S.
Elder MJ, Bernauer W, Leonard J, et al. Progression of disease in ocular cicatricial
pemphigoid. Br J Ophthalmol 1996;80:2926.
Elder MJ, Lightman S, Dart JK. Role of cyclophosphamide and high dose steroid in
ocular cicatricial pemphigoid. Br J Ophthalmol 1995;79:2646.
Dick AD, Forrseter JV, Liversidge J, et al. The role of tumour necrosis factor (TNFalpha) in experimental autoimmune uveoretinitis (EAU). Prog Retin Eye Res
2004;23:61737.
Teoh SCB, Sharma S, Hogan A, et al. Tailoring biological treatment: anakinra
treatment of posterior uveitis associated with the CINCA syndrome. Br J Ophthalmol
2007;91:2634.

Br J Ophthalmol April 2009 Vol 93 No 4

Downloaded from bjo.bmj.com on 31 March 2009

Education
Br. J. Ophthalmol. 2009;93;548
doi:10.1136/bjo.2007.129510a

Updated information and services can be found at:


http://bjo.bmj.com/cgi/content/full/93/4/548

These include:

References

This article cites 12 articles, 6 of which can be accessed free at:


http://bjo.bmj.com/cgi/content/full/93/4/548#BIBL

Rapid responses

You can respond to this article at:


http://bjo.bmj.com/cgi/eletter-submit/93/4/548

Email alerting
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Notes

To order reprints of this article go to:


http://journals.bmj.com/cgi/reprintform

To subscribe to British Journal of Ophthalmology go to:


http://journals.bmj.com/subscriptions/

Downloaded from bjo.bmj.com on 31 March 2009

Innovations
7.

8.

Salvi M, Vannucchi G, Campi I, et al. Efficacy of rituximab treatment for thyroidassociated ophthalmopathy as a result of intraorbital B-cell depletion in one
patient unresponsive to steroid immunosuppression. Eur J Endocrinol
2006;154:51117.
Vannucchi G, Campi I, Curro N, et al. Rituximab treatment of Graves disease and
thyroid-associated ophthalmopathy: effects on thyroid autoimmunity and thyroid

9.
10.

morphology at ultrasound. In Proceedings of the 31st Annual Meeting of the European


Thyroid Association, Naples, Italy, 2006:20 (Abstract).
Tappeiner C, Heinz C, Specker C, et al. Rituximab as a treatment option for
refractory endogenous anterior uveitis. Ophthalmic Res 2007;39:1846.
Popa C, Leandro MJ, Cambridge G, et al. Repeated B lymphocyte depletion with
rituximab in rheumatoid arthritis over 7 years. Rheumatology 2007;46:62630.

Education
ANSWERS
From questions on page 422

1. Describe the non-ocular findings


Figure 1B,C demonstrates cutaneous blistering on the plantar
aspect of the foot and penis respectively, which were preceded
by urticarial eruptions. The case demonstrates the importance
of a full systemic examination of patients presenting with
ocular manifestations, whereupon the diagnosis was only made
from a penile biopsy. A decision not to perform a conjunctival
biopsy was made to prevent any potential worsening of scarring
and/or course of disease,2 although some reports suggest that
bulbar conjunctival biopsies are safe and well tolerated in
patients with MMP.3

2. What is the diagnosis based on the penile biopsy?


This is the direct immunofluorescence image. The semithin
biopsy section demonstrates IgG deposition at the basement
membrane, consistent with a diagnosis of MMP. It should be
noted that a diagnosis of MMP should not be on biopsy alone,
as direct immunofluorescence techniques are not 100% sensitive. Immunoglobulin deposition at the basement membrane
may also occur in other pathological conditions such as linear
IgA disease, paraneoplastic pemphigus, bullous pemphigoid and
epidermolysis bullosa aquisita, and thus biopsy results must
always be interpreted in conjunction with the clinical findings.
Biopsy results may fluctuate from positive to negative within
the course of the disease and may not be related to disease
activity or treatment.4 Treatment should not be denied to
young patients with a clinical picture of severe presumed ocular
MMP and negative biopsies.

prevalence of opportunistic infections resulting in fatal outcome, our patient to date has tolerated therapy well. Rituximab
is a treatment that should be reserved only for severe refractory
cases of ocular MMP, where other more standard immunosuppressants have failed. Other alternatives include intravenous
immunoglobulin therapy, which has been shown to be a safe
and a potential treatment of patients with non-responsive and
progressive MMP.7
DISCUSSION
MMP with ocular involvement is a severe bilateral autoimmune
disease characterised by progressive conjunctival cicatrisation
and corneal vascularisation with scarring. Fifty per cent of
patients have systemic features, specifically oesophageal,
oropharyngeal lesions and cutaneous blisters. MMP typically
occurs in patients over 55 but should be considered in younger
patients with chronic conjunctival inflammation, as this group
may acquire severe and rapidly progressive ocular disease.8 The
majority of patients will require immunosuppression in an
attempt to limit disease progression.9 10
With the increasing understanding of the immunopathology
of blinding ocular autommune conditions alongside the available increasing armitarium of biological therapies, we are now
able to tailor therapies to treatment-refractory cases, such as
biological therapy in uveitis.11 12
Br J Ophthalmol 2009;93:548. doi:10.1136/bjo.2007.129510a

REFERENCES
1.
2.
3.

3. What is rituximab, and how does it work?


Rituximab is a humanised monoclonal antibody against CD20
antigen expressed by B lymphocytes and treatment induces
depletion of CD20+ B lymphocytes. The rationale of use was
based on the diagnosis of autoimmune MMP, a disorder
mediated by B cells leading to pathological antibody and
complement deposition, while treatment may also suppress
the antigen-presenting cell capacity of B cells.
Rituximab is approved for the treatment of non-Hodgkins
lymphoma and rheumatoid arthritis, and is increasingly being
utilised for the treatment of other autoimmune diseases. For
example, rituximab has successfully treated refractory bullous
autoimmune disorders such as bullous pemphigoid and pemphigus vulgaris5 as well as scleritis associated with Wegener
granulomatosis.6 Although complications of rituximab therapy
include fever, nausea, renal toxicity, cardiac arrhythmias
decreased immunoglobulins, neutropenia and thus increased
548

4.
5.
6.
7.
8.
9.
10.
11.
12.

Tauber J, Jabbur N, Foster S. Improved detection of disease progression in ocular


cicatricial pemphigoid. Cornea 1992;11:44651.
Frith PA, Venning VA, Wojnarowska F, et al. Conjunctival involvement in cicatricial
and bullous pemphigoid: A clinical and immunopathological study. Br J Ophthamol
1989;73:526.
Mondino BJ, Brown SI. Immunosupressive therapy in ocular cicatricial pemphigoid.
Am J Ophthamol 1983;96:4539.
Fern AI, Jay JL, Young H, et al. Dapsone therapy for the acute inflammatory phase of
ocular pemphigoid. Br J Ophthalmol 1992;76:3325.
Schmidt E, Seitz CS, Benoit S, et al. Rituximab in autoimmune bullous diseases:
mixed responses and adverse effects. Br J Dermatol 2007;156:3526.
Cheung CMG, Murray PI, Savage COS. Successful treatment of Wegeners
granulomatosis associated scleritis with rituximab. Br J Ophthalmol 2005;89:1542.
Sami N, Bhol KC, Razzaque AA. Intravenous immunoglobulin therapy in patients with
multiple mucosal involvement in mucous membrane pemphigoid. Clin Immunol
2002;102:5967.
Rauz S, Maddison RGN, Dart JKG. Evaluation of mucous membrane pemphigoid with
ocular involvement in young patients. Ophthalmology 2005;112:126874S.
Elder MJ, Bernauer W, Leonard J, et al. Progression of disease in ocular cicatricial
pemphigoid. Br J Ophthalmol 1996;80:2926.
Elder MJ, Lightman S, Dart JK. Role of cyclophosphamide and high dose steroid in
ocular cicatricial pemphigoid. Br J Ophthalmol 1995;79:2646.
Dick AD, Forrseter JV, Liversidge J, et al. The role of tumour necrosis factor (TNFalpha) in experimental autoimmune uveoretinitis (EAU). Prog Retin Eye Res
2004;23:61737.
Teoh SCB, Sharma S, Hogan A, et al. Tailoring biological treatment: anakinra
treatment of posterior uveitis associated with the CINCA syndrome. Br J Ophthalmol
2007;91:2634.

Br J Ophthalmol April 2009 Vol 93 No 4

Downloaded from bjo.bmj.com on 31 March 2009

Compression sutures with autologous blood


injection for leaking trabeculectomy blebs
S Biswas, I Zaheer, B Monsalve and J P Diamond
Br. J. Ophthalmol. 2009;93;549-550
doi:10.1136/bjo.2008.142497

Updated information and services can be found at:


http://bjo.bmj.com/cgi/content/full/93/4/549

These include:

References

This article cites 6 articles, 1 of which can be accessed free at:


http://bjo.bmj.com/cgi/content/full/93/4/549#BIBL

Rapid responses

You can respond to this article at:


http://bjo.bmj.com/cgi/eletter-submit/93/4/549

Email alerting
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Notes

To order reprints of this article go to:


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To subscribe to British Journal of Ophthalmology go to:


http://journals.bmj.com/subscriptions/

Downloaded from bjo.bmj.com on 31 March 2009

PostScript

LETTERS

Compression sutures with


autologous blood injection for
leaking trabeculectomy blebs
Leaks may follow trabeculectomy surgery,
particularly where antimetabolite useage has
resulted in thin or avascular filtration blebs.
Leaking
blebs
are
associated
with
endophthalmitis, low intraocular pressure
(IOP), hypotony maculopathy and choroidal
haemorrhage. Treatment aims to stop the
leak while preserving filtration.
Conservative management of bleb leaks
involves aqueous suppressants, pressure
patching, contact lens application or topical
autologous serum drops.1 Surgical treatments include application of trichloracetic
acid, cyanoacrylate glue, autologous fibrin
tissue glue, cryotherapy and argon laser or
Nd YAG Laser remodelling of the bleb.
Intrableb injection of autologous blood2 has
been successful in sealing bleb leaks,
although blood can track into the anterior
chamber (AC). Compression sutures3 have
been used to control overdraining blebs but
are used less often for bleb leaks. More major
procedures include conjunctival autografts
or amniotic membrane, scleral or processed
pericardial tissue transplantation.
Haynes and Alward4 used compression
sutures in conjunction with autologous
blood injection to enhance their efficacy in
the treatment of postfiltration hypotony
maculopathy. We have successfully used
compression sutures for some years to
remodel overdraining blebs in the absence
of leakage.5 We then proceeded to utilise
compression sutures with autologous blood
injection as the initial surgical intervention
for leaking filtering blebs.

MATERIALS AND METHODS


A retrospective study of patients who had
compression sutures and autologous blood
injection for leaking trabeculectomy blebs

over a 5-year period between April 1999 and


April 2003 was carried out. All patients with
leaking blebs during this period were
recruited for the study with no exclusion.
A single spatulated 8/0 or 9/0 nylon
compression suture was placed over the leak
as either a rectangular mattress or an Xshaped suture with bites just anterior to
the limbus at 50% of the corneal stromal
depth and posteriorly in the episclera to
achieve a satisfactory compression (fig 1,
table 1).
Up to 0.75 ml of autologous venous blood
was injected within the filtering bleb.
Postoperative antibiotic drops but no steroids were prescribed. Patients were followed
up weekly for the first month.
Sutures were removed after 8 weeks or
more, once scarring lines were seen in the
conjunctiva or if the sutures had come loose.
Most sutures embedded into the conjunctiva
with time. Repeat blood injections were used
if the leak persisted. Data collected included
control of the leak, visual outcome, further
procedures, final IOP and complications.
Surgical success was identified as resolution
of the bleb leak, a target pressure between 10
and 20 mm Hg with or without topical
medication, non-worsening of vision and a
non-requirement of further procedures.

RESULTS
Fourteen eyes of 12 patients underwent
compression sutures for bleb leaks over a
period of 5 years. Five were male and seven
female, with the mean age being 59.5 years
(range 3389 years). The mean period
between trabeculectomy and identification
of bleb leak was 17.9 months (range 1 week
to 5 years 8 months). None of the leaks was
from the wound edge. The mean duration of
the leak prior to treatment was 4 months
(range 2 weeks to 18 months). Ten eyes had
antimetabolites during the original trabeculectomy (71.4%). All had a single suture over
the leak site with concurrent autologous
blood injection, while seven patients had
further top-up of blood injections.

Figure 1 Rectangular Palmberg suture over


the filtering bleb. 1, anterior bite at 50% of the
corneal stromal depth; 2, posterior bite
anchored in the episclera.
The mean follow-up period following
compression suture was 3.9 years (range
5 months to 7 years). There were two
patients with a follow-up period of only
5 months, as they had moved away from
the area. The bleb leak stopped in eight cases
(57.1%) without further intervention, while
additional intervention to control persistent
leak was required in six (42.9%). Further
procedures included Tisseel glue injection
(two cases, 33%), and formal bleb revision
with or without conjunctival autograft (all
six cases requiring revision).
The leak was controlled in eight cases
undergoing compression suture with a mean
rise in IOP of 3.9 mm Hg, from 9.3 mm Hg
to 13.2 mm Hg (range 07 mm Hg). Visual
acuity remained the same or was better in all
patients. Complications included hyphaema
in four patients (which spontaneously
resolved). There was no significant anterior
chamber inflammation.

DISCUSSION
Given the range of treatments available for
bleb leaks, it is likely that no single method
will be effective for every case. In this study,
compression sutures with autologous blood
injection were effective in 57.1% of bleb
leaks. Similar studies in future with larger

Table 1 Particulars of each eye undergoing compression sutures with autologous blood
Eye no

Age of patient

Antimetabolite

Trab-leak delay (weeks)

Leak duration (weeks)

Blood injection no

Success

1
2
3
4
5
6
7
8
9
10
11
12
13
14

54
33
55
89
61
61
70
62
58
58
69
61
73
41

5FU
5FU
MMC
Nil
5FU
Nil
Nil
MMC
5FU
5FU
Nil
5FU
MMC
MMC

8
36
40
132
1
4
60
1
60
132
92
96
72
272

36
16
2
4
40
32
16
48
4
56
16
20
72
16

1
2
2
2
5
4
1
1
1
2
1
1
2
1

Yes
No
No
Yes
No
No
Yes
Yes
Yes
No
Yes
Yes
No
Yes

5FU, 5-fluoracil; MMC, mitomycin C.

Br J Ophthalmol April 2009 Vol 93 No 4

549

Downloaded from bjo.bmj.com on 31 March 2009

PostScript
number of cases might make it possible to
analyse the influence of age, race or type of
antimetabolite used in filtering surgery on
the success of this procedure. Euswas et al6
have reported success in five out of seven
eyes (71.4%) treated with compression
sutures for bleb leaks. However, our study
is the largest in terms of patient numbers
and follow-up period reported to date. Given
their simplicity compared with more major
procedures, we recommend that they be
considered the first line of surgical intervention for bleb leaks.

increased. Logically, therefore, chamber fluctuations and the chance of posterior capsular
damage should be reduced if segment
removal is performed without a second
instrument in the eye.
Many would argue, however, that the
second instrument is essential for repositioning and separating nuclear segments during
segment removal. Because no formal study
has been published, we undertook an observational analysis of the actual use of a
second instrument during segment removal.

S Biswas, I Zaheer, B Monsalve, J P Diamond

METHODS

Bristol Eye Hospital, Bristol, UK


Correspondence to: Dr S Biswas, Birmingham and
Midland Eye Centre, Birmingham B18 7QH, UK;
s.biswas@doctors.org.uk
Competing interests: None.
Presented as a poster at the International Glaucoma
Symposium, Athens, March 2007.
Accepted 10 September 2008
Br J Ophthalmol 2009;93:549550.
doi:10.1136/bjo.2008.142497

Two trainees reviewed 54 consecutive video


recordings of cataract phacoemulsification
performed this year in our unit. Of the 54
cases, 22 cases were performed by two
consultants and 32 cases performed by three
registrars. In all cases, the surgeons used
their preferred technique using a second
instrument and were not aware of the
purpose of this study. The second instrument was held intraocularly throughout the
segment removal process. Cases were randomly allocated to the two trainees, and a

subsample of cases was also reviewed by the


senior author to check for interobserver
variability.
We took the total time to be from when
segment removal begins until when the last
segment had been completely aspirated. Our
definition of idle time is when the second
instrument was stationary or performing
non-purposeful movements which did not
involve touching a nuclear fragment.

RESULTS
Statistical analysis was performed using
MedCalc Software version 9.6.4.0. Figure 1A
shows the distribution of percentage idle
time for all cases, while fig 1B shows the
distribution for the procedures performed by
registrars and consultants separately. In all
cases, the second instrument was used for a
very small fraction of time (the median
percentage idle time for entire dataset
(n = 54) was 90%), and the use of the second
instrument decreased with level of experience (median percentage idle time for consultants (n = 22) was 92.5%, for registrars
(n = 32) 86%). The two-tailed probability

REFERENCES
1.

2.

3.

4.

5.
6.

Matsuo H, Tomidokoro A, Tomita G, et al. Topical


application of autologous serum for the treatment of
late-onset aqueous oozing or point-leak through filtering
bleb. Eye 2005;19:238.
Smith MF, Magauran RG III, Betchkal J, et al.
Treatment of post filtration bleb leaks with autologous
blood. Ophthalmology 1995;102:86871.
Palmberg PF. Compression suturesa new
treatment for leaking or painful filtering blebs [ARVO
abstract]. Invest Ophthal Vis Sci 1996;37:44S.
Haynes WL, Alward WLM. Combination of autologous
blood injection and bleb compression sutures to treat
hypotony maculopathy. J Glaucoma 1999;8:3847.
Morgan JE, Diamond JP, Cook SD. Remodelling the
filtration bleb. Br J Ophthalmol 2002;86:8725.
Euswas A, Warrasak S, Methasiri S. Sequential
management of chronic leaking bleb. Asian J Ophthalmol
2005;7:269.

The use of a second instrument


during phacoemulsification: does
it really protect the posterior
capsule?
The technique of placing a second instrument between the posterior capsule and
nuclear fragment is generally encouraged
because it intuitively provides added protection against capsule aspiration and rupture
by the phaco tip.1 2 This is especially so
when the last segment is being phacoemulsified.
However, it has been shown in our recent
study3 that significant leakage occurs via a
side-port incision when a second instrument
is used through it. In fact the majority of
fluid used during phaco appears to be lost
through wound leakage, and a significant
proportion of this is through the second
instrument sideport. This inevitably contributes to chamber destabilisation and posterior capsule fluctuation, and it follows that
the risk of capsule aspiration is likely to be
550

Figure 1 (A) Distribution of percentage idle time for all cases (consultants and registrars). (B)
Breakdown of percentage idle time by cases performed by consultants and registrars.
Br J Ophthalmol April 2009 Vol 93 No 4

Downloaded from bjo.bmj.com on 31 March 2009

The use of a second instrument during


phacoemulsification: does it really protect the
posterior capsule?
J Tee, A Shah and B C Little
Br. J. Ophthalmol. 2009;93;550-551
doi:10.1136/bjo.2008.153718

Updated information and services can be found at:


http://bjo.bmj.com/cgi/content/full/93/4/550

These include:

Rapid responses

You can respond to this article at:


http://bjo.bmj.com/cgi/eletter-submit/93/4/550

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service

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the top right corner of the article

Notes

To order reprints of this article go to:


http://journals.bmj.com/cgi/reprintform

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http://journals.bmj.com/subscriptions/

Downloaded from bjo.bmj.com on 31 March 2009

PostScript
number of cases might make it possible to
analyse the influence of age, race or type of
antimetabolite used in filtering surgery on
the success of this procedure. Euswas et al6
have reported success in five out of seven
eyes (71.4%) treated with compression
sutures for bleb leaks. However, our study
is the largest in terms of patient numbers
and follow-up period reported to date. Given
their simplicity compared with more major
procedures, we recommend that they be
considered the first line of surgical intervention for bleb leaks.

increased. Logically, therefore, chamber fluctuations and the chance of posterior capsular
damage should be reduced if segment
removal is performed without a second
instrument in the eye.
Many would argue, however, that the
second instrument is essential for repositioning and separating nuclear segments during
segment removal. Because no formal study
has been published, we undertook an observational analysis of the actual use of a
second instrument during segment removal.

S Biswas, I Zaheer, B Monsalve, J P Diamond

METHODS

Bristol Eye Hospital, Bristol, UK


Correspondence to: Dr S Biswas, Birmingham and
Midland Eye Centre, Birmingham B18 7QH, UK;
s.biswas@doctors.org.uk
Competing interests: None.
Presented as a poster at the International Glaucoma
Symposium, Athens, March 2007.
Accepted 10 September 2008
Br J Ophthalmol 2009;93:549550.
doi:10.1136/bjo.2008.142497

Two trainees reviewed 54 consecutive video


recordings of cataract phacoemulsification
performed this year in our unit. Of the 54
cases, 22 cases were performed by two
consultants and 32 cases performed by three
registrars. In all cases, the surgeons used
their preferred technique using a second
instrument and were not aware of the
purpose of this study. The second instrument was held intraocularly throughout the
segment removal process. Cases were randomly allocated to the two trainees, and a

subsample of cases was also reviewed by the


senior author to check for interobserver
variability.
We took the total time to be from when
segment removal begins until when the last
segment had been completely aspirated. Our
definition of idle time is when the second
instrument was stationary or performing
non-purposeful movements which did not
involve touching a nuclear fragment.

RESULTS
Statistical analysis was performed using
MedCalc Software version 9.6.4.0. Figure 1A
shows the distribution of percentage idle
time for all cases, while fig 1B shows the
distribution for the procedures performed by
registrars and consultants separately. In all
cases, the second instrument was used for a
very small fraction of time (the median
percentage idle time for entire dataset
(n = 54) was 90%), and the use of the second
instrument decreased with level of experience (median percentage idle time for consultants (n = 22) was 92.5%, for registrars
(n = 32) 86%). The two-tailed probability

REFERENCES
1.

2.

3.

4.

5.
6.

Matsuo H, Tomidokoro A, Tomita G, et al. Topical


application of autologous serum for the treatment of
late-onset aqueous oozing or point-leak through filtering
bleb. Eye 2005;19:238.
Smith MF, Magauran RG III, Betchkal J, et al.
Treatment of post filtration bleb leaks with autologous
blood. Ophthalmology 1995;102:86871.
Palmberg PF. Compression suturesa new
treatment for leaking or painful filtering blebs [ARVO
abstract]. Invest Ophthal Vis Sci 1996;37:44S.
Haynes WL, Alward WLM. Combination of autologous
blood injection and bleb compression sutures to treat
hypotony maculopathy. J Glaucoma 1999;8:3847.
Morgan JE, Diamond JP, Cook SD. Remodelling the
filtration bleb. Br J Ophthalmol 2002;86:8725.
Euswas A, Warrasak S, Methasiri S. Sequential
management of chronic leaking bleb. Asian J Ophthalmol
2005;7:269.

The use of a second instrument


during phacoemulsification: does
it really protect the posterior
capsule?
The technique of placing a second instrument between the posterior capsule and
nuclear fragment is generally encouraged
because it intuitively provides added protection against capsule aspiration and rupture
by the phaco tip.1 2 This is especially so
when the last segment is being phacoemulsified.
However, it has been shown in our recent
study3 that significant leakage occurs via a
side-port incision when a second instrument
is used through it. In fact the majority of
fluid used during phaco appears to be lost
through wound leakage, and a significant
proportion of this is through the second
instrument sideport. This inevitably contributes to chamber destabilisation and posterior capsule fluctuation, and it follows that
the risk of capsule aspiration is likely to be
550

Figure 1 (A) Distribution of percentage idle time for all cases (consultants and registrars). (B)
Breakdown of percentage idle time by cases performed by consultants and registrars.
Br J Ophthalmol April 2009 Vol 93 No 4

Downloaded from bjo.bmj.com on 31 March 2009

PostScript
REFERENCES
1.
2.
3.

Khng C, Osher RH. Surgical options in the face of


positive pressure. J Cataract Refract Surg
2006;32:14235.
Vajpayee RB, Sharma N, Dada T, et al. Management
of posterior capsule tears. Surv Ophthalmol
2001;45:47388.
Liyanage S, Angunawela RI, Wong SC, et al. Theres a
hole in my bucketincisional leakage and chamber
instability in coaxial phacoemulsification. Poster
exhibited at ESCRS Annual Meeting, Stockholm, 2007.

Ramadan and eye-drops:


perspective of Muslims in the UK
Figure 2 Leakage occurring via a side-port
incision when a second instrument is used
through it.

value as calculated with the MannWhitney


test was p = 0.0008.

COMMENT
We can reasonably conclude that the second
instrument lies idle in the eye for the vast
majority of the time. When non-idle, it was
used to recrack nuclear segments or to
reposition them in relation to the phacoemulsification probe. The need to use a
second instrument during segment removal
can be greatly reduced if quadrants are
completely cracked prior to segment
removal.
Although antiintuitive, we suggest that
when performing segment removal, it is
probably safer to remove the second instrument from the eye when it is not being used.
Quite often, it can be left out altogether.
This generates a tangible increase in chamber stability as leakage from the side port is
reduced (fig 2). The phaco tip itself can be
used to manipulate the nuclear fragments.
However, if the use of a second instrument
is necessary, one can insert it and then
remove it after use in order to maintain a
stable chamber during phacoemulsification.
The presence of a second instrument can be
reassuring to the surgeon but may actually
generate a false sense of security. It causes
greater wound leakage and therefore chamber instability. We have a number of cases
on video demonstrating that during final
fragment removal, the flaccid posterior
capsule can readily wrap around a second
instrument and be aspirated by the phaco
tip.
J Tee, A Shah, B C Little
Department of Ophthalmology, Royal Free Hospital,
London, UK
Correspondence to: MrB C Little, Department of
Ophthalmology, Royal Free Hospital, London NW3 2QG, UK;
brianlittle@blueyonder.co.uk
Competing interests: None.
Accepted 3 December 2008
Br J Ophthalmol 2009;93:550551.
doi:10.1136/bjo.2008.153718

Br J Ophthalmol April 2009 Vol 93 No 4

Ramadan is a month of obligatory fasting


for adult Muslims during which they can
only consume food and beverages after
sunset and before dawn. Fasting is not
mandatory if it would affect an individuals
health or if they were unable to fast due to a
health condition.
A large proportion of Muslim patients
insist on fasting despite this exemption
which often leads to poor compliance with
prescribed medications with significant
health implications.15
There have been no studies to assess the
views of Muslims living in the UK regarding
the use of eye-drops during Ramadan.

METHODS
We conducted a questionnaire survey to
assess the views of Muslims in the UK
regarding the use of drops during Ramadan
and factors that may influence these views
(table 1).
Authors (NK/SJ) circulated the questionnaire at colleges and mosques in
Leicestershire, UK. Three UK Islamic societies circulated the questionnaire among its
national members. Participation in the survey was anonymous and voluntary with no
monetary incentive.

RESULTS
A total of 125 questionnaires were collected;
24 were excluded due to incomplete data
entry. There were 56 female and 45 male
respondents: 63 respondents had university

degrees, and 38 did not have university


education; 45 respondents were born in the
UK, and 56 respondents had immigrated to
the UK; 64 respondents fast for all days of
Ramadan, and 37 fast for only part of
Ramadan; 66 respondents would fast for
additional days after Ramadan if the fast
was broken for any reason; 45.5% believe
drops during fasting hours would break the
fast; 59.4% would continue their regular
treatment if it involved the use of drops
during fasting hours; 28.7% would use drops
during the fasting hours for a non-painful
eye condition whereas 80.2% would for a
painful eye condition; 38.6% would use
drops during the fasting hours for an eye
condition where sight was not affected,
whereas 86.1% would for an eye condition
if sight were affected.
There was no significant difference
between the views of males and females
and the views of those fasting all days of
Ramadan compared with those fasting only
part of the month.
There was no significant difference
between respondents with or without a
university education for all questions except
if vision was affected; 46% with university
education would use drops if vision was
affected compared with 26.3% without
university education.
Those respondents who would fast additional days after Ramadan if fast was broken
had significantly different views compared
with those who would not with significantly higher proportions believing drops
break the fast.
There was no significant difference
between Muslims born in the UK compared
with those who had immigrated except for
the question of whether they would use
drops during the fasting hours of Ramadan;
57.8% of Muslims born in the UK would use
drops compared with 35.7% immigrated
Muslims.

COMMENTS
Studies have assessed compliance with treatments for diabetes, asthma, anticoagulation

Table 1 Variables studied


1.
2.
3.
4.
5.
6.

Age
Sex
Education: university graduate/,university graduate
Occupation: employed/professionals/housewife/student/unemployed
No of days the respondents fast during Ramadan: all/not all
Were you born in the UK?
The following were yes/no responses:
7. Does using drops during the fasting period break the fast?
8. Would you use eye-drops during the fasting periods?
9. If drops are used during the fasting periods, should you fast for additional days?
10. Would you use eye-drops during the fasting periods
(a) if they were part of your regular treatment for an eye condition?
(b) for a painless eye condition?
(c) for a painful eye condition?
(d) for an eye condition which does not affect your sight?
(e) for an eye condition which affects your sight?

551

Downloaded from bjo.bmj.com on 31 March 2009

Ramadan and eye-drops: perspective of Muslims


in the UK
N Kumar, M Dherani and S Jivan
Br. J. Ophthalmol. 2009;93;551-552
doi:10.1136/bjo.2008.151001

Updated information and services can be found at:


http://bjo.bmj.com/cgi/content/full/93/4/551

These include:

References

This article cites 5 articles, 2 of which can be accessed free at:


http://bjo.bmj.com/cgi/content/full/93/4/551#BIBL

Rapid responses

You can respond to this article at:


http://bjo.bmj.com/cgi/eletter-submit/93/4/551

Email alerting
service

Receive free email alerts when new articles cite this article - sign up in the box at
the top right corner of the article

Notes

To order reprints of this article go to:


http://journals.bmj.com/cgi/reprintform

To subscribe to British Journal of Ophthalmology go to:


http://journals.bmj.com/subscriptions/

Downloaded from bjo.bmj.com on 31 March 2009

PostScript
REFERENCES
1.
2.
3.

Khng C, Osher RH. Surgical options in the face of


positive pressure. J Cataract Refract Surg
2006;32:14235.
Vajpayee RB, Sharma N, Dada T, et al. Management
of posterior capsule tears. Surv Ophthalmol
2001;45:47388.
Liyanage S, Angunawela RI, Wong SC, et al. Theres a
hole in my bucketincisional leakage and chamber
instability in coaxial phacoemulsification. Poster
exhibited at ESCRS Annual Meeting, Stockholm, 2007.

Ramadan and eye-drops:


perspective of Muslims in the UK
Figure 2 Leakage occurring via a side-port
incision when a second instrument is used
through it.

value as calculated with the MannWhitney


test was p = 0.0008.

COMMENT
We can reasonably conclude that the second
instrument lies idle in the eye for the vast
majority of the time. When non-idle, it was
used to recrack nuclear segments or to
reposition them in relation to the phacoemulsification probe. The need to use a
second instrument during segment removal
can be greatly reduced if quadrants are
completely cracked prior to segment
removal.
Although antiintuitive, we suggest that
when performing segment removal, it is
probably safer to remove the second instrument from the eye when it is not being used.
Quite often, it can be left out altogether.
This generates a tangible increase in chamber stability as leakage from the side port is
reduced (fig 2). The phaco tip itself can be
used to manipulate the nuclear fragments.
However, if the use of a second instrument
is necessary, one can insert it and then
remove it after use in order to maintain a
stable chamber during phacoemulsification.
The presence of a second instrument can be
reassuring to the surgeon but may actually
generate a false sense of security. It causes
greater wound leakage and therefore chamber instability. We have a number of cases
on video demonstrating that during final
fragment removal, the flaccid posterior
capsule can readily wrap around a second
instrument and be aspirated by the phaco
tip.
J Tee, A Shah, B C Little
Department of Ophthalmology, Royal Free Hospital,
London, UK
Correspondence to: MrB C Little, Department of
Ophthalmology, Royal Free Hospital, London NW3 2QG, UK;
brianlittle@blueyonder.co.uk
Competing interests: None.
Accepted 3 December 2008
Br J Ophthalmol 2009;93:550551.
doi:10.1136/bjo.2008.153718

Br J Ophthalmol April 2009 Vol 93 No 4

Ramadan is a month of obligatory fasting


for adult Muslims during which they can
only consume food and beverages after
sunset and before dawn. Fasting is not
mandatory if it would affect an individuals
health or if they were unable to fast due to a
health condition.
A large proportion of Muslim patients
insist on fasting despite this exemption
which often leads to poor compliance with
prescribed medications with significant
health implications.15
There have been no studies to assess the
views of Muslims living in the UK regarding
the use of eye-drops during Ramadan.

METHODS
We conducted a questionnaire survey to
assess the views of Muslims in the UK
regarding the use of drops during Ramadan
and factors that may influence these views
(table 1).
Authors (NK/SJ) circulated the questionnaire at colleges and mosques in
Leicestershire, UK. Three UK Islamic societies circulated the questionnaire among its
national members. Participation in the survey was anonymous and voluntary with no
monetary incentive.

RESULTS
A total of 125 questionnaires were collected;
24 were excluded due to incomplete data
entry. There were 56 female and 45 male
respondents: 63 respondents had university

degrees, and 38 did not have university


education; 45 respondents were born in the
UK, and 56 respondents had immigrated to
the UK; 64 respondents fast for all days of
Ramadan, and 37 fast for only part of
Ramadan; 66 respondents would fast for
additional days after Ramadan if the fast
was broken for any reason; 45.5% believe
drops during fasting hours would break the
fast; 59.4% would continue their regular
treatment if it involved the use of drops
during fasting hours; 28.7% would use drops
during the fasting hours for a non-painful
eye condition whereas 80.2% would for a
painful eye condition; 38.6% would use
drops during the fasting hours for an eye
condition where sight was not affected,
whereas 86.1% would for an eye condition
if sight were affected.
There was no significant difference
between the views of males and females
and the views of those fasting all days of
Ramadan compared with those fasting only
part of the month.
There was no significant difference
between respondents with or without a
university education for all questions except
if vision was affected; 46% with university
education would use drops if vision was
affected compared with 26.3% without
university education.
Those respondents who would fast additional days after Ramadan if fast was broken
had significantly different views compared
with those who would not with significantly higher proportions believing drops
break the fast.
There was no significant difference
between Muslims born in the UK compared
with those who had immigrated except for
the question of whether they would use
drops during the fasting hours of Ramadan;
57.8% of Muslims born in the UK would use
drops compared with 35.7% immigrated
Muslims.

COMMENTS
Studies have assessed compliance with treatments for diabetes, asthma, anticoagulation

Table 1 Variables studied


1.
2.
3.
4.
5.
6.

Age
Sex
Education: university graduate/,university graduate
Occupation: employed/professionals/housewife/student/unemployed
No of days the respondents fast during Ramadan: all/not all
Were you born in the UK?
The following were yes/no responses:
7. Does using drops during the fasting period break the fast?
8. Would you use eye-drops during the fasting periods?
9. If drops are used during the fasting periods, should you fast for additional days?
10. Would you use eye-drops during the fasting periods
(a) if they were part of your regular treatment for an eye condition?
(b) for a painless eye condition?
(c) for a painful eye condition?
(d) for an eye condition which does not affect your sight?
(e) for an eye condition which affects your sight?

551

Downloaded from bjo.bmj.com on 31 March 2009

PostScript
and epilepsy during Ramadan.15 They
showed that during the fasting periods, more
than 50% of patients change their drug
regimes.15 To help improve compliance, these
specialties have successfully formulated management plans in-keeping with the patients
religious practices.1
Ophthalmologists have investigated compliance with ocular treatment; however, the
impact of religious beliefs has not been
assessed.6
Our results highlight that non-compliance
with drops should be anticipated during
Ramadan, and it is not possible to predict
the views of an individual with regards to
the use of drops, based on demographic or
educational factors.
It may be possible to improve compliance
by educating patients regarding the potential long-term damage that can be caused by
non-compliance and formulating management strategies in keeping with the patients
religious beliefs and taboos.
N Kumar,1 M Dherani,2 S Jivan3
1

St Pauls Eye Unit, Royal Liverpool University Hospital,


Liverpool, UK; 2 University of Liverpool, Liverpool, Liverpool,
UK; 3 St James University Hospital, Leeds, UK
Correspondence to: Dr N Kumar, St Pauls Eye Unit, Royal
Liverpool University Hospital, Liverpool L3 8XP, UK;
nishant6377@gmail.com
Competing interests: None.
Accepted 12 September 2008
Br J Ophthalmol 2009;93:551552.
doi:10.1136/bjo.2008.151001

REFERENCES
1.
2.

3.
4.

5.

6.

Kumar N, Jivan S. Ramadan and eyedrops: the


Muslim perspective. Ophthalmology 2007;114:2356
60.
Topacoglu H, Karcioglu O, Yuruktumen A, et al.
Impact of Ramadan on demographics and frequencies
of disease-related visits in the emergency department.
Int J Clin Pract 2005;59:9005.
Aadil N, Houti IE, Moussamih S. Drug intake during
Ramadan. BMJ 2004;329:77882.
Salti I, Benard E, Detournay B, et al. A population-based
study of diabetes and its characteristics during the
fasting month of Ramadan in 13 countries: results of the
epidemiology of diabetes and Ramadan 1422/2001
(EPIDIAR) study. Diabetes Care 2004;27:230611.
Anon. Recommendations of the 9th Fiqh-Medical
seminar An Islamic View of Certain Contemporary
Medical Issues, 1417 June 1997, Casablanca,
Morocco. http://www.islamset.com/search/index.html
(accessed 22 Jul 2007).
Tsai JC. Medication adherence in glaucoma:
approaches for optimizing patient compliance. Curr
Opin Ophthalmol 2006;17:1905.

Short-term effect of intravitreal


anti-VEGFs delivery on intraocular
pressure
Since the successful introduction of antivascular endothelial growth factor (VEGF)
intravitreal injections (IVT) for the management of age-related macular degeneration
(AMD), this treatment has gained popularity. Several studies have reported on the
complications of anti-VEGF IVT, including a
transient rise in intraocular pressure (IOP).1
552

We aimed to determine whether IOP


measurement post-IVT is necessary following
injection of the commonly used anti-VEGF
agents: ranibizumab (Lucentis), bevacizumab
(Avastin) and pegabtanib (Macugen).

METHOD
This was a retrospective observational study
of postinjection change in IOP in patients
with neovascular AMD who received an
injection of an anti-VEGF drug between
September 2006 and March 2008. Patients
were treated with one of three anti-VEGF
drugs (ranibizumab 0.5 mg, bevacizumab 1.
25 mg, pegabtanib 0.3 mg) using a sterile
technique. Povidine iodine 5% preparation
and topical oxybuprocaine anaesthetic were
used. IOP was measured using Goldman
applanation tonometry prior to and 5 min
following IVT drug delivery. Any IOP higher
than 40 mm Hg was rechecked at 15 min
intervals until it normalised.

RESULTS
Data from 57 eyes of 57 patients (male
n = 14), with an age range of 3192 years
(mean 77, SD 9), were included in the
analysis. A statistically significant rise in
the IOP (7.94 mm Hg, SD 7.3) was noted at
5 min postinjection. In one-third of patients,
the change in IOP exceeded 10 mm Hg. In
three of these, the rise exceeded 20 mm Hg,
and in one the rise was 38 mm Hg. There
was no statistically significant difference in
IOP change noted between the drugs used
(see table 1). The standard deviation of the
change was much higher in the ranibizumab
subgroup (8.99 versus 2.31 for bevacizumab
and 5.72 for pegaptanib). Correlations
between the change in IOP and other
potential explanatory variables of age and
gender were not statistically significant.

as an increase in IOP of 10 mm Hg or more


from baseline. In a subsequent report, the
same author3 noted that 28% of patients
injected with escalating doses of ranibizumab
had significantly elevated IOP measured at
1 h postinjection. Frenkel et al,4 in a study of
75 eyes, reported that 5.3% of patients
developed immediate IOP elevation of sufficient severity to cause transient no perception
of light (NPL). Hariprasad et al5 found that
13% of patients developed IOP of 30 mm Hg
or higher 30 min after pegaptanib injection.
In both studies, IOP normalisation following
early spikes was noted within 30 min.
In the present study, IVT drug type, age or
gender did not appear to have a significant
effect on IOP changes. However, the pegaptanib subgroup in our study was very small. We
did observe that the standard deviation of IOP
change was highest in the ranibizumab subgroup. Both pegabtanib and bevacizumab are
supplied in preloaded syringes of fixed volume.
Small errors in syringe loading may occur
while drawing up ranibizumab from the glass
phial into the supplied syringe and contribute
to the higher variability in IOP change.
In conclusion, our findings suggest that
routine checks of IOP pre- and post-IVT
delivery of anti-VEGF agents in the management of neovascular AMD are not necessary.
However, when there is concern about the
status of the aqueous outflow systems, IOP
checks may be necessary.
S Nabili,1 M Stevenson,2 U Chakravarty,1,3 T Moutray1
1
Directorate of Ophthalmology, Head and Skeletal Division,
Royal Victoria Hospital Belfast, Belfast, UK; 2 Centre for
Population Sciences, The Queens University of Belfast,
Belfast, UK; 3 Centre for Vision Sciences, The Queens
University of Belfast, Belfast, UK

Correspondence to: Dr T Moutray, Department of


Ophthalmology, Royal Victoria Hospital, Belfast, UK;
tanya.moutray@btopenworld.com
Competing interests: None.
Accepted 20 September 2008

DISCUSSION
We report on the immediate postinjection
IOP change in patients who received intravitreal drug delivery. Overall, the mean rise
in IOP which was noted at 5 min was not
statistically significant. Although one-third
of our patients experienced rises of IOP
greater than 10 mm Hg, very few had a rise
in IOP of 20 mm Hg or higher, but a rapid
return to normal levels was observed. The
sole patient with an increase in excess of
30 mm Hg had an initial IOP of 28 mm Hg,
suggesting a degree of pre-existing compromised aqueous outflow.
Heier et al2 found that 22.6% of 64 patients
receiving repeated ranibizumab injections
developed significantly elevated IOP, defined

Br J Ophthalmol 2009;93:552553.
doi:10.1136/bjo.2008.151191

REFERENCES
1.

2.

3.

VEGF Inhibition Study in Ocular


Neovascularization (VISION) Clinical Trial Group.
Pegaptanib sodium for neovascularization age-related
macular degeneration: two-year safety results of the
two prospective, multimember, controlled clinical trials.
Ophthalmology 2006;113:9921001.
Heier JS, Antozyk AN, Pavan PR, et al. Ranibizumab
for treatment of neovascular age-related macular
degeneration: a phase I/II multicenter, controlled,
multidose study. Ophthalmology 2006;113:63342.
Rosenfeld PJ, Heier JS, Hantsbarger G, et al. Tolerability
and efficacy of multiple escalating doses of ranibizumab
(Lucentis) for neovascular age related macular
degeneration. Ophthalmology 2006;113:62332.

Table 1 Analysis of intraocular pressure change 5 min following intravitreal injections


Intravitreal injection of antivascular
endothelial growth factor

No

Mean intraocular pressure


change (mm Hg)

SD

Ranibizumab
Bevacizumab
Pegabtanib

29
25
3

8.04
5.33
8.18

8.99
2.31
5.72

Br J Ophthalmol April 2009 Vol 93 No 4

Downloaded from bjo.bmj.com on 31 March 2009

Short-term effect of intravitreal anti-VEGFs


delivery on intraocular pressure
S Nabili, M Stevenson, U Chakravarty and T Moutray
Br. J. Ophthalmol. 2009;93;552-553
doi:10.1136/bjo.2008.151191

Updated information and services can be found at:


http://bjo.bmj.com/cgi/content/full/93/4/552

These include:

Rapid responses

You can respond to this article at:


http://bjo.bmj.com/cgi/eletter-submit/93/4/552

Email alerting
service

Receive free email alerts when new articles cite this article - sign up in the box at
the top right corner of the article

Notes

To order reprints of this article go to:


http://journals.bmj.com/cgi/reprintform

To subscribe to British Journal of Ophthalmology go to:


http://journals.bmj.com/subscriptions/

Downloaded from bjo.bmj.com on 31 March 2009

PostScript
and epilepsy during Ramadan.15 They
showed that during the fasting periods, more
than 50% of patients change their drug
regimes.15 To help improve compliance, these
specialties have successfully formulated management plans in-keeping with the patients
religious practices.1
Ophthalmologists have investigated compliance with ocular treatment; however, the
impact of religious beliefs has not been
assessed.6
Our results highlight that non-compliance
with drops should be anticipated during
Ramadan, and it is not possible to predict
the views of an individual with regards to
the use of drops, based on demographic or
educational factors.
It may be possible to improve compliance
by educating patients regarding the potential long-term damage that can be caused by
non-compliance and formulating management strategies in keeping with the patients
religious beliefs and taboos.
N Kumar,1 M Dherani,2 S Jivan3
1

St Pauls Eye Unit, Royal Liverpool University Hospital,


Liverpool, UK; 2 University of Liverpool, Liverpool, Liverpool,
UK; 3 St James University Hospital, Leeds, UK
Correspondence to: Dr N Kumar, St Pauls Eye Unit, Royal
Liverpool University Hospital, Liverpool L3 8XP, UK;
nishant6377@gmail.com
Competing interests: None.
Accepted 12 September 2008
Br J Ophthalmol 2009;93:551552.
doi:10.1136/bjo.2008.151001

REFERENCES
1.
2.

3.
4.

5.

6.

Kumar N, Jivan S. Ramadan and eyedrops: the


Muslim perspective. Ophthalmology 2007;114:2356
60.
Topacoglu H, Karcioglu O, Yuruktumen A, et al.
Impact of Ramadan on demographics and frequencies
of disease-related visits in the emergency department.
Int J Clin Pract 2005;59:9005.
Aadil N, Houti IE, Moussamih S. Drug intake during
Ramadan. BMJ 2004;329:77882.
Salti I, Benard E, Detournay B, et al. A population-based
study of diabetes and its characteristics during the
fasting month of Ramadan in 13 countries: results of the
epidemiology of diabetes and Ramadan 1422/2001
(EPIDIAR) study. Diabetes Care 2004;27:230611.
Anon. Recommendations of the 9th Fiqh-Medical
seminar An Islamic View of Certain Contemporary
Medical Issues, 1417 June 1997, Casablanca,
Morocco. http://www.islamset.com/search/index.html
(accessed 22 Jul 2007).
Tsai JC. Medication adherence in glaucoma:
approaches for optimizing patient compliance. Curr
Opin Ophthalmol 2006;17:1905.

Short-term effect of intravitreal


anti-VEGFs delivery on intraocular
pressure
Since the successful introduction of antivascular endothelial growth factor (VEGF)
intravitreal injections (IVT) for the management of age-related macular degeneration
(AMD), this treatment has gained popularity. Several studies have reported on the
complications of anti-VEGF IVT, including a
transient rise in intraocular pressure (IOP).1
552

We aimed to determine whether IOP


measurement post-IVT is necessary following
injection of the commonly used anti-VEGF
agents: ranibizumab (Lucentis), bevacizumab
(Avastin) and pegabtanib (Macugen).

METHOD
This was a retrospective observational study
of postinjection change in IOP in patients
with neovascular AMD who received an
injection of an anti-VEGF drug between
September 2006 and March 2008. Patients
were treated with one of three anti-VEGF
drugs (ranibizumab 0.5 mg, bevacizumab 1.
25 mg, pegabtanib 0.3 mg) using a sterile
technique. Povidine iodine 5% preparation
and topical oxybuprocaine anaesthetic were
used. IOP was measured using Goldman
applanation tonometry prior to and 5 min
following IVT drug delivery. Any IOP higher
than 40 mm Hg was rechecked at 15 min
intervals until it normalised.

RESULTS
Data from 57 eyes of 57 patients (male
n = 14), with an age range of 3192 years
(mean 77, SD 9), were included in the
analysis. A statistically significant rise in
the IOP (7.94 mm Hg, SD 7.3) was noted at
5 min postinjection. In one-third of patients,
the change in IOP exceeded 10 mm Hg. In
three of these, the rise exceeded 20 mm Hg,
and in one the rise was 38 mm Hg. There
was no statistically significant difference in
IOP change noted between the drugs used
(see table 1). The standard deviation of the
change was much higher in the ranibizumab
subgroup (8.99 versus 2.31 for bevacizumab
and 5.72 for pegaptanib). Correlations
between the change in IOP and other
potential explanatory variables of age and
gender were not statistically significant.

as an increase in IOP of 10 mm Hg or more


from baseline. In a subsequent report, the
same author3 noted that 28% of patients
injected with escalating doses of ranibizumab
had significantly elevated IOP measured at
1 h postinjection. Frenkel et al,4 in a study of
75 eyes, reported that 5.3% of patients
developed immediate IOP elevation of sufficient severity to cause transient no perception
of light (NPL). Hariprasad et al5 found that
13% of patients developed IOP of 30 mm Hg
or higher 30 min after pegaptanib injection.
In both studies, IOP normalisation following
early spikes was noted within 30 min.
In the present study, IVT drug type, age or
gender did not appear to have a significant
effect on IOP changes. However, the pegaptanib subgroup in our study was very small. We
did observe that the standard deviation of IOP
change was highest in the ranibizumab subgroup. Both pegabtanib and bevacizumab are
supplied in preloaded syringes of fixed volume.
Small errors in syringe loading may occur
while drawing up ranibizumab from the glass
phial into the supplied syringe and contribute
to the higher variability in IOP change.
In conclusion, our findings suggest that
routine checks of IOP pre- and post-IVT
delivery of anti-VEGF agents in the management of neovascular AMD are not necessary.
However, when there is concern about the
status of the aqueous outflow systems, IOP
checks may be necessary.
S Nabili,1 M Stevenson,2 U Chakravarty,1,3 T Moutray1
1
Directorate of Ophthalmology, Head and Skeletal Division,
Royal Victoria Hospital Belfast, Belfast, UK; 2 Centre for
Population Sciences, The Queens University of Belfast,
Belfast, UK; 3 Centre for Vision Sciences, The Queens
University of Belfast, Belfast, UK

Correspondence to: Dr T Moutray, Department of


Ophthalmology, Royal Victoria Hospital, Belfast, UK;
tanya.moutray@btopenworld.com
Competing interests: None.
Accepted 20 September 2008

DISCUSSION
We report on the immediate postinjection
IOP change in patients who received intravitreal drug delivery. Overall, the mean rise
in IOP which was noted at 5 min was not
statistically significant. Although one-third
of our patients experienced rises of IOP
greater than 10 mm Hg, very few had a rise
in IOP of 20 mm Hg or higher, but a rapid
return to normal levels was observed. The
sole patient with an increase in excess of
30 mm Hg had an initial IOP of 28 mm Hg,
suggesting a degree of pre-existing compromised aqueous outflow.
Heier et al2 found that 22.6% of 64 patients
receiving repeated ranibizumab injections
developed significantly elevated IOP, defined

Br J Ophthalmol 2009;93:552553.
doi:10.1136/bjo.2008.151191

REFERENCES
1.

2.

3.

VEGF Inhibition Study in Ocular


Neovascularization (VISION) Clinical Trial Group.
Pegaptanib sodium for neovascularization age-related
macular degeneration: two-year safety results of the
two prospective, multimember, controlled clinical trials.
Ophthalmology 2006;113:9921001.
Heier JS, Antozyk AN, Pavan PR, et al. Ranibizumab
for treatment of neovascular age-related macular
degeneration: a phase I/II multicenter, controlled,
multidose study. Ophthalmology 2006;113:63342.
Rosenfeld PJ, Heier JS, Hantsbarger G, et al. Tolerability
and efficacy of multiple escalating doses of ranibizumab
(Lucentis) for neovascular age related macular
degeneration. Ophthalmology 2006;113:62332.

Table 1 Analysis of intraocular pressure change 5 min following intravitreal injections


Intravitreal injection of antivascular
endothelial growth factor

No

Mean intraocular pressure


change (mm Hg)

SD

Ranibizumab
Bevacizumab
Pegabtanib

29
25
3

8.04
5.33
8.18

8.99
2.31
5.72

Br J Ophthalmol April 2009 Vol 93 No 4

Downloaded from bjo.bmj.com on 31 March 2009

PostScript
4.

5.

Frenkel REP, Mani L, Toler AR, et al. Intraocular


pressure effects of pegaptanib (Macugen) injections in
patients with and without glaucoma. Am J Ophthalmol
2007;143:10345.
Hariprasad SM, Shah GK, Blinder KJ. Short-term
intraocular pressure trends following intravitreal
pegaptanib (Macugen) injection. Am J Ophthalmol
2006;141:2001.

Surgical management of macular


holes: a national survey of current
UK practice
Vitrectomising surgery is the conventional
treatment modality for idiopathic stage 3
and 4 macular holes; the exact surgical
method and postoperative care, however,
are not entirely agreed upon, with treatment
ultimately depending on the preferences of
the individual surgeon. We aimed to collect
information on macular hole surgery and
outcomes by conducting on online survey of
all members of the Britain and Eire VitreoRetinal Society regarding their preferred
surgical approach to evaluate current clinical
practice in the UK regarding management.
The validity of this study is dependent on
the accuracy of the responses we received.
Our response rate of 36% compares favourably with 34% for similar surveys in the
Germany, Austria and Switzerland in 2006.1
This survey may not reflect the practice of
all ophthalmologists in the UK, and we do
not claim to provide evidence of clinical
superiority of any one particular procedure
or technique over another.
Reports of dye toxicity were reflected in UK
practice with only 23% using Indocyanine
Green (ICG). Comments in ICG users
reflected the knowledge of potential concerns,
the dye being used at a low concentration (0.
05%) and for a minimal amount of time,
less than 30 s being the commonest.
The majority of surgeons preferred
sequential vitrectomy and phacoemulsification; the commonest problems encountered
when combining surgery were inconsistent
refractive results, intraocular lens dislocation, early posterior capsule opacification
and worse postoperative inflammation, all
of which are well reported in the literature
to differing extents,2 but again other authors
report minimal postoperative complications,3
the difference possibly being accounted for in
technique and learning curve.
Only 11% of surgeons were using 25G
systems, but it may be that the trend is
toward smaller gauge systems, and if the
survey was repeated the results are likely to
reflect this.
Reported outcomes are impressive. It is
uncertain, from the format of the survey,
whether a 100% closure rate was the result
of careful and selective case choice, meticulous surgical technique, postoperative regimens or likely a combination of all three. We
have limited ourselves to discussing surgical
methodology, assuming patient factors
would be similarly variable throughout the
Br J Ophthalmol April 2009 Vol 93 No 4

Table 1 Summary of the responses to the online questionnaire by 192 Britain and Eire VitreoRetinal Society members who were invited to participate
Response rate
36%
Vitrectomies per month per surgeon
.10
5%
510
27%
,5
68%
Choice of tamponade agent
C3F8
55%
SF6
17%
Silicone oil
1%
Other
27%
Posturing
No posture
22%
Face down
78%
,1 week
12%
1 week
33%
.1 week
55%
Posturing 100% of the day
14%
Posturing 75% of the day
80%
Posturing 50% of the day
6%
Internal limiting membrane peeling
Peel in all cases
72%
Peel specific cases
28%
Trypan Blue
69%
Indocyanine Green
23%
No stain
8%
Combined surgery (phacoemulsification, intraocular lens implantation, pars plana vitrectomy)
All cases
17%
Three-quarters of cases
9%
Half of cases
14%
Quarter of cases
60%
Instrumentation
20G
88%
23G
1%
Adjuvant agents
Never
88%
Sometimes
6%
No reply
6%
Outcomes
Mean closure rate
93%
Range closure rates
73100%
Mean gain of 2 Snellen lines
73%
Range gain 2 Snellen lines
4095%

UK, which may not be true, and may well


have an influence on surgical outcomes.
To our knowledge, there is only one other
survey on macular hole surgery from the
German Retinal Society.1 In their series, 86%
stained the internal limiting membrane, and
the dye of preference was ICG (80%), with
only 4% using Trypan Blue. There was a
large range of ICG concentrations used, the
most common being 0.1% ICG, but rather
surprisingly 7% of polled surgeons were
using ICG at a concentration of 10%. This
contrasts sharply with the use of vital dyes
by UK surgeons. SF6 was the choice of
gaseous endotamponade in 53% of European
surgeons, while their UK counterparts
favoured C3F8 to a similar extent (55%);
postoperative posturing routines did not
vary significantly. Similarities were in the
low use of adjuvant therapies (7% used
platelets) and few performing simultaneous

cataract surgery in all cases (7% in the


German paper, 17% in the UK).
This survey suggests that the practice of
surveyed UK Vitreoretinal surgeons falls
comfortably within the current evidence base
for macular hole surgery, and the surgical
method is varied according to hole size and
chronicity, and whether or not it is a repeat
procedure.
R S Khan, K N Khan, M T Costen
Hull and East Yorkshire Eye Hospital, Hull, UK
Correspondence to: Dr K N Khan, Hull and East Yorkshire
Eye Hospital, Fountain Street, Anlaby Road,
Hull HU3 2JZ, UK; kamronkhan@yahoo.com
Acknowledgements: We would like to acknowledge
Bausch & Lomb for the very kind donation of 70 for completed
responses. The money has been donated to Vision 2020.
Competing interests: None.
This work was presented at the Britain and Eire Vitreo-Retinal
Society Meeting at St Andrews in November 2007.

553

Downloaded from bjo.bmj.com on 31 March 2009

Surgical management of macular holes: a national


survey of current UK practice
R S Khan, K N Khan and M T Costen
Br. J. Ophthalmol. 2009;93;553-554
doi:10.1136/bjo.2008.144790

Updated information and services can be found at:


http://bjo.bmj.com/cgi/content/full/93/4/553

These include:

References

This article cites 3 articles, 1 of which can be accessed free at:


http://bjo.bmj.com/cgi/content/full/93/4/553#BIBL

Rapid responses

You can respond to this article at:


http://bjo.bmj.com/cgi/eletter-submit/93/4/553

Email alerting
service

Receive free email alerts when new articles cite this article - sign up in the box at
the top right corner of the article

Notes

To order reprints of this article go to:


http://journals.bmj.com/cgi/reprintform

To subscribe to British Journal of Ophthalmology go to:


http://journals.bmj.com/subscriptions/

Downloaded from bjo.bmj.com on 31 March 2009

PostScript
4.

5.

Frenkel REP, Mani L, Toler AR, et al. Intraocular


pressure effects of pegaptanib (Macugen) injections in
patients with and without glaucoma. Am J Ophthalmol
2007;143:10345.
Hariprasad SM, Shah GK, Blinder KJ. Short-term
intraocular pressure trends following intravitreal
pegaptanib (Macugen) injection. Am J Ophthalmol
2006;141:2001.

Surgical management of macular


holes: a national survey of current
UK practice
Vitrectomising surgery is the conventional
treatment modality for idiopathic stage 3
and 4 macular holes; the exact surgical
method and postoperative care, however,
are not entirely agreed upon, with treatment
ultimately depending on the preferences of
the individual surgeon. We aimed to collect
information on macular hole surgery and
outcomes by conducting on online survey of
all members of the Britain and Eire VitreoRetinal Society regarding their preferred
surgical approach to evaluate current clinical
practice in the UK regarding management.
The validity of this study is dependent on
the accuracy of the responses we received.
Our response rate of 36% compares favourably with 34% for similar surveys in the
Germany, Austria and Switzerland in 2006.1
This survey may not reflect the practice of
all ophthalmologists in the UK, and we do
not claim to provide evidence of clinical
superiority of any one particular procedure
or technique over another.
Reports of dye toxicity were reflected in UK
practice with only 23% using Indocyanine
Green (ICG). Comments in ICG users
reflected the knowledge of potential concerns,
the dye being used at a low concentration (0.
05%) and for a minimal amount of time,
less than 30 s being the commonest.
The majority of surgeons preferred
sequential vitrectomy and phacoemulsification; the commonest problems encountered
when combining surgery were inconsistent
refractive results, intraocular lens dislocation, early posterior capsule opacification
and worse postoperative inflammation, all
of which are well reported in the literature
to differing extents,2 but again other authors
report minimal postoperative complications,3
the difference possibly being accounted for in
technique and learning curve.
Only 11% of surgeons were using 25G
systems, but it may be that the trend is
toward smaller gauge systems, and if the
survey was repeated the results are likely to
reflect this.
Reported outcomes are impressive. It is
uncertain, from the format of the survey,
whether a 100% closure rate was the result
of careful and selective case choice, meticulous surgical technique, postoperative regimens or likely a combination of all three. We
have limited ourselves to discussing surgical
methodology, assuming patient factors
would be similarly variable throughout the
Br J Ophthalmol April 2009 Vol 93 No 4

Table 1 Summary of the responses to the online questionnaire by 192 Britain and Eire VitreoRetinal Society members who were invited to participate
Response rate
36%
Vitrectomies per month per surgeon
.10
5%
510
27%
,5
68%
Choice of tamponade agent
C3F8
55%
SF6
17%
Silicone oil
1%
Other
27%
Posturing
No posture
22%
Face down
78%
,1 week
12%
1 week
33%
.1 week
55%
Posturing 100% of the day
14%
Posturing 75% of the day
80%
Posturing 50% of the day
6%
Internal limiting membrane peeling
Peel in all cases
72%
Peel specific cases
28%
Trypan Blue
69%
Indocyanine Green
23%
No stain
8%
Combined surgery (phacoemulsification, intraocular lens implantation, pars plana vitrectomy)
All cases
17%
Three-quarters of cases
9%
Half of cases
14%
Quarter of cases
60%
Instrumentation
20G
88%
23G
1%
Adjuvant agents
Never
88%
Sometimes
6%
No reply
6%
Outcomes
Mean closure rate
93%
Range closure rates
73100%
Mean gain of 2 Snellen lines
73%
Range gain 2 Snellen lines
4095%

UK, which may not be true, and may well


have an influence on surgical outcomes.
To our knowledge, there is only one other
survey on macular hole surgery from the
German Retinal Society.1 In their series, 86%
stained the internal limiting membrane, and
the dye of preference was ICG (80%), with
only 4% using Trypan Blue. There was a
large range of ICG concentrations used, the
most common being 0.1% ICG, but rather
surprisingly 7% of polled surgeons were
using ICG at a concentration of 10%. This
contrasts sharply with the use of vital dyes
by UK surgeons. SF6 was the choice of
gaseous endotamponade in 53% of European
surgeons, while their UK counterparts
favoured C3F8 to a similar extent (55%);
postoperative posturing routines did not
vary significantly. Similarities were in the
low use of adjuvant therapies (7% used
platelets) and few performing simultaneous

cataract surgery in all cases (7% in the


German paper, 17% in the UK).
This survey suggests that the practice of
surveyed UK Vitreoretinal surgeons falls
comfortably within the current evidence base
for macular hole surgery, and the surgical
method is varied according to hole size and
chronicity, and whether or not it is a repeat
procedure.
R S Khan, K N Khan, M T Costen
Hull and East Yorkshire Eye Hospital, Hull, UK
Correspondence to: Dr K N Khan, Hull and East Yorkshire
Eye Hospital, Fountain Street, Anlaby Road,
Hull HU3 2JZ, UK; kamronkhan@yahoo.com
Acknowledgements: We would like to acknowledge
Bausch & Lomb for the very kind donation of 70 for completed
responses. The money has been donated to Vision 2020.
Competing interests: None.
This work was presented at the Britain and Eire Vitreo-Retinal
Society Meeting at St Andrews in November 2007.

553

Downloaded from bjo.bmj.com on 31 March 2009

PostScript
Accepted 24 September 2008
Br J Ophthalmol 2009;93:553554.
doi:10.1136/bjo.2008.144790

REFERENCES
1.

2.
3.

Schaal KB. Bartz-Schmidt KU. Dithmar S. Current


strategies for macular hole surgery in Germany, Austria
and Switzerland (in German). Ophthalmologe
2006;103:9226.
Simcock PR, Scalia S. Phacovitrectomy without prone
posture for full thickness macular holes. Br J Ophthalmol
2001;85:131619.
Fine HF, Iranmanesh R, Iturralde D, et al. Outcomes of
77 consecutive cases of 23-gauge transconjunctival
vitrectomy surgery for posterior segment disease.
Ophthalmology 2007;114:1197200.

Primary orbital lymphomatoid


granulomatosis
Lymphomatoid granulomatosis (LYG) is a
rare angiocentric and angiodestructive
EpsteinBarr virus (EBV)-associated B cell

lymphoproliferative disorder that involves


multiple organs including the lung, skin,
kidney and central nervous system. Ocular
LYG is an extremely rare tumour, which
appears as ocular granulomatous inflammation (conjunctival infiltration,1 posterior
uveitis,2 choroidal vasculitis,3 optic neuropathy,4 and retinal detachment5), with only
a few reports in the medical literature.
Furthermore, there are no reports of primary
orbital LYG without pulmonary LYG. We
describe the first case of primary orbital LYG
diagnosed by biopsy of an orbital tumour.

CASE REPORT
A 54-year-old man presenting with a 6-week
history of painless proptosis and ptosis of
the right eye was referred to our outpatient
clinic. Eye examination revealed marginal
blepharitis on the right eye (fig 1A), and the
right eye movement was restricted in all
directions. Funduscopy showed severe disc

swelling in the right eye (fig 1A). His bestcorrected visual acuity (BCVA) was 20/20 in
the right eye, and MRI T1-weighted scans
revealed a solitary fibrous tumour in the
right orbit (fig 1A). A chest CT and chest x
ray revealed a few pulmonary nodules in the
right upper lobe (fig 1B) but no pulmonary
LYG or symptoms. Laboratory examination
revealed an elevated CRP (5.94 mg/dl) and
an elevated anti-EBV viral capsid antigen
(VCA) IgG antibody titre (80 times, normal
range less than four times).
Two months after the first consultation,
the BCVA declined to 20/400 in the right
eye. The patient received radiation therapy
to the right orbital tumour with 30 Gy/15 fr
and oral prednisolone 50 mg daily for
1 week after which the prednisolone dose
was tapered down. The patient underwent
an incisional biopsy of the orbital tumour.
Macroscopic inspection of the resected
tumour segment showed a yellowish white

Figure 1 Ocular findings before and after the treatments (A) and chest x ray (B). Six weeks after treatments with radiation and oral prednisolone, orbital
tumour-related ocular symptoms of disc swelling, proptosis, ptosis and restricted ocular motility were resolved. The orbital tumour indicated by arrows in MRI
shows complete regression after treatments. (B) Chest x ray, CT and single photon emission computed tomography (SPECT) showing no signs of activity.
554

Br J Ophthalmol April 2009 Vol 93 No 4

Downloaded from bjo.bmj.com on 31 March 2009

Primary orbital lymphomatoid granulomatosis


F Araki, T Mimura, S Fukuoka, H Tsuji, K Izutsu, H Yamamoto, Y Takazawa and
T Kojima
Br. J. Ophthalmol. 2009;93;554-556
doi:10.1136/bjo.2008.140913

Updated information and services can be found at:


http://bjo.bmj.com/cgi/content/full/93/4/554

These include:

References

This article cites 5 articles, 2 of which can be accessed free at:


http://bjo.bmj.com/cgi/content/full/93/4/554#BIBL

Rapid responses

You can respond to this article at:


http://bjo.bmj.com/cgi/eletter-submit/93/4/554

Email alerting
service

Receive free email alerts when new articles cite this article - sign up in the box at
the top right corner of the article

Notes

To order reprints of this article go to:


http://journals.bmj.com/cgi/reprintform

To subscribe to British Journal of Ophthalmology go to:


http://journals.bmj.com/subscriptions/

Downloaded from bjo.bmj.com on 31 March 2009

PostScript
Accepted 24 September 2008
Br J Ophthalmol 2009;93:553554.
doi:10.1136/bjo.2008.144790

REFERENCES
1.

2.
3.

Schaal KB. Bartz-Schmidt KU. Dithmar S. Current


strategies for macular hole surgery in Germany, Austria
and Switzerland (in German). Ophthalmologe
2006;103:9226.
Simcock PR, Scalia S. Phacovitrectomy without prone
posture for full thickness macular holes. Br J Ophthalmol
2001;85:131619.
Fine HF, Iranmanesh R, Iturralde D, et al. Outcomes of
77 consecutive cases of 23-gauge transconjunctival
vitrectomy surgery for posterior segment disease.
Ophthalmology 2007;114:1197200.

Primary orbital lymphomatoid


granulomatosis
Lymphomatoid granulomatosis (LYG) is a
rare angiocentric and angiodestructive
EpsteinBarr virus (EBV)-associated B cell

lymphoproliferative disorder that involves


multiple organs including the lung, skin,
kidney and central nervous system. Ocular
LYG is an extremely rare tumour, which
appears as ocular granulomatous inflammation (conjunctival infiltration,1 posterior
uveitis,2 choroidal vasculitis,3 optic neuropathy,4 and retinal detachment5), with only
a few reports in the medical literature.
Furthermore, there are no reports of primary
orbital LYG without pulmonary LYG. We
describe the first case of primary orbital LYG
diagnosed by biopsy of an orbital tumour.

CASE REPORT
A 54-year-old man presenting with a 6-week
history of painless proptosis and ptosis of
the right eye was referred to our outpatient
clinic. Eye examination revealed marginal
blepharitis on the right eye (fig 1A), and the
right eye movement was restricted in all
directions. Funduscopy showed severe disc

swelling in the right eye (fig 1A). His bestcorrected visual acuity (BCVA) was 20/20 in
the right eye, and MRI T1-weighted scans
revealed a solitary fibrous tumour in the
right orbit (fig 1A). A chest CT and chest x
ray revealed a few pulmonary nodules in the
right upper lobe (fig 1B) but no pulmonary
LYG or symptoms. Laboratory examination
revealed an elevated CRP (5.94 mg/dl) and
an elevated anti-EBV viral capsid antigen
(VCA) IgG antibody titre (80 times, normal
range less than four times).
Two months after the first consultation,
the BCVA declined to 20/400 in the right
eye. The patient received radiation therapy
to the right orbital tumour with 30 Gy/15 fr
and oral prednisolone 50 mg daily for
1 week after which the prednisolone dose
was tapered down. The patient underwent
an incisional biopsy of the orbital tumour.
Macroscopic inspection of the resected
tumour segment showed a yellowish white

Figure 1 Ocular findings before and after the treatments (A) and chest x ray (B). Six weeks after treatments with radiation and oral prednisolone, orbital
tumour-related ocular symptoms of disc swelling, proptosis, ptosis and restricted ocular motility were resolved. The orbital tumour indicated by arrows in MRI
shows complete regression after treatments. (B) Chest x ray, CT and single photon emission computed tomography (SPECT) showing no signs of activity.
554

Br J Ophthalmol April 2009 Vol 93 No 4

Downloaded from bjo.bmj.com on 31 March 2009

PostScript

Figure 2 Histological examinations of orbital tumour. Biopsy of the orbital tumour shows angiocentric and angiodestructive infiltration of atypical
lymphoid cells (A, B, C), with frequent mitoses, expressing CD20 (D) and CD3 (E). EpsteinBarr virus-encoded small RNA (EBER) was detected in the
nuclei of lymphocytes (F). EVG, van Gieson elastic staining; HE, haematoxylin and eosin. Bars = 200 mm (A, B) and 100 mm (CF).

fat-containing
fibrous
tumour
10 mm64 mm63 mm in size. Histological
examination of the orbital tumour showed
angiocentric and angiodestructive lympoproliferation (haematoxylin and eosin; fig 2A,C,
and van Gieson elastic staining; fig 2B).
Immunohistochemical examination of these
specimens revealed a few CD20-positive B
cells (fig 2D) and many CD3-positive T cells
(fig 2E) in the tumour. In situ hybridisation
of EpsteinBarr virus-encoded small RNA
(EBER) showed that EBER could be detected
in a large proportion of the lymphocytes
(fig 2F) indicating the presence of LYG.
These histological and immunohistochemical analyses showed the presence of LYG.
BCVA improved to more than 20/20 in
the right eye within 6 weeks after the
initiation of treatment. Restricted eye movement with orbital fibrosis gradually subsided, and the cosmetic result was
considered excellent. The patient had no
evidence of recurrence of LYG for 34 months
after treatment (fig 1A).

COMMENT
LYG is a rare multiple-organ disease and
predominantly affects the lungs; therefore,
Br J Ophthalmol April 2009 Vol 93 No 4

it is normally diagnosed based on a lung


biopsy. To our knowledge, the present
study provides the first report of a case
with orbital LYG diagnosed by orbital
biopsy. Furthermore, there are surprisingly
no reports on orbital LYG. In the relatively few reports of ocular LYG,15
pulmonary LYG appeared first, followed
by ocular symptoms, while our patients
had no pulmonary symptoms. Although
the orbital LYG could not be seen in detail
with MRI, visual loss and disc swelling
might occur by compressing the optic
nerve and its blood supply, but not
direct invasion of orbital tumour. In our
patient, the early radiotherapy and oral
corticosteroid treatment before the diagnosis of LYG resulted in complete visual
recovery and rapid resolution of the clinical
findings. LYG is a poorly understood
inflammatory syndrome of uncertain
pathogenesis, with the CT appearance
resembling that of lymphoma and
lymphoreticular hyperplasia and with histological similarities to Wegener granulomatosis and malignant lymphoma. The
present case indicates that LYG can be
involved in the orbital tumour.

F Araki,1 T Mimura,1 S Fukuoka,1 H Tsuji,1,2 K Izutsu,3


H Yamamoto,1 Y Takazawa,4 T Kojima1,5
1
Department of Ophthalmology, University of Tokyo
Graduate School of Medicine, Tokyo, Japan; 2 Department of
Ophthalmology, The Cancer Institute Hospital of JFCR,
Tokyo, Japan; 3 Department of Hematology and Oncology,
University of Tokyo Graduate School of Medicine, Tokyo,
Japan; 4 Department of Pathology, University of Tokyo
Graduate School of Medicine, Tokyo, Japan; 5 Department of
Ophthalmology, Saitama Red-Cross Hospital, Saitama, Japan

Correspondence to: Dr T Mimura, Department of


Ophthalmology, University of Tokyo Graduate School of
Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655 Japan;
mimurat-tky@umin.ac.jp
Funding: None.
Competing interests: None.
Ethics approval: Ethics approval was provided by the
Institutional Review Board of Tokyo University Hospital.
Patient consent: Obtained.
Accepted 30 September 2008
Br J Ophthalmol 2009;93:554556.
doi:10.1136/bjo.2008.140913

REFERENCES
1.

Chung YM, Yeh TS, Tsai YY, et al. Conjunctival


involvement of lymphomatoid granulomatosis.
Ophthalmologica 1988;196:1616.

555

Downloaded from bjo.bmj.com on 31 March 2009

PostScript
2.

3.

4.

5.

Tse DT, Mandelbaum S, Chuck DA, et al.


Lymphomatoid granulomatosis with ocular
involvement. Retina 1985;5:947.
Pearson AD, Craft AW, Howe JM. Choroidal
involvement in lymphomatoid granulomatosis.
Br J Ophthalmol 1991;75:6889.
Forman S, Rosenbaum PS. Lymphomatoid
granulomatosis presenting as an isolated unilateral
optic neuropathy: a clinicopathologic report.
J Neuroophthalmol 1998;18:1502.
Cameron JR, Cackett P. Lymphomatoid granulomatosis
associated with bilateral exudative retinal detachments.
Arch Ophthalmol 2007;125:71213.

Unilateral leucocoria in clinically


normal eyes
Leucocoria may be caused by cataract,
retinal detachment, retinoblastoma and
other intraocular abnormalities.1 A delay in
the diagnosis of retinoblastoma can lead to
local tumour invasion, blindness and even
death.1 The presenting sign of retinoblastoma is commonly leucocoria which, despite
routine paediatric screening, is usually initially detected by a parent.2
Seven children are described, three male
and four female, who were referred due to
unilateral leucocoria detected in amateur
photographs. The mean age was 3 years
(range 18 months to 4.5 years). Cases 2 and
3 were siblings. The remaining children were
unrelated. Each case is outlined in table 1. In
case 1, presented in fig 1, this alternated in
subsequent photographs. In the remaining
six cases, two demonstrated right leucocoria
and four left leucocoria. In all cases, the child
was looking in the opposite directionfor
example right leucocoria evident in left gaze.
Each child had a normal fundus and media
examination; ocular alignment and motility
were also normal. The visual acuities were
normal and equal in either eye. Five did not
require spectacles, and two children required
glasses for a mild symmetrical refractive error.

Figure 1 Alternating leucocoria: case 1


showing alternating leucocoria dependent on
direction of gaze.

DISCUSSION
Each of the children described in this paper
had a clear presentation with leucocoria but
with subsequent normal ocular examination.
A literature review revealed only one
previous article describing leucocoria in
normal eyes.3 It appears that leucocoria in
normal eyes detected by flash photography
only occurs in off-axis fixation. The theory

behind this phenomenon is that the optic


nerve head acts as a mirror and may reflect
enough light to illuminate the entire pupil,
thus producing leucocoria. Incident light
striking the optic disc from an angle of
approximately 15u off axis needs to illuminate only 1/30 of the optic disc to produce
leucocoria.3
Each picture was an indoor flash photograph taken with an amateur camera, often
a digital camera. The subjects had undilated
pupils, were at varying distances from the
camera and were fixating off axis. In keeping
with the findings reported by Marshall and
Gole,3 leucocoria was unilateral and
observed in the eye in which the nasal retina
was illuminated.
The principle of reflected light in photography has been developed for screening
purposes in ophthalmology. Photographic
screening has been employed to identify
factors including strabismus, refractive error
and media opacity.46 In children with refractive errors, a crescent is seen within the red
reflex in the photoscreening image, the size
being proportional to the refractive error.
A study by Miller et al4 found that the size
of the crescents in both myopes and hyperopes increased as fixation shifted off axis.
This effect was not enough, however, to
create the impression of leucocoria even in
the patients with a large refractive error
with a magnitude of 7.00 dioptres.
Evidence from large-scale photoscreening
studies supports the theory that leucocoria
in normal eyes only occurs when fixation is
off-axis. In a photoscreening study involving
14 075 undilated children, there were no
reported cases of leucocoria in normal eyes.5
Furthermore, in a photoscreening study
involving 392 preverbal children, four falsepositive results with respect to the presence
of media opacities were reported in normal
eyes.6 The direction of fixation of the
subjects was not documented, and so it
can be speculated that off-axis fixation was
a possible cause.

Table 1 Cases of leucocoria


Case

Age

Gender

Leucocoria

FH

PMH

POH

F&M

RefError

VA

CT

OM

BV

1y 9m

Alternating

RetPig

Glasses not required

Equal

NAD

Full

+ve

4y 6m

Right

Glasses not required

Equal

XP

Full

+ve

2y

Left

Myopic
astig
Myopic
astig

Cleft
palate
Nil
Nil

Ref Error

R: +0.25/+2.06100

Equal

XP

Full

+ve

M
M
M

Right
Left
Left

Nil
Nil
Nil

Nil
Nil
Nil

Nil
Nil
Nil

N
N
N

Equal
Equal
Equal

NAD
NAD
NAD

Full
Full
Full

+ve
+ve
+ve

Left

Nil

nil

nil

Equal

NAD

Full

+ve

4
5
6
7

6m
18m
4y
4y
2m
2y 5m

L: plano/+1.5690
Glasses not required
Glasses not required
R: +2.50
L: +2.75
Glasses not required

+ve, positive response; astig, astigmatism; BV, binocular vision; CT, cover test; DS, dioptre sphere; EP, esophoria; F&M, fundus and media; F, female; FH, family history; m, months; M, male; N,
normal; NAD, no abnormal deviation; OM, ocular motility; PMH, previous medical history; POH, previous ocular history; RefError, refractive error; RetPig, retinitis pigmentosa; VA, visual acuity;
XP, exophoria; y, years.

556

Br J Ophthalmol April 2009 Vol 93 No 4

Downloaded from bjo.bmj.com on 31 March 2009

Unilateral leucocoria in clinically normal eyes


R Batra, F Rowe, A Rowlands and C Noonan
Br. J. Ophthalmol. 2009;93;556-557
doi:10.1136/bjo.2008.149864

Updated information and services can be found at:


http://bjo.bmj.com/cgi/content/full/93/4/556

These include:

References

This article cites 6 articles, 2 of which can be accessed free at:


http://bjo.bmj.com/cgi/content/full/93/4/556#BIBL

Rapid responses

You can respond to this article at:


http://bjo.bmj.com/cgi/eletter-submit/93/4/556

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http://journals.bmj.com/subscriptions/

Downloaded from bjo.bmj.com on 31 March 2009

PostScript
2.

3.

4.

5.

Tse DT, Mandelbaum S, Chuck DA, et al.


Lymphomatoid granulomatosis with ocular
involvement. Retina 1985;5:947.
Pearson AD, Craft AW, Howe JM. Choroidal
involvement in lymphomatoid granulomatosis.
Br J Ophthalmol 1991;75:6889.
Forman S, Rosenbaum PS. Lymphomatoid
granulomatosis presenting as an isolated unilateral
optic neuropathy: a clinicopathologic report.
J Neuroophthalmol 1998;18:1502.
Cameron JR, Cackett P. Lymphomatoid granulomatosis
associated with bilateral exudative retinal detachments.
Arch Ophthalmol 2007;125:71213.

Unilateral leucocoria in clinically


normal eyes
Leucocoria may be caused by cataract,
retinal detachment, retinoblastoma and
other intraocular abnormalities.1 A delay in
the diagnosis of retinoblastoma can lead to
local tumour invasion, blindness and even
death.1 The presenting sign of retinoblastoma is commonly leucocoria which, despite
routine paediatric screening, is usually initially detected by a parent.2
Seven children are described, three male
and four female, who were referred due to
unilateral leucocoria detected in amateur
photographs. The mean age was 3 years
(range 18 months to 4.5 years). Cases 2 and
3 were siblings. The remaining children were
unrelated. Each case is outlined in table 1. In
case 1, presented in fig 1, this alternated in
subsequent photographs. In the remaining
six cases, two demonstrated right leucocoria
and four left leucocoria. In all cases, the child
was looking in the opposite directionfor
example right leucocoria evident in left gaze.
Each child had a normal fundus and media
examination; ocular alignment and motility
were also normal. The visual acuities were
normal and equal in either eye. Five did not
require spectacles, and two children required
glasses for a mild symmetrical refractive error.

Figure 1 Alternating leucocoria: case 1


showing alternating leucocoria dependent on
direction of gaze.

DISCUSSION
Each of the children described in this paper
had a clear presentation with leucocoria but
with subsequent normal ocular examination.
A literature review revealed only one
previous article describing leucocoria in
normal eyes.3 It appears that leucocoria in
normal eyes detected by flash photography
only occurs in off-axis fixation. The theory

behind this phenomenon is that the optic


nerve head acts as a mirror and may reflect
enough light to illuminate the entire pupil,
thus producing leucocoria. Incident light
striking the optic disc from an angle of
approximately 15u off axis needs to illuminate only 1/30 of the optic disc to produce
leucocoria.3
Each picture was an indoor flash photograph taken with an amateur camera, often
a digital camera. The subjects had undilated
pupils, were at varying distances from the
camera and were fixating off axis. In keeping
with the findings reported by Marshall and
Gole,3 leucocoria was unilateral and
observed in the eye in which the nasal retina
was illuminated.
The principle of reflected light in photography has been developed for screening
purposes in ophthalmology. Photographic
screening has been employed to identify
factors including strabismus, refractive error
and media opacity.46 In children with refractive errors, a crescent is seen within the red
reflex in the photoscreening image, the size
being proportional to the refractive error.
A study by Miller et al4 found that the size
of the crescents in both myopes and hyperopes increased as fixation shifted off axis.
This effect was not enough, however, to
create the impression of leucocoria even in
the patients with a large refractive error
with a magnitude of 7.00 dioptres.
Evidence from large-scale photoscreening
studies supports the theory that leucocoria
in normal eyes only occurs when fixation is
off-axis. In a photoscreening study involving
14 075 undilated children, there were no
reported cases of leucocoria in normal eyes.5
Furthermore, in a photoscreening study
involving 392 preverbal children, four falsepositive results with respect to the presence
of media opacities were reported in normal
eyes.6 The direction of fixation of the
subjects was not documented, and so it
can be speculated that off-axis fixation was
a possible cause.

Table 1 Cases of leucocoria


Case

Age

Gender

Leucocoria

FH

PMH

POH

F&M

RefError

VA

CT

OM

BV

1y 9m

Alternating

RetPig

Glasses not required

Equal

NAD

Full

+ve

4y 6m

Right

Glasses not required

Equal

XP

Full

+ve

2y

Left

Myopic
astig
Myopic
astig

Cleft
palate
Nil
Nil

Ref Error

R: +0.25/+2.06100

Equal

XP

Full

+ve

M
M
M

Right
Left
Left

Nil
Nil
Nil

Nil
Nil
Nil

Nil
Nil
Nil

N
N
N

Equal
Equal
Equal

NAD
NAD
NAD

Full
Full
Full

+ve
+ve
+ve

Left

Nil

nil

nil

Equal

NAD

Full

+ve

4
5
6
7

6m
18m
4y
4y
2m
2y 5m

L: plano/+1.5690
Glasses not required
Glasses not required
R: +2.50
L: +2.75
Glasses not required

+ve, positive response; astig, astigmatism; BV, binocular vision; CT, cover test; DS, dioptre sphere; EP, esophoria; F&M, fundus and media; F, female; FH, family history; m, months; M, male; N,
normal; NAD, no abnormal deviation; OM, ocular motility; PMH, previous medical history; POH, previous ocular history; RefError, refractive error; RetPig, retinitis pigmentosa; VA, visual acuity;
XP, exophoria; y, years.

556

Br J Ophthalmol April 2009 Vol 93 No 4

Downloaded from bjo.bmj.com on 31 March 2009

PostScript
The presence of leucocoria in a child is of
concern for both parent and clinician, and
hence necessitates thorough clinical examination. Complete dilated fundus examination should be performed on all babies and
children in whom leucocoria is observed in
photographs. In the event of normal clinical
findings in a child presenting with leucocoria
seen on amateur photography, an awareness
of the possibility of the described phenomenon prevents unnecessary investigation and
can be used in discussion with parents as a
means of providing reassurance.
R Batra,1 F Rowe,2 A Rowlands,1 C Noonan1
1
Department of Ophthalmology, North Cheshire Hospitals
NHS Trust, Warrington, UK; 2 Division of Orthoptics,
University of Liverpool, Liverpool, UK

Correspondence to: Miss R Batra, Birmingham and


Midland Eye Centre, Dudley Road, Birmingham B18 7QH,
UK; ruchikabatra@aol.com
Competing interests: None.
Patient consent: Obtained from the parents.
Accepted 1 October 2008
Br J Ophthalmol 2009;93:556557.
doi:10.1136/bjo.2008.149864

REFERENCES
1.
2.

3.

4.

5.

6.

Shields A. Importance of early diagnosis of


retinoblastoma. Br J Ophthalmol 1999;83:131516.
Abramson DH, Beaverson K, Sangani P, et al.
Screening for retinoblastoma: presenting signs as
prognosticators of patient and ocular survival.
Pediatrics 2003;112:124855.
Marshall J, Gole G. Unilateral leukocoria in off axis
flash photographs of normal eyes. Am J Ophthalmol
2003;135:70911.
Miller JM, Schwiegerling J, Leising-Hall H, et al.
Detection of Improper fixation in MTI photoscreening
images. JAAPOS 2001;5:3543.
Morgan KS, Kennemer JC. Off-axis photorefractive
eye screening in children. J Cat Refract Surg
1997;23:4238.
Tong PY, Bassin RE, Enke-Miyazaki E, et al. Screening
for amblyopia in preverbal children with photoscreening
photographs: sensitivity and specificity of the MTI
photoscreener. Ophthalmol 2000;107:16239.

may also be used as an adjunctive therapy


for a mitomycin C (MMC) trabeculectomy
to treat NVG. It remains to be elucidated as
to how bevacizumab exerts its effects on the
neovascular tissue in NVG. This study was
carried out to examine the trabecular meshwork of eyes with NVG following the IVB.
A dose of 1.25 mg (0.05 ml) of IVB
(Avastin 100 mg/4 ml, Roche, Reinach,
Switzerland) was given in the superotemporal quadrant 4 mm posterior to the limbus
of the affected eyes of three patients. The
underlying diseases for neovascular glaucoma were proliferative diabetic retinopathy
(case 1), ocular ischaemic disease (case 2)
and severe uveitis (case 3). The iris and angle
were found to be free of neovascularisation according to a slit-lamp microscopic
examination in all patients. The IOP could
not be controlled with medical treatments,
so a trabeculectomy with 0.04% MMC was
performed in the three patients. A deep
scleral flap (2.5 mm62.5 mm) was removed
after creating a 4 mm64 mm sclerap flap of
half thickness. The surgical specimens
obtained by a trabeculectomy were examined by light and electron microscopy. The
halves of the specimens fixed in paraformaldehyde were embedded in paraffin. For
immunohistochemistry, incubation with
anti-human CD34 mouse monoclonal antibody (1:50) (Immunotech, Marseille, France)
was applied to the sections.
The sections viewed under light microsopy contained the Schlemm canal, juxtacanalicular connective tissue and almost all
parts of the corneoscleral meshwork in all
three cases. The light and electron microscopic findings of the trabecular meshwork
in the three cases showed very similar
findings. Capillary-like structures with scattered red blood cells were observed in the
trabecular meshwork. CD34 positively
stained in the vascular endothelial cells
consisting of the capillary-like structure
and the endothelial cells of the Schlemm
canal in the trabecular meshwork (fig 1).

Figure 2 Transmission electron micrographs


of the corneoscleral meshwork in the neovascular glaucoma eye after bevacizumab therapy
(case 2). (A) Single layer of vascular endothelial
cells forming a capillary-like structure. These
vascular endothelial cells contain no pigment
granules. The remaining trabecular cells contain
pigment granules (original magnification
61200). (B) Microfibrils (arrowheads) and a
layer of basal lamina (arrows), found just
beneath the vascular endothelial cells. The
vascular endothelial cells have no fenestration
(original magnification 612 000).

There were several capillary-like structures


consisting of a single layer of vascular
endothelial cells in an ultrathin section. A
small number of red blood cells were
observed in the lumen. The layer of vascular
endothelial cells demonstrated junctional
modifications. No fenestration was observed
in the vascular endothelial cells of the
capillary-like structures (fig 2).
In our previous study, we investigated
the histological changes in the trabecular

Trabecular meshwork in
neovascular glaucoma eyes after
the intravitreal injection of
bevacizumab
Neovascular glaucoma (NVG) is a severe
consequence of ocular ischaemic disease.
The mechanism of intraocular pressure
(IOP) elevation is considered to be the
increased permeability of the newly formed
vessels,1 angle closure by the peripheral
anterior synechia and intertrabecular neovascular tissue.2 3 The intravitreal injection
of bevacizumab (IVB) was reported to be
effective in the regression of new vessels.4
This injection may provide us with sufficient time to treat these patients with
retinal photocoagulation. In addition, it
Br J Ophthalmol April 2009 Vol 93 No 4

Figure 1 (A) Light microscopy of the trabecular meshwork (case 1) resected during a
trabeculectomy (6200), H&E staining. The Schlemm canal is open. The tissue contained the
Schlemm canal, juxtacanalicular connective tissue and almost all parts of the corneoscleral
meshwork. (B) CD34, a marker of the vascular endothelial cells, positively stained in the endothelial
cells forming capillary-like structures, and the endothelium of the Schlemm canal. The vascular
endothelial cells are present in the trabecular meshwork of neovascular glaucoma after the
intravitreal injection of bevacizumab.
557

Downloaded from bjo.bmj.com on 31 March 2009

Trabecular meshwork in neovascular glaucoma


eyes after the intravitreal injection of
bevacizumab
T Kubota, R Aoki, Y Harada, N Tou, Y Kohno, A Tawara, H Satoh and S
Shimajiri
Br. J. Ophthalmol. 2009;93;557-558
doi:10.1136/bjo.2008.148148

Updated information and services can be found at:


http://bjo.bmj.com/cgi/content/full/93/4/557

These include:

References

This article cites 6 articles, 3 of which can be accessed free at:


http://bjo.bmj.com/cgi/content/full/93/4/557#BIBL

Rapid responses

You can respond to this article at:


http://bjo.bmj.com/cgi/eletter-submit/93/4/557

Email alerting
service

Receive free email alerts when new articles cite this article - sign up in the box at
the top right corner of the article

Notes

To order reprints of this article go to:


http://journals.bmj.com/cgi/reprintform

To subscribe to British Journal of Ophthalmology go to:


http://journals.bmj.com/subscriptions/

Downloaded from bjo.bmj.com on 31 March 2009

PostScript
The presence of leucocoria in a child is of
concern for both parent and clinician, and
hence necessitates thorough clinical examination. Complete dilated fundus examination should be performed on all babies and
children in whom leucocoria is observed in
photographs. In the event of normal clinical
findings in a child presenting with leucocoria
seen on amateur photography, an awareness
of the possibility of the described phenomenon prevents unnecessary investigation and
can be used in discussion with parents as a
means of providing reassurance.
R Batra,1 F Rowe,2 A Rowlands,1 C Noonan1
1
Department of Ophthalmology, North Cheshire Hospitals
NHS Trust, Warrington, UK; 2 Division of Orthoptics,
University of Liverpool, Liverpool, UK

Correspondence to: Miss R Batra, Birmingham and


Midland Eye Centre, Dudley Road, Birmingham B18 7QH,
UK; ruchikabatra@aol.com
Competing interests: None.
Patient consent: Obtained from the parents.
Accepted 1 October 2008
Br J Ophthalmol 2009;93:556557.
doi:10.1136/bjo.2008.149864

REFERENCES
1.
2.

3.

4.

5.

6.

Shields A. Importance of early diagnosis of


retinoblastoma. Br J Ophthalmol 1999;83:131516.
Abramson DH, Beaverson K, Sangani P, et al.
Screening for retinoblastoma: presenting signs as
prognosticators of patient and ocular survival.
Pediatrics 2003;112:124855.
Marshall J, Gole G. Unilateral leukocoria in off axis
flash photographs of normal eyes. Am J Ophthalmol
2003;135:70911.
Miller JM, Schwiegerling J, Leising-Hall H, et al.
Detection of Improper fixation in MTI photoscreening
images. JAAPOS 2001;5:3543.
Morgan KS, Kennemer JC. Off-axis photorefractive
eye screening in children. J Cat Refract Surg
1997;23:4238.
Tong PY, Bassin RE, Enke-Miyazaki E, et al. Screening
for amblyopia in preverbal children with photoscreening
photographs: sensitivity and specificity of the MTI
photoscreener. Ophthalmol 2000;107:16239.

may also be used as an adjunctive therapy


for a mitomycin C (MMC) trabeculectomy
to treat NVG. It remains to be elucidated as
to how bevacizumab exerts its effects on the
neovascular tissue in NVG. This study was
carried out to examine the trabecular meshwork of eyes with NVG following the IVB.
A dose of 1.25 mg (0.05 ml) of IVB
(Avastin 100 mg/4 ml, Roche, Reinach,
Switzerland) was given in the superotemporal quadrant 4 mm posterior to the limbus
of the affected eyes of three patients. The
underlying diseases for neovascular glaucoma were proliferative diabetic retinopathy
(case 1), ocular ischaemic disease (case 2)
and severe uveitis (case 3). The iris and angle
were found to be free of neovascularisation according to a slit-lamp microscopic
examination in all patients. The IOP could
not be controlled with medical treatments,
so a trabeculectomy with 0.04% MMC was
performed in the three patients. A deep
scleral flap (2.5 mm62.5 mm) was removed
after creating a 4 mm64 mm sclerap flap of
half thickness. The surgical specimens
obtained by a trabeculectomy were examined by light and electron microscopy. The
halves of the specimens fixed in paraformaldehyde were embedded in paraffin. For
immunohistochemistry, incubation with
anti-human CD34 mouse monoclonal antibody (1:50) (Immunotech, Marseille, France)
was applied to the sections.
The sections viewed under light microsopy contained the Schlemm canal, juxtacanalicular connective tissue and almost all
parts of the corneoscleral meshwork in all
three cases. The light and electron microscopic findings of the trabecular meshwork
in the three cases showed very similar
findings. Capillary-like structures with scattered red blood cells were observed in the
trabecular meshwork. CD34 positively
stained in the vascular endothelial cells
consisting of the capillary-like structure
and the endothelial cells of the Schlemm
canal in the trabecular meshwork (fig 1).

Figure 2 Transmission electron micrographs


of the corneoscleral meshwork in the neovascular glaucoma eye after bevacizumab therapy
(case 2). (A) Single layer of vascular endothelial
cells forming a capillary-like structure. These
vascular endothelial cells contain no pigment
granules. The remaining trabecular cells contain
pigment granules (original magnification
61200). (B) Microfibrils (arrowheads) and a
layer of basal lamina (arrows), found just
beneath the vascular endothelial cells. The
vascular endothelial cells have no fenestration
(original magnification 612 000).

There were several capillary-like structures


consisting of a single layer of vascular
endothelial cells in an ultrathin section. A
small number of red blood cells were
observed in the lumen. The layer of vascular
endothelial cells demonstrated junctional
modifications. No fenestration was observed
in the vascular endothelial cells of the
capillary-like structures (fig 2).
In our previous study, we investigated
the histological changes in the trabecular

Trabecular meshwork in
neovascular glaucoma eyes after
the intravitreal injection of
bevacizumab
Neovascular glaucoma (NVG) is a severe
consequence of ocular ischaemic disease.
The mechanism of intraocular pressure
(IOP) elevation is considered to be the
increased permeability of the newly formed
vessels,1 angle closure by the peripheral
anterior synechia and intertrabecular neovascular tissue.2 3 The intravitreal injection
of bevacizumab (IVB) was reported to be
effective in the regression of new vessels.4
This injection may provide us with sufficient time to treat these patients with
retinal photocoagulation. In addition, it
Br J Ophthalmol April 2009 Vol 93 No 4

Figure 1 (A) Light microscopy of the trabecular meshwork (case 1) resected during a
trabeculectomy (6200), H&E staining. The Schlemm canal is open. The tissue contained the
Schlemm canal, juxtacanalicular connective tissue and almost all parts of the corneoscleral
meshwork. (B) CD34, a marker of the vascular endothelial cells, positively stained in the endothelial
cells forming capillary-like structures, and the endothelium of the Schlemm canal. The vascular
endothelial cells are present in the trabecular meshwork of neovascular glaucoma after the
intravitreal injection of bevacizumab.
557

Downloaded from bjo.bmj.com on 31 March 2009

PostScript
meshwork of enucleated eyes with NVG.3
The ultrastructural study showed that the
neovascular tissue in the intertrabecular
spaces may be one of the factors responsible
for the IOP elevation. The layers of vascular
endothelial cells have junctional modifications and fenestrations. In the present
study, we showed that CD34 positive
vascular endothelial cells formed capillarylike structures in the trabecular meshwork
of NVG following the IVB. Although the
slit-lamp and gonioscopic examinations
revealed a regression of the newly formed
vessels after the IVB, we morphologically
showed that the vascular endothelial cells
are still present in the trabecular meshwork.
However, there were few fenestrations of
the vascular endothelial cells in the trabecular meshwork of the NVG eyes with
bevacizumab therapy. Peters et al5 reported
on the ultrastructural findings in the primate eye after an IVB. They showed that
the choriocapillaris endothelial fenestrations
decreased dramatically after the injection.
The absence of VEGF may cause a loss of
endothelial fenestrations.6 A reduced number of fenestrations of the vascular endothelial cells may be one of the factors
contributing to the clinical effects of IVB
for NVG.
T Kubota,1 R Aoki,1 Y Harada,1 N Tou,1 Y Kohno,1
A Tawara,1 H Satoh,2 S Shimajiri2
1
Department of Ophthalmology, School of Medicine,
University of Occupational and Environmental Health,
Kitakyushu, Japan; 2 Department of Surgical Pathology,
School of Medicine, University of Occupational and
Environmental Health, Kitakyushu, Japan

Correspondence to: Dr T Kubota, Department of


Ophthalmology, School of Medicine, University of
Occupational and Environmental Health, Japan, 1-1
Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan;
tkubota@med.uoeh-u.ac.jp
Acknowledgements: We would like to thank K Yokota for
her excellent technical assistance.
Funding: This work was supported in part by Grants in Aid
(Nos 16591777 and 18591945) for Scientific Research from
the Ministry of Education, Science, Sports and Culture of the
Japanese government.
Competing interests: None.
Ethics approval: Ethics approval was provided by the
Institutional Review Boards of the University of Occupational
and Environmental Health, Japan.

5.

6.

bevacizumab in patients with proliferative diabetic


retinopathy. Am J Ophthalmol 2006;142:1558.
Peters S, Heiduschka P, Julien S, et al. Ultrastructural
findings in the primate eye after intravitreal injection of
bevacizumab. Am J Ophthalmol 2007;143:9951002.
Roberts GW, Palade GE. Increased vascular
permeability and endothelial cell fenestration induced
by vascular endothelial growth factor. J Cell Sci
1995;108:236979.

Safety of DSAEK in pseudophakic


eyes with anterior chamber
lenses and Fuchs endothelial
dystrophy
Descemet stripping automated endothelial
keratoplasty (DSAEK) has recently gained
popularity as the procedure of choice in the
management of corneal endothelial disease.
The advantages of DSAEK over penetrating keratoplasty (PK) include the avoidance
of open sky surgery, minimal induced
postsurgical astigmatism and faster visual
rehabilitation.1 2 Ongoing innovations in the
surgical technique have significantly
improved the most important outcome,
which is, of course, donor endothelial
survival.3 Most surgeons currently recommend, in cases of endothelial disease with
the presence of an anterior chamber (AC)
intraocular lens (IOL), the removal of the
implant and the use of scleral fixated or iris
fixated IOLs prior or simultaneous to the
DSAEK in order to improve the endothelial
survival. IOL exchange is associated with
significant complications that include infections, haemorrhage, expulsive haemorrhage,
cystoid macular oedema, iritis and late
dislocations.
We report three cases of DSAEK successfully performed in the presence of Fuchs
endothelial dystrophy and well-positioned
AC IOL with endothelial survival rates
comparable with larger series previously
published.4 5 This chart review was conducted with a waiver from the Rand Eye

Institutes review board and conforms to


HIPPA regulations.
Prior to surgery, a Pentacam Scheimpflug
image was performed to assess the AC
depth, position and centration of the AC
IOL. In all three cases, the AC depth was
greater than 3 mm, and the AC IOL was
correctly centred and positioned.
Surgery was performed under local anaesthesia. The donor corneal lenticle was
prepared using a Moria CB microkeratome
head (350 mm blade depth) and an artificial
anterior chamber maintainer filled with air
(Moria, Doyleston, Pennsylvania). After the
microkeratome pass, the posterior lamella
tissue was punched from the endothelial
side using a disposable trephine with diameters between 7.0 and 8.5 mm. The donor
tissue was then covered with Optisol solution
(Chiron
Ophthalmics,
Irvine,
California) until use.
Three paracentheses were performed in
the host cornea in the nasal, inferior and
temporal quadrants. An irrigating corneal
scraper was used to remove the Descemet
membrane from the central cornea. A 4 mm
clear corneal incision was made superiorly.
The donor tissue was folded 6040% over
Healon and was inserted into the recipient
anterior chamber through the superior incision. The corneal disc was unfolded with
balanced salt solution and air, and was
positioned against the recipient bed. The
position and centration of the AC IOL were
verified (fig 1). The anterior chamber was
filled 100% with air for 10 min, and then
50% of the air was exchanged with balanced
salt solution. At 1, 6 and 12 months postoperatively, a manifest refraction, best spectacle-corrected visual acuity, corneal
topography, manual keratometry, endothelial cell density (ECD), corneal pachymetry
and topography measurement using the
Pentacam
topographer
(Oculus
Inc,
Lynnwood, Washington) were performed.
Table 1 illustrates the preoperative data
and the 6-month and 12-month ECD for
each patient. As can be seen, the endothelial
survival rate is compatible with previous
reports showing 34% and 35% mean cell loss
at 6 months and 1 year postoperatively.4 No

Patient consent: Obtained.


Accepted 26 October 2008
Br J Ophthalmol 2009;93:557558.
doi:10.1136/bjo.2008.148148

REFERENCES
1.

2.

3.

4.

558

Johnson M, Gong H, Freddo TF, et al. Serum proteins


and aqueous outflow resistance in bovine eyes. Invest
Ophthalmol Vis Sci 1993;34:354957.
Gartner S, Henkind P. Neovasuclarization of
the iris (rubeosis iridis). Surv Ophthalmol
1978;22:291312.
Kubota T, Tawara A, Hata Y, et al. Neovascular tissue
in the intertrabecular spaces in eyes with neovascular
glaucoma. Br J Ophthalmol 1996;80:7504.
Oshima Y, Sakaguchi H, Gomi F, et al. Regression of
iris neovascularization after intravitreal injection of

Figure 1 One-month postoperative appearance of patient with Fuchs corneal dystrophy and
anterior chamber intraocular lens that underwent Descemet stripping automated endothelial
keratoplasty (DSAEK) surgery. The best-corrected visual acuity is 20/30. Arrows indicate the edge
of the DSAEK graft.
Br J Ophthalmol April 2009 Vol 93 No 4

Downloaded from bjo.bmj.com on 31 March 2009

Safety of DSAEK in pseudophakic eyes with


anterior chamber lenses and Fuchs endothelial
dystrophy
S Esquenazi
Br. J. Ophthalmol. 2009;93;558-559
doi:10.1136/bjo.2008.154914

Updated information and services can be found at:


http://bjo.bmj.com/cgi/content/full/93/4/558

These include:

Rapid responses

You can respond to this article at:


http://bjo.bmj.com/cgi/eletter-submit/93/4/558

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Notes

To order reprints of this article go to:


http://journals.bmj.com/cgi/reprintform

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http://journals.bmj.com/subscriptions/

Downloaded from bjo.bmj.com on 31 March 2009

PostScript
meshwork of enucleated eyes with NVG.3
The ultrastructural study showed that the
neovascular tissue in the intertrabecular
spaces may be one of the factors responsible
for the IOP elevation. The layers of vascular
endothelial cells have junctional modifications and fenestrations. In the present
study, we showed that CD34 positive
vascular endothelial cells formed capillarylike structures in the trabecular meshwork
of NVG following the IVB. Although the
slit-lamp and gonioscopic examinations
revealed a regression of the newly formed
vessels after the IVB, we morphologically
showed that the vascular endothelial cells
are still present in the trabecular meshwork.
However, there were few fenestrations of
the vascular endothelial cells in the trabecular meshwork of the NVG eyes with
bevacizumab therapy. Peters et al5 reported
on the ultrastructural findings in the primate eye after an IVB. They showed that
the choriocapillaris endothelial fenestrations
decreased dramatically after the injection.
The absence of VEGF may cause a loss of
endothelial fenestrations.6 A reduced number of fenestrations of the vascular endothelial cells may be one of the factors
contributing to the clinical effects of IVB
for NVG.
T Kubota,1 R Aoki,1 Y Harada,1 N Tou,1 Y Kohno,1
A Tawara,1 H Satoh,2 S Shimajiri2
1
Department of Ophthalmology, School of Medicine,
University of Occupational and Environmental Health,
Kitakyushu, Japan; 2 Department of Surgical Pathology,
School of Medicine, University of Occupational and
Environmental Health, Kitakyushu, Japan

Correspondence to: Dr T Kubota, Department of


Ophthalmology, School of Medicine, University of
Occupational and Environmental Health, Japan, 1-1
Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan;
tkubota@med.uoeh-u.ac.jp
Acknowledgements: We would like to thank K Yokota for
her excellent technical assistance.
Funding: This work was supported in part by Grants in Aid
(Nos 16591777 and 18591945) for Scientific Research from
the Ministry of Education, Science, Sports and Culture of the
Japanese government.
Competing interests: None.
Ethics approval: Ethics approval was provided by the
Institutional Review Boards of the University of Occupational
and Environmental Health, Japan.

5.

6.

bevacizumab in patients with proliferative diabetic


retinopathy. Am J Ophthalmol 2006;142:1558.
Peters S, Heiduschka P, Julien S, et al. Ultrastructural
findings in the primate eye after intravitreal injection of
bevacizumab. Am J Ophthalmol 2007;143:9951002.
Roberts GW, Palade GE. Increased vascular
permeability and endothelial cell fenestration induced
by vascular endothelial growth factor. J Cell Sci
1995;108:236979.

Safety of DSAEK in pseudophakic


eyes with anterior chamber
lenses and Fuchs endothelial
dystrophy
Descemet stripping automated endothelial
keratoplasty (DSAEK) has recently gained
popularity as the procedure of choice in the
management of corneal endothelial disease.
The advantages of DSAEK over penetrating keratoplasty (PK) include the avoidance
of open sky surgery, minimal induced
postsurgical astigmatism and faster visual
rehabilitation.1 2 Ongoing innovations in the
surgical technique have significantly
improved the most important outcome,
which is, of course, donor endothelial
survival.3 Most surgeons currently recommend, in cases of endothelial disease with
the presence of an anterior chamber (AC)
intraocular lens (IOL), the removal of the
implant and the use of scleral fixated or iris
fixated IOLs prior or simultaneous to the
DSAEK in order to improve the endothelial
survival. IOL exchange is associated with
significant complications that include infections, haemorrhage, expulsive haemorrhage,
cystoid macular oedema, iritis and late
dislocations.
We report three cases of DSAEK successfully performed in the presence of Fuchs
endothelial dystrophy and well-positioned
AC IOL with endothelial survival rates
comparable with larger series previously
published.4 5 This chart review was conducted with a waiver from the Rand Eye

Institutes review board and conforms to


HIPPA regulations.
Prior to surgery, a Pentacam Scheimpflug
image was performed to assess the AC
depth, position and centration of the AC
IOL. In all three cases, the AC depth was
greater than 3 mm, and the AC IOL was
correctly centred and positioned.
Surgery was performed under local anaesthesia. The donor corneal lenticle was
prepared using a Moria CB microkeratome
head (350 mm blade depth) and an artificial
anterior chamber maintainer filled with air
(Moria, Doyleston, Pennsylvania). After the
microkeratome pass, the posterior lamella
tissue was punched from the endothelial
side using a disposable trephine with diameters between 7.0 and 8.5 mm. The donor
tissue was then covered with Optisol solution
(Chiron
Ophthalmics,
Irvine,
California) until use.
Three paracentheses were performed in
the host cornea in the nasal, inferior and
temporal quadrants. An irrigating corneal
scraper was used to remove the Descemet
membrane from the central cornea. A 4 mm
clear corneal incision was made superiorly.
The donor tissue was folded 6040% over
Healon and was inserted into the recipient
anterior chamber through the superior incision. The corneal disc was unfolded with
balanced salt solution and air, and was
positioned against the recipient bed. The
position and centration of the AC IOL were
verified (fig 1). The anterior chamber was
filled 100% with air for 10 min, and then
50% of the air was exchanged with balanced
salt solution. At 1, 6 and 12 months postoperatively, a manifest refraction, best spectacle-corrected visual acuity, corneal
topography, manual keratometry, endothelial cell density (ECD), corneal pachymetry
and topography measurement using the
Pentacam
topographer
(Oculus
Inc,
Lynnwood, Washington) were performed.
Table 1 illustrates the preoperative data
and the 6-month and 12-month ECD for
each patient. As can be seen, the endothelial
survival rate is compatible with previous
reports showing 34% and 35% mean cell loss
at 6 months and 1 year postoperatively.4 No

Patient consent: Obtained.


Accepted 26 October 2008
Br J Ophthalmol 2009;93:557558.
doi:10.1136/bjo.2008.148148

REFERENCES
1.

2.

3.

4.

558

Johnson M, Gong H, Freddo TF, et al. Serum proteins


and aqueous outflow resistance in bovine eyes. Invest
Ophthalmol Vis Sci 1993;34:354957.
Gartner S, Henkind P. Neovasuclarization of
the iris (rubeosis iridis). Surv Ophthalmol
1978;22:291312.
Kubota T, Tawara A, Hata Y, et al. Neovascular tissue
in the intertrabecular spaces in eyes with neovascular
glaucoma. Br J Ophthalmol 1996;80:7504.
Oshima Y, Sakaguchi H, Gomi F, et al. Regression of
iris neovascularization after intravitreal injection of

Figure 1 One-month postoperative appearance of patient with Fuchs corneal dystrophy and
anterior chamber intraocular lens that underwent Descemet stripping automated endothelial
keratoplasty (DSAEK) surgery. The best-corrected visual acuity is 20/30. Arrows indicate the edge
of the DSAEK graft.
Br J Ophthalmol April 2009 Vol 93 No 4

Downloaded from bjo.bmj.com on 31 March 2009

PostScript
Table 1 Preoperative data and 6-month and 12-month endothelial cell densities (cells/m2)
Patient

Age
(years)

AC depth
(mm)
BSCVA

ECD 1 month
POP

ECD/% cell loss


6 months POP

ECD/% cell loss


12 months POP

IOP

1
2
3
Mean

73
67
59
66

3.2
3.1
3.4
3.2

1973
2065
1937
2005

1394/30
1466/29
1388/28
1416/29

1343/32
1409/33
1264/34
1338/33

17
19
14
16

20/40
20/25
20/30
20/30

AC depth, anterior chamber depth measured by Pentacam Scheimpflug image; BSCVA, best spectacle-corrected visual acuity;
ECD, endothelial cell density; IOP, intraocular pressure; POP, postoperative.

complications were reported in any of the


three cases.
Here we report three cases of Fuchs
endothelial dystrophy with AC IOL successfully treated with DSAEK with endothelial
survival rates similar to those previously
described in the literature for PC IOL. We
postulate that in cases of Fuchs dystrophy
with well-positioned AC IOL and AC depth
greater than 3 mm, DSAEK is a safe procedure that has good endothelial survival that
obviates the complications of IOL exchange.
The results mentioned above cannot be
correlated to pseudophakic bullous keratopathy cases with malpositioned or decentred
IOLs. In the later cases, the author recommends the standard approach of removal
and replacement of the lens with a scleral
fixated IOL. Further studies with longer
follow-up periods should be performed to
compare the endothelial cell loss over time in
this group as opposed to DSAEK with
posterior chamber lenses.
S Esquenazi1,2
1

Rand Eye Institute, Deerfield Beach, Florida, USA; 2 LSU Eye


and Neuroscience Center Louisiana State University, New
Orleans, Louisiana, USA
Correspondence to: Dr S Esquenazi, LSU Eye and
Neuroscience Center, 2020 Gravier Street, Suite D, 8th
Floor, New Orleans, LA 70112, USA; sesque@lsuhsc.edu
Funding: This work was supported by P20RR021970 (LSU
Translational COBRE Grant) from the National Institute of
Health (SE).
Competing interests: None.
Patient consent: Obtained.
Accepted 3 December 2008
Br J Ophthalmol 2009;93:558559.
doi:10.1136/bjo.2008.154914

REFERENCES
1.

2.

3.

4.

5.

Mearza AA, Qureshi MA, Rostron CK. Experience and


12 month results of Descemet stripping endothelial
keratoplasty with a small incision technique. Cornea
2007;26:27983.
Rao SK, Leung CKS, Cheung CYL, et al. Descemet
stripping endothelial keratoplasty: Effect of the
surgical procedure on corneal optics. Am J Ophthalmol
2008;145:9916.
Suh LH, Yoo SH, Deobhakta A, et al.
Complications of Descemets stripping with automated
endothelial keratoplasty. Ophthalmology
2008;115:151724.
Terry MA, Chen ES, Shamie N, et al. Endothelial cell
loss after Descemets stripping endothelial keratoplasty
in a large prospective series. Ophthalmology
2008;115:48896.
Price MO, Price FW Jr. Endothelial cell loss after
Descemet stripping with endothelial keratoplasty.
Ophthalmology 2008;115:85765.

Br J Ophthalmol April 2009 Vol 93 No 4

MAILBOX

Tobacco smoking influences on


eye diseases and vision
I read the article of Lois et al1 with great
interest. I believe, however, that at least in
some points it should be supplemented. My
recent survey2 concerning a similar subject,
which was limited to articles published in
the last 2 years, revealed more aspects of the
effects of tobacco smoking on the eye
physiology and pathology than presented
in the paper of Lois et al.

optical density is inversely related.6 Moreover,


it was observed that the concentration of
cadmium, an environmentally toxic trace
metal, is fourfold higher in the retinas of
smokers than in non-smokers. It was also
shown in in vitro studies that retinal pigment
epithelium cells exposed to cadmium showed
altered morphology, decreased cell survival,
elevated reactive oxygen species levels and
concentration-dependent disruption of membrane integrity.
In another recent study, the copper and
zinc distribution in the human retina was
studied. It was shown that the relative
tissue distribution of these metals was
highest in Bruch membrane-choroid, lower
in retinal pigment epithelium and the lowest
in neural retina. In addition, both copper
and zinc levels in males were positively
correlated with cadmium content, which
might influence the retinal antioxidant
balance and finally increase the risk of agerelated macular degeneration.

VISION AND CORTICAL FUNCTIONS


CYSTOID MACULAR OEDEMA
It has just been demonstrated that actively
smoking at presentation was associated
with a fourfold increased risk of cystoid
macular oedema (CMO) versus never smoking.3 Former smoking also increased the risk
of CMO, but the result was of borderline
statistical significance (p = 0.055).3 It was
calculated that there was a 4% increased risk
of CMO at presentation for each cigarette
smoked per day.3

RETINA AND OPTIC NERVE FUNCTION


It was shown in recent years that acute
exposure to cigarette smoking may stimulate the central retinal areas measured by the
increase of P1 amplitudes of multifocal
electroretinography (mfERG)4 and have stimulant effects of pattern visual-evoked
potentials (PERG).5 It was speculated that
this effect might be related to the stimulant
effect of nicotine on neurotransmission,
deleterious effects on retinal and/or choroidal circulation, carbon monoxide toxicity
and nicotine withdrawal.4

AGE-RELATED MACULAR DEGENERATION


PATHOPHYSIOLOGY
Several aspects of tobacco consumption and
age-related macular degeneration were
described in the article of Lois et al,1 however
some important results were not included. It
is known that macular pigment is composed
of the two dietary carotenoids, lutein and
zeaxanthin, which are believed to protect
against age-related maculopathy. It was
shown recently that smoking frequency for
the current smokers and macular pigment

Antenatal smoking was associated with


poor stereovision and the presence of esotropia7 It was also shown that even after a
15 min abstinence from smoking, smokers
exhibited compromised functional efficiency
in the right frontal eye field and adjacent
precentral sulcus in a test of selective
attention.8 Smoking ameliorated this condition.8
In conclusion, there is increasing evidence
that tobacco smoking is a risk factor in the
case of many eye diseases. However, the
underlying mechanisms of these effects are
not yet understood, so experimental studies
are needed to elucidate these problems in
future.
A Grzybowski1,2
1
Department of Ophthalmology, City Hospital, Poznan,
Poland; 2 Department of History of Medicine, Poznan
University of Medical Sciences, Poznan, Poland

Correspondence to: Dr A Grzybowski, Department of


Ophthalmology, Szwajcarska 6, 61-285 Poznan, Poland;
grzyb@am.poznan.pl
Competing interests: None.
Accepted 15 October 2008
Br J Ophthalmol 2009;93:559560.
doi:10.1136/bjo.2008.151902

REFERENCES
1.

2.

3.

Lois N, Abdelkader E, Reglitz K, et al.


Environmental tobacco smoke exposure
and eye disease. Br J Ophthalmol
2008;92:130410.
Grzybowski A. Wspoczesny stan wiedzy
na temat wpywu palenia tytoniu na choroby
narzadu wzroku [Present knowledge on the effects
of smoking tobacco on the eye diseases]. Przegl Lek.
In press.
Thorne JE, Daniel E, Jabs DA, et al.
Smoking as a risk factor for cystoid macular edema
complicating intermediate uveitis. Am J Ophthalmol
2008;145:8416.

559

Downloaded from bjo.bmj.com on 31 March 2009

Tobacco smoking influences on eye diseases and


vision
A Grzybowski
Br. J. Ophthalmol. 2009;93;559-560
doi:10.1136/bjo.2008.151902

Updated information and services can be found at:


http://bjo.bmj.com/cgi/content/full/93/4/559

These include:

References

This article cites 7 articles, 1 of which can be accessed free at:


http://bjo.bmj.com/cgi/content/full/93/4/559#BIBL

Rapid responses

You can respond to this article at:


http://bjo.bmj.com/cgi/eletter-submit/93/4/559

Email alerting
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Notes

To order reprints of this article go to:


http://journals.bmj.com/cgi/reprintform

To subscribe to British Journal of Ophthalmology go to:


http://journals.bmj.com/subscriptions/

Downloaded from bjo.bmj.com on 31 March 2009

PostScript
Table 1 Preoperative data and 6-month and 12-month endothelial cell densities (cells/m2)
Patient

Age
(years)

AC depth
(mm)
BSCVA

ECD 1 month
POP

ECD/% cell loss


6 months POP

ECD/% cell loss


12 months POP

IOP

1
2
3
Mean

73
67
59
66

3.2
3.1
3.4
3.2

1973
2065
1937
2005

1394/30
1466/29
1388/28
1416/29

1343/32
1409/33
1264/34
1338/33

17
19
14
16

20/40
20/25
20/30
20/30

AC depth, anterior chamber depth measured by Pentacam Scheimpflug image; BSCVA, best spectacle-corrected visual acuity;
ECD, endothelial cell density; IOP, intraocular pressure; POP, postoperative.

complications were reported in any of the


three cases.
Here we report three cases of Fuchs
endothelial dystrophy with AC IOL successfully treated with DSAEK with endothelial
survival rates similar to those previously
described in the literature for PC IOL. We
postulate that in cases of Fuchs dystrophy
with well-positioned AC IOL and AC depth
greater than 3 mm, DSAEK is a safe procedure that has good endothelial survival that
obviates the complications of IOL exchange.
The results mentioned above cannot be
correlated to pseudophakic bullous keratopathy cases with malpositioned or decentred
IOLs. In the later cases, the author recommends the standard approach of removal
and replacement of the lens with a scleral
fixated IOL. Further studies with longer
follow-up periods should be performed to
compare the endothelial cell loss over time in
this group as opposed to DSAEK with
posterior chamber lenses.
S Esquenazi1,2
1

Rand Eye Institute, Deerfield Beach, Florida, USA; 2 LSU Eye


and Neuroscience Center Louisiana State University, New
Orleans, Louisiana, USA
Correspondence to: Dr S Esquenazi, LSU Eye and
Neuroscience Center, 2020 Gravier Street, Suite D, 8th
Floor, New Orleans, LA 70112, USA; sesque@lsuhsc.edu
Funding: This work was supported by P20RR021970 (LSU
Translational COBRE Grant) from the National Institute of
Health (SE).
Competing interests: None.
Patient consent: Obtained.
Accepted 3 December 2008
Br J Ophthalmol 2009;93:558559.
doi:10.1136/bjo.2008.154914

REFERENCES
1.

2.

3.

4.

5.

Mearza AA, Qureshi MA, Rostron CK. Experience and


12 month results of Descemet stripping endothelial
keratoplasty with a small incision technique. Cornea
2007;26:27983.
Rao SK, Leung CKS, Cheung CYL, et al. Descemet
stripping endothelial keratoplasty: Effect of the
surgical procedure on corneal optics. Am J Ophthalmol
2008;145:9916.
Suh LH, Yoo SH, Deobhakta A, et al.
Complications of Descemets stripping with automated
endothelial keratoplasty. Ophthalmology
2008;115:151724.
Terry MA, Chen ES, Shamie N, et al. Endothelial cell
loss after Descemets stripping endothelial keratoplasty
in a large prospective series. Ophthalmology
2008;115:48896.
Price MO, Price FW Jr. Endothelial cell loss after
Descemet stripping with endothelial keratoplasty.
Ophthalmology 2008;115:85765.

Br J Ophthalmol April 2009 Vol 93 No 4

MAILBOX

Tobacco smoking influences on


eye diseases and vision
I read the article of Lois et al1 with great
interest. I believe, however, that at least in
some points it should be supplemented. My
recent survey2 concerning a similar subject,
which was limited to articles published in
the last 2 years, revealed more aspects of the
effects of tobacco smoking on the eye
physiology and pathology than presented
in the paper of Lois et al.

optical density is inversely related.6 Moreover,


it was observed that the concentration of
cadmium, an environmentally toxic trace
metal, is fourfold higher in the retinas of
smokers than in non-smokers. It was also
shown in in vitro studies that retinal pigment
epithelium cells exposed to cadmium showed
altered morphology, decreased cell survival,
elevated reactive oxygen species levels and
concentration-dependent disruption of membrane integrity.
In another recent study, the copper and
zinc distribution in the human retina was
studied. It was shown that the relative
tissue distribution of these metals was
highest in Bruch membrane-choroid, lower
in retinal pigment epithelium and the lowest
in neural retina. In addition, both copper
and zinc levels in males were positively
correlated with cadmium content, which
might influence the retinal antioxidant
balance and finally increase the risk of agerelated macular degeneration.

VISION AND CORTICAL FUNCTIONS


CYSTOID MACULAR OEDEMA
It has just been demonstrated that actively
smoking at presentation was associated
with a fourfold increased risk of cystoid
macular oedema (CMO) versus never smoking.3 Former smoking also increased the risk
of CMO, but the result was of borderline
statistical significance (p = 0.055).3 It was
calculated that there was a 4% increased risk
of CMO at presentation for each cigarette
smoked per day.3

RETINA AND OPTIC NERVE FUNCTION


It was shown in recent years that acute
exposure to cigarette smoking may stimulate the central retinal areas measured by the
increase of P1 amplitudes of multifocal
electroretinography (mfERG)4 and have stimulant effects of pattern visual-evoked
potentials (PERG).5 It was speculated that
this effect might be related to the stimulant
effect of nicotine on neurotransmission,
deleterious effects on retinal and/or choroidal circulation, carbon monoxide toxicity
and nicotine withdrawal.4

AGE-RELATED MACULAR DEGENERATION


PATHOPHYSIOLOGY
Several aspects of tobacco consumption and
age-related macular degeneration were
described in the article of Lois et al,1 however
some important results were not included. It
is known that macular pigment is composed
of the two dietary carotenoids, lutein and
zeaxanthin, which are believed to protect
against age-related maculopathy. It was
shown recently that smoking frequency for
the current smokers and macular pigment

Antenatal smoking was associated with


poor stereovision and the presence of esotropia7 It was also shown that even after a
15 min abstinence from smoking, smokers
exhibited compromised functional efficiency
in the right frontal eye field and adjacent
precentral sulcus in a test of selective
attention.8 Smoking ameliorated this condition.8
In conclusion, there is increasing evidence
that tobacco smoking is a risk factor in the
case of many eye diseases. However, the
underlying mechanisms of these effects are
not yet understood, so experimental studies
are needed to elucidate these problems in
future.
A Grzybowski1,2
1
Department of Ophthalmology, City Hospital, Poznan,
Poland; 2 Department of History of Medicine, Poznan
University of Medical Sciences, Poznan, Poland

Correspondence to: Dr A Grzybowski, Department of


Ophthalmology, Szwajcarska 6, 61-285 Poznan, Poland;
grzyb@am.poznan.pl
Competing interests: None.
Accepted 15 October 2008
Br J Ophthalmol 2009;93:559560.
doi:10.1136/bjo.2008.151902

REFERENCES
1.

2.

3.

Lois N, Abdelkader E, Reglitz K, et al.


Environmental tobacco smoke exposure
and eye disease. Br J Ophthalmol
2008;92:130410.
Grzybowski A. Wspoczesny stan wiedzy
na temat wpywu palenia tytoniu na choroby
narzadu wzroku [Present knowledge on the effects
of smoking tobacco on the eye diseases]. Przegl Lek.
In press.
Thorne JE, Daniel E, Jabs DA, et al.
Smoking as a risk factor for cystoid macular edema
complicating intermediate uveitis. Am J Ophthalmol
2008;145:8416.

559

Downloaded from bjo.bmj.com on 31 March 2009

PostScript
4.

5.

560

Gundogan FC, Erdurman C, Durukan AH, et al.


Acute effects of cigarette smoking on multifocal
electroretinogram. Clin Exp Ophthalmol
2007;35:327.
Gundogan FC, Durukan AH, Mumcuoglu T, et al.
Acute effects of cigarette smoking on pattern
electroretinogram. Doc Ophthalmol 2006;113:11521.

6.

7.

Nolan JM, Stack J, O Donovan O, et al. Risk factors


for age-related maculopathy are associated with a
relative lack of macular pigment. Exp Eye Res
2007;84:6174.
Ponsonby AL, Brown SA, Kearns LS, et al. The
association between maternal smoking in pregnancy,
other early life characteristics and childhood vision: the

8.

Twins Eye Study in Tasmania. Ophthalmic Epidemiol


2007;14:3519.
Xu J, Mendrek A, Cohen MS, et al.
Effect of cigarette smoking on prefrontal cortical
function in nondeprived smokers performing the
Stroop Task. Neuropsychopharmacology
2007;32:14218.

Br J Ophthalmol April 2009 Vol 93 No 4