Retinitis pigmentosa (RP) is an inherited condition that features degeneration of rod and cone photoreceptors. In all forms of RP, the genetic mutation is expressed exclusively in rods; however, cones die too. The secondary death of cones in RP remains somewhat mysterious. A better understanding of the mechanisms that cause cone degeneration in RP could lead to novel treatments that preserve cones. There are a number of prevailing theories that attempt to explain cone degeneration in RP. One concept is that cone survival is dependent on trophic factors produced by rods. Another hypothesis is that cones suffer from a nutrient shortage after rods have been lost. Additionally, oxidative stress and pro-inflammatory microglial activation have also been suggested to play a role in cone death. The present review evaluates the evidence supporting these theories and provides an update on the mechanisms of cone degeneration in RP.
Photoreceptors are the first-order neurons of the visual pathway, converting light into electrical signals. Rods and cones are the two main types of photoreceptors in the mammalian retina. Rods are specialized for sensitivity at the expense of resolution and are responsible for vision in dimly lit conditions. Cones are responsible for high acuity central vision and colour vision. Many human retinal diseases are characterized by a progressive loss of photoreceptors. Photoreceptors consist of four primary regions: outer segments, inner segments, cell bodies and synaptic terminals. Photoreceptors consume large amounts of energy, and therefore, energy metabolism may be a critical juncture that links photoreceptor function and survival. Cones require more energy than rods, and cone degeneration is the main cause of clinically significant vision loss in retinal diseases. Photoreceptor segments are capable of utilizing various energy substrates, including glucose, to meet their large energy demands. The pathways by which photoreceptor segments meet their energy demands remain incompletely understood. Improvements in the understanding of glucose metabolism in photoreceptor segments may provide insight into the reasons why photoreceptors degenerate due to energy failure. This may, in turn, assist in developing bio-energetic therapies aimed at protecting photoreceptors.
Background The Pde6brd1 (Rd1) mouse is widely used as a murine model for human retinitis pigmentosa. Understanding the spatio-temporal patterns of cone degeneration is important for evaluating potential treatments. In the present study we performed a systematic characterization of the spatio-temporal patterns of S- and M/L-opsin + cone outer segment and cell body degeneration in Rd1 mice, described the distribution and proportion of dual cones in Rd1 retinas, and examined the kinetics of microglial activation during the period of cone degeneration. Results Outer segments of S- and M/L-cones degenerated far more rapidly than their somas. Loss of both S- and M/L-opsin + outer segments was fundamentally complete by P21 in the central retina, and 90% complete by P45 in the peripheral retina. In comparison, degeneration of S- and M/L-opsin + cell bodies proceeded at a slower rate. There was a marked hemispheric asymmetry in the rate of S-opsin + and M/L-opsin + cell body degeneration. M/L-opsin + cones were more resilient to degeneration in the superior retina, whilst S-opsin + cones were relatively preserved in the inferior retina. In addition, cone outer segment and cell body degeneration occurred far more rapidly in the central than the peripheral retina. At P14, the superior retina comprised a minority of genuine S-cones with a much greater complement of genuine M/L-opsin cones and dual cones, whilst the other three retinal quadrants had broadly similar numbers of genuine S-cones, genuine M/L-cones and dual cones. At P60, approximately 50% of surviving cones in the superior, nasal and temporal quadrants were dual cones. In contrast, the inferior peripheral retina at P60 contained almost exclusively genuine S-cones with a tiny minority of dual cones. Microglial number and activity were stimulated during rod breakdown, remained relatively high during cone outer segment degeneration and loss of cone somas in the central retina, and decreased thereafter in the period coincident with slow degeneration of cone cell bodies in the peripheral retina. Conclusion The results of the present study provide valuable insights into cone degeneration in the Rd1 mouse, substantiating and extending conclusions drawn from earlier studies.
Recent studies suggest cone degeneration in retinitis pigmentosa (RP) may result from intracellular energy depletion. We tested the hypothesis that cones die when depleted of energy by examining the effect of two bioenergetic, nutraceutical agents on cone survival. The study had three specific aims: firstly, we, studied the neuroprotective efficacies of glucose and creatine in an in vitro model of RP. Next, we utilized a well-characterized mouse model of RP to examine whether surviving cones, devoid of their inner segments, continue to express genes vital for glucose, and creatine utilization. Finally, we analyzed the neuroprotective properties of glucose and creatine on cone photoreceptors in a mouse model of RP. Two different bioenergy-based therapies were tested in rd1 mice: repeated local delivery of glucose and systemic creatine. Optomotor responses were tested and cone density was quantified on retinal wholemounts. The results showed that glucose supplementation increased survival of cones in culture subjected to mitochondrial stress or oxidative insult. Despite losing their inner segments, surviving cones in the rd1 retina continued to express the various glycolytic enzymes. Following a single subconjunctival injection, the mean vitreous glucose concentration was significantly elevated at 1 and 8 h, but not at 16 h after injection; however, daily subconjunctival injection of glucose neither enhanced spatial visual performance nor slowed cone cell degeneration in rd1 mice relative to isotonic saline. Creatine dose-dependently increased survival of cones in culture subjected to mitochondrial dysfunction, but not to oxidative stress. Despite the loss of their mitochondrial-rich inner segments, cone somas and axonal terminals in the rd1 retina were strongly positive for both the mitochondrial and cytosolic forms of creatine kinase at each time point examined. Creatine-fed rd1 mice displayed enhanced optomotor responses compared to mice fed normal chow. Moreover, cone density was significantly greater in creatine-treated mice compared to controls. The overall results of this study provide tentative support for the hypothesis that creatine supplementation may delay secondary degeneration of cones in individuals with RP.
Primary optic nerve sheath meningiomas (PONSM) are rare in children. Cystic meningiomas are an uncommon subgroup of meningiomas. We report a case of paediatric PONSM managed using observation alone that underwent cystic change and radiological regression. A 5-year-old girl presented with visual impairment and proptosis. Magnetic resonance (MR) imaging demonstrated a PONSM. The patient was left untreated and followed up with regular MR imaging. Repeat imaging at 16 years of age showed the tumour had started to develop cystic change. Repeat imaging at 21 years of age showed the tumour had decreased in size.
This is the largest PPONSM case series with long-term data on patients treated conservatively. We highlight that a small subset of these tumours are indolent and can be managed using observation alone.
Orbital Langerhans cell histiocytosis (LCH) without bone involvement is rare. Isolated involvement of an extraocular muscle without bone change, to the best of the authors' knowledge, has not been previously reported. They describe a unique case of unifocal LCH of the superior oblique muscle with no bone involvement. A 16-year-old girl presented with a 2-week history of diplopia and headache. CT and MRI showed an enlarged right superior oblique muscle with no associated bone involvement. Biopsy with partial debulking revealed LCH and staging confirmed unifocal disease. The lesion underwent complete radiologic resolution following surgery. There was no recurrence after 16 months follow up.
Background:To investigate visual and anatomical outcomes in eyes with exudative age-related macular degeneration treated with intravitreal aflibercept following prior treatment with intravitreal ranibizumab.Materials and Methods:Retrospective, single-center study of 192 eyes treated with 0.5 mg intravitreal ranibizumab every 4 weeks for three consecutive doses followed by a variable dose schedule. After more than 12 months of ranibizumab treatment, eyes that required ranibizumab injections at 4-week or 6-week intervals were switched to aflibercept therapy.Results:After 12–69 months (42 months ± 18 months, mean ± standard deviation [SD]) of treatment with intravitreal ranibizumab, 80 eyes were changed to 2 mg intravitreal aflibercept treatment with follow-up after 12–18 months (16 months ± 1 month, mean ± SD). Thirty-nine eyes had persistent macular fluid after treatment with ranibizumab. Mean logMAR visual acuity (VA) in eyes treated with ranibizumab changed by − 0.089 ± 0.310 (mean ± SD; P = 0.0003), which correlates to an approximate gain of 4.5 letters. The number of eyes with macular fluid decreased from 39 to 23 after aflibercept treatment. Mean logMAR VA in eyes with intraretinal macular fluid treated with aflibercept changed by −0.079 ± 0.134 (mean ± SD; P = 0.006), which correlates to an approximate gain of 4 letters. Mean logMAR VA in eyes with submacular fluid was not significantly different after aflibercept treatment.Conclusion:Eyes with persistent intraretinal macular fluid had visual and anatomic response after changing from ranibizumab to aflibercept treatment.
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