A Novel Quantitative Assessment Method of Disease Activity in Susac's Syndrome Based on Ultra-Wide Field Imaging.

PURPOSE: Susac's syndrome (ScS) is a rare, potentially life-threatening auto-immune disease. Ophthalmic imaging can depict characteristic branch retinal arteriolar occlusions (BRAO) and arterial wall hyperfluorescences that form one of the three diagnostic pillars of this condition. We aim to demonstrate that ophthalmological ultrawide-field (UWF) imaging allows for a qualitative and quantitative assessment in ScS, with application in diagnostics, monitoring of treatment response, and titration of therapy. METHODS: In seven ScS patients (♀:♂ = 2:5), with a median age of 36 years, range 18 to 57 years, serial ultrawide-field fluoresceine angiography (UWF-FA) studies were performed, with adjunctive wide-field optical coherence tomography angiography analyses (WF-OCTA) in five patients. Mean follow-up was 12.5 months, range 1 to 46 months. RESULTS: In all seven patients, BRAO and arterial wall hyperfluorescences were present in UWF-FA and calculated as a quantitative score of disease activity in fluorescein angiography (DA-FA) during follow-up visits. Treatment response was accessible in follow-up imaging as partial reperfusion of retinal vessels, resolution of arterial wall hyperfluorescences and consequently, in reduction of DA-FA score. While qualitative analysis of WF-OCTA provided further information about retinal micro-perfusion, quantitative analysis did not demonstrate a vectored treatment response as it was accessible in FA. CONCLUSION: DA-FA score, as a comprehensive disease activity parameter in ScS has potential to facilitate optimal communication between subspecialties and thereby treatment success.

International Society of Cardiovascular Infectious Diseases Guidelines for the Diagnosis, Treatment and Prevention of Disseminated Mycobacterium chimaera Infection Following Cardiac Surgery with Cardiopulmonary Bypass.

Mycobacterial infection-related morbidity and mortality in patients following cardiopulmonary bypass surgery is high and there is a growing need for a consensus-based expert opinion to provide international guidance for diagnosing, preventing and treating in these patients. In this document the International Society for Cardiovascular Infectious Diseases (ISCVID) covers aspects of prevention (field of hospital epidemiology), clinical management (infectious disease specialists, cardiac surgeons, ophthalmologists, others), laboratory diagnostics (microbiologists, molecular diagnostics), device management (perfusionists, cardiac surgeons) and public health aspects.

Torpedo Maculopathy Associated with Choroidal Neovascularization.

Background Torpedo maculopathy is a very rare, congenital, usually unilateral hypopigmented lesion in the temporal macula. Material and Methods This retrospective case series describes three patients with torpedo maculopathy. Results The first two cases demonstrate typical clinical and imaging findings of torpedo maculopathy in asymptomatic patients. The third case relates to a symptomatic young patient with a torpedo lesion, a smaller satellite lesion, and evidence of choroidal neovascularization confirmed by fluorescence angiography. In the area of the clinically visible torpedo lesion, spectral domain optical coherence tomography showed atrophy of the outer retina with increased choroidal signalling and a hyperreflective lesion above the retinal pigment epithelium suggestive of choroidal neovascularization. Fundus autofluorescence imaging revealed a hyperautofluorescent rim along the margin of the hypoautofluorescent torpedo lesion. Conclusion In the literature, torpedo lesions are usually regarded as benign lesions with no tendency for progression. The third case demonstrates that torpedo lesions may be associated with choroidal neovascularization, which has been successfully treated with anti-VEGF therapy.

Ocular Toxoplasmosis: Therapy-Related Adverse Drug Reactions and Their Management.

Background There are different treatment options for ocular toxoplasmosis (OT). "Classic" therapy consists of pyrimethamine, sulfadiazine and folinic acid combined with systemic steroids and is still widely used. However, potentially severe side effects of this therapy have been reported. The aim of this retrospective study was to evaluate the incidence and types of adverse drug reactions in patients treated for OT. Clinical management of each adverse drug reaction was assessed. Patients and Methods In this retrospective analysis, we reviewed data of patients with OT, who were consecutively examined between December 2011 and December 2015 at the Department of Ophthalmology, University Hospital Zurich. Results In total, 49 patients had at least one episode of active OT. In 54 (83.0 %) of 65 treated episodes, the classic regimen was used. Of the 37 patients who received classic treatment, 9 (24.3 %) developed at least one adverse drug reaction which led to drug discontinuation, including elevated creatinine (5.4 %), elevated liver enzymes (5.4 %), vomiting (5.4 %), rash (5.4 %) and facial swelling (2.7 %). In 5 patients, treatment was switched to another drug, while in the other 4 patients, therapy was stopped. In these 9 patients, inflammation was well controlled 8 weeks after onset of therapy. No patient suffered from severe side effects, such as potentially life-threatening allergic reactions or pancytopenia. Conclusions In OT patients who were treated with classic therapy, adverse drug reactions are common. Therefore, clinical and laboratory monitoring is mandatory. Adverse drug reactions may require interdisciplinary management.

[Long-Term Outcome in Patients with Intravitreal Anti-VEGF Therapy for Exudative AMD]. / Langzeit-Verlauf bei Patienten mit intravitrealer Anti-VEGF Therapie für neovaskuläre AMD.

BACKGROUND: Randomized controlled phase III studies have shown that intravitreal anti-VEGF therapy is effective for exsudative age-related macular degeneration (AMD) over two years. Recently, the seven-year outcomes in ranibizumab-treated patients of the ranibizumab phase III studies have been published. Only a few other studies with such a long follow-up for intravitreal anti-VEGF therapy in patients with exsudative AMD have been published so far. We report on the outcome of patients receiving intravitreal anti-VEGF therapy for exudative AMD at the Department of Ophthalmology, University Hospital of Zurich with follow-up of 3 to 7 years. PATIENTS: Retrospective chart review of all patients treated at our institution for exudative AMD with begin of treatment since 2006. RESULTS: The numbers of patients with a follow-up of 3 to 4, 4 to 5, 5 to 6, 6 to 7, and more than 7 years were 430, 277, 151, 87, and 47, respectively. Mean follow-up time was 4.9 years, and median was 4.6 years. Changes in visual acuity for these patients were -5.0, -7.8, -11.7, -12.8, and -19.2 ETDRS letters, respectively. CONCLUSIONS: Whereas in patients with exudative AMD during the first two years of intravitreal anti-VEGF treatment visual acuity can at least be stabilised, after three and more years visual acuity decreases in spite of continued treatment.

Long-term efficacy of selective laser trabeculoplasty in patients on prostaglandin therapy.

BACKGROUND: The aim of the study was to analyse the efficacy of selective laser trabeculoplasty in patients on medical therapy and to evaluate a possible influence of prostaglandin therapy on intraocular pressure reduction. PATIENTS AND METHODS: A retrospective chart review was undertaken of patients with ocular hypertension or open angle glaucoma who underwent selective laser trabeculoplasty between 3/2008 and 12/2010. Data were collected preoperatively, on the day of intervention, 1 day, 1 month and then every 3 months post selective laser trabeculoplasty. The main outcome measure was mean intraocular pressure reduction. RESULTS: 109 eyes (76 on prostaglandins) were included. Mean preoperative intraocular pressure was 22.3 ± 4.5 mmHg (prostaglandin naïve) and 19.2 ± 4.8 mmHg (on prostaglandin) (p=0.003). Up to 1 year follow-up, intraocular pressure was statistically significantly reduced in both groups (p ≤ 0.019). Eyes with a higher preoperative intraocular pressure had a greater pressure reduction (Spearman rho=0.387, p=0.002). Eyes naïve to prostaglandins initially had a greater reduction in intraocular pressure, although after 1 year of follow-up the difference was no longer statistically significant. CONCLUSIONS: Selective laser trabeculoplasty significantly reduces intraocular pressure in patients already on medical therapy. A sustained influence of prostaglandin therapy on the efficacy of selective laser trabeculoplasty was not found.

Long-term efficacy of selective laser trabeculoplasty in pseudophakic patients - a "real-life" analysis.

BACKGROUND: The aim of this study was to report on the course and long-term effect of selective laser trabeculoplasty on intraocular pressure of pseudophakic patients suffering from open angle glaucoma or ocular hypertension with insufficient intraocular pressure lowering despite maximally tolerated topical and systemic intraocular pressure lowering medication. PATIENTS AND METHODS: A retrospective chart review of patients who underwent selective laser trabeculoplasty (360°) between 2008 and 2010 at the University hospital Zurich was undertaken. Intraocular pressure values before intervention, on the day of the intervention, 1 day, 1 month, 3 months and every 3 months up to 43 months after the intervention were analysed with respect to lens status. RESULTS: Out of 153 treated eyes of 111 patients (mean age 70.6 years ± 11.13 SD) 40 were pseudophakic. Mean baseline intraocular pressures were 19.00 mmHg ± 4.61 in the pseudophakic group and 20.12 mmHg ± 4.89 in the phakic group. One month after selective laser trabeculoplasty intraocular pressure reduction measured between -0.33 and -4.10 mmHg (CI 95%) in the pseudophakic group and between -3.64 and -5.58 mmHg (CI 95%) in the phakic group, the difference at this time point was significant (p=0.01). Beyond one month after selective laser trabeculoplasty there was no statistically significant difference in intraocular pressure reduction between pseudophakic and phakic patients. The mean decrease in intraocular pressure from baseline to the last follow-up of 43 months was 0.67 mmHg in the pseudophakic group and 0.25 mmHg in the phakic group (p=0.72). CONCLUSIONS: One month after selective laser trabeculoplasty pseudophakic patients showed a statistically significant diminished reduction of intraocular pressure compared to phakic patients. Later on there was no statistically significant difference in intraocular pressure reduction between pseudophakic and phakic patients. Therefore we conclude that there was no clinically relevant influence of pseudophakia on the long-term effect of selective laser trabeculoplasty.

Preliminary results of aflibercept in treatment-naive choroidal neovascularization of wet age-related macular degeneration.

BACKGROUND: The aim of this study was to evaluate the early response of aflibercept as first-line therapy in treatment-naive patients with newly diagnosed choroidal neovascularization (CNV) in age-related macular degeneration (AMD). PATIENTS AND METHODS: An analysis of 35 eyes (35 patients, 28 female, 7 male) with treatment-naive active CNV was undertaken. Lesion activity was determined based on fluorescein angiography, clinical and optical coherence tomography (OCT) findings, including the presence of sub-, intraretinal fluid, retinal pigment epithelial (RPE) detachment and hemorrhage. Logarithm of the minimum angle of resolution (LogMAR) charts were used for testing best corrected or best available visual acuity (BCVA). Treatment response was evaluated based on changes in BCVA and lesion activity. RESULTS: Classic or predominantly classic CNV was diagnosed in 7 eyes (20.0%), occult or minimally classic in 21 eyes (60.0%), retinal angiomatous proliferation in 5 eyes (14.3%) and polypoidal choroidal vasculopathy in 2 eyes (5.7%). Lesion activity was evaluated as unchanged in only one eye. In all other eyes, a definite treatment response was observed with complete resolution of fluid in 20 eyes after a single injection. Three eyes did not show improved sub-RPE fluid with smaller pigment epithelial detachments. A rip of the RPE was seen in 3 eyes. All patients maintained vision, 7 patients (7 eyes) gained >15 letters from baseline to month 2 follow-up, of whom 4 reached this level of visual acuity after one injection. The visual acuity gains in this study were maintained through 6 months. CONCLUSION: There seems to be a rapid treatment response to aflibercept independent of the underlying CNV. Aflibercept may be beneficial even in eyes with large pigment epithelial detachments due to exudative AMD.

Intravitreal anti-VEGF therapy for retinal macroaneurysm.

BACKGROUND: We evaluated the effect of intravitreal anti-vascular endothelial growth factor therapy using bevacizumab or ranibizumab for retinal macroaneurysms with macular exudation. METHODS: In a retrospective interventional case series patients with retinal macroaneurysms were treated with either 1.25 mg intravitreal bevacizumab or 0.5 mg ranibizumab as first-line therapy. Patients were imaged by fluorescein angiography and optical coherence tomography. Retreatment was performed in case of persistent intraretinal or subretinal fluid in optical coherence tomography. RESULTS: Ten patients (10 eyes) with macroaneurysm involving the macula were treated with an average of 3.0 intravitreal anti-vascular endothelial growth factor injections. Mean best corrected visual acuity of all patients improved by 17 letters from baseline to the last follow-up visit. In 7 out of 10 patients, the fovea was affected by a secondary edema. In cases with foveal involvement, central retinal thickness decreased from 366 µm at baseline to 266 µm at the last follow-up visit. In the course of treatment 8 out of 10 patients showed evidence of marked regression of macular exsudation. CONCLUSION: Intravitreal anti-vascular endothelial growth factor therapy appears to be a promising treatment alternative to laser treatment in cases of retinal macroaneurysms with macular exudation.

[Effectiveness of selective laser trabeculoplasty in patients with insufficient control of intraocular pressure despite maximum tolerated medical therapy]. / Wirksamkeit der selektiven Lasertrabekuloplastik bei Patienten mit unzureichender Augendrucksenkung unter maximaler Therapie.

BACKGROUND: Reduction of intraocular pressure (IOP) is still the primary goal of glaucoma treatment. The aim of this prospective study was to examine the IOP lowering effect of selective laser trabeculoplasty (SLT) in patients on maximum tolerated medical therapy (MTMT), especially with regard to a potential influence of pseudophakia and topical prostaglandin analogues (PGA) on IOP reduction. MATERIAL AND METHODS: A total of 30 patients with a diagnosis of primary open angle glaucoma, normal tension glaucoma and pseudoexfoliative glaucoma with uncontrolled IOP despite MTMT underwent SLT treatment circumferentially over 360°. Follow-up visits were conducted 1 day after SLT and then 1, 3, 6, 9, and 12 months post-treatment. The initial medication was continued unchanged for 3 months. RESULTS: Median follow-up was 11.97 ± 3.1 months, mean IOP at baseline was 19.60 ± 4.69 mmHg, mean IOP reduction was -19.95 ± 17.14% 1 month after and -14.07 ± 23.57% 12 months after SLT (p < 0.001 and p = 0.003, respectively). Patients with higher baseline IOP had greater reduction of IOP after SLT (R(2) = 0.482, p < 0.001). Phakic patients had a significantly greater IOP reduction compared to pseudophakic patients (- 4.55 ± 4.45 mmHg and + 2.75 ± 6.75 mmHg, respectively, p = 0.010). Patients without PGA had a statistically insignificant greater IOP reduction compared to patients with PGA (- 7.40 ± 4.72 mmHg and -2.48 ± 5.22 mmHg, respectively, p = 0.066) and four patients needed additional surgery to lower IOP. CONCLUSION: Even in patients already on maximum IOP lowering medication, SLT has the potential to significantly reduce IOP up to 1 year after treatment. The IOP reduction is most pronounced in phakic eyes with high preoperative IOP.

Multimodal imaging of autosomal dominant drusen.

BACKGROUND: Malattia Leventinese (ML) is a dominantly inherited macular dystrophy characterized by a radial pattern of drusen in the macular area and on the nasal edge of the optic disc. This case series describes the morphological features of drusen associated with ML using multimodal imaging. HISTORY AND SIGNS: Three patients (two of the same family but only one with the ML phenotype) were analyzed by multimodal imaging including spectral domain optical coherence tomography (SD OCT) and genetic testing. In two patients multiple drusen in the macular region and around the optic nerve head were observed bilaterally. A radial pattern was only seen in one patient. These drusenoid deposits showed early hyperfluorescence in fluorescein angiography (FA) and intense staining in indocyanine green angiography similar to cuticular drusen (basal laminar drusen). The corresponding SD OCT scan revealed two types of deposits. The first, more prominent type, were focal nodular sub-retinal pigment epithelium (RPE) deposits. The second type of deposit appears to be localized on the anterior part of the RPE comparable to subretinal drusenoid deposits (SDD; reticular pseudodrusen). THERAPY AND OUTCOME: A single nucleotide variation c.1033C>T (p.R345 W) in the EFEMP1 gene was found in case 1 (classic ML), but could not be detected in case 2 and 3. So far our patients have not suffered from any visual complaints and have not developed choroidal neovascularization. They will be followed up regularly. DISCUSSION: Multimodal imaging including SD OCT provided new information about the appearance of drusen in eyes with ML/early onset drusen. In addition to the sub-RPE deposits some deposits appear above the RPE, however have different characteristic findings on FA/ICG, autofluorescence, near infrared reflectance and blue light imaging than SDD observed in patients with age-related macular degeneration. SD OCT alone might not be sufficient to characterize these type of drusen in ML.

[Continuous intraocular pressure measurement: First results with a pressure-sensitive contact lens]. / Kontinuierliche Augeninnendruckmessung : Erste Ergebnisse einer drucksensitiven Kontaktlinse.

BACKGROUND: A prototype of a pressure-sensitive contact lens (CL-DCT) based on dynamic contour tonometry (DCT) has been developed for continuous intraocular pressure (IOP) monitoring. The purpose of the present study was to assess the clinical applicability of this CL-DCT. MATERIAL AND METHODS: In 24 healthy subjects continuous IOP recording with the CL-DCT for 100 s was accomplished including IOP monitoring during 2 consecutive Valsalva manoeuvres. The measurement procedure was repeated after 5 min on the same eye and compared with the initial measurement. RESULTS: Continuous pressure curves were recorded in 20 subjects. The CL-DCT revealed an individual increase in IOP from 0.74 to 8.26 mmHg during the Valsalva manoeuvres. Comparison of the 2 consecutive IOP measurements yielded a mean deviation of +/-0.4 mmHg. CONCLUSIONS: CL-DCT allows non-invasive and continuous measurements of IOP. The measured values are comparable to the expected ones. Further studies are necessary to compare the measurement accuracy of CL-DCT with that of slit lamp adapted DCT (SL-DCT).

Use of lycorine and DAPI staining in Saccharomyces cerevisiae to differentiate between rho0 and rho- cells in a cce1/delta cce1 nuclear background.

In the yeast Saccharomyces cerevisiae, mutants are viable with large deletions (rho-), or even complete loss of the mitochondrial genome (rho0). One class of rho- mutants, which is called hypersuppressive, is characterised by a high transmission of the mutated mitochondrial genome to the diploid progeny when mated to a wild-type (rho+) haploid. The nuclear gene CCE1 encodes a cruciform cutting endonuclease, which is located in the mitochondrion and is responsible for the highly biased transmission of the hypersuppressive rho- genome. CCE1 is a Holliday junction specific endonuclease that resolves recombination intermediates in mitochondrial DNA. The cleavage activity shows a strong preference for cutting after a 5'-CT dinucleotide. In the absence of the CCE1 gene product, the mitochondrial genomes remain interconnected and have difficulty segregating to the daughter cells. As a consequence, there is an increase in the fraction of daughter cells that are rho0. In this paper we demonstrate the usefulness of lycorine, together with staining by 4',6-diamidino-2-phenylindole (DAPI), to assay for the mitotic stability of a variety of mitochondrial genomes. We have found that rho+ and rho- strains that contain CT sequences produce a large fraction of rho0 progeny in the absence of CCE1 activity. Only those rho- mitochondrial genomes lacking the CT recognition sequence are unaffected by the cce1 allele.

A role for recombination junctions in the segregation of mitochondrial DNA in yeast.

In S. cerevisiae, mitochondrial DNA (mtDNA) molecules, in spite of their high copy number, segregate as if there were a small number of heritable units. The rapid segregation of mitochondrial genomes can be analyzed using mtDNA deletion variants. These small, amplified genomes segregate preferentially from mixed zygotes relative to wild-type mtDNA. This segregation advantage is abolished by mutations in a gene, MGT1, that encodes a recombination junction-resolving enzyme. We show here that resolvase deficiency causes a larger proportion of molecules to be linked together by recombination junctions, resulting in the aggregation of mtDNA into a small number of cytological structures. This change in mtDNA structure can account for the increased mitotic loss of mtDNA and the altered pattern of mtDNA segregation from zygotes. We propose that the level of unresolved recombination junctions influences the number of heritable units of mtDNA.

A nuclear mutation reversing a biased transmission of yeast mitochondrial DNA.

The highly biased transmission of p- mitochondrial DNA that occurs in hypersuppressive matings between p- and p+ cells of the yeast Saccharomyces cerevisiae is thought to be a consequence of the replication advantage of the p- mtDNA. A nuclear gene, MGT1, that is required for this displacement of p+ mtDNA from zygotic clones has been identified through mutation. When one haploid parent carries the mgt1 allele, transmission of p- mtDNA is substantially reduced. When both haploid parents carry the mgt1 allele, p- mtDNA is essentially eliminated from the zygotic progeny. Thus in the absence of the MGT1 gene there is a switch in the transmission bias; p+ mtDNA rather than the hypersuppressive p- mtDNA is inherited by most zygotic clones. In contrast to its semi-dominant behavior in haploid matings, mgt1 behaves as a recessive allele in diploid matings since the p+ genome in MGT1/mgt1 diploids is efficiently displaced when mated with a MGT1/mgt1 hypersuppressive p- diploid strain. We find that p+ genomes can be comaintained along with hypersuppressive p- mtDNA for extended periods in clonal lines derived from MGT1 x mgt1 matings. However, as expected from the recessive nature of the mgt1 mutation, these p+ genomes are eventually eliminated. Our work indicates that MGT1 plays a crucial role in the competition for inheritance between hypersuppressive p- mtDNAs and the p+ mitochondrial genome. The MGT1 gene product may be a component of a mtDNA replication system that acts preferentially at the rep sequences found in hypersuppressive mtDNAs.

Creation of ARS activity in yeast through iteration of non-functional sequences.

Replication origins in Saccharomyces cerevisiae have been identified through the cloning of autonomous replication sequence (ARS) elements that allow the extrachromosomal maintenance of plasmid molecules. ARS activity requires a close match to an 11 bp consensus sequence and A + T-rich flanking DNA. ARS elements with a wide range of capacities for promoting plasmid maintenance have been described. We determined the ARS activity of plasmids with inserts consisting of repetitions of a 64 bp 100% A + T sequence that has sequence similarities to known ARS elements. An insert with approximately four repeats did not yield transformants, but inserts with either eight or eleven repeats did. The cooperative production of ARS activity did not require a contiguous arrangement since a plasmid containing two inserts of four repeats each, separated by about 1 kb, was functional. Our results show that a change from non-function to function can be accomplished by the cumulative action of individually inactive sequences. We conclude that the probability of replication initiation is too low with only four repeats to allow plasmid maintenance, but the overall probability is increased by further sequence iteration to provide origin activity. We suggest that chromosomes may contain stretches with dispersed, weak origin elements, each undetected by the conventional ARS assay, that in sum provide origin function.