A Comprehensive Review of Leber Hereditary Optic Neuropathy and Its Association with Multiple Sclerosis-Like Phenotypes Known as Harding's Disease.

Leber Hereditary Optic Neuropathy (LHON) stands as a distinctive maternally inherited mitochondrial disorder marked by painless, subacute central vision loss, primarily affecting young males. This review covers the possible relationship between LHON and multiple sclerosis (MS), covering genetic mutations, clinical presentations, imaging findings, and treatment options. LHON is associated with mutations in mitochondrial DNA (mtDNA), notably m.11778G>A, m.3460G>A, and m.14484T>C, affecting complex I subunits. Beyond ocular manifestations, LHON can go beyond the eye into a multi-systemic disorder, showcasing extraocular abnormalities. Clinical presentations, varying in gender prevalence and outcomes, underscore the nature of mitochondrial optic neuropathies. Hypotheses exploring the connection between LHON and MS encompass mitochondrial DNA mutations triggering neurological diseases, immunologically mediated responses inducing demyelination, and the possibility of coincidental diseases. The research on mtDNA mutations among MS patients sheds light on potential associations with specific clinical subgroups, offering a unique perspective into the broader landscape of MS. Imaging findings, ranging from white matter alterations to cerebrospinal fluid biomarkers, further emphasize shared pathological processes between LHON-MS and classical MS. This comprehensive review contributes to the understanding of the complex relationship between LHON and MS.

Sensitivity and specificity of the uniform field electroretinogram in glaucoma detection in comparison to the pattern electroretinogram.

PURPOSE: To determine the ability of the photopic negative response (PhNR) of the uniform field electroretinogram (UF-ERG) to identify early glaucomatous changes in comparison to the checkerboard and bar stimuli of the pattern electroretinogram (PERG). METHODS: Forty-nine glaucoma patients were classified into two groups: glaucoma-suspect (23 eyes) and early to moderate glaucoma (30 eyes), based on their clinical examination and the results of standard automated perimetry. Thirty patients (30 eyes) with intraocular pressures (IOP) of 21 mmHg or less, with no history of reported high IOP, were included as controls. PERG and UF-ERG recordings were obtained on a Diagnosys D-341 Attaché-Envoy System. Visual field testing was done only for glaucoma-suspect and glaucoma patients. RESULTS: All three tests (PERG bar stimulus, PERG checkerboard stimulus and PhNR) displayed significantly prolonged peak times for glaucoma and glaucoma-suspect patients, with delays ranging from 7.8 to 14.8%, depending on the test. The PERG bar stimulus also showed a significantly lower N95 amplitude for both glaucoma groups (with reductions of 26.0% and 33.0% for glaucoma-suspect and glaucoma groups, respectively). The PERG checkerboard N95 amplitude component had high sensitivity for detecting glaucoma patients but a low specificity (97% and 37%, respectively; AUC = 0.61). Overall, the PhNR peak time showed the highest sensitivity and specificity (77% and 90%, respectively; AUC = 0.87). CONCLUSIONS: PERG bar stimuli and the PhNR of the UF-ERG can be used in the clinical setting to detect glaucoma-related changes in glaucoma-suspect and glaucoma patients. However, our data confirm that the PhNR peak time has the best combined sensitivity and specificity.

Detecting seasonal trends in optic neuritis within the Ottawa region.

OBJECTIVE: In this study we aim to determine seasonal patterns underlying optic neuritis (ON) onset that may provide valuable epidemiologic information and help delineate causative or protective factors. DESIGN: Single-centre retrospective chart review. METHODS: A database search of centralized electronic health records was completed using diagnostic codes employed at the Ottawa Eye Institute for data collection. Charts were reviewed for documentation supporting a diagnosis of ON falling into the following categories: multiple sclerosis ON and clinically isolated syndrome ON, myelin oligodendrocyte glycoprotein ON, neuromyelitis optica ON, and idiopathic ON. Date of onset, biological sex, and age were extracted from each chart. Data were analyzed for calculation of frequency by season and overall pooled seasonal trends of all cases of ON. RESULTS: From the 218 included patients with ON, there was no statistically significant seasonal correlation. The overall trend of ON was lowest in winter and spring (22% and 23%, respectively) and highest in summer and fall (28% and 27% respective). Divided further, multiple sclerosis ON or clinically isolated syndrome ON rates (n = 144) were lowest in the spring (21%) and highest in fall (29%); myelin oligodendrocyte glycoprotein ON rates (n = 25) were lowest in winter (16%) and highest in summer and fall (both at 32%); neuromyelitis optica ON rates (n = 16) were lowest in fall (12.5%) and highest in winter and summer (both at 31.25%); and idiopathic ON rates (n = 33) were lowest in fall (18%) and highest in spring (33%). CONCLUSIONS: The overall ON seasonal trend appears to have a predilection for the summer and fall months, which may be explained by warmer weather and viral infections as risk factors for multiple sclerosis relapse during those seasons.

Elamipretide Topical Ophthalmic Solution for the Treatment of Subjects with Leber Hereditary Optic Neuropathy: A Randomized Trial.

PURPOSE: This study aimed to assess the safety, tolerability, and potential efficacy of topical elamipretide in patients affected with Leber hereditary optic neuropathy (LHON). DESIGN: This phase II, prospective, randomized, vehicle-controlled, single-center clinical trial involved administration of elamipretide 1% topical ophthalmic solution to patients with LHON over a 52-week double-masked treatment period, followed by an open-label extension (OLE) for up to 108 additional weeks of treatment. PARTICIPANTS: Twelve patients with LHON were included in this study. Patients aged 18 to 50 years with decreased vision for at least ≥ 1 year and ≤ 10 years, and a genetically confirmed diagnosis of m.11778G>A LHON were eligible for this trial. METHODS: For the first 52 weeks of the study, patients were randomized to 1 of 3 groups: elamipretide in both eyes or elamipretide in 1 eye (left eye and right eye were considered separate groups) and vehicle in the other eye, followed by an OLE in which both eyes were treated with elamipretide. MAIN OUTCOME MEASURES: The primary outcome measure was assessment of adverse events (AEs) from the administration of topical elamipretide, and the primary efficacy end point was change in best-corrected visual acuity (BCVA). Secondary outcome measures included changes in color vision, visual field mean deviation, and electrophysiological outcomes. RESULTS: Elamipretide was well tolerated with the majority of AEs being mild to moderate and resolving spontaneously. The change from baseline in BCVA in elamipretide-treated eyes was not significantly different from the vehicle eyes at any time point. Six of 12 subjects met the criteria for clinically relevant benefit (CRB). In the post hoc analysis, change from baseline in mean deviation in the central visual field was significantly greater in elamipretide-treated eyes versus the vehicle eyes. Compared with baseline, both treatment groups showed improvement in color discrimination and contrast sensitivity in the OLE. CONCLUSIONS: Elamipretide treatment was generally well tolerated, with no serious AEs reported. Although this study did not meet its primary BCVA efficacy end point, improvements across assessments on visual function during the OLE and the post hoc findings of the Humphrey automated visual field central region were encouraging and require further exploration. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Neuro-Ophthalmic Complications of COVID-19 Infection and Vaccination.

The COVID-19 pandemic has led to the identification of new disease phenotypes associated with infection by the SARS-CoV-2 virus. This includes multiple neuro-ophthalmological sequelae, which have been associated with COVID-19 infection and administration of COVID-19 vaccines. Some of these associations have a plausible pathophysiological link to the infection or vaccination but true causation has yet to be established. We review the literature for associations reported between COVID-19 infection or vaccination and neuro-ophthalmic sequelae and review the potential pathophysiological processes that may underlie these associations.

Indirect Comparison of Lenadogene Nolparvovec Gene Therapy Versus Natural History in Patients with Leber Hereditary Optic Neuropathy Carrying the m.11778G>A MT-ND4 Mutation.

INTRODUCTION: Lenadogene nolparvovec is a promising novel gene therapy for patients with Leber hereditary optic neuropathy (LHON) carrying the m.11778G>A ND4 mutation (MT-ND4). A previous pooled analysis of phase 3 studies showed an improvement in visual acuity of patients injected with lenadogene nolparvovec compared to natural history. Here, we report updated results by incorporating data from the latest phase 3 trial REFLECT in the pool, increasing the number of treated patients from 76 to 174. METHODS: The visual acuity of 174 MT-ND4-carrying patients with LHON injected in one or both eyes with lenadogene nolparvovec from four pooled phase 3 studies (REVERSE, RESCUE and their long-term extension trial RESTORE; and REFLECT trial) was compared to the spontaneous evolution of an external control group of 208 matched patients from 11 natural history studies. RESULTS: Treated patients showed a clinically relevant and sustained improvement in their visual acuity when compared to natural history. Mean improvement versus natural history was - 0.30 logMAR (+ 15 ETDRS letters equivalent) at last observation (P < 0.01) with a maximal follow-up of 3.9 years after injection. Most treated eyes were on-chart as compared to less than half of natural history eyes at 48 months after vision loss (89.6% versus 48.1%; P < 0.01) and at last observation (76.1% versus 44.4%; P < 0.01). When we adjusted for covariates of interest (gender, age of onset, ethnicity, and duration of follow-up), the estimated mean gain was - 0.43 logMAR (+ 21.5 ETDRS letters equivalent) versus natural history at last observation (P < 0.0001). Treatment effect was consistent across all phase 3 clinical trials. Analyses from REFLECT suggest a larger treatment effect in patients receiving bilateral injection compared to unilateral injection. CONCLUSION: The efficacy of lenadogene nolparvovec in improving visual acuity in MT-ND4 LHON was confirmed in a large cohort of patients, compared to the spontaneous natural history decline. Bilateral injection of gene therapy may offer added benefits over unilateral injection. TRIAL REGISTRATION NUMBERS: NCT02652780 (REVERSE); NCT02652767 (RESCUE); NCT03406104 (RESTORE); NCT03293524 (REFLECT); NCT03295071 (REALITY).

Altering neuronal circuitry with 4-aminopyridine for visual improvement in Leber's hereditary optic neuropathy (LHON).

In this retrospective, interventional, longitudinal small case series, we looked at the visual effects of pharmacologic intervention with 4-aminopyridine (4-AP) in chronic Leber's Hereditary Optic Neuropathy (LHON) patients who are non-responders to idebenone. We illustrate, as examples, the visual progression of three LHON patients with 4-AP as add-on therapy to idebenone. Each patient had a different primary LHON mutation and was treated with idebenone within one year of onset. No response to idebenone at 300 mg orally three times a day ranged from less than one year to 2.5 years, and the addition of 4-AP at 10 mg orally two times a day ranged from 24 to 29 months. Outcome measures included best-corrected distance visual acuity, color vision, automated perimetry, the average retinal nerve fiber layer (RNFL) thickness, and the full-field photopic negative response (PhNR) amplitude. The 19-year-old man with the LHON mutation 11778A > G had no response to the addition of 4-AP to idebenone. The 27-year-old man with the LHON mutation 3460A > G experienced a significant response to 4-AP. Finally, the 40-year-old man with the LHON mutation 14484 T > C had a milder response. Although this case series was too small to demonstrate the efficacy of idebenone with add-on 4AP, it allowed us to consider a new hypothesis that neuronal activity generated from 4-AP can add more potential for visual recovery in LHON patients.

Pathophysiology of central serous chorioretinopathy: a literature review with quality assessment.

The pathogenesis of central serous chorioretinopathy (CSCR), a pachychoroid disease, is poorly understood. While choroid hyperpermeability and retinal pigment epithelium dysfunction are cornerstones for developing CSCR, the mechanisms at the retinal, vascular, retinal pigment epithelium, and cellular level continue to be an enigma. A few preclinical studies and the development of small-sized, poorly controlled clinical trials have resulted in limited insight into the disease mechanism. Effective treatments for CSCR are still lacking as current trials have produced inconsistent results for functional and structural gains. Thus, critically evaluating the literature to explore disease mechanisms and provide an up-to-date understanding of pathophysiology can provide valuable information and avenues to new treatments. In this study, a comprehensive summary of the mechanistic insight into CSCR is presented while highlighting the shortcomings of current literature. The mechanism was divided into seven sub-categories including mechanical obstruction, inflammation, oxidative stress, paracrine factors, autonomic dysfunction, mineralocorticoid receptors activation, and medications. We implemented validated tools like the JBI and CAMARADES to objectively analyze the quality of both clinical and preclinical studies, respectively. Overall, our analysis of the literature showed that no single mechanism was populated with a large number of sufficiently sized and good-quality studies. However, compiling these studies gave hints not only to CSCR pathogenesis but also pachychoroid disease in general while providing suggestions for future exploration.

Natural history of patients with Leber hereditary optic neuropathy-results from the REALITY study.

BACKGROUND/OBJECTIVES: REALITY is an international observational retrospective registry of LHON patients evaluating the visual course and outcome in Leber hereditary optic neuropathy (LHON). SUBJECTS/METHODS: Demographics and visual function data were collected from medical charts of LHON patients with visual loss. The study was conducted in 11 study centres in the United States of America and Europe. The collection period extended from the presymptomatic stage to at least more than one year after onset of vision loss (chronic stage). A Locally Weighted Scatterplot Smoothing (LOWESS) local regression model was used to analyse the evolution of best-corrected visual acuity (BCVA) over time. RESULTS: 44 LHON patients were included; 27 (61%) carried the m.11778G>A ND4 mutation, 8 (18%) carried the m.3460G>A ND1 mutation, and 9 (20%) carried the m.14484T>C ND6 mutation. Fourteen (32%) patients were under 18 years old at onset of vision loss and 5 (11%) were below the age of 12. The average duration of follow-up was 32.5 months after onset of symptoms. At the last observed measure, mean BCVA was 1.46 LogMAR in ND4 patients, 1.52 LogMAR in ND1 patients, and 0.97 LogMAR in ND6 patients. The worst visual outcomes were reported in ND4 patients aged at least 15 years old at onset, with a mean BCVA of 1.55 LogMAR and no tendency for spontaneous recovery. The LOESS modelling curve depicted a severe and permanent deterioration of BCVA. CONCLUSIONS: Amongst LHON patients with the three primary mtDNA mutations, adult patients with the m.11778G>A ND4 mutation had the worst visual outcomes, consistent with prior reports.

Benefit of Stimulus Size V Perimetry for Patients With a Dense Central Scotoma From Leber's Hereditary Optic Neuropathy.

Purpose: Leber's hereditary optic neuropathy (LHON) is the most common mtDNA optic neuropathy. It most frequently causes dense bilateral central scotomas that are often characterized in clinical studies by Humphrey visual field testing (HVF) using a stimulus size III. This provides numerical quantification of the visual field defect using the mean deviation. However, this size III testing strategy has limitations. We used stimulus size V to monitor these patients and evaluated intertest variability and dynamic range to determine the testing reliability and reproducibility. Methods: This was a longitudinal retrospective cohort study comparing Stimulus III and Stimulus V HVF of 62 LHON patients who had reached the plateau stage of the disease. The intertest variability and mean defect were calculated for both stimulus sizes for 38 patients. The mean defect for stimulus size V was calculated using an algorithm developed by the University of Iowa Visual Field Reading Center. Results: Stimulus size V HVFs had lower inter-test variability as measured by mean defect standard deviation (Z = 169, P < 0.01). The floor effect seen with Stimulus III HVF in LHON, was less pronounced with Stimulus V HVF. The correlation of stimulus size III and V mean defect was strong (r = 0.90, P < 0.01), and a mathematical model was constructed to calculate the Stimulus size V mean defect from the Stimulus size III results (MDstimV = 0.988 x MDStimIII + 1.35, R2 = 0.82 P < 0.01). Conclusions: Stimulus size V HVF had lower intertest variability and a better dynamic range than Stimulus size III HVF in LHON patients. This makes the stimulus V HVF a more reliable metric to follow LHON patients especially in clinical trials. The mathematical model presented can be used to generate a Stimulus V equivalent mean defect from Stimulus III HVFs. Translational Relevance: Using Stimulus V HVF in LHON patients increases its ability to detect and quantify a response to treatment, making it a useful metric for future LHON clinical trials and the clinical setting.

Cross-Sectional Analysis of Baseline Visual Parameters in Subjects Recruited Into the RESCUE and REVERSE ND4-LHON Gene Therapy Studies.

OBJECTIVE: This report presents a cross-sectional analysis of the baseline characteristics of subjects with Leber hereditary optic neuropathy enrolled in the gene therapy trials RESCUE and REVERSE, to illustrate the evolution of visual parameters over the first year after vision loss. METHODS: RESCUE and REVERSE were 2 phase III clinical trials designed to assess the efficacy of rAAV2/2-ND4 gene therapy in ND4-LHON subjects. At enrollment, subjects had vision loss for ≤6 months in RESCUE, and between 6 and 12 months in REVERSE. Functional visual parameters (best-corrected visual acuity [BCVA], contrast sensitivity [CS], and Humphrey Visual Field [HVF]) and structural parameters assessed by spectral-domain optical coherence tomography were analyzed in both cohorts before treatment. The cross-sectional analysis of functional and anatomic parameters included the baseline values collected in all eyes at 2 different visits (Screening and Inclusion). RESULTS: Seventy-six subjects were included in total, 39 in RESCUE and 37 in REVERSE. Mean BCVA was significantly worse in RESCUE subjects compared with REVERSE subjects (1.29 and 1.61 LogMAR respectively, P = 0.0029). Similarly, mean CS and HVF were significantly more impaired in REVERSE vs RESCUE subjects (P < 0.005). The cross-sectional analysis showed that the monthly decrease in BCVA, ganglion cell layer macular volume, and retinal nerve fiber layer thickness was much more pronounced in the first 6 months after onset (+0.24 LogMAR, -0.06 mm3, and -6.00 µm respectively) than between 6 and 12 months after onset (+0.02 LogMAR, -0.01 mm3, and -0.43 µm respectively). CONCLUSION: LHON progresses rapidly in the first months following onset during the subacute phase, followed by relative stabilization during the dynamic phase.

Intravitreal Gene Therapy vs. Natural History in Patients With Leber Hereditary Optic Neuropathy Carrying the m.11778G>A ND4 Mutation: Systematic Review and Indirect Comparison.

Objective: This work aimed to compare the evolution of visual outcomes in Leber hereditary optic neuropathy (LHON) patients treated with intravitreal gene therapy to the spontaneous evolution in prior natural history (NH) studies. Design: A combined analysis of two phase three randomized, double-masked, sham-controlled studies (REVERSE and RESCUE) and their joint long-term extension trial (CLIN06) evaluated the efficacy of rAAV2/2-ND4 vs. 11 pooled NH studies used as an external control. Subjects: The LHON subjects carried the m.11778G>A ND4 mutation and were aged ≥15 years at onset of vision loss. Methods: A total of 76 subjects received a single intravitreal rAAV2/2-ND4 injection in one eye and sham injection in the fellow eye within 1 year after vision loss in REVERSE and RESCUE. Both eyes were considered as treated due to the rAAV2/2-ND4 treatment efficacy observed in the contralateral eyes. Best corrected visual acuity (BCVA) from REVERSE, RESCUE, and CLIN06 up to 4.3 years after vision loss was compared to the visual acuity of 208 NH subjects matched for age and ND4 genotype. The NH subjects were from a LHON registry (REALITY) and from 10 NH studies. A locally estimated scatterplot smoothing (LOESS), non-parametric, local regression model was used to modelize visual acuity curves over time, and linear mixed model was used for statistical inferences. Main Outcome Measures: The main outcome measure was evolution of visual acuity from 12 months after vision loss, when REVERSE and RESCUE patients had been treated with rAAV2/2-ND4. Results: The LOESS curves showed that the BCVA of the treated patients progressively improved from month 12 to 52 after vision loss. At month 48, there was a statistically and clinically relevant difference in visual acuity of -0.33 logarithm of the minimal angle of resolution (LogMAR) (16.5 ETDRS letters equivalent) in favor of treated eyes vs. NH eyes (p < 0.01). Most treated eyes (88.7%) were on-chart at month 48 as compared to 48.1% of the NH eyes (p < 0.01). The treatment effect at last observation remained statistically and clinically significant when adjusted for age and duration of follow-up (-0.32 LogMAR, p < 0.0001). Conclusions: The m.11778G>A LHON patients treated with rAAV2/2-ND4 exhibited an improvement of visual acuity over more than 4 years after vision loss to a degree not demonstrated in NH studies. Clinical Trial Registration: NCT02652767, NCT02652780, NCT03406104, and NCT03295071.

Retinal ganglion cell dysfunction in preclinical Alzheimer's disease: an electrophysiologic biomarker signature.

The current study evaluated retinal function using electroretinography (ERG) in cognitively healthy (CH) participants with preclinical Alzheimer's disease (AD), as classified by cerebral spinal fluid (CSF) Aß42/Tau ratio. Individuals with normal retinal morphology ascertained by spectral-domain optical coherence tomography were enrolled. Full-field ERG, pattern PERG, and photopic negative response (PhNR) were performed in 29 adult participants (58 eyes). Amplitude and implicit times of the ERG wave components were analyzed. Preclinical AD participants showed marked retinal ganglion cell dysfunction relative to controls. The PhNR was significantly diminished in preclinical AD relative to controls. PhNR amplitude and N95 implicit time differentiated CH individuals with CSF biomarkers of AD pathology with 87% sensitivity and 82% specificity. These quantitative electrophysiologic findings expand our understanding of early retinal functional changes that precede cognitive decline in AD. Retinal ganglion cell dysfunction, as detected by ERG, may be a clinically useful, non-invasive in vivo biomarker for early disease detection, which is necessary for ultimately pursuing early intervention.

Efficacy and Safety of Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy Treated within 6 Months of Disease Onset.

PURPOSE: To evaluate the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON). DESIGN: RESCUE is a multicenter, randomized, double-masked, sham-controlled, phase 3 clinical trial. PARTICIPANTS: Subjects with the m.11778G>A mitochondrial DNA mutation and vision loss ≤6 months from onset in 1 or both eyes were included. METHODS: Each subject's right eye was randomly assigned (1:1) to treatment with rAAV2/2-ND4 (single injection of 9 × 1010 viral genomes in 90 µl) or to sham injection. The left eye received the treatment not allocated to the right eye. MAIN OUTCOME MEASURES: The primary end point was the difference of the change from baseline in best-corrected visual acuity (BCVA) between rAAV2/2-ND4-treated and sham-treated eyes at week 48. Other outcome measures included contrast sensitivity, Humphrey visual field perimetry, retinal anatomic measures, and quality of life. Follow-up extended to week 96. RESULTS: Efficacy analysis included 38 subjects. Mean age was 36.8 years, and 82% were male. Mean duration of vision loss at time of treatment was 3.6 months and 3.9 months in the rAAV2/2-ND4-treated eyes and sham-treated eyes, respectively. Mean baseline logarithm of the minimum angle of resolution (logMAR) BCVA (standard deviation) was 1.31 (0.52) in rAAV2/2-ND4-treated eyes and 1.26 (0.62) in sham-treated eyes, with a range from -0.20 to 2.51. At week 48, the difference of the change in BCVA from baseline between rAAV2/2-ND4-treated and sham-treated eyes was -0.01 logMAR (P = 0.89); the primary end point of a -0.3 logMAR (15-letter) difference was not met. The mean BCVA for both groups deteriorated over the initial weeks, reaching the worst levels at week 24, followed by a plateau phase until week 48, and then an improvement of +10 and +9 Early Treatment Diabetic Retinopathy Study letters equivalent from the plateau level in the rAAV2/2-ND4-treated and sham-treated eyes, respectively. CONCLUSIONS: At 96 weeks after unilateral injection of rAAV2/2-ND4, LHON subjects carrying the m.11778G>A mutation treated within 6 months after vision loss achieved comparable visual outcomes in the injected and uninjected eyes.

Photopic negative response using a handheld mini-ganzfeld stimulator in healthy adults: normative values, intra- and inter-session variability.

PURPOSE: To determine normative values, intra- and inter-session variability for a range of parameters derived from the photopic negative response (PhNR) using a handheld mini-Ganzfeld stimulator in healthy normal adults. METHODS: Light-adapted flash full-field electroretinograms (ERGs) were recorded from healthy individuals with no visual complaints, visual acuity equal to or better than 0.0 logMAR (20/20 Snellen), and negative family history for visual diseases. ERGs were recorded from both eyes using a DTL® type fiber electrode after dilation of the pupils with instillation of 1 drop of tropicamide eye drops (1%). The full-field PhNR stimulus conditions were produced by a LED-based ColorBurst™ (Diagnosys LLC, Lowell, MA, USA) handheld stimulator. Red flashes of 1, 5 and 7 cd.s/m2 on a blue background of 10 cd/m2 were presented. A-wave, b-wave and PhNR amplitude (determined by both baseline to trough-BT and peak to trough-PT) and peak times were analyzed. Normal limits were determined as 5% percentile for amplitudes and 95% percentile for latencies. Intra- and inter-session variability were assessed with Wilcoxon signed-rank test, intraclass correlation coefficient (ICC) and the coefficient of variability (COV). RESULTS: Normative limits for PhNR amplitude (µV) using 1, 5 and 7 cd.s./m2 stimuli were, respectively: 20.81; 18.06 and 19.60 for BT and 69.11; 77.98; 76.51 for PT. Peak times (ms) normative limits for 1, 5 and 7 cd.s/m2 intensities were, respectively, 65.98; 78.20 and 77.96. Overall, intra-session variability assessed by coefficients of variation ranged from 1.35 to 10.28%. Inter-session variability disclosed significant intraclass correlation values for all PhNR parameters only for 1 cd.s/m2 stimuli. CONCLUSIONS: The normative values provided by this study are clinically helpful in the diagnosis of inner retinal disorders, especially those affecting retinal ganglion cells such as glaucoma and other optic neuropathies. Further studies, including a larger sample with variable age range would extend the validity of the current results.

OCT parameters of the optic nerve head and the retina as surrogate markers of brain volume in a normal population, a pilot study.

The relationship between optical coherence tomography (OCT) measurements of the retinal structures has been described for various neurological diseases including Multiple Sclerosis (MS), Alzheimer's disease (AD) and Parkinson's disease (PD). Brain volume changes, both globally and by area, are associated with some of these same diseases, yet the correlation of OCT and disease is not fully elucidated. Our study looked at normal subjects, at the correlation of OCT measurements and brain volumes, both globally and for specific regions including the pericalcarine grey matter, entorhinal grey matter, and cerebellar volume using a retrospective, cross-sectional cohort study design. Thickness of the retinal nerve fiber layer (RNFL) as measured by OCT, correlated with volume of the pericalcarine grey matter, when adjusted for age and gender. Similarly, thickness of the ganglion cell layer-inner plexiform layer complex may be associated with both entorhinal grey matter volumes and total cerebellar volumes, although our pilot study did not reach statistical significance. This suggests that both eye and brain volumes follow a similar trajectory and understanding the inter-relationship of these structures will aid in the analysis of changes seen in disease. Further studies are needed to longitudinally demonstrate these relationships.

Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy.

REVERSE is a randomized, double-masked, sham-controlled, multicenter, phase 3 clinical trial that evaluated the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON). A total of 37 subjects carrying the m.11778G>A (MT-ND4) mutation and with duration of vision loss between 6 to 12 months were treated. Each subject's right eye was randomly assigned in a 1:1 ratio to treatment with rAAV2/2-ND4 (GS010) or sham injection. The left eye received the treatment not allocated to the right eye. Unexpectedly, sustained visual improvement was observed in both eyes over the 96-week follow-up period. At week 96, rAAV2/2-ND4-treated eyes showed a mean improvement in best-corrected visual acuity (BCVA) of -0.308 LogMAR (+15 ETDRS letters). A mean improvement of -0.259 LogMAR (+13 ETDRS letters) was observed in the sham-treated eyes. Consequently, the primary end point, defined as the difference in the change in BCVA from baseline to week 48 between the two treatment groups, was not met (P = 0.894). At week 96, 25 subjects (68%) had a clinically relevant recovery in BCVA from baseline in at least one eye, and 29 subjects (78%) had an improvement in vision in both eyes. A nonhuman primate study was conducted to investigate this bilateral improvement. Evidence of transfer of viral vector DNA from the injected eye to the anterior segment, retina, and optic nerve of the contralateral noninjected eye supports a plausible mechanistic explanation for the unexpected bilateral improvement in visual function after unilateral injection.