Enrique Cervera

Beneficial Effect of Docosahexanoic Acid and Lutein on Retinal Structural, Metabolic, and Functional Abnormalities in Diabetic Rats

Purpose: To assess the effect of docosahexanoic acid (DHA) and lutein (both compounds with anti-inflammatory and antioxidant properties) on experimental diabetic retinopathy. Methods: Male Wistar rats were studied: non-diabetic controls, untreated diabetic controls, and diabetic rats were treated with DHA and lutein or the combination of DHA + insulin and lutein + insulin for 12 weeks. Oxidative stress and inflammatory markers, apoptosis, and functional tests were studied to confirm biochemical and functional changes in the retina of diabetic rats. Malondialdehyde (MDA), glutathione concentrations (GSH), and glutathione peroxidase activity (GPx) were measured as oxidative stress markers. TUNEL assay and caspase-3 immunohistochemistry and electroretinogram were performed. Results: Diabetes increases oxidative stress, nitrotyrosine concentrations, and apoptosis in the retina. At 12 weeks after onset of diabetes, total thickness of retinas of diabetic rats was significantly less than that in control rats. Specifically, the thickness of the outer and inner nuclear layers was reduced significantly in diabetic rats and demonstrated a loss of cells in the GCL. These retinal changes were avoided by the administration of insulin and DHA and lutein alone or in combination with insulin. Impairment of the electroretinogram (b-wave amplitude and latency time) was observed in diabetic rats. DHA and lutein prevented all these changes even under hyperglycemic conditions. Conclusions: Lutein and DHA are capable of normalizing all the diabetes-induced biochemical, histological, and functional modifications. Specifically, the cell death mechanisms involved deserve further studies to allow the proposal as potential adjuvant therapies to help prevent vision loss in diabetic patients.

Intravitreal bevacizumab (Avastin) for choroidal metastasis secondary to breast carcinoma: short-term follow-up.

Intravitreal bevacizumab (Avastin) for choroidal metastasis secondary to breast carcinoma: short-term follow-up

Retinal pigment epithelial tear following ranibizumab use.

Retinal pigment epithelium (RPE) tears are a major complication in patients with pigment epithelial detachments (PED) secondary to exudative age-related macular degeneration (ARMD). They also occur following treatment of PEDs with photocoagulation, photodynamic therapy, and intraocular injections of bevacizumab (Avastin, Genentech) and pegabtanib sodium (Macugen, Eyetech Pharmaceutical). In this report, we describe a patient who developed an RPE tear following an intravitreal injection of ranibizumab (Lucentis, Genentech).

Papulopustular eruption after intravitreal bevacizumab (Avastin).

Editor, A 61-year-old White woman came to our institution complaining of blurred vision in her left eye. She was taking no medication and had no relevant medical history. On examination, she had a right best-corrected visual acuity (BCVA) of 20 ⁄ 20 and a left BCVA of 20 ⁄ 80. The spherical equivalent refractive error was )7.0 D in the right eye and )10.0 D in the left eye. Choroidal neovascularization secondary to pathological myopia in the left eye was diagnosed. An uneventful intravitreal injection of bevacizumab (2.5 mg) was performed in the left eye. The patient exhibited a positive response to bevacizumab except for the development of multiple scattered, erythematous papules involving especially the head and trunk, which started 6 days after the intravitreal injection (Fig. 1). A skin-punch biopsy revealed hyperkeratotic follicular infundibulum with a surrounding dermal inflammatory cell infiltrate. Three weeks after the injection, BCVA improved to 20 ⁄50. Two months after the initial presentation, the patient had another sudden reduction in left visual acuity. The left BCVA had decreased to 20 ⁄40 and a second intravitreal injection of bevacizumab (2.5 mg) was performed in the left eye with good results. Five days after the injection, appearance of papulopustular reaction on her forehead was again documented. After 6 months of follow-up, the left visual acuity remains at 20 ⁄ 40. Bevacizumab is a monoclonal antibody to vascular endothelial growth factor (VEGF), a key mediator in tumour angiogenesis. VEGF receptors are overexpressed in various retinal disorders, including age-related macular degeneration (ARMD), diabetic retinopathy and myopic choroidal neovascularization (Sakaguchi et al. 2007). The drug is Food and Drug Administration (FDA)-approved for use in oncology patients in combination with different chemotherapeutic agents and has been used off-label with some success in treating neovascularization in ARMD, diabetic retinopathy and myopic choroidal neovascularization (Sakaguchi et al. 2007). In this case of choroidal neovascularization secondary to pathological myopia, a dose of 2.5 mg bevacizumab was injected intravitreally. Although comparisons of the 2.5and 1.25-mg doses suggest that there is not likely to be a large difference in short-term effect between the two doses, there are no conclusions about their long-term comparative effects (Diabetic Retinopathy Clinical Research Network et al. 2007). Intravenous bevacizumab is typically well tolerated, and its major side-effects include hypertension, proteinuria, bleeding, gastrointestinal perforation and arterial thrombotic events (Gotlib et al. 2006). Although exfoliative dermatitis, with an incidence of 19%, is the most common cutaneous adverse event among patients receiving intravenous bevacizumab, a papulopustular skin rash has also been described (Gotlib et al. 2006). A recent study on the pharmacokinetics of intravitreal bevacizumab (1.25 mg) in the rabbit showed that a maximum serum concentration of 3.3 lg ⁄ml was achieved 8 days after intravitreal injection and the concentration fell below 1 lg ⁄ml 29 days after injection (Bakri et al. 2007). Therefore, systemic complications could potentially occur after intravitreal injection of bevacizumab. Some authors have reported a rate of systemic complications of <4.6% after intravitreal injection of bevacizumab (Arevalo et al. 2007), but none of them have reported any cutaneous reaction. Skin rashes are known to typically develop with epidermal growth factor receptor (EGFR) antagonists, including tyrosine kinase inhibitors and antibodies such as cetuximab (Erbitux ) and erlotinib (Tarceva ). The current theory is that EGFR inhibition results in abnormal epidermal differentiation, which leads to follicular obstruction and subsequent inflammation (Lynch et al. 2007). This toxicity usually occurs in the first 2 weeks of treatment, and affects the face, trunk and extremities. EGFR antagonist-induced skin rashes are characterized by clusters of monomorphic pustular lesions, with a histological examination revealing neutrophilic infiltration of the dermis. The skin rashes are dose-dependent and can improve or resolve spontaneously. The functional similarity of EGFR and VEGF points to the possibility of a correlation between skin Fig. 1. Papulopustular eruption (acneiform rash) after intravitreal bevacizumab (Avastin ): multiple scattered, erythematous papules involving especially the head, 8 days after intravitreal injection of bevacizumab (2.5 mg) in a patient with myopic choroidal neovascularization. Acta Ophthalmologica 2009

Intravitreal pegaptanib sodium for refractory pseudophakic macular oedema

PurposeEvaluate the efficacy of intravitreal pegaptanib sodium (Macugen®) in refractory pseudophakic cystoid macular oedema (CME).Design and methodsProspective, nonrandomized, interventional case series. Four eyes of four patients with refractory pseudophakic CME to pars plana vitrectomy and intravitreal bevacizumab and triamcinolone, were treated with pegaptanib sodium, with a mean follow up of 4 months. Pre- and postinfection examinations included assessment of best-corrected visual acuity (BCVA) using the Early Treatment Diabetic Retinopathy Study chart (ETDRS), fluorescein angiography (FA), and optical coherence tomography (OCT).ResultsVisual acuity increased in all patients after intravitreal pegaptanib sodium. OCT showed improvement of the retinal thickness in the macular area.ConclusionIntravitreal pegaptanib sodium (Macugen®) is a promising treatment for pseudophakic cystoid macular oedema resistant to other medical treatment strategies. However, further study is needed to assess the treatments long term efficacy and the need for retreatment.

A delphi study to detect deficiencies and propose actions in real life treatment of neovascular age-related macular degeneration.

Purpose. Spanish retina specialists were surveyed in order to propose actions to decrease deficiencies in real-life neovascular age macular degeneration treatment (nv-AMD). Methods. One hundred experts, members of the Spanish Vitreoretinal Society (SERV), were invited to complete an online survey of 52 statements about nv-AMD management with a modified Delphi methodology. Four rounds were performed using a 5-point Linkert scale. Recommendations were developed after analyzing the differences between the results and the SERV guidelines recommendations. Results. Eighty-seven specialists completed all the Delphi rounds. Once major potential deficiencies in real-life nv-AMD treatment were identified, 15 recommendations were developed with a high level of agreement. Consensus statements to reduce the burden of the disease included the use of treat and extend regimen and to reduce the amount of diagnostic tests during the loading phase and training technical staff to perform these tests and reduce the time between relapse detection and reinjection, as well as establishing patient referral protocols to outside general ophthalmology clinics. Conclusion. The level of agreement with the final recommendations for nv-AMD treatment among Spanish retinal specialist was high indicating that some actions could be applied in order to reduce the deficiencies in real-life nv-AMD treatment.

Individualized Therapy with Ranibizumab in Wet Age-Related Macular Degeneration

Individualized treatment regimens may reduce patient burden with satisfactory patient outcomes in neovascular age-related macular degeneration. Intravitreal anti-VEGF drugs are the current gold standard. Fixed monthly injections offer the best visual outcome but this regimen is not commonly followed outside clinical trials. A PRN regimen requires monthly visits where the patient is treated in the presence of signs of lesion activity. Therefore, an early detection of reactivation of the disease with immediate retreatment is crucial to prevent visual acuity loss. Several trials suggest that “treat and extend” and other proactive regimens provide a reasonable approach. The rationale of the proactive regimens is to perform treatment anticipating relapses or recurrences and therefore avoid drops in vision while individualizing patient followup. Treat and extend study results in significant direct medical cost savings from fewer treatments and office visits compared to monthly treatment. Current data suggest that, for one year, PRN is less expensive, but treat and extend regimen would likely be less expensive for subsequent years. Once a patient is not a candidate to continue with treatment, he/she should be sent to an outpatient unit with adequate resources to follow nAMD patients in order to reduce the burden of specialized ophthalmologist services.

Pegaptanib sodium for acute retinal necrosis- induced macular oedema

35-year-old immunocompromisedwoman with umbilical cordblood transplantation for adult lym-phoma presented with a 2-week his-tory of redness and blurred vision inboth eyes following initial herpes zos-ter encephalitis. Examination revealedvitritis, retinal whitening (Fig. 1), vas-culitis and optic nerve head oedema.Best-corrected visual acuity (BCVA)was 20⁄40 right eye (OD) and 20⁄60left eye (OS). Optical coherencetomography (OCT) showed no cystoidmacular oedema (CMO).Polymerase chain reaction testing ofthe aqueous fluid revealed varicellazoster virus and the patient was diag-nosed with bilateral acute retinalnecrosis (ARN).The retinitis was controlled withoral valacyclovir and intravitrealfoscarnet (2.4 mg) every 3 days,followed 10 days later by pars-planavitrectomy and endolaser in both eyes.BCVA improved to 20⁄25 OD and20⁄20 OS with no signs of ocularinflammation.One month later, the clinical coursewas complicated by severe CMO inthe right eye with a central fovealthickness of 410 lm and a BCVA of20⁄60, with no signs of ocular inflam-mation.After discussion of periocularand⁄or intravitreal use of steroids, thepatient refused to have this treatmentbecause of his family history of glau-coma and the increased potential riskof cataract formation. After a lengthydiscussion of the potential risks andbenefits of off-label intravitreal bev-acizumab or intravitreal pegaptanibsodium use, the patient requestedintravitreal pegaptanib sodium.An intravitreal injection of pegap-tanib sodium (Macugen; Eyetech⁄Pfizer, New York, NY, USA) wasadministered in the right eye withoutcomplication. Two weeks after injec-tion, OCT demonstrated a markedimprovement of the macular oedema,with a central foveal thickness of 197lm and a BCVA of 20⁄25 in theright eye (Fig. 2). Three months aftertreatment, there was no ocularinflammation and the OCT revealedno CMO.Acute retinal necrosis (ARN) syn-drome is a distinct infectious retinitiscaused by members of the herpes virusfamily that can impair vision. Itoccurs mostly in adult patients,especially those severely immunocom-promised, in association with a reacti-vation of a herpes virus infection (Lauet al. 2007).Active vasculitis is characterized byvascular sheathing and perivascularintraretinal haemorrhages. Vesselobstruction affects the central retinalartery more often than the vein and isa contributing factor to severe visionloss (Chang & Young 2007). Retinalischaemia is the major trigger ofvascular endothelial growth factor(VEGF) over-expression; it can leadto chronic inflammation and thedevelopment of retinal neovasculari-zation (Nishijima et al. 2007).Active inflammation secondary toARN progresses despite antiviraltreatment. High-dose systemic cortico-steroid therapy improves intraocularinflammation and improves vitreousopacity (Chang & Young 2007).However, some patients have CMOthat is resistant or non-responsive tosteroids.Bevacizumab is an anti-VEGFmonoclonal antibody that blocksall VEGF isoforms. Intravitrealbevacizumab has been used success-fully for the treatment of uveitic-resistant CMO (Cordero Coma et al.2007) with short-term improvementin BCVA and decreased OCT retinalthickness in a considerable propor-tion of patients. However, VEGF-Ais a survival factor for retinal neu-rons and a critical neuroprotectantduring the adaptative response toischaemic injury (Nishijima et al.2007).Pegaptanib sodium is a selectiveRNA aptamer that inhibits VEGF-165, the VEGF isoform primarilyresponsible for pathological ocularneovascularization and vascular per-meability, while sparing the physiolog-ical isoform VEGF-121. Retrospectivedata suggest that pegaptanib may pro-vide therapeutic benefit for patientswith diabetic macular oedema, prolif-erative diabetic retinopathy and reti-nal vein occlusion (Ng & Adamis2006).

Efficacy and Safety of an Aflibercept Treat-and-Extend Regimen in Treatment-Naïve Patients with Macular Oedema Secondary to Central Retinal Vein Occlusion (CRVO): A Prospective 12-Month, Single-Arm, Multicentre Trial

Objectives To evaluate efficacy and safety of an aflibercept treat-and-extend (TAE) regimen in patients with macular oedema (MO) secondary to central retinal vein occlusion (CRVO). Design, Setting, and Patients Phase IV, prospective, open-label, single-arm trial in 11 Spanish hospitals. Treatment-naïve patients with <6 month diagnosis of MO secondary to CRVO and best-corrected visual acuity (BCVA) of 73-24 ETDRS letters were included between 23 January 2015 and 17 March 2016. Intervention Intravitreal aflibercept 2 mg monthly (3 months) followed by proactive individualized dosing. Main Outcomes Mean change in BCVA after 12 months. Results 24 eyes (24 patients) were included; mean (SD) age: 62.8 (15.0) years; 54.2% male; median (IQR) time since diagnosis: 7.6 (3.0, 15.2) days. Mean BCVA scores significantly improved between baseline (56.0 (16.5)) and Month 12 (74.1 (17.6)); mean (95% CI) change: 14.8 (8.2, 21.4); P=0.0001. Twelve (50.0%) patients gained ≥15 ETDRS letters. Foveal thickness improved between baseline (mean: 569.4 (216.8) µm) and Month 12 (mean 257.4 (48.4) µm); P < 0.0001. At Month 12, 8.3% patients had MO. The mean (SD) number of injections: 8.3 (3.0). No treatment-related AEs were reported. Five (20.8%) patients experienced ocular AEs. Two nonocular serious AEs were reported. Conclusions An aflibercept TAE regimen improves visual acuity in patients with MO secondary to CRVO over 12 months with good tolerability.

Reply to: IL-2 and IFN-gamma and diabetic retinopathy

It is well-known that retinal changes in diabetes are thought to be initiated by sustained hyperglycemia and fluctuation of blood glucose, as suggested by Dr Viroj Wiwanitkit, leading to biochemical abnormalities, that include all alterations of various vasoactive and growth factors [1], nonenzymatic glycation [2, 3], increase in the polyol pathway and redox imbalance [1, 4–9], and activation of protein kinase C (PKC) [10, 11]. It is also known that hyperglycemia reduces antioxidant levels and concomitantly increases the production of free radicals. These effects contribute to tissue damage in diabetes mellitus (DM), leading to alterations in the redox potential of the cell with subsequent activation of redox-sensitive genes [12]. Furthermore, the retina is the neurosensorial tissue of the eye, and is extremely rich in polyunsaturated lipid membranes. This feature makes it especially sensitive to oxygenand/or nitrogen-activated species and lipid peroxidation. Inflammation has also been related to diabetic retinopathy, but it is not clear if inflammation participates in the initiation, propagation, or resolution of the injury in diabetic retinopathy. Chronic inflammation is characterized by increased vascular permeability, edema, inflammatory cell infiltration, cytokine and chemokine expression, tissue destruction, and neovascularization [13], and diabetic retinopathy exhibits all these characteristics. We agree with Dr Wiwanitkit that another important cause of cellular damage in diabetes is the exothermic energy from fluctuation of blood glucose. But we should consider that after blood glucose increase and/or fluctuation, multiple processes begin in the retina, including all the mentioned above (inflammation, oxidative stress, exothermic energy, etc) and that treatment of this retinal pathology should focus in all of these aspects.