Pupillary light reflex deficits in a canine model of late infantile neuronal ceroid lipofuscinosis

Abstract

Late-infantile neuronal ceroid lipofuscinosis (CLN2) is a hereditary neurological disorder characterized by progressive retinal degeneration and vision loss, cognitive and motor decline, seizures, and pronounced brain atrophy. The progressive loss of neurological functions eventually leads to death, usually by the early teenage years. Utilizing a canine model of CLN2, therapeutic studies to inhibit the brain and retinal degenerations are currently under way. Using this dog model, studies were undertaken to compare quantitative assessments of the pupillary light reflex (PLR) and electroretinography (ERG) as tools for evaluating the effects of the disease on retinal function. The PLR and ERG were recorded in normal and CLN2-affected Dachshunds at 2 month intervals between the ages of 4 and 10 months. Using custom instrumentation for quantitative PLR assessments, a series of white light stimuli of varying intensity was used to elicit pupil constriction, and pupil images were recorded using continuous infrared illumination and an infrared-sensitive camera. Electroretinography was used to evaluate retinal function in the same dogs. As the disease progressed, affected dogs exhibited progressive and profound declines in ERG amplitudes under both scotopic and photopic conditions. With low intensity light stimuli, CLN2 was also accompanied by progressive deficits in the PLR. Changes in the PLR to dim light stimuli included significant deficits in latency, constriction velocity, constriction amplitude, and redilation velocity. However, despite the almost complete loss of detectable ERG responses by disease end stage, the PLR to bright stimuli was well preserved throughout the disease progression. These findings demonstrate that the PLR is much more sensitive than the ERG in detecting residual retinal function in animal models of retinal degenerative disease. The preservation of the PLR in dogs with profoundly depressed ERGs correlates with a preservation of visually-mediated behavior even late in the disease progression. Quantitative analysis of the PLR has potential as a biomarker in animal models of retinal degenerative diseases and in evaluating the efficacy of therapeutic interventions in preserving retinal function.

Multifocal retinopathy in Dachshunds with CLN2 neuronal ceroid lipofuscinosis

“…Previous reports have shown significant reduction in the ERG b-wave amplitudes of TPP1−/− dogs by 6 months of age with relative preservation of a-wave amplitude (Katz et al, 2005b; Whiting et al, 2013a). In this study a-wave amplitude was selected and examined to compare retinal function in TPP1−/− dogs of various lesion statuses (no lesions and Grade 1–3 lesions), since the b-wave amplitude was already significantly decreased due to the CLN2 disease.…”

“…Bilateral electroretinogram (ERG) evaluations were performed as previously described (Whiting et al, 2013a) on a selection of untreated TPP1−/− dogs at either 8 months or 10 months of age. An ERG was obtained from eleven 8 month-old TPP1−/− dogs [Grade 0 (n=6), Grade 1 (n=3), Grade 2 (n=1), Grade 3 (n=1)] and from eight 10 month-old TPP1−/− dogs [Grade 0 (n=3), Grade 1 (n=3), Grade 2 (n=1), Grade 3 (n=1)].…”

“…This was immediately followed by evaluation of responses to 30-Hz photopic flicker stimuli at the same light intensity. ERG waveforms in all recordings were evaluated, and the amplitudes and implicit times for the a- and b-waves were measured as previously described (Whiting et al, 2013a). …”

“…Affected Dachshunds reach end-stage disease status at 10–11 months of age (Katz et al, 2014). These TPP−/− dogs have normal visual behavior and retinal function at 3 months, show clear vision impairment and ERG deficits at 7 months, and suffer continued visual and neurologic decline through 10 months of age (Katz et al, 2008; Katz et al, 2014; Whiting et al, 2013a). Histological examination of the retina in affected dogs revealed inner nuclear layer cell loss, thinning of the inner plexiform layer, reduced photoreceptor cell density and the accumulation of autofluorescent storage material in ganglion cells and adjacent to the outer limiting membrane (Katz et al, 2008).…”

“…Histological examination of the retina in affected dogs revealed inner nuclear layer cell loss, thinning of the inner plexiform layer, reduced photoreceptor cell density and the accumulation of autofluorescent storage material in ganglion cells and adjacent to the outer limiting membrane (Katz et al, 2008). The TPP1−/− dog has been adopted as a model for human CLN2 disease and has been bred extensively for laboratory studies since the initial retinal investigative study (Awano et al, 2006a; Katz et al, 2008; Katz et al, 2014; Sanders et al, 2011; Vuillemenot et al, 2011; Whiting et al, 2013a). Therapeutic intervention studies with this dog model served as the basis for a human clinical trial of an enzyme replacement therapy treatment for the CLN2 disease that is currently under way.…”