Advertisement

Disinhibition of intrinsic photosensitive retinal ganglion cells in patients with X-linked congenital stationary night blindness

  • Andreas SchatzEmail author
  • Carina Kelbsch
  • Christina Zeitz
  • Susanne Kohl
  • Eberhart Zrenner
  • Florian Gekeler
  • Helmut Wilhelm
  • Barbara Wilhelm
  • Gabriel Willmann
Retinal Disorders
  • 25 Downloads

Abstract

Purpose

To assess the pupil light response (PLR) to chromatic stimulation in patients with different types of X-linked congenital stationary night blindness (CSNB).

Methods

Eight patients with CSNB due to CACNA1F and NYX mutations were exposed to blue and red light stimuli, and PLR was evaluated using infrared video pupillography. Pupil responses were compared between CSNB patients and healthy subjects (n = 34) at baseline, at maximum of constriction, for post-illumination pupil responses (PIPR) and the slope of redilation using Cohen’s d. A subgroup comparison was performed descriptively between CACNA1F and NYX associated CSNB patients using the same parameters.

Results

In CSNB, smaller baseline pupil diameters compared to healthy subjects were measured both before blue and red light stimulation (d = 1.44–1.625). The maximum constriction to blue light stimuli was smaller for the CSNB group compared to healthy subjects (d = 1.251) but not for red light stimuli (d = 0.449). Pupil response latencies were prolonged in CSNB for both light stimuli (d = −1.53 for blue and d = −1.011 for red stimulation). No relevant differences were found between the CSNB group and healthy subjects for PIPR (d = 0.01), but the slope of redilation was smaller for CSNB patients (d = 2.12). Paradoxical pupil constriction at light offset was not seen in our patients.

Conclusion

A reduced redilation and smaller baseline pupil diameters for patients with CSNB indicate a disinhibition of intrinsically photosensitive retinal ganglion cells due to affected post-photoreceptor transduction via bipolar cells and can explain the pupillary behavior in our patient group.

Keywords

Pupillography CSNB Night blindness CACNA1F NYX Retinal degeneration 

Notes

Funding information

This study was funded by the Fortüne program of the University of Tübingen (Fortüne number 2079-0-0).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Loewenfeld IE (1999) The pupil. Anatomy, Physiology and clinical applications. Butterworth-Heinemann, OxfordGoogle Scholar
  2. 2.
    Gamlin PD (2006) The pretectum: connections and oculomotor-related roles. Prog Brain Res 151:379–405.  https://doi.org/10.1016/s0079-6123(05)51012-4 CrossRefGoogle Scholar
  3. 3.
    Xue T, Do MT, Riccio A, Jiang Z, Hsieh J, Wang HC, Merbs SL, Welsbie DS, Yoshioka T, Weissgerber P, Stolz S, Flockerzi V, Freichel M, Simon MI, Clapham DE, Yau KW (2011) Melanopsin signalling in mammalian iris and retina. Nature 479:67–73.  https://doi.org/10.1038/nature10567 CrossRefGoogle Scholar
  4. 4.
    Kozicz T, Bittencourt JC, May PJ, Reiner A, Gamlin PD, Palkovits M, Horn AK, Toledo CA, Ryabinin AE (2011) The Edinger-Westphal nucleus: a historical, structural, and functional perspective on a dichotomous terminology. J Comp Neurol 519:1413–1434.  https://doi.org/10.1002/cne.22580 CrossRefGoogle Scholar
  5. 5.
    Wilhelm BJ, Wilhelm H, Moro S, Barbur JL (2002) Pupil response components: studies in patients with Parinaud’s syndrome. Brain J Neurol 125:2296–2307CrossRefGoogle Scholar
  6. 6.
    Kelbsch CB, Maeda F, Strasser T, Peters TM, Wilhelm BJC, Wilhelm HM (2017) Color pupillography in dorsal midbrain syndrome. J Neuroophthalmol 37:247–252.  https://doi.org/10.1097/wno.0000000000000527 CrossRefGoogle Scholar
  7. 7.
    Sabeti F, James AC, Carle CF, Essex RW, Bell A, Maddess T (2017) Comparing multifocal pupillographic objective perimetry (mfPOP) and multifocal visual evoked potentials (mfVEP) in retinal diseases. Sci Rep 7:45847.  https://doi.org/10.1038/srep45847 CrossRefGoogle Scholar
  8. 8.
    Rosli Y, Carle CF, Ho Y, James AC, Kolic M, Rohan EMF, Maddess T (2018) Retinotopic effects of visual attention revealed by dichoptic multifocal pupillography. Sci Rep 8:2991.  https://doi.org/10.1038/s41598-018-21196-1 CrossRefGoogle Scholar
  9. 9.
    Dacey DM, Liao HW, Peterson BB, Robinson FR, Smith VC, Pokorny J, Yau KW, Gamlin PD (2005) Melanopsin-expressing ganglion cells in primate retina signal colour and irradiance and project to the LGN. Nature 433:749–754.  https://doi.org/10.1038/nature03387 CrossRefGoogle Scholar
  10. 10.
    Gamlin PD, McDougal DH, Pokorny J, Smith VC, Yau KW, Dacey DM (2007) Human and macaque pupil responses driven by melanopsin-containing retinal ganglion cells. Vis Res 47:946–954.  https://doi.org/10.1016/j.visres.2006.12.015 CrossRefGoogle Scholar
  11. 11.
    McDougal DH, Gamlin PD (2010) The influence of intrinsically-photosensitive retinal ganglion cells on the spectral sensitivity and response dynamics of the human pupillary light reflex. Vis Res 50:72–87.  https://doi.org/10.1016/j.visres.2009.10.012 CrossRefGoogle Scholar
  12. 12.
    Zhu Y, Tu DC, Denner D, Shane T, Fitzgerald CM, Van Gelder RN (2007) Melanopsin-dependent persistence and photopotentiation of murine pupillary light responses. Invest Ophthalmol Vis Sci 48:1268–1275.  https://doi.org/10.1167/iovs.06-0925 CrossRefGoogle Scholar
  13. 13.
    Lucas RJ (2013) Mammalian inner retinal photoreception. Curr Biol 23:R125–R133.  https://doi.org/10.1016/j.cub.2012.12.029 CrossRefGoogle Scholar
  14. 14.
    Bailes HJ, Lucas RJ (2013) Human melanopsin forms a pigment maximally sensitive to blue light (lambdamax approximately 479 nm) supporting activation of G(q/11) and G(i/o) signalling cascades. Proc Biol Sci 280:20122987.  https://doi.org/10.1098/rspb.2012.2987 CrossRefGoogle Scholar
  15. 15.
    Doyle SE, Castrucci AM, McCall M, Provencio I, Menaker M (2006) Nonvisual light responses in the Rpe65 knockout mouse: rod loss restores sensitivity to the melanopsin system. Proc Natl Acad Sci U S A 103:10432–10437.  https://doi.org/10.1073/pnas.0600934103 CrossRefGoogle Scholar
  16. 16.
    Melyan Z, Tarttelin EE, Bellingham J, Lucas RJ, Hankins MW (2005) Addition of human melanopsin renders mammalian cells photoresponsive. Nature 433:741–745.  https://doi.org/10.1038/nature03344 CrossRefGoogle Scholar
  17. 17.
    Berson DM, Dunn FA, Takao M (2002) Phototransduction by retinal ganglion cells that set the circadian clock. Science 295:1070–1073.  https://doi.org/10.1126/science.1067262 CrossRefGoogle Scholar
  18. 18.
    Asakawa K, Ishikawa H (2016) Electroretinography and pupillography in unilateral foveal hypoplasia. J Pediatr Ophthalmol Strabismus 53 online:e26–e28.  https://doi.org/10.3928/01913913-20160509-04 Google Scholar
  19. 19.
    Kelbsch C, Maeda F, Lisowska J, Lisowski L, Strasser T, Stingl K, Wilhelm B, Wilhelm H, Peters T (2016) Analysis of retinal function using chromatic pupillography in retinitis pigmentosa and the relationship to electrically evoked phosphene thresholds. Acta Ophthalmol.  https://doi.org/10.1111/aos.13259
  20. 20.
    Kelbsch C, Maeda F, Strasser T, Blumenstock G, Wilhelm B, Wilhelm H, Peters T (2016) Pupillary responses driven by ipRGCs and classical photoreceptors are impaired in glaucoma. Graefes Arch Clin Exp Ophthalmol 254:1361–1370.  https://doi.org/10.1007/s00417-016-3351-9 CrossRefGoogle Scholar
  21. 21.
    Rao HL, Kadambi SV, Mehta P, Dasari S, Puttaiah NK, Pradhan ZS, Rao DA, Shetty R (2016) Diagnostic ability of automated pupillography in glaucoma. Curr Eye Res 1–5.  https://doi.org/10.1080/02713683.2016.1238944
  22. 22.
    Richter P, Wilhelm H, Peters T, Luedtke H, Kurtenbach A, Jaegle H, Wilhelm B (2017) The diagnostic accuracy of chromatic pupillary light responses in diseases of the outer and inner retina. Graefes Arch Clin Exp Ophthalmol 255:519–527.  https://doi.org/10.1007/s00417-016-3496-6 CrossRefGoogle Scholar
  23. 23.
    Takayama K, Ito Y, Kaneko H, Nagasaka Y, Tsunekawa T, Sugita T, Terasaki H (2016) Cross-sectional pupillographic evaluation of relative afferent pupillary defect in age-related macular degeneration. Medicine 95:e4978.  https://doi.org/10.1097/md.0000000000004978 CrossRefGoogle Scholar
  24. 24.
    Takizawa G, Miki A, Maeda F, Goto K, Araki S, Ieki Y, Kiryu J, Yaoeda K (2015) Association between a relative afferent pupillary defect using pupillography and inner retinal atrophy in optic nerve disease. Clin Ophthalmol 9:1895–1903.  https://doi.org/10.2147/opth.s91278 CrossRefGoogle Scholar
  25. 25.
    Kardon R, Anderson SC, Damarjian TG, Grace EM, Stone E, Kawasaki A (2011) Chromatic pupillometry in patients with retinitis pigmentosa. Ophthalmology 118:376–381.  https://doi.org/10.1016/j.ophtha.2010.06.033 CrossRefGoogle Scholar
  26. 26.
    Lorenz B, Strohmayr E, Zahn S, Friedburg C, Kramer M, Preising M, Stieger K (2012) Chromatic pupillometry dissects function of the three different light-sensitive retinal cell populations in RPE65 deficiency. Invest Ophthalmol Vis Sci 53:5641–5652.  https://doi.org/10.1167/iovs.12-9974 CrossRefGoogle Scholar
  27. 27.
    Kankipati L, Girkin CA, Gamlin PD (2011) The post-illumination pupil response is reduced in glaucoma patients. Invest Ophthalmol Vis Sci 52:2287–2292.  https://doi.org/10.1167/iovs.10-6023 CrossRefGoogle Scholar
  28. 28.
    Adhikari P, Zele AJ, Thomas R, Feigl B (2016) Quadrant field pupillometry detects melanopsin dysfunction in glaucoma suspects and early glaucoma. Sci Rep 6:33373.  https://doi.org/10.1038/srep33373 CrossRefGoogle Scholar
  29. 29.
    Najjar RP, Sharma S, Atalay E, Rukmini AV, Sun C, Lock JZ, Baskaran M, Perera SA, Husain R, Lamoureux E, Gooley JJ, Aung T, Milea D (2018) Pupillary responses to full-field chromatic stimuli are reduced in patients with early-stage primary open-angle glaucoma. Ophthalmology 125:1362–1371.  https://doi.org/10.1016/j.ophtha.2018.02.024 CrossRefGoogle Scholar
  30. 30.
    Feigl B, Zele AJ (2014) Melanopsin-expressing intrinsically photosensitive retinal ganglion cells in retinal disease. Optom Vis Sci 91:894–903.  https://doi.org/10.1097/opx.0000000000000284 CrossRefGoogle Scholar
  31. 31.
    Maynard ML, Zele AJ, Feigl B (2015) Melanopsin-mediated post-illumination pupil response in early age-related macular degeneration. Invest Ophthalmol Vis Sci 56:6906–6913.  https://doi.org/10.1167/iovs.15-17357 CrossRefGoogle Scholar
  32. 32.
    Hoda JC, Zaghetto F, Koschak A, Striessnig J (2005) Congenital stationary night blindness type 2 mutations S229P, G369D, L1068P, and W1440X alter channel gating or functional expression of Ca(v)1.4 L-type Ca2+ channels. J Neurosci 25:252–259.  https://doi.org/10.1523/jneurosci.3054-04.2005 CrossRefGoogle Scholar
  33. 33.
    Bech-Hansen NT, Naylor MJ, Maybaum TA, Pearce WG, Koop B, Fishman GA, Mets M, Musarella MA, Boycott KM (1998) Loss-of-function mutations in a calcium-channel alpha1-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness. Nat Genet 19:264–267.  https://doi.org/10.1038/947 CrossRefGoogle Scholar
  34. 34.
    Strom TM, Nyakatura G, Apfelstedt-Sylla E, Hellebrand H, Lorenz B, Weber BH, Wutz K, Gutwillinger N, Ruther K, Drescher B, Sauer C, Zrenner E, Meitinger T, Rosenthal A, Meindl A (1998) An L-type calcium-channel gene mutated in incomplete X-linked congenital stationary night blindness. Nat Genet 19:260–263.  https://doi.org/10.1038/940 CrossRefGoogle Scholar
  35. 35.
    Knoflach D, Schicker K, Glosmann M, Koschak A (2015) Gain-of-function nature of Cav1.4 L-type calcium channels alters firing properties of mouse retinal ganglion cells. Channels (Austin) 9:298–306.  https://doi.org/10.1080/19336950.2015.1078040 CrossRefGoogle Scholar
  36. 36.
    Bech-Hansen NT, Naylor MJ, Maybaum TA, Sparkes RL, Koop B, Birch DG, Bergen AA, Prinsen CF, Polomeno RC, Gal A, Drack AV, Musarella MA, Jacobson SG, Young RS, Weleber RG (2000) Mutations in NYX, encoding the leucine-rich proteoglycan nyctalopin, cause X-linked complete congenital stationary night blindness. Nat Genet 26:319–323.  https://doi.org/10.1038/81619 CrossRefGoogle Scholar
  37. 37.
    Morgans CW, Ren G, Akileswaran L (2006) Localization of nyctalopin in the mammalian retina. Eur J Neurosci 23:1163–1171.  https://doi.org/10.1111/j.1460-9568.2006.04647.x CrossRefGoogle Scholar
  38. 38.
    Pusch CM, Zeitz C, Brandau O, Pesch K, Achatz H, Feil S, Scharfe C, Maurer J, Jacobi FK, Pinckers A, Andreasson S, Hardcastle A, Wissinger B, Berger W, Meindl A (2000) The complete form of X-linked congenital stationary night blindness is caused by mutations in a gene encoding a leucine-rich repeat protein. Nat Genet 26:324–327.  https://doi.org/10.1038/81627 CrossRefGoogle Scholar
  39. 39.
    Pearring JN, Bojang P Jr, Shen Y, Koike C, Furukawa T, Nawy S, Gregg RG (2011) A role for nyctalopin, a small leucine-rich repeat protein, in localizing the TRP melastatin 1 channel to retinal depolarizing bipolar cell dendrites. J Neurosci 31:10060–10066.  https://doi.org/10.1523/jneurosci.1014-11.2011 CrossRefGoogle Scholar
  40. 40.
    Winn B, Whitaker D, Elliott DB, Phillips NJ (1994) Factors affecting light-adapted pupil size in normal human subjects. Invest Ophthalmol Vis Sci 35:1132–1137Google Scholar
  41. 41.
    Jones R (1990) Do women and myopes have larger pupils? Invest Ophthalmol Vis Sci 31:1413–1415Google Scholar
  42. 42.
    Lisowska J, Lisowski L, Kelbsch C, Maeda F, Richter P, Kohl S, Zobor D, Strasser T, Stingl K, Zrenner E, Peters T, Wilhelm H, Fischer MD, Wilhelm B (2017) Development of a chromatic pupillography protocol for the first gene therapy trial in patients with CNGA3-linked achromatopsia. Invest Ophthalmol Vis Sci 58:1274–1282.  https://doi.org/10.1167/iovs.16-20505 CrossRefGoogle Scholar
  43. 43.
    Lucas RJ (2006) Chromophore regeneration: melanopsin does its own thing. Proc Natl Acad Sci U S A 103:10153–10154.  https://doi.org/10.1073/pnas.0603955103 CrossRefGoogle Scholar
  44. 44.
    Leon L, Crippa SV, Borruat FX, Kawasaki A (2012) Differential effect of long versus short wavelength light exposure on pupillary re-dilation in patients with outer retinal disease. Clin Exp Ophthalmol 40:e16–e24.  https://doi.org/10.1111/j.1442-9071.2011.02665.x CrossRefGoogle Scholar
  45. 45.
    Kardon R, Anderson SC, Damarjian TG, Grace EM, Stone E, Kawasaki A (2009) Chromatic pupil responses: preferential activation of the melanopsin-mediated versus outer photoreceptor-mediated pupil light reflex. Ophthalmology 116:1564–1573.  https://doi.org/10.1016/j.ophtha.2009.02.007 CrossRefGoogle Scholar
  46. 46.
    Holder GE (2001) Pattern electroretinography (PERG) and an integrated approach to visual pathway diagnosis. Prog Retin Eye Res 20:531–561CrossRefGoogle Scholar
  47. 47.
    Raghuram A, Hansen RM, Moskowitz A, Fulton AB (2013) Photoreceptor and postreceptor responses in congenital stationary night blindness. Invest Ophthalmol Vis Sci 54:4648–4658.  https://doi.org/10.1167/iovs.13-12111 CrossRefGoogle Scholar
  48. 48.
    Miyake Y (2006) Electrodiagnosis of retinal diseases. Springer, TokyoGoogle Scholar
  49. 49.
    Miyake Y, Horiguchi M, Terasaki H, Kondo M (1994) Scotopic threshold response in complete and incomplete types of congenital stationary night blindness. Invest Ophthalmol Vis Sci 35:3770–3775Google Scholar
  50. 50.
    Porciatti V (2015) Electrophysiological assessment of retinal ganglion cell function. Exp Eye Res 141:164–170.  https://doi.org/10.1016/j.exer.2015.05.008 CrossRefGoogle Scholar
  51. 51.
    Sidiki SS, Hamilton R, Dutton GN (2003) Fear of the dark in children: is stationary night blindness the cause? BMJ 326:211–212CrossRefGoogle Scholar
  52. 52.
    Myers GA, Barricks ME, Stark L (1985) Paradoxic pupillary constriction in a patient with congenital stationary night blindness. Invest Ophthalmol Vis Sci 26:736–740Google Scholar
  53. 53.
    Barricks ME, Flynn JT, Kushner BJ (1977) Paradoxical pupillary responses in congenital stationary night blindness. Arch Ophthalmol 95:1800–1804CrossRefGoogle Scholar
  54. 54.
    Price MJ, Thompson HS, Judisch GF, Corbett JJ (1985) Pupillary constriction to darkness. Br J Ophthalmol 69:205–211CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of OphthalmologyKlinikum StuttgartStuttgartGermany
  2. 2.Centre for OphthalmologyUniversity of TübingenTübingenGermany
  3. 3.Pupil Research Group, Centre for OphthalmologyUniversity of TübingenTübingenGermany
  4. 4.Sorbonne Université, INSERM, CNRS, Institut de la VisionParisFrance

Personalised recommendations