Symmetric Age Association of Retinal Degeneration in Patients with CLN2-Associated Batten Disease

Kovacs, Kyle D.; Patel, Sudi; Orlin, Anton; Kim, Keunpyo; Everen, Sherri Van; Conner, TM; Sondhi, Dolan; Kaminsky, Stephen M.; D’Amico, Donald J.; Crystal, Ronald G.; Kiss, Szilárd

doi:10.1016/j.oret.2020.01.011

Cited by 17 publications

(38 citation statements)

References 30 publications

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“…Our large case series of children with CLN2 demonstrate a wide phenotypic variability with age, but the classical disease retinopathy fits broadly within the CST OCT prediction interval suggested by Kovacs et al [26]. Those with classic CLN2 disease also show similar rapid rates of ERG loss from different starting ages.…”

Section: Foveal Depositsupporting

confidence: 86%

An ERG and OCT study of neuronal ceroid lipofuscinosis CLN2 Battens retinopathy

Thompson

Handley

Henderson

et al. 2021

Eye

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Background Late infantile neuronal ceroid lipofuscinosis (CLN2 Batten disease) is a rare, progressive neurodegenerative disease of childhood. The natural history of motor and language regression is used to monitor the efficacy of CNS treatments. Less is known about CLN2 retinopathy. Our aim is to elaborate the nature, age of onset, and symmetry of CLN2 retinopathy using visual electrophysiology and ophthalmic imaging. Subjects and methods We reviewed 22 patients with genetically confirmed CLN2 disease; seventeen showing classical and five atypical disease. Flash electroretinograms (ERGs), flash and pattern reversal visual evoked potentials (VEPs), recorded from awake children were collated. Available fundus images were graded, optical coherence tomography (OCT) central subfoveal thickness (CST) measured, and genotype, age, clinical vision assessment and motor language grades assembled. Results ERGs show cone/rod system dysfunction preceded by localised macular ellipsoid zone disruption on OCT from 4.8 years. Electroencephalogram (EEG) time-locked spikes confounded both pattern 6/17 (35%) and flash VEPs 12/16 (75%). Paired right eye (RE) and left eye (LE) ERG amplitudes did not differ significantly for each flash stimulus at the p 0.001 level, Wilcoxon ranked signed test. Cone ERGs show a functional deficit before CST thinning in classical disease. Optomap hyper fundus autofluorescence (FAF) at the fovea was noted in three patients with normal ERGs. The oldest patient showed an ovoid aggregate above the external limiting membrane at the fovea, which did not affect the PERG. Conclusion ERG findings in CLN2 retinopathy show symmetrical cone-rod dysfunction, from 4y10m in this series, but a broad range of ages when ERG function is preserved.

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Section: Foveal Depositsupporting

confidence: 86%

An ERG and OCT study of neuronal ceroid lipofuscinosis CLN2 Battens retinopathy

Thompson

Handley

Henderson

et al. 2021

Eye

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“…OCTs were binned into various cohorts bracketed by age based on anticipated time points of degeneration onset from prior studies: 30 to 38 months, 39 to 45 months, 46 to 52 months, 53 to 59 months, 60 to 66 months, and 67 months and older. 21,22 These represent 6-month intervals starting just before (hypothesizing that segmentation measurements may prove more sensitive than previously used conventional degeneration parameters like retinal thickness) and running through a previously identified critical period in the retinal degeneration between 48 and 72 months of age. Measurements for the various retinal layer thickness measurements were compared between adjacent age cohorts using a mixed effect model analysis of variance, treating right and left eyes from the same patient as repeat observations.…”

Section: Discussionmentioning

confidence: 99%

“…Informed consent was obtained for all patients before enrollment. These patients are a subset of the same cohort previously reported as part of a retinal natural history report 22 ; however, only those with adequate imaging were included in the present study (imaging specifications are provided elsewhere in this article).…”

Section: Methodsmentioning

confidence: 99%

“…Comprehensive assessments were performed as previously reported. 21,22 For the present study, all included patients had imaging with spectral domain OCT (Heidelberg Engineering). Gathered clinical information included age at time of diagnosis, age at time of examination, gender, and laterality of eye being examined.…”

Section: Examinations and Patient Informationmentioning

confidence: 99%

“…20 Prior studies have reported on multimodal imaging characterizing retinal findings in patients' with confirmed CLN2 mutations, established and validated a scoring system (Weill Cornell Batten Severity Score [WCBS]), 21 as well as a delineated the natural history and symmetry of the disease in anticipation of future retina-specific therapeutic interventions. 22 However, most measurements of the degeneration as delineated by OCT (including in our own prior work) focused on central macular thickness measurements, which may not be the most accurate means of accurately classifying the degeneration. Classically, the retinopathy associated with CLN2 disease manifests as a "bull's eye" maculopathy and atrophy of the retinal pigment epithelium, autofluorescence changes, peripheral retinal pigmentary changes, and marked reduction in electroretinogram.…”

Section: Introductionmentioning

confidence: 99%

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Automated Retinal Layer Segmentation in CLN2-Associated Disease: Commercially Available Software Characterizing a Progressive Maculopathy

Kovacs

Orlin

Sondhi

et al. 2021

Trans. Vis. Sci. Tech.

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CLN2-associated disease is a hereditary, fatal lysosomal storage disorder characterized by progressive brain and retinal deterioration. Here, we characterize the inner and outer retinal degeneration using automated segmentation software in optical coherence tomography scans, providing an objective, quantifiable metric for monitoring subtle changes previously identified with a validated disease classification scale (the Weill Cornell Batten Scale).Methods: This study is a retrospective, single-center cohort review of images from examinations under anesthesia in treatment-naïve patients with CLN2-associated disease. Automated segmentation software was used to delineate retinal nerve fiber, ganglion cell layer (GCL), and outer nuclear layer (ONL) thickness measurements in the fovea, parafovea, and perifovea based on age groups (months): 30 to 38, 39 to 45, 46 to 52, 53 to 59, 60 to 66, and 67 or older.Results: Twenty-seven eyes from 14 patients were included, with 8 serial images yielding 36 interpretable optical coherence tomography scans. There was a significant difference in parafoveal ONL thickness between 39 to 45 and 46 to 52 months of age (P = 0.032) not seen in other regions or retinal layers. Perifoveal ONL demonstrated a difference in thickness between the 60 to 66 and greater than 67 months age cohorts (P = 0.047). There was strong symmetry between eyes, and high segmentation repeatability. Conclusions:Parafoveal ONL thickness represents a sensitive, early age indicator of CLN2-associated degeneration. Outer retinal degeneration is apparent at younger ages than inner retinal changes though in treatment-naïve patients all retinal layers showed significant differences between 60 to 66 and more than 67 months of age.Translational Relevance: This study establishes sensitive, quantitative biomarkers for assessing retinal degeneration in a large cohort natural history study in anticipation of future clinical trials.

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