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Clinical electrophysiology of vision plays a unique role in the investigation and management of the patient suspected of visual pathway disease by providing an objective assessment of visual pathway function. Although there have been major advances in structural imaging, both in neuroradiology and in ophthalmic imaging, electrophysiological investigation remains of paramount importance in the diagnosis and monitoring of patients with visual symptoms or of possible visual pathway dysfunction. This short account of my personal experiences also pays homage to a few individuals, as mentors or colleagues, who were instrumental to my journey.
My initial appointment, after being introduced to visual evoked potentials (VEP) by Graham Harding, was to set up evoked potentials in the regional neurosciences unit at the Brook Hospital, also doing auditory and somatosensory EPs. During this setting up period and over the following 20 years, great support was provided by a neurologist, George Harwood. The Head of Neurophysiology, Walter Kennedy, insisted on high technical standards, and it was soon shown that localisation of VEP abnormality in patients with chiasmal compression was strongly affected by stimulus and recording parameters. A number of neurologically related publications followed, including the only publication relating intraventricular metabolite levels to scalp recorded evoked potentials.
By the late 1970’s I had formed an association with John Shilling, my initial mentor in ophthalmology, and had realised that delayed VEPs, although associated with optic nerve disease were not diagnostic and could also occur in maculopathy. Thus, when Geoffrey Arden, another mentor, reported the gold foil electrode, enabling the recording of ERG signals without having to use contact lens electrodes (which affect the optics of the eye), those electrodes were rapidly adopted and a strong interest in both ERG and pattern ERG (PERG) ensued. Being in the enviable position of working with both neurological and ophthalmological patients enabled the observation that of the two main components of the PERG, now known as P50 and N95, P50 was invariably affected in macular dysfunction but could be completely spared, and selective reduction in N95 occur, in optic nerve/retinal ganglion cell dysfunction (after my initial proposal the component nomenclature was adopted by ISCEV, the International Society for Clinical Electrophysiology of Vision).
The role of the PERG in the distinction between optic neuropathy and maculopathy, often difficult clinically, and in the objective assessment of central retinal ganglion cell function, not previously possible, was established (see Fig 1). This led to the first Guidelines for PERG being published by ISCEV. Also developed was a grading system to evaluate the usefulness and clinical impact of electrophysiological investigation. The suggestion that the PERG N95 component arises in the retinal ganglion cells was later confirmed by the definitive experimental work of Laura Frishman’s group.
I was then appointed to Moorfields following Arden’s retirement and thus began a long-term collaboration with Alan Bird. They were exciting times with the importance of molecular biology coming to the fore and a large series of genotype-phenotype correlation studies were published in association with molecular biologists Shomi Bhattacharya and David Hunt, ophthalmologist Tony Moore, and psychophysicist Fred Fitzke, who at that time was developing fundus autofluorescence imaging (FAF), now an established and important part of retinal diagnostics. Andrew Webster later became an important colleague in inherited disease. Gene discovery and/or novel observations were reported in many disorders, which included enhanced S-cone syndrome (NR2E3), cone dystrophy with supernormal rod ERG (KCNV2), X-linked retinoschisis (RS1), recessive congenital stationary night blindness (TRPM1) and many others, always stressing the relationship (or lack of it) between structure and function.
In association with Noemi Lois it was proposed that ERG could classify Stargardt disease (ABCA4 retinopathy) into 3 groups, with Group 1 having normal full field ERGs (abnormal PERG), Group 2 having abnormal full field cone ERGs, and Group 3 having additional rod ERG abnormality. Cross sectional data suggested that group 1 was associated with a better prognosis, and the prognostic value of ERG was confirmed by approximately 10 year longitudinal data from the same cohort showing that every patient with rod ERG involvement at presentation had progressive disease, both clinically and electrophysiologically, whereas only 20% of group 1 patients showed significant progression; such patients can be expected to at least maintain navigational vision. FAF imaging was an important feature of those studies, and as our experience developed it became apparent that many patients with retinitis pigmentosa have a ring of increased FAF surrounding the fovea, the significance of which was uncertain. Using pattern ERG and psychophysics we were able to establish that function within the ring is preserved, function outside the ring is lost, and there is a loss of sensitivity across the ring (see Fig 2). Subsequent developments in OCT showed the area within the ring to correspond to preservation of outer retinal structure.
Accurate ERG interpretation requires an extensive knowledge of the origins of ERG signals and an understanding of the pathophysiology of the disorder under consideration. The demonstration of return to normal retinal function following administration of vitamin A in vitamin A deficiency, and following overnight dark adaptation in RDH5 retinopathy (fundus albipunctatus; rhodopsin levels normalise following extended DA), showed that the a “pseudo-negative ERG”, where the b-wave is of lower amplitude than the a-wave, has origins in dark adapted cones in the absence of rod function by exposing the so-called “photopic hill” phenomenon, actually a property of cones rather than the adaptive state of the retina and showed the importance of using a red stimulus under dark adaptation to give a dark-adapted cone response (see Fig 3).
The value of objective monitoring of function as an indicator of therapeutic effect was further demonstrated in birdshot retinochoroidopathy and diagnostic criteria proposed for AZOOR (acute zonal occult outer retinopathy). The phenomenon of sudden visual loss following removal of silicon oil was reported for the first time. I continued to contribute to the ISCEV Standard documents and had the privilege to Chair a committee on recommendations for visual testing in Clinical Neurophsyiology.
The next major event was the advent of treatment intervention for inherited disease. The first clinical trial in humans, for RPE65 variant Leber Congenital Amaurosis, started by Robin Ali, utilised electrophysiology both as a potential outcome measure, but also as a safety measure, showing retention of whatever function there was prior to treatment, but unfortunately there was no ERG recovery. Collaboration with Robert MacLaren on gene therapy for choroideremia utilised PERG, and in one patient during phase 1 there was loss of PERG in the untreated eye, but improvement in the treated eye. Electrophysiology was also used in the stem cell replacement therapy trial for age-related macular degeneration with Linden da Cruz. Cell replacement therapy may play a large role in the future.
The return to “the back” of the visual system, having gone from cortical VEPs to retina, arose through collaboration with Ursula Schmidt-Erfurt and Christian Windischberger in Vienna, using f-MRI to examine cortical activation in ABCA4-related disease and RP. This is an exciting area and one which I hope will further develop.
After leaving Moorfields for a new challenge in Singapore, I have been privileged to work with Xinyi Su on the development of an artificial vitreous, which may replace silicon oil as a tamponade following retinal detachment surgery. In addition, there are many aspects of visual pathway disease in Asia which are rarely seen in Europe, just waiting for appropriate electrophysiological investigation and characterisation!
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Hong-Leong Professor
National University of Singapore
National University Hospital
No. 1E Kent Ridge Road
National University Health System Tower Block
Department of Ophthalmology, Level 7
Singapore 119228
Tel: (+65) 6772 3975
Fax: (+65) 6777 7161
email: ophgeh[at]nus.edu.sg