Escolar Documentos
Profissional Documentos
Cultura Documentos
Clinical science
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.
Clinical science
Acknowledgements: The authors thank M Amschl, C Hirn and G Stock for
performing fluorescein angiograms.
Competing interests: None declared.
11.
12.
13.
REFERENCES
14.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
456
Cugati S, Wang JJ, Rochtchina E, et al. Ten-year incidence of retinal vein occlusion
in an older population: the Blue Mountains Eye Study. Arch Ophthalmol
2006;124:72632.
Hayreh SS, Zimmerman B, McCarthy MJ, et al. Systemic diseases associated with
various types of retinal vein occlusion. Am J Ophthalmol 2001;131:6177.
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
control study. Ophthalmology 1992;99:50914.
Koizumi H, Ferrara DC, Brue` C, et al. Central vein occlusion casecontrol study.
Am J Ophthalmol 2007;144:85863.
Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid
of patients with diabetic retinopathy and other retinal disorders. N Engl J Med
1994;331:14807.
Branch Vein Occlusion Study Group. Argon laser photocoagulation for macular
edema in branch vein occlusion. Am J Ophthalmol 1984;98:27182.
The Central Vein Occlusion Study Group. Evaluation of grid pattern
photocoagulation for macular edema in central vein occlusion. The Central Vein
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.
Am J Ophthalmol 2005;140:695702.
Karacorlu M, Karacorlu SA, Ozdemir H, et al. Intravitreal triamcinolone acetonide for
treatment of serous macular detachment in central vein occlusion. Retina
2007;27:102630.
15.
16.
17.
18.
19.
20.
21.
22.
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.
These include:
References
Rapid responses
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
Clinical science
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.
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
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.
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
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
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
1
2
3
4
5
6
7
8
Pain
Case no
Table 2
Yes
Yes
No
Yes
Yes
No
Yes
Yes
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
Clinical science
459
Clinical science
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).
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
Report of case 8
Response to treatment
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
Clinical science
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
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
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
Heier JS, Antoszyk AN, Pavan PR, et al. Ranibizumab for treatment of neovascular
age-related macular degeneration: a phase I/II multicenter, controlled, multidose
study. Ophthalmology 2006;113:642e14.
Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related
macular degeneration. N Engl J Med 2006;355:141931.
Adamis AP, Altaweel M, Bressler NM, et al. Changes in retinal neovascularization
after pegaptanib (Macugen) therapy in diabetic individuals. Ophthalmology
2006;113:238.
Pieramici DJ, Avery RL. Ranibizumab: treatment in patients with neovascular agerelated macular degeneration. Expert Opin Biol Ther 2006;6:123745.
Rosenfeld PJ, Rich RM, Lalwani GA. Ranibizumab: Phase III clinical trial results.
Ophthalmol Clin North Am 2006;19:36172.
Gillies MC. What we dont know about avastin might hurt us. Arch Ophthalmol
2006;124:14789.
Avery RL, Pieramici DJ, Rabena MD, et al. Intravitreal bevacizumab (Avastin) for
neovascular age-related macular degeneration. Ophthalmology 2006;113:36372e5.
Arevalo JF, Fromow-Guerra J, Quiroz-Mercado H, et al. Primary intravitreal
bevacizumab (Avastin) for diabetic macular edema: results from the Pan-American
Collaborative Retina Study Group at 6-month follow-up. Ophthalmology
2007;114:74350.
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.
Kiss C, Michels S, Prager F, et al. Evaluation of anterior chamber inflammatory
activity in eyes treated with intravitreal bevacizumab. Retina 2006;26:87781.
Aiello LP, Brucker AJ, Chang S, et al. Evolving guidelines for intravitreous injections.
Retina 2004;24(5 Suppl):319S.
Ta CN. Minimizing the risk of endophthalmitis following intravitreous injections.
Retina 2004;24:699705.
Jager RD, Aiello LP, Patel SC, et al. Risks of intravitreous injection: a comprehensive
review. Retina 2004;24:67698.
Pieramici DJ, Avery RL, Castellarin AA, et al. Case of anterior uveitis after
intravitreal injection of bevacizumab. Retina 2006;26:8412.
Aggio FB, Farah ME, de Melo GB, et al. Acute endophthalmitis following intravitreal
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
neovascularization secondary to age-related macular degeneration. Retina
2006;26:38390.
Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of uveitis nomenclature
for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol
2005;140:50916.
These include:
References
Rapid responses
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
Clinical science
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.
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
Br J Ophthalmol 2009;93:463467. doi:10.1136/bjo.2008.138453
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
Yes = 32
No = 34
Yes = 2
No = 73
Data NA = 27
Data NA = 18
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.
465
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
REFERENCES
1.
2.
3.
4.
Clinical science
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
Access all our original articles online even before they appear in a print issue!
Online First is an exciting innovation that allows the latest clinical research papers to go from
acceptance to your browser within days, keeping you at the cutting edge of medicine.
Simply follow the Online First link on the homepage and read the latest Online First articles that are
available as unedited manuscripts in downloadable PDF form. The articles are peer reviewed, accepted
for publication and indexed by PubMed but not yet included in a journal issue, so youll be among the
first to read them!
467
These include:
References
Rapid responses
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
Clinical science
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.
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
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.
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
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
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
Clinical science
Table 2 Mean best-corrected visual acuity and contrast sensitivity at specified time points
Month
Baseline
12
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
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
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
Clinical science
Table 4 Reasons for failure to complete follow-up at 12 and 24 months from baseline
Period (months)
012
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.
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
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
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy: the Beaver Dam
Eye Study. Ophthalmology 1992;99:93343.
Vingerling JR, Dielemans I, Hofman A, et al. The prevalence of age-related
maculopathy in the Rotterdam study. Ophthalmology 1995;102:20510.
Bressler NM, Bressler SB, Fine SL. Age-related macular degeneration. Surv
Ophthalmol 1988;32:375413.
TAP study group. Photodynamic therapy of subfoveal choroidal neovascularisation in
age-related macular degeneration with verteporfin: one-year results of 2 randomised
clinical trials. TAP report 1. Arch Ophthalmol 1999;117:123945.
TAP study group. Photodynamic therapy of subfoveal choroidal neovascularisation in
age-related macular degeneration with verteporfin: two-year results of 2 randomised
clinical trials. TAP report 2. Arch Ophthalmol 2001;119:198207.
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.
473
These include:
References
Rapid responses
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
Clinical science
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.
Clinical science
Figure 1
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
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
Clinical science
476
Figure 4
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
These include:
References
Rapid responses
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
Clinical science
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.
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
Clinical science
Table 1 Clinical characteristics of 29 patients with intermediate uveitis
and a follow-up of at least 10 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)
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)
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)
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
Clinical science
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
1.
2.
3.
4.
5.
480
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
These include:
References
Rapid responses
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
Clinical science
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.
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
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
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
Br J Ophthalmol 2009;93:481485. doi:10.1136/bjo.2008.147322
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
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,
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.
483
Clinical science
Table 2 Intraocular pressure (IOP) reduction from baseline (mm Hg)
Time points
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)
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)
484
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.
1.
2.
Barnebey HS, Orengo-Nania S, Flowers BE, et al. The safety and efficacy of
travoprost 0.004%/timolol 0.5% fixed combination ophthalmic solution.
Am J Ophthalmol 2005;140:17.
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.
21.
485
These include:
References
Rapid responses
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
Clinical science
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
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.
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
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
487
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)*
488
Clinical science
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
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
Clinical science
Competing interests: None.
11.
Ethics approval: Ethics approval was provided by the Ethics Committee of the
Medical University of Vienna.
12.
REFERENCES
13.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
491
These include:
References
Rapid responses
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
Clinical science
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.
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.
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
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.
493
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
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 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
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) (%)
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.
495
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.
REFERENCES
1.
2.
3.
496
Azuara BA, Burr JM, Thomas R, et al. The accuracy of accredited glaucoma
optometrists in the diagnosis and treatment recommendation for glaucoma.
Br J Ophthalmol 2007;91:193943.
Rudnicka AR, Mt-Isa S, Owen CG, et al. Variations in primary open-angle glaucoma
prevalence by age, gender, and race: a Bayesian meta-analysis. Invest Ophthalmol Vis
Sci 2006;47:425461.
Fraser S, Bunce C, Wormald R. Risk factors for late presentation in chronic
glaucoma. Invest Ophthalmol Vis Sci 1999;40:22517.
27.
28.
29.
Harper RA, Reeves BC. Glaucoma screening: the importance of combining test data.
Optom Vis Sci 1999;76:53743.
College of Optometrists. Common eye diseases & problems. www.collegeoptometrists.org/index.aspx/pcms/site.Public_Related_Links.
Common_Eye_Diseases_and_Problems.Glaucoma/ (accessed 13 November 2008).
College of Optometrists. What happens in an eye examination? www.collegeoptometrists.org/index.aspx/pcms/site.Public_Related_Links.The_eye_examination.
What_Happens_in_/ (accessed 13 November 2008)
Association of Optometrists. The eye examination. www.assoc-optometrists.org
(accessed 25 April 2008)
Bowling B, Chen SD, Salmon JF. Outcomes of referrals by community optometrists
to a hospital glaucoma service. Br J Ophthalmol 2005;89:11024.
Vernon SA, Ghosh G. Do locally agreed guidelines for optometrists concerning the
referral of glaucoma suspects influence referral practice? Eye 2001;15:45863.
General Optical Council. Annual Report 2006/7. 2008; 12 August.
Blakeney SL. Clinical practice survey. In Focus: Newsletter of College of
Optometrists 2002;80:710.
Shah R, Edgar D, Evans BJ. Measuring clinical practice. Ophthalmic Physiol Opt
2007;27:11325.
Adamo G. Simulated and standardized patients in OSCEs: achievements and
challenges 19922003. Med Teach 2003;25:26270.
Ebbert DW, Connors H. Standardized patient experiences: evaluation of clinical
performance and nurse practitioner student satisfaction. Nurs Educ Perspect
2004;25:125.
College of Optometrists. Code of ethics and guidelines for professional conduct.
www.college-optometrists.org/index.aspx/pcms/site.publication.Ethics_Guidelines.
recent/ (accessed 13 November 2008).
World Medical Association. Declaration of Helsinki. www.wma.net/e/policy/b3.
htm (accessed 13 November 2008)
Bachmann MO, Colvin MS, Nsibande D, et al. Quality of primary care for sexually
transmitted diseases in Durban, South Africa: influences of patient, nurse,
organizational and socioeconomic characteristics. Int J STD AIDS 2004;15:38894.
Shah R, Edgar D, Rabbetts RB, et al. The content of optometric eye examinations for
a young myope with headaches. Ophthalmic Physiol Opt 2008;28:40421.
Shah R, Edgar D, Harle DE, et al. The content of optometric eye examinations for a
presbyopic patient presenting with recent onset flashing lights. Ophthalmic Physiol
Opt 2009;29:10526.
OLeary CI, Evans BJ. Criteria for prescribing optometric interventions: literature
review and practitioner survey. Ophthalmic Physiol Opt 2003;23:42939.
Willis CE, Rankin SJ, Jackson AJ. Glaucoma in optometric practice: a survey of
optometrists. Ophthalmic Physiol Opt 2000;20:705.
Medix UK & The College of Optometrists. The College of Optometrists Clinical
Practice Survey: Market Research Report. London: Medix UK, 2008
Weinreb RN, Khaw PT. Primary open-angle glaucoma. Lancet 2004;363:171120.
Vernon SA. The changing pattern of glaucoma referrals by optometrists. Eye
1998;12:8547.
Henson DB, Spencer AF, Harper R, et al. Community refinement of glaucoma
referrals. Eye 2003;17:216.
Salmon NJ, Terry HP, Farmery AD, et al. An analysis of patients discharged from a
hospital-based glaucoma case-finding clinic over a 3-year period. Ophthalmic Physiol
Opt 2007;27:399403.
Association of Optometrists. General ophthalmic services (GOS) in Wales and
Scotland. www.aop.org.uk/1189009433380.html (accessed 13 November 2008).
Ang GS, Ng WS, Azuara BA. The influence of the new general ophthalmic services
(GOS) contract in optometrist referrals for glaucoma in Scotland. Eye 2007;30:15.
Ramsey PG, Curtis JR, Paauw DS, et al. History-taking and preventive medicine skills
among primary care physicians: an assessment using standardized patients. Am J Med
1998;104:1528.
These include:
References
Rapid responses
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
Clinical science
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.
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.
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)
Clinical science
Table 3 Percentage of patients with successfully controlled intraocular pressure in study eye
Follow-up
Latanoprost (%)
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.
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
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
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
REFERENCES
1.
2.
3.
4.
5.
Clinical science
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Ashburn FS, Goldberg I, Kass MA. Compliance with ocular therapy. Surv Ophthalmol
1980;24:23748.
Medeiros FA, Pinheiro A, Moura FC, et al. Intraocular pressure fluctuation in medical
versus surgically treated glaucomatous patients. J Ocul Pharmacol Ther
2002;18:48998.
Latina MA, Leon JM. Selective laser trabeculoplasty. Ophthalmol Clin N Am
2005;182:40919.
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.
16.
17.
18.
19.
20.
21.
22.
23.
501
These include:
References
Rapid responses
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
Clinical science
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.
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.
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
503
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
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
504
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.
19.
REFERENCES
1.
2.
3.
4.
5.
Cibis PA, Becker B, Okun E, et al. The use of liquid silicone in retinal detachment
surgery. Arch Ophthalmol 1962;68:5909.
Brourman ND, Blumenkranz MS, Cox MS, et al. Silicone oil for the treatment of
severe proliferative diabetic retinopathy. Ophthalmology 1989;96:75964.
Gonvers M. Temporary silicone oil tamponade in the treatment of complicated
retinal detachments. Grafes Arch Clin Exp Ophthalmol 1990;228:41522.
Spiegel D, Nasemann J, Nawrocki J, et al. Severe ocular trauma managed with
primary pars plana vitrectomy and silicone oil. Retina 1997;17:275285.
Baer RM, Aylward WG, Leaver PK. Cataract extraction following vitrectomy and
silicone oil tamponade. Eye 1995;70:3826.
20.
21.
22.
23.
24.
25.
Larkin GB, Flaxel CJ, Leaver PK. Phacoemulsification and silicone oil removal through
a single corneal incision. Ophthalmology 1998;105:20237.
Assi A, Woodruff S, Gotzaridis E, et al. Combined phacoemulsification and
transpupillary drainage of silicone oil:results and complications. Br J Ophthalmol
2001;85:9425.
Ghoraba HH, El-Dorghamy AA, Atia AF, et al. The problems of biometry in combined
silicone oil removal and cataract extraction. A clinical trial. Retina 2002;22:589596.
Byrne SF. A-scan axial eye length measurementsa handbook for IOL calculations.
Mars Hill, NC: Grove Park Publishers, 1995.
Shammas HJ. IOL power Calculationsavoiding the errors. Glendale, CA: News
Circle Publishing, 1996.
Haigis W, Lege B, Miller N, et al. Comparison of immersion ultrasound biometry and
partial coherence interferometry for intraocular lens calculation according to Haigis.
Graefes Arch Clin Exp Ophthalmol 2000;238:76573.
Rajan MS, Keilhorn I, Bell JA. Partial coherence laser interferometry vs. conventional
biometry in intraocular lens power calculations. Eye 2002;16:5526.
Findl O, Drexler W, Menapace R, et al. Optical biometry in cataract surgery. In:
Kohnen T, ed. Modern cataract surgery. Basel: Karger, 2002:13140.
Hitzenberger CK, Drexler W, Dolezal C, et al. Measurement of the axial length of
cataract eyes by laser Doppler interferometry. Invest Ophthalmol Vis Sci
1993;34:188693.
Nepp J, Krepler K, Jandrasits K, et al. Biometry and refractive outcome of eyes filled
with silicone oil by standardized echography and partial coherence interferometry.
Graefes Arch Clin Exp Ophthalmol 2005;243:96772.
Takei K, Sekine Y, Okamoto F, et al. Measurement of axial length of eyes with
incomplete filling of silicone oil in the vitreous cavity using x-ray computed
tomography. Br J Ophthalmol 2002;86:4750.
Altman DG. Practical statistics for medical research. London: Chapman and Hall,
2000:456.
Murray DC, Potamitis T, Good P, et al. Biometry of the silicone oil-filled eye. Eye
1999;13:319324.
Smiddy WE, Loupe DN, Michels RG, et al. Refractive changes after scleral buckling
surgery. Arch Ophthalmol 1989;107:146971.
Malukiewicz A, Wismewska G, Stafiej J. Changes in axial length after retinal
detachment surgery. Eur J Ophthalmol 1999;9:115119.
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
lens power calculation at silicone oil removal. Eur J Ophthalmol 2003;13:6226.
Haigis W. Optische Biometrie als Alternative zur Ultraschallbiometrie. In:
Sonderdruck der Ophthalmo-Chirurgie. Heidelberg: Kaden-Verlag, 2000;12:7580.
Murray DC, Durrami OM, Good P, et al. Biometry of the silicone oil-filled eye: II. Eye
2002;16:727730.
Habibababi HF, Hashemi H, Jalali KH, et al. Refractive outcome of silicone oil
removal and intraocular lens implantation using laser interferometry. Retina
2005;25:1626.
505
These include:
References
Rapid responses
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
Clinical science
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.
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
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).
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
507
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.
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.
BMJ Masterclasses
BMJ Masterclasses are educational meetings designed specifically to meet the learning needs of
doctors. They help doctors keep up to date with the latest evidence and recent guidelines in major
clinical areas, enabling them to use the latest evidence to make better decisions. The latest evidence,
recent guidelines and best practice are delivered in an interactive and informative manner by leading
experts. The speakers are specifically chosen as highly-skilled communicators who can authoritatively
enthuse the audience and interpret the latest research and guidelines into practical tips for busy
doctors. BMJ Masterclasses have proved a huge hit with clinicians, with many saying they have
influenced their clinical practice.
http://masterclasses.bmj.com/
509
These include:
References
Rapid responses
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
Clinical science
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.
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
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?
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
Clinical science
(97%); flashes of light (86%); movement (96%); instruments
(81%); surgeons hands or fingers (65%); surgeon (51%); and
changes in light brightness (95%).
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.
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.
These include:
References
Rapid responses
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
Clinical science
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.
Clinical science
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
Group
Symptoms
Papilla
Cornea
F0
F1
F2
Sporadic
Frequent
Constant
P0P1
P2
P3
Normal
Occasional SPK
Severe SPK, ulcer
Table 2
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
Clinical science
Figure 4
DISCUSSION
Figure 5
Figure 6
Figure 7
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.
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
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
517
These include:
References
Rapid responses
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
Clinical science
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.
Clinical science
Pascal photocoagulation system
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.
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
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
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
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.
519
Clinical science
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
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
Br J Ophthalmol 2009;93:518525. doi:10.1136/bjo.2008.148833
Clinical science
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%).
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
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
Clinical science
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
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.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
525
These include:
References
Rapid responses
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
Clinical science
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.
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.
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.
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
39 (33 to 42)
38 (27 to 41)
40 (35 to 42)
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.
527
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
Hydrocephalus
Controls
p Value
0.01
NS
0.002
,0.001
,0.001
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 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).
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
FEBS Lett
et al
Exp Eye Res
J Biol Chem
Apoptosis
et al
et al
FASEB J
et al
J Biol Chem
Br J Ophthalmol
Education
Br. J. Ophthalmol. 2009;93;545
doi:10.1136/bjo.2008.144303a
These include:
References
Rapid responses
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
Education
ANSWERS
From questions on page 423
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
These include:
References
Rapid responses
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
Innovations
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.
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
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
26
22
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
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.
Education
ANSWERS
From questions on page 422
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.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Education
Br. J. Ophthalmol. 2009;93;548
doi:10.1136/bjo.2007.129510a
These include:
References
Rapid responses
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
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.
Education
ANSWERS
From questions on page 422
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.
4.
5.
6.
7.
8.
9.
10.
11.
12.
These include:
References
Rapid responses
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
PostScript
LETTERS
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.
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
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
549
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.
METHODS
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.
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
These include:
Rapid responses
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
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.
METHODS
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.
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
PostScript
REFERENCES
1.
2.
3.
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
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
COMMENTS
Studies have assessed compliance with treatments for diabetes, asthma, anticoagulation
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
These include:
References
Rapid responses
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
PostScript
REFERENCES
1.
2.
3.
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
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
COMMENTS
Studies have assessed compliance with treatments for diabetes, asthma, anticoagulation
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
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
REFERENCES
1.
2.
3.
4.
5.
6.
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.
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.
No
SD
Ranibizumab
Bevacizumab
Pegabtanib
29
25
3
8.04
5.33
8.18
8.99
2.31
5.72
These include:
Rapid responses
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
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
REFERENCES
1.
2.
3.
4.
5.
6.
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.
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.
No
SD
Ranibizumab
Bevacizumab
Pegabtanib
29
25
3
8.04
5.33
8.18
8.99
2.31
5.72
PostScript
4.
5.
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%
553
These include:
References
Rapid responses
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
PostScript
4.
5.
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%
553
PostScript
Accepted 24 September 2008
Br J Ophthalmol 2009;93:553554.
doi:10.1136/bjo.2008.144790
REFERENCES
1.
2.
3.
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
These include:
References
Rapid responses
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
PostScript
Accepted 24 September 2008
Br J Ophthalmol 2009;93:553554.
doi:10.1136/bjo.2008.144790
REFERENCES
1.
2.
3.
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
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
REFERENCES
1.
555
PostScript
2.
3.
4.
5.
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
Age
Gender
Leucocoria
FH
PMH
POH
F&M
RefError
VA
CT
OM
BV
1y 9m
Alternating
RetPig
Equal
NAD
Full
+ve
4y 6m
Right
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
These include:
References
Rapid responses
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
PostScript
2.
3.
4.
5.
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
Age
Gender
Leucocoria
FH
PMH
POH
F&M
RefError
VA
CT
OM
BV
1y 9m
Alternating
RetPig
Equal
NAD
Full
+ve
4y 6m
Right
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
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
REFERENCES
1.
2.
3.
4.
5.
6.
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
These include:
References
Rapid responses
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
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
REFERENCES
1.
2.
3.
4.
5.
6.
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
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
5.
6.
REFERENCES
1.
2.
3.
4.
558
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
These include:
Rapid responses
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
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
5.
6.
REFERENCES
1.
2.
3.
4.
558
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
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
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.
REFERENCES
1.
2.
3.
4.
5.
MAILBOX
REFERENCES
1.
2.
3.
559
These include:
References
Rapid responses
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
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
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.
REFERENCES
1.
2.
3.
4.
5.
MAILBOX
REFERENCES
1.
2.
3.
559
PostScript
4.
5.
560
6.
7.
8.