Impairment of the transient pupillary light reflex in Rpe65(-/-) mice and humans with leber congenital amaurosis

Invest Ophthalmol Vis Sci. 2004 Apr;45(4):1259-71. doi: 10.1167/iovs.03-1230.

Abstract

Purpose: To determine the impairment of the transient pupillary light reflex (TPLR) due to severe retinal dysfunction and degeneration in a murine model of Leber congenital amaurosis (LCA) and in patients with the disease.

Methods: Direct TPLR was elicited in anesthetized, dark-adapted Rpe65(-/-) and control mice with full-field light stimuli (0.1 second duration) of increasing intensities (-6.6 to +2.3 log scot-cd. m(-2)). 9-cis-Retinal was administered orally to a subset of Rpe65(-/-) mice, and TPLR was recorded 48 hours after the treatment. TPLR was also measured in a group of patients with LCA.

Results: Baseline pupillary diameters in Rpe65(-/-) and control mice were similar. TPLR thresholds of Rpe65(-/-) mice were elevated by 5 log units compared with those of control animals. The waveform of the TPLR in Rpe65(-/-) mice was similar to that evoked by 4.8-log-unit dimmer stimuli in control mice. Treatment of Rpe65(-/-) mice with 9-cis-retinal lowered the TPLR threshold by 2.1 log units. Patients with LCA had baseline pupillary diameters similar to normal, but the TPLR was abnormal, with thresholds elevated by 3 to more than 6 log units. When adjusted to the elevation of TPLR threshold, pupillary constriction kinetics in most patients were similar to those in normal subjects.

Conclusions: Pupillometry was used to quantify visual impairment and to probe transmission of retinal signals to higher nervous centers in a murine model of LCA and in patients with LCA. Mouse results were consistent with a dominant role of image-forming photoreceptors driving the early phase of the TPLR when elicited by short-duration stimuli. The objective and noninvasive nature of the TPLR measurement, and the observed post-treatment change toward normal in the animal model supports the notion that this may be a useful outcome measure in future therapeutic trials of LCA.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Blindness / complications*
  • Blindness / congenital
  • Carrier Proteins
  • Child
  • Child, Preschool
  • Dark Adaptation
  • Diterpenes
  • Electrophysiology
  • Eye Proteins
  • Female
  • Humans
  • Infant
  • Light
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Proteins / genetics*
  • Pupil Disorders / etiology*
  • Pupil Disorders / physiopathology
  • Reflex, Pupillary / physiology*
  • Retinal Degeneration / complications*
  • Retinal Degeneration / genetics
  • Retinaldehyde / administration & dosage
  • cis-trans-Isomerases

Substances

  • Carrier Proteins
  • Diterpenes
  • Eye Proteins
  • Proteins
  • 9-cis-retinal
  • retinoid isomerohydrolase
  • cis-trans-Isomerases
  • Retinaldehyde