Comparative Analysis of Functional and Structural Decline in Retinitis Pigmentosas.

Retinitis pigmentosa (RP) is a category of inherited retinal dystrophies that is best prognosticated using electroretinography (ERG). In this retrospective cohort study of 25 patients with RP, we evaluated the correlation between 30 Hz flicker ERG and structural parameters in the retina. Internationally standardized 30 Hz flicker ERG recordings, short-wavelength autofluorescence (SW-AF), and spectral domain-optical coherence tomography (SD-OCT) were acquired at two visits at least one year apart. Vertical and horizontal hyperautofluorescent ring diameter measurements with SW-AF, as well as ellipsoid zone (EZ) line width measurements with SD-OCT, were used as structural parameters of disease progression. The 30 Hz flicker ERG amplitude decreased by 2.2 ± 0.8 µV/year (p = 0.011), while implicit times remained unchanged. For SD-OCT, the EZ line decreased by 204.1 ± 34.7 µm/year (p < 0.001). Horizontal and vertical hyperautofluorescent ring diameters decreased by 161.9 ± 25.6 µm/year and 146.9 ± 34.6 µm/year, respectively (p = 0.001), with SW-AF. A correlation was found between the progression rates of the 30 Hz flicker amplitude recorded with Burian-Allen electrodes and both the horizontal ring diameter (p = 0.020) and EZ line (p = 0.044). SW-AF and SD-OCT, two readily available imaging techniques, may be used to prognosticate disease progression because of the reliability of their measurements and correlation with functional outcome.

Tacrolimus Optic Neuropathy.

BACKGROUND: Tacrolimus (FK506, Prograf) is a potent immunosuppressant, which inhibits cytokine synthesis and blocks T-cell development. Optic neuropathy from tacrolimus toxicity is very uncommon but, when present, can result in severe vision loss. METHODS: Case series and review of the literature. RESULTS: We present 3 patients with tacrolimus optic neuropathy after bone marrow transplantation complicated by graft-vs-host disease and demonstrate the differing clinical and radiologic presentation of this presumed toxic optic neuropathy. CONCLUSIONS: Tacrolimus optic neuropathy can manifest in a multitude of clinical presentations and can have devastating visual consequences.

Diagnostic genetic testing for patients with bilateral optic neuropathy and comparison of clinical features according to OPA1 mutation status.

PURPOSE: Inherited optic neuropathy is genetically heterogeneous, and genetic testing has an important role in risk assessment and counseling. The purpose of this study is to determine the prevalence and spectrum of mutations in a group of patients referred for genetic testing to a tertiary center in the United States. In addition, we compared the clinical features of patients with and without mutations in OPA1, the gene most commonly involved in dominantly inherited optic atrophy. METHODS: Clinical data and genetic testing results were reviewed for 74 unrelated, consecutive patients referred with a history of insidious, relatively symmetric, bilateral visual loss secondary to an optic neuropathy. Patients were evaluated for disease-causing variants in OPA1, OPA3, WFS1, and the entire mitochondrial genome with DNA sequencing and copy number variation (CNV) testing. RESULTS: Pathogenic DNA variants were found in 25 cases, with the majority (24 patients) located in OPA1. Demographics, clinical history, and clinical features for the group of patients with mutations in OPA1 were compared to those without disease-causing variants. Compared to the patients without mutations, cases with mutations in OPA1 were more likely to have a family history of optic nerve disease (p = 0.027); however, 30.4% of patients without a family history of disease also had mutations in OPA1. OPA1 mutation carriers had less severe mean deviation and pattern standard deviation on automated visual field testing than patients with optic atrophy without mutations in OPA1 (p<0.005). Other demographic and ocular features were not statistically significantly different between the two groups, including the fraction of patients with central scotomas (42.9% of OPA1 mutation positive and 66.0% of OPA1 mutation negative). CONCLUSIONS: Genetic testing identified disease-causing mutations in 34% of referred cases, with the majority of these in OPA1. Patients with mutations in OPA1 were more likely to have a family history of disease; however, 30.4% of patients without a family history were also found to have an OPA1 mutation. This observation, as well as similar frequencies of central scotomas in the groups with and without mutations in OPA1, underscores the need for genetic testing to establish an OPA1 genetic diagnosis.

Atypical Optic Neuritis.

Classic demyelinative optic neuritis is associated with multiple sclerosis and typically carries a good prognosis for visual recovery. This disorder is well characterized with respect to its presentation and clinical features by baseline data obtained through the optic neuritis treatment trial and numerous other studies. Atypical optic neuritis entails clinical manifestations that deviate from this classic pattern of features. Clinical signs and symptoms that deviate from the typical presentation should prompt consideration of less common etiologies. Atypical features to consider include lack of pain, simultaneous or near-simultaneous onset, lack of response to or relapse upon tapering from corticosteroids, or optic nerve head or peripapillary hemorrhages. The most important alternative etiologies to consider and the steps towards their respective diagnostic evaluations are suggested for these atypical features.

MULTIMODAL IMAGING AND ELECTRORETINOGRAPHY IN LONG-CHAIN 3-HYDROXYACYL COENZYME A DEHYDROGENASE DEFICIENCY.

PURPOSE: To report a case of pigmentary retinopathy in long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency using multimodal imaging techniques. METHODS: Case report. RESULTS: An 8-year-old boy with a history of failure to thrive and a diagnosis of long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency was referred for examination. Examination revealed a pigmentary retinopathy with macular atrophy; electroretinography results were consistent with a rod-cone dystrophy. Fundus autofluorescence and optical coherence tomography revealed retinal pigment epithelium atrophy. Follow-up examination findings showed increased severity of retinopathy on electroretinography, with optical coherence tomography angiography revealing enhanced visualization of choroidal vessels. CONCLUSION: This report reveals that long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency can be characterized as a progressive rod-cone dystrophy, with multi-modal imaging techniques used to describe this condition. In particular, optical coherence tomography angiography can be used to further characterize this condition.

Efficacy of rituximab in non-paraneoplastic autoimmune retinopathy.

BACKGROUND: Autoimmune retinopathy (AIR) is a rare but potentially blinding condition that is often underdiagnosed. Common features in AIR presentation include rapidly progressive vision loss with abnormal electrophysiological responses of the retina associated with positive anti-retinal antibodies. AIR is also challenging to treat, and thus, the introduction of new potential therapeutic agents is welcomed. The goal of this communication is to assess the effects of rituximab infusions on electroretinogram (ERG) responses and visual function outcomes in patients with non-paraneoplastic autoimmune retinopathy (npAIR). RESULTS: Following infusion(s), three out of five patients showed no evidence of disease progression or improved, while two patients continued to progress on ERG. One patient demonstrated improvement in visual acuity (2 lines) in both eyes. ERG responses provided objective monitoring of patients' visual function and response to immunosuppression over time. CONCLUSIONS: These findings suggest that patients with npAIR unresponsive to other immunosuppression therapies may benefit from rituximab infusion, although stabilization rather than improvement was more frequently the outcome in our case series. Furthermore, regularly scheduled ERG follow-up examinations are recommended for monitoring patients' progression during treatment.

PHENOTYPING CHOROIDEREMIA AND ITS CARRIER STATE WITH MULTIMODAL IMAGING TECHNIQUES.

PURPOSE: To describe findings in a patient with choroideremia (CHM) and his mother, an obligate CHM carrier. METHODS: Case report. RESULTS: A 25-year-old man with nyctalopia and poor peripheral vision since childhood, as well as a family history consistent with an X-linked retinal disorder was diagnosed with CHM. His asymptomatic 50-year-old mother, an obligate carrier, was also examined. Fundus examination of the affected man showed significant atrophy of the choroid and retinal pigment epithelium, whereas the carrier woman showed patchy pigmentary mottling. Imaging of the affected man showed diffuse retinal pigment epithelium atrophy on optical coherence tomography and extensive areas of decreased choriocapillaris flow on optical coherence tomography angiography. By contrast, the carrier woman showed subtle retinal pigment epithelium changes on optical coherence tomography and mild flow alterations on optical coherence tomography angiography. CONCLUSION: This case demonstrates the findings seen in CHM, and while CHM carrier women are often asymptomatic, they may exhibit a mosaic pattern of pigmentary change on fundus examination. Optical coherence tomography angiography may show mild choroidal flow abnormalities. This finding serves to further characterize the extent of dysfunction in CHM and its carrier state.

Retrospective Analysis of Structural Disease Progression in Retinitis Pigmentosa Utilizing Multimodal Imaging.

In this report, we assess the natural progression rate of retinitis pigmentosa (RP) over an average of three years using spectral-domain optical coherence tomography (SD-OCT) and short wavelength fundus autofluorescence (SW-AF). Measurement of the ellipsoid zone (EZ) line width and hyperautofluorescent ring diameters was performed in 81 patients with RP in a retrospective, longitudinal fashion. Rate of structural disease progression, symmetry between eyes, and test-retest variability were quantified. We observed on average, EZ-line widths decreased by 140 µm (5.2%, p < 0.001) per year, and average horizontal and vertical hyperautofluorescent ring diameters decreased by 149 µm (3.6%, p < 0.001) and 120 µm (3.9%, p < 0.001) per year, respectively. The 95th percentile of this cohort had differences in progression slopes between eyes that were less than 154 µm, 118 µm, and 132 µm for EZ-line width and horizontal and vertical ring diameters, respectively. For all measures except horizontal ring diameter, progression rates were significantly slower at end-stage disease. From our data, we observed a statistically significant progression rate in EZ line width and SW-AF ring diameters over time, verifying the utility of these measurements for disease monitoring purposes. Additionally, calculated differences in progression slopes between eyes may prove useful for investigators evaluating the efficacy of unilateral treatments for RP in clinical trials.

Electroretinography Reveals Difference in Cone Function between Syndromic and Nonsyndromic USH2A Patients.

Usher syndrome is an inherited and irreversible disease that manifests as retinitis pigmentosa (RP) and bilateral neurosensory hearing loss. Mutations in Usherin 2A (USH2A) are not only a frequent cause of Usher syndrome, but also nonsyndromic RP. Although gene- and cell-based therapies are on the horizon for RP and Usher syndrome, studies characterizing natural disease are lacking. In this retrospective analysis, retinal function of USH2A patients was quantified with electroretinography. Both groups had markedly reduced rod and cone responses, but nonsyndromic USH2A patients had 30 Hz-flicker electroretinogram amplitudes that were significantly higher than syndromic patients, suggesting superior residual cone function. There was a tendency for Usher syndrome patients to have a higher distribution of severe mutations, and alleles in this group had a higher odds of containing nonsense or frame-shift mutations. These data suggest that the previously reported severe visual phenotype seen in syndromic USH2A patients could relate to a greater extent of cone dysfunction. Additionally, a genetic threshold may exist where mutation burden relates to visual phenotype and the presence of hearing deficits. The auditory phenotype and allelic hierarchy observed among patients should be considered in prospective studies of disease progression and during enrollment for future clinical trials.

Quantitative Autofluorescence Intensities in Acute Zonal Occult Outer Retinopathy vs Healthy Eyes.

Importance: Acute zonal occult outer retinopathy (AZOOR) remains a challenging diagnosis. Early recognition of the disease depends on advances in imaging modalities that can improve phenotyping and contribute to the understanding of the underlying pathogenesis. Objectives: To expand the range of approaches available to assist in the identification of AZOOR by multimodal imaging and to analyze the fundus lesions by quantifying short-wavelength fundus autofluorescence (quantitative fundus autofluorescence [qAF]) and spectral-domain optical coherence tomography. Design, Setting, and Participants: In this observational study, patients underwent imaging at Columbia University Medical Center between November 2010 and March 2016 and were analyzed between September 2015 and August 2016. Six patients diagnosed as having AZOOR were studied by qAF and spectral-domain optical coherence tomography and were compared with 30 age and race/ethnicity­matched controls from a database of 277 healthy control eyes. Main Outcomes and Measures: In unaffected regions of the macula, qAF was calculated within predetermined circularly arranged segments (qAF8). In addition, qAF was measured within specified regions of interest positioned at the autofluorescent lesion border (AZOOR line). Electroretinograms and electro-oculograms were recorded in 5 of 6 patients. Results: Among 6 patients (age range, 26-61 years; 4 female; 4 of white race/ethnicity, 1 Asian, and 1 Hispanic), 5 exhibited an autofluorescent AZOOR line in short-wavelength fundus autofluorescence images, delineating the peripapillary lesion. The mean (SD) region-of-interest qAF measured on the AZOOR line was 60 (26) times higher than in healthy control eyes (P = .03) at equivalent fundus locations. The qAF8 within nondiseased macular regions were within the normal range. At the lesion border, spectral-domain optical coherence tomography revealed a loss of outer retinal integrity in all patients. Single-flash cone b-wave latency and 30-Hz flicker latency responses were significantly delayed bilaterally. Lesions with smooth, homogeneous borders exhibited only minimal expansion in size over time, while the lesion in a patient with a heterogeneous border progressed more rapidly. Conclusions and Relevance: The finding that qAF is elevated at the border between diseased and nondiseased retina in patients with AZOOR contributes to the understanding of the natural history of the disease.

Structural modeling of a novel SLC38A8 mutation that causes foveal hypoplasia.

BACKGROUND: Foveal hypoplasia (FH) in the absence of albinism, aniridia, microphthalmia, or achromatopsia is exceedingly rare, and the molecular basis for the disorder remains unknown. FH is characterized by the absence of both the retinal foveal pit and avascular zone, but with preserved retinal architecture. SLC38A8 encodes a sodium-coupled neutral amino acid transporter with a preference for glutamate as a substrate. SLC38A8 has been linked to FH. Here, we describe a novel mutation to SLC38A8 which causes FH, and report the novel use of OCT-angiography to improve the precision of FH diagnosis. More so, we used computational modeling to explore possible functional effects of known SLC38A8 mutations. METHODS: Fundus autofluorescence, SD-OCT, and OCT-angiography were used to make the clinical diagnosis. Whole-exome sequencing led to the identification of a novel disease-causing variant in SLC38A8. Computational modeling approaches were used to visualize known SLC38A8 mutations, as well as to predict mutation effects on transporter structure and function. RESULTS: We identified a novel point mutation in SLC38A8 that causes FH. A conclusive diagnosis was made using OCT-angiography, which more clearly revealed retinal vasculature penetrating into the foveal region. Structural modeling of the channel showed the mutation was near previously published mutations, clustered on an extracellular loop. Our modeling also predicted that the mutation destabilizes the protein by altering the electrostatic potential within the channel pore. CONCLUSION: Our results demonstrate a novel use for OCT-angiography in confirming FH, and also uncover genotype-phenotype correlations of FH-linked SLC38A8 mutations.

Investigation-Directed Approach to Inflammatory Optic Neuropathies.

Any presentation of an optic neuropathy with features that suggest inflammation should be addressed promptly because of blindness and the potential for effective treatment in some cases. A step-wise approach, including laboratory testing and imaging, is often informative, although the diagnosis may remain elusive despite detailed investigation.