Michele Carbonelli

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.

The influence of axial length on retinal nerve fibre layer thickness and optic-disc size measurements by spectral-domain OCT

Background To evaluate the influence of axial length on measurements of the retinal nerve fibre layer (RNFL) thickness and optic nerve head (ONH) parameters in healthy subjects. Methods Using Cirrus HD-OCT, RNFL thickness and ONH parameters (disc and rim area) were measured in 15 short (<22.5 mm), 15 medium (22.51–25.5 mm) and 15 long (>25.51 mm) eyes. Results The mean axial length was 21.5±0.5 mm in short eyes, 24.1±0.8 mm in medium eyes and 26.6±1.0 mm in long eyes. The RNFL thickness decreased with longer axial lengths in the superior (r=−0.52, r2=0.27, p=0.0003), inferior (r=−0.72, r2=0.52, p<0.0001), nasal (r=−0.60, r2=0.37, p<0.0001) and temporal (r=−0.30, r2=0.09, p=0.0485) quadrants, as well as in the 360° mean measurement (r=−0.69, r2=0.48, p<0.0001). The optic-disc area (r=−0.74, r2=0.54, p<0.0001) and rim area (r=−0.41, r2=0.17, p=0.0051) decreased with longer axial lengths. Correcting for axial length-induced ocular magnification by means of the Littmann formula resolved the relationship between axial length and both RNFL thickness and ONH area. Discussion Axial length influences measurements of RNFL thickness and ONH parameters in healthy subjects. Caution is recommended when comparing the measured values of myopic and hyperopic eyes with the normative database of the instrument.

Repeatability of automatic measurements by a new Scheimpflug camera combined with Placido topography

PURPOSE: To assess the repeatability of anterior segment measurements performed by a Scheimpflug camera combined with Placido corneal topography (Sirius) in unoperated, post‐refractive surgery, and keratoconus eyes. SETTING: Private clinical ophthalmology practice. DESIGN: Evaluation of diagnostic test or technology. METHODS: Three consecutive scans were acquired for each eye. The following parameters were evaluated: simulated keratometry, posterior corneal power, mean pupil power (ie, corneal power assessed by ray tracing through the anterior and posterior corneal surfaces), corneal asphericity, thinnest and apex corneal thickness, aqueous depth, anterior chamber volume, and corneal spherical aberration. Repeatability was assessed using test–retest variability, the coefficient of variation, and the intraclass correlation coefficient (ICC). RESULTS: Sixty‐four unoperated eyes, 17 eyes that had myopic excimer laser surgery, and 13 eyes with keratoconus were analyzed. High repeatability was achieved for most parameters in the 3 groups, with an ICC higher than 0.99 for all measurements except posterior corneal power and mean pupil power in keratoconus (ICC, 0.868 and 0.976, respectively), anterior and posterior asphericity in normal eyes (ICC, 0.904 and 0.977, respectively), and spherical aberration in normal eyes (ICC, 0.806), post‐refractive surgery eyes (ICC, 0.980), and keratoconus eyes (ICC, 0.981). CONCLUSION: The anterior segment measurements provided by the new Scheimpflug camera–Placido corneal topography system were highly repeatable and can be relied on in clinical routine and for research purposes. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned.

Repeatability of automatic measurements performed by a dual Scheimpflug analyzer in unoperated and post-refractive surgery eyes

PURPOSE: To assess the repeatability of the anterior segment measurements performed with a dual Scheimpflug analyzer (Galilei) in unoperated and post‐refractive surgery eyes. SETTING: Private practice. DESIGN: Evaluation of diagnostic test. METHODS: Three consecutive scans were acquired in unoperated eyes and in eyes that had excimer laser surgery for myopia. Unoperated eyes were enrolled from 3 subgroups: younger than 50 years, aged between 50 and 70 years, and older than 70 years. The following parameters were evaluated: simulated keratometry, posterior corneal power, total corneal power, anterior and posterior best‐fit sphere radius, mean and thinnest central corneal thickness, anterior chamber depth and volume, horizontal and vertical corneal diameter, iridocorneal angle in the 4 quadrants, and corneal spherical aberration. Repeatability was assessed using analysis of variance (ANOVA), the coefficient of variation (COV), intraclass correlation (ICC), and test–retest variability. RESULTS: The study evaluated 45 unoperated eyes (n = 45) and 15 post‐refractive surgery eyes (n = 15). Each age subgroup in the unoperated group comprised 15 eyes. The ANOVA did not detect significant differences between the 3 measurements for any parameter. The COV was less than 0.5% for corneal power measurements and less than 3.5% for all remaining parameters except spherical aberration (16.68%). The ICC was more than 0.99 for corneal power measurements and more than 0.94 for all remaining parameters. CONCLUSIONS: The anterior segment measurements provided by the dual Scheimpflug analyzer were highly repeatable. Repeatability did not change with age or after myopic photorefractive keratectomy or laser in situ keratomileusis. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned.

Comparison of anterior segment measurements by 3 Scheimpflug tomographers and 1 Placido corneal topographer.

PURPOSE: To compare the anterior segment measurements provided by 3 Scheimpflug tomographers and a Placido corneal topographer. SETTING: Private clinical ophthalmology practice. DESIGN: Evaluation of diagnostic test or technology. METHODS: In a sample of 25 consecutive patients having either refractive or cataract surgery, the anterior eye segment was analyzed by means of a rotating Scheimpflug camera (Pentacam), 2 devices with a Scheimpflug camera combined with a Placido disk (Sirius and TMS‐5), and a Placido disk corneal topographer (Keratron). Measurement results were compared using analysis of variance. Agreement was assessed using Bland‐Altman plots. RESULTS: The mean simulated keratometry (K) was different between the 4 instruments (P<.0001), with Keratron providing the highest value (44.43 diopters [D] ± 1.28 [SD]). The Pentacam and Sirius provided the lowest values (44.05 ± 1.21 D and 44.05 ± 1.27 D, respectively), without statistical difference (posttest). The mean posterior corneal power and minimum corneal thickness were statistically different between the 3 Scheimpflug cameras (P<.0001 and P=.0210, respectively); 95% limits of agreement, however, were narrow for posterior corneal power and large for corneal thickness. The only 2 devices measuring the distance between the corneal endothelium and the anterior lens surface showed a statistically but not clinically significant difference (2.90 ± 0.48 mm and 2.94 ± 0.47 mm, respectively). There were no statistically significant differences in anterior corneal asphericity between the 4 instruments. CONCLUSION: Although the measurements of some parameters by different instruments were similar, caution is warranted before using them interchangeably. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned.

Melanopsin retinal ganglion cell loss in Alzheimer disease

Melanopsin retinal ganglion cells (mRGCs) are photoreceptors driving circadian photoentrainment, and circadian dysfunction characterizes Alzheimer disease (AD). We investigated mRGCs in AD, hypothesizing that they contribute to circadian dysfunction.

Syndromic parkinsonism and dementia associated with OPA1 missense mutations.

Mounting evidence links neurodegenerative disorders such as Parkinson disease and Alzheimer disease with mitochondrial dysfunction, and recent emphasis has focused on mitochondrial dynamics and quality control. Mitochondrial dynamics and mtDNA maintenance is another link recently emerged, implicating mutations in the mitochondrial fusion genes OPA1 and MFN2 in the pathogenesis of multisystem syndromes characterized by neurodegeneration and accumulation of mtDNA multiple deletions in postmitotic tissues. Here, we report 2 Italian families affected by dominant chronic progressive external ophthalmoplegia (CPEO) complicated by parkinsonism and dementia.

Association of Optic Disc Size with Development and Prognosis of Leber’s Hereditary Optic Neuropathy

PURPOSE To study the optic nerve head (ONH) morphology of patients with Lebers hereditary optic neuropathy (LHON) in a large family from Brazil carrying the 11778/ND4 mutation and in a case series of unrelated Italian families bearing different mitochondrial DNA (mtDNA) pathogenic mutations. METHODS Enrolled in the study were 15 LHON-affected patients (LHON-affected) and 45 LHON unaffected mutation carriers (LHON carriers) belonging to the previously reported Brazilian SOA-BR LHON pedigree and 56 LHON-affected and 101 LHON carriers from 45 unrelated LHON Italian pedigrees molecularly defined. The LHON-affected were subgrouped according to the extent of visual recovery. All individuals underwent optic nerve head (ONH) analysis by optical coherence tomography. RESULTS In the Brazilian sample, the mean optic disc area was significantly larger in LHON carriers than in the control group (P=0.002). In the Italian sample, the mean optic disc area and vertical disc diameter were significantly higher in LHON carriers than in both LHON-affected (respectively, P=0.008 and P<0.001) and control subjects (P<0.001 in both cases). The LHON-affected with visual recovery had a significantly larger vertical disc diameter when compared with those without visual recovery (P=0.03). CONCLUSIONS The results, revealing that the ONH size is larger in LHON carriers than in LHON-affected, suggest a protective role for this anatomic trait. Such a hypothesis is reinforced by the observation that, among the LHON-affected, larger discs correlated with visual recovery and better visual outcome. The findings may be relevant for prognosis and provide a mechanism for identifying nuclear-modifying genes implicated in the variability of penetrance in LHON.

Spectral-domain optical coherence tomography for the diagnosis and follow-up of glaucoma.

Purpose of review As spectral-domain optical coherence tomography (SD-OCT) progressively replaces time-domain OCT (TD-OCT) in the clinical and research setting, several commercially available instruments and new software upgrades for glaucoma diagnosis and progression analysis have been developed. Over the last year, several studies have been performed to assess the diagnostic performance of most of these instruments necessitating a review of their findings. Recent findings When compared with the measurements provided by TD-OCT, the conventional peripapillary circular scans by SD-OCT, which aim to measure the retinal nerve fiber layer (RNFL) thickness, show higher repeatability and similar diagnostic sensitivity. New software capabilities, such as the RNFL deviation map of Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA) or the macular Ganglion Cell Complex scan of RTVue (Optovue, Fremont, CA), provide complementary information that enhances our ability to discriminate between healthy and glaucomatous eyes. Summary SD-OCT-based instruments represent a technological advancement in the diagnosis of glaucoma. Improved repeatability will facilitate more reliable follow-up and progression analysis.