[Proliferative vitreoretinopathy prophylaxis : Mission (im)possible]. / Proliferative Vitreoretinopathieprophylaxe : Mission (im)possible.

BACKGROUND: Proliferative vitreoretinopathy (PVR) is one of the most important complications following vitreoretinal surgery. So far, surgical strategies have been the gold standard in treatment. Pharmacological approaches for prevention and treatment of PVR are under clinical investigation and intervene in different phases of the PVR cascade. METHODS: The relevant literature as well as own data and experience with PVR are discussed in this review article. The most important aspects of pharmacological approaches for PVR prophylaxis and treatment are explained. RESULTS: A prophylactic use of systemic prednisone administration as an anti-inflammatory substance showed contradictory results, while there was no additional benefit for intravitreal triamcinolone. Orally administered isotretinoin also seems to be able to minimize the formation of PVR after retinal reattachment surgery, whereas there was no improvement in the success rate in established PVR. Cell proliferation inhibitors have already been extensively studied. The combined intravitreal prophylactic approach of 5­fluorouracil and low molecular weight heparin was recently further investigated in a multicenter, placebo-controlled study and showed a positive effect in some studies. New preclinical and experimental approaches include the inhibition of growth factors, modulation of integrin activity and the induction of apoptosis. CONCLUSION: Most clinical studies dealt with an anti-inflammatory or antiproliferative approach. So far, no pharmacological substance has been established for the treatment of PVR but there are promising approaches for prophylaxis.

Early local activation of complement in aqueous humour of patients with age-related macular degeneration.

OBJECTIVE: To investigate complement activation in aqueous humour of patients with early, intermediate and neovascular age-related macular degeneration (AMD). PATIENTS AND METHODS: Aqueous humour of 79 AMD patients (early, intermediate and neovascular) and 77 age-matched controls was prospectively collected. The levels of the complement protein 3 (C3), activation products complement factor 3a (C3a) and Ba, C3b/iC3b, complement factors B, H and I (CFB, CFH and CFI), and total protein concentration were measured. Data were modelled using covariate analysis to assess the impact of age and glaucoma status of patients and total protein concentration of samples on complement protein concentration across groups. RESULTS: C3a concentration was significantly increased in the aqueous humour of early (p = 0.016), intermediate (p = 0.003) and neovascular (p = 0.018) AMD patients, whilst C3 concentration was significantly increased in early AMD patients only (p = 0.019). Levels of CFB and CFH were significantly increased in the aqueous humour of neovascular AMD patients (p = 0.023 and p = 0.018, respectively). CONCLUSIONS: Our findings provide evidence for early local complement dysregulation in AMD patients, suggesting that complement pathway inhibition may be a clinically relevant intervention for early stages of AMD.

[Laser flare photometry for identification of high-risk patients for proliferative vitreoretinopathy]. / Laser Flare Photometrie zur Identifizierung von Hochrisikopatienten für proliferative Vitreoretinopathie.

Proliferative vitreoretinopathy (PVR) is a complication of rhegmatogenous retinal detachment and trauma, which occurs in approximately 10% following vitreoretinal surgery. The visual prognosis for established PVR is poor and so far there is no established conservative treatment for PVR. In the currently recruiting PRIVENT trial the aim is to find a prophylactic treatment possibility for PVR. The PRIVENT study examines the influence of intraoperative adjuvant pharmacotherapy on reducing the incidence of PVR; however, this requires the identification of eyes with increased risk for PVR. Laser flare photometry is a simple method to predict the individual risk for PVR. It is a non-invasive technique that objectifies the Tyndall effect. Various laser flare meter devices are available on the market. In previous studies it could be shown that laser flare photometry can predict the development of PVR in eyes with primary rhegmatogenous retinal detachment with a sensitivity of 80%. The identification of these high-risk eyes for PVR could be the first step towards solving the problem of PVR.

[Indications for Retinal Laser Therapy Revisited]. / Wann wird heute noch gelasert?

BACKGROUND: Laser therapy is an important treatment option in retinal diseases, especially in cases of vascular involvement. Most approaches are based on coagulation of retinal structures. As there is increasing use of agents targetting vascular endothelial growth factor in the treatment of macular diseases, indications for the use of laser treatment need to be reviewed carefully, especially with respect to their significance in first line therapy. This article explains recent strategies and treatment protocols. MATERIALS AND METHODS: Review of current literature in PubMed as well as synopsis of relevant guidelines. RESULTS AND CONCLUSION: Retinal laser therapy is still widely used within retinal opthalmology and covers a large spectrum of indications. Despite the success of medical approaches, retinal laser therapy remains an indispensable treatment option for proliferative diabetic retinopathy, central or peripheral vein occlusion and less frequent pathologies, such as retinopathy of prematurity or Coats's disease.

Intrathecal immunoglobulin synthesis in patients with symptomatic epilepsy and epilepsy of unknown etiology ('cryptogenic').

BACKGROUND AND PURPOSE: To compare the frequency of intrathecal immunoglobulin (Ig) synthesis in patients with symptomatic epilepsy and epilepsy of unknown etiology ('cryptogenic'). METHODS: Patients with epileptic (n = 301) and non-epileptic (n = 10) seizures were retrospectively screened for autochthonous intrathecal Ig synthesis and oligoclonal bands (OCBs) in the cerebrospinal fluid. RESULTS: Intrathecal IgG/OCBs were detected in 8% of patients with epilepsies of unknown etiology, 5% of patients with first seizures of unknown cause and 0-4% of patients with epilepsy due to brain tumors, cerebrovascular disease or other etiologies. Intrathecal IgG/OCBs were not seen in patients with psychogenic seizures. Identical OCBs in serum and cerebrospinal fluid were more common in all patient groups (10-40% depending on underlying etiology). CONCLUSIONS: Intrathecal IgG synthesis/OCBs were observed slightly more frequently in patients with 'cryptogenic' epilepsy and with first seizures of unknown etiology than in other patient groups. However, this remained an infrequent finding and thus we could not confirm humoral immunity as a leading disease mechanism in patients with epilepsy in general or with unknown etiology in particular.

Local complement activation in aqueous humor in patients with age-related macular degeneration.

PurposeTo investigate complement activation in aqueous humor and in plasma of patients with neovascular age-related macular degeneration (nAMD).Patients and methodsAqueous humor and EDTA-plasma of 31 nAMD patients and 30 age-matched controls was collected. The levels of the complement factor 3 (C3), the regulators factor H (FH), and factor I (FI), and of the complement activation products Ba, C3a, and the terminal complement complex (sC5b-9) were measured. Associations between complement levels and phenotype were determined using Mann-Whitney U-test.ResultsIn plasma, no significant differences were found between the nAMD group and the control group. In aqueous humor, significantly increased levels of Ba (P=0.002), and C3a (P=0.002) indicate local complement activation in nAMD patients and a trend for a concomitant upregulation of the complement regulators FH (P=0.02) and FI (P=0.04).ConclusionsOur findings provide strong evidence for a local complement dysregulation in nAMD patients.

[Proliferative Vitreoretinopathy: Therapeutic Strategies]. / Proliferative Vitreoretinopathie: therapeutische Strategien.

BACKGROUND: Development of proliferative vitreoretinopathy (PVR) is one of the most important complications of vitreoretinal surgery. Reaching the decision to treat and surgical treatment itself are both challenging. MATERIALS AND METHODS: Our own data and a review of the literature in PubMed are summarised. RESULTS: Pharmacological approaches to the prevention and treatment of proliferative vitreoretinopathy have been limited to concepts that have been investigated in preclinical and a few clinical studies. Anti-inflammatory and antiproliferative substances may be mentioned in this context. Surgical techniques range from scleral buckling to the gold standard pars plana vitrectomy, preferably with silicone oil endotamponade. Applying an encircling band, retinotomy or retinectomy can be useful in reattaching the tractional shortened retina. CONCLUSION: Surgery is still the method of choice for the treatment of PVR. Pharmacological strategies to prevent or treat PVR have not been established.

Comparison of subthreshold micropulse laser (577 nm) treatment and half-dose photodynamic therapy in patients with chronic central serous chorioretinopathy.

PurposeTo compare the short-term treatment outcome of the 577 nm subthreshold micropulse laser (SML) and half-dose photodynamic therapy (PDT) in patients with chronic central serous chorioretinopathy (cCSC) and persistent subretinal fluid (SRF).MethodsThis retrospective study included 100 eyes of 100 consecutive patients who were treated with the 577 nm SML (Supra Scan, Quantel Medical) (n=42) or half-dose PDT (n=58) for cCSC. The treatment was applied at the leakage sites in the fluorescein and indocyanine green angiography. The treatment success was evaluated 6 weeks after treatment using best-corrected visual acuity, central retinal thickness, and resolution of SRF in spectral domain optical coherence tomography.ResultsPatients showed treatment response more often in the SML group compared with the PDT group (treatment response after SML: 33 eyes (79%), PDT: 34 eyes (59%), P=0.036, χ2 test). The CRT decreased significantly after both treatments (mean CRT before SML: 445±153 µm, after SML: 297±95, P<0.001; mean CRT before PDT: 398±88 µm, after PDT: 322±93 µm, P<0.001, Wilcoxon's signed-rank test). The decrease in CRT was statistically significantly higher in the SML group (decrease in CRT after SML: -148±163 µm, after PDT: -76±104 µm, P=0.041, Mann-Whitney U-test).ConclusionsBoth the half-dose PDT and the 577 nm SML are potent treatments for cCSC with persistent SRF. More patients showed treatment response to the SML treatment and SML leads to a greater decrease in CRT.

Variability of disease activity in patients treated with ranibizumab for neovascular age-related macular degeneration.

PurposeTo analyze choroidal neovasularization (CNV) activity and recurrence patterns in patients with neovascular age-related macular degeneration (nAMD) treated with ranibizumab, and the correlation with individual intraocular vascular endothelial growth factor (VEGF) suppression time (VST).MethodsPost-hoc analysis of data from a prospective, non-randomized clinical study. Patients with nAMD treated with ranibizumab on a pro re nata regimen. Disease activity was analyzed monthly by spectral-domain optical coherence tomography and correlated with VSTs.ResultsOverall, 73 eyes of 73 patients were included in the study with a mean follow-up of 717 days (range: 412-1239 days). Overall, the mean CNV-activity-free interval was 76.5 days (range: 0-829 days). The individual range of the length of dry intervals was high. A total of 42% of patients had a range of more than 90 days. Overall, 16% of patients showed persistent activity. And 12% stayed dry after the initial ranibizumab treatment. No significant correlation was found between the CNV-recurrence pattern and VST (P=0.12).ConclusionsCNV activity in nAMD is irregular, which is reflected in the range of the duration of dry intervals and late recurrences. The biomarker VST solely seems not to be sufficient to explain recurrence pattern of CNV in all AMD patients.

Transcutaneous Vagus Nerve Stimulation (tVNS) for Treatment of Drug-Resistant Epilepsy: A Randomized, Double-Blind Clinical Trial (cMPsE02).

BACKGROUND: Various brain stimulation techniques are in use to treat epilepsy. These methods usually require surgical implantation procedures. Transcutaneous vagus nerve stimulation (tVNS) is a non-invasive technique to stimulate the left auricular branch of the vagus nerve at the ear conch. OBJECTIVE: We performed a randomized, double-blind controlled trial (cMPsE02) to assess efficacy and safety of tVNS vs. control stimulation in patients with drug-resistant epilepsy. METHODS: Primary objective was to demonstrate superiority of add-on therapy with tVNS (stimulation frequency 25 Hz, n = 39) versus active control (1 Hz, n = 37) in reducing seizure frequency over 20 weeks. Secondary objectives comprised reduction in seizure frequency from baseline to end of treatment, subgroup analyses and safety evaluation. RESULTS: Treatment adherence was 84% in the 1 Hz group and 88% in the 25 Hz group, respectively. Stimulation intensity significantly differed between the 1 Hz group (1.02 ± 0.83 mA) and the 25 Hz group (0.50 ± 0.47 mA; p = 0.006). Mean seizure reduction per 28 days at end of treatment was -2.9% in the 1 Hz group and 23.4% in the 25 Hz group (p = 0.146). In contrast to controls, we found a significant reduction in seizure frequency in patients of the 25 Hz group who completed the full treatment period (20 weeks; n = 26, 34.2%, p = 0.034). Responder rates (25%, 50%) were similar in both groups. Subgroup analyses for seizure type and baseline seizure frequency revealed no significant differences. Adverse events were usually mild or moderate and comprised headache, ear pain, application site erythema, vertigo, fatigue, and nausea. Four serious adverse events were reported including one sudden unexplained death in epilepsy patients (SUDEP) in the 1 Hz group which was assessed as not treatment-related. CONCLUSIONS: tVNS had a high treatment adherence and was well tolerated. Superiority of 25 Hz tVNS over 1 Hz tVNS could not be proven in this relatively small study, which might be attributed to the higher stimulation intensity in the control group. Efficacy data revealed results that justify further trials with larger patient numbers and longer observation periods.

Extramacular drusen are highly associated with age-related macular degeneration, but not with CFH and ARMS2 genotypes.

BACKGROUND: To evaluate the association of extramacular drusen (EMD) with age-related macular degeneration (AMD) and with complement factor H (CFH rs1061170) and age-related maculopathy susceptibility 2 (ARMS2 rs10490924) polymorphisms in individuals with and without AMD. METHODS: In this case-control study, AMD staging was performed in 622 individuals. EMD were defined as ≥10 drusen (including ≥1 intermediate drusen) outside the Early Treatment of Diabetic Retinopathy Study Grid within field 2. Genotype associations for CFH and ARMS2 variants were assessed using logistic regression analysis. RESULTS: EMD (n=213) showed a strong association with AMD (OR=3.85; p=1.66×10(-13)). AMD (n=316) was strongly associated with CFH (p=1.78×10(-7)) and ARMS2 genotypes (p=1.67×10(-8)). After adjustment for AMD, age and gender, EMD were neither associated with CFH (p=0.11) nor with ARMS2 (p=0.45) genotypes. In individuals without AMD, the groups with and without EMD showed no differences regarding both genetic variants. CONCLUSIONS: The strong association between drusen within and outside of the macula suggests a common pathogenesis. However, EMD were not AMD-independently associated with CFH or ARMS2 genotypes. Our results indicate that patients without AMD but with EMD can serve as controls in studies evaluating AMD risk factors. Further studies are required to elucidate the aetiology and clinical relevance of EMD.

[Rebound tonometry after vitreoretinal surgery]. / Reboundtonometrie nach vitreoretinaler Chirurgie.

PURPOSE: The aim of this study was to analyze the practicability and comparability of the Icare rebound tonometer (RT) versus the Schiötz indentation tonometer (SIT) and the Goldmann applanation tonometer (GAT) for measuring intraocular pressure (IOP) in patients after pars plana vitrectomy (PPV). METHODS: A total of 100 eyes from 100 patients who underwent vitreoretinal surgery in the Department of Ophthalmology, University of Cologne were included in this prospective analysis. The IOP was measured using RT preoperatively, on the day of surgery and 2 days after surgery, using SIT on the day of surgery and GAT preoperatively and 2 days after surgery. For the evaluation eyes were divided into subgroups with respect to the endotamponade selected and the IOP level. RESULTS: The mean preoperative IOP for all enrolled eyes was 15.4 ± 8.0 mmHg for RT and 16.1 ± 7.9 mmHg for GAT. Bland-Altman analysis revealed a bias between RT and GAT of - 0.6 mmHg. Bland-Altman analysis for the postoperative course of all eyes revealed a bias of 3.0 mmHg between RT and SIT on the day of surgery and no bias between RT and GAT in the further postoperative follow-up. CONCLUSION: Rebound tonometry seems to provide precise IOP values after vitreoretinal surgery. Divergence from SIT values on the day of surgery is presumably due to a general tendency of SIT to underestimate IOP values. Therefore, RT can be used in the clinical routine after vitreoretinal surgery as an alternative to GAT.

[Retrospective investigation of anti-VEGF treatment reality and effectiveness in patients with neovascular age-related macular degeneration (AMD) in Germany: treatment reality of ranibizumab for neovascular AMD in Germany]. / Retrospektive Untersuchung der Anti-VEGF-Behandlungsrealität und Wirksamkeit bei Patienten mit neovaskulärer altersabhängiger Makuladegeneration (nAMD) in Deutschland : Behandlungsrealität von Ranibizumab bei nAMD in Deutschland.

BACKGROUND: Neovascular (wet) age-related macular degeneration (wAMD) is a progressive and degenerative retinal disease. This study reports the real-life use in Germany of the standard anti-vascular endothelial growth factor (VEGF) therapy for wAMD as an intravitreal operative drug application. PATIENTS AND METHODS: Within the framework of an international retrospective study the medical records of patients with wAMD who were first treated with ranibizumab between 1 January and 31 August 2009 were evaluated. Data were collected until the end of treatment and/or monitoring or until 31 August 2011. The primary objective was to evaluate changes in visual acuity after the start of anti-VEGF therapy. Secondary outcomes included determining real-life anti-VEGF treatment regimens and disease-monitoring practices. RESULTS: Out of 2227 patients who received ≥ 1 anti-VEGF injection with a baseline visual acuity assessment and ≥ 1 post-baseline visual acuity assessment for the treated eye, 420 were included in the German cohort. Visual acuity improved until about day 90 but these gains in visual acuity were not maintained. The mean changes in visual acuity scores from baseline to years 1 and 2 were 1.1 ± 15.7 and - 0.8 ± 17.2 letters, respectively. Patients received a mean of 4.3 ± 1.9 and 1.3 ± 2.2 injections in years 1 and 2, respectively. The majority of visits ( 98.6 %) were conducted irregularly and outside the time frame recommended at the time of the study, with an average of 47.7 ± 36.7 days between visits. More frequent visits and injections were associated with greater improvements in visual acuity. CONCLUSION: Treatment intensity was not sufficient to maintain the initial improvement in visual acuity by ranibizumab treatment. Real-life results for visual acuity and injection frequency in the German cohort were worse at that time than in other countries. Regular follow-up visits as well as timely retreatment in the presence of signs of disease activity are required to achieve optimal results in wAMD when applying a pro re nata-based strategy.

Cathepsin proteases promote angiogenic sprouting and laser-induced choroidal neovascularisation in mice.

Cysteine cathepsins are a family of proteases involved in intracellular protein turnover and extracellular matrix degradation. Cathepsin B (Ctsb) and cathepsin Z (Ctsz) promote tumorigenesis and Ctsb is a known modulator of tumor angiogenesis. We therefore investigated the angiomodulatory function of these cathepsins in vitro as well as in a mouse model of laser-induced choroidal neovascularization (laser-CNV). Ctsb(-/-), Ctsz(-/-), Ctsb/Ctsz double-knockout (Ctsb/z DKO), and wild type (WT) mice underwent argon laser treatment to induce choroidal neovascularization (CNV). The neovascularized area was quantified individually for each lesion at 14 days after laser coagulation. In vitro the effects of cathepsin inhibitors on angiogenesis were analysed by endothelial cell (EC) spheroid sprouting and EC invadosome assays. Retinas from cathepsin KO mice did not show gross morphological abnormalities. In the laser CNV model, however, Ctsb/z DKO mice displayed a significantly reduced neovascularized area compared to WT (0.027 mm(2) vs. 0.052 mm(2); p = 0.012), while single knockouts did not differ significantly from WT. In line, VEGF-induced EC spheroid sprouting and invadosome formation were not significantly altered by a specific cathepsin B inhibitor alone, but significantly suppressed when more than one cathepsin was inhibited. Our results demonstrate that laser-CNV formation is significantly reduced in Ctsb/z DKO mice. In line, EC sprouting and invadosome formation are blunted when more than one cathepsin is inhibited in vitro. These results reveal an angiomodulatory potential of cathepsins with partial functional redundancies between different cathepsin family members.

[Cost of illness of age-related macular degeneration. Systematic review on the development of a costs diary]. / Krankheitskosten der altersbedingten Makuladegeneration. Systematischer Review zur Entwicklung eines Kostentagebuchs.

Due to demographic changes in the German population a significant rise in incident cases of age-related macular degeneration (AMD) is to be expected in the coming years. Also the corresponding increase in costs of the illness requires appropriate survey instruments to allow accurate estimations of costs. The cost diary for patients with AMD developed in this study is based on a previously established systematic review. The seven studies that were included were evaluated regarding their quality in order to then extract the listed cost items. The result is a prospective survey instrument with six different cost sectors of AMD.

Management of cortical dysplasia in epilepsy.

Focal cortical dysplasias (FCD) are increasingly diagnosed as a cause of symptomatic focal epilepsy in paediatric and adult patients. Nowadays, focal cortical dysplasias are identified as the underlying pathology in up to 25% of patients with focal epilepsies. The histological appearance can vary from mild architectural disturbances to severe malformation containing atypical cellular elements like dysmorphic neurons and Balloon cells. Clinical presentation depends on the age at onset of epilepsy, the location and size of the lesion. In most patients seizures begin in early childhood and the course of epilepsy is often severe and pharmaco-resistant. For the majority of patients, epilepsy surgery is the only treatment option in order to become seizure free.In this review an overview on the literature of the last ten years is provided, focussing on histological appearance and classification, pathogenetic mechanisms and clinical presentation of cortical dysplasias. Recent developments in the presurgical diagnostic and outcome after operative treatment as well as prognostic factors are summarized. Finally, an outlook is given on the development of future novel treatment options that might be minimally invasive and help especially the patient group who is inoperable or has failed epilepsy surgery.

Changes in interhemispheric inhibition following successful epilepsy surgery: a TMS study.

Epileptic foci can influence cortical excitability, brain perfusion and metabolism not only directly in the focus or perifocally, but also in remote areas. Effects of successful epilepsy surgery on cortical networks and changes in excitability have rarely been addressed. We report a study on changes in interhemispheric inhibition following successful surgical removal of an epileptic focus. Eighteen patients (11 females, 7 males, mean age 34.2 years) were enrolled in this transcranial magnetic stimulation (TMS) study. All patients were seizure free after surgery and had identical antiepileptic medication pre- and postsurgically. Investigations were performed before and at least 3 months after surgery. Motor thresholds (MT) and motor evoked potentials (MEPs) of interhemispheric paired pulse paradigms were investigated on both hemispheres. Resection of the epileptic focus resulted in a significant change in interhemispheric inhibition (IHI). The ability of the non-focal hemisphere to inhibit the motor cortex (M1) of the focal hemisphere significantly increased (p=0.02) and normalized to the level of the other hemisphere. In summary, this TMS study suggests that an epileptic focus can modulate interhemispheric inhibitory interactions between the motor cortices. A decreased susceptibility of M1 of the focal hemisphere or alterations in the non-focal hemispheric inhibitory output may be underlying mechanisms. These findings may contribute to a better understanding of widespread functional impairments in focal epilepsy.

[Unexplained loss of visual acuity in a 22-year-old woman]. / Unklare Visusminderung bei einer 22-jährigen Patientin.

Developmental disorders of the fovea are almost always accompanied by loss of visual acuity (VA) and are usually associated with different syndromes. We report on a young female patient with an unclear loss in VA, inconspicuous medical history and normal results for funduscopy, electrophysiology and clinical examinations. The presence of fovea plana could be confirmed by spectral-domain optical coherence tomography (OCT).