Mark E. Pennesi

Assessing photoreceptor structure in retinitis pigmentosa and usher syndrome

Purpose The purpose of this study was to examine cone photoreceptor structure in retinitis pigmentosa (RP) and Usher syndrome using confocal and nonconfocal split-detector adaptive optics scanning light ophthalmoscopy (AOSLO). Methods Nineteen subjects (11 RP, 8 Usher syndrome) underwent ophthalmic and genetic testing, spectral-domain optical coherence tomography (SD-OCT), and AOSLO imaging. Split-detector images obtained in 11 subjects (7 RP, 4 Usher syndrome) were used to assess remnant cone structure in areas of altered cone reflectivity on confocal AOSLO. Results Despite normal interdigitation zone and ellipsoid zone appearance on OCT, foveal and parafoveal cone densities derived from confocal AOSLO images were significantly lower in Usher syndrome compared with RP. This was due in large part to an increased prevalence of non-waveguiding cones in the Usher syndrome retina. Although significantly correlated to best-corrected visual acuity and foveal sensitivity, cone density can decrease by nearly 38% before visual acuity becomes abnormal. Aberrantly waveguiding cones were noted within the transition zone of all eyes and corresponded to intact inner segment structures. These remnant cones decreased in density and increased in diameter across the transition zone and disappeared with external limiting membrane collapse. Conclusions Foveal cone density can be decreased in RP and Usher syndrome before visible changes on OCT or a decline in visual function. Thus, AOSLO imaging may allow more sensitive monitoring of disease than current methods. However, confocal AOSLO is limited by dependence on cone waveguiding, whereas split-detector AOSLO offers unambiguous and quantifiable visualization of remnant cone inner segment structure. Confocal and split-detector thus offer complementary insights into retinal pathology.

Long-term Follow-up of Patients With Retinitis Pigmentosa Receiving Intraocular Ciliary Neurotrophic Factor Implants

PURPOSEnTo evaluate the long-term efficacy of ciliary neurotrophic factor delivered via an intraocular encapsulated cell implant for the treatment of retinitis pigmentosa.nnnDESIGNnLong-term follow-up of a multicenter, sham-controlled study.nnnMETHODSnThirty-six patients at 3 CNTF4 sites were randomly assigned to receive a high- or low-dose implant in 1 eye and sham surgery in the fellow eye. The primary endpoint (change in visual field sensitivity at 12xa0months) had been reported previously. Here we measure long-term visual acuity, visual field, and optical coherence tomography (OCT) outcomes in 24 patients either retaining or explanting the device at 24xa0months relative to sham-treated eyes.nnnRESULTSnEyes retaining the implant showed significantly greater visual field loss from baseline than either explanted eyes or sham eyes through 42xa0months. By 60xa0months and continuing through 96xa0months, visual field loss was comparable among sham-treated eyes, eyes retaining the implant, and explanted eyes, as was visual acuity and OCT macular volume.nnnCONCLUSIONSnOver the short term, ciliary neurotrophic factor released continuously from an intravitreal implant led to loss of total visual field sensitivity that was greater than the natural progression in the sham-treated eye. This additional loss of sensitivity related to the active implant was reversible when the implant was removed. Over the long term (60-96xa0months), there was no evidence of efficacy for visual acuity, visual field sensitivity, or OCT measures of retinal structure.

Measurement and Reproducibility of Preserved Ellipsoid Zone Area and Preserved Retinal Pigment Epithelium Area in Eyes With Choroideremia

PURPOSEnTo identify valid and reproducible methods for quantifying anatomic outcome measures for eyes with choroideremia (CHM) in clinical trials.nnnDESIGNnReliability analysis study.nnnMETHODSnIn this multicenter study, patients with confirmed genetic diagnosis of CHM were enrolled. All cases underwent spectral-domain optical coherence tomography (SDOCT) and fundus autofluorescence (FAF) imaging. Two graders independently delineated boundaries of preserved autofluorescence (PAF) and preserved ellipsoid zone (EZ) on FAF and OCT images, respectively. The results of the 2 independent gradings of both FAF and OCT images were compared to assess the reproducibility of the grading methods.nnnRESULTSnA total of 148 eyes from 75 cases were included. In 21% of eyes PAF and in 43% of eyes preserved EZ had extended beyond the image capture area. After exclusion of these eyes and low-quality images, 114 FAF and 77xa0OCT images were graded. The mean PAF areas from 2 independent gradings were 3.720 ± 3.340xa0mm2 and 3.692xa0±xa03.253xa0mm2, respectively. Intraclass correlation coefficient (ICC) for these gradings was 0.996. The mean preserved EZ areas from 2 independent gradings were 2.746xa0±xa02.319xa0mm2 and 2.858xa0±xa02.446xa0mm2, respectively. ICC for these gradings was 0.991.nnnCONCLUSIONSnQuantifying preserved retinal pigment epithelium and EZ areas on FAF and OCT images, respectively, in CHM patients is highly reproducible. These variables would be potential anatomic outcome measures for CHM clinical trials and could be studied and tracked longitudinally in choroideremia.

Optical Coherence Tomography Angiography in Choroideremia: Correlating Choriocapillaris Loss With Overlying Degeneration

IMPORTANCEnNovel therapies for choroideremia, an X-linked recessive chorioretinal degeneration, demand a better understanding of the primary site(s) of cellular degeneration. Optical coherence tomography angiography allows for choriocapillaris (CC) imaging. We compared the extent of structural alterations of the CC, retinal pigment epithelium, and photoreceptors with multimodal imaging.nnnOBSERVATIONSnIn a clinical case series conducted from September 15, 2014, through February 5, 2015, 14 eyes of 7 male patients with choroideremia (median age, 34 years [interquartile range, 15-46 years]; age range, 13-48 years), 4 eyes of 2 women with choroideremia carrier state (both in mid-50s), and 6 eyes of 6 controls (median age, 42.5 years [interquartile range, 33-55 years]; age range, 24-55 years) underwent multimodal imaging with optical coherence tomography angiography and electroretinography. The mean (SD) macular CC density was 82.9% (13.4%) in patients with choroideremia, 93.0% (3.8%) in female carriers, and 98.2% (1.3%) in controls. The mean (SD) CC density in affected eyes was higher in regions with preserved (92.6% [5.8%]) vs absent (75.9% [12.6%]) ellipsoid zone (mean difference, 16.7%; 95% CI, 12.1% to 21.3%; Pu2009<u2009.001). Seventeen of 18 eyes of the patients and carriers had outer retinal tubulations forming pseudopod-like extensions from islands of preserved ellipsoid zone. Outer retinal tubulations were associated with absence of underlying retinal pigment epithelium and were longer (ru2009=u2009-0.62; 95% CI, -0.84 to -0.19; Pu2009<u2009.001) and more numerous (ru2009=u2009-0.71; 95% CI, -0.91 to -0.27; Pu2009<u2009.001) in more severely affected eyes.nnnCONCLUSIONS AND RELEVANCEnThese findings suggest that regional changes in CC density correlate with photoreceptor structural alterations in choroideremia. Although closely coupled, the results suggest that retinal pigment epithelium loss is more extensive than photoreceptor loss.

A possible neural mechanism for photosensitivity in chronic pain.

Abstract Patients with functional pain disorders often complain of generalized sensory hypersensitivity, finding sounds, smells, or even everyday light aversive. The neural basis for this aversion is unknown, but it cannot be attributed to a general increase in cortical sensory processing. Here, we quantified the threshold for aversion to light in patients with fibromyalgia, a pain disorder thought to reflect dysregulation of pain-modulating systems in the brain. These individuals expressed discomfort at light levels substantially lower than that of healthy control subjects. Complementary studies in lightly anesthetized rat demonstrated that a subset of identified pain-modulating neurons in the rostral ventromedial medulla unexpectedly responds to light. Approximately half of the pain-facilitating “ON-cells” and pain-inhibiting “OFF-cells” sampled exhibited a change in firing with light exposure, shifting the system to a pronociceptive state with the activation of ON-cells and suppression of OFF-cell firing. The change in neuronal firing did not require a trigeminal or posterior thalamic relay, but it was blocked by the inactivation of the olivary pretectal nucleus. Light exposure also resulted in a measurable but modest decrease in the threshold for heat-evoked paw withdrawal, as would be expected with engagement of this pain-modulating circuitry. These data demonstrate integration of information about light intensity with somatic input at the level of single pain-modulating neurons in the brain stem of the rat under basal conditions. Taken together, our findings in rodents and humans provide a novel mechanism for abnormal photosensitivity and suggest that light has the potential to engage pain-modulating systems such that normally innocuous inputs are perceived as aversive or even painful.

Test–Retest Variability of Functional and Structural Parameters in Patients with Stargardt Disease Participating in the SAR422459 Gene Therapy Trial

Purpose The goal of this analysis was to determine the test–retest variability of functional and structural measures from a cohort of patients with advanced forms of Stargardt Disease (STGD) participating in the SAR422459 (NCT01367444) gene therapy clinical trial. Methods Twenty-two participants, aged 24 to 66, diagnosed with advanced forms of STGD, with at least one pathogenic ABCA4 mutation on each chromosome participating in the SAR422459 (NCT01367444) gene therapy clinical trial, were screened over three visits within 3 weeks or less. Functional visual evaluations included: best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score, semiautomated kinetic perimetry (SKP) using isopters I4e, III4e, and V4e, hill of vision (HOV) calculated from static visual fields (SVF) by using a 184n point centrally condensed grid with the stimulus size V test target. Retinal structural changes such as central macular thickness and macular volume were assessed by spectral-domain optical coherence tomography (SD-OCT). Repeatability coefficients (RC) and 95% confidential intervals (CI) were calculated for each parameter using a hierarchical mixed-effects model and bootstrapping. Results Criteria for statistically significant changes for various parameters were found to be the following: BCVA letter score (8 letters), SKP isopters I4e, III4e, and V4e (3478.85; 2488.02 and 2622.46 deg2, respectively), SVF full volume HOV (VTOT, 14.62 dB-sr), central macular thickness, and macular volume (4.27 μm and 0.15 mm3, respectively). Conclusions This analysis provides important information necessary to determine if significant changes are occurring in structural and functional assessments commonly used to measure disease progression in this cohort of patients with STGD. Moreover, this information is useful for future trials assessing safety and efficacy of treatments in STGD. Translational Relevance Determination of variability of functional and structural measures in participants with advanced stages of the STGD is necessary to assess efficacy and safety in treatment trials involving STGD patients.

REPEATABILITY AND LONGITUDINAL ASSESSMENT OF FOVEAL CONE STRUCTURE IN CNGB3-ASSOCIATED ACHROMATOPSIA.

Purpose: Congenital achromatopsia is an autosomal recessive disease causing substantial reduction or complete absence of cone function. Although believed to be a relatively stationary disorder, questions remain regarding the stability of cone structure over time. In this study, the authors sought to assess the repeatability of and examine longitudinal changes in measurements of central cone structure in patients with achromatopsia. Methods: Forty-one subjects with CNGB3-associated achromatopsia were imaged over a period of between 6 and 26 months using optical coherence tomography and adaptive optics scanning light ophthalmoscopy. Outer nuclear layer (ONL) thickness, ellipsoid zone (EZ) disruption, and peak foveal cone density were assessed. Results: ONL thickness increased slightly compared with baseline (0.184 &mgr;m/month, P = 0.02). The EZ grade remained unchanged for 34/41 subjects. Peak foveal cone density did not significantly change over time (mean change 1% per 6 months, P = 0.126). Conclusion: Foveal cone structure showed little or no change in this group of subjects with CNGB3-associated achromatopsia. Over the time scales investigated (6–26 months), achromatopsia seems to be a structurally stable condition, although longer-term follow-up is needed. These data will be useful in assessing foveal cone structure after therapeutic intervention.

OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF CHOROIDAL NEOVASCULARIZATION IN FOUR INHERITED RETINAL DYSTROPHIES

Purpose: To demonstrate the clinical utility of optical coherence tomography (OCT) angiography (OCT-A) in inherited retinal dystrophies complicated by choroidal neovascularization (CNV). Methods: Optical coherence tomography angiography and structural OCT were performed using a 70-kHz spectral domain OCT system using the split-spectrum amplitude-decorrelation angiography algorithm. Semiautomated image processing software was used to segment and measure the CNV. Results: Four participants were enrolled to study the following inherited retinal dystrophies complicated by CNV: choroideremia, EFEMP1-related retinopathy, Best vitelliform dystrophy, and adult-onset vitelliform dystrophy. Interpretation of fluorescein angiography was difficult because of abnormal retinal architecture but suggested the presence of CNV. Structural OCT revealed subretinal or subretinal pigment epithelium fibrovascular tissue, within which flow signal was observed on OCT-A. The CNV morphology varied from dense capillary networks in active lesions to asymptomatic large caliber loops. Baseline CNV vessel areas ranged from 0.07 mm2 to 0.98 mm2. After treatment with intravitreal bevacizumab, the CNV in choroideremia decreased in the vessel area then rebounded, whereas the one in EFEMP1-related retinopathy remained largely unchanged. Conclusion: Optical coherence tomography angiography enables morphologic characterization and quantification of CNV in patients with retinal dystrophies despite distorted retinal architecture, can assess response to treatment, and may facilitate differentiation between active and regressed lesions.

Characterization of Chorioretinopathy Associated with Mitochondrial Trifunctional Protein Disorders: Long-Term Follow-up of 21 Cases

PURPOSEnTo assess long-term effects of genotype on chorioretinopathy severity in patients with mitochondrial trifunctional protein (MTP) disorders.nnnDESIGNnRetrospective case series.nnnPARTICIPANTSnConsecutive patients with MTP disorders evaluated at a single center from 1994 through 2015, including 18 patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) and 3 patients with trifunctional protein deficiency (TFPD).nnnMETHODSnLocal records from all visits were reviewed. Every participant underwent a complete ophthalmic examination and was evaluated by a metabolic physician and dietitian. Nine patients underwent ancillary funduscopic imaging including optical coherence tomography (OCT) and OCT angiography.nnnMAIN OUTCOME MEASURESnThe primary outcome measure was best-corrected visual acuity at the final visit. Secondary outcome measures included spherical equivalent refraction, visual fields, electroretinography B-wave amplitudes, and qualitative imaging findings.nnnRESULTSnParticipants were followed up for a median of 5.6 years (range 0.3-20.2 years). The median age of LCHADD participants at initial and final visits was 2.3 and 11.9 years, whereas that for TFPD participants at initial and final visits was 4.7 and 15.5 years, respectively. Four long-term survivors older than 16 years were included (3 with LCHADD and 1 with TFPD). The LCHADD participants demonstrated a steady decline in visual acuity from an average of 0.23 logarithm of the minimum angle of resolution (logMAR; Snellen equivalent, 20/34) at baseline to 0.42 logMAR (Snellen equivalent, 20/53) at the final visit, whereas TFPD patients maintained excellent acuity throughout follow-up. Participants with LCHADD, but not TFPD, showed an increasing myopia with a mean decrease in spherical equivalent refraction of 0.24 diopters per year. Visual fields showed sensitivity losses centrally associated with defects on OCT. Multimodal imaging demonstrated progressive atrophy of the outer retina in LCHADD, often preceded by the formation of outer retinal tubulations and choriocapillaris dropout. Electroretinography findings support the more severe clinical profile of LCHADD patients compared with TFPD patients; the function of both rods and cones are attenuated diffusely in LCHADD patients, but are within normal limits for TFPD patients.nnnCONCLUSIONSnDespite improved survival with early diagnosis, medical management, and dietary treatment, participants with the LCHADD subtype of MTP disorder continue to demonstrate visually disabling chorioretinopathy. Multimodal imaging is most consistent with choriocapillaris loss exceeding photoreceptor loss.

Detailed Clinical Phenotype and Molecular Genetic Findings in CLN3-Associated Isolated Retinal Degeneration

Importance Mutations in genes traditionally associated with syndromic retinal disease are increasingly found to cause nonsyndromic inherited retinal degenerations. Mutations in CLN3 are classically associated with juvenile neuronal ceroid lipofuscinosis, a rare neurodegenerative disease with early retinal degeneration and progressive neurologic deterioration, but have recently also been identified in patients with nonsyndromic inherited retinal degenerations. To our knowledge, detailed clinical characterization of such cases has yet to be reported. Objective To provide detailed clinical, electrophysiologic, structural, and molecular genetic findings in nonsyndromic inherited retinal degenerations associated with CLN3 mutations. Design, Setting, and Participants A multi-institutional case series of 10 patients who presented with isolated nonsyndromic retinal disease and mutations in CLN3. Patient ages ranged from 16 to 70 years; duration of follow-up ranged from 3 to 29 years. Main Outcomes and Measures Longitudinal clinical evaluation, including full ophthalmic examination, multimodal retinal imaging, perimetry, and electrophysiology. Molecular analyses were performed using whole-genome sequencing or whole-exome sequencing. Electron microscopy studies of peripheral lymphocytes and CLN3 transcript analysis with polymerase chain reaction amplification were performed in a subset of patients. Results There were 7 females and 3 males in this case series, with a mean (range) age at last review of 37.1 (16-70) years. Of the 10 patients, 4 had a progressive late-onset rod-cone dystrophy, with a mean (range) age at onset of 29.7 (20-40) years, and 6 had an earlier onset rod-cone dystrophy, with a mean (range) age at onset of 12.1 (7-17) years. Ophthalmoscopic examination features included macular edema, mild intraretinal pigment migration, and widespread atrophy in advanced disease. Optical coherence tomography imaging demonstrated significant photoreceptor loss except in patients with late-onset disease who had a focal preservation of the ellipsoid zone and outer nuclear layer in the fovea. Electroretinography revealed a rod-cone pattern of dysfunction in 6 patients and were completely undetectable in 2 patients. Six novel CLN3 variants were identified in molecular analyses. Conclusions and Relevance This report describes detailed clinical, imaging, and genetic features of CLN3-associated nonsyndromic retinal degeneration. The age at onset and natural progression of retinal disease differs greatly between syndromic and nonsyndromic CLN3 disease, which may be associated with genotypic differences.