Making diagnostic use of electrical events in the retina
Scandinavian researchers have contributed considerably to the analysis and clinical introduction of electro-retinography referred to in all standard reference books [1, 2].
Here, (in the frame of this short article) the generation of the electrical activity of the vertebrate retina can only be briefly summarized. The activation of photoreceptors by light elicits phototransduction and major amplification enabling the propagation of the signals to following neurons. Second-order neurons, the ON- and OFF- bipolar cells as well as laterally interacting horizontal cells modulate visual information to be transmitted to third order neurons, the ganglion cells and the signal-modulating amacrine cells. The axons of the ganglion cells form the optic nerve to carry spike-coded visual information to the lateral geniculate and to the visual cortex. Retinal mechanisms such as amplification, feedback, and network adaptation in the inner retina as well as anatomical convergence and divergence of neurons enable complex modulation of visual information within the retina.
Depolarization or hyperpolarization of single neurons generate major changes in the ionic composition of the extracellular fluid. The concert of changes within and along the multitude of retinal neurons as well as along the Müller cells gives rise to a number of electroretinographic potentials. The electrical current flow is transiently “disturbed” by light flashes, generating the field potential electroretinogeam, theERG, with its fast and slow components. The field- or mass- potential becomes carried via the passive volume conductors vitreous, lens, anterior chamber to the cornea and even, although in attenuated form, to the eyelids. Although small in size - from 1 to about 700 µV - these field potentials, recordable from the cornea, are reproducible in amplitude and timing. They reflect the reaction to graded flash-intensities, the adaptational state of the retina, selective rod- and cone- contributions and On- and Off- mechanisms [1-4].
Standardized ERG recording
It is the diagnostic value of the ERG that makes it worthwhile to record and analyze this intrinsically complex field potential in a standardized manner. Conditions necessary for reproducible adaptation and recording, normative rod-driven, cone-driven and mixed ERG signals are recommended by the International Society for Clinical Electrophysiology of Vision (I.S.C.E.V.) [8]
In infants and children under 5 years of age, Sevoflurane-induced anaesthesia provides an opportunity to combine abbreviated ERG testing with ophthalmoscopy, fundus photograph to document the functional state of the retina. Following only several minutes of dark adaptation we use white flashes of low and high intensity as well as a long wavelengths broad band filter. The resulting red flash facilitates to distinguish qualitatively the early cone-driven b-wave from the later rod driven b-wave. This technique allows early diagnosis in infants with visual problems and, potentially detection of multiple handicaps. Among 188 patients with ERGs recorded in brief general anaesthesia, 50% revealed normal ERGs, 32% subnormal data and in 18% the ERG was non-recordable. [9, 10]
Useful indications for ERG testing, or: why allocate resources for electroretinography?
Conceptually, a decrease in the amplitude of the b-wave can be caused by congenital, degenerative, inflammatory, circulatory or toxic conditions of the retina [1,2,4]. Electrophysiology can document widespread retinal dysfunction or exclude a retinal cause for impaired visual function. The latter proved important in infants, i.e. using ERG testing in brief general anaesthesia [9, 10]. Consequently a wide spectrum of diagnostic entities builds up a list of indications to use the ERG as a diagnostic tool (Table I). A list can only be a guideline, whereas the clinician interested in documenting retinal function for special studies should enlarge this list.
Table I: Meaningful indications for ERG recording
-Tapetoretinal degenerations, including all the variable phenotypes of retinitis pigmentosa (RP), such as sine pigmento stage, sectorial, paravenous or unilateral manifestation
·syndromic RP: Usher, Kearns, Friedreich, Laurence-Moon-Bardet-Biedl, Refsums disease, neurological degenerative and paediatric metabolic entities with retinal involvement
- potential carriers of X-linked RP
· Leber's congenital amaurosis (LCA)
· choroideremia and potential female carriers
· vitreoretinal degenerations, Wagner's and Goldmann Favre
· X-linked juvenile retinoschisis
· progressive cone dystrophies
· juvenile macula degenerations, flecked retina syndromes
· non-progressive inherited conditions
- achromatopsia (rod monochromatism; blue cone monochomatism)
- congenital stationary night blindness
· retinopathy of prematurity
· uveitis with retinal involvement and opacities of the media
· cancer-associated retinopathies
· toxic, or drug-induced changes
· metallic intraocular foreign bodies
· suspected retinal dysfunction in presence of opacities of the optical media
· deficits in retinal function in presence of inconspicuous fundus
· unclear visual field defects
· non-organic visual disturbance (dissociative visual disorder)
Physicians confronted with a “medical retina patient” ofte have to decide if they are dealing primarily with night blindness or with day blindness, and then determine whether the retinal dysfunction is stationary or progressive, as illustrated in Fig.4.Impaired retinal function in the presence of inconspicuous or discreet pathological fundus features can be uncovered by ERG testing [7]. Respective examples of typical patterns of ERG abnormalities are illustrated in Fig 5 . The traces are responses to single flashes, revealing both variability and reproducibility. The noise level in these single traces is informative to the electrophysiolgist but can be reduced by averaging.
In conclusion, the non-invasive ERG recording complements the standard psychophysical tests and retinal imaging in the entire diagnostic spectrum of “medical retina”. The ERG should be interpreted in the context of the psychophysical tests in opthalmology. Selected diagnoses are hard to establish without ERG, including LCA, achromatopsia, CSNB, early RP in infancy, and impaired visual function in presence of inconspicuous fundi. The I.S.C.E.V. standard protocol allows to compare a patient’s rod- and cone-driven ERG to normative data across laboratories and countries. Special techniques such as pattern ERG, multifocal ERG, retinal imaging and autofluorescence, traditional and multifocal visual evoked cortical potentials extend the spectrum of electrophysiologic diagnostic means to assess inner retinal and cortical visual function. The spectrum of flash- or pattern-evoked signals from retina and pigment epithelium serves fine-tuned clinical differential diagnosis.
Acknowledgement: in part supported by the Paul Schiller Stiftung, Zürich. I thank Prof.Urs Gerber,M.D., Zürich for his comments on the manuscript
Günter Niemeyer, M.D., is Prof. emeritus from the Deptm. of Ophthalmology,University Hospital, CH 8091Zürich/Switzerland. Current address: Wissmannstr.16, CH 8057 Zürich/Switzerland
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LITERATURE
1 Principles and Practice of Clinical Electrophysiology of Vision, edited by J. R. Heckenlively and G. B. Arden, St. Louis: Mosby Year Book, 1991, p. 151-162
2 Electrophysiologic testing in disorders of the retina, optic nerve, and visual pathway. Fishman GA, Birch DG, Holder GE, Brigell MG: Amer.Acad. of Ophthalmololy (San Francisco) 2001.
3 Gouras P:Electroretinography: some basic principles. Invest Ophthamol 1970;9:577-569.
4 Niemeyer G. Das Elektroretinogramm: Nützlich und nicht kompliziert. Ophta Schweizer. Fachzeitschrift augenärztliche Medizin 2004(5):7-13, 2004.
5 Niemeyer G. Retina Research using the perfused Eye. Prog Retinal and Eye Research 2001;Vol 20, No 3:289-318
7 Niemeyer G, Schaefer A: Differentialdiagnosen. Normal fundus and abnormal electroretinogram: differential diagnosis. Klin Monatsbl Augenheilkd 2002; 219(4):259-263
8 Marmor MF, Holder GE., SeeligerMW, Yamamoto S:Standard for clinical Electroretinography (2004 update) Documenta Ophthalmol 2004;108: 107-114.
9 Niemeyer G, Grbovic B, Gloor B: Elektroretinographie-Diagnostik beim Kleinkind. Klin Mbl Augenheilkd 1993; 202: 417-421.
10 Fleischhauer JC, Landau K, Grbovic B, Niemeyer G: ERG Recordings in brief general anesthesia in infants: Abstract Proceedings of the annual meeting of the Association for Vision and Ophthalmology 2003; No 1898 p78
Fig. 1: Light-evoked electrical events in the mammalian retina and sites of their generation. The cartoon of the retina illustrates the retinal pigment epithelium (RPE) as the source of the ocular standing potential, which increases during light exposure after dark adaptation (electrooculogram, EOG). The c-wave reflects K+ -related changes in the subretinal space following a light stimulus. The a-wave of the ERG is a negative field potential generated by light-evoked hyper-polarization of the rod (R) and cone (C) photoreceptors. The b-wave is generated by ON and OFF bipolar cell (B) activity, probably containing contributions from the glial Müller cells (M). Interactions among amacrine cells (A) in the inner retina are understood to generate the oscillatory potentials (OPs) of the ERG at higher intensities of light. The activity of the ganglion cells (G) can be assessed to a certain extent applying special adaptation and recording techniques: pattern ERG (PERG), photopic negative response (PhNR) and scotopic threshold response (STR). H, horizontal cell; I, interplexiforme cell. Modified from Fig.11 in [5].
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Fig 2A above, 2B below: Cartoons of typical electroretinograms. 2A:Example of a light adapted ERG waveform revealing the major components as described in the legend of Fig.1. -2B: sketch of changes in ERG confidguration due to congenitalor acquired retinal diseases. The trace “Normal” corresponds to a dark adapted ERG in response to an intense flash eliciting a mixed rod/cone signal. The term “normal” is meant to comprise the variations within healthy people in a given age group plus/minus 2 standard deviations. (from[4] by permission of Ophta/Switzerland)
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Fig.3 ISCEV standard [8] ERGs from a healthy 30year-old person, recorded using an LKC UTAS 3000 Ganzfeld system. -24 bd indicates the respective flash attenuation to record a rod-driven, and white 0 db to record a mixed rod/cone “maximal” response.The two lower traces are typical cone-driven ERGs elicited by single flashes or by a 30 Hz flicker stimulus, respectively. (from [4] by permission of Ophtha/Switzerland)
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Fig.4 Short differential diagnosis of the primary symptoms night-blind vs. day-blind. (from [4] by permission of Ophta/Switzerland)
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Fig.5 Normal (left) and typical ERG configurations of diagnostic entities, which present with inconspicuous fundus features. Single Ganzfeld flash responses adhering to the ISCEV standard, revealing both variaability and reproducibility of the responses. Note the “negative” ERG configuration following bright flash stimulation in X-linked juvenile retionoschisis and also the absence of measurable cone ERGs in achromatopsia. (modified from [7]).
I met prof. Niemeyer at FORUM BALTIKUM in August 2004 after having listened to his excellent account of ERG; I almost understood it. Prof. N was kind enough to provide TBE with the text, so we could reprint the lecture.
R. Martinoni in a note in Retina Suisse 2002 quotes a significant Niemeyer statement:
«von meinen Patienten habe ich gelernt...» Als ich Günter Niemeyer das 1. Mal diese Worte sagen hörte – es ist lange her, es war an einer GV in den frühen 80er Jahren – dachte ich nicht recht verstanden zu haben... (der Patient als unmündiges Wesen und der Professor als Herrgott in weiss waren ja noch stark in den Köpfen und im Erleben präsent)
"J'ai appris de mes patients...» Lorsque j'ai entendu, la première fois, Günter Niemeyer prononcer ces mots, c'était il y a bien longtemps, au cours d'une AG au début des années 80, j'ai cru avoir mal compris... (l'image du patient, être immature, et du professeur, seigneur tout puissant en blouse blanche, était encore fortement ancrée dans les esprits et dans le vécu).
To learn from ones patients is indeed a very wise thing to do We probably do it much too little oh