Publications by authors named "Frank C Schlichtenbrede"

23 Publications

  • Page 1 of 1

Valacyclovir versus acyclovir for the treatment of herpes zoster ophthalmicus in immunocompetent patients.

Cochrane Database Syst Rev 2016 11 14;11:CD011503. Epub 2016 Nov 14.

Department of Ophthalmology, University Medical Center Mainz, Langenbeckstr. 1, Mainz, Germany, 55131.

Background: Herpes zoster ophthalmicus affects the eye and vision, and is caused by the reactivation of the varicella zoster virus in the distribution of the first division of the trigeminal nerve. An aggressive management of acute herpes zoster ophthalmicus with systemic antiviral medication is generally recommended as the standard first-line treatment for herpes zoster ophthalmicus infections. Both acyclovir and its prodrug valacyclovir are medications that are approved for the systemic treatment of herpes zoster. Although it is known that valacyclovir has an improved bioavailability and steadier plasma concentration, it is currently unclear as to whether this leads to better treatment results and less ocular complications.

Objectives: To assess the effects of valacyclovir versus acyclovir for the systemic antiviral treatment of herpes zoster ophthalmicus in immunocompetent patients.

Search Methods: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register; 2016, Issue 5), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to June 2016), Embase (January 1980 to June 2016), Web of Science Conference Proceedings Citation Index-Science (CPCI-S; January 1990 to June 2016), BIOSIS Previews (January 1969 to June 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 13 June 2016.

Selection Criteria: We considered all randomised controlled trials (RCTs) in which systemic valacyclovir was compared to systemic acyclovir medication for treatment of herpes zoster ophthalmicus. There were no language restrictions.

Data Collection And Analysis: Two review authors independently selected trials, evaluated the risk of bias in included trials, and extracted and analysed data. We did not conduct a meta-analysis, as only one study was included. We assessed the certainty of the evidence for the selected outcomes using the GRADE approach.

Main Results: One study fulfilled the inclusion criteria. In this multicentre, randomised double-masked study carried out in France, 110 immunocompetent people with herpes zoster ophthalmicus, diagnosed within 72 hours of skin eruption, were treated, with 56 participants allocated to the valacyclovir group and 54 to the acyclovir group. The study was poorly reported and we judged it to be unclear risk of bias for most domains.Persistent ocular lesions after 6 months were observed in 2/56 people in the valacyclovir group compared with 1/54 people in the acyclovir group (risk ratio (RR) 1.93 (95% CI 0.18 to 20.65); very low certainty evidence. Dendritic ulcer appeared in 3/56 patients treated with valacyclovir, while 1/54 suffered in the acyclovir group (RR 2.89; 95% confidence interval (CI) 0.31 to 26.96); very low certainty evidence), uveitis in 7/56 people in the valacyclovir group compared with 9/54 in the acyclovir group (RR 0.96; 95% CI 0.36 to 2.57); very low certainty evidence). Similarly, there was uncertainty as to the comparative effects of these two treatments on post-herpetic pain, and side effects (vomiting, eyelid or facial edema, disseminated zoster). Due to concerns about imprecision (small number of events and large confidence intervals) and study limitations, the certainty of evidence using the GRADE approach was rated as low to very low for the use of valacyclovir compared to acyclovir.

Authors' Conclusions: This review included data from only one study, which had methodological limitations. As such, our results indicated uncertainty of the relative benefits and harms of valacyclovir over acyclovir in herpes zoster ophthalmicus, despite its widespread use for this condition. Further well-designed and adequately powered trials are needed. These trials should include outcomes important to patients, including compliance.
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http://dx.doi.org/10.1002/14651858.CD011503.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6464932PMC
November 2016

Choroidal Thickness in Open-angle Glaucoma.

J Glaucoma 2015 Oct-Nov;24(8):619-23

Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University, Heidelberg, Germany.

Purpose: To examine choroidal thickness in open-angle glaucoma.

Methods: The hospital-based case series study included a study group with patients with open-angle glaucoma and a control group. Choroidal thickness was measured by enhanced depth imaging by spectral domain optical coherence tomography.

Results: The study group included 39 patients (71 eyes) and the control group consisted of 189 patients (228 eyes) with no significant difference between both groups in age (P=0.16) and refractive error (P=0.07). Choroidal thickness in the foveal region (P=0.18), at a distance of 1000 μm from the fovea (P=0.39), 2000 μm from the fovea (P=0.46), and 2500 μm from the fovea (P=0.53) did not vary significantly between both groups. In multivariable analysis with adjustment for age and refractive error, choroidal thickness at the fovea [P=0.12; regression coefficient B: minus-8.60; 95% confidence interval (CI): -19.3, 2.1], at a horizontal distance of 1000 μm from the fovea (P=0.30; regression coefficient B: -4.98; 95% CI: -14.3, 4.4), 2000 μm from the fovea (P=0.20; regression coefficient B: -20.9; 95% CI: -53.2, 11.3), and 2500 μm from the fovea (P=0.45; regression coefficient B: -2.70; 95% CI: -9.67, 4.27) was not significantly associated with the diagnosis of glaucoma. In binary regression analysis with adjustment for age and refractive error, presence of glaucoma was significantly associated neither with subfoveal choroidal thickness [P=0.12; odds ratio (OR): 0.997; 95% CI: 0.993, 1.001] nor with choroidal thickness at a horizontal distance of 1000 μm from the fovea (P=0.47; OR: 0.998; 95% CI: 0.993, 1.002), 2000 μm from the fovea (P=0.23; OR: 0.997; 95% CI: 0.993, 1.002), or 2500 μm from the fovea (P=0.46; OR: 0.998; 95% CI: 0.992, 1.004).

Conclusions: After adjusting for age and refractive error, open-angle glaucoma was not significantly associated with a marked thinning or a thickening of the choroid in the foveal and parafoveal region.
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http://dx.doi.org/10.1097/IJG.0000000000000063DOI Listing
January 2016

Choroidal thickness in nonarteritic anterior ischemic optic neuropathy.

Am J Ophthalmol 2014 Dec 8;158(6):1342-1347.e1. Epub 2014 Sep 8.

Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University, Heidelberg, Germany.

Purpose: To examine choroidal thickness in nonarteritic anterior ischemic optic neuropathy (AION).

Design: Retrospective case control study.

Methods: In the eye clinic of the University Medical Center in Mannheim, Germany, we studied a group that consisted of patients with nonarteritic AION and a control group that consisted of individuals with normal fundus. Choroidal thickness was measured by the enhanced-depth imaging of spectral-domain optical coherence tomography. The main outcome measure was choroidal thickness.

Results: The study group consisted of 20 patients: 11 patients with acute nonarteritic AION and an unaffected contralateral eye and 9 patients with acute unilateral nonarteritic AION and previously nonarteritic AION in the contralateral eye. The control group consisted of 58 patients (58 eyes). In multivariate analysis, thinner subfoveal choroidal thickness was associated with the diagnosis of nonarteritic AION (P = 0.001; regression coefficient B, -55.1), after adjusting for age (P < 0.001) and refractive error (P = 0.20). Similarly, unaffected eyes contralateral to eyes with acute nonarteritic AION as compared to control eyes showed thinner subfoveal choroidal thickness (P = 0.037) after adjusting for age (P = 0.001) and refractive error (P = 0.06). In a reverse manner, nonarteritic AION was associated with thinner subfoveal choroidal thickness (P = 0.007) after adjusting for age, optic disc diameter, gender, and refractive error.

Conclusions: Eyes affected by nonarteritic AION and unaffected contralateral eyes showed significantly thinner macular choroids than eyes of a control group after adjusting ocular and systemic parameters. A thin choroid may be added to the diagnostic features of nonarteritic AION. Future studies may examine the pathophysiologic meaning of the finding.
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http://dx.doi.org/10.1016/j.ajo.2014.09.008DOI Listing
December 2014

Ratio of primary episcleral buckling surgery versus primary vitrectomy for rhegmatogenous retinal detachment.

Eye Sci 2014 Mar;29(1):53-4

Purpose: To assess the ratio of the frequency of primary scleral buckling procedures versus the frequency of vitrectomies performed as treatment for rhegmatogenous retinal detachments in a primary retinal surgical department.

Methods: The study included all patients with rhegmatogenous retinal detachments who underwent retinal or vitreoretinal surgery in the study period from 2002 to 2006. The size of the retinal defect and the amount of proliferative vitreoretinopathy were not exclusion criteria. Patients with tractional retinal detachment due to proliferative ischemic retinopathies were excluded.

Results: In the study period, 875 primary retinal and vitreoretinal surgeries were performed on 875 eyes. Among the surgeries, episcleral sponges (42.9%) formed the largest part, followed by pars plana vitrectomies (35.0%) and encircling bands (22.2%). Combining episcleral sponges and encircling bands into an episcleral surgery group revealed that two thirds (65%) of the surgeries were episcleral interventions. In the episcleral sponge group, the retinal re-detachment rate after the first surgery was 13%.

Conclusion: In a university department as a primary referral unit for retinal detachments, episcleral retinal surgery can still outnumber vitreoretinal interventions, with retinal re-detachment rates which do not differ markedly from the re-detachment rates reported in randomized trials comparing vitreoretinal surgery with episcleral surgery.
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March 2014

Target refraction for best uncorrected distance and near vision in cataract surgery.

Eur J Ophthalmol 2014 Jul-Aug;24(4):509-15. Epub 2013 Dec 16.

Department of Ophthalmology, Medical Faculty Mannheim, Ruprecht-Karls-University Heidelberg - Germany.

Purpose: To assess the target refractive error after cataract surgery to achieve best uncorrected visual acuity for both distance vision and reading vision.

Methods: The study included patients consecutively undergoing routine phacoemulsification with clear corneal incisions and implantation of a foldable monofocal intraocular lens (IOL). Uncorrected distance visual acuity (UCDVA), best-corrected distance visual acuity (BCDVA), uncorrected near visual acuity (UCNVA,) and best-corrected near visual acuity were measured at 93 ± 47 days (minimum 4 weeks) after surgery. Inclusion criteria were a postoperative cylindrical refractive error ≤1.5 D and an unremarkable postoperative status.

Results: The study included 493 eyes of 493 patients with a mean age of 74.2 ± 8.7 years and mean axial length 23.4 ± 1.1 mm. The UCDVA significantly (p<0.001) increased with decreasing myopic refractive error (spherical equivalent) towards emmetropia and then significantly (p<0.001) decreased with increasing hyperopic refractive error. The UCNVA significantly (p<0.001) decreased with decreasing myopic and increasing hyperopic refractive error. The ascending UCDVA line and the descending UCNVA line intersected in the refractive error range (spherical equivalent) of -1.00 D to -1.50 D. For patients with a BCDVA of ≥20/25, the lines of UCDVA and UCNVA intersected at a UCDVA range between 20/40 (logMAR 0.30; -1.5 D) and 20/32 (logMAR 0.26; -1.0 D) and at a UCNVA range between Jaeger 3 (logMAR 0.26) and Jaeger 4 (logMAR 0.32).

Conclusions: For routine unilateral cataract surgery with implantation of monofocal IOLs, target refractive error to achieve best uncorrected distance and near vision was in the range of -1.00 D to -1.50 D (spherical equivalent).
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http://dx.doi.org/10.5301/ejo.5000414DOI Listing
October 2014

Choroidal thickness in age-related macular degeneration.

Retina 2014 Jun;34(6):1149-55

Department of Ophthalmology, Medical Faculty Mannheim, Ruprecht-Karls-University, Heidelberg, Germany.

Purpose: To examine choroidal thickness in age-related macular degeneration (AMD).

Methods: The hospital-based case series study included patients with nonexudative or exudative AMD as study group, and the control group consisted of subjects with a normal fundus. Choroidal thickness was measured by enhanced depth imaging of spectral domain optical coherence tomography.

Results: The study group (126 patients; 204 eyes) included a nonexudative subgroup (n = 50 eyes) and an exudative subgroup (n = 154 eyes), differentiated into eyes with mostly retinal pigment epithelium detachment (n = 35), mostly retinal edema (n = 36), and a subretinal fibrotic scar (n = 83). For 29 patients with unilateral AMD, contralateral normal eyes were compared with affected eyes. The control group consisted of 189 patients (228 eyes). Comparing choroidal thickness between the affected eyes and contralateral unaffected eyes in patients with unilateral AMD revealed no statistically significant differences (all P > 0.20). After adjusting for age and refractive error, subfoveal choroidal thickness was not significantly (all P > 0.10) related with AMD neither as a whole nor with the nonexudative or exudative AMD subgroup nor with the single exudative AMD subtypes (except for the subretinal fibrotic scar subgroup; P = 0.03). Correspondingly, choroidal thickness at a horizontal distance of 1000 μm from the fovea was not significantly (all P ≥ 0.30) associated with any subgroup of AMD. In binary regression analysis, the presence of AMD or of its subtypes (except for subretinal fibrotic scar type) was not significantly (all P ≥ 0.20) associated with subfoveal or parafoveal choroidal thickness after adjustment for age and refractive error. After matching for age, refractive error, and axial length, study group and control group did not differ significantly (all P ≥ 0.25) in foveal or parafoveal choroidal thickness measurements.

Conclusion: After adjusting for age and refractive error, AMD, neither in its nonexudative form nor exudative form, was significantly associated with a marked thinning or thickening of the choroid in the foveal and parafoveal region.
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http://dx.doi.org/10.1097/IAE.0000000000000035DOI Listing
June 2014

Intravitreal low-dosage bevacizumab for retinopathy of prematurity.

Acta Ophthalmol 2014 Sep 11;92(6):577-81. Epub 2013 Sep 11.

Department of Ophthalmology, Medical Faculty Mannheim, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.

Purpose: To report on the therapeutic effect of intravitreal low-dose bevacizumab for treatment for retinopathy of prematurity (ROP).

Methods: The single-centre retrospective, non-comparative case series study included all infants who consecutively underwent intravitreal injection of 0.375 mg bevacizumab (0.03 ml) under light sedation in topical anaesthesia as therapy of ROP in zone I or zone II.

Results: The clinical charts of 29 patients (57 eyes) with a median birth weight of 630 g (range: 290-1390 g) and median gestational age of 25 + 1 weeks (range: 23 + 1-30 weeks) were reviewed. Six children (12 eyes) were graded as ROP with zone I retinopathy and plus disease. The 23 remaining infants had extraretinal neovascularizations in zone II or partly zone I. The intravitreal bevacizumab injection was injected at a median age of 12 + 1 weeks (range: 7 + 4-21 + 4), the median follow-up was 4.2 months (range: from 3 days to 45.1 months). In all eyes treated, a regression of plus disease occurred within two to six days, retinal neovascularizations regressed within 2-3 weeks and pupillary rigidity improved. None except one child in exceptionally bad general health conditions needed a second intravitreal bevacizumab injection. In none of the infants, any ophthalmologic side-effects of the bevacizumab application were detected during the follow-up period.

Conclusions: The intravitreal injection of a low dose of 0.375 mg bevacizumab showed a high efficacy as treatment for ROP. The question arises whether the low dosage of bevacizumab as compared to the dosage of 0.625 mg bevacizumab may be preferred.
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http://dx.doi.org/10.1111/aos.12266DOI Listing
September 2014

Intravitreal bevacizumab for retinopathy of prematurity: refractive error results.

Am J Ophthalmol 2013 Jun 12;155(6):1119-1124.e1. Epub 2013 Mar 12.

Department of Ophthalmology, Medical Faculty Mannheim, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.

Purpose: To evaluate refractive error in infants who underwent intravitreal bevacizumab injection for treatment of threshold retinopathy of prematurity (ROP).

Design: Retrospective nonrandomized interventional comparative study.

Methods: The study group included all infants who consecutively received a single intravitreal bevacizumab (0.375 mg or 0.625 mg) injection for therapy of threshold ROP in fundus zone I or zone II. The control group included infants who had previously undergone retinal argon laser therapy of ROP. The follow-up examination included refractometry under cycloplegic conditions.

Results: The study group included 12 children (23 eyes; mean birth weight: 622 ± 153 g; gestational age: 25.2 ± 1.6 weeks) and the control group included 13 children (26 eyes; birth weight: 717 ± 197 g; gestational age: 25.3 ± 1.8 weeks). Both groups did not differ significantly in birth age and weight and follow-up. At the end of follow-up at 11.4 ± 2.3 months after birth, refractive error was less myopic in the study group than in the control group (-1.04 ± 4.24 diopters [median: 0 diopters] vs -4.41 ± 5.50 diopters [median: -5.50 diopters]; P = .02). Prevalence of moderate myopia (17% ± 8% vs 54% ± 10%; P = .02; OR: 0.18 [95% CI: 0.05, 0.68]) and high myopia (9% ± 6% vs 42% ± 10%; P = .01; OR: 0.13 [95% CI: 0.03, 0.67]) was significantly lower in the bevacizumab group. Refractive astigmatism was significantly lower in the study group (-1.0 ± 1.04 diopters vs 1.82 ± 1.41 diopters; P = .03). In multivariate analysis, myopic refractive error and astigmatism were significantly associated with laser therapy vs bevacizumab therapy (P = .04 and P = .02, respectively).

Conclusions: In a 1-year follow-up, a single intravitreal bevacizumab injection as compared to conventional retinal laser coagulation was helpful for therapy of ROP and led to less myopization and less astigmatism.
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http://dx.doi.org/10.1016/j.ajo.2013.01.014DOI Listing
June 2013

Intravitreal bevacizumab for retinopathy of prematurity.

J Ocul Pharmacol Ther 2011 Dec 8;27(6):623-7. Epub 2011 Aug 8.

Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University, Heidelberg, Germany.

Background: To evaluate the therapeutic effect of a single intravitreal injection of bevacizumab for treatment of threshold retinopathy in retinopathy of prematurity (ROP).

Methods: The retrospective study consisted of all infants who developed threshold ROP in fundus zone I or zone II and who consecutively received an intravitreal injection of bevacizumab (0.375 mg, 0.03 mL) in local anesthesia.

Results: Twelve infants (23 eyes) were included into the study. The mean birth weight was 625±187 g (mean±standard deviation; range: 450-810 g), mean gestational age was 25.1±1.4 weeks (range: 24.0-28.7 weeks), mean age at the time of intervention was 38.1±3.7 gestational weeks (range: 32.1-45.6 weeks), and mean follow-up was 30.4±25.9 weeks. Three children (6 eyes) showed aggressive posterior ROP. After the injection, all eyes showed a regression of plus disease within 2-6 days, a decrease in pupillary rigidity, a resolution of any tunica vasculosa lentis, and a complete regression of the retinal neovascularization within 2-3 weeks. In none of the children a second intravitreal injection of bevacizumab was performed.

Conclusions: A single intravitreal bevacizumab injection of 0.375 mg in 0.03 mL appears to be potentially helpful for the therapy of threshold ROP avoiding side effects of conventional retinal laser coagulation such as irreversible retinal scarring. Long-term effects and side effects may be assessed in future prospective randomized trials.
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http://dx.doi.org/10.1089/jop.2011.0060DOI Listing
December 2011

Intravitreal bevacizumab for exudative age-related macular degeneration in clinical practice.

J Ocul Pharmacol Ther 2011 Oct 17;27(5):467-70. Epub 2011 Jun 17.

Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University, Heidelberg, Germany.

Purpose: The purpose of this study was to evaluate whether baseline visual acuity and baseline anatomy of the macula influence visual outcome in patients receiving intravitreal bevacizumab as treatment of exudative age-related macular degeneration (AMD) in clinical practice.

Methods: This clinical case series study included 319 patients (406 eyes) who consecutively received intravitreal injections of bevacizumab for treatment of exudative AMD. The intervals between injections were 6 weeks and postinjection examinations were performed at 4 weeks after injection. Mean follow-up was 3.6 months.

Results: After 3 injections of bevacizumab, best-corrected visual acuity (BCVA) significantly (P<0.01) improved in eyes with a baseline BCVA of less than 0.2 (group 1; 138 eyes; -0.10±0.43 LogMAR) and in eyes with a baseline BCVA ≥0.2 and <0.4 (group 2; 117 eyes; -0.06±0.24 LogMAR), but BCVA deteriorated in eyes with a baseline BCVA of ≥0.4 (group 3; 151 eyes; 0.09±0.32 LogMAR). Correspondingly, regression analysis revealed that improvement in BCVA after 3 intravitreal bevacizumab injections was significantly (P=0.001) associated with a low baseline BCVA. After the first injection of bevacizumab, changes in optical coherent tomography measurements of the macula (height of subretinal fluid, macular tissue thickness) were statistically significant for group 1 (P=0.03, P=0.03, respectively) and group 2 (P=0.01, P=0.02, respectively), but not for group 3 (P=0.85, P=0.22, respectively).

Conclusions: In clinical practice, patients with exudative AMD and a baseline BCVA of <0.2 have a better prognosis for an increase in BCVA after intravitreal bevacizumab injections than patients with a higher baseline BCVA.
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http://dx.doi.org/10.1089/jop.2011.0038DOI Listing
October 2011

Postoperative mycotic endophthalmitis.

J Cataract Refract Surg 2010 Jul;36(7):1233-4

Department of Ophthalmology, Medical Faculty Mannheim of Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.

Unlabelled: We report a series of 4 patients who experienced a low-grade mycotic endophthalmitis 3 to 7 months after uneventful cataract surgery. In all patients, the capsular bag was irrigated several times and amphotericin B was instilled intraocularly as well as systemically. In the fourth patient, a pars plans vitrectomy was been performed. Microbiological examination of aqueous humor samples revealed Candida parapsilosis in 3 patients and Candida albicans in 1 patient as causative microorganisms. At follow-up examinations performed up to 12 months after the lavage, visual acuities were 0.2, 0.1, 0.1, and hand motion in the 4 patients, respectively. The main reason for the remaining reduction in visual acuity was retinal and optic nerve atrophy. The findings show that a mycotic etiology of postoperative low-grade infectious endophthalmitis should be considered.

Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned.
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http://dx.doi.org/10.1016/j.jcrs.2010.04.025DOI Listing
July 2010

Retinal re-detachment after scleral buckling procedure.

Graefes Arch Clin Exp Ophthalmol 2010 Dec 5;248(12):1841-3. Epub 2010 Mar 5.

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http://dx.doi.org/10.1007/s00417-010-1327-8DOI Listing
December 2010

Toxicity assessment of intravitreal triamcinolone and bevacizumab in a retinal explant mouse model using two-photon microscopy.

Invest Ophthalmol Vis Sci 2009 Dec 2;50(12):5880-7. Epub 2009 Jul 2.

Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.

Purpose: Intravitreal drug administration leads to high intraocular concentrations with potentially toxic effects on ocular tissues. This study was an assessment of the toxicity of triamcinolone and bevacizumab in living retinal explants using two-photon (2P) microscopy.

Methods: Wild-type mice received intravitreal injections of triamcinolone, bevacizumab, or vehicle. Ten and 45 days after injection, wholemounted retinal explants were incubated with the fluorescent dye sulforhodamine 101 (SR101) to analyze morphology and tissue damage with 2P microscopy ex vivo. Retinas that received the same treatment were stained for apoptosis (TUNEL) and glial activation (GFAP). An intravitreal injection of NMDA (N-methyl-d-aspartate) was used as a positive control to ensure the fidelity of detection of retinal damage with ex vivo 2P microscopy.

Results: Overall retinal morphology was undisturbed after all procedures and time points. NMDA injection resulted in a strong increase in the number of SR101-labeled cells and increased apoptosis and glial activation when compared with sham-injected eyes. This result was in contrast to exposure to bevacizumab, which caused no appreciable damage. After triamcinolone treatment, marked damage in the inner retina was observed. However, damaged cells were restricted to sharply demarcated areas, and only mild changes in TUNEL-positive cells and GFAP activation was observed when compared to sham-injected eyes.

Conclusions: 2P microscopy in combination with SR101 staining allows fast morphologic assessment of living retinal explants and can be used to evaluate adverse effects on retinal viability of test substances. Bevacizumab treatment did not cause any detectable retinal damage, whereas triamcinolone was associated with substantial, although spatially restricted, damage.
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http://dx.doi.org/10.1167/iovs.08-3078DOI Listing
December 2009

Lens capsular bag irrigation for low-grade endophthalmitis.

Graefes Arch Clin Exp Ophthalmol 2009 Sep 24;247(9):1273-6. Epub 2009 Apr 24.

Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.

Purpose: In postoperative low-grade endophthalmitis, microorganisms of low pathogenicity exhibit prolonged survival times by sequestration into the capsular bag. Thus, removal or irrigation of the capsular bag as nidus of the microorganisms is an essential therapeutic step. Correspondingly, guidelines suggest pars plana vitrectomy, capsulectomy and/or intraocular lens removal. Here, we report on capsular bag irrigation alone as an alternative, minimally invasive therapeutic method for postoperative infectious low-grade endophthalmitis.

Methods: Nine patients consecutively presenting with whitish precipitates in the capsular bag, anterior chamber inflammation and mild vitritis 2 weeks to 6 months following uncomplicated cataract surgery were included. Using an irrigation/aspiration cannula, synechiae were opened, the intraocular lens was rotated within the intact capsular bag and irrigated with 30 ml Ringer's solution containing 0.16 mg/ml gentamicin and 0.04 mg/ml vancomycin in topical anaesthesia.

Results: In all patients, the inflammation subsided within 2 days to 2 weeks. Visual acuity improved in all patients, mostly to post cataract surgery levels. Visual acuity remained stable during follow-up ranging from 2 to 39 months. No further interventions were required.

Conclusions: The results suggest that capsular bag irrigation as first and single surgical step can be a useful, minimally invasive procedure in the surgical armamentarium for the treatment of infectious low-grade endophthalmitis. It may avoid removal of the intraocular lens and reduce the surgical risks of more complex procedures.
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http://dx.doi.org/10.1007/s00417-009-1085-7DOI Listing
September 2009

In contrast to AAV-mediated Cntf expression, AAV-mediated Gdnf expression enhances gene replacement therapy in rodent models of retinal degeneration.

Mol Ther 2006 Nov 26;14(5):700-9. Epub 2006 Jul 26.

Division of Molecular Therapy, Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK.

While AAV- and lentivirus-mediated gene replacement therapy can produce structural and functional improvements in various animal models of inherited retinal degeneration, this approach often has very limited effects on the rate of photoreceptor cell loss. Neurotrophic factors such as ciliary neurotrophic factor (CNTF) and glial cell line-derived neurotrophic factor (GDNF) have been shown to prolong photoreceptor survival in rodent models of retinal degeneration, but AAV-mediated Cntf expression also results in suppression of electrophysiological responses from the retina. In this study using mice, we show that while the deleterious effects mediated by CNTF are dose-dependent, administering a dose of CNTF that does not adversely affect retinal function precludes its ability to delay photoreceptor cell death. In evaluating GDNF as a neuroprotective agent, we show that AAV-mediated Gdnf expression does not produce adverse effects similar to those of CNTF. In addition, we demonstrate the ability of AAV-mediated delivery of Gdnf to slow cell death in two rodent models of retinitis pigmentosa and to enhance retinal function in combination with the relevant gene replacement therapy. These data show for the first time that a combination of these approaches can provide enhanced rescue over gene replacement or growth factor therapy alone.
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http://dx.doi.org/10.1016/j.ymthe.2006.05.019DOI Listing
November 2006

Minocycline delays photoreceptor death in the rds mouse through a microglia-independent mechanism.

Exp Eye Res 2004 Jun;78(6):1077-84

University Division of Ophthalmology, Bristol Eye Hospital, University of Bristol, Lower Maudlin St., Bristol BS1 2LX, UK.

Purpose: Minocycline, a semi-synthetic tetracycline antibiotic is reported to be neuroprotective in degenerative and ischaemic models of central nervous system disease, via mechanisms involving suppression of both cytotoxic microglial activity and caspase-dependent apoptosis. We have investigated the effect of minocycline treatment on a mouse model of retinitis pigmentosa, an inherited photoreceptor neurodegenerative disorder, and contrasted this with the effect of depleting retinal microglia using liposomal clodronate.

Methods: rds mice were treated intraperitoneally from the second postnatal day (P2) with either daily minocycline until P16, P18, P21, P24 and P27 or alternative day clodronate liposomes until P16. Immunohistochemical and immunofluorescent methods were applied for the detection of microglia (F4/80) and apoptosis (TUNEL and caspase 3 activation).

Results: Photoreceptor apoptosis was delayed by minocycline treatment but not, ultimately, prevented. Markedly reduced expression of activated caspase 3 was observed in photoreceptors at the early time point, corresponding with the reduced level of apoptosis. Delayed photoreceptor apoptosis due to minocycline treatment was associated with a 50% reduction in the numbers of microglia at early timepoints. Liposomal clodronate treatment also resulted in a marked reduction in the number of microglia (63% reduction in microglia), but in contrast to minocycline treatment, this had no effect on photoreceptor apoptosis.

Conclusions: Minocycline appears to delay photoreceptor apoptosis through a microglia-independent action. Although microglial cytotoxicity has been implicated during other models of neurodegeneration, microglia are unlikely to play such a role in this model of photoreceptor dystrophy.
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http://dx.doi.org/10.1016/j.exer.2004.02.002DOI Listing
June 2004

Long-term evaluation of retinal function in Prph2Rd2/Rd2 mice following AAV-mediated gene replacement therapy.

J Gene Med 2003 Sep;5(9):757-64

Department of Molecular Genetics, Institute of Ophthalmology, University College London, UK.

Background: Prph2(Rd2/Rd2) mice have a retinal degeneration due to a null mutation for the Prph2 gene which encodes a photoreceptor-specific glycoprotein, peripherin2, essential for outer-segment formation. We have previously shown improvement of photoreceptor function at a single time point following AAV-mediated gene replacement therapy. Here we quantify the functional rescue over a 15-week time course and present a detailed analysis of the improvement in retinal function.

Methods: An AAV2 vector, AAV.rho.rds, carrying a peripherin2 c-DNA, was in injected subretinally into 10-day-old Prph2(Rd2/Rd2) mice. One group was injected at a single time point while in a second group the injections were repeated after 5 days. The effect of treatment was analysed histologically using electron microscopy and electroretinography (ERG) was used to assess functional changes. Treated mice were recorded at regular intervals over 15 weeks. Untreated contralateral eyes served as internal control.

Results: A significant increase in b-wave amplitude was first noted 3 weeks after treatment of 10-day-old Prph2(Rd2/Rd2) mice and persisted for up to 14 weeks. An increase in the area of retina exposed to vector resulted in a significant increase in both b-wave amplitude and persistence.

Conclusions: In this study AAV-mediated gene replacement in Prph2(Rd2/Rd2) mice resulted in a significant functional improvement over a period of 14 weeks. These results support the utility of gene therapy approaches as treatment for photoreceptor dystrophies.
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http://dx.doi.org/10.1002/jgm.401DOI Listing
September 2003

AAV-Mediated gene transfer slows photoreceptor loss in the RCS rat model of retinitis pigmentosa.

Mol Ther 2003 Aug;8(2):188-95

Molecular Genetics, Institute of Ophthalmology, London, United Kingdom.

In the Royal College of Surgeons (RCS) rat, the retinal pigment epithelium (RPE) cannot phagocytose the outer segment discs that are continually shed from photoreceptors. The resulting accumulation of debris in the subretinal space leads to a progressive loss of photoreceptors. The defect results from a mutation in the Mertk gene, which is normally expressed in the RPE. Mertk is a receptor tyrosine kinase, involved in the binding of photoreceptor debris. Mutations in MERTK have also been described in patients with retinitis pigmentosa (RP). Here we demonstrate that subretinal injection of recombinant adeno-associated virus (AAV) expressing the murine Mertk gene can significantly prolong photoreceptor cell survival in the RCS rat. Electroretinographic analysis of treated eyes showed that functional photoreceptors were still present at 9 weeks, when there is virtually no activity in untreated control eyes. Histological analysis of treated eyes revealed a decrease in the amount of debris in the subretinal space, suggesting that RPE function was restored. Moreover, 9 weeks after treatment the number of photoreceptors was 2.5-fold higher in treated than in control eyes. This study provides strong support for the development of AAV-mediated gene therapy for RP caused by mutations in the MERTK gene.
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http://dx.doi.org/10.1016/s1525-0016(03)00144-8DOI Listing
August 2003

Generation of activated sialoadhesin-positive microglia during retinal degeneration.

Invest Ophthalmol Vis Sci 2003 May;44(5):2229-34

Division of Ophthalmology, University of Bristol, Bristol, United Kingdom.

Purpose: The retina contains a rich network of myeloid-derived cells (microglia) within the retinal parenchyma and surrounding vessels. Their response and behavior during inflammation and neurodegeneration remain largely undefined. In the present study, the behavior of microglia was closely examined during the onset of photoreceptor degeneration in the rds mouse, to assess their role in photoreceptor apoptosis. The results may have relevance to similar degeneration in humans (retinitis pigmentosa).

Methods: Retinas from rds and wild-type CBA mice aged 8, 14, 16, 17, 19, 21, 30, and 40 days were examined immunohistochemically, with antibodies to macrophage cell surface markers, inducible nitric oxide synthase (iNOS), and proliferating cell nuclear antigen (PCNA), during the most active phase of the disease. TUNEL was used to assess photoreceptor apoptosis.

Results: In the rds mouse, microglia proliferated in situ (PCNA), migrated to the subretinal space, and adopted an activated phenotype. Maximum microglial cells occurred at postnatal day (P)21, 5 days after the peak in photoreceptor apoptosis (P16). Microglia did not express iNOS, and nitrotyrosine was absent. Sialoadhesin was expressed on microglia from P14, and expression was greatest at P21.

Conclusions: During retinal degeneration, microglia are activated and express sialoadhesin. The temporal relationship between photoreceptor apoptosis and microglial response suggests that microglia are not responsible for the initial wave of photoreceptor death, and this is corroborated by the absence of iNOS and nitrotyrosine. Expression of sialoadhesin may indicate blood-retinal barrier breakdown, which has immune implications for subretinal gene therapeutic strategies.
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http://dx.doi.org/10.1167/iovs.02-0824DOI Listing
May 2003