Elsevier

Survey of Ophthalmology

Volume 53, Issue 1, January–February 2008, Pages 16-40
Survey of Ophthalmology

Major Review
The Negative ERG: Clinical Phenotypes and Disease Mechanisms of Inner Retinal Dysfunction

https://doi.org/10.1016/j.survophthal.2007.10.010Get rights and content

Abstract

Inner retinal dysfunction is encountered in a number of retinal disorders, either inherited or acquired, as a primary or predominant defect. Fundus examination is rarely diagnostic in these disorders, although some show characteristic features, and careful electrophysiological assessment of retinal function is needed for accurate diagnosis. The ERG in inner retinal dysfunction typically shows a negative waveform with a preserved a-wave and a selectively reduced b-wave. Advances in retinal physiology and molecular genetics have led to a greater understanding of the pathogenesis of these disorders. This review summarizes current knowledge on normal retinal physiology, the investigative techniques used and the range of clinical disorders in which there is predominantly inner retinal dysfunction.

Introduction

There is a wide spectrum of retinal disorders where the primary or predominant site of dysfunction is in the inner retina. These can be either inherited or acquired, and although some are associated with characteristic fundus abnormalities, the diagnosis in the majority of these disorders is dependent upon careful electrophysiological assessment of retinal function. Full-field electroretinography (ERG) will usually show a negative (electronegative) waveform to a high intensity flash under scotopic conditions such that the inner nuclear layer derived b-wave, a positive component, is selectively reduced and the waveform is dominated by the negative a-wave. Karpe originally defined an electronegative or “negative” ERG as a waveform evoked by a bright flash with a larger a-wave than b-wave resulting in a b/a ratio below 1.0.126 In a large referral center, such as that of the authors, a negative ERG has been shown to occur in approximately 3–5% of cases referred for assessment.141, 210 In recent years advances in the fields of retinal physiology and molecular genetics have revealed data that allow a greater understanding of the pathogenesis of these disorders. This review addresses the range of disorders in which there is predominantly inner retinal dysfunction, initially summarizing the techniques used clinically to explore abnormal retinal function.

Section snippets

Photoreceptors and Phototransduction

Retinal processing involves complex mechanisms of spatio-temporal and chromatic contrast coding from the rod and cone photoreceptor outer segments to the retinal ganglion cells. The rod system is involved in scotopic or dim light vision and has low temporal resolution, characteristics that may be exploited in attempts to selectively stimulate rod and cone systems (see subsequent description). Light perception in vertebrates is mediated by a group of G protein–coupled receptors called opsins,

Probing Inner Retinal Function in Humans

Inner retinal function can be assessed through different electrophysiological and psychophysical techniques. Psychophysical tests such as dark adaptometry, color vision, or contrast sensitivity may be abnormal in inner retinal function, but do not allow the localization of dysfunction and distinction between photoreceptor and post-receptoral dysfunction. Electrophysiological techniques allow the major sites of dysfunction in the retina to be identified. The main electrophysiological procedures

Clinical Conditions

The clinician may encounter many different disorders selectively or predominantly affecting inner retinal function. The following discussion is organized according to whether the disorders are inherited, stationary or progressive, or acquired.

Conclusion

Many disorders can give rise to primary or predominant dysfunction that is post-phototransduction or inner retinal. Fundus examination is often normal in inherited inner retinal dysfunction and objective data obtained from electrophysiology is of particular importance in diagnosis. Identification of the causative genetic mutations has led to new insights into the generation of the inner retinal ERG responses. In acquired disease, the objective documentation of post-receptoral function may have

Method of Literature Search

The authors performed a Medline search with Pubmed for articles published from 1966 until September 2007. The search was restricted to publication in English language and other languages when an English abstract was available. Search terms included inner retina, inner retinal dysfunction, negative ERG, and inherited retinal disorders with inner retinal dysfunction.

References (303)

  • C.A. Curat et al.

    Mapping of epitopes in discoidin domain receptor 1 critical for collagen binding

    J Biol Chem

    (2001)
  • H. Daneshvar et al.

    Symptomatic and asymptomatic visual loss in patients taking vigabatrin

    Ophthalmology

    (1999)
  • N.W. Daw et al.

    Rod pathways in mammalian retinae

    Trends Neurosci

    (1990)
  • T.P. Dryja

    Molecular genetics of Oguchi disease, fundus albipunctatus, and other forms of stationary night blindness: LVII Edward Jackson Memorial Lecture

    Am J Ophthalmol

    (2000)
  • R.N. Fariss et al.

    Abnormalities in rod photoreceptors, amacrine cells, and horizontal cells in human retinas with retinitis pigmentosa

    Am J Ophthalmol

    (2000)
  • G.A. Fishman et al.

    Acquired unilateral night blindness associated with a negative electroretinogram waveform

    Ophthalmology

    (1996)
  • K.M. Fitzgerald et al.

    Autosomal dominant inheritance of a negative electroretinogram phenotype in three generations

    Am J Ophthalmol

    (2001)
  • R.W. Flower et al.

    Electroretinographic changes and choroidal defects in a case of central retinal artery occlusion

    Am J Ophthalmol

    (1977)
  • J.D. Gass et al.

    Diffuse unilateral subacute neuroretinitis

    Ophthalmology

    (1978)
  • J.W. Gittinger et al.

    Cutaneous melanoma-associated paraneoplastic retinopathy: histopathologic observations

    Am J Ophthalmol

    (1999)
  • H.H. Goebel et al.

    The fine structure of the retina in neuronal ceroid-lipofuscinosis

    Am J Ophthalmol

    (1974)
  • M.A. Goldberg et al.

    Diffuse unilateral subacute neuroretinitis. Morphometric, serologic, and epidemiologic support for Baylisascaris as a causative agent

    Ophthalmology

    (1993)
  • L. Gurevich et al.

    Comparison of the waveforms of the ON bipolar neuron and the b-wave of the electroretinogram

    Vision Res

    (1993)
  • Functional implications of the spectrum of mutations found in 234 cases with X-linked juvenile retinoschisis. The Retinoschisis Consortium

    Hum Mol Genet

    (1998)
  • Isolation of a novel gene underlying Batten disease, CLN3. The International Batten Disease Consortium

    Cell

    (1995)
  • M.J. Abramowicz et al.

    Congenital stationary night blindness: report of an autosomal recessive family and linkage analysis

    Am J Med Genet A

    (2005)
  • G. Adamus et al.

    Autoantibodies against retinal proteins in paraneoplastic and autoimmune retinopathy

    BMC Ophthalmol

    (2004)
  • K.R. Alexander et al.

    On-response deficit in the electroretinogram of the cone system in X-linked retinoschisis

    Invest Ophthalmol Vis Sci

    (2001)
  • K.R. Alexander et al.

    ‘On’ response defect in paraneoplastic night blindness with cutaneous malignant melanoma

    Invest Ophthalmol Vis Sci

    (1992)
  • N. al-Jandal et al.

    A novel mutation within the rhodopsin gene (Thr-94-Ile) causing autosomal dominant congenital stationary night blindness

    Hum Mutat

    (1999)
  • M.A. Apushkin et al.

    Fundus findings and longitudinal study of visual acuity loss in patients with X-linked retinoschisis

    Retina

    (2005)
  • G.B. Arden et al.

    Monitoring of patients taking canthaxanthin and carotene: an electroretinographic and ophthalmological survey

    Hum Toxicol

    (1989)
  • C.F. Arndt et al.

    Outer retinal dysfunction in patients treated with vigabatrin

    Neurology

    (1999)
  • V.Y. Arshavsky et al.

    G proteins and phototransduction

    Annu Rev Physiol

    (2002)
  • I. Audo et al.

    Progressive retinal dysfunction in diffuse unilateral subacute neuroretinitis

    Br J Ophthalmol

    (2006)
  • G.S. Baarsma et al.

    Association of birdshot retinochoroidopathy and HLA-A29 antigen

    Curr Eye Res

    (1990)
  • G. Bach et al.

    Mucopolysaccharide accumulation in cultured skin fibroblasts derived from patients with mucolipidosis IV

    Am J Hum Genet

    (1977)
  • M. Bach et al.

    Standard for pattern electroretinography. International Society for Clinical Electrophysiology of Vision

    Doc Ophthalmol

    (2000)
  • P. Bacon et al.

    Blindness from quinine toxicity

    Br J Ophthalmol

    (1988)
  • E. Banin et al.

    Retinal function abnormalities in patients treated with vigabatrin

    Arch Ophthalmol

    (2003)
  • R. Bargal et al.

    Identification of the gene causing mucolipidosis type IV

    Nat Genet

    (2000)
  • C.S. Barnes et al.

    ON-pathway dysfunction in a patient with acquired unilateral night blindness

    Retina

    (1998)
  • N.T. Bech-Hansen et al.

    Loss-of-function mutations in a calcium-channel alpha1-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness

    Nat Genet

    (1998)
  • N.T. Bech-Hansen et al.

    Mutations in NYX, encoding the leucine-rich proteoglycan nyctalopin, cause X-linked complete congenital stationary night blindness

    Nat Genet

    (2000)
  • J. Behrman et al.

    Electrodiagnostic findings in quinine amblyopia

    Br J Ophthalmol

    (1968)
  • S.R. Bennett et al.

    Autosomal dominant neovascular inflammatory vitreoretinopathy

    Ophthalmology

    (1990)
  • L. Berggren et al.

    Quinine amblyopia

    Acta Ophthalmol

    (1995)
  • D. Besch et al.

    Visual field constriction and electrophysiological changes associated with vigabatrin

    Doc Ophthalmol

    (2002)
  • K. Bradshaw et al.

    Mutations of the XLRS1 gene cause abnormalities of photoreceptor as well as inner retinal responses of the ERG

    Doc Ophthalmol

    (1999)
  • J.H. Brandstätter

    Glutamate receptors in the retina: the molecular substrate for visual signal processing

    Curr Eye Res

    (2002)
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    The authors want to thank the Foundation Fighting Blindness for their grant support (in particular Isabelle Audo, MD, PhD, FFB carrier development award) as well as the European Commission IP EVI-GenoRet LSHG-CT-512036 and the NHS National Institute for Healthcare Research. The authors reported no proprietary or commercial interest in any product mentioned or concepet discussed in this article.

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