Pediatric visual electrophysiology – objective measurement of visual function

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Introduction

Visual electrophysiology has an important role in modern pediatric ophthalmology. It offers unique functional measures of each part of the visual pathway, from the retina to the striate cortex. For children objective tests are critical for early clinical diagnosis, prognosis, and monitoring of neurologic and ocular sequelae. Visual electrophysiology findings also inform natural history studies and genotype–phenotype correlations. In this genomic era, electrophysiological measurements of function are likely to prove increasingly important in identifying therapeutic windows for patients to benefit from novel therapies. Further, by monitoring the functional consequences of treatment, electrophysiology can offer objective outcome measures of safety and efficacy in clinical trials.

New and exciting treatments for childhood blindness depend upon international collaboration. In visual electrophysiology this translates to meaningful international guidelines and minimum standards for performing visual electrophysiology investigations. Consensus standards are published by the International Society for Clinical Electrophysiology of Vision [ISCEV] at http://www.iscev.org and recommendations by the International Federation of Clinical Neurophysiology (IFCN) at http://www.ifcn.info . These standard protocols aim to ensure that the same patient will receive the same results irrespective of testing center. ISCEV also recognizes the need for shorter visual electrophysiology tests that are more accessible and understandable, and the need to improve patient safety by sharing pooled reference data to support service development by new units.

Standard tests and guidelines in visual electrophysiology

ISCEV standard and extended protocols are possible in children who are able to comply with instructions for 60 minutes or more, but these tests need to be shortened and adapted to provide comparable results in less compliant, alert toddlers and infants, without restraint, sedation, or anesthesia. Diagnostic tests can be stressful. The aim of pediatric practice is to optimize test results and increase the chances of reliable monitoring by making every episode as close to a child’s home circumstances and as much fun as possible. As children relax it alleviates the anxiety of carers and in turn staff, and we obtain higher quality data. This means, of course, that we and the test protocols have to be nimble and agile. We prioritize tests to answer the clinical question, but adapt test order in response to real time data and children’s compliance. This allows us to meet the needs of each child in ways they enjoy, and in a time-efficient manner!

The tests – the electrophysiological toolkit

There are five standard ISCEV tests. Figure 7.1 links the parts of the visual pathway assessed by each test, the test time typically taken in compliant adult practice, and the nomenclature of the recorded responses. Together the electro-oculogram (EOG), electroretinogram (ERG), multifocal ERG (mfERG), pattern ERG (PERG), and the visual evoked potential (VEP) check the visual hardware from retina to striate cortex. A limitation is that these tests do not test the “software,” the higher associated visual areas after the striate cortex, which are used to interpret and make sense of visual information. Although the VEP may show the pathway to the striate cortex functions well, dysfunction of visual association areas can contribute to cerebral visual impairment such as can occur in lissencephaly. The time and fixation compliance needed for EOG, mfERG, and PERG means that they are better suited to children over 5 years of age, who have no other neurological or developmental problems. An EOG requires accurate saccades every minute for 15 minutes in the dark then 15 minutes in the light. The mfERG and PERG require steady fixation; in addition the PERG needs good optical focus. A full-field ERG (ffERG) demands 20 minutes of dark adaptation (DA) and 10 minutes of light adaptation (LA) with a dilated pupil. mfERGs in particular, also PERGs and ffERGs, optimally require corneal electrodes, though for the ffERG skin electrodes are now accepted as part of the ISCEV standard. A monocular flash and pattern VEP test takes around 10 minutes.

Fig. 7.1, The electrophysiological toolkit. The acronym, typical time taken to perform the test in a compliant adult, the anatomical cellular substrate and the labeling of each test result are tabulated for easy reference. OPs, oscillatory potentials; PR, photoreceptors; RGC, retinal ganglion cells.

Chair time for a child

The authors typically combine tests of generalized retinal function (flash ERG) and pathway (flash VEP) alongside macular pathway function (PVEP) in a single test session. Our experience suggests 30 minutes chair time interleaved with distraction can be tolerated by most children and carers. Switching quickly between the stimulus and a cartoon on the same display during the test maintains attention, whilst a separate audio output provides soundtrack and music continuity when patterns are presented. This time is divided between electrode placement and test time. If electrode placement takes a long time then test time is curtailed. Electrode placement in 5 minutes provides time for pattern VEPs (PVEPs), followed by contemporaneous flash VEPs and flash ERGs in alert infants. The ffERG protocol is modified for toddlers by using skin electrodes, natural pupils and no formal dark adaptation (DA). Skin electrodes and natural pupils each reduce the amplitude of the ERG, but not its shape or timing. Recent studies suggest that halving DA time to 10 minutes in healthy retina affects only the DA 0.01 ERG, reducing its amplitude by 10%. It is also possible to use scotopic blue and red flashes delivered by a hand-held stimulator to preferentially stimulate rod and cone systems. The authors typically use a range of flash strengths, including a dim blue and stronger red flash in the dark, presented after a child has adapted to a patterned stimulus in a darkened room. Then the lights are turned on and photopic flashes presented. This modified test produces data that are physiologically similar to the results from adult protocols and the findings are reported in comparison to robust reference limits acquired under similar conditions.

Which test to request?

It is rare that a single, isolated test is used to investigate young children who present with poor vision. Young children’s fundi often appear normal and the reason for poor visual behavior is not always detected or predicted at presentation, even by the most experienced pediatric ophthalmologist. It is more efficient diagnostically to apply a combination of tests to fully address the clinical question, e.g. simultaneous flash ERG and flash VEP, or simultaneous PERG and PVEP. As an example, the authors’ audit of 300 children presenting with nystagmus, revealed almost equal proportions of children with retinal conditions and chiasmal conditions, such as albinism. Both flash ERG and monocular VEPs were required to make this distinction. Premature children, children with trisomy 21 or neonatal abstinence syndrome with nystagmus most often do not have an obvious sensory cause for nystagmus.

Each test, however, has a specific core purpose and to help understand these at a glance the key points below are in bold type and where possible with original and review references to make this easier to explore further. The toolkit of tests is summarized in Fig. 7.1 . In addition, an example array of ERGs, PERGs, and PVEPs are shown from a healthy child in Fig. 7.2 . Single traces are shown for clarity, but in practice all responses should be repeated at least twice for repeatability and to exclude artifacts, which may mimic physiologic responses, before interpretation. Tables 7.1 and 7.2 list physiological artifacts with tips to reduce these and a guide to interpreting reports. Rows B–I in Fig. 7.2 display electrophysiological findings in a range of retinal conditions that exemplify the common characteristic waveform changes interpreted during diagnosis.

Fig. 7.2, Template of diagnostic electroretinograms. Row A shows an array of ISCEV standard ffERGs recorded from a healthy child for comparison with children with retinal diseases in the rows below. The columns moving from left to right show dark-adapted (DA) and light-adapted (LA) ffERGs next to macular findings such as the PERG from large (30 degree) and small (15 degree) fields, or macular optical coherence tomography (OCT) images. The additional columns demonstrate further diagnostic imaging or extended electrophysiological data, e.g. prolonged ON–OFF ERGs (LA ON/OFF), oscillatory potentials (OPs), pattern-reversal VEPs to 50′ check widths, (PVEP), fundus autofluorescence (FAF) or Optomap ultra wide-field imaging. Characteristic waveforms are shown for DA 0.01: large rod-driven b-wave and no a-wave; DA 3: a- and b-waves from mixed rod and cone system contributions, DA 200: enhances a single trough rod a-wave; LA 3: a-wave and b-wave from cone PR and ON- and OFF-bipolar cell activity, respectively; LA 30 Hz flicker is a cone-sensitivity response from the inner retina; LA prolonged ON/OFF flashes that separate ON and OFF pathways, the PERG P50 driven by macular cones followed by N95 from retinal ganglion cell and optic nerve function.

Table 7.1

Key points and questions to check in a report to help clinical interpretation

1. Corrected age Was the infant premature?	Use corrected age to compare with reference data from 40 weeks (not chronological age if premature). Retinal sensitivity is poor at birth. ISCEV-standard flash stimuli include the possibility of non-detectable ERGs in early infancy. In essence, strong flash stimuli are needed. A newborn PVEP latency is around 240 ms which shortens rapidly to within 10% of adult values in the first 7 months of life. It is better to stimulate at 1/second and increase the acquisition time window to 450 ms to capture baby VEPs. After 8 weeks of age, stimulation of 3/second and shortening the time window to 300 ms speeds up data acquisition.
2. Spectacles Was refractive correction OK for pattern testing?	The PERG is sensitive to 0.50 DS blur, but the pattern reversal VEP is robust to 8.00 DS blur when testing to 60′ check width. The PERG and PVEP can be recorded simultaneously to ensure accurate focus (if the child can tolerate corneal electrodes for the PERG). If there is a doubt about focus, as may occur in patients with suspected functional overlay, then PERGs and/or PVEPs may be recorded after cycloplegia and correction for viewing distance, e.g. +1.00 DS added for 1 m or +3.00 DS for 33 cm.
3. Behavior How did the child tolerate testing?	Children can cause a range of physiological artifacts, some can mimic responses. A summary of these artifacts and tips to manage them is given in Table 7.2 .
4. Pupil size Dilated or anisocoria?	The authors’ pediatric protocol combines PVEP and flash ERG. Best focus for pattern-reversal VEPs is required, i.e. natural pupils. The authors do not dilate for the modified flash ERG protocol for young children, which immediately follows the PVEP recording. Pupillary dilation aims to standardize ffERG amplitudes, but causes only 12%–15% amplitude change. Extremes of pupil size or anisocoria are noted. Correction factors for pupil size effects on retinal illuminance can be applied, but recording ERGs to a wide a range of flash strengths helps overcome this empirically.
5. Dark adaptation Was the patient dark-adapted? How long for?	Children may not tolerate 20 minutes DA, but it is impractical to have reference data for abbreviated dark adaptation. Separate ranges would be required for each 5-minute dark interval for each month of the first year of life. The authors take the same time point under darkened conditions and use dim blue flashes to bias the photoreceptor contribution to be predominantly rod-driven. The ERG waveform shape provides feedback about the predominant contributing cells as the retina acts like an adaptive photometer. If the ISCEV ffERG appear cone-isolated longer DA times are needed to reveal conditions associated with delayed retinoid cycle, e.g. RDH5 retinopathy, Oguchi disease (see Fig. 7.2I ).
6. Field size What field sizes were used for patterns?	Large field sizes (around 30 degrees) allow a child some variation of gaze direction whilst still fully stimulating a central, macular, 10 degree field. Smaller fields are more prone to spurious transoccipital asymmetries when fixation direction varies to the edge of the field. PERG P50 is larger from 30 degree than 15 degree fields in proportion to stimulus area.
7. Check widths What check widths were recorded?	Responses to a wide range of check widths corroborate findings, provide a broad baseline for monitoring, and allow intraocular comparison. Each averaged response should be recorded twice, at least, for repeatability. The diagonal dimension of a single check gives the cycle per degree equivalent.
8. ERG electrode What type of electrode was used to record the child’s ERG?	Electrode type determines ERG amplitude, but the shape and timing are the same. Disposable corneal electrodes, e.g. DTL, gold foil, HK loop electrodes, are preferred as a range of different-sized contact lens electrodes would be needed for pediatric work and there is concern about re-use and cross-infection in some countries. Inferior periorbital skin electrodes are used frequently in younger children as they are better tolerated. Although, a skin ERG is smaller, 12%–15% of the amplitude of a corneal electrode, it is still substantial and has the same peak times. (For comparison, amplitude of a skin ERG exceeds 10 µV, with corneal electrodes mfERG are measured in nanovolts, PERGs are under 2–5 µV, and adult VEPs ≤5 µV). The cornea needs to be positioned towards a skin ERG electrode, e.g. a child is encouraged to look downwards, or if there is strabismus, or a shallow midface, the skin electrode may be displaced and gaze directed over it. If the child’s eye rolls up, e.g. in sleep, it is possible to record a completely inverted ERG trace.

Table 7.2

Eliminating common physiological artifacts caused by patients in pediatric practice

Problem	Test	Artifact features	Solutions
1. Background EEG	PVEP FVEP	Large amplitude or abnormal background activity (e.g. CVI) Sharp transients, spikes, or other paroxysmal activity (e.g. Batten’s disease)	If it is intermittent, try adjusting amplitude rejection settings to allow trial inclusion only when EEG activity is minimal. It is not always possible to overcome this and record any consistent VEPs, particularly in children with severe EEG abnormalities (due to reduced signal to noise ratio). Compare recorded VEPs to averaged non-stimulus trials.
2. Sleepiness	FVEP PVEP	Slow large background EEG intrusion Alpha rhythm intrusion in older children Child appears drowsy on observation	Sometimes it is possible to overcome this with averaging. Shorter bursts of pattern stimulation with distraction breaks to maintain concentration. Encourage and engage child to maintain alertness – ask them about school, hobbies, etc. Ask children to spell, count or do basic maths questions. In infants, make occasional loud noises or sing an interactive nursery rhyme. Make sure the patient is not too warm, cool the room, give a cold drink, open the window.
3. Defocus	PERG PVEP	PERG affected more than PVEP Observe inter-trial variability in responses with variable focus Pupil changes noted on CCTV observation Intermittent convergence or esotropia observed with changes in accommodation	Asking them to concentrate on the patterns. Talking to maintain alertness (see sleepiness). Observe pupils closely to guide periods of data acquisition. Beware malingerers purposely defocusing. Consider simultaneous PERG and PVEP with cycloplegia and appropriate refractive correction for both refractive error and stimuli distance – particularly if purposely defocusing. Consider monocular testing – harder to defocus without binocular cues.
4. Muscle	PERG PVEP FERG FVEP	Surges in high frequency activity electromyography (EMG) Spurious and asynchronous though may be synchronized to observed patient movement, e.g. chewing	Reassure to alleviate any anxiety. Change child’s posture to try to identify site of muscle and align neck and spine. Encourage shoulders down, head leaning back into chair, alter chair position. If due to raised eyebrows or forehead, consider moving reference further back on the scalp. Make sure child is not clenching teeth or chewing – encourage to open mouth slightly. Praise when muscle is relaxed– so they know what you want through the test. If intermittent bursts of muscle cannot be controlled (i.e. an upset infant) consider altering lower the high frequency filter (if know how this will alter the VEP)
5. Blinks	FERG PERG	Large amplitude deflections, usually several hundred microvolts, seen 50–100 ms after the flash. Confirm by observing blink and artifact timing.	Controlled episodes of “10 seconds of pattern looking” followed by a break to build up response by interrupted averaging. Trigger flash irregularly so the child cannot predict it coming. Blink can affect slower b-waves in particular, e.g. DA 0.01. Encourage “Big look” and distraction “Guess the next color of the light.”
6. Eye uproll to flash	FERG FVEP	Reduced FERG and FVEP amplitudes Can fully invert FERG (skin electrodes) Photo-aversive response	Distract child by attracting interest in downgaze for FERG using small noisy toys. Put your face lower than the infant (i.e. kneel or crouch) and talk/sing as infants like to look at faces, and severely visually impaired children will look towards the noise. Follow the child’s eyes with the photic stimulator for FVEP (red and blue flashes may be better tolerated).

Common physiological artifacts encountered in pediatric practice as well as some possible solutions to help rectify these problems and improve data quality. The test(s) are listed as pattern (P) and flash (F) visual evoked potentials (VEP) and electroretinograms (ERG).

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