C. Speeg-Schatz

Ocular manifestations in the inherited DNA repair disorders.

Deoxyribonucleic acid (DNA) repair is a fundamental process designed to keep the integrity of genomic DNA that is continuously challenged by intrinsic or environmental induced alterations. Numerous genes involved in DNA repair have been cloned and are involved in different DNA repair pathways: base excision repair, nucleotide excision repair, mismatch repair, DNA recombination. Inherited conditions due to mutations in DNA repair genes include mainly: xeroderma pigmentosum, Cockayne syndrome, Trichothiodystrophy, Bloom syndrome, Rothmund-Thomson syndrome, and Werner syndrome. Minor to major ocular manifestations occur in these syndromes. For example, eyelid skin cancers in xeroderma pigmentosum and retinal dystrophy in Cockayne syndrome are major features of these syndromes. This review focuses on the DNA repair pathways, the general and ocular features of the related syndromes, the laboratory tests useful for diagnosis, and the general processes implied with DNA repair (ultraviolet sensitivity, carcinogenesis, apoptosis, oxydative stress, and premature aging).

Cytokine Profiles in Toxoplasmic and Viral Uveitis

BACKGROUND Uveitis is a major cause of visual impairment throughout the world. Analysis of cytokine profiles in aqueous humor specimens may provide insight into the physiopathological processes that underly retinal damage in this context. METHODS Using a multiplex assay, we determined the concentrations of 17 cytokines and chemokines in aqueous humor specimens obtained from patients with ocular toxoplasmosis or viral uveitis and compared these concentrations with those in specimens obtained from patients with noninfectious intermediate uveitis or cataract. RESULTS Five mediators (interleukin [IL]-8, monocyte chemoattractant protein-1, tumor necrosis factor-alpha, IL-4, and IL-10) were detected in >50% of patients in all groups. In contrast, IL-5 and IL-12 were specific for ocular toxoplasmosis, and granulocyte monocyte colony-stimulating factor and IL-1 were specific for viral uveitis; these mediators could present specific markers for diagnostic purposes. Interferon-gamma, IL-6, and macrophage inflammatory protein-1beta were common markers of ocular toxoplasmosis and viral uveitis. IL-17 was a common marker of ocular toxoplasmosis and intermediate uveitis. CONCLUSIONS We found specific cytokine profiles for each type of uveitis, with large interindividual variations and no etiological or clinical correlations. Ocular cytokine mapping contributes to a better understanding of the physiopathology of specific forms of uveitis and provides guidance for new targeted treatment.

Channel-Forming Leucotoxins from Staphylococcus Aureus cause Severe Inflammatory Reactions in a Rabbit Eye Model

Panton-Valentine leucocidin arises from the combination of one S component (LukS-PV) with one F component (LukF-PV), whereas gamma-haemolysin comprises two S components (HlgA and HlgC) with one F component HlgB. The intravitreal injection of rabbit eye with the six combinations (S + F) of channel-forming leucotoxins produced by Staphylococcus aureus ATCC 49775 induced acute inflammatory reactions depending on time and doses of toxins. These reactions involved posterior chamber as well as anterior chamber and conjunctiva, eyelids and annexes. Histological examination confirmed the involvement of eye tissues and the disruption of the retinal barrier. The lesions began only 4 h after injections and persisted for at least 5 days. Clinical and biological effects of each leucotoxin were modulated by the speed of onset and intensity of inflammation and necrosis, leading to a functional classification according to the severity of the lesions (HlgA + LukF-PV > HlgA + HlgB > or = LukS-PV + HlgB > or = LukS-PV + LukF-PV > HlgC + HlgB > or = HlgC + LukF-PV). Moreover, N-acetyl beta-D glucosaminidase assays on crude extracts of vitreous revealed granules and granule secretions from polymorphonuclear cells with levels according the above classification. These results show that channel-forming leucotoxins have a very significant inflammatory activity. As most S. aureus strains produce two or even six leucotoxins depending on the production of Panton-Valentine leucocidin, these compounds could be considered to be virulence factors.

In Vitro Efficacy of Antifungal Treatment Using Riboflavin/UV-A (365 nm) Combination and Amphotericin B

PURPOSE To demonstrate the antimicrobial properties of riboflavin/UV-A (365 nm) against fungal pathogens. METHODS The antimicrobial properties of riboflavin/UV-A (365 nm), with or without previous treatment with amphotericin B, were tested on three groups of fungi selected from severe cases of keratomycosis: Candida albicans, Fusarium sp, and Aspergillus fumigatus. They were tested by using Kirby-Bauer discs with empty disc (control), riboflavin 0.1% alone (R), UV-A alone (UV-A), riboflavin 0.1% and additional UV-A exposure (R+UV-A), amphotericin B alone (A), amphotericin B and riboflavin 0.1% (A+R), amphotericin B and UV-A (A+UV-A), amphotericin B and riboflavin 0.1%, and additional UV-A exposure (A+R+UV-A). The mean growth inhibition zone (GIZ) was measured around the discs. RESULTS C. albicans, Fusarium sp, and A. fumigatus did not show any increased GIZ after treatment without previous amphotericin B medication. However, GIZ was significantly greater after pretreatment with amphotericin B and riboflavin/UV-A (A+R+UV-A) for C. albicans (P = 0.0005), Fusarium sp (P = 0.0023) and A. fumigatus (P = 0.0008) compared with A, A+R, and A+UV-A. CONCLUSIONS Amphotericin B is believed to interact with fungi membrane sterols to produce aggregates that form transmembrane channels. Given that collagen is one of the principal components of the cornea, it is also probable that amphotericin B may diffuse easily after cross-linking. Previous treatment with amphotericin B allowed riboflavin/UV-A effectiveness against C. albicans, Fusarium sp, and A. fumigatus. This schema might be used in the future for the treatment of keratomycosis.

Severe South American ocular toxoplasmosis is associated with decreased Ifn-γ/Il-17a and increased Il-6/Il-13 intraocular levels.

In a cross sectional study, 19 French and 23 Colombian cases of confirmed active ocular toxoplasmosis (OT) were evaluated. The objective was to compare clinical, parasitological and immunological responses and relate them to the infecting strains. A complete ocular examination was performed in each patient. The infecting strain was characterized by genotyping when intraocular Toxoplasma DNA was detectable, as well as by peptide-specific serotyping for each patient. To characterize the immune response, we assessed Toxoplasma protein recognition patterns by intraocular antibodies and the intraocular profile of cytokines, chemokines and growth factors. Significant differences were found for size of active lesions, unilateral macular involvement, unilateral visual impairment, vitreous inflammation, synechiae, and vasculitis, with higher values observed throughout for Colombian patients. Multilocus PCR-DNA sequence genotyping was only successful in three Colombian patients revealing one type I and two atypical strains. The Colombian OT patients possessed heterogeneous atypical serotypes whereas the French were uniformly reactive to type II strain peptides. The protein patterns recognized by intraocular antibodies and the cytokine patterns were strikingly different between the two populations. Intraocular IFN-γ and IL-17 expression was lower, while higher levels of IL-13 and IL-6 were detected in aqueous humor of Colombian patients. Our results are consistent with the hypothesis that South American strains may cause more severe OT due to an inhibition of the protective effect of IFN-γ.

Prevention of retinochoroiditis in congenital toxoplasmosis: Europe versus South America.

Congenital toxoplasmosis is suspected when seroconversion occurs in a pregnant woman, and it is confirmed by one or more biologic tests (polymerase chain reaction on amniotic fluid or neonatal serodiagnosis). The methods used are diagnostic in more than 95% of cases at birth and in 100% of cases by the age of 9 months. Ocular lesions represent the most frequent complication of congenital toxoplasmosis, independent of any treatment. The risk of toxoplasmic retinochoroiditis is highly unpredictable, however, mainly because the pathophysiology is poorly understood. By school age, 10% to 20% of children with congenital toxoplasmosis have one or more retinochoroidal lesions, but more than 90% of them have normal vision in both eyes; bilateral blindness is very rare. This article focuses on the controversy surrounding the effectiveness of screening and treatment for children with congenital toxoplasmosis.

Long-term outcomes of acute traumatic maculopathy.

Purpose: To report immediate and long-term outcomes of acute traumatic maculopathy. Methods: Retrospective case series. Acute traumatic maculopathy was defined as a macular opacification after blunt trauma. Patients were examined at presentation, 1 week, and 6 months. Retinography and time-domain and spectral-domain optical coherence tomographies were performed in all patients. Central macular thickness, the qualitative aspect of the macular profile, and retinal nerve fiber layer thickness were assessed. Multifocal electroretinography was performed at presentation and after 6 months. Results: Twenty patients (20 eyes) were studied. Their mean age was 20.8 years, and the initial visual acuity was 20/100. In all cases, initial optical coherence tomographies revealed an increase in reflectivity of the inner and outer segment junction, with an apposition of the latter to the retinal pigment epithelium. Optical coherence tomography profiles were back to normal at the 1-week visit. Initial multifocal electroretinography performed in six patients showed a decrease in amplitudes in the central area but not in the periphery. There was no delay in latency. Similar electroretinal dysfunction persisted after 6 months. Conclusion: Macular opacification observed in acute traumatic maculopathy is associated with an increase in reflectivity of the inner and outer segment photoreceptor junction on optical coherence tomography. Although visual recovery is excellent, reduction in the electroretinal activity observed 6 months after the trauma suggests that the retina does not fully recover from the initial disorganization of its external layers.

Use of digital camera imaging of eye fundus for telemedicine in children suspected of abusive head injury

Aim: Pilot study of the role of RetCam imaging for telemedicine in lieu of availability of ophthalmologist examination for cases of suspected abusive head injury. Design: Cross-sectional observational study. Participants: 21 children admitted in the paediatric units of the University Hospital of Strasbourg (France) with suspicion of abusive head trauma were included. Methods: Children were examined by standard ophthalmoscopy. Photographs were taken using the RetCam-120 Digital Retinal Camera. Eye fundus images were stored and remotely read by an ophthalmologist. Patients also had radiographic skeletal series to look for bone fractures, and CT scan and/or MRI of the head to look for intracranial haemorrhages. Main outcome measures: The absence or presence of retinal haemorrhages was assessed by both methods. Feasability, sensitivity and specificity of the digital camera procedure were determined. Results: 85.7% of the children presented cerebral bleeding, and 14 out of the 21 (66.7%) had retinal haemorrhages on ophthalmoscopy. The digital camera detected the retinal abnormalities in all cases. One false-positive case was also reported. The sensitivity of the digital camera detection method was 100% with a specificity of 85.7%. 14 patients were eventually diagnosed as suffering from abusive trauma. RetCam helped establishing the diagnosis of abuse in 92.8% of these cases. Conclusions: Digital photography compared with ophthalmoscopy has a good sensitivity and specificity in detecting retinal haemorrhages. Remote reading of RetCam-120 photographs could be a promising strategy in detecting children with abusive head trauma.

A novel nonsense B3GALTL mutation confirms Peters plus syndrome in a patient with multiple malformations and Peters anomaly

Peters plus syndrome is an autosomal recessive rare congenital disorder defined by corneal Peters anomaly with short disproportionate stature, development delay and dysmorphic facial features. In addition, cardiac, genito-urinary and/or central nervous system malformations can be present. Mutations in the beta-1,3-galactosyltransferase-like glycosyltransferase gene (B3GALTL) have been reported in patients with Peters plus syndrome prompting phenotype-genotype studies because of the variable clinical spectrum related to the syndrome. A 20 month old boy presenting with bilateral Peters anomaly in association with multiple developmental anomalies including cerebral malformations was found to carry a novel homozygous B3GALTL nonsense mutation [p.Tyr366X]. This is the first stop mutation described in association with this gene. The present report confirms the wide clinical spectrum of Peters plus syndrome, underlines the major clinical criteria of the syndrome and the major implication of B3GALTL gene in this condition. Ophthalmologic examination in multiple developmental anomalies remains an important clinical issue that may lead to specific gene screening. In Peters plus syndrome B3GALTL molecular test provides diagnosis confirmation and improves dramatically genetic counselling for the families.

Impairment of contrast sensitivity in long-term lorazepam users

RationaleOculomotor balance and contrast sensitivity are known to be impaired after an intake of a single dose of lorazepam. To the best of our knowledge, these effects have not been explored in long-term users of lorazepam, despite the potential importance of such deficits in everyday life.ObjectiveWe tested the ophthalmological effects and contrast sensitivity for static stimuli in long-term lorazepam users.Materials and methodsThere were 15 lorazepam users and 15 sex-, age- and education level-matched control subjects tested, using a simple blind procedure.ResultsThe ophthalmological effects were scarce, with a discrete exophoria. Visual acuity was preserved. Contrast sensitivity, however, was more markedly impaired, consistent with the effects of an acute dose of lorazepam. The effects were not correlated with anxiety or sedation.ConclusionsThe results are discussed in terms of their possible impact on everyday life. As visual acuity does not allow the detection of the impairments that are observed in the present study, it is suggested that a more systematic exploration of contrast sensitivity be carried out in long-term users of benzodiazepines.