The coma in glaucoma: Retinal ganglion cell dysfunction and recovery

Fry, Lewis E; Fahy, Eamonn; Chrysostomou, Vicki; Hui, Flora; Tang, Junqing; Wijngaarden, Peter van; Petrou, Steven; Crowston, Jonathan G

doi:10.1016/j.preteyeres.2018.04.001

Cited by 85 publications

(61 citation statements)

References 177 publications

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“…We attribute this to a reactivated signal transduction in surviving dysfunctional RGCs in the chronic disease state. There is growing evidence also from other chronic optic neuropathies, most prominently in glaucoma, that a recovery of visual function can occur following medical treatment, which suggests that it may be possible to restore the function of injured RGC and hence improve vision [16].…”

Section: Discussionmentioning

confidence: 99%

Visual function in chronic Leber’s hereditary optic neuropathy during idebenone treatment initiated 5 to 50 years after onset

Pemp

Kircher

Reitner

2019

Graefes Arch Clin Exp Ophthalmol

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Purpose Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease characterized by a subacute and progressive impairment and subsequent degeneration of retinal ganglion cells (RGCs). In most cases, it results in optic nerve atrophy and permanently reduced visual acuity (VA). Idebenone has recently been approved in Europe for treating LHON. However, published clinical data has only focused on efficacy in patients within the first years after disease onset. The present study is the first to evaluate possible effects of idebenone treatment in patients with LHON when initiated after more than 5 years from disease onset. Methods Oral treatment with idebenone 300 mg tid was started in seven patients 5 to 51 years after LHON onset. All patients had genetically confirmed primary LHON mutations (m11778G>A, m14484T>C, and m13051G>A). Visual function of all fourteen eyes was tested every 3 months using logarithmic reading charts and automated static threshold perimetry. The obtained clinical data were analyzed retrospectively using a multivariate analysis for VA and the Wilcoxon signed-rank test for visual field data. Results Before treatment, VA was 0.78 ± 0.38 logMAR (range 0.24 to 1.50 logMAR). During the first year of therapy, VA improved significantly by an average of − 0.20 ± 0.10 logMAR or 10 ± 5 ETDRS letters (P = 0.002; VA range 0.06 to 1.30 logMAR). Seven of fourteen eyes showed an improvement of 2 or more lines. Visual field mean deviation increased from − 8.02 ± 6.11 to − 6.48 ± 5.26 dB after 12 months, but this change was not statistically significant (P = 0.056). Conclusions The increase in VA of patients who have had LHON for more than 5 years observed soon after start of treatment may not constitute a coincidental spontaneous recovery. We hypothesize that the treatment response in chronic LHON was the result of a reactivated signal transduction in surviving dysfunctional RGCs. The results of this study indicate a beneficial effect of idebenone on improvement of visual function in LHON patients with established optic atrophy.Open Access This article is distributed under the terms of the Creative Comm ons Attribution 4.0 International License (http:// creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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Section: Discussionmentioning

confidence: 99%

Visual function in chronic Leber’s hereditary optic neuropathy during idebenone treatment initiated 5 to 50 years after onset

Pemp

Kircher

Reitner

2019

Graefes Arch Clin Exp Ophthalmol

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“…Structural changes associated with neuroplasticity in response to the glaucomatous process may include dendritic sprouting and changes in cytoplasm content and could conceivably cause an increase in thickness. 12 Similarly, the RNFL contains the axons of the retinal ganglion cells, and their axoplasmic contents may be influenced by the characteristics of axoplasmic flow and status of the axon, 12 – 16 which in turn may cause dynamic changes in the thickness of this layer. The present analysis raises important questions about the increase in variance of the distribution of slopes of the GCL and RNFL in glaucoma patients compared to normal subjects.…”

Section: Discussionmentioning

confidence: 99%

Assessing Trends in Functional and Structural Characteristics: A Survey of Statistical Methods With an Example From Ophthalmology

Ledolter

Kardon

2018

Trans. Vis. Sci. Tech.

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PurposeClinical decisions on treatment are usually based on short-term records of consecutive measurements of structure and function. Useful models for analyzing average trends and a description of statistical methods for classifying individual subjects on the basis of subject-specific trend progressions are presented.MethodsRandom effects trend models allow intercepts and slopes of the trend regression to vary across subjects around group-specific mean intercepts and mean slopes. Model results assess whether average intercepts and slopes and subject variability in intercepts and slopes are the same across groups. Fisher's discriminant functions are used for classification.ResultsMethods are presented and illustrated on structural visual data from a multiyear perimetry study. Average thickness of the ganglion cell layer from the optical coherence tomography macula scan and of the retinal nerve fiber layer from the optic disc scan for both glaucoma patients on optimal treatment and normal subjects are analyzed. The random effects trend model shows that average intercepts of glaucoma patients and normal subjects are quite different, but that average slopes are the same, and that the subject variability in both intercepts and slopes is larger for the glaucoma group. These findings explain why the subject-specific trend progression is not a good classifier; it is the level of the measurement (intercept or baseline value) that carries useful information in this particular cohort example.Translational RelevanceClinicians base decisions on short-term records of consecutive measurements and need simple statistical tools to analyze the information. This paper discusses useful methods for analyzing short time series data. Model results assess whether there exist significant trends and whether average trends are different across groups. The paper discusses whether clinical measures classify patients reliably into disease groups, given their variability. With ever more available data, classification plays a central role of personalized medicine.

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“…[26][27][28][29][30] RGC function has been shown to recover after acute and chronic IOP insults even after prolonged periods of functional loss. [31][32][33][34][35] Capacity for recovery is reduced with advancing age 36 and can be modified by interventions such as exercise and diet restriction. 37,38 Using ERG protocols similar to those validated in rodent studies, we have demonstrated improvements in RGC function in humans, as early as 3-months following IOP-lowering in glaucoma.…”

Section: Main Textmentioning

confidence: 99%

Improvement in Inner Retinal Function in Glaucoma with Nicotinamide (Vitamin B₃) Supplementation: A Crossover Randomised Clinical Trial

Hui

Tang

Williams

et al. 2020

Preprint

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Importance: Retinal ganglion cells endure significant metabolic stress with ageing and glaucoma-related stressors. Injured cells require increased energy for repair but maintain capacity to recover function despite periods of functional loss. Nicotinamide, a precursor of redox co-factor and metabolite, NAD+, is low in serum of patients with primary open-angle glaucoma and its supplementation provides robust protection of retinal ganglion cells by targeting mitochondrial health in glaucoma models. However, the potential of nicotinamide to improve retinal ganglion cell function in humans with glaucoma is yet unknown. Objective: To determine whether nicotinamide supplementation taken in conjunction with conventional IOP-lowering therapy leads to early improvement in retinal ganglion cell function in people with glaucoma. Design: Crossover, double-masked, randomized clinical trial conducted between October 2017 to January 2019. Setting: Study participants recruited from two tertiary care centers in Melbourne, Australia. Participants: Adults diagnosed and treated for primary glaucoma. Ninety-four participants assessed for study eligibility. Intervention: Participants randomized to first receive oral placebo or nicotinamide and reviewed six-weekly. Accelerated dosing method utilized; participants commenced 6-week course of 1.5 grams/day followed by 6 weeks of 3.0 grams/day. After 12 weeks, participants crossed over to other intervention for 12 weeks without washout. At each visit, visual function measured using full-field flash electroretinography and white-on-white perimetry. Main outcome measures: Primary endpoint was change in inner retinal function determined a-priori as change in photopic negative response (PhNR) parameters: saturated PhNR amplitude (Vmax), ratio of PhNR/b-wave amplitude (Vmax ratio). Results: Fifty-seven participants (65.5±10.0 years, 39% female) enrolled. PhNR Vmax improved beyond 95% coefficient of repeatability (COR) in 23% of participants following 12 weeks of nicotinamide versus 9% on placebo. Conversely, PhNR Vmax deteriorated in 9% on placebo and 7% on nicotinamide. Overall, Vmax improved by 14.8% [95% CI: 2.8%, 26.9%], (p=0.02) on nicotinamide and 5.2% [-4.2%, 14.6%], (p=0.27) on placebo. Vmax ratio improved on average by 12.6% [5.0%, 20.2%], (p=0.002) following nicotinamide and 3.6% [-3.4%, 10.5%], (p=0.30) on placebo. A concomitant trend for improved visual field mean deviation was observed with 27% improving ≥1dB on nicotinamide and fewer deteriorating ≥1dB (4%) compared to placebo (p=0.02). Moderate correlation was observed between PhNR and visual field change with treatment. Participants demonstrated excellent treatment adherence rates (>94%) and nicotinamide was well tolerated with minimal side effects. Conclusions and Relevance: Nicotinamide supplementation can improve inner retinal function in patients receiving concurrent IOP-lowering glaucoma therapy. Further studies are underway to elucidate the effects of long-term nicotinamide supplementation on glaucoma progression.

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The coma in glaucoma: Retinal ganglion cell dysfunction and recovery

Cited by 85 publications

References 177 publications

Visual function in chronic Leber’s hereditary optic neuropathy during idebenone treatment initiated 5 to 50 years after onset

Visual function in chronic Leber’s hereditary optic neuropathy during idebenone treatment initiated 5 to 50 years after onset

Assessing Trends in Functional and Structural Characteristics: A Survey of Statistical Methods With an Example From Ophthalmology

Improvement in Inner Retinal Function in Glaucoma with Nicotinamide (Vitamin B₃) Supplementation: A Crossover Randomised Clinical Trial

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The coma in glaucoma: Retinal ganglion cell dysfunction and recovery

Cited by 85 publications

References 177 publications

Visual function in chronic Leber’s hereditary optic neuropathy during idebenone treatment initiated 5 to 50 years after onset

Visual function in chronic Leber’s hereditary optic neuropathy during idebenone treatment initiated 5 to 50 years after onset

Assessing Trends in Functional and Structural Characteristics: A Survey of Statistical Methods With an Example From Ophthalmology

Improvement in Inner Retinal Function in Glaucoma with Nicotinamide (Vitamin B3) Supplementation: A Crossover Randomised Clinical Trial

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Improvement in Inner Retinal Function in Glaucoma with Nicotinamide (Vitamin B₃) Supplementation: A Crossover Randomised Clinical Trial