Multifocal electroretinography: indications

Multifocal electroretinography is a method that allows for the simultaneous assessment of the local function of multiple retinal regions in the central fundus. Unlike full-field electroretinography, which obtains the total response of the entire retina, the multifocal technique constructs a response map by rings and sectors, showing where exactly in the macula electrical activity is reduced or delayed. This makes the method indispensable for macular diseases, when it is important to understand the topography of the lesion. [1]

The test is based on a rapid succession of contrasting hexagonal stimuli arranged in a honeycomb pattern, covering a field of approximately forty to fifty degrees around the fixation point. Each element flashes in a predetermined pseudo-random sequence, and mathematical analysis of the signals extracts local temporal responses, from which a topographic map is assembled. Clinically, fields of sixty-one or one hundred three elements are typically used, allowing for a balance between recording speed and spatial resolution. [2]

Of primary interest are the amplitude and peak time of the first positive wave, traditionally called P-one, as well as the ring ratios, for example, between the first and second rings. These parameters are sensitive to the functions of the cone system and depolarizing bipolar cells, and therefore reflect well the disturbances in the outer layers of the retina characteristic of macular dystrophies and toxic lesions. [3]

The method is used for both primary diagnostics and for monitoring treatment effectiveness or drug toxicity. It is objective, does not require active patient responses to each burst, and can detect dysfunction before changes are noticeable in psychophysical tests. However, recording and interpretation require standardized protocols and experience; otherwise, the risk of artifacts and errors increases. [4]

How does recording work?

The stimulus is a hexagonal mosaic grid, the elements of which increase in size toward the periphery to equalize the contributions of different eccentricities. During recording, each element changes brightness according to a given M-sequence, and specialized correlation processing isolates the local responses corresponding to each hexagon. This produces a set of short time curves, placed on a map according to the element's position. [5]

To improve the signal-to-noise ratio, the standard recommends an M-sequence length of at least 4,095 steps for typical protocols with 61 or 103 elements. This requirement ensures consistent average responses and acceptable examination times in most patients with good gaze fixation. [6]

The resulting local curves are typically averaged over concentric rings from the center to the periphery. Absolute amplitudes and peak times in the rings, as well as their ratios, are compared. For example, in the case of hydroxychloroquine toxicity, a common early sign is a relative decrease in amplitude in the second ring relative to the first, which increases detection sensitivity to clinically significant levels. [7]

The final report includes original charts, ring charts, and numerical tables, as well as comments on the quality of recording, fixation, and the presence of artifacts. The standard requires indicating which protocol points were changed and why to ensure comparability between laboratories and for repeat studies of the same patient. [8]

When multifocal electroretinography really helps

The method is particularly informative for macular diseases: hereditary central dystrophies, Stargardt disease, cone dystrophies, vitelliform and so-called "latent" maculopathies, when visual acuity may remain relatively intact and subjective tests are insensitive. A topographic map of the electrophysiological response reveals early "dips" in the parafoveal zone, which helps establish a diagnosis and assess the prognosis. [9]

In cases of hydroxychloroquine toxicity, multifocal electroretinography is used as one of the primary objective tests, along with optical coherence tomography and automated perimetry. A decrease in the amplitude of the second ring and changes in the ring ratios may appear in the early stages, when structural changes are still minimal. This is important because unjustified drug discontinuation is undesirable, and missing early toxicity can lead to irreversible maculopathy. [10]

In diabetes, this method allows for the detection of subclinical functional impairments of the macular in patients without overt retinopathy. Studies demonstrate a link between the topography of electroretinographic changes and metabolic control, as well as a connection with future sensitivity dynamics during perimetry. This opens the possibility of early intervention and monitoring before the onset of severe clinical symptoms. [11]

Furthermore, multifocal electroretinography is useful in assessing treatment outcomes and in complex differential diagnoses, when it is necessary to objectively distinguish between lesions of the outer retina and the intraocular nerve. In some situations, combination with optical coherence tomography, microperimetry, and full-field electroretinography provides the most complete picture of function and structure. [12]

Table 1. Key components of the response and their clinical meaning

Component	What are we measuring?	What does it reflect?	Clinical interpretation
N-one	Negative phase before the first peak	Mainly photoreceptor contribution	Reduction in generalized dysfunction of the outer layers
P-one	The first positive phase and its peak time	Depolarizing bipolar cells and synaptic transmission	The most stable parameter for the macula and rings
Amplitude density	Amplitude taking into account the area of the element	Normalization by eccentricity	Comparability of rings and eyes
Ring ratios	Amplitude relationships between rings	Spatial profile of the function	Early signs of toxicity and paracentral dysfunction

The source of measurement and interpretation principles are the standards and guidelines for multifocal electroretinography. [13]

Patient preparation and examination

Before the examination, the fixation task is explained, the near correction is adjusted for the distance to the screen, and, if necessary, the pupil is dilated to stabilize the conditions. It is important to ensure a comfortable position and stable fixation, as gaze shifts reduce the accuracy of local responses and can mimic pathology. For children and people with anxiety, a short fixation training session and a demonstration of the test are useful. [14]

Skin or corneal electrodes are installed according to the selected laboratory's standard, and heart rate, artifacts, and background network noise are recorded. The electrode type and recording filters are always specified in the report. To improve reliability, multiple series are recorded and the reproducibility of the maps is checked, as random artifacts may disappear with repeated averaging. [15]

Stimulus parameters are selected according to a standard: a field of approximately forty to fifty degrees, an array of sixty-one or one hundred three elements, sufficient average brightness, and a sequence length for a stable signal-to-noise ratio. The equipment and stimulators must be regularly tested and calibrated according to current guidelines. [16]

The procedure duration is generally acceptable for most patients. In cases of poor fixation, media opacities, and significant discomfort, shorter protocols with fewer elements or concentric rings are possible. These are better tolerated and faster to perform while maintaining high diagnostic value in clinical scenarios where screening assessment is required. [17]

Table 2. Minimum protocol parameters according to the standard

Parameter	Standard recommendation	Why is this necessary?
Stimulation field size	About forty to fifty degrees	Complete coverage of the parafoveal zone and blind spot area
Number of elements	Sixty-one or one hundred and three	Balance between recording time and spatial resolution
Sequence length	No less than four thousand ninety-five steps	Sufficient signal-to-noise ratio
Averaging over rings	Required in the report	Comparability between patients and visits
System calibration	According to current recommendations	Comparability between centers and over time

Based on updated standards and guidelines. [18]

How to read results: norms, maps, and typical patterns

A normal map shows the greatest amplitude in the fovea and a moderate decrease toward the periphery of the macula. The peak time of the first positive wave in the center is shorter than in the annuli, reflecting faster processes in the foveal zone. When comparing eyes, it is important to consider fixation asymmetries and differences in optics to avoid mistaking them for pathology. [19]

Reduced amplitude and prolongation of peak time in one or more rings indicate localized dysfunction of the outer layers, characteristic of macular degeneration, toxic, and inflammatory processes. If the amplitude drop predominates in the second ring while the first is relatively intact, this is a typical early sign of toxicity from hydroxychloroquine and related drugs. [20]

Ring ratios increase sensitivity to early changes and reduce the influence of global factors such as media turbidity or general enhancement errors. For repeat visits, a consistent protocol and conditions are crucial: comparison with the patient's own initial chart is usually more informative than comparison with generalized "norms" from another laboratory. [21]

Finally, the values should be considered in conjunction with optical coherence tomography, automated perimetry, and clinical examination data. Coincidence of the functional infundibulum on multifocal electroretinography with thinning of the outer layers on optical coherence tomography and with a paracentral scotoma on perimetry increases diagnostic confidence and helps determine management tactics. [22]

Table 3. Common clinical scenarios and expected findings

Situation	What is typically seen on multifocal electroretinography?	Practical interpretation
Toxic maculopathy due to hydroxychloroquine	Reduction of amplitude in the second ring, change in the ratio of the rings	Early objective verification, assistance in deciding on treatment tactics
Hereditary macular degeneration	Central and paracentral amplitude "dips"	Topographic confirmation and monitoring
Early diabetic macular dysfunction	Moderate parafoveal reductions with normal ophthalmoscopy	Early risk marker and intervention monitoring
Ambiguous vision loss	Dissociation between structure and function	Distinction between lesions of the outer retina and optic nerve

The summary data is based on clinical reviews and studies.[23]

Comparison with other methods: strengths and weaknesses

Compared to full-field electroretinography, the multifocal technique shows a localized rather than a cumulative response, making it more suitable for the macular area. Full-field electroretinography remains the gold standard for generalized dystrophies, where the condition of the entire retina must be assessed. Optimal practice is to combine both approaches as indicated. [24]

Optical coherence tomography visualizes microstructure, while multifocal electroretinography reveals function based on the same topography. In toxic and hereditary maculopathies, functional changes often anticipate obvious structural shifts or, conversely, explain ambiguous tomographic findings, helping to avoid erroneous decisions. [25]

Psychophysical tests such as microperimetry and standard perimetry rely on patient attention and training. Multifocal electroretinography is more objective but is sensitive to recording artifacts and recording quality. When properly combined, these methods complement each other, increasing the accuracy of diagnosis and monitoring. [26]

In cases of optic nerve damage, pattern electroretinography and evoked potentials are more useful for assessing ganglion cells and pathways. Multifocal electroretinography provides a better assessment of the condition of photoreceptors and macular bipolar cells. The clinical task determines the choice of examination set. [27]

Table 4. Strengths and weaknesses of the methods

Method	What does it measure first?	Where is strong?	Restrictions
Multifocal electroretinography	Local function of the outer layers of the macula	Early macular dysfunction, toxicity, dystrophy	Demanding fixation, artifacts, standardization
Full-field electroretinography	The total function of the entire retina	Generalized dystrophies, assessment of the rod and cone systems	Low localization of the defect
Optical coherence tomography	Microstructure	Verification of morphology, staging	Does not measure function
Perimetry and microperimetry	Threshold sensitivity	Subjective functional assessment of the field	Dependence on the patient's attention

Summary of standards and clinical reviews. [28]

Limitations and typical artifacts: how to avoid mistakes

The most common problem is unstable fixation. Even small gaze drifts shift local responses and can create false "gaps." In patients with nystagmus or severe central fixation pathology, interpretation is particularly challenging, and alternative protocols with larger elements or shorter series are sometimes advisable. [29]

Electrode contact quality, line interference, and improper recording filters result in noise, crosstalk, and distortion of the true waveform. These artifacts are partially controlled by repeat runs, reproducibility testing, and strict adherence to protocols. The reporting protocol should document any deviations and their causes. [30]

Medial turbidity and slight myosomal variability may reduce amplitude without specific topography, masking subtle paracentral changes. In such cases, it is useful to analyze ring relationships and compare them with optical coherence tomography morphology to distinguish diffuse from focal reduction. [31]

Finally, field scaling errors and incorrect centering on the fixation point distort the map and hinder repeated comparisons. Standards emphasize the need for stimulator calibration and regular verification of brightness, contrast, and geometry parameters, otherwise intersession and intercenter comparability is impaired. [32]

Table 5. Common sources of errors and how to prevent them

Source of error	What's happening	How to prevent
Unstable fixation	Local response bias, false defects	Fixation training, shortened series, enlarged elements
Poor electrode contact	Noise, amplitude drop	Impedance check, correct fixation of the electrode thread
Network interference and muscle artifacts	Sawtooth noise, waveform distortion	Shielding, muscle relaxation, repeated series
Field geometry errors	Distorted map, poor comparability	Display calibration and alignment check
Turbidity of the media	Diffuse decrease in amplitude	Use ring ratios and compare with morphology

Summary of publications on artifact causes and standards. [33]

Special clinical topics: hydroxychloroquine, diabetes, pediatric practice

For monitoring hydroxychloroquine toxicity, international guidelines recommend relying on a combination of objective methods and agreed-upon criteria. Multifocal electroretinography is included in cases of suspected toxicity, when there is a structure-function discrepancy, or when confirmation of a specific paracentral pattern is required. Decisions to discontinue therapy should be based on repeatable changes and confirmation by multiple tests. [34]

New research confirms that machine learning algorithms trained on full time traces of multifocal electroretinography can improve the accuracy of toxic maculopathy detection compared to models using only summary parameters. This approach is particularly promising for centers with a high caseload, where standard interpretation can be complicated by data heterogeneity. [35]

In diabetes mellitus, multifocal electroretinography reveals functional abnormalities of the macular region before the onset of clinical retinopathy and helps predict changes in visual field sensitivity. Regular monitoring allows for the assessment of the effect of glycemic control and interventions at the earliest stages, when structural changes are minimal. [36]

In pediatrics, the method is effective for hereditary dystrophies and atypical maculopathies. The key to success is proper preparation, friendly communication, and, if necessary, modifying the protocol to reduce the number of elements. In some cases, sedation may be required for young children, and here the team's experience and adherence to safety standards are particularly important. [37]

Table 6. Multifocal electroretinography in hydroxychloroquine toxicity

What are we looking for?	Reliable signs	How to format a conclusion
Early functional changes	Decreased amplitude in the parafoveal second ring, change in the ratio of the rings	Indicate changes compared to the base record and confirm with structure and field
Test consistency	Compatibility with optical coherence tomography and automated perimetry	If there is a discrepancy, repeat the recording and avoid premature discontinuation of therapy.
Dynamics	Changes on repeat visits	Draw conclusions based on repeatability and consistency
New technologies	Analysis of complete time traces using machine learning methods	Consider as an additional tool in large centers

Summary of recommendations and new research. [38]

How to prepare a high-quality protocol and report

The report should include a description of the study conditions, electrode type, field size, number of elements, sequence duration, and confirmation of stimulator calibration. Recording quality and interference are noted separately, and representative curves and maps are provided, as well as ring averages with numerical values. This is necessary to ensure comparability between visits and with other centers. [39]

Normative limits should be based on the laboratory's own database, taking into account age and interocular differences. Universal "norms" from the literature are only suitable as a guide. It is advisable to indicate in the report whether the patient falls within the established range and the extent of the shift relative to their own baseline. [40]

If the protocol has been modified due to poor fixation or discomfort, this should be clearly described. For screening purposes, shorter designs, such as five concentric rings, are acceptable, provided the laboratory has validated them against the standard hexagonal stimulus. This reduces test time and improves tolerability. [41]

It is useful for the practicing physician to provide a report template that automatically populates key parameters, their position relative to the norm, and a comment on consistency with optical coherence tomography and perimetry. This format reduces the likelihood of missing early changes and facilitates communication with the treating specialist. [42]

Table 7. Qualitative Research Checklist

Block	What to check	Why is this important?
Preparation	Correction, fixation, mydriasis if necessary	Recording stability and comfort
Stimulus parameters	Field size, number of elements, sequence length	Comparability and sensitivity
Equipment	Brightness and Geometry Calibration	Stability and accuracy
Recording	Repeatability of series, noise assessment	Elimination of random artifacts
Report	Cards, rings, numerical values, comments	Completeness and reproducibility

Based on standards and guidelines. [43]

Brief practical conclusions

Multifocal electroretinography is the best choice when an objective topographic portrait of macular function is needed. It is particularly useful in the treatment of hydroxychloroquine toxicity, hereditary macular degeneration, and subclinical changes in diabetes. However, the method requires strict standardization and expert interpretation, ideally based on a proprietary reference base and a consistent set of accompanying tests. [44]