Manuel M. Hermann

Vascular Endothelial Growth Factor in Patients with Exudative Age-related Macular Degeneration Treated with Ranibizumab

OBJECTIVES To analyze the temporal correlations of vascular endothelial growth factor (VEGF) suppression, morphologic recurrence of choroidal neovascularization (CNV), and visual acuity loss in eyes with exudative age-related macular degeneration (AMD) treated with ranibizumab. DESIGN Nonrandomized, prospective, clinical study. PARTICIPANTS Forty-seven eyes of 47 patients with exudative AMD undergoing intravitreal ranibizumab injections. METHODS Aqueous humor specimens were taken before each intravitreal ranibizumab injection. Visual acuity testing, spectral domain optical coherence tomography (SD-OCT), and fundoscopy were performed before each injection. Vascular endothelial growth factor A was measured by Luminex multiplex bead analysis (Luminex Inc., Austin, TX). MAIN OUTCOME MEASURES Intraocular VEGF concentration, recurrence of CNV activity shown by SD-OCT, and vision loss. RESULTS Ranibizumab resulted in complete VEGF suppression within a mean period of 37.8 days (standard deviation [SD] ± 4.8 days; range, 26-49 days). Recurrences of CNV activity as determined by SD-OCT occurred 93.7 days (SD ± 69.9 days; range, 57-368 days) after the last ranibizumab treatment. The VEGF levels were never suppressed when a recurrence occurred. Functional recurrence (visual acuity) occurred 114.3 days (SD ± 81.4 days; range, 57-398 days) after previous treatment. The VEGF levels did not differ significantly between baseline and recurrence (69.3 pg/ml vs. 74.14 pg/ml; 95% confidence interval, -18.87 to 9.12). CONCLUSIONS A monthly intravitreal injection of 0.5 mg ranibizumab yields a durable VEGF inhibition. The recurrences of CNV as determined by SD-OCT are always preceded by a loss of intraocular VEGF suppression and usually followed by loss of visual acuity in the further course.

Optic nerve head morphometry in healthy adults using confocal laser scanning tomography.

Background/aims: To study the optic nerve head (ONH) characteristics in a cross sectional study with confocal laser scanning tomography using the Heidelberg retina tomograph (HRT I) and thereby to obtain a new HRT database for comparison of healthy and glaucomatous eyes. Methods: White adults with no history of ocular pathology were eligible for the study. The examination comprised: assessment of visual acuity; slit lamp examination of the anterior and posterior segment; Goldmann applanation tonometry; computerised perimetry, and optic nerve head tomography with HRT. Eyes with ocular pathology were excluded. Mean (standard deviation, SD) and difference between right and left eye (RE–LE) were calculated for HRT I measurements. Differences in mean topographic parameters between male and female participants and between the age quartiles were analysed. The study included 1764 eyes of 882 healthy adults (154 females and 728 males, mean age of 46.8 (SD 8.6) years). The population investigated was larger and older in comparison with similar studies using confocal laser scanning tomography. Results: With HRT I, a mean disc area of 1.82 (SD 0.39) mm2, a mean cup area of 0.44 (SD 0.32) mm2 and a mean cup:disc area ratio of 0.22 (SD 0.13) was observed. Right eyes showed a larger mean retinal nerve fibre layer thickness (RNFLT) (0.263 (SD 0.066) mm) compared with left eyes (0.252 (SD 0.065) mm, p<0.001). Higher values in younger volunteers (mean age 35.7 years) in comparison with elderly participants (mean age 59.1 years) were noted for disc area (1.84 mm2 v 1.78 mm2) and mean RNFLT (0.263 (SD 0.06) mm v 0.249 (SD 0.07) mm) but were not significant (p>0.01). The presented results differ from published data on ONH measurements of healthy volunteers with different techniques. Conclusion: The observed differences in ONH measurements between left and right eyes seem not to be of clinical importance. This is also true for age or sex dependent changes in ONH topographies. The presented data provide a new basis for comparison of optic disc characteristics between healthy eyes and glaucomatous eyes.

Intraocular growth factors and cytokines in patients with dry and neovascular age-related macular degeneration.

Purpose: To analyze intraocular growth factor and cytokine concentrations in eyes with different stages of age-related macular degeneration (AMD) compared with controls. Methods: The Clinical Age-Related Maculopathy Staging (CARMS) system was used for assignment of patients into the respective categories. Aqueous humor specimens were taken before cataract surgery in 21 controls (CARMS 1) and in 17 early (CARMS 2) and 16 intermediate (CARMS 3) AMD patients. In 18 neovascular (CARMS 5) AMD patients, specimens were taken immediately before anti–vascular endothelial growth factor intravitreal therapy. Luminex multiplex bead assays were conducted for endostatin, angiogenin, vascular endothelial growth factor, platelet-derived growth factor AA, placental growth factor, thrombospondin 2, and fibroblast growth factor a. Results: Vascular endothelial growth factor concentrations were elevated in CARMS 3 (P = 0.037) and tended to be elevated in CARMS 5 (P = 0.093), whereas levels in CARMS 2 (P = 0.425) were similar to CARMS 1. Platelet-derived growth factor levels were diminished in CARMS 2 (P = 0.020), with a trend to lower levels for CARMS 3 (P = 0.099) and CARMS 5 (P = 0.082) compared with CARMS 1. For CARMS 5, antiangiogenic endostatin was elevated (P < 0.002), while antiangiogenic thrombospondin 2 was reduced (P = 0.029). Conclusion: Clinical Age-Related Maculopathy Staging 3 dry AMD was associated with higher vascular endothelial growth factor levels than CARMS 5 neovascular AMD. Therefore, intraocular vascular endothelial growth factor concentrations do not seem to reflect choroidal neovascularization activity in neovascular AMD directly. Platelet-derived growth factor was decreased in most forms of AMD. The antiangiogenic endostatin was exclusively elevated in neovascular AMD, while thrombospondin 2 was reduced. Age-related macular degeneration disease seems to be associated with a generally altered cytokine system.

Measurement of adherence to brimonidine therapy for glaucoma using electronic monitoring.

PurposeTo assess the patient adherence and behavior with brimonidine twice daily (bid) or 3 times daily (tid) in patients used to topical glaucoma medication. Patients and MethodsSeventy-five patients with glaucoma or ocular hypertension were enrolled in a prospective, observational cohort study. Consenting patients were randomly assigned to brimonidine bid or tid and received conventional brimonidine eye drops with attached electronic monitoring devices for 4 weeks. Patients were not explicitly informed on the compliance monitoring. ResultsThe study was completed by 67 patients (89%). In 65 patients (97%), at least 1 dosing interval exceeded 24 hours. The mean adherence rates were better in the brimonidine bid group (72±19% vs. 62±16%, P=0.04), although dosing frequency was higher in the tid group (1.9±0.5 vs. 1.4±0.4 per day; P<0.001). On average medication coverage was 70% for the bid group and 67% for the tid group; 19 patients (28%) had a coverage rate above 75%, 42 patients (63%) 50% to 75%, and 6 (9%) below 50%. Patients with normal-tension glaucoma had lower coverage rates than patients with primary open-angle glaucoma and ocular hypertension (P<0.05). Data also showed that on average 20% of the glaucoma medication was wasted owing to inefficient drug delivery by using more than 1 drop per dosing. ConclusionsIndividual adherence with brimonidine was highly variable and pharmacologically insufficient for more than two-third of the patients. Special attention should be paid to compliance of patients with normal-tension glaucoma. Our findings underline the need to improve individual adherence and drug delivery in topical glaucoma therapy.

Long-term stability of vascular endothelial growth factor suppression time under ranibizumab treatment in age-related macular degeneration.

PURPOSE To determine intra-individual long-term stability of vascular endothelial growth factor (VEGF) suppression time in eyes with neovascular age-related macular degeneration (AMD) treated with ranibizumab. DESIGN Nonrandomized, prospective clinical study. METHODS Eighty-three eyes of 83 patients with neovascular AMD undergoing intravitreal ranibizumab injections were included in the study. A total of 859 aqueous humor specimens were taken before each intravitreal ranibizumab injection. Vascular endothelial growth factor A was measured by multiplex bead analysis. RESULTS Ranibizumab resulted in complete VEGF suppression within a mean period of 36.4 days (standard deviation ±6.7 days; range, 26-69 days). Intra-individual suppression time was stable within a period of up to 3 years. Among 859 VEGF measurements, only 5 (0.58%) deviated from this pattern. Nonsuppressed VEGF levels did not differ significantly between baseline and recurrence (68.0 pg/mL vs 69.3 pg/mL) and did not correlate with choroidal neovascularization size and lesion type. CONCLUSIONS Both the long-term stability and the broad range of individual suppression times after ranibizumab injections would allow and justify adjustment of continuous injections individually in order to achieve permanent VEGF suppression in patients.

Upregulation of TGF-ß1 in experimental proliferative vitreoretinopathy is accompanied by epithelial to mesenchymal transition

BackgroundProliferative vitreoretinopathy (PVR) is characterized by epithelial to mesenchymal transition (EMT) of retinal pigment epithelium (RPE) cells and consecutive formation of fibrous membranes, leading to retinal redetachment. Transforming growth factor beta (TGF-ß) has been suggested to play an important role in this process, but the role of TGF-ß isoforms is unknown.MethodsIn pigmented rabbits (n = 14), PVR was induced by cryopexy and a full-thickness limbus-parallel incision. PVR was evaluated by indirect ophthalmoscopy. Concentrations of TGF-ß isoforms were determined by multiplex bead assay analysis in aqueous humor (AH) and vitreous samples. EMT marker vimentin was analyzed by western blot. Masson’s-trichrome, haematoxilin and eosine (H&E), and immunohistochemical analysis for EMT marker alpha SMA were performed on cross-sections of eyes.ResultsPVR was induced in all treated eyes. The number of quadrants affected by PVR was 1 (n = 5), 2 (n = 2), 3 (n = 2), 4 (n = 5). Vimentin and alpha SMA were expressed during PVR development. During PVR development, both TGF-ß1 levels (AH: p = 0.001; vitreous: p = 0.002) and TGF-ß2 levels increased (AH: p = 0.027; vitreous: p = 0.02), while TGF-ß3 was not detected at any timepoint. The increase was more pronounced for TGF-ß1 than for TGF- ß2 (AH: p = 0.002; vitreous: p = 0.0005), and only TGF-ß1 correlated with the amount of PVR (p = 0.024, r = 0,723).ConclusionsDevelopment of PVR membranes was accompanied by a pronounced upregulation of TGF-ß1, rather than TGF-ß2. Therefore TGF-ß1 could be a promising target for inhibition of PVR.

Profibrotic cytokines in aqueous humour correlate with aqueous flare in patients with rhegmatogenous retinal detachment.

Background Aqueous flare as determined by laser flare photometry in the anterior chamber is a strong preoperative predictor for proliferative vitreoretinopathy (PVR) in patients with primary retinal detachment (RD). We analysed various cytokines in aqueous humour samples in relation to aqueous flare and postoperative PVR incidence in patients with RD. Methods Preoperatively, the aqueous flare of patients with RD was measured quantitatively with a laser flare metre and aqueous humour samples were collected and analysed for interferon γ, tumour necrosis factor α, monocyte chemoattractant protein (MCP)-1, interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, vascular endothelial growth factor (VEGF)-A, platelet derived growth factor (PDGF)-aa, transforming growth factor (TGF)-β1, TGF-β2, TGF-β3, fibroblast growth factor (FGF)-aa and FGF-bb by multiplex fluorescent bead-based immunoassays. Three months after RD surgery patients were examined for PVR development. Results Of 67 consecutive patients, 10 developed at least PVR grade C. Patients with flare values >15 pc/ms (n=20) and the 10 patients with postoperative PVR all had significantly elevated levels of IL-6, IL-8, MCP-1 and TGF-β1 in aqueous humour (p≤0.05). Levels of VEGF-A, PDGF-aa and TGF-β2 were not significantly changed. Other cytokines were below the detection threshold. Eight of the 10 patients (80%) with PVR had elevated flare values of >15 pc/ms and 8 of the 20 patients (40%) with flare >15 pc/ms developed PVR. The OR for PVR with flare values >15 pc/ms was 30.7 (p=0.0001). Conclusions Laser flare photometry allows simple risk estimation for later PVR development. Elevated laser flare values correspond to an altered profibrotic intraocular cytokine milieu. These factors therefore constitute promising targets for a prophylactic intervention.

Haloperidol versus Haloperidol plus Ondansetron for the Prophylaxis of Postoperative Nausea and Vomiting after Ophthalmologic Surgery

Introduction: In this prospective, randomized, and double-blinded study we investigated the efficacy of haloperidol (10 μg/kg) and the combination of haloperidol (10 μg/kg) with ondansetron (0.1 mg/kg) for the prophylaxis of postoperative nausea and vomiting (PONV) after ophthalmologic surgery. Methods: 60 patients (ASA status 1–3) with risk factors for PONV (female, non-smoker, motion sickness or PONV in history, opioids for postoperative analgesia) undergoing retinal or strabismus surgery were included into the study and randomised to the haloperidol group (H-Group) or the haloperidol-ondansetron group (H/O-Group). 20 min before the end of anaesthesia the study medication was given. Nausea, vomiting, pain scores, and adverse events were assessed postoperatively over 24 h. Results: The incidence of PONV was lower for the H/O-Group (23 vs. 57% for the H-Group). Especially the incidence of vomiting was reduced for the H/O-Group (7 vs. 27% in the H-Group). No significant differences could be detected regarding adverse events. Conclusion: The single use of haloperidol for the prophylaxis of PONV is doubtful. Better results were obtained with the combination therapy of haloperidol with ondansetron, especially for vomiting.

The medical and surgical treatment of glaucoma.

BACKGROUND Ongoing demographic changes in Europe are heightening the importance of adequate treatment for glaucoma, a disorder that is markedly more common in the elderly. METHOD A selective search for relevant literature, including Cochrane Reviews and the guidelines of the European Glaucoma Society, regarding the topical and surgical treatment of glaucoma. RESULTS It is recommended that the intraocular pressure (IOP) should be lowered by 20% to 50% from its baseline value, depending on the extent of already existing damage, the rate of progression, the baseline IOP, and the age of the patient. Topical monotherapy can lower the IOP by 15% to 30%. The success rate of filtration surgery has risen because of the intraoperative application of topical antimetabolites and currently ranges from 50% to 90%, depending on the study. CONCLUSIONS The goal of glaucoma treatment is to protect the patient from blindness and visual impairment while keeping the treatment-related decline in quality of life to a minimum. Any type of glaucoma treatment, be it medical or surgical, must further this aim in consideration of the situation of the individual patient.

Microprocessor controlled compliance monitor for eye drop medication

Background/aims: The effectiveness of a self administered eye drop medication can only be assessed if the compliance is known. The authors studied the specificity and sensitivity of a new microprocessor controlled monitoring device. Methods: The monitoring system was conducted by an 8 bit microcontroller for data acquisition and storage with sensors measuring applied pressure to the bottle, temperature, and vertical position. 10 devices were mounted under commercial 10 ml eye drops. Test subjects had to note down each application manually. A total of 15 applications each within 3 days was intended. Results: Manual reports confirmed 15 applications for each of the 10 bottles. The monitoring devices detected a total of 149 events; one was missed; comprising a sensitivity of 99%. Two devices registered three applications, which did not appear in the manual protocols, indicating a specificity of about 98%. Refrigerated bottles were correctly identified. The battery lifetime exceeded 60 days. Conclusion: The new monitoring device demonstrated a high reliability of the collected compliance data. The important, yet often unknown, influence of compliance in patient care and clinical trials shall be illuminated by the new device. This may lead to a better adapted patient care. Studies will profit from a higher credibility and results will be less influenced by non-compliance.