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Idebenone Treatment In Leber's Hereditary Optic Neuropathy

Sir, We have read with great interest the results presented by Klopstock et al. (2011) concerning the RHODOS study on a clinical trial with idebenone in Lebers hereditary optic neuropathy (LHON) and we would like to share our own experience of idebenone therapy in LHON. Idebenone has been an approved drug (Mnesis®, Takeda Italia Farmaceutici) in Italy since the early 1990s and, after the initial report by Mashima et al . (1992) on its possible efficacy in LHON, we offered this therapeutic option to all of our new consecutive patients with LHON, almost all of whom accepted treatment. Idebenone was given after informed consent following the regulation for ‘off-label’ drug administration and was provided for free by the National Health Service, under the legislation for certified rare disorders. Patients were initially treated with 270 mg/day (Cortelli et al ., 1997; Carelli et al ., 1998 a , b ), but following the reports on idebenone treatment in Friedreich ataxia, the dosages were increased to 540–675 mg/day (Rustin et al ., 1999; Kearney et al ., 2009). To evaluate retrospectively the efficacy of idebenone therapy, we reviewed all of our patients with LHON, idebenone treated and untreated, after approval of the institutional Internal Review Board. Inclusion criteria for treated patients were the initiation of therapy within 1 year after visual loss in the second eye, and for all patients (treated and untreated) age at onset of at least 10 years and a follow-up of at least 5 years. We included only patients treated within 1 year after onset because this is the time frame to reach the nadir of the visual loss and the probability of spontaneous recovery of vision is highest in the following 5 years (Nikoskelainen et al ., 1983; Barboni et al ., 2005, 2010; …

Natural History of Leber's Hereditary Optic Neuropathy: Longitudinal Analysis of the Retinal Nerve Fiber Layer by Optical Coherence Tomography

PURPOSE To investigate by optical coherence tomography (OCT) the topographic pattern and temporal sequence of fiber loss in the peripapillary retinal nerve fiber layer (RNFL) of patients with Lebers hereditary optic neuropathy (LHON) in a longitudinal follow-up. DESIGN Cohort study. PARTICIPANTS Six eyes of 4 patients with molecularly defined LHON were enrolled before the subacute period of visual loss. METHODS Subjects were studied by StratusOCT (Carl Zeiss Meditec, Inc., Dublin, CA) during a 9-month follow-up starting from the presymptomatic stage of the disease. Examinations were carried out at 4 different time points: presymptomatic stage, time of visual loss, and 3 and 9 months later. MAIN OUTCOME MEASURES Peripapillary RNFL thickness for each quadrant of the optic nerve. Statistical comparisons were performed by ordinary analysis of variance with Dunnetts post-test. RESULTS A significant increase of RNFL thickness was detected in the temporal and inferior quadrants between the presymptomatic stage and the disease onset (P<0.05). The 360-degree average and the superior and nasal quadrants showed a nonstatistically significant increase of thickness at this time. In the 360-degree average (P<0.01), superior (P<0.01), nasal (P<0.05), and inferior (P<0.01) quadrants, RNFL thickening showed statistically significant changes between the presymptomatic stage and the 3-month follow-up. At 3 months, a nonsignificant reduction of RNFL thickness was detected in the temporal quadrant. A significant reduction of RNFL was detected in all but the nasal quadrants between the presymptomatic stage and the 9-month Follow-up. CONCLUSIONS The RNFL thickness increase first appeared at the temporal and inferior quadrants. Conversely, at 3 months the thickening fibers were more evident in the superior and nasal quadrants. These findings are consistent with the established preferential early involvement of the papillomacular bundle in LHON. We also demonstrated the previously unrecognized simultaneous early involvement of the inferior quadrant. The late involvement of both superior and nasal quadrants suggests a dynamic evolution of the acute stage that continues for 3 months and may represent a therapeutic window of opportunity.

Oxidative Stress and Age-Related Cataract

The authors review the available evidence supporting the possible role of oxidative stress in cataract formation from an epidemiological and a clinical point of view. They discuss in more detail what is presently known about the molecular mechanisms of response of the mammalian lens to an oxidative insult and report unpublished data on gene modulation upon oxidative stress in a bovine lens model. Main research endeavors that seem to be a most promising source of new insights into the problem of age-related cataract formation are briefly discussed.

Visual prognosis after indirect traumatic optic neuropathy

Objective: To investigate a possible correlation between final visual acuity and the presence at baseline of various systemic and local (orbital/ocular) signs in patients affected by indirect traumatic optic neuropathy. Methods: 35 cases of traumatic optic neuropathy were examined retrospectively and 13 variables were tested. Univariate analysis with “no recovery of visual acuity” as the primary outcome was performed. Relative risk (RR) and 95% confidence intervals (CI) were calculated. Fisher’s exact test was used for two variables to test differences between proportions. Results: Four variables showed a significantly increased risk for no recovery of visual acuity: presence of blood within the posterior ethmoidal cells (RR = 2.25, 95% CI 1.25 to 4.04); age over 40 years (RR = 1.79, 1.07 to 2.99); loss of consciousness associated with traumatic optic neuropathy (RR = 2.21, 1.17 to 4.16); and absence of recovery after 48 hours of steroid treatment (p < 0.01, Fisher’s exact test). Recovery documented at the first follow up visit after treatment was significantly associated with recovery at the last follow up visit (p < 0.01, Fisher’s exact test). Conclusions: These four negative prognostic signs in patients affected by traumatic optic neuropathy may be useful in predicting the visual outcome in patients developing visual loss after head trauma and in deciding on the need for surgical treatment.

Anterior Segment Optical Coherence Tomography–Guided Big-Bubble Technique

PURPOSE To evaluate the feasibility of intraoperative anterior segment (AS) optical coherence tomography (OCT) for quantification of the corneal depth reached with the dissecting cannula used for deep anterior lamellar keratoplasty, as well as its correlation with the success rate of big-bubble formation. DESIGN Retrospective, noncomparative, interventional case series. PARTICIPANTS One hundred consecutive keratoconus patients. INTERVENTION Deep anterior lamellar keratoplasty was performed using the big-bubble technique. During surgery, the cannula used for pneumatic dissection was inserted into the peripheral stroma and advanced as deep and far toward the center as believed adequate by the surgeon. Then, after retracting the cannula, AS OCT was performed. The cannula was placed back in position and creation of the big bubble was attempted. MAIN OUTCOME MEASURES Stromal depth reached with the cannula tip, success rate in achieving big-bubble formation, and complication rate. RESULTS Bubble formation was obtained in 70 of 100 eyes (70%). In all remaining eyes, the procedure was completed by manual deep lamellar dissection. The average depth reached by the cannula tip was 104.3±34.1 μm from the internal corneal surface; the mean value recorded in cases of successful big-bubble formation (90.4±27.7 μm) was statistically lower than that measured in failed procedures (136.7±24.2 μm). In 1 case, corneal perforation occurred during the insertion of the cannula and required conversion to penetrating keratoplasty (PK). In 8 eyes, small microperforations occurred during stromal excision but could be managed conservatively, avoiding conversion to PK. In 2 advanced cones, an incomplete bubble formation was obtained, necessitating manual peripheral stromal removal. CONCLUSIONS Successful big-bubble formation can be anticipated if pneumatic dissection is attempted at a sufficiently deep level. Although an ideal depth could not be defined, AS OCT allows objective evaluation of the depth reached by the cannula tip used for pneumatic dissection. The AS OCT findings may confirm the decision to proceed with air injection. It is possible that cannula repositioning based on the AS OCT depth may improve the success rate for big-bubble formation.

Ophthalmologic and Systemic Features in Möbius Syndrome: An Italian Case Series

PURPOSE To describe clinical features in a large series of Möbius syndrome (MBS) cases, investigating whether specific neuro-ophthalmologic patterns of disease may provide further insight into MBS pathogenesis. DESIGN Observational, prospective study. PARTICIPANTS Fifty-five affected subjects. METHODS To make an MBS diagnosis, the criteria recommended in the First Scientific Conference on Möbius Syndrome were followed. Patients who did not meet the minimal criteria were classified as Möbius-like cases and were considered separately. Complete ophthalmologic evaluation, eyelid measurements, presence of abnormal tearing, and ocular motility also were assessed. MAIN OUTCOME MEASURES Pattern of ocular motility alteration, visual function disturbances, and eyelid and tearing defect. RESULTS Forty-six sporadic cases of true MBS were identified, with 3 specific patterns of ocular motility alterations. Pattern A, consisting of orthotopia in primary position with a complete defect in both abduction and adduction ocular movements, was found in 41% of cases. Pattern B, with large-angle esotropia, crossed fixation, and a relative sparing of convergence and adduction, was documented in 50% of cases. Pattern C, characterized by a large-angle exotropia in primary position with torticollis, absence of convergence, and vertical eye misalignment, was present in the minority of the patients (9%). Bilateral complete facial nerve palsy with lagophthalmos was present in 83% of patients; lacrimation showed abnormalities in 33% of cases. Visual acuity was good or impaired only moderately in all tested patients. Binocular function was testable in 31 of 46 patients, and all of them showed a complete absence of stereopsis with suppressive scotoma. CONCLUSIONS Based on the observed 3 different ocular motility defect patterns, the most compatible site and extension of the brainstem damage was inferred. Each pattern may reflect a different type of injury likely occurred during embryogenesis. The comparison of the characteristics of this series with those reported in different geographic areas supports the evidence that MBS does not differ phenotypically worldwide. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Ultrasound biomicroscopy and iris pigment dispersion: a case―control study

Background/aims The study involved eyes affected by pigment dispersion syndrome (PDS) or pigmentary glaucoma (PG) investigated by ultrasound biomicroscopy (UBM). Different irido-corneal parameters were assessed and compared with those from healthy controls. The aim was to investigate the capacity of the UBM in differentiating the cases and, potentially, in confirming the pathogenic mechanisms. Methods Patients with a first diagnosis of PDS or PG were included. A cohort of healthy volunteers matched for sex, age and refractive errors was recruited. All underwent UBM examination: the following parameters were assessed in relaxed and stimulated accommodative state in one eye: iris–lens contact (ILC), irido-corneal angle (ICA) and iris concavity (IC). A receiver operating characteristic (ROC) analysis assessed the ability of UBM to discriminate between subjects with and without PDS/PG. Results There were 24 eyes in the case group: four diagnosed as PG and the remaining 20 as PDS. There were 25 eyes in the control group. The two groups were statistically superimposable except for baseline intraocular pressure, which was higher in the case group (p=0.0001). All UBM parameters were statistically different between the two groups. ICA in near vision was the best-performing parameter, reaching a sensitivity (=specificity) of 0.875 with a cut-off at 53.0°. The second most sensitive parameter was IC, still in near vision. Conclusion All UBM parameters examined were statistically different between the two groups. ROC analysis showed ICA and IC in near vision to be the most discriminatory parameters. This evidence confirms the importance of iris movements in inducing the particular features of PDS/PG.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency in nonarteritic anterior ischemic optic neuropathy in a Sardinian population, Italy.

PURPOSE Glucose-6-phosphate dehydrogenase (G6PD) deficiency is one of the most common human genetic abnormalities, with a high prevalence in Sardinia, Italy. Evidence indicates that G6PD-deficient patients are protected against ischemic heart and cerebrovascular disease and retinal vein occlusion. The purpose of this study was to assess the frequency of G6PD deficiency in Sardinian patients with nonarteritic anterior ischemic optic neuropathy (NAION) and ascertain whether G6PD deficiency may offer protection against NAION. METHODS Erythrocyte G6PD activity was determined by using a quantitative assay in 140 patients with NAION and 280 age- and gender-matched comparison patients. Conditional logistic regression models were used to investigate the association between G6PD deficiency and NAION. RESULTS G6PD deficiency was found in 7 (5%) patients with NAION and 34 (12.1%) control subjects. Differences between cases and controls were statistically significant (P = 0.02). Conditional logistic regression analysis, including as covariates G6PD deficiency, hypertension, diabetes, and hypercholesterolemia, revealed that G6PD deficiency was significantly associated with decreased risk for NAION (odds ratio [OR] = 0.4, 95% confidence interval [CI] = 0.17-0.94, P = 0.035). Conditional logistic regression analyses, including systolic or diastolic blood pressure and plasma glucose and cholesterol levels confirmed that G6PD deficiency was associated with a decreased risk for NAION, but the ORs were not significant at the 0.05 significance level (P = 0.085 and P = 0.071). Models including gender x G6PD deficiency interaction disclosed that gender was not an effect modifier of G6PD deficiency (P > 0.20). CONCLUSIONS The frequency of G6PD deficiency in patients with NAION was significantly lower than expected. Results suggest that G6PD-deficient patients in the Sardinian population have a significantly decreased risk of having NAION.

Detection of virulence factors in Serratia strains isolated from contact lens-associated corneal ulcers

Purpose:  This paper reports on the microbiological findings pertaining to three Serratia isolates from soft contact lens‐related corneal ulcers, which represent a complication of contact lens wear reported with increasing frequency.

Human extraocular muscles in mitochondrial diseases: comparing chronic progressive external ophthalmoplegia with Leber’s hereditary optic neuropathy

Aims: To compare the ultrastructural aspects of human extraocular muscles in two types of mitochondrial disease: chronic progressive external ophthalmoplegia (CPEO) and Leber’s hereditary optic neuropathy (LHON). Methods: Muscle samples of the medial rectus obtained from surgery in a sporadic case of CPEO associated with deleted mitochondrial DNA, and post mortem in a case of 3460/ND1 LHON were processed for electron microscopy (EM). The medial rectus from an autoptic time to fixation matched control was used to exclude postmortem artefacts. Results: The CPEO specimen revealed focal areas of disruption and abnormalities of mitochondria in some muscle fibres, creating a “mosaic-like” pattern. In the LHON specimen a diffuse increase in both number and size of mitochondria (mean diameter 0.85 μm v 0.65 μm of control, p<0.0001) with swollen appearance and disorganised cristae filled all spaces of sarcoplasmic reticulum. In some areas the excessive number of mitochondria slightly distorted myofibrils. Conclusion: EM investigation of extraocular muscles in CPEO and LHON reveals marked differences. A “mosaic-like” pattern caused by a selective damage of muscle fibres was evident in CPEO, whereas a diffuse increase in mitochondria with preservation of myofibrils characterised the LHON case. These ultrastructural changes may relate to the different expression of the two diseases, resulting in ophthalmoplegia in CPEO and normal eye movements in LHON.