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Characterization of pupil responses to blue and red light stimuli in autosomal dominant retinitis pigmentosa due to NR2E3 mutation
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
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2012 (English)In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 53, no 9, 5562-5569 p.Article in journal (Refereed) Published
Abstract [en]

Purpose. We characterized the pupil responses that reflect rod, cone, and melanopsin function in a genetically homogeneous cohort of patients with autosomal dominant retinitis pigmentosa (adRP).

Methods. Nine patients with Gly56Arg mutation of the NR2E3 gene and 12 control subjects were studied. Pupil and subjective visual responses to red and blue light flashes over a 7 log-unit range of intensities were recorded under dark and light adaptation. The pupil responses were plotted against stimulus intensity to obtain red-light and blue-light response curves.

Results. In the dark-adapted blue-light stimulus condition, patients showed significantly higher threshold intensities for visual perception and for a pupil response compared to controls (P = 0.02 and P = 0.006, respectively). The rod-dependent, blue-light pupil responses decreased with disease progression. In contrast, the cone-dependent pupil responses (light-adapted red-light stimulus condition) did not differ between patients and controls. The difference in the retinal sensitivity to blue and red stimuli was the most sensitive parameter to detect photoreceptor dysfunction. Unexpectedly, the melanopsin-mediated pupil response was decreased in patients (P = 0.02).

Conclusions. Pupil responses of patients with NR2E3-associated adRP demonstrated reduced retinal sensitivity to dim blue light under dark adaptation, presumably reflecting decreased rod function. Rod-dependent pupil responses were quantifiable in all patients, including those with non-recordable scotopic electroretinogram, and correlated with the extent of clinical disease. Thus, the chromatic pupil light reflex can be used to monitor photoreceptor degeneration over a larger range of disease progression compared to standard electrophysiology.

Place, publisher, year, edition, pages
2012. Vol. 53, no 9, 5562-5569 p.
National Category
Ophthalmology
Identifiers
URN: urn:nbn:se:umu:diva-58602DOI: 10.1167/iovs.12-10230PubMedID: 22807301OAI: oai:DiVA.org:umu-58602DiVA: diva2:549261
Available from: 2012-09-04 Created: 2012-09-04 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Selective wavelength pupillometry to evaluate outer and inner retinal photoreception
Open this publication in new window or tab >>Selective wavelength pupillometry to evaluate outer and inner retinal photoreception
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Purpose

Intrinsically photosensitive retinal ganglion cells (ipRGCs) express a unique photopigment called melanopsin. Capable of direct phototransduction, the ipRGCs are also influenced by rods and cones via synaptic inputs.  Thus, the photoinput that mediates the pupil light reflex derives from both outer (rods and cones) and inner (melanopsin-mediated) retinal photoreception. This thesis has aimed to develop a pupillometric test that provides quantitative information about the functional status of outer and inner retinal photoreception in healthy eyes and in eyes with retinal degeneration. In addition to regulating the pupil light reflex, the ipRGCs signal light information for the circadian rhythm, thus, these two non-visual physiologic responses to inner retinal photoreception were examined simultaneously.

Methods

Pupil responses to a long and short wavelength light over a range of intensities (under conditions of light, mesopic and dark adaptation) were recorded using a customized infrared computerized pupillometer. Results were compared for two groups: patients with retinitis pigmentosa and controls. The response function threshold intensity and a half-max intensity was determined from the rod-weighted and cone-weighted pupil responses and correlated to extent of visual loss. The pupil response to light offset was assessed as a measure of direct melanopsin activation. Lastly, pupil responses to red and blue light at equal photo flux were recorded hourly during a 24-hour period and correlated to salivary melatonin concentrations in healthy subjects.

Results

In normal eyes, the blue light evoked greater pupil responses compared to equiluminant red light. With increasing intensity, pupil contraction became more sustained which was most apparent with the brightest blue light. In patients with retinitis pigmentosa, the pupil responses mediated predominantly by rod and cone activation were significantly reduced compared to controls, (p<0.001) and the relative decrease in their contribution resulted in a greater influence of melanopsin on the post-stimulus response. Even at endstage retinal degeneration, pupil responses that derived predominantly from residual cone activity were detectable. The threshold intensity of the rod-mediated, but not cone-mediated, pupil response was also significantly reduced (p=0.006) in patients and the half-maximal intensity of rods correlated with severity of visual loss (r2=0.7 and p=0.02). In healthy controls, the melanopsin-mediated pupil response demonstrated a circadian modulation whereas the cone-mediated pupil response did not.

Conclusion

Early and progressive loss of rod function in mild-moderate stages of retinitis pigmentosa is detectable and quantifiable as a progressive loss of pupillary sensitivity to extremely dim blue lights obtained under conditions of dark adaptation. In advanced stages of retinal degeneration, chromatic pupillometry is more sensitive than standard electroretinography for detecting residual levels of rod and especially cone activity. In addition, selective wavelength pupillometry can assess non-visual light-dependent functions. The timing of the post-stimulus pupil response to blue light is in phase with melatonin secretion, suggesting a circadian regulation of this pupil parameter.

Abstract [sv]

Bakgrund

Jätteganglieceller (intrinsically photosensitive retinal ganglion cells, ipRGCs) är en klass av fotoreceptorer som utnyttjar ett unikt vitamin-A-baserat fotopigment som kallas melanopsin. Utöver deras direkta ljuskänslighet, mottar ipRGCs stimulerande och hämmande synaptiska signaler från andra fotoreceptorer (tappar och stavar) som därigenom kan modulera aktiviteten hos ipRGCs. Ögats pupillreflex medieras alltså av ljus både via yttre (stavar och tappar) och inre (melanopsin-medierad) retinal fotoreception, och den gemensamma afferenta pupillomotor-signalen leds till den pretectala nucleus olivarius via axoner från ipRGCs.

Arbetet i denna avhandling syftar till att utveckla ett kliniskt pupilltest som ger kvantitativ information om yttre och inre retinala fotoreceptorers funktionella status hos friska försökspersoner och patienter med retinal degeneration. Förutom att styra pupillreflexen, skickar ipRGCs även impulser som påverkar kroppens dygnsrytm. Därför ingår även en delstudie i vilken ipRGCs aktivitet studeras genom att avläsa icke-visuella fysiologiska reaktioner på inre retinal fotoreception.

Metoder

Ljus av lång (röd) respektive kort (blå) våglängd presenterades med stegvis ökad ljusstyrka för att selektivt stimulera stavar, tappar eller melanopsin. Pupillreaktionerna registrerades med en infraröd datoriserad pupillometer och jämfördes mellan friska kontroller och patienter med retinitis pigmentosa. I uppföljande experiment gjordes mer noggranna tester i syfte att isolera aktiveringen av varje ljusmottagande element. Tröskelintensiteten för stav- eller tapp-medierad pupillreaktion bestämdes med linjär regressionsanalys. Reaktionskurvan för stavmedierad pupillreflex kvantifierades (halv-maximal intensitet) och jämfördes med svårighetsgraden av sjukdomen i två familjer med samma sjukdomsframkallande mutation för retinitis pigmentosa. För att undersöka icke-visuella reaktioner på inre fotoreception från ipRGCs, undersöktes pupillreaktion på rött och blått ljus varje timme under en 24-timmarsperiod och korrelerades till melatoninkoncentration i saliv hos friska personer med normal syn.

Resultat

I normala ögon, gav blått ljus en kraftigare pupillreaktion jämfört med rött ljus av samma ljusstyrka. Med ökande intensitet, blev pupillkontraktionen mer ihållande, vilket var tydligast med starkt blått ljus. Hos patienter med retinitis pigmentosa, var både tapp- och stav-medierad pupillreaktion signifikant reducerad jämfört med kontroller, (p<0,001). Patienter med avancerad sjukdom och icke-reaktivt elektro-retinogram hade fortfarande mätbar pupillreflex, huvudsakligen härrörande från kvarvarande stavaktivitet. I två familjer med retinitis pigmentosa beroende på en enda missense-mutation av NR2E3 genen, var tröskelvärdet för stavmedierad pupillreflex signifikant reducerat (p= 0,006) och korrelerade till sjukdomens svårighetsgrad. Tappmedierad pupillreflex hos dessa patienter skilde sig dock inte signifikant från kontroller, trots att fotopiskt (tapp) elektroretinogram var klart avvikande. Hos friska kontroller visade melanopsinmedierat pupillsvar en dygnsvariation medan tapp-medierat pupillsvar inte gjorde det.

Slutsatser

Som tillägg till standardundersökningar kan selektiv våglängds-pupillometri (kromatisk pupillometri) vara användbart för utvärdering av funktionen hos stavar och tappar. Denna avhandling visar att tidig och gradvis förlust av stav-funktion i milt-måttligt stadium av retinitis pigmentosa är detekterbar och mätbar som en progressiv förlust av pupillens känslighet för mycket svagt blått ljus, efter mörkeradaptation. I avancerade stadier av retinal degeneration är kromatisk pupillometri känsligare än standardelektroretinografi för att detektera kvarvarande nivåer av stav- och speciellt tapp-aktivitet. Hos unga patienter, där elektroretinografi kan vara tekniskt svårt, är pupillometri en lovande teknik för att värdera yttre retinal fotoreception relaterad till synfunktion. Dessutom kan selektiv våglängdspupillometri ge information om icke-visuella ljusberoende funktioner. Pupillreaktionen på blått ljus varierar med melatoninsekretionen, vilket tyder på en cirkadisk reglering. Ytterligare studier krävs för att undersöka om selektiv våglängds-pupillometri även kan användas i samband med sjukdomar relaterade till störd dygnsrytm, som sömnlöshet och årstidsbunden depression.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2013. 41 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1588
Keyword
pupil, pupil light reflex, melanopsin, photoreceptor, intrinsically photosensitive retinal ganglion cell
National Category
Ophthalmology
Research subject
Ophtalmology
Identifiers
urn:nbn:se:umu:diva-79628 (URN)978-91-7459-708-0 (ISBN)
Public defence
2013-09-26, Hörsal 135, Unod X 1, Norrlands universitetssjukhus, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2013-09-05 Created: 2013-08-27 Last updated: 2013-09-05Bibliographically approved

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