Intravitreal faricimab for neovascular age-related macular degeneration previously treated with traditional anti-VEGF compounds: a real-world prospective study.

BACKGROUND/AIMS: To evaluate the efficacy, safety and durability of intravitreal faricimab in patients with neovascular age-related macular degeneration (nAMD) with unsatisfactory response to traditional anti-vascular endothelial growth factor (anti-VEGF) agents. METHODS: Single-centre, prospective cohort study of all consecutive patients with nAMD who were switched to intravitreal faricimab from intravitreal ranibizumab or aflibercept, due to unsatisfactory treatment response (maximal fluid-free interval ≤ 8 weeks). Intravitreal faricimab was administered with a loading dose of four 4-weekly injections, followed by an 8-week extension. A treat and extend (T&E) regime was adopted thereafter. Primary outcome was the difference between the maximal fluid-free interval achieved with faricimab, and the one achieved before the switch. Morpho-functional outcomes were also assessed. Secondary outcome was accordance with clinical management when applying faricimab pivotal trial criteria versus our real-world T&E protocol, measured as a proportion. RESULTS: Twenty-six eyes of 26 patients with a median age of 82 years (range 77-85) were included. Patients were followed for 30.2 weeks (range 26.3-33.1). Maximal fluid-free interval after switch to faricimab (Mdn = 6.0 weeks; IQR = 4-8) was longer than the maximum interval before the switch (Mdn = 4.0 weeks; IQR = 4-4), p < 0.001. Comparing real-world T&E protocol with pivotal trial criteria, 8 (30.8%) eyes received the same clinical management while 18 (69.2%) eyes were kept at a shorter interval when following our T&E protocol. No serious adverse events were recorded. CONCLUSIONS: Faricimab appears to increase the fluid-free interval and allow extension of dosing interval in patients with nAMD poorly responsive to traditional anti-VEGF drugs.

Management of Coats-Like Disease in a Forty-Four-Year-Old Patient with FSHD Type I.

A forty-four-year-old female patient known for FSHD type I, with unremarkable past ocular history, complained of progressive visual acuity deterioration during a routine ophthalmological visit. Best-corrected visual acuity (BCVA) was 1.0 decimal Snellen equivalent bilaterally. Dilated fundus examination showed evidence of retinal Coats-like disease in the left eye, while the right eye showed significant retinal vascular tortuosity. Multimodal examinations (OCT scans and FA-fluorescein angiography) revealed large areas of retinal ischemia, thus confirming a retinal vascular disorder compatible with the diagnosis of Coats-like disease. Left eye laser photocoagulation of the ischemic areas was performed to avoid neovascular complications that had not been detected during follow-up visits (12 months), and BCVA in the left eye remained stable at 1.0 decimals Snellen equivalent. Coats-like disease in a patient affected by FSHD type I should always be screened even in the absence of any prior ocular diseases. Guidelines concerning the ophthalmological management of adults affected by FSHD are lacking. Based on this case, we recommend performing a yearly complete ophthalmological checkup with dilated fundus examination and retinal imaging. Patients should, furthermore, be encouraged to seek medical attention when noticing deterioration of visual acuity or other visual symptoms in order to avoid missing potential sight-threatening ocular complications.

Functional Analysis of a Novel, Non-Canonical RPGR Splice Variant Causing X-Linked Retinitis Pigmentosa.

X-linked retinitis pigmentosa (XLRP) caused by mutations in the RPGR gene is one of the most severe forms of RP due to its early onset and intractable progression. Most cases have been associated with genetic variants within the purine-rich exon ORF15 region of this gene. RPGR retinal gene therapy is currently being investigated in several clinical trials. Therefore, it is crucial to report and functionally characterize (all novel) potentially pathogenic DNA sequence variants. Whole-exome sequencing (WES) was performed for the index patient. The splicing effects of a non-canonical splice variant were tested on cDNA from whole blood and a minigene assay. WES revealed a rare, non-canonical splice site variant predicted to disrupt the wildtype splice acceptor and create a novel acceptor site 8 nucleotides upstream of RPGR exon 12. Reverse-transcription PCR analyses confirmed the disruption of the correct splicing pattern, leading to the insertion of eight additional nucleotides in the variant transcript. Transcript analyses with minigene assays and cDNA from peripheral blood are useful tools for the characterization of splicing defects due to variants in the RPGR and may increase the diagnostic yield in RP. The functional analysis of non-canonical splice variants is required to classify those variants as pathogenic according to the ACMG's criteria.

Comparison of visual performances of enhanced monofocal versus standard monofocal IOLs in a mini-monovision approach.

PURPOSE: To compare visual performance and quality of life in patients who received either monofocal intraocular lenses (IOLs) or an enhanced monofocal IOL in a mini-monovision target approach. BACKGROUND: Monofocal lenses are the most common intraocular IOLs employed during cataract surgery because of their relatively low cost and good performance for distance sight. However, these lenses, generally, do not exonerate patients from spectacle use for near or intermediate tasks. On the other hand, enhanced monofocal IOLs (e.g., Tecnis Eyhance®) feature optical properties providing patients with good intermediate visual outcomes. Satisfactory near visual acuity results, regardless of IOL type, may be achieved through mini-monovision. We assessed visual performance outcomes between these IOLs, in a mini-monovision approach. METHODS: Retrospective case series of patients who underwent bilateral cataract surgery at our institution with implantation of Alcon SN60WF, J&J Tecnis DCB00 or J&J Tecnis Eyhance® DIB00 with a pre-operative mini-monovision target. The postoperative spherical equivalent was measured by a Nidek® auto-refractometer. Best-uncorrected binocular visual acuity (BUBVA) at far (3 m), intermediate (66 cm), and near (40 cm) distance and binocular contrast sensitivity (100%, 25%, and 5%, all at 1 m) were measured using Snellen and Pelli-Robson charts, respectively. Visual performance in daily life was evaluated with the Cataract VF-14 quality of life survey. RESULTS: 71 patients (35 in the monofocal IOL and 37 enhanced IOL group) were enrolled. Patients implanted with enhanced IOL exhibited statistically significant better BUBVA results at 66 cm and 40 cm distances compared to patients in the monofocal group. Additionally, patients in the enhanced IOL group presented a better contrast sensitivity in lower contrast conditions (5%) than patients with monofocal IOL. The quality of life survey showed statistically significant higher scores in daily activities without spectacles for patients with enhanced IOL. CONCLUSION: Enhanced monofocal IOLs, combined with a mini-monovision approach, provided patients with good visual performance at all tested distances, with superiority of enhanced monofocal IOLs at near and intermediate distances.

Inner retinal thickening affects microperimetry thresholds in the presence of photoreceptor thinning in patients with RPGR retinitis pigmentosa.

BACKGROUND: Loss of photoreceptors cause degeneration in areas of the retina beyond the photoreceptors. The pattern of changes has implications for disease monitoring and measurement of functional changes. The aim of the study was to study the changes in inner retinal structure associated with photoreceptor disease, and the impact of these on microperimetry threshold. METHODS: This retrospective cohort study was conducted on optical coherence tomography (OCT) images and microperimetry tests collected between 2013 and 2019. 22 eyes with RPGR retinitis pigmentosa completed both OCT imaging and microperimetry assessment. 18 control eyes underwent OCT imaging. Photoreceptor layer and inner retinal thickness calculated for different eccentric areas were obtained. The relationship between the photoreceptor layer and inner retinal thickness, and microperimetry threshold was explored. RESULTS: Central 1° photoreceptor layer and inner retinal thickness were 96±34 and 139±75 µm in RPGR patients, and 139±15 and 62±14 µm in controls. Photoreceptor layer thickness differed between patient and control groups across increasing visual field areas (p<0.01, Kruskal-Wallis 1-way ANOVA), whereas the inner retinal thickness significantly differed between groups for the central 1° and 3° only. Microperimetry thresholds were explained by a combination of photoreceptor thickness (coefficient 0.15, 95% CI 0.13 to 0.18) and inner retinal thickness (coefficient 0.05, 95% CI 0.03 to 0.06). CONCLUSION: OCT shows evidence of remodelling in the inner retinal layers secondary to photoreceptor disease. This appears to have an impact on microperimetry threshold measurements.

High-Throughput Sequencing to Identify Mutations Associated with Retinal Dystrophies.

Retinal dystrophies (RD) are clinically and genetically heterogenous disorders showing mutations in over 270 disease-associated genes. Several millions of people worldwide are affected with different types of RD. Studying the relevance of disease-associated sequence alterations will assist in understanding disorders and may lead to the development of therapeutic approaches. Here, we established a whole exome sequencing (WES) pipeline to rapidly identify disease-associated mutations in patients. Sanger sequencing was applied to identify deep-intronic variants and to verify the co-segregation of WES results within families. We analyzed 26 unrelated patients with different syndromic and non-syndromic clinical manifestations of RD. All patients underwent ophthalmic examinations. We identified nine novel disease-associated sequence variants among 37 variants identified in total. The sequence variants located to 17 different genes. Interestingly, two cases presenting with Stargardt disease carried deep-intronic variants in ABCA4. We have classified 21 variants as pathogenic variants, 4 as benign/likely benign variants, and 12 as variants of uncertain significance. This study highlights the importance of WES-based mutation analyses in RD patients supporting clinical decisions, broadly based genetic diagnosis and support genetic counselling. It is essential for any genetic therapy to expand the mutation spectrum, understand the genes' function, and correlate phenotypes with genotypes.

ACUTE RETINAL NECROSIS ASSOCIATED WITH HERPES ZOSTER VACCINATION.

PURPOSE: To report a case of Zostavax-associated acute retinal necrosis in a patient with chronic lymphocytic leukemia. METHODS: Case report. PATIENTS: A 76-year-old white man. RESULTS: Unilateral acute retinal necrosis with obliterative angiopathy developed in close proximity of a Zostavax vaccine. Treatment with valacyclovir hydrochloride (1 g orally three times a day) and intravitreal ganciclovir (4 mg/0.1 mL) was initiated on presentation. Because of continuous increase of the retinal necrosis, patient was switched to intravenous acyclovir (7.5 mg/kg body weight, adapted to reduced glomerular filtration rate) and given intravitreal foscarnet (2.4 mg/0.1 mL). Despite being on maximal antiviral therapy, the patient suffered a central retinal artery occlusion. DISCUSSION: Acute retinal necrosis is a severe complication and potentially blinding disease of herpes zoster, and can occur in association with herpes zoster immunization, in particular, in immune suppressed patients.

Early Cone Photoreceptor Outer Segment Length Shortening in RPGR X-Linked Retinitis Pigmentosa.

INTRODUCTION: Introduction of retinal gene therapy requires established outcome measures along with thorough understanding of the pathophysiology. Evidence of early, thinned outer segments in RPGR X-linked retinitis pigmentosa could help understand how the level of cone photoreceptor involvement translates to visual potential. OBJECTIVE: Analysis of foveal photoreceptor outer segment length in a young cohort of RPGR patients to help clarify the reason for absent maximal visual acuity seen. METHODS: Case-control study of RPGR patients. Quantitative measurement of photoreceptor outer segment by OCT. RESULTS: Eighteen male RPGR patients and 30 normal subjects were included. Outer segment thickness differed significantly between the RPGR and normal eyes (p < 0.0005). Mean outer segment values were 35.6 ± 2.3 µm and 35.4 ± 2.6 µm for RPGR right and left eyes, respectively. In normal eyes, the mean outer segment thickness was 61.4 ± 0.7 µm for right eyes and 62.4 ± 0.7 µm for left eyes. CONCLUSIONS: Patients with RPGR X-linked retinitis pigmentosa show thinning of the foveal photoreceptor outer segment thickness early in the disease course, which could be an explanation for the lower maximum visual acuity seen. These findings must be taken into consideration when assessing efficacy outcome measures in retinal gene therapy trials.

RTVue XR AngioVue Optical Coherence Tomography Angiography Software Upgrade Impacts on Retinal Thickness and Vessel Density Measurements.

Purpose: To determine the impact of an AngioVue software upgrade on total retinal thickness (RT) and inner retinal vessel density (VD) measurements derived from optical coherence tomography angiography (OCTA). Methods: Optovue OCTA images (3 × 3 mm) from 126 individuals (105 healthy eyes and 72 eyes with retinal disease) were acquired before an upgrade of the AngioVue software, which resulted in an inward shift of the outer boundary of the inner retinal vessels and improved Bruch's membrane segmentation. Total RT and inner retinal VD values were extracted before and after the software upgrade for comparison. Bias and limits of agreement (LA) were calculated. Results: The mean (SD) age of participants was 46 (17) years. Mean (LA) foveal RT increased by 3.0 (-11 to +17) and 3.7 (-11 to +18) µm (P < 0.001) and parafoveal RT increased by 9.7 (-3.8 to +23) and 6.4 (-2.5 to +15) µm (P < 0.001) in healthy and diseased retina, respectively. Mean (LA) foveal inner retinal VD decreased by 6.6 (2.5-11) and 7.7 (0.4-15) percentage units (P < 0.001) and parafoveal inner retinal VD decreased by 4.1 (1.2-7.0) and 4.7 (0.5-8.9) percentage units (P < 0.001) in healthy and diseased retina, respectively. Conclusions: The AngioVue software upgrade resulted in an unexpected increase in total RT and an expected reduction in inner retinal VD measurements in all regions due to altered segmentation. Translational Relevance: RT and VD measures derived from the newer AngioVue software version are not directly comparable to the reported normative data derived from the older software.

Monitoring progression of retinitis pigmentosa: current recommendations and recent advances.

INTRODUCTION: Retinitis pigmentosa (RP) is the most common form of inherited retinal degenerations with an estimated prevalence of 1 in 4,000 and more than 1 million individuals affected worldwide. With the introduction of the first retinal gene therapy in 2017 the importance of understanding the mechanisms of retinal degeneration and its natural progression has shifted from being of academic interest to being of pivotal for the development of new therapies. AREAS COVERED: This review covers standard and innovative diagnostic techniques and complementary examinations needed for the evaluation and treatment of RP. It includes chapters on the assessment of visual function, retinal morphology, and genotyping. EXPERT OPINION: Monitoring the progression of RP can best be achieved by combining assessments of both visual function and morphology. Visual acuity testing using ETDRS charts should be complemented by low-luminance visual acuity and colour vision tests. Assessment of the visual field can also be useful in less advanced cases. In those with central RP involvement measuring retinal sensitivity using microperimetry is recommended. Retinal morphology is best assessed by OCT and autofluorescence. Genetic testing is pivotal as it contributes to the pathophysiological understanding and can guide clinical management as well as identify individuals that could benefit from retinal gene therapy.

Clinical validation of the RTVue optical coherence tomography angiography image quality indicators.

IMPORTANCE: All automated image quality indicators for en face optical coherence tomography angiography (OCTA) images require gold standard validation for determining optimum thresholds. BACKGROUND: A manual grading system (gold standard) for OCTA images was validated and compared to two automated image quality indicators: signal strength index (SSI) and scan quality index (SQI) generated by different software versions of the Optovue OCTA device. DESIGN: Retrospective cross-sectional study. PARTICIPANTS: A total of 52 eyes of 52 healthy individual and 77 eyes of 51 patients with retinal vascular diseases. METHODS: A total of 129 OCTA images of the superficial vascular plexus were graded manually by three independent examiners. Each image was assigned grades 1 to 4 (1-2, unacceptable; 3-4, acceptable) masked to the software-generated quality indicators. MAIN OUTCOME MEASURES: Inter-grader agreement and comparison of the utility of SSI and SQI in discriminating between acceptable and unacceptable OCTA images. RESULTS: There was a substantial agreement between the three graders (κ = 0.63). Mean SSI and SQI was significantly different between acceptable and unacceptable images (P < .001). SQI outperformed SSI in separating acceptable from unacceptable images (areas under the receiver operating characteristic curve: 0.87 vs 0.80) and the optimum cut-off was ≥7 for SQI and ≥70 for SSI for acceptable images. Up to 30% of images with quality indicators reaching the optimum SQI and SSI cut-off thresholds still had unacceptable quality on manual grading. Unacceptable images were found in 33% and 66% of healthy and diseased eyes, respectively. CONCLUSIONS AND RELEVANCE: SQI is closely related to manual grading but we caution reliance on the optimized threshold to determine image quality. SQI is superior to SSI in discriminating between acceptable and unacceptable images.

A novel splice-site variant in CDH23 in a patient with Usher syndrome type 1.

Background: Gene editing has shown huge potential in correcting aberrant splicing and Cas13 has been identified as being particularly suitable for targeting RNA. It has therefore become increasingly important to highlight new splice site mutations that may be correctable, particularly in genes that are too large to be encoded by AAV vectors. About 20% of Usher Type 1 cases are caused by mutations in CDH23.Purpose: To report a novel splice site mutation of CDH23 associated with Usher Type 1D.Materials and Methods: Case report.Results: A 35-year-old Caucasian female who is congenitally deaf with vestibular dysfunction presented with visual acuity of 6/12 in both eyes. Fundus examination revealed findings typical of retinitis pigmentosa with foveal preservation of photoreceptor layer. Next generation sequencing analysis revealed a novel homozygous variant, c.9319 + 1G>T in CDH23 consistent with the diagnosis of Usher Syndrome Type 1D. The c.9319 + 1G>T variant is predicted to affect splicing at the exon 65/intron 65 boundary, which highly likely leads to complete skipping of exon 65.Conclusions: We describe a case of a typical Usher Syndrome Type 1D caused by a novel splice site variant in CDH23. Currently there are no treatments for CDH23 related retinal degeneration, partly because the cDNA size of 10kb is too large for AAV vector gene augmentation therapy. Alternative strategies include CRISPR-Cas9 adenine base editors and RNA editing with CRISPR-Cas13. Single-nucleotide editing represents a promising approach for targeting this variant in CDH23 to restore the wildtype splice donor site at this position.

Intrasession Repeatability and Interocular Symmetry of Foveal Avascular Zone and Retinal Vessel Density in OCT Angiography.

PURPOSE: To measure intrasession repeatability and interocular symmetry of the foveal avascular zone area (FAZA) and superficial retinal vessel density (SRVD) using AngioVue Analytics optical coherence tomography angiography (OCTA). METHODS: Fifty healthy individuals were prospectively enrolled. OCTA scans (3 × 3 and 6 × 6 mm) were acquired twice in right and once in left eyes. FAZA (with and without rescaling) and SRVD for 18 regions (whole, fovea, parafovea, six parafoveal subregions, and nine square zones) were compared between two scans in right eyes (repeatability) and between both eyes (symmetry). Coefficients of repeatability (CRs) and limits of agreement (LAs) were calculated. RESULTS: Axial length-based image size rescaling had negligible impact on the intrasession CR of FAZA in both 3 × 3- and 6 × 6-mm images. The intrasession CRs for the foveal SRVD were 3.3% and 6.1% in the 3 × 3- and 6 × 6-mm OCTA images, respectively. Age and axial length did not influence test-retest variability of FAZA or SRVD. The interocular LAs in FAZA (0.039-0.059 mm2) was comparable to its CR. However, the interocular LAs in foveal SRVD were -4.5% to +3.8%, with 13% of the cohort showing an interocular difference greater than the CR. CONCLUSIONS: FAZA repeatability is not influenced by image size correction, and foveal SRVD is more variable in 6 × 6- than 3 × 3-mm OCTA images. Low image quality may contribute to interocular SRVD asymmetry. TRANSLATIONAL RELEVANCE: CRs and LAs can be used to set a threshold for true changes in FAZA and SRVD in longitudinal studies of healthy individuals.

ASSESSMENT OF DRUSEN AND OTHER RETINAL DEGENERATIVE CHANGES IN PATIENTS WITH HEREDITARY HEMOCHROMATOSIS.

PURPOSE: Iron can exert oxidative damage, and increased accumulation is believed to play a role in age-related macular degeneration. Hereditary hemochromatosis leads to an increase in total body iron. Patients with HH were assessed for drusen and other retinal changes. METHODS: Descriptive uncontrolled study of spectral-domain optical coherence tomography, short-wavelength autofluorescence, and color fundus images from patients with HH were used. Diagnosis of HH was established by measuring ferritin and transferrin saturation, and confirmed by genetic testing. Classification of the patients according to initial ferritin level was: Group A >1,032 µg/L; Group B below. RESULTS: Twenty-five percent of the invited participants were enrolled. Mean age at diagnosis was 46 ± 15 years in Group A, and 38 ± 13 years in Group B, P = 0.07, whereas mean age at imaging was 60 ± 13 years in Group A, and 48 ± 15 years in Group B (P = 0.003). The median of the initial ferritin level was 1,869 (1,262-3,256) ng/mL in Group A, and 534 (439-679) ng/mL in Group B. No subject in either group revealed multiple drusen, unambiguous changes of the retinal pigment epithelium, or increased lipofuscin in any of the images. CONCLUSION: The study results did not show an increased prevalence of drusen or other retinal degenerative changes in patients with HH. Thus, it was concluded that increased intestinal iron absorption as well as increased blood iron concentration are not risk factors for the early development of retinal degenerative changes in this study population.

Axial Length Variation Impacts on Superficial Retinal Vessel Density and Foveal Avascular Zone Area Measurements Using Optical Coherence Tomography Angiography.

Purpose: To evaluate the impact of image magnification correction on superficial retinal vessel density (SRVD) and foveal avascular zone area (FAZA) measurements using optical coherence tomography angiography (OCTA). Methods: Participants with healthy retinas were recruited for ocular biometry, refraction, and RTVue XR Avanti OCTA imaging with the 3 × 3-mm protocol. The foveal and parafoveal SRVD and FAZA were quantified with custom software before and after correction for magnification error using the Littman and the modified Bennett formulae. Relative changes between corrected and uncorrected SRVD and FAZA were calculated. Results: Forty subjects were enrolled and the median (range) age of the participants was 30 (18-74) years. The mean (range) spherical equivalent refractive error was -1.65 (-8.00 to +4.88) diopters and mean (range) axial length was 24.42 mm (21.27-28.85). Images from 13 eyes were excluded due to poor image quality leaving 67 for analysis. Relative changes in foveal and parafoveal SRVD and FAZA after correction ranged from -20% to +10%, -3% to +2%, and -20% to +51%, respectively. Image size correction in measurements of foveal SRVD and FAZA was greater than 5% in 51% and 74% of eyes, respectively. In contrast, 100% of eyes had less than 5% correction in measurements of parafoveal SRVD. Conclusions: Ocular biometry should be performed with OCTA to correct image magnification error induced by axial length variation. We advise caution when interpreting interocular and interindividual comparisons of SRVD and FAZA derived from OCTA without image size correction.

Ocular Phenotype of a Family with FAM161A-associated Retinal Degeneration.

BACKGROUND: Characterization of retinal degeneration (RD) using high-resolution retinal imaging and exome sequencing may identify phenotypic features that correspond with specific genetic defects. MATERIALS AND METHODS: Six members from a non-consanguineous Indian family (three affected siblings, their asymptomatic parents and an asymptomatic child) were characterized clinically, using visual acuity, perimetry, full-field electroretinography (ERG), optical coherence tomography and cone structure as outcome measures. Cone photoreceptors were imaged in the proband using adaptive optics scanning laser ophthalmoscopy. The exome was captured using Nimblegen SeqCap EZ V3.0 probes and sequenced using lllumina HiSeq. Reads were mapped to reference hg19. Confirmation of variants and segregation analysis was performed using dideoxy sequencing. RESULTS: Analysis of exome variants using exomeSuite identified five homozygous variants in four genes known to be associated with RD. Further analysis revealed a homozygous nonsense mutation, c.1105 C > T, p.Arg335Ter, in the FAM161A gene segregating with RD. Three additional variants were found to occur at high frequency. Affected members showed a range of disease severity beginning at different ages, but all developed severe visual field and outer retinal loss. CONCLUSIONS: Exome analysis revealed a nonsense homozygous mutation in FAM161A segregating with RD with severe vision loss and a range of disease onset and progression. Loss of outer retinal structures demonstrated with high-resolution retinal imaging suggests FAM161A is important for normal photoreceptor structure and survival. Exome sequencing may identify causative genetic variants in autosomal recessive RD families when other genetic test strategies fail to identify a mutation.

Repeatability of Cone Spacing Measures in Eyes With Inherited Retinal Degenerations.

PURPOSE: To determine short-term variability of adaptive optics scanning laser ophthalmoscopy (AOSLO)-derived cone spacing measures in eyes with inherited retinal degenerations (IRD) and in normal eyes. METHODS: Twenty IRD patients and 10 visually normal subjects underwent AOSLO imaging at two visits separated by no more than 1 month (NCT00254605). Cone spacing was measured in multiple macular regions in each image by three independent graders. Variability of cone spacing measures between visits, between graders, and between eyes was determined and correlated with standard clinical measures. RESULTS: Cone spacing was measured in 2905 regions. Interobserver agreement was high both in normal eyes and eyes with IRD (mean intraclass correlation coefficient [ICC] = 0.838 for normal and 0.892 for eyes with IRD). Cone spacing measures were closely correlated between visits (ICC > 0.869 for both study groups). Mean relative intervisit spacing difference (absolute difference in measures divided by the mean at each region) was 4.0% for normal eyes and 4.9% for eyes with IRD. Cone spacing measures from fellow eyes of the same subject showed strong agreement for all subjects (ICC > 0.85 for both study groups). CONCLUSIONS: Adaptive optics scanning laser ophthalmoscopy-derived macular cone spacing measures were correlated between observers, visits, and fellow eyes of the same subject in normal eyes and in eyes with IRD. This information may help establish the role of cone spacing measures derived from images of the cone mosaic obtained with AOSLO as a sensitive biomarker for longitudinal tracking of photoreceptor loss during disease progression and in response to treatment. (ClinicalTrials.gov number, NCT00254605.).

Correlation of outer nuclear layer thickness with cone density values in patients with retinitis pigmentosa and healthy subjects.

PURPOSE: We studied the correlation between outer nuclear layer (ONL) thickness and cone density in normal eyes and eyes with retinitis pigmentosa (RP). METHODS: Spectral-domain optical coherence tomography (SD-OCT) scans were acquired using a displaced pupil entry position of the scanning beam to distinguish Henle's fiber layer from the ONL in 20 normal eyes (10 subjects) and 12 eyes with RP (7 patients). Cone photoreceptors were imaged using adaptive optics scanning laser ophthalmoscopy. The ONL thickness and cone density were measured at 0.5° intervals along the horizontal meridian through the fovea nasally and temporally. The ONL thickness and cone density were correlated using Spearman's rank correlation coefficient r. RESULTS: Cone densities averaged over the central 6° were lower in eyes with RP than normal, but showed high variability in both groups. The ONL thickness and cone density were significantly correlated when all retinal eccentricities were combined (r = 0.74); the correlation for regions within 0.5° to 1.5° eccentricity was stronger (r = 0.67) than between 1.5° and 3.0° eccentricity (r = 0.23). Although cone densities were lower between 0.5° and 1.5° in eyes with RP, ONL thickness measures at identical retinal locations were similar in the two groups (P = 0.31), and interindividual variation was high for ONL and cone density measures. Although ONL thickness and retinal eccentricity were important predictors of cone density, eccentricity was over 3 times more important. CONCLUSIONS: The ONL thickness and cone density were correlated in normal eyes and eyes with RP, but both were strongly correlated with retinal eccentricity, precluding estimation of cone density from ONL thickness. (ClinicalTrials.gov number, NCT00254605.).

Diagnosis and complementary examinations.

Development of neuroprotective therapies requires an understanding of the mechanisms of retinal degeneration and a way to monitor response to treatment. With the increasing availability of genetic testing, precise characterization of the retinal degeneration phenotype is essential. This chapter covers standard and innovative diagnostic techniques and complementary examinations needed for the evaluation and treatment of retinal degenerative diseases. It aims to provide an overview of functional and structural diagnostic tools for the evaluation of retinal degenerative diseases, but is not intended as a comprehensive reference. Subjective assessment of visual function includes psychophysical tests, such as perimetry and microperimetry. Electrophysiology tests, such as the electroretinogram and electro-oculogram, are crucial in the assessment of retinal degenerative diseases and provide an objective assessment of global photoreceptor and retinal pigment epithelial cell function. Retinal structural measures are correlated with measures of retinal function to characterize the disease phenotype, including fundus photography using color, near-infrared, and autofluorescence imaging. Ocular perfusion can be assessed using fluorescein, indocyanine green, and noninvasive angiography. Optical coherence tomography provides information about retinal structure. Resolution of all images of retinal structure can be improved using adaptive optics, which permits visualization of individual photoreceptors and retinal pigment epithelial cells in the macula.