New Antimycotics in the Pipeline - For Ophthalmology Too? / Neue Antimykotika in der Pipeline ­ auch für die Augenheilkunde?

Seven new antimycotics are presented that are at different points of development or approval. These substances are mainly first-in-class drugs. They are primarily developed for systemic administration. However, with the support of a pharmacist, the intravenous formulation may be used as eyedrops. In this short review, the activities of the substances against various fungal infections are described. After unsuccessful conventional therapy of fungal eye infections, one of these new substances might be suitable to cure the mycosis.

Keratomycosis due to Tintelnotia destructans refractory to common therapy treated successfully with systemic and local terbinafine in combination with polyhexamethylene biguanide.

PURPOSE: To report on a wearer of rigid gas-permeable contact lenses with a keratomycosis due to Tintelnotia-a new genus of Phaeosphaeriaceae-treated with terbinafine and polyhexamethylene biguanide. METHODS: Chart review of a patient with fungal keratitis treated additionally with systemic and topical terbinafine 0.25% after symptoms increased under conventional antimycotic therapy with voriconazole. Antifungal susceptibility had been tested in vitro. RESULTS: After starting an additional treatment with systemic and topical terbinafine, the severe corneal infection was sufficiently resolved. The drug was well tolerated without any neurological, dermatological or gastroenterological problems. Terbinafine revealed a marked in vitro antifungal activity of 0.12 µg/ml. The fungus was identified as Tintelnotia destructans. CONCLUSIONS: Terbinafine might be considered as a therapeutic option in severe cases of fungal keratitis refractory to common antifungal therapy.

VEP-based acuity assessment in low vision.

PURPOSE: Objective assessment of visual acuity (VA) is possible with VEP methodology, but established with sufficient precision only for vision better than about 1.0 logMAR. We here explore whether this can be extended down to 2.0 logMAR, highly desirable for low-vision evaluations. METHODS: Based on the stepwise sweep algorithm (Bach et al. in Br J Ophthalmol 92:396-403, 2008) VEPs to monocular steady-state brief onset pattern stimulation (7.5-Hz checkerboards, 40% contrast, 40 ms on, 93 ms off) were recorded for eight different check sizes, from 0.5° to 9.0°, for two runs with three occipital electrodes in a Laplace-approximating montage. We examined 22 visually normal participants where acuity was reduced to ≈ 2.0 logMAR with frosted transparencies. With the established heuristic algorithm the "VEP acuity" was extracted and compared to psychophysical VA, both obtained at 57 cm distance. RESULTS: In 20 of the 22 participants with artificially reduced acuity the automatic analysis indicated a valid result (1.80 logMAR on average) in at least one of the two runs. 95% test-retest limits of agreement on average were ± 0.09 logMAR for psychophysical, and ± 0.21 logMAR for VEP-derived acuity. For 15 participants we obtained results in both runs and averaged them. In 12 of these 15 the low-acuity results stayed within the 95% confidence interval (± 0.3 logMAR) as established by Bach et al. (2008). CONCLUSIONS: The fully automated analysis yielded good agreement of psychophysical and electrophysiological VAs in 12 of 15 cases (80%) in the low-vision range down to 2.0 logMAR. This encourages us to further pursue this methodology and assess its value in patients.

Feasibility study: 7 T MRI in giant cell arteritis.

OBJECTIVES: To assess the detectability of vasculitic changes of the superficial cranial arteries with contrast-enhanced 7 T MRI in three patients with GCA and intraindividual comparison with 3 T MRI. METHODS: Three patients (two female, one male) with suspected GCA underwent contrast-enhanced T1-weighted high-resolution MRI at 3 T and 7 T magnetic field strength. The clinical diagnosis, based on criteria of the American College of Rheumatology, was confirmed by biopsy of the superficial temporal artery after MRI. MR images were visually assessed for detection of vasculitic mural contrast enhancement and vessel wall thickening of the superficial cranial arteries. RESULTS: Both 3 T and 7 T MRI allows for visualisation of mural inflammatory changes and assessment of the vasculitic involvement pattern. Image quality of 7 T MRI was rated superior to image quality of 3 T MRI scans. CONCLUSIONS: 7 T MR imaging of vasculitic changes in patients with GCA is possible, and suggests superior image quality. Larger patient studies are necessary to quantify the diagnostic advantages of 7 T MRI.

Impact of chiasma opticum malformations on the organization of the human ventral visual cortex.

Congenital malformations of the optic chiasm, such as enhanced and reduced crossing of the optic nerve fibers, are evident in albinism and achiasma, respectively. In early visual cortex the resulting additional visual input from the ipsilateral visual hemifield is superimposed onto the normal retinotopic representation of the contralateral visual field, which is likely due to conservative geniculo-striate projections. Counterintuitively, this organization in early visual cortex does not have profound consequences on visual function. Here we ask, whether higher stages of visual processing provide a correction to the abnormal representation allowing for largely normal perception. To this end we assessed the organization patterns of early and ventral visual cortex in five albinotic, one achiasmic, and five control participants. In albinism and achiasma the mirror-symmetrical superposition of the ipsilateral and contalateral visual fields was evident not only in early visual cortex, but also in the higher areas of the ventral processing stream. Specifically, in the visual areas VO1/2 and PHC1/2 no differences in the extent, the degree of superposition, and the magnitude of the responses were evident in comparison to the early visual areas. Consequently, the highly atypical organization of the primary visual cortex was propagated downstream to highly specialized processing stages in an undiminished and unchanged manner. This indicates largely unaltered cortico-cortical connections in both types of misrouting, i.e., enhanced and reduced crossing of the optic nerves. It is concluded that main aspects of visual function are preserved despite sizable representation abnormalities in the ventral visual processing stream.

Differential effects of head-mounted displays on visual performance.

Head-mounted displays (HMDs) virtually augment the visual world to aid visual task completion. Three types of HMDs were compared [look around (LA); optical see-through with organic light emitting diodes and virtual retinal display] to determine whether LA, leaving the observer functionally monocular, is inferior. Response times and error rates were determined for a combined visual search and Go-NoGo task. The costs of switching between displays were assessed separately. Finally, HMD effects on basic visual functions were quantified. Effects of HMDs on visual search and Go-NoGo task were small, but for LA display-switching costs for the Go-NoGo-task the effects were pronounced. Basic visual functions were most affected for LA (reduced visual acuity and visual field sensitivity, inaccurate vergence movements and absent stereo-vision). LA involved comparatively high switching costs for the Go-NoGo task, which might indicate reduced processing of external control cues. Reduced basic visual functions are a likely cause of this effect.

Systemic iodine absorption associated with the use of preoperative ophthalmic antiseptics containing iodine.

BACKGROUND: Polyvinylpyrrolidone-Iodine (PVP-I) is routinely used as preoperative antiseptic during ophthalmic surgery. Iodine absorption from iodine-containing antiseptics can lead to the development of thyroid disorders. Therefore, a quantitative measurement of iodine absorption from these antiseptics was performed in patients undergoing elective cataract surgery. METHODS: This study enrolled 241 patients to evaluate systemic iodine absorption after exposure to conjunctival and/or periorbital 1.25% and 10% PVP-I compared to an iodine-free antiseptic. RESULTS: All patients who received the 10% PVP-I regardless of the application site showed a 1.2-1.5-fold increase in urinary iodine excretion after 24 h (p = 0.01). In 17 out of 110 (15.5%) patients in whom 10% PVP-I was used, the critical threshold of urinary iodine excretion as defined by WHO (>300 µg/L) was exceeded. In contrast, no significant ioduria was observed with the use of 1.25% PVP-I except in patients after 48 h (p = 0.01) and with a concurrent conjunctival and periorbital application. The proportion of the excreted iodine in urine ranged from 0.24% to 1.77%. No correlation was found between the total applied concentration of iodine and the amount excreted in urine. CONCLUSION: Based on our findings, we believe that the use of 10% PVP-I as preoperative ophthalmic antiseptic should undergo further clinical evaluation in regard to its impact on thyroid function. Conjunctival or periorbital application of 1.25% PVP-I does not result in significant ioduria.

Malignant Keratitis Caused by a Highly-Resistant Strain of Fusarium Tonkinense from the Fusarium Solani Complex.

Fusarium spp. are moulds ubiquitously distributed in nature and only occasionally pathogenic for humans. Species of the Fusarium solani complex are the predominant keratitis-inducing pathogens, because they are endowed with proper virulence factors. These fungi can adhere to the cornea creating a biofilm and, with the help of enzymes and cytotoxins, penetrate the cornea. Whereas an intact cornea is hardly able to be invaded by Fusarium spp. in spite of appropriate virulence factors, these opportunistic fungi may profit from predisposing conditions, for example mechanical injuries. This can lead to a progressive course of corneal infection and may finally affect the whole eye up to the need for enucleation. Here, we present and discuss the clinical, microbiological and histopathological aspects of a particular case due to Fusarium tonkinense of the Fusarium solani complex with severe consequences in a patient without any obvious predisposing factors. A broad portfolio of antifungal agents was applied, both topically and systemically as well as two penetrating keratoplasties were performed. The exact determination of the etiologic agent of the fungal infection proved likewise to be very challenging.

Colorimetric analysis of three editions of the Velhagen-Broschmann pseudoisochromatic colour plates.

PURPOSE: Chromatic variations across different copies and different editions of pseudoisochromatic tests and violation of underlying principles of construction for individual plates can influence test results. METHODS: We analysed the colorimetric characteristics of three different editions of Velhagen-Broschmann pseudoisochromatic plates (30th edition printed in 1995, 31st edition printed in 1997, 32nd edition printed in 2000). One hundred and twelve coloured dots of 18 plates were chosen from each edition. We measured RGB and CIE XYZ values using a spectrophotometer. Differences in lightness and chromaticity between corresponding dots of different editions were analysed in terms of Delta L* and Delta u'v', respectively. For each plate deviations from dichromatic confusion lines were analysed. Furthermore, we determined the relative luminance of a target compared to its background in terms of the Weber contrast. RESULTS: The mean Delta L* across editions was 2.05 (+/-1.4) and the mean Delta u'v' was 0.0078 (+/-0.0029). For two plates the deviations of targets from dichromatic confusion lines exceeded suggested values. For a number of plates, the lightness contrast between the symbol and its background was high. Comparison with psychophysical data showed that these colour plates are easily detectable by colour-deficient observers. CONCLUSIONS: Lightness and chromatic variation across the three editions was moderate except for a small number of plates perhaps due to inaccuracies in the printing process. The design of several plates should be revised according to standard principles of construction of colour deficiency tests.

Toric intraocular lenses--theory, matrix calculations, and clinical practice.

PURPOSE: To describe 1) how to determine toric (posterior chamber) intraocular lenses (IOLs) with standard formulas, 2) a matrix-based calculation scheme for determining toric IOLs using 4x4 matrices, 3) a method to determine residual refraction after implantation of an arbitrary toric lens, and 4) to address clinical aspects. METHODS: Formulas and metrics are reviewed for determining IOL power and residual refraction after toric IOL implantation. RESULTS: From 4x4 refraction and translation matrices characterizing refractive surfaces and interspaces between refractive surfaces, a system matrix is determined characterizing the entire optical system paraxially. Toric posterior chamber IOLs are determined by solving a linear equation system. In a second step, the same methodology is used for estimation of the residual refraction at the spectacle plane after implantation of an arbitrary toric lens. The methodology is applied to working examples, and the calculation procedure is described in a step-by-step approach. CONCLUSIONS: A straight-forward en bloc concept is demonstrated for determination of toric IOLs and estimation of the residual refraction. The applicability is shown in working examples, and clinical aspects such as rotation of the lens implant are addressed.

Retinal vein occlusion and low-dose fibrinolytic therapy (R.O.L.F.): a prospective, randomized, controlled multicenter study of low-dose recombinant tissue plasminogen activator versus hemodilution in retinal vein occlusion.

PURPOSE: To investigate the efficacy of intravenous thrombolysis with low-dose recombinant tissue plasminogen activator (rt-PA) in recent-onset central retinal vein occlusion (CRVO) or branch retinal vein occlusion. METHODS: This was a prospective, randomized, controlled multicenter trial in patients with CRVO or branch retinal vein occlusion, best-corrected visual acuity < or =20/50, and onset of symptoms within 11 days before treatment. In each group, patients were randomized to either hemodilution or thrombolysis with 50 mg of rt-PA with concomitant intravenous heparinization. The primary clinical outcome measure was improvement in best-corrected visual acuity from baseline at 1 year. RESULTS: Fifty-two subjects were enrolled in the study. Patients with CRVO (n = 41) who were treated with rt-PA exhibited a significant improvement in best-corrected visual acuity compared with those who received hemodilution (P < 0.0001). At 1-year follow-up, the proportion of eyes with CRVO achieving an improvement in visual acuity of three or more lines was 45% after treatment with rt-PA and 21% after hemodilution therapy. The median final best-corrected visual acuity among CRVO patients given rt-PA was 20/60 (light perception, 20/15) compared with 20/400 (light perception, 20/20) in the hemodilution group. There were no significant differences among patients with branch retinal vein occlusion (n = 11). We observed no serious adverse events. No significant differences were found regarding the development of ocular neovascularization. CONCLUSION: Treatment with intravenous low-dose rt-PA improved visual outcome in CRVO. Thrombolysis was not associated with a lower risk of ocular neovascularization, indicating that the mechanisms involved in this process occur at an early stage.

Multifocal visual evoked potentials reveal normal optic nerve projections in human carriers of oculocutaneous albinism type 1a.

PURPOSE: In albinism, part of the temporal retina projects abnormally to the contralateral hemisphere. A residual misprojection is also evident in feline carriers that are heterozygous for tyrosinase-related albinism. This study was conducted to test whether such residual abnormalities can also be identified in human carriers of oculocutaneous tyrosinase-related albinism (OCA1a). METHODS: In eight carriers heterozygous for OCA1a and in eight age- and sex-matched control subjects, monocular pattern-reversal and -onset multifocal visual evoked potentials (mfVEPs) were recorded at 60 locations comprising a visual field of 44 degrees diameter (VERIS 5.01; EDI, San Mateo, CA). For each eye and each stimulus location, interhemispheric difference potentials were calculated and correlated with each other, to assess the lateralization of the responses: positive and negative correlations indicate lateralizations on the same or opposite hemispheres, respectively. Misrouted optic nerves are expected to yield negative interocular correlations. The analysis also allowed for the assessment of the sensitivity and specificity of the detection of projection abnormalities. RESULTS: No significant differences were obtained for the distributions of the interocular correlation coefficients of controls and carriers. Consequently, no local representation abnormalities were observed in the group of OCA1a carriers. For pattern-reversal and -onset stimulation, an assessment of the control data yielded similar specificity (97.9% and 94.6%) and sensitivity (74.4% and 74.8%) estimates for the detection of projection abnormalities. CONCLUSIONS: The absence of evidence for projection abnormalities in human OCA1a carriers contrasts with the previously reported evidence for abnormalities in cat-carriers of tyrosinase-related albinism. This discrepancy suggests that animal models of albinism may not provide a match to human albinism.

Trypan-blue-assisted anterior continuous curvilinear capsulorhexis in a case of ocular pemphigoid.

PURPOSE: To report on trypan-blue-assisted anterior continuous curvilinear capsulorhexis (ACCC) in a case of ocular pemphigoid. METHODS: Interventional case report. RESULTS: Due to the reduced visibility especially in the corneal periphery caused by the ocular pemphigoid, trypan blue 0,06% (Acri.Blue) was used to stain the anterior capsule of the lens. Then anterior continuous curvilinear capsulorhexis was performed. Due to the blue staining, the visualization of the margin of the rhexis was always good and phacoemulsification procedure was successfully performed afterwards. During the follow-up period of 12-months-postsurgically, no exacerbation of the ocular pemphigoid occurred. CONCLUSIONS: The use of trypan blue staining of the anterior capsule enabled the surgeon to perform a safe anterior continuous curvilinear capsulorhexis and a subsequent phacoemulsification in ocular pemphigoid. No progression of the ocular pemphigoid was seen within the 12-months-post-surgery period.

Inadvertent scleral perforation in eye muscle versus retinal detachment buckle surgery.

PURPOSE: Inadvertent scleral perforation is a recognized complication of eye muscle and retinal detachment buckle surgery. If these operations are performed by the same surgeon, it is unknown which of these procedures has a higher risk of scleral perforation. METHODS: In the period from 1999 until 2004, 427 eyes of 317 patients were operated using eye muscle surgery and 81 eyes of 80 patients with retinal detachment buckle surgery. All operations were performed by the same surgeon (JK). In a retrospective, single-center, comparative, observational study, the records of these patients were assessed to determine the number of scleral perforations with retinal damage or drainage of subretinal fluid. RESULTS: In the group receiving retinal detachment buckle surgery there were two cases of scleral perforation. In one case, scleral perforation occurred during buckle installation and in the other case during placement of a cerclage. The rate of scleral perforation was 2.5 % per patient and per eye in this group. In the group receiving eye muscle surgery no scleral perforations occurred. CONCLUSION: The number of scleral perforations was higher in retinal detachment buckle surgery than in eye muscle surgery, with all procedures having been performed by the same surgeon.

Pupil signs of sympathetic autonomic neuropathy in patients with type 1 diabetes.

OBJECTIVE: Pupillary autonomic neuropathy is considered an early sign of the development of systemic autonomic neuropathy. Sympathetic denervation is related to the duration of diabetes and the development of systemic autonomic dysfunction. We investigated pupil responsiveness to directly and indirectly acting sympathomimetics in type 1 diabetic patients with and without long-term complications, defined as cardiac autonomic neuropathy (CAN), peripheral sensomotor neuropathy, retinopathy, and nephropathy, and in healthy subjects. RESEARCH DESIGN AND METHODS: A total of 47 randomly chosen type 1 diabetic patients and 20 healthy subjects were selected for this study. Patients were divided into groups determined by whether they had long-term diabetic complications. Pharmacological tests were performed with cocaine 4%, epinephrine 1%, and pholedrine 5% eye drops. Horizontal pupil diameter (HPD) was measured at the beginning of the pharmacological tests and at defined time points after instillation of the eye drops. RESULTS: Statistical analysis showed a significantly smaller HPD in the patients before instillating eye drops (P = 0.011). In particular, the HPD was significantly smaller in the patient group without CAN when compared with healthy subjects (P = 0.004). Maximal cocaine reaction was diminished in the complication group (P < 0.001). Epinephrine test, visual acuity, ocular pressure, and HbA(1c) did not differ in patients with or without long-term complications. The noncomplication group showed no significant differences in pupillary responses as compared with healthy subjects. The complication group showed a smaller HPD (P = 0.022), reduced pupillary responses in the cocaine (P = 0.037) and pholedrine tests (P < 0.001), and anisocor pupil sizes after instillation of the eye drops (P = 0.034). CONCLUSIONS: Our results clearly show that sympathetic denervation does exist in the pupil of diabetic patients and that it can be rapidly assessed using the cocaine test. These data and the results of the epinephrine test suggest a mixed pre- and postganglionic dysfunction of the sympathetic plexus. The significant smaller HPD in patients without CAN compared with that of healthy subjects could be a sign for early involvement of the pupil function before cardiac manifestation of systemic autonomic diabetic neuropathy.

Combined topical fluconazole and corticosteroid treatment for experimental Candida albicans keratomycosis.

PURPOSE: To determine the most efficient time point and concentration of topical corticosteroids in Candida albicans keratitis treated with fluconazole. METHODS: Corneas of 105 rabbits were infected with viable yeast cells of C. albicans (2.5 x 10(5)). After a 48-hour incubation period, seven groups of animals were treated for 21 days with fluconazole, with group I acting as a control, and groups II to VII receiving adjunct therapy with the corticosteroid prednisolone (5 or 10 times daily; 3, 9, or 15 days after infection). The degree of corneal infiltration, ulceration, corneal clouding, hypopyon, conjunctivitis, neovascularization, and corneal perforation was monitored over a 24-day period, as well as recultivation and resistance to fluconazole of the C. albicans pathogen. RESULTS: The control group showed the highest level of corneal clouding and neovascularization. In comparison, by day 24, the majority of groups also treated with prednisolone displayed significantly less corneal clouding and neovascularization. An immediate decrease in corneal clouding was observed in groups treated with additional low- or high-dose prednisolone from day 9 after inoculation. After additional prednisolone treatment from day 9 or 15 after inoculation, no significant difference was detected in the recultivation rate of C. albicans compared with the control. Early administration of prednisolone (day 3, low and high dose) resulted in the recultivation of significantly more C. albicans. CONCLUSIONS: Fluconazole plus adjunct high-dose prednisolone treatment was most effective when administered 9 days after infection. The delayed application of corticosteroids after treatment with antimycotic drugs in cases of fungal keratitis is therefore not contraindicated and may be beneficial in patients.

Changes of retinal glutamate transporter GLT-1 mRNA levels following optic nerve damage.

PURPOSE: Under physiological conditions, levels of the excitatory neurotransmitter glutamate within the retina are regulated by retinal glutamate transporters to prevent toxic accumulation. Alterations in this glutamate buffering have been implicated in retinal ganglion cell (RGC) death. We quantified the changes in the level of glutamate transporter mRNA in a model of acute rat optic nerve injury. METHODS: Optic nerve damage was induced in one eye of 25 adult Wistar rats by partial optic nerve crush (ONC). Total mRNA levels of the retinal glutamate transporter GLT-1 (EAAT-2) were determined by quantitative real-time PCR. GLT-1 mRNA levels were measured 1, 3, 7, 14, and 28 days following optic nerve injury. Additionally, control values were obtained from the retinas of five control rats (sham-crush). RESULTS: In the very early phase (1 day post-ONC), a 3.9 fold increase in levels of GLT-1 mRNA was observed in the ONC retinae compared with control eyes. This was followed by a rapid decrease towards control levels at day 3 post-ONC. GLT-1 mRNA levels remained up to 14 days post-crush. However, in the late phase post-ONC (day 28), the level of GLT-1 mRNA increased again, but still remained not significant to control levels. CONCLUSIONS: Changes in GLT-1 mRNA expression following axonal trauma of RGCs can lead to an imbalance of glutamate homeostasis. This may cause local accumulation of toxic concentrations of the neurotransmitter glutamate and further irreversible excitotoxic damage of RGCs.

Cataract surgery in cataracta membranacea.

A 27-year-old man with no history of intraocular surgery presented with progressive blurred vision in both eyes. Slitlamp evaluation revealed a white, thin membrane in the pupillary area that resembled posterior capsule opacification. A naturally formed lens was absent. Ultrasound biomicroscopy demonstrated a rarefaction of lens fibers in the equator region with a loss of the normal anatomic lens structure on the left side. Visual acuity was 20/32 with +10.00 -0.75 x 170 in the right eye and 20/100 with +11.50 -0.50 x 25 in the left eye. After capsulotomy and excision of the membranous capsule, an anterior vitrectomy, and implantation of a sulcus-fixed intraocular lens in both eyes, the patient was highly satisfied with the final visual outcome. The patient had stereopsis, which supported his history of good visual function in childhood.