Treating Severe Pediatric Keratoconjunctivitis with Topical Cyclosporine A. / Behandlung der chronischen Keratokonjunktivitis im Kindesalter mit topischem Ciclosporin A.

The incidence of chronic keratoconjunctivitis, which potentially causes long-term loss of visual acuity due to corneal opacity, is considerably less common in children than in adults. It is therefore in danger of being overlooked. In children the appropriate treatment is therefore often introduced too late, or to an insufficient extent. In this article we would like to raise awareness about the diagnosis of chronic keratoconjunctivitis in children, and to present an effective treatment plan for severe stages of the disease. There are two forms of chronic keratoconjunctivitis that occur most frequently in children: hyperergic blepharokeratoconjunctivitis (hBKC) and vernal keratoconjunctivitis (VKC). With hBKC, the patient often has a history of recurring hordeolum and also presents with blepharitis; it is characterized by the marked presence of corneal neovascularization in the lower circumference of the cornea. VKC is typically characterized by changes under the upper eyelid, with marked changes to the superior limbus. If there is a risk of complications involving the cornea, or in the presence of such complications, a consistent long-term topical immunosuppressive and anti-inflammatory treatment is required. Both of these properties are combined in the active ingredient cyclosporine A. Other advantages of topical CSA treatment are its steroid-sparing effect and the long-term reduction of exacerbations. Parents need to be informed about the chronic nature of these two diseases and their tendency to recur; because of these characteristics, treatment, in most cases, should be envisaged for at least one year in order to effectively disrupt the complex immunologic processes. This safeguards the child's visual development and prevents amblyopia caused by scarring and astigmatism. We hope that the data presented will lower the barriers related to prescribing CSA for topical eye application in children.

Consideration of eyeball length and prismatic side-effects of spectacle lenses in strabismus surgery-a randomised, double-blind interventional study.

PURPOSE: Potential sources of error in dosage planning in strabismus surgery are (a) prismatic side-effects of spectacle lenses when measuring the preoperative angle with the alternating prism cover test and (b) a potential influence of eye ball axial length on dose response. As both errors take effect in opposite directions, many strabismus surgeons set aside their consideration. This study investigates whether considering both factors for dosage planning yields better operative results. METHODS: In this prospective, randomised, double-blind, interventional pilot study, we included patients scheduled for purely horizontal strabismus surgery and determined each patient's surgical dose (total amount of recession/plication) either with (study group) or without (control) consideration of the two factors. The deviation of the resulting angle from the target angle 3 months postoperatively was the primary endpoint. RESULTS: One hundred one patients were included, 51 of which in the intervention group and 50 in the control group. The primary endpoint showed a median deviation from the target of 3.0° in the intervention group and 4.8° in the control group. We observed a group difference of 1.8° in favour of the intervention group (p = 0.053). Subgroup analysis showed a difference between groups of 2.2° for esotropic patients and of 5.1° for patients with hyperopia > + 2 D. CONCLUSION: Taking prismatic side-effects of spectacle lenses and eye ball length into account when calculating strabismus surgery doses showed a trend towards more accurate results. Esotropic patients and patients with hyperopia > + 2 D seemed to benefit most. TRIAL REGISTRATION: International Clinical Trials Registry Platform: DRKS00011121.

Current Recommendations on Optic Neuritis. / Aktuelle Empfehlungen zur Optikusneuritis.

BACKGROUND: Optic neuritis is a special challenge to the ophthalmologist. It is a relatively frequent condition but difficult to seize morphologically. It has neurological implications and is subject matter of recent trials. METHODS: Selective literature search including the authors' professional experience. RESULTS: Practical aids for the ophthalmological management of optic neuritis are derived from the best available evidence and the recent literature is discussed. CONCLUSIONS: The present paper provides evidence-based recommendations for a safe handling of optic neuritis as well as information on current issues.

The Swinging Flashlight Test - Flawed Execution and Interpretation in Ophthalmological Routine. / Der Swinging-Flashlight-Test ­ mangelhafte Durchführung und Interpretation in der augenärztlichen Routine.

BACKGROUND: The swinging flashlight test is a standard diagnostic procedure to detect relative afferent pupillary defects. The advantages of the test lie within its objectivity and minimal effort. However, its value depends on its correct execution and interpretation. This questionnaire-based survey investigates whether this is given among German speaking ophthalmologists. METHODS: A multiple-choice questionnaire with 14 questions on the use of the swinging flashlight test was designed. It was presented to German speaking ophthalmology specialists (primary data) and orthoptists (secondary data) on specialist conferences or by telephone interviews. RESULTS: 249 ophthalmologists and 76 orthoptists participated in the survey. Only 2% of ophthalmologists answered all 14 questions correctly. On average 66% (range 29 - 100%) of the questions were answered correctly by the ophthalmologists. The question with the lowest result had a rate of 19%, the question with the highest result was correctly answered by 95%. The orthoptists achieved similar results. CONCLUSION: The rate of correct answers appears disturbingly low. The swinging flashlight test being a basic tool and an obligatory test in a number of guidelines should rather be performed nearly error-free. In light of the high error rates, misdiagnoses and treatment errors must be feared. Better training seems necessary.

Biallelic Mutations in NBAS Cause Recurrent Acute Liver Failure with Onset in Infancy.

Acute liver failure (ALF) in infancy and childhood is a life-threatening emergency. Few conditions are known to cause recurrent acute liver failure (RALF), and in about 50% of cases, the underlying molecular cause remains unresolved. Exome sequencing in five unrelated individuals with fever-dependent RALF revealed biallelic mutations in NBAS. Subsequent Sanger sequencing of NBAS in 15 additional unrelated individuals with RALF or ALF identified compound heterozygous mutations in an additional six individuals from five families. Immunoblot analysis of mutant fibroblasts showed reduced protein levels of NBAS and its proposed interaction partner p31, both involved in retrograde transport between endoplasmic reticulum and Golgi. We recommend NBAS analysis in individuals with acute infantile liver failure, especially if triggered by fever.

Recurrent acute liver failure due to NBAS deficiency: phenotypic spectrum, disease mechanisms, and therapeutic concepts.

BACKGROUND: Acute liver failure (ALF) in infancy and childhood is a life-threatening emergency and in about 50% the etiology remains unknown. Recently biallelic mutations in NBAS were identified as a new molecular cause of ALF with onset in infancy, leading to recurrent acute liver failure (RALF). METHODS: The phenotype and medical history of 14 individuals with NBAS deficiency was studied in detail and functional studies were performed on patients' fibroblasts. RESULTS: The phenotypic spectrum of NBAS deficiency ranges from isolated RALF to a multisystemic disease with short stature, skeletal dysplasia, immunological abnormalities, optic atrophy, and normal motor and cognitive development resembling SOPH syndrome. Liver crises are triggered by febrile infections; they become less frequent with age but are not restricted to childhood. Complete recovery is typical, but ALF crises can be fatal. Antipyretic therapy and induction of anabolism including glucose and parenteral lipids effectively ameliorates the course of liver crises. Patients' fibroblasts showed an increased sensitivity to high temperature at protein and functional level and a disturbed tethering of vesicles, pointing at a defect of intracellular transport between the endoplasmic reticulum and Golgi. CONCLUSIONS: Mutations in NBAS cause a complex disease with a wide clinical spectrum ranging from isolated RALF to a multisystemic phenotype. Thermal susceptibility of the syntaxin 18 complex is the basis of fever dependency of ALF episodes. NBAS deficiency is the first disease related to a primary defect of retrograde transport. Identification of NBAS deficiency allows optimized therapy of liver crises and even prevention of further episodes.

Marked dissociation of photopic and mesopic contrast sensitivity even in normal observers.

AIM: Although contrast vision is not routinely tested, it is important: for instance, it predicts traffic incidents better than visual acuity. Mesopic contrast sensitivity (CS) testing approximates low-lighting conditions but entails dark adaptation, which can disrupt clinical routine. In receptor-specific diseases, a dissociation of photopic and mesopic sensitivity would be expected, but can photopic CS act as a surrogate measure for mesopic CS, at least for screening purposes? METHODS: Photopic and mesopic contrast sensitivities were studied in three groups: 47 normal subjects, 23 subjects with glaucoma, and three subjects with cataract. Twenty-eight of the normal subjects were additionally tested with artificial blur. Photopic contrast sensitivity was assessed with both the Freiburg Acuity and Contrast Test (FrACT) and the Mars Letter Contrast Sensitivity Charts. Mesopic contrast sensitivity, without and with glare, was measured with the Mesoptometer IIb. Coefficients of repeatability and limits of agreement were calculated for all tests. RESULTS: Test-retest limits of agreement were ± 0.17 logCS for Mars, ± 0.21 logCS for FrACT, and ±0.20 logCS / ± 0.14 logCS for Mesoptometer IIb without and with glare, respectively. In terms of inter-test comparison, Mars and FrACT largely agreed, except for ceiling effects in the Mars test. While mesopic and photopic contrast sensitivities correlate significantly (r  = 0.51, p < 0.01), only 27 % of the variance is in common. In particular, subjects with high photopic results may be nearly as likely to have low as well as high mesopic results. CONCLUSIONS: The photopic contrast sensitivity tests assessed here cannot serve as surrogate measures for current mesopic contrast sensitivity tests. Low photopic CS predicts low mesopic CS, but with normal photopic CS, mesopic CS can be normal or pathologic.

Assessment of functional and morphometric endpoints in patients with non-arteritic anterior ischemic optic neuropathy (NAION).

BACKGROUND: The primary objective of this bi-center explorative pilot study was the quantitative assessment of visual field defects and retinal nerve fiber layer thickness (RNFT) over 6 months in patients with acute non-arteritic anterior ischemic optic neuropathy (NAION), in order to elucidate the natural course of NAION and provide a reference dataset for future treatment studies. METHODS: 16 patients (age 41-80 years, nine males, seven females) suffering from acute NAION and presenting within 7 days after onset of symptoms were included in this study. The following examinations were carried out at the initial visit (month 0) and at months 2, 4 and 6: entire (90°) visual field examination with automated static white-on-white perimetry, quantified by mean defect (MD); peripapillary retinal nerve fiber layer thickness (RNFT) measurement with spectral domain optical coherence tomography (SD-OCT); assessment of distant best correct visual acuity (D-BCVA) and a quantification of the relative afferent pupillary defect (RAPD) using the swinging flashlight test with neutral density filters. Perimetric Mean Defect (MD) and RNFT values were each compared between the consecutive visits using the non-parametric Friedman test. RESULTS: The initial MD was 6.2 dB (IQR 5.0-7.4) without significant changes further on. RNFT was 183 µm (IQR 148-252) initially, decreased significantly at month 2 (78 µm (IQR 71-93) and further at month 4 (64 µm (IQR 58-74) and 6 (61 µm (IQR 52-81), Friedman test, p < 0.001). Initially, RNFT was above normal limits (due to swelling) in 15/16 patients; at month 2 it was below normal limits in 13/16 patients, at month 4 in 12/13 patients and at month 6 in 9/10 patients. 7/16 patients exhibited segmental swelling of the optic disc, whereas the entire circumference of the optic disc showed RNFL thickening in 9/16 patients. CONCLUSION: Functional deficits were present directly after onset of NAION and did not change relevantly further on. Morphological changes comprise severe swelling after onset of NAION, which rapidly turns into atrophy. Already after 2 months more than 80 % of the patients showed a RNFT below normal limits. Progressive RNFL thinning between month 2 and month 4 suggests ongoing atrophy, whereas a stable morphologic end point is reached after month 4.

Treatment With Erythropoietin for Patients With Optic Neuritis: Long-term Follow-up.

BACKGROUND AND OBJECTIVE: Erythropoietin (EPO) is a candidate neuroprotective drug. We assessed its long-term safety and efficacy as an adjunct to methylprednisolone in patients with optic neuritis and focused on conversions to multiple sclerosis (MS). METHODS: The TONE trial randomized 108 patients with acute optic neuritis but without previously known MS to either 33,000 IU EPO or placebo in conjunction with 1,000 mg methylprednisolone daily for 3 days. After reaching the primary end point at 6 months, we conducted an open-label follow-up 2 years after randomization. RESULTS: The follow-up was attended by 83 of 103 initially analyzed patients (81%). There were no previously unreported adverse events. The adjusted treatment difference of peripapillary retinal nerve fiber layer atrophy in relation to the fellow eye at baseline was 1.27 µm (95% CI -6.45 to 8.98, p = 0.74). The adjusted treatment difference in low-contrast letter acuity was 2.87 on the 2.5% Sloan chart score (95% CI -7.92 to 13.65). Vision-related quality of life was similar in both treatment arms (National Eye Institute Visual Functioning Questionnaire median score [IQR]: 94.0 [88.0 to 96.9] in the EPO and 93.4 [89.5 to 97.4] in the placebo group). The rate of multiple sclerosis-free survival was 38% in the placebo and 53% in the EPO group (hazard ratio: 1.67, 95% CI 0.96 to 2.88, p = 0.068). DISCUSSION: In line with the results at 6 months, we found neither structural nor functional benefits in the visual system of patients with optic neuritis as a clinically isolated syndrome, 2 years after EPO administration. Although there were fewer early conversions to MS in the EPO group, the difference across the 2-year window was not statistically significant. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with acute optic neuritis, EPO as an adjunct to methylprednisolone is well tolerated and does not improve long-term visual outcomes. TRIAL REGISTRATION INFORMATION: The trial was preregistered before commencement at clinicaltrials.gov (NCT01962571).

Safety and efficacy of erythropoietin for the treatment of patients with optic neuritis (TONE): a randomised, double-blind, multicentre, placebo-controlled study.

BACKGROUND: The human cytokine erythropoietin conveys neuroprotection in animal models but has shown ambiguous results in phase 2 clinical trials in patients with optic neuritis. We assessed the safety and efficacy of erythropoietin in patients with optic neuritis as a clinically isolated syndrome in a multicentre, prospective, randomised clinical trial. METHODS: This randomised, placebo-controlled, double-blind phase 3 trial, conducted at 12 tertiary referral centres in Germany, included participants aged 18-50 years, within 10 days of onset of unilateral optic neuritis, with visual acuity of 0·5 or less, and without a previous diagnosis of multiple sclerosis. Participants were randomly assigned (1:1) to receive either 33 000 IU erythropoietin or placebo intravenously for 3 days as an adjunct to high-dose intravenous methylprednisolone (1000 mg per day). Block randomisation was performed by the trial statistician using an SAS code that generated randomly varying block sizes, stratified by study site and distributed using sealed envelopes. All trial participants and all study staff were masked to treatment assignment, except the trial pharmacist. The first primary outcome was atrophy of the peripapillary retinal nerve fibre layer (pRNFL), measured by optic coherence tomography (OCT) as the difference in pRNFL thickness between the affected eye at week 26 and the unaffected eye at baseline. The second primary outcome was low contrast letter acuity at week 26, measured as the 2·5% Sloan chart score of the affected eye. Analysis was performed in the full analysis set of all randomised participants for whom treatment was started and at least one follow-up OCT measurement was available. Safety was analysed in all patients who received at least one dose of the trial medication. This trial is registered at ClinicalTrials.gov, NCT01962571. FINDINGS: 108 participants were enrolled between Nov 25, 2014, and Oct 9, 2017, of whom 55 were assigned to erythropoietin and 53 to placebo. Five patients were excluded from the primary analysis due to not receiving the allocated medication, withdrawn consent, revised diagnosis, or loss to follow-up, yielding a full analysis set of 52 patients in the erythropoietin group and 51 in the placebo group. Mean pRNFL atrophy was 15·93 µm (SD 14·91) in the erythropoietin group and 14·65 µm (15·60) in the placebo group (adjusted mean treatment difference 1·02 µm; 95% CI -5·51 to 7·55; p=0·76). Mean low contrast letter acuity scores were 49·60 (21·31) in the erythropoietin group and 49·06 (21·93) in the placebo group (adjusted mean treatment difference -4·03; -13·06 to 5·01). Adverse events occurred in 43 (81%) participants in the erythropoietin group and in 42 (81%) in the placebo group. The most common adverse event was headache, occuring in 15 (28%) patients in the erythropoietin group and 13 (25%) patients in the placebo group. Serious adverse events occurred in eight (15%) participants in the erythropoietin and in four (8%) in the placebo group. One patient (2%) in the erythropoietin group developed a venous sinus thrombosis, which was treated with anticoagulants and resolved without sequelae. INTERPRETATION: Erythropoietin as an adjunct to corticosteroids conveyed neither functional nor structural neuroprotection in the visual pathways after optic neuritis. Future research could focus on modified erythropoietin administration, assess its efficacy independent of corticosteroids, and investigate whether it affects the conversion of optic neuritis to multiple sclerosis. FUNDING: German Federal Ministry of Education and Research (BMBF).

Bilateral trifocal IOL implantation in a pediatric case of cataract following steroid-therapy for acute lymphoblastic leukemia.

PURPOSE: To present the case of a 9-year-old child with bilateral posterior subcapsular cataract developed through steroid treatment for acute lymphoblastic leukemia. Cataract surgery with trifocal intraocular lens implantation was performed in both eyes. OBSERVATIONS: Uncorrected distance visual acuity increased from +0.3 and + 0.4 logMAR preoperatively to 0.00 and + 0.04 logMAR after surgery. Binocular uncorrected values for intermediate and near visual acuity were -0.04 logMAR and 0.02 logMAR after surgery, respectively. The patient did not report side effects like halos or glare and was able to participate in his daily activities (school and sports) without spectacles. CONCLUSIONS AND IMPORTANCE: This report represents the first description of a bilateral implantation of trifocal intraocular lenses in a pediatric cataract case with restoration of visual function in far, intermediate and near distance. Trifocal intraocular lenses to compensate for the loss of accommodation can be an option in selected cases of children with cataract.

Treatment of optic neuritis with erythropoietin (TONE): a randomised, double-blind, placebo-controlled trial-study protocol.

INTRODUCTION: Optic neuritis leads to degeneration of retinal ganglion cells whose axons form the optic nerve. The standard treatment is a methylprednisolone pulse therapy. This treatment slightly shortens the time of recovery but does not prevent neurodegeneration and persistent visual impairment. In a phase II trial performed in preparation of this study, we have shown that erythropoietin protects global retinal nerve fibre layer thickness (RNFLT-G) in acute optic neuritis; however, the preparatory trial was not powered to show effects on visual function. METHODS AND ANALYSIS: Treatment of Optic Neuritis with Erythropoietin (TONE) is a national, randomised, double-blind, placebo-controlled, multicentre trial with two parallel arms. The primary objective is to determine the efficacy of erythropoietin compared to placebo given add-on to methylprednisolone as assessed by measurements of RNFLT-G and low-contrast visual acuity in the affected eye 6 months after randomisation. Inclusion criteria are a first episode of optic neuritis with decreased visual acuity to ≤ 0.5 (decimal system) and an onset of symptoms within 10 days prior to inclusion. The most important exclusion criteria are history of optic neuritis or multiple sclerosis or any ocular disease (affected or non-affected eye), significant hyperopia, myopia or astigmatism, elevated blood pressure, thrombotic events or malignancy. After randomisation, patients either receive 33,000 international units human recombinant erythropoietin intravenously for 3 consecutive days or placebo (0.9% saline) administered intravenously. With an estimated power of 80%, the calculated sample size is 100 patients. The trial started in September 2014 with a planned recruitment period of 30 months. ETHICS AND DISSEMINATION: TONE has been approved by the Central Ethics Commission in Freiburg (194/14) and the German Federal Institute for Drugs and Medical Devices (61-3910-4039831). It complies with the Declaration of Helsinki, local laws and ICH-GCP. TRIAL REGISTRATION NUMBER: NCT01962571.