Altered serum levels of autophagy proteins Beclin-1 and mTOR in patients with exudative age-related macular degeneration.

Autophagy is a key process in the maintenance of cellular survival and homeostasis. Inhibition of autophagy results in degenerative changes resembling ageing. We wondered if autophagy can contribute to the pathogenesis of age-related macular degeneration (AMD). We aimed to investigate the serum concentrations of two key autophagy regulators, Beclin-1 and mechanistic target of rapamycin (mTOR), in patients with exudative AMD. This retrospective case-control study included 38 patients with exudative AMD and 36 sex- and age-matched controls selected among senile cataract patients. Circulating Beclin-1 and mTOR were assessed using an enzyme-linked immunosorbent assay. The proteins levels were correlated with age, sex, duration of ocular symptoms, as well as angiographic and optical coherence tomography findings. Serum Beclin-1 levels were much lower in patients with AMD than in controls (median, 0.100 ng/ml versus 1.123 ng/ml; p = 0.0033), while mTOR levels did not differ (median, 4.377 ng/ml versus 3.608 ng/ml; p = 0.4522). Participants of the study older than 70 years had lower Beclin-1 levels than younger ones (p = 0.0444). However, this difference was the most evident in patients with AMD (p = 0.0024). Serum mTOR levels increased with age. In patients with AMD, lower mTOR levels were associated with drusen, while higher levels were observed in those with a fibrous scar in the contralateral eye (p = 0.0212). Our findings suggest that circulating Beclin-1 decreases with age and that is downregulated in patients with AMD.

Effect of photodynamic therapy with verteporfin on tumor thickness and best corrected visual acuity in patients with circumscribed choroidal hemangioma: a single-center experience.

The management of circumscribed choroidal hemangioma (CCH) with photodynamic therapy (PDT) using verteporfin has resulted in significant functional and clinical improvement compared with the pre-PDT era. Literature data on factors influencing clinical outcomes and predictors of response to PDT in symptomatic CCH are inconsistent. The aim of this study was to investigate the efficacy of PDT with verteporfin in patients with CCH depending on symptom duration and tumor thickness at baseline. We analyzed the medical records of 37 patients with symptomatic CCH divided into 3 groups according to symptom duration (≤ 50 weeks, 51 - 100 weeks, and > 100 weeks) and into 2 groups according to tumor thickness (≤ 2.3 mm and > 2.3 mm). Patients were subjected to PDT with verteporfin at a concentration of 6 mg/m2 body surface area and a light dose of 50 J/cm2 at a wavelength of 689 nm. The mean number of treatment sessions was 1.57 (range, 1 - 3). Tumor thickness, the transverse and longitudinal diameters of the tumor base, and best corrected visual acuity (BCVA) were evaluated at baseline and at 12 - 15 months after treatment. After PDT, the mean tumor thickness in the whole study group decreased by 1.19 ± 0.66 mm (from 3.14 mm to 1.95 mm). Subgroup analyses revealed no significant differences between the 2 groups divided according to tumor thickness (p = 0.49). However, tumor thickness differed significantly between the 3 groups divided according to symptom duration (p < 0.05). BCVA increased in 22 patients (59.5%), remained unchanged in 12 patients (16.2%), and decreased in 3 patients (10.1%). Our study provides evidence for the efficacy of PDT with verteporfin in terms of improving or stabilizing visual function as well as reducing tumor thickness in patients with CCH, including those with long-lasting disease.

Central serous chorioretinopathy induced by drugs metabolized by cytochrome P450 3A4.

The purpose of this study was investigate whether replacing or discontinuing drugs that are inhibitors or substrates of cytochrome P450 3A4 (CYP3A4) may improve the clinical course of central serous chorioretinopathy (CSC). A retrospective observational study included 43 patients with active CSC. Twenty seven patients (32 eyes, group 1) were using drugs that act as substrates or inhibitors of CYP3A4. In 25 of these 27 patients, treatments including steroids, calcium channel blockers, anticoagulants, statins, beta-adrenolytics, angiotensin receptor antagonists, antidepressants, muscarinic receptor antagonists, phosphodiesterase type 5 inhibitors, and others were discontinued or replaced with medications not affecting CYP3A4. Sixteen patients (19 eyes, group 2) not using any medication that affects CYP3A4, were given eplerenone, rifampicin, or laser treatment. Main outcomes measures were assessed by functional and anatomical images obtained using multimodal imaging techniques. The average follow-up time was 12 months. In group I after discontinuing or replacing substrates or inhibitors of CYP3A4, improvements were observed in 18 patients (22 eyes). None of the patients that were using drugs affecting CYP3A4 improved with eplerenone therapy, however, all 18 patients improved after discontinuing the drugs. All these drugs had a blocking effect on eplerenone therapy. Best corrected visual acuity (BCVA) improved in 14 eyes, remained unchanged in 5 eyes, and worsened in 3 eyes. In 21 of the 22 eyes, subretinal fluid absorption was observed with optical coherence tomography (OCT). Mean central retinal thickness decreased from 361 µm to 219 µm. One patient (2 eyes) was unable to change treatment (due to neoplasm), one patient (1 eye) did not agree to change or stop treatment, and seven patients (7 eyes) were lost to follow-up. Of the 16 patients (19 eyes) who were treated with eplerenone, rifampicin, or laser, improvements were observed in 14 patients (16 eyes), two patients (2 eyes) were lost to follow-up, and CSC worsened in 1 eye. We concluded that patients with CSC should not take substrates or inhibitors of CYP3A4. These drugs should be replaced with alternatives that act through other metabolic pathways.

Differences in anti-endothelial and anti-retinal antibody titers: implications for the pathohysiology of acute and chronic central serous chorioretinopathy.

The aim of the study was to evaluate the prevalence of serum anti-retinal (ARAs) and anti-endothelial cell antibodies (ACEAs) in patients with acute and chronic central serous chorioretinopathy (CSC). We enrolled 28 patients with acute CSC, 42 patients with chronic CSC, and 40 healthy controls. The presence of ARAs was determined by indirect immunofluorescence using monkey retina as an antigen substrate, while the presence of AECAs was determined using cultivated human umbilical vein endothelial cells (HUVECs) and primate skeletal muscle according to the manufacturer's instructions (Euroimmun AG). There were no differences in the prevalence of antibodies against rods, cones, cytoplasmic components of retinal nuclear layer cells, and retinal vessels between the acute and chronic CSC groups and the control group (P = 0.27, P = 0.16, P = 0.71, and P = 0.06, respectively). However, AECAs reactive with HUVECs were observed in 46% of patients with acute CSC, 45% of those with chronic CSC, and 22% of controls, whereas AECAs reactive with the skeletal muscle were present in 46%, 45%, and 15%, respectively (difference between groups: P = 0.045 for HUVECs and P = 0.005 for the skeletal muscle). Furthermore, AECA titers were higher in CSC patients than in controls (P = 0.004). This study provides evidence for the possible involvement of an autoimmune process directed against vessel antigens in the pathogenesis of CSC. AECAs may be more important than ARAs in this disease and may be involved in endothelial damage in the choroidal vessels and choriocapillaris, leading to hyperpermeability, which is central to the pathophysiology of CSC.

Mydrane intracameral injection site can be an alternative to mydriatic drops instillation in cataract surgery.

The aim of this study is to compare Mydrane (combination of tropicamide 0.02%, phenylephrine 0.31% and lidocaine 1%) and mydriatic drops (tropicamide 1% and phenylephrine 10%) used for cataract surgery in terms of efficacy in pupil dilation and impact on corneal endothelial cell density (CD) and central corneal thickness (CCT). Prospective study including 64 eyes of 64 patients that underwent phacoemulsification with intraocular lens implantation. Patients were randomized into two groups: Mydrane group received: tropicamide and phenylephrine one day preoperatively and Mydrane during the surgery. Reference group received: tropicamide and phenylephrine preoperatively. Pupil size was measured only in Mydrane group, in the same eye of the same patient one day preoperatively after mydriatic drops were given and during the surgery, after intracameral Mydrane injection. CD and CCT were evaluated one day preoperatively and one month postoperatively in all patients and compared between Mydrane and reference groups. The results show CCT and CD significantly decreased after surgery in both groups. There is no difference in this decrease between groups. In Mydrane group there was no difference in dilated pupil diameter between Mydrane and mydriatic drops. Gender, diabetes mellitus, POAG, alpha-1 blocker treatment failed to affect pupil dilation obtained with Mydrane. Cataract surgery affects CCT and CD regardless of which mydriatic protocol had been used. Pupil diameter was similar after drops instillation and after Mydrane injection in all patients from the Mydrane group.

Non-responsiveness and tachyphylaxis to anti-vascular endothelial growth factor treatment in naive patients with exudative age-related macular degeneration.

Age-related macular degeneration (AMD) is a leading cause of central visual loss in people aged over 50 years in well developed countries. Although the anti-vascular endothelial growth factor (VEGF) therapy has become a standard treatment for exudative AMD, its effectiveness may be limited in some cases. We aimed to assess the prevalence of non-responsiveness and tachyphylaxis to anti-VEGF drugs in patients with exudative AMD. The study included 63 initially treatment-naive AMD patients who were analyzed for non-responsiveness and tachyphylaxis to intravitreal injections (IVI) of ranibizumab and aflibercept. The participants were enrolled in a National Healthcare Fund (NHF) Therapeutic Program for the Treatment of Exudative AMD. Best-corrected visual acuity (BCVA) and morphological features of a disease activity assessed in optical coherence tomography (OCT) were evaluated during a 12-month follow-up. The percentage of non-responders achieved 22.2% (14 eyes). No significant correlation was found between the type of VEGF inhibitor and a negative response to therapy. Eight patients (12.7%) developed early tachyphylaxis, which was more common in eyes treated with aflibercept (P = 0.04). The presence of serous pigment epithelium detachment (sPED) at baseline was associated with non-responsiveness as determined by both BCVA (OR 18.2, 95% CI 2.86 - 248; P = 0.021) and OCT features (OR 23.0, 95% CI 1.80 - 321; P = 0.030). Eyes treated with aflibercept showed statistically significant greater BCVA improvement (P = 0.0034) and central retinal thickness (CRT) reduction (P = 0.0129) as compared to ranibizumab group during a loading phase of therapy. In a maintain phase of treatment the differences in BCVA and CRT between these two groups were not statistically significant, however eyes treated with aflibercept still showed better functional and anatomical results. Anti-VEGF therapy is an effective method of treatment for exudative AMD, however some patients may show week or no positive reaction or may develop tachyphylaxis. Awareness of these possible negative effects is an important clinical problem in the long-term management of AMD patients with VEGF inhibitors.

[The use of indocyanine green angiography in differential diagnosis in intraocular tumors]. / Zastosowanie angiografii indocyjaninowej w diagnostyce róznicowej guzów wewnatrzgalkowych.

The author presents current opinions about the usefulness of indocyanine green angiography in differential diagnosis of choroidal tumors: melanomas, naevi, haemangiomas and choroidal metastasis.

[Immunologic disturbances in patients with idiopathic posterior uveitis]. / Zaburzenia ukladu immunologicznego u chorych na samoistne zapalenie tylnego odcinka blony naczyniowej.

PURPOSE: This study aimed to evaluate the immune system function in patients with idiopathic posterior uveitis. MATERIAL AND METHODS: 50 patients--29 women (58%) and 21 men (42%)--were examined. Intraocular inflammation intensity was scored on standard uveitis grading system prepared by BenEzra et al. In all cases selected parameters of serum immune system activity--immunoglobulins IgA, IgG, IgM, IgE, complement proteins C3c and C4, circulating immune complexes (CIC) and autoantibodies: ANA, ANCA, ACA were detected. All immune system parameters were assessed in active stage of the disease and then 1, 3, 6, 12 months after the beginning of immunosuppressive therapy. RESULTS: Among 50 patients immunological abnormalities were found in 38 cases (76%). Changes in serum immunoglobulin concentrations were present in 28 patients and the most common pathology was the deficiency of serum IgG in 11 subjects. In 34 cases abnormalities of the complement system were present. In 43 subjects serum CIC were detected. ANA in indirect immunofluorescence test were found in 9 patients. Neither ANCA nor ACA were present in serum of this group of patients. CONCLUSIONS: Non specific abnormalities of immune system parameters found in serum of 38 patients with idiopathic posterior uveitis can indicate their role in pathogenesis of this disease. The deficiency of IgG can be related to CIC formation in this group of patients. Probably circulating immune complexes (CIC) are involved in the pathogenesis of endogenous posterior uveitis and they can act as an aggressor or protector against the retinal autoimmune mechanisms.

[Interdependency between titers of aniretinal antibodies and selected immune system parameters in serum of patients with endogenous posterior uveitis]. / Zaleznosc pomiedzy mianem przeciwcial przeciwsiatkówkowych a wybranymi parametrami aktywnosci ukladu immunologicznego w surowicy chorych na endogenne zapalenie tylnego odcinka blony naczyniowej.

PURPOSE: To evaluate serum antiretinal antibodies and selected immune system activity parameters in patients with endogenous posterior uveitis. MATERIAL AND METHODS: 50 patients--29 women (58%) and 21 men (42%)--aged 15-70 with idiopathic posterior uveitis were examined. Intraocular inflammation intensity was scored on standard uveitis grading system prepared by BenEzra et al. In all cases selected parameters of serum immune system activity--immunoglobulins: IgA, IgG, IgM, IgE, complement proteins: C3c, C4, circulating immune complexes (CIC) and autoantibodies: ANA, ANCA, ACA, were detected. The serum levels of ARA were determined by indirect immunofluorescence test on normal monkey retina as a substrate and FITC-labelled anti-human IgA, IgG, IgM serum (Euroimmun, Germany). All immune system parameters were assessed in active stage of the disease and 1, 3, 6, 12 months after the beginning of immunosuppressive therapy. RESULTS: In 38 patients (76%) non specific abnormalities of serum immune system activity parameters were found. During the follow-up period the changes in serum concentrations of immune system parameters were not statistically significant. Before treatment ARA were present in serum of 40 patients (80%). The distinct decreasing of serum ARA levels was present during the whole time of observation. The statistical analysis did not show any correlation between the serum concentration of selected immune system parameters and ARA. However, the presence of two various tendencies between ARA and CIC serum levels co-fluctuations were observed. In subjects with absence or low CIC serum concentrations, high serum ARA levels were found and the uveitis was severe. In cases with high CIC serum concentrations, low ARA levels were present and the disease course was mild. CONCLUSION: The interdependency between CIC and ARA has probably an essential role in the pathogenesis of idiopathic posterior uveitis.

[Immunologic tests in patients with idiopathic uveitis--preliminary reports]. / Badania immunologiczne u chorych z samoistnym zapaleniem tylnego odcinka blony naczyniowej--doniesienie wstepne.

AIM: This study aimed to evaluate the immune system function in patients with uveitis of unknown aetiology. METHODS: The clinical material comprised 19 patients with endogenous uveitis. In all cases the following immunological tests were performed: serum immunoglobulins A, G, M, total IgE, circulating immune complexes, complement components C3c and C4-all determined by laser nephelometry; antinuclear antibodies assessed with indirect immunofluorescence method using HEp-2 cell lines; and antineutrophil cytoplasmic antibodies using indirect immunofluorescence test. In 4 cases lupus anticoagulant was measured with APTT and dRVVT assays. RESULTS: Among our 19 examined patients immunological abnormalities were found in 12 cases. Changes in immunoglobulin concentrations were found in 8 cases. In 4 patients abnormalities of the complement system were observed. Antinuclear antibodies with speckled pattern in indirect immunofluorescence were present in 7 cases. CONCLUSION: In a proportion of patients with endogenous uveitis mild immunological abnormalities were present, suggesting an autoimmune background of the disease. Studies of the immunological profile can therefore help in better evaluation of the patients. It remains to be determined whether the observed immunological alterations are of any importance in the pathogenesis of the studied disease.

[Long-term observations of ocular toxocariasis in children and youth]. / Odlegle obserwacje toksokarozy ocznej u dzieci i mlodziezy.

PURPOSE: To evaluate the clinical status and ELISA test changes in a group of children with ocular toxocariasis. METHODS: We enrolled 37 patients in the studies. The follow-up period lasted at least 3 years (3-15 years) after the diagnosis had been established. In all cases a complete ophthalmological examination and actual ELISA test were performed. We compared the clinical status in two groups of patients: one with positive and the other with negative ELISA test at the time of control examination. RESULTS: In a majority of initially positive serological patients the control ELISA test for Toxocara canis antigen was negative. In these cases various post-inflammatory lesions in the anterior and posterior pole of the eye were present. In 8 cases the ELISA test was positive, despite the absence of active inflammatory process. In 5 serologically positive patients the active inflammation was observed. In more than 50% of cases the visual acuity was decreased. CONCLUSION: Ocular toxocariasis is a long-lasting, severe type of uveitis that requires long treatment and causes dramatic visual impairment. ELISA test is a sensitive method indicating the intensity of inflammation in ocular toxocariasis.