Optic Neuropathy and Myelopathy in a Teenager With Biotinidase Deficiency.

ABSTRACT: A 19-year-old man presented with 3 years of gradually progressive, painless vision loss in both eyes. The ophthalmic examination showed bilateral diminished visual acuity, dyschromatopsia, and temporal optic nerve pallor. The neurological examination was consistent with a mild myelopathy with decreased pin-prick sensation starting at T6-T7 and descending through the lower extremities. Hyperreflexia was also present in the lower more than upper extremities. Infectious, inflammatory, and nutritional serum workup and cerebrospinal fluid analysis were both unrevealing. MRI of the brain and spinal cord showed abnormal T2 hyperintensity of the fornix, corpus callosum, optic nerves, and lateral columns of the cervical and thoracic spine, with diffusion restriction in the inferior-posterior corpus callosum and fornix. Biotinidase serum enzyme activity was tested and showed a decreased level of activity. Biotinidase gene testing showed a homozygous pathogenic variant, c.424C>A (p.P142T), confirming the diagnosis of biotinidase deficiency and prompting oral biotin supplementation. Three months after starting treatment, the patient's visual acuity, color vision, visual fields, and MRI spine abnormalities all improved significantly. Biotinidase deficiency is an important diagnostic consideration in patients with unexplained optic neuropathy and/or myelopathy.

Vitamin B3 Supplementation for Optic Neuropathies: A Comprehensive Review.

Optic neuropathies, such as glaucoma, are some of the leading causes of irreversible blindness worldwide. There has been a lot of research for potential therapies that could attenuate and even reduce the impact of the pathological pathways that lead to the loss of retinal ganglion cells (RGCs). In recent years, vitamin B3 (nicotinamide) has gained some interest as a viable option for these neurodegenerative diseases due to its fundamental role in enhancing the mitochondria metabolism of the RGCs. This review focuses on elucidating the impact of vitamin B3 on retinal cells, especially when in a dysfunctional state like what happens in optic neuropathies, especially glaucoma. This review also summarizes the existing and future research on the clinical effects of vitamin B3 in these optic neuropathies, and determines appropriate recommendations regarding its dosing, efficacy, and eventual side effects.

Cell-Based Therapies for Glaucoma.

Glaucomatous optic neuropathy (GON) is the major cause of irreversible visual loss worldwide and can result from a range of disease etiologies. The defining features of GON are retinal ganglion cell (RGC) degeneration and characteristic cupping of the optic nerve head (ONH) due to tissue remodeling, while intraocular pressure remains the only modifiable GON risk factor currently targeted by approved clinical treatment strategies. Efforts to understand the mechanisms that allow species such as the zebrafish to regenerate their retinal cells have greatly increased our understanding of regenerative signaling pathways. However, proper integration within the retina and projection to the brain by the newly regenerated neuronal cells remain major hurdles. Meanwhile, a range of methods for in vitro differentiation have been developed to derive retinal cells from a variety of cell sources, including embryonic and induced pluripotent stem cells. More recently, there has been growing interest in the implantation of glial cells as well as cell-derived products, including neurotrophins, microRNA, and extracellular vesicles, to provide functional support to vulnerable structures such as RGC axons and the ONH. These approaches offer the advantage of not relying upon the replacement of degenerated cells and potentially targeting earlier stages of disease pathogenesis. In order to translate these techniques into clinical practice, appropriate cell sourcing, robust differentiation protocols, and accurate implantation methods are crucial to the success of cell-based therapy in glaucoma. Translational Relevance: Cell-based therapies for glaucoma currently under active development include the induction of endogenous regeneration, implantation of exogenously derived retinal cells, and utilization of cell-derived products to provide functional support.

Sphenoid Bone Dysplasia: A Rare Cause of Compressive Optic Neuropathy Mimicking Glaucoma.

Fibrous dysplasia is a benign, rare bone disease in which bone is replaced by fibro-osseous tissue to varying degrees. It can present differently depending on the amount of compression caused by the fibro-osseous tissue. Patients are usually asymptomatic, but symptoms related to cranial nerve compression may occur. In this case report, we describe a 45-year-old woman with sphenoid bone dysplasia which compressed the optic nerve and caused unilateral optic disc cupping that mimicked glaucoma. Our case highlights the importance of including compressive etiologies associated with optic disc cupping in the differential diagnosis of glaucoma.

Bilateral compressive optic neuropathy and outer retinopathy due to optic canal hyperostosis in a child with isolated vitamin a deficiency.

PURPOSE: Vitamin A plays a crucial role in rod phototransduction, with deficient levels manifesting as night blindness. Animal models have demonstrated bone dysplasia in the setting of hypovitaminosis A. We present a rare case of bony overgrowth leading to bilateral compressive optic neuropathy, combined with outer retinopathy, in a paediatric patient secondary to isolated vitamin A deficiency. METHODS: A single case report was conducted from Toronto, Canada. RESULTS: A 12-year-old boy with known autism spectrum disorder presented with a 9-month history of progressive painless vision loss. Vision was 20/300 and hand motion in the right and left eye, respectively. Fundus photography demonstrated bilateral optic atrophy and yellow lesions notably in the right eye far periphery. Optical coherence tomography (OCT) imaging demonstrated thinning of the retinal nerve fibre layer, alterations in the ellipsoid zone, as well as retinal pigment epithelium deposits. Computed tomography imaging demonstrated sphenoid bone thickening with narrow optic canals and moderate optic atrophy bilaterally. Full-field electroretinogram (ERG) demonstrated mildly reduced dark adapted (DA) 0.01 b-wave amplitudes and electronegative configuration of DA 3.0 and DA 10.0 ERG; the light adapted ERGs were normal. The patient was treated with pulse vitamin A therapy. Subsequently, the DA ERG normalized, outer retinal changes reversed and vision stabilised; no surgical intervention was conducted. CONCLUSION: This case represents a rare presentation of compressive optic neuropathy with concomitant outer retinopathy secondary to isolated vitamin A deficiency. Despite improvement in outer retinal integrity on OCT imaging and ERG testing results following vitamin A supplementation, no functional improvement was obtained due to severe optic atrophy.

The Role of NAD+ and Nicotinamide (Vitamin B3) in Glaucoma: A Literature Review.

Glaucoma is a collection of irreversible optic neuropathies which, if left untreated, lead to severe visual field loss. These diseases are a leading cause of blindness across the globe and are estimated to affect approximately 80 million people, particularly women and people of Asian descent (Quigley HA, Broman AT. 2006. Br J Ophthalmol 90: 262-267). This represents a major burden on healthcare systems worldwide. Recently, there has been increasing interest in the potential of nicotinamide (vitamin B3) as a novel option in the management of glaucoma. This review aims to analyse the currently available literature to determine whether there is evidence of an association between nicotinamide adenine dinucleotide (NAD+) and glaucomatous optic neuropathy, and whether nicotinamide has the potential to prevent or reverse these effects. The literature showed a strong connection between reduced NAD+ levels and retinal ganglion cell dysfunction through multiple different studies. There is also evidence of the positive effect of nicotinamide supplementation on retinal ganglion cell function in models of mouse glaucoma and in a study involving humans. Based on the literature findings, a recommendation has been made that more research into the efficacy, appropriate dosing, and potential side effects of nicotinamide supplementation is needed before it can be definitively determined whether it is appropriate for widespread prophylactic and therapeutic use against glaucoma in humans.

Visual loss and optic neuropathy in a patient with Klinefelter's syndrome, open-angle glaucoma, vitamin B12 (cobalamin) and folate deficiency.

A 54-year-old man with Klinefelter's syndrome presented to the neuro-ophthalmology clinic with progressive painless visual blurring in the right eye over 2 years. He was receiving intramuscular testosterone therapy for hypogonadism and hypromellose for dry eye. Acuity was reduced bilaterally, and the right optic nerve head appeared pale and asymmetrically cupped. Optical coherence tomography revealed loss of retinal nerve fibre layer thickness in the right eye and visual field testing showed a developing right-ring scotoma. Blood tests showed vitamin B12 and folate deficiencies and polycythaemia. The patient was managed with intramuscular hydroxocobalamin, oral folate administration and re-initiation of his glaucoma medication. In Klinefelter's syndrome, signs of comorbid deficiency can be masked by the polycythaemic effect of testosterone therapy. For patients on long-term testosterone therapy, such as those with Klinefelter's syndrome, we recommend baseline ophthalmic examination and assessment, including intraocular pressure measurement, pachymetry, gonioscopy and screening 24-2 visual field testing.

Optic Disc Cupping Due to Dolichoectatic Internal Carotid Artery Optic Nerve Compression.

BACKGROUND: To determine whether significant compression of the optic nerve by the internal carotid artery (ICA) can produce an optic neuropathy with optic disc cupping that resembles glaucoma in patients without elevated intraocular pressure (IOP). METHODS: This was a retrospective case series of patients referred to neuro-ophthalmology for a possible nonglaucomatous optic neuropathy. Patients were included in the study if they had preserved visual acuity, optic disc-related visual field defects, optic nerve cupping, IOP less than 21 mm Hg, open angles, and unequivocal radiological compression of the ipsilateral optic nerve by an intracranial blood vessel. RESULTS: Three patients were included with a mean age of 56.3 (range 29-82) years. Patient 1 was a 58-year-old man incidentally noted to have left optic nerve cupping on a routine examination. He had an inferior arcuate defect and the left prechiasmatic optic nerve was elevated and compressed by a tortuous left ICA. Patient 2 was a 29-year-old man with a normal-tension glaucoma (NTG) diagnosis for 7 years in the right eye treated with latanoprost. He had a superior greater than inferior arcuate defect and there was vascular compression of the optic nerve between the supraclinoid ICA and A1 segment of the anterior cerebral artery. Patient 3 was an 82-year-old woman with an NTG diagnosis for 10 years who had progression of her visual field defects despite low IOPs. MRI showed mass effect on the right optic nerve by a dolichoectatic right supraclinoid ICA. CONCLUSIONS: Significant compression of the optic nerve by a normal, tortuous, or dolichoectatic ICA may result in an optic neuropathy with optic disc cupping that resembles glaucoma.

Sarcoidosis of the central nervous system: Safety and efficacy of treatment, and experience of biological therapies.

OBJECTIVES: Neurological complications of sarcoidosis are uncommon and the natural history and optimal treatments under-researched. With the advent of biological therapies, it is important to define the clinical characteristics and immunopathology of the disease. PATIENTS AND METHODS: Patients referred to and treated within the Centre for Neurosarcoidosis over a 15 year period who had biopsy proven "highly probable" disease of the central nervous system were studied prospectively. RESULTS: Corticosteroids were used effectively in all patients, immunosuppression in 79 % and TNFα antagonists in 23 %. Treatment with steroids alone inevitably led to relapse, and low dose immunosuppression was ineffective in those with severe forms of the disease. Use of biological therapies substantially improved outcome. Patients with cranial neuropathy had an excellent outcome. Those with pachymeningitis had marked radiological abnormalities but less disablement. Those with leptomeningitis had an invasive, destructive disease which responded well to treatment but with residual neurological impairments. Treatment was required for many years, but the risk of relapse following treatment withdrawal was low. Infective complications arose in six. There were two deaths, neither directly related to the neurological disease, nor its treatment. CONCLUSIONS: This prospective study of the natural history and treatment response in neurosarcoidosis provides evidence that the use of high dose immunosuppression and early and prolonged use of biological therapies is associated with greatly improved outcomes and lower mortality. The data may be used to plan further studies and treatment trials, and provide class IV evidence for the effectiveness of biological agents in the treatment of Neurosarcoidosis.

An Association Between Large Optic Nerve Cupping and Cognitive Function.

PURPOSE: To determine if a larger cup-to-disc ratio is associated with poor cognitive function in postmenopausal women without glaucoma or ocular hypertension. METHODS: We used data from the Women's Health Initiative (WHI) hormone trial, originally designed to test effects of hormone therapy (HT) on various health outcomes. Large cup-to-disc ratio was defined as greater than 0.6 in either eye based on stereoscopic optic nerve photographs. Global cognitive function was assessed annually by Modified Mini-Mental State Examination (3MSE) in the WHI Memory Study. Exclusions were no information on optic nerve grading; no 3MSE scores at the time of the eye examination, ocular hypertension (intraocular pressure >23 mm Hg, Goldmann applanation tonometry), or glaucoma medication use. A generalized linear model for log-transformed 3MSE scores was used for determining the association between large cup-to-disc ratio and 3MSE scores, adjusting for age, race, diabetes, body mass index, cardiovascular disease, smoking, HT randomization, education, and diabetic retinopathy. RESULTS: Analyses included 1636 women (mean age ± standard deviation, 69.57 ± 3.64 years; 90.39% white). Of those, 122 women had large cup-to-disc ratio. The mean 3MSE scores in women with vs without large cup-to-disc ratio were 95.4 ± 6 vs 96.6 ± 5. In the adjusted model, women with large cup-to-disc ratio had statistically significantly lower 3MSE scores, compared with those without large cup-to-disc ratio, yielding the predicted mean difference in 3MSE scores of 0.75 with a standard error of 0.05 units (P = .04). CONCLUSIONS: Postmenopausal women who had large cup-to-disc ratio without glaucoma or ocular hypertension exhibited lower global cognitive function. Further investigation is warranted. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

Optic Nerve Sheath Fenestration for Treatment of Retrolaminar Silicone Oil Migration.

The authors report the case of a 75-year-old man with preexisting glaucoma and recurrent retinal detachment who underwent intraocular silicone oil placement OD resulting in subsequent retrolaminar silicone oil migration to the optic chiasm and vision loss OS. MRI showed silicone oil tracking posteriorly along the right optic nerve to the chiasm. He was placed on high-dose corticosteroids and underwent a successful optic nerve sheath fenestration with improvement of vision in the contralateral eye. Clinicians should be cognizant of the potential for translaminar posterior migration of intraocular silicone oil, as well as the utility of optic nerve sheath fenestration to decompress the anterior visual pathways and restore vision.

Utility of multicolor optic disc photography in evaluation of glaucomatous optic disc in myopic eyes: A novel approach.

Interpretation of optic disc cupping and neuroretinal rim is challenging in myopic eyes because of large, shallow, and tilted disc, myopic crescent, and macular degeneration. Color and red-free optic disc photographs do not reveal the cup/disc ratio often in myopic eyes. We report characteristics of multicolor optic disc photography in three myopic eyes. All eyes underwent multicolor imaging Spectralis SDOCT system (Heidelberg Engineering, Germany). Owing to use of three laser lights in a confocal design, multicolor optic disc photography was able to delineate the neuroretinal rim and optic cup more clearly than color and red-free optic disc photographs.

Benefit of hyperbaric oxygen therapy treatment in direct traumatic optic neuropathy: case report.

Direct traumatic optic neuropathy (TON) is a devastating condition and clinical challenge. Its adequate treatment remains controversial. Hyperbaric oxygen (HBO2) therapy has been proposed as an adjunctive treatment for eye disease but has rarely been used in optic neuropathy. The patient was a 57-year-old woman who had direct TON and brain injury after contusion injury. After receiving delayed HBO2 therapy her visual acuity got better - from hand motion to 6/60 - along with improvement of visual field and color vision. She was treated at 2.5 atmospheres absolute for 100 minutes, five times a week, for a total of 61 sessions. Our case highlights that HBO2 may be beneficial as an alternative treatment for direct TON, particularly when combined with brain injury. Although this entity is promising, further randomized controlled trials will be needed to clarify the efficacy of HBO2 in the treatment of direct TON.

Efficacy of a Deep Learning System for Detecting Glaucomatous Optic Neuropathy Based on Color Fundus Photographs.

PURPOSE: To assess the performance of a deep learning algorithm for detecting referable glaucomatous optic neuropathy (GON) based on color fundus photographs. DESIGN: A deep learning system for the classification of GON was developed for automated classification of GON on color fundus photographs. PARTICIPANTS: We retrospectively included 48 116 fundus photographs for the development and validation of a deep learning algorithm. METHODS: This study recruited 21 trained ophthalmologists to classify the photographs. Referable GON was defined as vertical cup-to-disc ratio of 0.7 or more and other typical changes of GON. The reference standard was made until 3 graders achieved agreement. A separate validation dataset of 8000 fully gradable fundus photographs was used to assess the performance of this algorithm. MAIN OUTCOME MEASURES: The area under receiver operator characteristic curve (AUC) with sensitivity and specificity was applied to evaluate the efficacy of the deep learning algorithm detecting referable GON. RESULTS: In the validation dataset, this deep learning system achieved an AUC of 0.986 with sensitivity of 95.6% and specificity of 92.0%. The most common reasons for false-negative grading (n = 87) were GON with coexisting eye conditions (n = 44 [50.6%]), including pathologic or high myopia (n = 37 [42.6%]), diabetic retinopathy (n = 4 [4.6%]), and age-related macular degeneration (n = 3 [3.4%]). The leading reason for false-positive results (n = 480) was having other eye conditions (n = 458 [95.4%]), mainly including physiologic cupping (n = 267 [55.6%]). Misclassification as false-positive results amidst a normal-appearing fundus occurred in only 22 eyes (4.6%). CONCLUSIONS: A deep learning system can detect referable GON with high sensitivity and specificity. Coexistence of high or pathologic myopia is the most common cause resulting in false-negative results. Physiologic cupping and pathologic myopia were the most common reasons for false-positive results.

Pattern noise (PANO): a new automated functional glaucoma test.

PURPOSE: To present a newly developed visual field device (pattern noise: PANO) designed to be sensitive to glaucoma defects, cost-effective, material-practical and easy to repair and therefore particularly suited for low-income countries, where glaucoma can be highly prevalent (e.g. sub-Saharan Africa). METHODS: This is primarily a descriptive paper, but it also includes a prospective matched case-control pilot study. Hardware, stimulus, target configuration, testing strategy and result sheet are described. The main outcome measure is the contrast level (range 2-64). Targets are composed of bright/dark pixels flickering with 18 Hz and have a size of 5°. Pixel size is approximated to the hill of vision. Average luminance of targets is constant and equals background luminance.The study was performed in the West Region in Cameroon. Twenty eyes of 20 newly presenting patients with glaucomatous optic disc cupping on funduscopy were compared with 20 eyes of 20 normal patients matched in age and laterality of eye. RESULTS: Mean age was 32.9 ± 18.8 years for glaucoma patients and 32.2 ± 15.6 years for healthy subjects. Mean contrast threshold was significantly higher in eyes with abnormal disc (16.2 ± 14.3 vs. 4.4 ± 0.8, P = 0.002). Correlation of mean contrast thresholds and cup-to-disc ratio was significant (r = 0.59; P = 0.006). Average examination time was significantly longer for glaucoma eyes compared to healthy eyes (8.2 vs. 6.1 min, P < 0.001), whereas error rate did not differ (4.8 ± 2.5% vs. 4.1 ± 1.8%, P = 0.33). CONCLUSION: PANO demonstrated visual field defects in patients with glaucomatous optic disc. Defects correlated significantly with glaucomatous optic nerve head morphological alterations. Healthy eyes obtained normal results. More studies are needed to establish PANO.

The connective tissue phenotype of glaucomatous cupping in the monkey eye - Clinical and research implications.

In a series of previous publications we have proposed a framework for conceptualizing the optic nerve head (ONH) as a biomechanical structure. That framework proposes important roles for intraocular pressure (IOP), IOP-related stress and strain, cerebrospinal fluid pressure (CSFp), systemic and ocular determinants of blood flow, inflammation, auto-immunity, genetics, and other non-IOP related risk factors in the physiology of ONH aging and the pathophysiology of glaucomatous damage to the ONH. The present report summarizes 20 years of technique development and study results pertinent to the characterization of ONH connective tissue deformation and remodeling in the unilateral monkey experimental glaucoma (EG) model. In it we propose that the defining pathophysiology of a glaucomatous optic neuropathy involves deformation, remodeling, and mechanical failure of the ONH connective tissues. We view this as an active process, driven by astrocyte, microglial, fibroblast and oligodendrocyte mechanobiology. These cells, and the connective tissue phenomena they propagate, have primary and secondary effects on retinal ganglion cell (RGC) axon, laminar beam and retrolaminar capillary homeostasis that may initially be "protective" but eventually lead to RGC axonal injury, repair and/or cell death. The primary goal of this report is to summarize our 3D histomorphometric and optical coherence tomography (OCT)-based evidence for the early onset and progression of ONH connective tissue deformation and remodeling in monkey EG. A second goal is to explain the importance of including ONH connective tissue processes in characterizing the phenotype of a glaucomatous optic neuropathy in all species. A third goal is to summarize our current efforts to move from ONH morphology to the cell biology of connective tissue remodeling and axonal insult early in the disease. A final goal is to facilitate the translation of our findings and ideas into neuroprotective interventions that target these ONH phenomena for therapeutic effect.