A Case of Transient Monocular Vision Loss and Paracentral Acute Middle Maculopathy.

ABSTRACT: A 77-year-old man with multiple cerebrovascular risk factors presented with a history of transient monocular vision loss and residual paracentral visual disturbance in the right eye. Carotid ultrasounds, erythrocyte sedimentation rate, and C-reactive protein were all within normal limits. He was found to have retinal whitening within the macula in the right eye, corresponding to an area of decreased retinal perfusion on optical coherence topography (OCT)-angiography and a hyperreflective middle retina band on spectral domain-OCT. This was consistent with a diagnosis of paracentral acute middle maculopathy (PAMM). PAMM should be considered a part of the differential diagnosis in patients with focal visual disturbances, and OCT studies are recommended as part of the work up as subtle fundus findings may be missed.

Severe retinal degeneration in a patient with Canavan disease.

Background: Canavan disease is an autosomal recessive, neurodegenerative disorder caused by mutations in ASPA, a gene encoding the enzyme aspartoacylase. Patients present with macrocephaly, developmental delay, hypotonia, vision impairment and accumulation of N-acetylaspartic acid. Progressive white matter changes occur in the central nervous system. The disorder is often fatal in early childhood, but milder forms exist. Materials and methods: Case report. Results: We present the case of a 31-year-old male with mild/juvenile Canavan disease who had severe vision loss due to a retinal degeneration resembling retinitis pigmentosa. Prior to this case, vision loss in Canavan disease had been attributed to optic atrophy based on fundoscopic evidence of optic nerve pallor. Investigations for an alternative cause for our patient's retinal degeneration were non-revealing. Conclusion: We wonder if retinal degeneration may not have been previously recognized as a feature of Canavan disease. We highlight findings from animal models of Canavan disease to further support the association between Canavan disease and retinal degeneration.

Toxic Optic Neuropathy From Quinine Overdose.

A 45-year-old man presented with longstanding poor vision in both eyes. His medical history was significant for a remote overdose of quinine. After the ingestion, he fell into a coma and on awakening was not able to see light out of both eyes. Several days later, his central vision began to gradually recover and continued to improve over the span of several months. Presently, he had 20/20 visual acuity in both eyes with severely constricted peripheral visual fields. There were bilateral iris transillumination defects, and both optic nerves were diffusely pale with attenuated vasculature and inner retinal thinning on ocular coherence tomography. We present a patient with the stereotypical findings and natural history of quinine toxicity, a rare and not widely known cause of toxic optic neuropathy and retinopathy.

Multifocal Stroke From Ozone Gas Emboli.

A 34-year-old man with chronic neck pain was treated with regular cervical paravertebral ozone injections. After his last injection, he experienced a syncopal episode and, upon awakening, was found to have ataxia, aphasia, hemiparesis, and left sixth nerve palsy. Computed tomographic angiography demonstrated intra-arterial gas in the right vertebral artery; multiple posterior circulation infarcts were seen on brain MRI. This case illustrates the potential dangers of paravertebral injections of ozone.

THE NATURAL HISTORY OF FULL-FIELD STIMULUS THRESHOLD DECLINE IN CHOROIDEREMIA.

PURPOSE: To evaluate full-field sensitivity thresholds (FSTs) across a wide range of choroideremia (CHM) disease stages and to determine their applicability as functional endpoints for CHM clinical trials. METHODS: Thirty CHM subjects (60 eyes) and 50 healthy controls (50 eyes) underwent FST testing under dark-adapted conditions to determine rod- and cone-mediated FSTs. Central retinal structure and function were assessed using fundus autofluorescence and microperimetry. Correlation and regression analyses were performed to compare FST responses with the residual area of retinal pigment epithelium in the peri- and parafoveal regions, as well as the mean and highest macular microperimetry sensitivity. RESULTS: All patients with CHM had a baseline of 18 dB elevation in dark-adapted rod FSTs, including the least affected individuals. Further FST sensitivity loss was exponentially associated with decrease in the area of residual peri- and parafoveal retinal pigment epithelium, with precipitous loss of sensitivity noted for fundus autofluorescence areas less than 5 mm. Cone FSTs were comparable with controls, except for advanced stages of CHM. Full-field sensitivity threshold responses showed high correlation with both mean and highest macular microperimetry thresholds (P < 0.001). In some cases of absent macular fundus autofluorescence, the peripheral retina could contribute to detectable rod FST responses but with severely diminished cone-driven responses. CONCLUSION: Full-field sensitivity threshold testing demonstrated a baseline level of rod dysfunction in CHM present in all rod photoreceptors. Further decline in FST responses correlated strongly with the extent of central retina structural and functional loss. Full-field sensitivity threshold allowed quantification of residual rod function in peripheral islands of vision, which cannot be reliably achieved with other conventional tests. As such, the FST can serve as a complimentary tool to guide patient selection and expand the eligibility criteria for current and future CHM clinical trials.

Analysis of a large choroideremia dataset does not suggest a preference for inclusion of certain genotypes in future trials of gene therapy.

BACKGROUND: Choroideremia (CHM) is an X-linked degeneration of the retinal pigment epithelium, photoreceptors, and choroid, which causes nyctalopia and progressive constriction of visual fields leading to blindness. The CHM gene encodes Rab escort protein 1 (REP-1). In this work, we reviewed the phenotypes and genotypes of affected males with the purpose of understanding the functional effects of CHM mutations and their relationship with the phenotypes. METHODS: A retrospective review of 128 affected males was performed analyzing the onset of symptoms, visual acuity, and visual fields with respect to their mutations in the CHM gene. RESULTS: In rank order, reflecting data from this report, the most common mutations found in the CHM gene were nonsense mutations (41%), exon deletions (37%), and splice sites (14%) associated with a loss of functional protein. In the pool of 106 CHM mutations, we discovered four novel missense mutations (c.238C>T; p.L80F, c.819G>T; p.Q273H, c.1327A>G; p.M443V, and c.1370C>T; p.L457P) predicted to be severe changes affecting protein stability and folding with the effect similar to that of other types of mutations. No significant genotype-phenotype correlation was found with respect to the onset of nyctalopia, the onset of other visual symptoms, visual acuity, or width of visual fields. CONCLUSION: There is no evidence to support exclusion of CHM patients from clinical trials based on their genotypes or any potential genotype-phenotype correlations.

Choroideremia research: Report and perspectives on the second international scientific symposium for choroideremia.

PURPOSE: To discuss progress in research on choroideremia (CHM) and related retinopathies with special emphasis on gene therapy approaches. METHODS: Biomedical and clinical researchers from across the world as well as representatives of the social science research community were convened to the 2nd International Scientific Symposium for Choroideremia in Denver, Colorado in June 2014 to enhance our understanding of CHM and accelerate the translation of research to clinical application for the benefit of those affected by CHM. RESULTS: Pre-clinical research using cell and animal models continues to further our understanding in the pathogenesis of CHM as well as to demonstrate proof-of-concept for gene transfer strategies. With the advent of modern imaging technology, better outcome measures are being defined for upcoming clinical trials. Results from the first gene therapy trial in CHM show promise, with sustained visual improvement over 6 months post-treatment. Current and next-generation gene transfer approaches may make targeted vector delivery possible in the future for CHM and other inherited retinal diseases. CONCLUSIONS: While no accepted therapies exist for CHM, promising approaches using viral-vectored gene therapy and cell therapies are entering clinical trials for eye diseases, with gene therapy trials underway for CHM.

Changes in rod and cone-driven oscillatory potentials in the aging human retina.

PURPOSE: We recorded oscillatory potentials (OPs) to document how age impacts on rod- and cone-driven inner retina function. METHODS: Dark- and light-adapted electroretinogram (ERG) luminance-response functions were recorded in healthy human subjects aged 20 to 39, 40 to 59, and 60 to 82 years. Raw ERG traces (0.1-300 Hz) were filtered (75-300 Hz) to measure OPs trough-to-peak in the time-amplitude domain. Morlet wavelet transform (MWT) allowed documenting OPs time-amplitude-frequency distribution from raw traces. RESULTS: Under dark adaptation, both methods revealed reduced OP amplitudes and prolonged implicit times by 40 years of age. The MWT identified a high-frequency band as the main oscillator, which frequency (150-155 Hz) was unaffected by age. Under light adaptation, most OP peaks were delayed by 40 years of age. Peak-trough measures yielded inconsistent results in relation to luminance. Contrastingly, MWT distinguished two frequency bands at all luminances: high frequency (135 ± 6 Hz) time locked to the onset of early OPs and low frequency (82 ± 7 Hz), giving rise to early and late OPs. By 60 years, there was a consistent power reduction specific to the low-frequency band. CONCLUSIONS: Age-related OP changes precede those seen with a- (photoreceptoral) and b-waves (postphotoreceptoral). In addition, MWT allows quantifying distinct low- and high-frequency oscillators in the human retina, which complement traditional OP analysis methods. The identification of an age-independent OP marker (light-adapted high frequency band) opens a new dimension for the screening of retinal degenerations and their impact on inner retina function.

Advances in the genetics of eye diseases.

PURPOSE OF REVIEW: An update on heritable eye disease will allow informed patient counseling and improved patient care. RECENT FINDINGS: New loci and genes have been associated with identifiable heritable ocular traits. Molecular genetic analysis is available for many of these genes either as part of research or for clinical testing. The advent of gene array technologies has enabled screening of samples for known mutations in genes linked to various disorders. Exomic sequencing has proven to be particularly successful in research protocols in identifying the genetic causation of rare genetic traits by pooling patient resources and discovering new genes. Further, genetic analysis has led improvement in patient care and counselling, as exemplified by the continued advances in our treatment of retinoblastoma. SUMMARY: Patients and families are commonly eager to participate in either research or clinical testing to improve their understanding of the cause and heritability of an ocular condition. Many patients hope that testing will then lead to appropriate treatments or cures. The success of gene therapy in the RPE65 form of Leber congenital amaurosis has provided a brilliant example of this hope; that a similar trial may become available to other patients and families burdened by genetic disease.

Subjects with unilateral neovascular AMD have bilateral delays in rod-mediated phototransduction activation kinetics and in dark adaptation recovery.

PURPOSE: To assess the impact of early (dry) and late (wet/neovascular and/or atrophic) forms of AMD on panretinal function. METHODS: Light- and dark-adapted full-field ERG recordings were obtained over a 5-log-unit intensity range from both eyes of 25 patients with unilateral wet AMD. Fellow eyes showed various signs of dry AMD ranging from multiple medium-sized drusen to noncentral geographic atrophy. The leading edges of rod-isolated ERG a-waves were fitted to a quantitative model of phototransduction. ERG a- and b-wave amplitudes and implicit times were compared between wet and dry AMD eyes and from non-AMD eyes of age-matched subjects. A quantitative and objective assessment of dark adaptation was achieved by recording the recovery of the pure rod b-wave (postsynaptic depolarization of rod bipolar cells); b-wave amplitudes were measured at 120-second intervals for 20 minutes and normalized to the amplitude recorded at t = 20 minutes. RESULTS: Delays in mixed a- and b-wave implicit times were recorded in both wet and dry AMD eyes. Time required to reach 50% of fully recovered responses was delayed in all wet and dry AMD eyes independently of dry AMD severity in the fellow eye. Generalized cone dysfunction and slower activation of the rod phototransduction cascade was noted in a subgroup of patients with advanced features of dry AMD in the fellow eye. CONCLUSIONS: Patients with unilateral wet AMD display rod dysfunction in both their wet and dry AMD eyes. A subset of these patients display, in addition, bilateral cone dysfunction and delayed rod phototransduction activation, which may either reflect extensive morphologic change in advanced stages of AMD and/or represent a distinct phenotypic manifestation within the heterogeneous context of AMD as a disease.

Differential changes in retina function with normal aging in humans.

We evaluated the full field electroretinogram (ERG) to assess age-related changes in retina function in humans. ERG recordings were performed on healthy subjects with normal fundus appearance, lack of cataract and 20/20 acuity, aged 20-39 years (n = 27; mean age 25 ± 5, standard deviation), 40-59 years (n = 20; mean 53 ± 5), and 60-82 years (n = 18; mean 69 ± 5). Multiple ERG tests were applied, including light and dark-adapted stimulus-response function, dark adaptation and dynamic of recovery from a single bright flash under dark-adapted conditions. Changes in ERG properties were found in the oldest age group when compared with the two younger age groups. (1) The photopic hill effect was less pronounced. (2) Both photopic a-wave and b-wave amplitudes and implicit times were increased at high stimulus strengths. (3) Dark adaptation time was delayed for pure rod and L/M cone-driven responses, respectively. (4) Dark-adapted a-wave but not b-wave amplitudes were reduced, yielding higher B/A ratios. (5) Dark-adapted a- and b-waves implicit times were prolonged: there was a direct proportional correlation between minimal a-wave implicit times and age. (6) The dynamic of dark current recovery from a bright flash, under dark-adapted conditions, was transiently faster at intervals between 0.9 and 2 s. These results denote that aging of the healthy retina is accompanied by specific functional changes, which must be taken into account to optimally diagnose potential pathologies.

Inner retina remodeling in a mouse model of stargardt-like macular dystrophy (STGD3).

Purpose. To investigate the impact of progressive age-related photoreceptor degeneration on retinal integrity in Stargardt-like macular dystrophy (STGD3). Methods. The structural design of the inner retina of the ELOVL4 transgenic mouse model of STGD3 was compared with that of age-matched littermate wild-type (WT) mice from 1 to 24 months of age by using immunohistofluorescence and confocal microscopy and by relying on antibodies against cell-type-specific markers, synapse-associated proteins, and neurotransmitters. Results. Müller cell reactivity occurred at the earliest age studied, before photoreceptor loss. This finding is perhaps not surprising, considering the cell's ubiquitous roles in retina homeostasis. Second-order neurons displayed salient morphologic changes as a function of photoreceptoral input loss. Age-related sprouting of dendritic fibers from rod bipolar and horizontal cells into the ONL did not occur. In contrast, with the loss of photoreceptor sensory input, these second-order neurons progressively bore fewer synapses. After rod loss, the few remaining cones showed abnormal opsin expression, revealing tortuous branched axons. After complete ONL loss (beyond 18 months of age), localized areas of extreme retinal disruptions were observed in the central retina. RPE cell invasion, dense networks of strongly reactive Müller cell processes, and invagination of axons and blood vessels were distinctive features of these regions. In addition, otherwise unaffected cholinergic amacrine cells displayed severe perturbation of their cell bodies and synaptic plexi in these areas. Conclusions. Remodeling in ELOVL4 transgenic mice follows a pattern similar to that reported after other types of hereditary retinopathies in animals and humans, pointing to a potentially common pathophysiologic mechanism.