Adam Elias Brøndsted

Short wavelength light filtering by the natural human lens and IOLs – implications for entrainment of circadian rhythm

Purpose:  Photoentrainment of circadian rhythm begins with the stimulation of melanopsin containing retinal ganglion cells that respond directly to blue light. With age, the human lens becomes a strong colour filter attenuating transmission of short wavelengths. The purpose of the study was to examine the effect the ageing human lens may have for the photoentrainment of circadian rhythm and to compare with intraocular implant lenses (IOLs) designed to block UV radiation, violet or blue light.

The Effect of Cataract Surgery on Circadian Photoentrainment: A Randomized Trial of Blue-Blocking versus Neutral Intraocular Lenses

PURPOSE Cataract decreases blue light transmission. Because of the selective blue light sensitivity of the retinal ganglion cells governing circadian photoentrainment, cataract may interfere with normal sleep-wake regulation and cause sleep disturbances. The purpose was to investigate the effect of cataract surgery on circadian photoentrainment and to determine any difference between blue-blocking and neutral intraocular lenses (IOLs). DESIGN The study was a single-center, investigator-driven, double-masked, block-randomized clinical trial. PARTICIPANTS One eye in 76 patients with bilateral age-related cataract eligible for cataract surgery was included. METHODS Intervention was cataract surgery by phacoemulsification. Patients were randomized to receive a blue-blocking or neutral IOL. MAIN OUTCOME MEASURES Primary outcome was activation of intrinsic photosensitive ganglion cells using post-illumination pupil response (PIPR) to blue light from 10 to 30 seconds after light exposure as a surrogate measure. Secondary outcomes were circadian rhythm analysis using actigraphy and 24-hour salivary melatonin measurements. Finally, objective and subjective sleep quality were determined by actigraphy and the Pittsburgh Sleep Quality Index. RESULTS The blue light PIPR increased 2 days (17%) and 3 weeks (24%) after surgery (P < 0.001). The majority of circadian and sleep-specific actigraphy parameters did not change after surgery. A forward shift of the circadian rhythm by 22 minutes (P = 0.004) for actigraphy and a tendency toward an earlier melatonin onset (P = 0.095) were found. Peak salivary melatonin concentration increased after surgery (P = 0.037). No difference was detected between blue-blocking and neutral IOLs, whereas low preoperative blue light transmission was inversely associated with an increase in PIPR (P = 0.021) and sleep efficiency (P = 0.048). CONCLUSIONS Cataract surgery increases photoreception by the photosensitive retinal ganglion cells. Because of inconsistency between the significant findings and the many parameters that were unchanged, we can conclude that cataract surgery does not adversely affect the circadian rhythm or sleep. Longer follow-up time and fellow eye surgery may reveal the significance of the subtle changes observed. We found no difference between blue-blocking and neutral IOLs, and, because of the minor effect of surgery in itself, an effect of IOL type seems highly unlikely.

Effect of cataract surgery on regulation of circadian rhythms

UNLABELLED This review looked at the effect of cataract surgery on the regulation of circadian rhythms and compared the effect of blue light-filtering and clear intraocular lenses (IOLs) on circadian rhythms. A systematic review and metaanalysis were performed, and the level of evidence was evaluated based on the principles described in the Grading of Recommendations Assessment, Development, and Evaluation system. A literature search of PubMed, Embase, and Cochrane Library databases was performed, as well as a search for unpublished trials at the U.S. National Institutes of Health Clinical Trials web site. Trials that reported the effect of cataract surgery on circadian rhythms were included. Outcomes were the Pittsburgh Sleep Quality Index (PSQI) global score, number of poor sleepers, Epworth Sleepiness Score, sleep efficiency, and mean concentration of melatonin. Cataract surgery improved regulation of circadian rhythms measured by the PSQI questionnaire, but the clinical relevance is uncertain. There was no difference between the effect of the 2 IOL types. FINANCIAL DISCLOSURE No author has a financial or proprietary interest in any material or method mentioned.

Effect of topical anti-glaucoma medications on late pupillary light reflex, as evaluated by pupillometry.

Purpose The late post-illumination pupillary response (PIPR10–30s) to blue light is reduced in glaucoma, suggesting that pupillometry can be used in clinical glaucoma evaluation. Since animal studies have indicated that common anti-glaucomatous agents affect the iris muscle, we investigated the short-term effect of the anti-glaucoma drugs on the pupillary light reflex and in particular on the PIPR10–30s. Methods In this randomized, double-masked, crossover trial, pupillometry was performed before and after topical administration of latanoprost, dorzolamide, and timolol in 20 healthy subjects. Stimulus was blue (463 nm) and red light (633 nm) of 2 log (lux). Main outcome was the PIPR10–30s to blue light. Additionally, pupil size, maximal contraction, and the early post-illumination pupillary response (PIPR0–10s) to blue and red light were investigated. Pupil response variations between 8 a.m. and 2 p.m. were also assessed. Intraocular pressure (IOP) was measured before and 3.5 h after drug instillation. Results We found no drug effect on the blue light PIPR10–30s or any other blue light pupil parameters. During the control day, the only significant variation over time was observed for the red light PIPR0–10s (p = 0.02). Pupillary size decreased slightly with timolol (0.1 mm, p = 0.03) and dorzolamide (0.2 mm, p < 0.001), but not with latanoprost. Timolol also reduced the maximal contraction amplitude significantly during red light (p = 0.02). Intraocular pressure was significantly reduced by all three drugs after 3.5 h (p < 0.01), while it remained unchanged during the control day (p = 0.3). Conclusion Anti-glaucoma medications did not interfere with the blue light elicited PIPR. Dorzolamide reduced pupil size, while timolol reduced both pupil size and maximal contraction to red light, but the effect was minute and not of clinical importance.

The effect of blue-blocking and neutral intraocular lenses on circadian photoentrainment and sleep one year after cataract surgery

To compare the long‐term effect on circadian photoentrainment and sleep in patients implanted with neutral and blue‐blocking intraocular lenses 1 year after cataract surgery.

Prior Light Exposure Enhances the Pupil Response to Subsequent Short Wavelength (Blue) Light

Background and Purpose: The photo pigment melanopsin initiates cell depolarization in response to highintensity, short-wavelength light. Antecedent long-wavelength light may potentiate regeneration of the melanopsin photo pigment, We investigated the influence of red or blue exposure on the pupil response to subsequent blue light. Methods: Nine healthy subjects were examined using chromatic pupillometry. With a sequence of 3 consecutive blue exposures or a sequence in which the middle exposure was red light, both sequences repeated in the darkadapted state. The summed pupil response during light was obtained as the area under the curve and the percentage difference (diff %) between the first and last blue stimulus was calculated for each sequence. Findings: The pupil response to the third blue exposure was greater than to first blue light. No significant difference was seen in the diff% when comparing a sequence with a blue intervening versus red intervening light, in the light adapted (P = 0.39) or dark adapted state (P = 0.58). Conclusion: Prior light exposure enhances the pupil response to subsequent blue light stimulation, no differential effect was found between blue and red light. This study suggests that antecedent light history is important when designing protocols and evaluating results of chromatic pupillometry.

Will preoperative scoring of patients referred for cataract surgery change indications for surgery? Preliminary results using the Swedish NIKE system in Copenhagen

of the anterior chamber in trabeculectomy, no endothelial damage has been reported (Fiore et al. 1989). We started a prospective trial in which we evaluated preand postoperative endothelial cell counts at 1, 3 and 6 months of patients undergoing vitrectomy randomized to ICSAC or no ICSAC (NTR 3046). We restricted the inclusion to phakic patients undergoing vitrectomy for vitreousfloaters,macular pucker and macular hole. Unfortunately, inclusion of patients proved to be much slower than anticipated and we had to abort the study after inclusion of only 11 patients. In these patients, endothelial cell loss was limited and not noticeably different between patients with or without ICSAC. Therefore, with the caveats associated with conclusions drawn from small data sets, but with our own experience over 10 years (J. van Meurs, unpublished data, presented at the Euretina Barcelona 2004) of having no corneal decompensation after ICSAC, we conclude that when clinical circumstances warrant the preservation of the patients’ lens, intentional shallowing of the anterior chamber is a feasible option.

Effect of Intermittent versus Continuous Light Exposure on Pupillary Light Response, As Evaluated by Pupillometry

Objective Continuous and intermittent stimuli with green light affect the pupillary light response (PLR) differently. Since the majority of pupillometric studies use blue and red lights, we investigated the effect of continuous and intermittent stimulations on the PLR using red and blue lights. Methods Seventeen healthy subjects underwent continuous- and intermittent light stimuli, using red (643 nm) and blue light (463 nm). To avoid the influence of pupil size on the amount of light entering the eye, the procedures were repeated with the stimulus–eye in dilated condition. The maximal pupillary constriction and the early redilation phase of post-illumination pupillary response (PIPREarly) represented the mixed response of melanopsin and rod–cone photoreceptors. The late redilation phase of PIPR (PIPRLate) was the marker of melanopsin-containing retinal ganglion cells. Results Intermittent stimuli with blue light elicited significantly larger maximal contraction during dilated condition (P = 0.001), and larger sustained pupillary contraction under dilated as well as undilated condition (P < 0.001) compared to continuous light exposure. Except the PIPREarly during undilated condition, none of the PIPR metrics were significantly different between intermittent and continuous blue light stimuli. Intermittent red light stimuli elicited also a more sustained pupillary contraction regardless of mydriatic instillation (P ≤ 0.02). In addition, intermittent red light exposure resulted in a slightly larger PIPREarly under undilated condition (P = 0.02) and a slightly larger PIPRLate under dilated condition (P = 0.049). Except the PIPRLate to continuous red light stimulus, all PIPR parameters were larger when the light was presented after induction of unilateral mydriasis. Conclusion PLR parameters during and after light exposures depend on both the light stimulation mode and the entrance pupillary size.

Cataract surgery affects the pupil size and pupil constrictions, but not the late post-illumination pupil response

firmed by Sanger sequencing in both affected siblings. Amino acid position 264, which we found to be altered in our patients, is conserved between vertebrates, insects and C. elegans. Consequently, in silico analyses using various predictionprograms suchasPolyPhen-2 [http://genetics.bwh.harvard.edu/pph2/ ] and Mutation Taster [http://www.mutationtaster.org/] predict this variant to affect protein function.

Pupillary response to direct and consensual chromatic light stimuli

To assess whether the direct and consensual postillumination (ipRGC‐driven) pupil light responses to chromatic light stimuli are equal in healthy subjects.