Skip to main content

Advertisement

SpringerLink
Log in

Trans-synaptic Retrograde Degeneration in the Human Visual System: Slow, Silent, and Real

  • Neuro-Ophthalmology (A Kawasaki, Section Editor)
  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Degeneration of neuron and axons following injury to cells with which they synapse is termed trans-synaptic degeneration. This phenomenon may be seen in postsynaptic neurons (anterograde) or in presynaptic neurons (retrograde). Retrograde trans-synaptic degeneration (RTSD) of the retinal ganglion cells and retinal nerve fiber layer following injury to the occipital lobe has been well documented histologically in animal studies, but its occurrence in the human retina was, for many years, felt to be limited to cases of neonatal injury during a critical period of neuronal development. Over the last decade, imaging techniques such as MRI and optical coherence tomography have allowed us to visualize and quantify RTSD and analyze its time course and relationship to degree of vision loss and age of cortical injury. A deeper understanding of RTSD in the human visual system may allow us to interfere with its occurrence, potentially allowing for greater recovery following visual cortex injury.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Nissl: Allg. Ztschr. f. Psychiat., 1891–1892, xlviii, p. 197.

  2. James: Arch. Ophth., 1933, ix, p. 338.

  3. Ranvier: Quoted by Ramon y Cajal, Degeneration and regeneration of the nervous system (translated by R. M. May). London: Oxford University Press; 1928, i, p. 6.

  4. Bielschowsky: Bumke and Foerster, Handbuch der Neurologie. Berlin: Julius Springer; 1935, i, p. 155.

  5. Leinfelder PJ. Retrograde degeneration in the optic nerves and retinal ganglion cells. Trans Am Ophthalmol Soc. 1938;36:307–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Campbell A. Histological studies on the localisation of cerebral function. Cambridge: Cambridge University Press; 1905.

  7. Smith MC. Histological findings after hemicerebellectomy in man: anterograde, retrograde and transneuronal degeneration. Brain Res. 1975;95:423–42.

    Article  CAS  PubMed  Google Scholar 

  8. Cajal S, Ramon Y. Histologie du systeme nerveux de l’homme et des verte’bres. vol. 2, Paris: Maloine; 1911.

  9. Minkowski M. Experimentelle Untersuchungen über die Beziehungen der Grosshirnrinde und der Netzhaut zu den primären optischen Zentren, besonders zum Corpus geniculatum externum. Arb. a. d. hirnanat. Inst., Zürich. 1913;7:255.

  10. Clark WEL. A morphological study of the lateral geniculate body. Br J Ophthalmol. 1932;16:264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gartner S. Ocular pathology in the chiasmal syndrome. Am J Ophthalmol. 1951;34(4):593–6.

    Article  CAS  PubMed  Google Scholar 

  12. Juba A, Szatmari A. Ueber seltene hirnanatomische Befunde in Fällen von einseitiger peripherer Blindheit, Klin. Monatsbl. f. Augenh. 1937;99:173.

  13. Perry VH, Cowey A. The effects of unilateral cortical and tectal lesions on retinal ganglion cells in rats. Exp Brain Res. 1979;35(1):85–95.

    CAS  PubMed  Google Scholar 

  14. Hendrickson AE, Wilson JR, Ogren MP. The neuroanatomical organization of pathways between dorsal lateral geniculate nucleus and visual cortex in Old and New World primates. J Comp Neurol. 1978;182:123–36.

    Article  CAS  PubMed  Google Scholar 

  15. Harting JK, Huerta MF, Hashikawa T, van Lieshout DP. Projection of the mammalian superior colliculus upon the dorsal lateral geniculate nucleus: organization of tectogeniculate pathways in nineteen species. J Comp Neurol. 1991;304:275–306.

    Article  CAS  PubMed  Google Scholar 

  16. Hendry SHC. Striate and extrastriateoutput of a third geniculate channel in macaques. Invest Opthalmol Vis Sci. 1995;36:S292.

    Google Scholar 

  17. Rizzo III JF. Embryology, anatomy, and physiology of the afferent visual pathway. In: Miller NR, Newman NJ, editors. Walsh and Hoyt’s clinical neuro-ophthalmology. 6th ed. Philadelphia: Lippincott, Williams and Wilkins; 2005. p. 3–82.

    Google Scholar 

  18. Pearson HE, Labar DR, Payne BR, Cornwell P, Aggarwal N. Transneuronal retrograde degeneration in the cat retina following neonatal ablation of visual cortex. Brain Res. 1981;212(2):470–5.

    Article  CAS  PubMed  Google Scholar 

  19. Tong L, Spear PD, Kalil RE, Callahan EC. Loss of retinal X-cells in cats with neonatal or adult visual cortex damage. Science. 1982;217(4554):72–5.

    Article  CAS  PubMed  Google Scholar 

  20. Bowling DB, Michael CR. Projection patterns of single physiologically characterized optic tract fibres in cat. Nature. 1980;286(5776):899-902.

  21. Théoret H, Herbin M, Boire D, Ptito M. Transneuronal retrograde degeneration of retinal ganglion cells following cerebral hemispherectomy in cats. Brain Res. 1997;775(1–2):203–8.

    Article  PubMed  Google Scholar 

  22. Rowe MH. Evidence for degeneration of retinal W cells following early visual cortical removal in cats. Brain Behav Evol. 1990;35(5):253–67.

    Article  CAS  PubMed  Google Scholar 

  23. Sturrock RR. Changes in the number of axons in the human embryonic optic nerve from 8 to 18 weeks gestation. J Hirnforsch. 1987;28:649–52.

    CAS  PubMed  Google Scholar 

  24. Ng AYK, Stone J. The optic nerve of the cat: appearance and loss of axons during normal development. Dev Brain Res. 1982;5:263–71.

    Article  Google Scholar 

  25. Carpenter P, Sefton AJ, Dreher B, Lim WL. Role of target tissue in regulating the development of retinal ganglion cells in the albino rat: effects of kainate lesions in the superior colliculus. J Comp Neurol. 1986;251(2):240–59.

    Article  CAS  PubMed  Google Scholar 

  26. Klüver H. Certain effects of lesions of the occipital lobes in macaques. J Psychol. 1937;4:383.

    Article  Google Scholar 

  27. Van Buren JM. Trans-synaptic retrograde degeneration in the visual system of primates. J Neurol Neurosurg Psychiatry. 1963;26:402-9.

  28. Cowey A. Atrophy of retinal ganglion cells after removal of striate cortex in a rhesus monkey. Perception. 1974;3:257–60.

    Article  CAS  PubMed  Google Scholar 

  29. Weller RE, Kaas JH, Wetzel AB. Evidence for the loss of X-cells of the retina after long-term ablation of visual cortex in monkeys. Brain Res. 1979;160:134–8.

    Article  CAS  PubMed  Google Scholar 

  30. Weller RE, Kaas JH, Ward J. Preservation of retinal ganglion cells and normal patterns of retinogeniculate projections in prosimian primates with long-term ablations of striate cortex. Invest Ophthalmol Vis Sci. 1981;20(2):139–48.

    CAS  PubMed  Google Scholar 

  31. Cowey A, Stoerig P, Perry VH. Transneuronal retrograde degeneration of retinal ganglion cells after damage to striate cortex in macaque monkeys: selective loss of P beta cells. Neuroscience. 1989;29(1):65–80.

    Article  CAS  PubMed  Google Scholar 

  32. Ajina S, Pestilli F, Rokem A, Kennard C, Bridge H. Human blindsight is mediated by an intact geniculo-extrastriate pathway. Elife. 2015;20:4.

    Google Scholar 

  33. Herbin M, Boire D, Théoret H, Ptito M. Transneuronal degeneration of retinal ganglion cells in early hemispherectomized monkeys. Neuroreport. 1999;10(7):1447–52.

    Article  CAS  PubMed  Google Scholar 

  34. Cowey A, Stoerig P, Williams C. Variance in transneuronal retrograde ganglion cell degeneration in monkeys after removal of striate cortex: effects of size of the cortical lesion. Vis Res. 1999;39(21):3642–52.

    Article  CAS  PubMed  Google Scholar 

  35. Kupersmith MJ, Vargas M, Hoyt WF, Berenstein AB. Optic atrophy with cerebral arteriovenous malformations: direct and transsynaptic degeneration. Neurology. 1994;44:80–3.

    Article  CAS  PubMed  Google Scholar 

  36. Johnson H, Cowey A. Transneuronal retrograde degeneration of retinal ganglion cells following restricted lesions of striate cortex in the monkey. Exp Brain Res. 2000;132(2):269–75.

    Article  CAS  PubMed  Google Scholar 

  37. Scarlett HU, Ingham SD. Visual defects caused by occipital lobe lesions: report of 13 cases. Arch Neurol Psychiatr. 1922;8:225.

    Article  Google Scholar 

  38. Austin GM, Lewey FH, Grant FC. Studies on the occipital lobe. 1. Significance of small areas of preserved central vision. Arch Neurol Psychiatr. 1949;62(2):204–21.

    Article  Google Scholar 

  39. Wilbrand H, Saenger A. Die Erkrankungen des Opticusstammes, in Die Neurologie des Auges, Wiesbaden, J. F. Bergman. 1913;5.

  40. Euzière J, Viallefont H, Vidal J. Double atrophie optique et hèmianopsie gauche consecutives à une blessure occipitale droite. Arch. Soc. d. sc. méd. et biol. de Montpellier. 1933;4:212.

  41. Fledelius M. A propos de l’hémianopsie d’origine traumatique. Arch. d’opht. 1934;51:561.

  42. Haddock JN, Berlin L. Transsynaptic degeneration in the visual system; report of a case. Arch Neurol Psychiatr. 1950;64(1):66–73.

    Article  CAS  Google Scholar 

  43. Fletcher WA, Hoyt WF, Narahara MH. Congenital quadrantanopia with occipital lobe ganglioglioma. Neurology. 1988;38(12):1892–4.

    Article  CAS  PubMed  Google Scholar 

  44. Hoyt WF, Rios-Montenegro EN, Behrens MM, Eckelhoff RJ. Homonymous hemioptic hypoplasia. Fundoscopic features in standard and red-free illumination in three patients with congenital hemiplegia. Br J Ophthalmol. 1972;56(7):537–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Jacobson L, Hellström A, Flodmark O. Large cups in normal-sized optic discs: a variant of optic nerve hypoplasia in children with periventricular leukomalacia. Arch Ophthalmol. 1997;115(10):1263–9.

    Article  CAS  PubMed  Google Scholar 

  46. Beatty RM, Sadun AA, Smith L, Vonsattel JP, Richardson Jr EP. Direct demonstration of transsynaptic degeneration in the human visual system: a comparison of retrograde and anterograde changes. J Neurol Neurosurg Psychiatry. 1982;45(2):143–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Uggetti C, Egitto MG, Fazzi E, et al. Transsynaptic degeneration of lateral geniculate bodies in blind children: in vivo MR demonstration. AJNR Am J Neuroradiol. 1997;18(2):233–8.

    CAS  PubMed  Google Scholar 

  48. Guedes ME, Almeida AC, Patricio MS, Costa JM. Acquired retrograde transsynaptic degeneration. BMJ Case Rep. 2011.

  49. Bridge H, Jindahra P, Barbur J, Plant GT. Imaging reveals optic tract degeneration in hemianopia. Invest Ophthalmol Vis Sci. 2011;52(1):382–8.

    Article  PubMed  Google Scholar 

  50. • Millington RS, Yasuda CL, Jindahra P, et al. Quantifying the pattern of optic tract degeneration in human hemianopia. J Neurol Neurosurg Psychiatry. 2014;85(4):379–86. Millington et al. demonstrated trans-synaptic retrograde degeneration of the optic tract using diffusion-weighted imaging and T1 MRI in 22 patients following cortical injury, 13 with adult-onset hemianopsia and nine with congenital hemianopsia.

    Article  PubMed  Google Scholar 

  51. • Patel KR, Ramsey LE, Metcalf NV, Shulman GL, Corbetta M. Early diffusion evidence of retrograde transsynaptic degeneration in the human visual system. Neurology. 2016;87(2):198–205. Patel et al. used diffuse tensor imaging (DTI) MRI to demonstrate a greater asymmetry of fractional isometry in the optic tracts of 12 patients who were status post-injury to cortical visual pathways as compared to 12 patients with non-visual strokes and 28 healthy controls.

    Article  PubMed  Google Scholar 

  52. Stoerig P, Zrenner E. A pattern-ERG study of transneuronal retrograde degeneration in the human retina after a postgeniculate lesion. In: Kulikowski JJ, Dickinson CM, Murray JJ, editors. Seeing contour and colour. Oxford: Pergamon; 1989. p. 553–6.

    Google Scholar 

  53. Porrello G, Falsini B. Retinal ganglion cell dysfunction in humans following post-geniculate lesions: specific spatio-temporal losses revealed by pattern ERG. Vis Res. 1999;39(9):1739–45.

    Article  CAS  PubMed  Google Scholar 

  54. Azzopardi, King SM, Cowey A. Pattern electroretinograms after cerebral hemispherectomy. Brain. 2001;124(Pt 6):1228–40.

    Article  CAS  PubMed  Google Scholar 

  55. Mehta JS, Plant GT. Optical coherence tomography (OCT) findings in congenital/longstanding homonymous hemianopia. Am J Ophthalmol. 2005;140:727–9.

    Article  PubMed  Google Scholar 

  56. • Jindahra P, Petrie A, Plant G. Retrograde trans-synaptic retinal ganglion cell loss identified by optical coherence tomography. Brain. 2009;132:628–34. Here, Jindahra et al. demonstrated, for the first time, retrograde trans-synaptic degeneration in the human retina using optical coherence tomography following acquired lesions. Corresponding thinning of the retinal nerve fiber layer was observed in both patients with congenital lesions and in those with acquired lesions as compared to controls.

    Article  PubMed  Google Scholar 

  57. Miller NR, Newman SA. Transsynaptic degeneration. Arch Ophthalmol. 1981;99:1654.

    Article  CAS  PubMed  Google Scholar 

  58. Jindahra P, Petrie A, Plant GT. Thinning of the retinal nerve fibre layer in homonymous quadrantanopia: further evidence for retrograde trans-synaptic degeneration in the human visual system. Neuro-Ophthalmology. 2012;36:79–84.

    Article  Google Scholar 

  59. •• Jindahra P, Petrie A, Plant GT. The time course of retrograde trans-synaptic degeneration following occipital lobe damage in humans. Brain. 2012;135:534–41. Jindahra et al. used cross-sectional data and longitudinal studies of individual patients to study the speed of RTSD in the retina. They also found that those patients with less RTSD in the first few years experienced greater recovery of visual field.

    Article  PubMed  Google Scholar 

  60. Goto K, Miki A, Yamashita T, et al. Sectoral analysis of the retinal nerve fiber layer thinning and its association with visual field loss in homonymous hemianopia caused by post-geniculate lesions using spectral-domain optical coherence tomography. Graefes Arch Clin Exp Ophthalmol. 2016;254(4):745–56.

    Article  PubMed  Google Scholar 

  61. Ueda K, Kanamori A, Akashi A, Matsumoto Y, Yamada Y, Nakamura M. Evaluation of the distribution pattern of the circumpapillary retinal nerve fibre layer from the nasal hemiretina. Br J Ophthalmol. 2015;99:1419–23.

  62. • Park HY, Park YG, Cho AH, Park CK. Transneuronal retrograde degeneration of the retinal ganglion cells in patients with cerebral infarction. Ophthalmology. 2013;120(6):1292–9. Park et al. showed RTSD in the retina of patients following infarcts of the ACA (n = 8), MCA (n = 21), and, most notably, of the PCA (n = 17). A logarithmic relationship between the degree of RNFL thinning and time since injury was demonstrated.

    Article  PubMed  Google Scholar 

  63. Garway-Heath DF, Poinoosawmy D, Fitzke FW, Hitchings RA. Mapping the visual field to the optic disc in normal tension glaucoma eyes. Ophthalmology. 2000;107(10):1809–15.

    Article  CAS  PubMed  Google Scholar 

  64. Yamashita T, Miki A, Iguchi Y, Kimura K, Maeda F, Kiryu J. Reduced retinal ganglion cell complex thickness in patients with posterior cerebral artery infarction detected using spectral-domain optical coherence tomography. Jpn J Ophthalmol. 2012;56(5):502–10.

    Article  PubMed  Google Scholar 

  65. Keller J, Sánchez-Dalmau BF, Villoslada P. Lesions in the posterior visual pathway promote trans-synaptic degeneration of retinal ganglion cells. PLoS One. 2014;9(5):e97444.

    Article  PubMed  PubMed Central  Google Scholar 

  66. • Mitchell JR, Oliveira C, Tsiouris AJ, Dinkin MJ. Corresponding ganglion cell atrophy in patients with postgeniculate homonymous visual field loss. J Neuroophthalmol. 2015;35(4):353–9. Mitchell et al. devised a normalized asymmetry score to quantify RTSD in the GCL using OCT in 15 patients with adult-onset cortical injury, noting its onset by 1 year post-injury. They found that the time course of GCL atrophy extended as far out as 10 years. Of note is that RTSD was not observed in two patients with quadrantanopia from lesions that were over a decade old, demonstrating that RTSD of the GCL does not occur in every case.

    Article  PubMed  Google Scholar 

  67. Herro AM, Lam BL. Retrograde degeneration of retinal ganglion cells in homonymous hemianopsia. Clin Ophthalmol. 2015;9:1057–64.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Shin HY, Park HY, Choi JA, Park CK. Macular ganglion cell-inner plexiform layer thinning in patients with visual field defect that respects the vertical meridian. Graefes Arch Clin Exp Ophthalmol. 2014;252(9):1501–7.

    Article  PubMed  Google Scholar 

  69. •• Gabilondo I, Martínez-Lapiscina EH, Martínez-Heras E, et al. Trans-synaptic axonal degeneration in the visual pathway in multiple sclerosis. Ann Neurol. 2014;75(1):98–107. Gabilondo et al. showed that loss of visual cortex volume on MRI and a decrease in NAA signal on MR spectroscopy correlated with RNFL thinning, even when accounting for the occurrence of optic neuritis (ON), suggesting that this relationship was due to RTSD. Anterior trans-synaptic degeneration was also demonstrated as patients with optic neuritis had lower volume of their visual cortex, but not of the precentral gyrus.

    Article  CAS  PubMed  Google Scholar 

  70. Petracca M, Cordano C, Cellerino M, Button J, Krieger S, Vancea R, Ghassemi R, Farrell C, Miller A, Calabresi PA, Lublin F, Inglese M. Retinal degeneration in primary-progressive multiple sclerosis: a role for cortical lesions? Mult Scler. 2016. 2017;23(1):43-50

  71. Lee JY, Kim JM, Ahn J, Kim HJ, Jeon BS, Kim TW. Retinal nerve fiber layer thickness and visual hallucinations in Parkinson’s disease. Mov Disord. 2014;29(1):61–7.

    Article  PubMed  Google Scholar 

  72. Lee JY, Yoon EJ, Lee WW, Kim YK, Lee JY, Jeon B. Lateral geniculate atrophy in Parkinson’s with visual hallucination: a trans-synaptic degeneration? Mov Disord. 2016;31(4):547–54.

    Article  PubMed  Google Scholar 

  73. Bodis-Wollner I, Kozlowski PB, Glazman S, Miri S. α-synuclein in the inner retina in Parkinson disease. Ann Neurol. 2014;75:964–6.

    Article  CAS  PubMed  Google Scholar 

  74. Yamashita T, Miki A, Goto K, Araki S, Takizawa G, Leki Y, Kiryu J, Tabuchi A, Iguchi Y, Kimura K, Yagita Y. Retinal ganglion cell atrophy in homonymous hemianopia due to acquired occipital lesions observed using cirrus high-definition-OCT. J Ophthalmol. 2016.

  75. Meier PG, Maeder P, Kardon RH, Borruat FX. Homonymous ganglion cell layer thinning after isolated occipital lesion: macular OCT demonstrates transsynaptic retrograde retinal degeneration. J Neuroophthalmol. 2015;35(2):112–6.

    PubMed  Google Scholar 

  76. Vien L, DalPorto C, Yang D. Retrograde degeneration of retinal ganglion cells secondary to head trauma. Optom Vis Sci. 2017;94(1):125–34.

  77. Al-Zubidi N, Ansari W, Fung SH, Lee AG. Diffusion tensor imaging in traumatic optic tract syndrome. J Neuroophthalmol. 2014;34(1):95–8.

    Article  PubMed  Google Scholar 

  78. Schwartz SG, Pasol J, Lam BL, Flynn Jr HW. Spectral-domain optical coherence tomography documentation of transsynaptic retinal degeneration. Ophthalmic Surg Lasers Imaging Retina. 2016;47(8):768–72.

    Article  PubMed  Google Scholar 

  79. Yücel YH, Gupta N, Zhang Q, Mizisin AP, Kalichman MW, Weinreb RN. Memantine protects neurons from shrinkage in the lateral geniculate nucleus in experimental glaucoma. Arch Ophthalmol. 2006;124(2):217–25.

    Article  PubMed  Google Scholar 

  80. Ito Y, Nakamura S, Tanaka H, et al. Lomerizine, a Ca2+ channel blocker, protects against neuronal degeneration within the visual center of the brain after retinal damage in mice. CNS Neurosci Ther. 2010;16(2):103–14.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Ophthalmology, Weill Cornell Medical College, New York Presbyterian Hospital, 1305 York Avenue, New York, NY, 10065, USA

    Marc Dinkin

  2. Department of Neurology, Weill Cornell Medical College, New York Presbyterian Hospital, 25 East 68th Street, PO Box 117, New York, NY, 10065, USA

    Marc Dinkin

Authors
  1. Marc Dinkin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marc Dinkin.

Ethics declarations

Conflict of Interest

Marc Dinkin declares that he has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Neuro-Ophthalmology

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dinkin, M. Trans-synaptic Retrograde Degeneration in the Human Visual System: Slow, Silent, and Real. Curr Neurol Neurosci Rep 17, 16 (2017). https://doi.org/10.1007/s11910-017-0725-2

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11910-017-0725-2

Keywords

Search

Navigation