Carina Kelbsch

Analysis of retinal function using chromatic pupillography in retinitis pigmentosa and the relationship to electrically evoked phosphene thresholds

To analyse pupil responses to specific chromatic stimuli in patients with advanced retinitis pigmentosa (RP) to ascertain whether chromatic pupillography can be used as an objective marker for residual retinal function. To examine correlations between parameters of the pupil response and the perception threshold of electrically evoked phosphenes.

Pupillographic campimetry: an objective method to measure the visual field

Abstract Pupillographic campimetry allows measuring the visual field objectively by analyzing the pupil response to perimetric stimuli. One of the drawbacks of this technique, similar to static perimetry, is the need of reliable fixation of the subject. By using stimulus sizes comparable to static perimetry and applying gaze tracking, we enable a retinotopic visual field examination regardless of fixation problems and with an increased stability and improved spatial resolution. Here, we present the results of applying the method in eight normal sighted subjects as well as in three patients suffering from diseases usually diagnosed by perimetry. The results in normal sighted subjects show a reduction in the amplitude of the pupil response with increasing eccentricity as expected. We also demonstrate that gaze-controlled campimetry is able to detect organic visual field defects objectively in a patient group and classify the visual field defects without an organic background. Moreover, we show that our method is able to evaluate the visual field sensitivity loss beyond classical perimetry in patients with late-stage retinitis pigmentosa. Thus, gaze-controlled pupil campimetry can be used in addition to classical perimetry, allowing for an objective monitoring of disease progression, rendering it as a biomarker for novel treatments.

Color Pupillography in Dorsal Midbrain Syndrome

Objective: The purpose of this study was to evaluate the pupil response to chromatic stimuli in patients with lesions in the dorsal midbrain and possibly gain new insights into the afferent pupillary pathways. Methods: Color pupillography was performed in 5 patients with dorsal midbrain syndrome (DMS), and their results were compared with those of 20 healthy control subjects. We used full-field red stimuli (605 nm) that primarily address the rod/cone system and blue stimuli (420 nm) that preferentially activate intrinsically photosensitive retinal ganglion cells (ipRGCs) directly, with a duration of 4 seconds and a stimulus intensity of 28 lx corneal illumination under mesopic conditions. One eye was stimulated, and the consensual pupil response was recorded and analyzed. Results: The pupillary light reflex in patients with DMS was reduced, differed in shape, and showed a prolonged latency time compared to normal subjects. The blue response was less affected than the red response: the mean maximal relative amplitude (M) was 15.8% (SD = 7.8) in patients with DMS compared with 43.0% (SD = 5.5) in normal subjects for red stimulation, and M = 40.8%, SD = 8.4 (DMS) with M = 58.3%, SD = 4.8 (normals) for blue stimulation. The reduction was 63% for red stimulation but only 30% for blue stimulation in patients with DMS. Moreover, there was a preserved postillumination pupil response to blue stimulation in DMS patients. Conclusions: In DMS, the melanopsin-mediated ipRGC pathway appeared relatively preserved.

Phosphene perception and pupillary responses to sinusoidal electrostimulation - For an objective measurement of retinal function

&NA; The purpose was to evaluate retinal function by measuring pupillary responses to sinusoidal transcorneal electrostimulation in healthy young human subjects. This work also translates data from analogous in vitro experiments and connects it to the pupillary responses obtained in human experiments. 14 healthy human subjects participated (4 males, 10 females); for the in vitro experiments, two male healthy mouse retinas (adult wild‐type C57B/6J) were used. Pupillary responses to sinusoidal transcorneal electrostimulation of varying stimulus carrier frequencies (10, 20 Hz; envelope frequency constantly kept at 1.2 Hz) and intensities (10, 20, 50 &mgr;A) were recorded and compared with those obtained with light stimulation (1.2 Hz sinusoidal blue, red light). A strong correlation between the sinusoidal stimulation (electrical as well as light) and the pupillary sinusoidal response was found. The difference between the lag of electrical and light stimulation allowed the estimation of an intensity threshold for pupillary responses to transcorneal electrostimulation (mean ± SD: 30 ± 10 &mgr;A (10 Hz); 38 ± 10 &mgr;A (20 Hz)). A comparison between the results of the two stimulation frequencies showed a not statistically significant smaller lag for 10 Hz (10 Hz: 633 ± 90 ms; 20 Hz: 725 ± 178 ms; 50 &mgr;A intensity). Analogous in vitro experiments on murine retinas indicated a selective stimulation of photoreceptors and bipolar cells (lower frequencies) and retinal ganglion cells (higher frequencies) and lower stimulation thresholds for the retinal network with sinusoidal compared to pulsatile stimulation – emphasizing that sinusoidal waveforms are well‐suited to our purposes. We demonstrate that pupillary responses to sinusoidal transcorneal electrostimulation are measurable as an objective marker in healthy young subjects, even at very low stimulus intensities. By using this unique approach, we unveil the potential for an estimation of the individual intensity threshold and a selective activation of different retinal cell types in humans by varying the stimulation frequency. This technique may have broad clinical utility as well as specific relevance in the monitoring of patients with hereditary retinal disorders, especially as implemented in study protocols for novel therapies, e.g. retinal prostheses or gene therapies. HighlightsFunctional evaluation of the retina in humans based on pupillary responses.New paradigm for transcorneal sinusoidal electrical stimulation.Method for an easy estimation of individual thresholds for pupillary responses.Possibility for a selective activation of different retinal cell types.Verification of sinusoidal stimulation in animal in vitro model.

Pupil response components: attention-light interaction in patients with Parinaud’s syndrome

Covertly shifting attention to a brighter or darker image (without moving one’s eyes) is sufficient to evoke pupillary constriction or dilation, respectively. One possibility is that this attentional modulation involves the pupillary light response pathway, which pivots around the olivary pretectal nucleus. We investigate this possibility by studying patients with Parinaud’s syndrome, where the normal pupillary light response is strongly impaired due to lesions in the pretectal area. Four patients and nine control participants covertly attended (while maintaining fixation at the center of a monitor screen) to one of two disks located in the left and right periphery: one brighter, the other darker than the background. Patients and control subjects behaved alike, showing smaller pupils when attending to the brighter stimulus (despite no eye movements); consistent results were obtained with a dynamic version of the stimulus. We interpret this as proof of principle that attention to bright or dark stimuli can dynamically modulate pupil size in patients with Parinaud’s syndrome, suggesting that attention acts independently of the pretectal circuit for the pupillary light response and indicating that several components of the pupillary response can be isolated – including one related to the focus of covert attention.

Development of a Chromatic Pupillography Protocol for the First Gene Therapy Trial in Patients With CNGA3-Linked Achromatopsia

Purpose To establish a feasible and sensitive pupillographic protocol to assess outer and inner retinal function for the first gene therapy trial in achromatopsia patients (ACHM) with mutations in CNGA3. Methods Twenty-seven CNGA3-ACHM patients and 22 age-matched control subjects were tested using chromatic pupillography. Three different protocols were established to assess the pupillary light reflex parameters and to create the final protocol. In the individual protocols, various stimulus parameters (i.e., intensity, duration, wavelength, adaptation states) were applied to evaluate the impact of these stimuli on the pupillary response in untreated ACHM patients. Results In the light-adapted conditions, CNGA3-ACHM patients showed significantly reduced maximal amplitudes compared with the control group when using a 1-second high intensity (28-lux corneal illumination) blue or red stimulus (P < 0.005). In the dark-adapted conditions, CNGA3-ACHM patients unexpectedly revealed significantly increased maximal amplitudes when stimulating with red (1 second) or blue (4 ms and 1 second) stimuli of low intensity (0.01-lux corneal illumination; P < 0.05). Pupil responses of CNGA3-ACHM patients after high intensity (28 lux) red and blue 1-second stimuli were within the normal range. Conclusions Chromatic pupillography demonstrated significant reduced pupil responses to stimuli addressing primarily cone function, an increased sensitivity to rod-favoring stimuli and evidence for disinhibition of intrinsically photosensitive retinal ganglion cells in CNGA3-ACHM patients. A final protocol was established based on these findings. These conclusions may be useful for the objective assessment of efficacy gained by gene therapy or other innovative interventions in this hereditary retinal disorder.