Management of patients with dysthyroid optic neuropathy treated with intravenous corticosteroids and/or orbital decompression surgery.

PURPOSE: To assess the characteristics and long-term outcomes of adult patients with dysthyroid optic neuropathy (DON) who underwent orbital decompression surgery and/or received intravenous (IV) methylprednisolone. METHODS: Retrospective chart review of 98 eyes of 49 patients who were diagnosed and treated with bilateral DON between 2007 and 2018 at the Department of Ophthalmology and Optometry and Oral and Maxillofacial Surgery of the Medical University of Vienna. RESULTS: The mean follow-up period was 4.1 ± 2.7 years. The most common presenting symptoms were eyelid and periorbital swelling (45%) representing active inflammation. Upgaze restriction was the most common clinical finding (73%). At time of diagnosis, the mean clinical activity score was 4 ± 1/4 ± 1 (right/left eye, respectively). Sixty-three percent (31/49) of the patients were treated both with IV methylprednisolone and underwent orbital decompression surgery, 22% (11/49) were treated with IV methylprednisolone alone and 14% (7/49) underwent surgical decompression only. Seventy-one percent (30/42) of the patients underwent 3-wall decompression. The mean reduction of proptosis in patients treated with both IV methylprednisolone and orbital decompression surgery was 4/5 mm. Mean of reduction in proptosis in patients receiving IV methylprednisolone only was 1/0 mm and in patients with surgical decompression only was 5/5 mm. Mean VA was 0.1 ± 0.5/0.1 ± 0.5 logMAR at baseline and 0.05 ± 0.7/0.05 ± 0.7 at final follow-up. In 92% (45/49), VA was preserved or improved at final follow-up. CONCLUSIONS: The majority of patients with DON were treated both with IV corticosteroids and 3-wall decompression surgery. Vision could be successfully preserved in most cases and reduction of proptosis was achieved, especially after orbital decompression surgery.

Visual outcome and surgical results in children with Marfan syndrome.

IMPORTANCE: To determine visual and surgical results in children with Marfan syndrome. BACKGROUND: Marfan syndrome involves ocular complications which can lead to visual disturbance and amblyopia. Data about the visual and surgical results in children with Marfan syndrome is vital for the clinical management of these patients. DESIGN: Retrospective data analysis. PARTICIPANTS: Eighty-two eyes of 41 patients with a genetically proved diagnosis of Marfan syndrome. METHODS: Medical records of patients with Marfan syndrome were reviewed between 2007 and 2017. Ocular complications, visual acuity (VA) of patients with/without lensectomy and surgical method were evaluated. MAIN OUTCOME MEASURES: VA outcomes of patients with Marfan syndrome with/without surgical repair of ectopia lentis. RESULTS: In 27 (66%) of the 41 patients a bilateral subluxation of the lens was visible and 14 (52%) patients received lensectomy. The mean age at initial presentation was 12.3 ± 9 years and mean follow-up was 3 years (range 1-7). VA varied from 1.2 to -0.1 logMAR at first examination. At initial presentation, mean VA was 0.1 ± 0.7 logMAR in patients with a normal lens status (n = 14) and 0.3 ± 0.5 logMAR in patients with subluxation of the lens (n = 27) (P < .01). VA improved from 0.2 ± 0.5 logMAR to 0.1 ± 0.5 logMAR (P = .06) in children with subluxation of the lens who did not need a lensectomy (n = 12) and from 0.5 ± 0.5 logMAR to 0.2 ± 0.5 logMAR (P = .02) in patients who were referred to lensectomy with/without secondary lens implantation. CONCLUSIONS AND RELEVANCE: In Marfan syndrome subluxation of the lens was found in the majority of children. Improvement of VA resulted in children with subluxation of the lens and following lensectomy.

Total thyroidectomy (Tx) versus thionamides (antithyroid drugs) in patients with moderate-to-severe Graves' ophthalmopathy - a 1-year follow-up: study protocol for a randomized controlled trial.

BACKGROUND: Graves' disease (GD) is characterized by thyrotoxicosis and goiter and arises through circulating autoantibodies that bind to, and stimulate, the thyroid hormone receptor (TSHR). A temporal relation between the onset of hyperthyroidism and the onset of ophthalmopathy, a common extrathyroidal manifestation, has been demonstrated. Graves' ophthalmopathy (GO) is typically characterized by an inflammation and expansion of the extraocular muscles and an increase in retroorbital fat. There are currently three forms of therapies offered for hyperthyroidism caused by Graves' disease: antithyroid drugs (ATD) (thionamides), radioiodine ablation (RAI) and thyroidectomy (Tx). To date, there is no clear recommendation on the treatment of Graves' disease and GO, mainly due to the individuality of the disease in each patient. The aim of the study is to examine the difference in the outcome of GO in patients with moderate-to-severe GO who receive Tx versus further ATD after suffering their first relapse of GO, or in which GO stays the same following the initial decrease in ATD therapy after 6 months. METHODS/DESIGN: This prospective randomized clinical trial with observer-blinded analysis will analyze 60 patients with moderate-to-severe GO who receive Tx versus ATD without surgery. Main outcome variables include: muscle index measurements via ultrasound and thyroid antibody levels. Additional outcome variables include: Clinical Activity Score (CAScore), NOSPECS score, superonasal index measurements via ultrasound, and quality of life score. DISCUSSION: This study should allow for better therapeutic choices in patients with moderate-to-severe GO. In addition, it should demonstrate whether the outcome of GO in patients with moderate-to-severe GO is better in those who receive early Tx versus further ATD. Furthermore, this study will aim to establish a standard glucocorticoid scheme before and after Tx in patients with moderate-to-severe EO. TRIAL REGISTRATION: Eudra-CT: 2015-003515-38; Medical University of Vienna Protocol Record 1839/2015. Date of Ethics Committee approval: 19 January 2017. Registered on 27 January 2017.

EFFECT OF PATIENTS' CLINICAL INFORMATION ON THE DIAGNOSIS OF AND DECISION TO TREAT RETINOPATHY OF PREMATURITY.

PURPOSE: To evaluate the effect of patients' clinical information on experts' diagnoses of retinopathy of prematurity (ROP) and decisions to treat. METHODS: Seven experts assessed wide-field fundus photographs of eyes of 52 premature infants of ≤30 weeks' gestational age or ≤1,500 g birthweight (BW) for ROP diagnosis (stage, plus disease, and aggressive posterior ROP) and the necessity for treatment for 2 days. On Day 1, they were masked to all patient data. On Day 2, they were given information on gestational age and BW. RESULTS: A significant shift in the experts' ratings toward a less aggressive ROP grading stage (P = 0.006) and less frequent decision for intervention (P = 0.021) was observed after receipt of patients' clinical information. This was truer for heavier/less premature infants (gestational age ≥ 28 0/7 weeks or BW ≥ 900 g) than those with very low BWs/high prematurity (gestational age < 24 0/7 weeks or BW < 600 g) (ROP stage P = 0.009 vs. P = 0.399, treatment decision P = 0.022 vs. P = 0.648). CONCLUSION: These results suggest knowledge of patients' clinical information influences the grading of ROP disease and decision for treatment. Retinopathy of prematurity staging seemed to be set at a lower level and the decision for treatment at a higher threshold for heavier/less premature babies. Our findings may have implications for further refinements in ROP assessment.

Severe pediatric Graves orbitopathy in adolescents of African origin.

This article reports on two cases of severe pediatric Graves orbitopathy (GO) in two adolescents of African origin. Two black male adolescents presented with highly active GO and signs of beginning compressive optic neuropathy. Neither of them were smokers nor had a family history of GO. Besides urgent referral to pediatric endocrinologists, intravenous methylprednisolon pulse therapy was initiated. In spite of the fluctuating thyroid hormone levels in the initial phase of antithyroid therapy, intravenous steroid administration stopped the progression of malignant GO rapidly in both of our patients without any considerable side effects. Although the course of GO during childhood is considered to be mild, severe, sight threatening GO-requiring immunosuppression-may occur at young age, as in the reported adolescent patients of African descent.

Inter-expert and intra-expert agreement on the diagnosis and treatment of retinopathy of prematurity.

PURPOSE: To evaluate inter-expert and intra-expert agreement on the diagnosis and treatment of retinopathy of prematurity (ROP). DESIGN: Prospective intra- and inter-rater reliability analysis. METHODS: In this multicenter study, 260 wide-field digital photographs of 52 patients were presented to 7 recognized ROP experts on 2 consecutive assessment days 8 weeks apart. Experts were asked to assess the patients for ROP stage, presence of plus disease, presence of aggressive posterior ROP, necessity for treatment, and suggested treatment. Agreement levels were measured with Fleiss' kappa and Cohen's kappa. RESULTS: Inter-expert agreement was fair for the ROP stage (κ = 0.24), plus disease (κ = 0.32), and aggressive posterior ROP (κ = 0.35); moderate for the necessity for treatment (κ = 0.41); and fair for the kind of treatment (κ = 0.38). Perfect inter-expert agreement was found in 9.6% of all patients for ROP stage 0-5, 45.1% for ≥ stage 2 ROP, 17.3% for plus disease, 57.7% for aggressive posterior ROP, and 25% for the necessity for treatment. Intra-expert agreement was higher than inter-expert agreement and was moderate for the ROP stage (κ = 0.56) and plus disease (κ = 0.51), moderate to substantial for aggressive posterior ROP (κ = 0.60), moderate for the necessity for treatment (κ = 0.47), and substantial for the kind of treatment (κ = 0.63). CONCLUSIONS: ROP diagnosis and treatment decisions differ between experts and by 1 expert made on different days, indicating that the grading process is subjective and there is an observer bias when diagnosing ROP. These results could influence current practice in ROP assessment and training, and prompt further refinement of international ROP guidelines.

Twin-twin transfusion syndrome as a possible risk factor for the development of retinopathy of prematurity.

PURPOSE: The objective of this study was to evaluate the correlation between twin-twin transfusion syndrome (TTTS) and the development of retinopathy of prematurity (ROP) in premature infants. METHODS: Fifty-one infants who were less than 32 postmenstrual gestational weeks at birth or with a birth weight less than 1,501grams were included in this longitudinal observational study. The infants were matched by gestational age and birth weight, and divided into three groups: multiples with TTTS, multiples without TTTS, and singletons. The primary outcome variable was the incidence of ROP in infants affected by TTTS versus infants not affected by TTTS. Secondary outcome variables were multiple pregnancy, gestational age, and birth weight. RESULTS: Infants affected by TTTS showed a significantly higher incidence of ROP than infants not affected by TTTS (p < 0.01). TTTS donors and TTTS recipients were both at greater risk of developing ROP. ROP occurred in infants with TTTS whose gestational age at birth was significantly higher than that of infants with ROP who were not affected by TTTS (p = 0.01). Multiple pregnancy itself was not a risk factor for ROP disease. CONCLUSIONS: Infants affected by TTTS during pregnancy are at high risk of developing ROP, even if they were born at an older gestational age. Special awareness in ROP screening is necessary for these infants.

Influence of the vitreomacular interface on outcomes of ranibizumab therapy in neovascular age-related macular degeneration.

PURPOSE: To investigate the influence of the vitreomacular interface (VMI) on the functional and anatomic efficacy of ranibizumab therapy in patients with neovascular age-related macular degeneration (AMD). DESIGN: Subanalysis of a prospective, 12-month, multicenter, phase IIIb trial. PARTICIPANTS: A total of 353 treatment-naïve patients with subfoveal choroidal neovascularization (CNV) receiving quarterly or monthly ranibizumab therapy. METHODS: On monthly optical coherence tomography (OCT) scan sets, the VMI configuration was graded by a certified reading center into one of the following conditions: continuous posterior vitreoretinal attachment (PVA), vitreomacular adhesion (VMA), partial vitreous detachment without vitreomacular contact, or complete posterior vitreous detachment (PVD). Best-corrected visual acuity (BCVA) and central retinal thickness (CRT) measurements were performed at monthly intervals. Analysis included patients with a minimum of 10 OCT examinations, including baseline and month 12 (n = 251). After integration of the VMI configuration over 12 months, patients were divided into one of the following categories: PVD (n = 162), release of vitreomacular contact (RELEASE; n = 48), VMA (n = 37), or PVA (n = 4). General estimation equation analyses were applied to test for noninferiority of quarterly versus monthly treatment. MAIN OUTCOME MEASURES: The BCVA and CRT changes at month 12. RESULTS: Mean BCVA changes in letters were +4.7 (PVD), +3.2 (RELEASE), and -0.2 (VMA) in the quarterly regimen and +4.9 (PVD), +12.7 (RELEASE), and +7.5 (VMA) in the monthly regimen. No difference in therapeutic efficiency between monthly and quarterly intervention was found in eyes with PVD, and quarterly treatment was noninferior to monthly treatment (P = 0.001). However, monthly treatment was superior to quarterly treatment in the RELEASE (P = 0.008) and VMA (P = 0.043) groups. Mean CRT changes were -98 and -96 µm (PVD), -117 and -136 µm (RELEASE), and -93 and -87 µm (VMA) in the monthly and quarterly regimens, respectively, without statistically significant differences. CONCLUSIONS: The configuration of the VMI seems to have an important effect on visual outcomes and need for retreatment. In patients with PVD, a lower treatment frequency may be feasible, whereas patients with RELEASE or VMA may benefit from intensive retreatment. These findings may serve as a basis for individualized treatment decisions in anti-angiogenic therapy of neovascular AMD and perhaps other indications.

Aspartic acid scaffold in bradykinin B1 antagonists.

Several novel bradykinin B1 receptor (B1R) antagonists were synthesized utilizing a new aspartic acid scaffold. This core is derived from the highly potent dihydroquinoxalinone scaffold published recently by researchers at Merck (Ha et al. Biochem. Biophys. Res. Commun. 2005, 331, 159-166). Despite the considerably limited chemical space of B1 antagonists, the synthesized compounds still showed significant biological activity. None of the four most potent compounds showed significant activity on the bradykinin B2 receptor (B2R), consequently they can be considered as valuable starting points for designing more potent and selective B1 antagonists. Furthermore, the synthesis of these aspartic acid derivatives is much simpler than that of the original Merck compounds suggesting efficient parallel synthesis approaches during their optimization. Docking known and novel B1 antagonists into the refined B1R homology model including the second extracellular loop (EC2) underlined the importance of this loop in ligand binding. Comparative binding mode analysis revealed that our novel compounds bind similar to the dihydroquinoxalinone template. Our results indicate that the rigid core of the dihydroquinoxalinone containing B1 antagonists is not crucial for maintaining B1 activity.

Visible light induces matrix metalloproteinase-9 expression in rat eye.

Up-regulation of matrix metalloproteinase-9 (MMP-9, gelatinase B) in the nervous system has been demonstrated when excitotoxicity-induced tissue remodeling and neuronal death occurs. Induction of MMP-9 by a natural stimulus has not been observed yet. Using RT-PCR and gelatin-zymography we demonstrated MMP-9 induction at transcriptional and protein levels in different structures of the rat eye following over-stimulation with white light. MMP-9 elevation occurred in the retina without reduction in photoreceptor number or major anatomical reorganization. A transient decrease in electroretinogram b-wave indicated the functional recovery. Retrobulbar injection of a broad-spectrum MMP-inhibitor GM6001, slowed the recovery rate of b-wave amplitude. Even room-light applied to dark-adapted awake animals induced MMP-9 increase in the retina, which suggests a role for MMP-9 in physiological functional plasticity of the nervous system, such as light adaptation. This is the first demonstration of MMP-9 induction by a sensory stimulus.

Phase-dependent molecular requirements for memory reconsolidation: differential roles for protein synthesis and protein kinase A activity.

After consolidation, a process that requires gene expression and protein synthesis, memories are stable and highly resistant to disruption by amnestic influences. Recently, consolidated memory has been shown to become labile again after retrieval and to require a phase of reconsolidation to be preserved. New findings, showing that the dependence of reconsolidation on protein synthesis decreases with the age of memory, point to changing molecular requirements for reconsolidation during memory maturation. We examined this possibility by comparing the roles of protein synthesis (a general molecular requirement for memory consolidation) and the activation of protein kinase A (PKA) (a specific molecular requirement for memory consolidation), in memory reconsolidation at two time points after training. Using associative learning in Lymnaea, we show that reconsolidation after the retrieval of consolidated memory at both 6 and 24 h requires protein synthesis. In contrast, only reconsolidation at 6 h after training, but not at 24 h, requires PKA activity, which is in agreement with the measured retrieval-induced PKA activation at 6 h. This phase-dependent differential molecular requirement for reconsolidation supports the notion that even seemingly consolidated memories undergo further selective molecular maturation processes, which may only be detected by analyzing the role of specific pathways in memory reconsolidation after retrieval.

Refractive laser surgery in children with coexisting medical and ocular pathology.

PURPOSE: To report the visual, refractive, and functional outcomes of photorefractive keratectomy (PRK) and of laser-assisted subepithelial keratectomy in a group of children with significant refractive error and underlying medical conditions or ocular pathology who were noncompliant with traditional management. SETTING: Nonhospital surgical facility and a hospital clinic. METHODS: This case series comprised 5 individual cases of anisometropic amblyopia and/or high myopia. Underlying medical and ocular conditions were as follows: upper eyelid hemangioma with oblique myopic astigmatism, Pelizaeus-Merzbacher leukodystrophy with nystagmus, Klippel-Trenaunay-Weber syndrome with glaucoma, incontinentia pigmenti with unilateral optic nerve atrophy, and Goldenhar syndrome with unilateral optic nerve hypoplasia. Photorefractive keratectomy or LASEK was performed in 6 eyes of 5 patients. Age range at the time of surgery was 1.0 to 7.0 years. All procedures were performed under general anesthesia. RESULTS: Best corrected visual acuity improved by 2 lines in 2 patients and 1 line in 2 patients by 6 months after surgery. Stereopsis and/or fusional status improved in 3 patients. Amblyopia treatment compliance improved in 1 patient. Alignment improved without strabismus surgery in 2 cases. A functional vision survey demonstrated a positive effect on the ability of all 5 children to function in their environment. CONCLUSION: During the period of visual cortical plasticity, refractive surgery, by eliminating the refractive component of amblyopia and by promoting fusional ability, provides considerable improvement in children, even those with underlying medical conditions associated with ocular pathology.

[Etiologic factors of malignant melanoma in young adults]. / Fiatalkori melanomák etiológiai tényezoi.

BACKGROUND: Malignant melanoma is the most aggressive type of skin cancers, involving the cutis and the mucosa. Its incidence keeps increasing dramatically in the last decades. It appears rarely in childhood. The main environmental risk factors are: excessive sun exposure and severe sunburns in both childhood and adolescence. Skin phototype, number of nevi, presence of congenital nevi (especially giant congenital nevi) and non-melanoma skin cancer in previous history refer to increased risk. Investigations of genetical factors have come to the front. The role of hormonal influences and traumas are recurring questions. AIM: The presence of melanoma typically concerns the middle-aged population. The purpose of this study was to determine the main risk factors, etiology factors and predisposing pediatric conditions in development of melanoma in young adulthood (under the age of 30). METHOD: A total of 70 new, histologically verified melanoma patient under 30 years were examined between 1993-2003 with a retrospective study. Results of questionnaire based survey and clinical data base about melanoma risk factors were also analysed. RESULTS: 5% of patients had giant congenital nevi, although in half of the patients (19/40) more than 20 moles were found. On the basis of patients' histories 57.5% of melanomas developed on a nevus existing from birth or childhood. 30% of melanomas developed on a pigmented brown alteration which rose on the normal skin. About 1/3 of patients had fair skin type and almost all patients (38/40) suffered from erythematous sunburn at first sunbath. Melanoma developed mostly on the trunk and lower extremities. 51.5% of patients belonged to Stage I (Breslow thickness below 1 mm in 33%). CONCLUSION: There were 70 young (under 30 years) patients were treated for malignant melanoma at the Dermatology Department of the National Institute of Oncology in Budapest from 1993 till 2003. The incidence of melanoma under the age of 30 was 3.3%. In young adulthood the main risk factors were the number of atypical nevi and repeated or severe sunburns in childhood. The skin type was also an important risk factor. 50% of the melanomas in young women developed on the trunk. Authors could not prove any relationship among hormonal factors, pregnancy and the development of the melanoma.

Cyclic AMP response element-binding (CREB)-like proteins in a molluscan brain: cellular localization and learning-induced phosphorylation.

The phosphorylation and the binding to DNA of the nuclear transcription factor, cyclic adenosine 3',5'-monophosphate (cAMP) response element-binding protein (CREB) are conserved key steps in the molecular cascade leading to the formation of long-term memory (LTM). Here, we characterize, for the first time, a CREB1-like protein in the central nervous system (CNS) of Lymnaea, a model system used widely for the study of the fundamental mechanisms of learning and memory. We demonstrate cAMP response element (CRE)-binding activity in CNS protein extracts and show that one of the CRE-binding proteins is recognized by a polyclonal antibody raised to mammalian (human) CREB1. The same antibody detects specific CREB1 immunoreactivity in CNS extracts and in the nuclei of most neurons in the brain. Moreover, phospho-CREB1-specific immunoreactivity is increased significantly in protein extracts of the CNS by forskolin, an activator of adenylate cyclase. The forskolin-induced increase in phospho-CREB1 immunoreactivity is localized to the nuclei of CNS neurons, some of which have an important role in the formation of LTM. Significantly, classical food-reward conditioning increases phospho-CREB1 immunoreactivity in Lymnaea CNS protein extracts. This increase in immunoreactivity is specific to the ganglia that contain the feeding circuitry, which undergoes cellular changes after classical conditioning. This work establishes the expression of a highly conserved functional CREB1-like protein in the CNS of Lymnaea and opens the way for a detailed analysis of the role of CREB proteins in LTM formation in this model system.

Xanthine oxidase activation in mild gestational hypertension.

OBJECTIVE: We hypothesized that activation of the xanthine oxidase (XO) enzyme system is a potential source of free radicals in pregnancy-induced hypertension (PIH). METHODS: A prospective observational study was carried out on 16 pregnant women who met the criteria of gestational hypertension [rise in blood pressure (BP) of 30 mm Hg systolic or 15 mm Hg diastolic after 20 weeks gestation or BP>140/90 mm Hg if earlier pressure is unknown] without proteinuria or any signs of renal impairment. Fourteen women with a clinically normal pregnancy matched for maternal age, parity, and gestational age acted as pregnant controls. Nonpregnant control women were members of the laboratory staff ( n=15). MAIN OUTCOME MEASURES: Concentrations of free sulfhydryl (SH) groups, purine catabolites, lipid peroxidation products in plasma, and blood carboxyhemoglobin levels were used to follow oxidative stress and potential hemolysis. A noninvasive measurement of functional XO activity was carried out (i.e., the urinary ratio of the two metabolites of caffeine was estimated). RESULTS: A pronounced oxidative stress was demonstrated in plasma samples of patients with hypertension by the elevated concentrations of uric acid and lipid peroxidation products. A reduced level of free sulfhydryl groups and an increased concentration of hypoxanthine (HX) were shown in normotensive pregnant individuals. The XO activity index was substantially higher in overweight pregnant subjects with mild hypertension [0.849+/-0.096 ( p<0.01)] than in normotensive pregnant women or in age-matched nonpregnant subjects [0.596+/-0.105, 0.542+/-0.049 (means+/-SD), respectively]. CONCLUSIONS: Our study of mildly hypertensive pregnant subjects provides additional evidence of the putative role of XO activation as a source of free radicals in the early stage of endothelial dysfunction.

Neurotoxicity of lindane and picrotoxin: neurochemical and electrophysiological correlates in the rat hippocampus in vivo.

In the present study, we compared in vivo changes of extracellular amino acid levels and nucleotide derivatives to a single ip dose of lindane (10-60 mg/kg) and picrotoxin (5 mg/kg) in the hippocampus of halothane anaesthetized rat by microdialysis-coupled HPLC analysis. Brain activity was monitored by EEG. The effects of lindane and picrotoxin on EEG pattern of rats as well as on hippocampal amino acid and nucleotide status were studied in 0-50 min, 50-100 min and 100-150 min periods post-dosing. Significant decreases in Glu and Asp were found after picrotoxin treatment. After 50-100 min post-dosing, hippocampal hypoxanthine and inosine levels increased to both lindane (10 mg/kg) and picrotoxin whereas xanthine and uridine levels increased to picrotoxin, only. Lindane elicited a dose-dependent occurrence of negative spikes accompanied with rhythmic activity at 4-5 Hz. The picrotoxin-induced 4-5 Hz activity did not display negative sharp waves and was accompanied by 10 Hz oscillations.