1. No category

Novel treatment (new drug/intervention; established drug/procedure in new situation)
Chronic cystoid macular oedema treated with intravitreal
dobesilate
Pedro Cuevas,1 Luis A Outeiriño,2 Javier Angulo,1 Guillermo Giménez-Gallego3
1
Department of Research, Hospital Ramon y Cajal, Madrid, Spain
Department of Ophthalmology, Hospital de Día Pio XII, Madrid, Spain
Department of Qiimica de Proteinas, Centro de Investigaciones Biológicas, Madrid, Spain
2
3
Correspondence to Professor Pedro Cuevas, pedro.cuevas@hrc.es
Summary
Dobesilate is an anti-inflammatory and antipermeability agent. Intravitreal administration of this compound is a therapeutically beneficial
agent in the treatment of chronic cystoid macular oedema.
CASE PRESENTATION
A 75-year-old woman, who underwent bilateral cataract
surgery 2 years ago, presented with a 6-month history of
poor vision, and referred a great reduction of visual acuity
in her right phakic eye. Ophthalmic examination includes
best-corrected Snellen visual acuity test and optical coherence tomography (OCT). Visual acuity was 0.05 and OCT
scan showed typical features of cystoid macular oedema
(CME) (figure 1A). After approval of our Institution
Ethical Committee, the patient signed an informed
consent form, which included a comprehensive description
of dobesilate and the proposed procedure. The patient
received an intravitreal solution of dobesilate (150 μl)
under sterile conditions, following the International
Guidelines for intravitreal injections1 in her right eye.
Dobesilate was administered as a 12.5% solution of diethylammonium 2.5-dihydroxybenzenesulphonate (etamsylate; Dicynone Sanofi-Aventis, Paris, France). After 6 days
of treatment vision acuity was improved (0.4) and the
structural changes in the fovea resolved with resolution of
the intraretinal cystic spaces (figure 1B). Intraocular pressure was 14 mm Hg before treatment, raised to 28 mm Hg
after 2 min of injection and returned to baseline 24 h after.
No ocular side effects were observed during treatment. The
patient was clinically stable on a 10-week follow-up after
injection.
Different approaches, medical and surgical, are currently
used in treating CME.6 Many studies have shown an association between CME and inflammation.7 8 For this reason,
CME is commonly treated with anti-inflammatory agents.
Corticosteroids are, indeed, effective in CME prevention
and treatment,9 but are associated with serious side effects,
including elevate ocular pressure, posterior subcapsular
cataract and exacerbation of an increased susceptibility to
DISCUSSION
CME is a common cause of visual loss that is the result of
cystic accumulation of extracellular intraretinal fluid predominantly in the outer plexiform and inner nuclear
layers of the retina, as a result of the breakdown of the
blood retinal barrier.2 Common causes of CME are postsurgical (cataract, glaucoma and laser surgeries), intraocular inflammatory diseases, medications, diabetic
retinopathy, genetic chorioretinal dystrophy (choroideraemia) and retinal vein occlusions.3 4 Acute CME, defined as
oedema of less than 4 months duration, often resolved
spontaneously, while CME that persists for 4 months or
more is termed as chronic.5
BMJ Case Reports 2012; doi:10.1136/bcr-2012-006376
Figure 1 Effect of the intravitreal administration of dobesilate in
cystoid macular oedema (CME). Optical coherence tomography
(OCT) was used before and after treatment to determine the
presence of CME. OCT signs of macular oedema were observed
before treatment (A). Resolution of macular oedema was depicted
in OCT scan after six days of treatment (B). Horizontal arrows
indicate the localisation of the performed OCT scans.
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concomitant infections.10 Thus, safer alternative treatments of CME are desirable. The inflammasome, a pathogen and danger-sensing system triggering innate immunity,
involves the interaction of immune and tissue cells, as well
as the production and release of cytokines and growth
factors by the different cell types.11 Sometimes a feedback
mechanism resulting from an over-reaction causes acute
inflammation to become chronic, with the subsequent
alteration of organs and tissues. In these cases, the suppression of the innate immune response is an inevitable therapeutic objective. The fibroblast growth factor (FGF) is one
of the participants of the inflammosome.11 Gene expression of FGF-stimulated endothelial cells shows, together
with a prominent proangiogenic profile, a proinflammatory
signature characterised by the upregulation of proinflammatory cytokines/chemokines and their receptors, endothelial cell adhesion molecules and members of the
eicosanoid pathway.12 Furthermore, upregulation of FGF
was associated with an increase in the vascular permeability.13 Thus, inhibition of FGF signals could constitute a
therapeutic strategy for attenuating excessive or chronic
inflammatory responses.
The rapid resolution of CME after intravitreal administration of dobesilate, a synthetic FGF inhibitor14 with
important antipermeability15 and anti-inflammatory
activities16 is presented in this case report. Normalising
the histological structure of the retina was parallel to a
considerable improvement of visual acuity.
The use of dobesilate to treat ocular diseases caused by
an excess of angiogenesis has been repeatedly proposed.
Nevertheless, a careful clinical study recently published
was unable to show that the use of this drug has any significant therapeutic advantage for treating these diseases.17 In this respect it is necessary to remark that, in
that study, dobesilate was orally administered as a calcium
salt that is very insoluble at the stomach pH, and that it
readily oxidises (and inactivates) once it dissolves when it
encounters more alkaline regions of the digestive system.
All these limitations in our study are overcome by the
direct application to the vitreous of a soluble salt of
2.5-dihydroxybenzenesulfonate.
Competing interests None.
Patient consent Obtained.
REFERENCES
1. Aiello LP, Brucker AJ, Chang S, et al. Evolving guidelines for intravitreous
injections. Retina 2004;24:S3–19.
2. Quinn CJ. Cystoid macular edema. Optom Clin 1996;5:111–30.
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Volume 2. St. Louis, USA: Mosby 1994;61:999–1008.
4. Genead MA, Fishman GA. Cystic macular oedema on spectral-domain
optical coherence tomography in choroideremia patients without cystic
changes on fundus examination. Eye (Lond). 2011;25:84–90.
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agents for treating cystoid macular oedema following cataract surgery.
Cochrane Database Syst Rev 2012;2:CD004239.
6. Hariprasad SM, Akduman L, Clever JA, et al. Treatment of cystoid macular
edema with the new-generation NSAID nepafenac 0.1%. Clin Ophthalmol
2009;3:147–54.
7. Flach AJ. The incidence, pathogenesis and treatment of cystoid macular
edema following cataract surgery. Trans Am Ophthalmol Soc
1998;96:557–634.
8. Gulkilik G, Kocabora S, Taskapili M, et al. Cystoid macular edema after
phacoemulsification: risk factors and effect on visual acuity. Can J Ophthalmol
2006;41:699–703.
9. Heier JS, Topping TM, Baumann W, et al. Ketorolac versus prednisolone
versus combination therapy in the treatment of acute pseudophakic cystoid
macular edema. Ophthalmology 2000;107:2034–8.
10. Choi JY, Buzney SM, Weiter JJ. Cystoid macular edema: current modes of
therapy. Int Ophthalmol Clin 2005;45:143–51.
11. Strowig T, Henao-Mejía J, Elinav E, et al. Inflammosomes in health and
disease. Nature 2012;481:278–96.
12. Andrés G, Leali D, Mitola S, et al. A pro-inflammatory signatura mediates
FGF2-induced angiogenesis. J Cell Mol Med 2009;13:2083–108.
13. Kaga T, Kawano H, Sakaguchi M, et al. Hepatocyte growth factor stimulated
angiogenesis without inflammation: differential actions between hepatocyte
growth factor, vascular endothelial growth factor and basic fibroblast growth
factor. Vascul Pharmacol 2012;57:3–9.
14. Fernández IS, Cuevas P, Angulo J, et al. Gentisic acid, a compound
associated with plant defence and a metabolite of aspirin, heads a new class
of in vivo FGF inhibitor. J Biol Chem 2010;285:1714–29.
15. Angulo J, Peiró C, Romacho T, et al. Inhibition of vascular endothelial growth
factor (VEGF)-induced endothelial proliferation, arterial relaxation, vascular
permeability and angiogenesis by dobesilate. Eur J Pharmacol
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16. Cuevas P, Outeiriño LA, Angulo J, et al. Treatment of dry age-related macular
degeneration with dobesilate. BMJ Case Report 2012;10.1136/bcr.02.2012.
5942, Published 22 June.
17. Haritoglou C, Gerss J, Sauerland C, et al. CALDIRET study group. Effect of
calcium dobesilate on occurrence of diabetic macular oedema (CALDIRECT
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2009;373:1364–71.
Learning points
▸ Cystoid macular oedema (CME) is a common cause of
visual loss that is the result of cystic accumulation of
intraretinal fluid.
▸ Many studies have shown an association between
CME and inflammation.
▸ Corticosteroids have been used in the treatment of
CME, but are associated with serious ocular side
effects.
▸ Fibroblast growth factor (FGF) has been implicated in
inflammation.
▸ Dobesilate, a synthetic FGF inhibitor, may offer a
therapeutic benefit in macular oedema through its
anti-inflammatory and antipermeability activities.
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BMJ Case Reports 2012; doi:10.1136/bcr-2012-006376
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Cuevas P, Outeiriño LA, Angulo J, Giménez-Gallego G. Chronic cystoid macular oedema treated with intravitreal dobesilate. BMJ Case Reports 2012;
10.1136/bcr-2012-006376, Published XXX
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