Electroretinography
Number: 0854
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Scope of Policy
This Clinical Policy Bulletin addresses electroretinography.
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Medical Necessity
Aetna considers the following medically necessary:
- Electroretinogram or electroretinography (ERG) as an adjunctive modality in establishing loss of retinal function and distinguishing retinal from optic nerve lesions;
- Multi-focal ERG (mfERG) for detecting chloroquine (Aralen) and hydroxychloroquine (Plaquenil) toxicity;
- Full-field ERG (ffERG) for diagnosis of congenital stationary night blindness, and evaluation of Vogt-Koyanagi-Harada disease and exudative retinal detachment;
- ffERG or mfERG for evaluating Stargardt disease in children.
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Experimental, Investigational, or Unproven
The following procedures are considered experimental, investigational, or unproven because the effectiveness of these approaches has not been established:
- Full-field flash ERG for monitoring during endoscopic trans-sphenoidal pituitary mass resection;
- Global flash ERGs for evaluation of refractive errors (astigmatism, hyperopia, myopia, and presbyopia);
- Pattern ERG for anti-depressant selection in individuals with depression, and the diagnosis of amblyopia, depression, glaucoma, management of individuals with macular drusen, and all other indications;
- ERG for the following indications (not an all-inclusive list):
- Anti-depressant selection in individuals with depression
- Diagnosis / evaluation of glaucoma
- Diagnosis of psychiatric disorders (including but not limited to attention deficit hyperactivity disorder, eating disorder, major depressive disorder, panic disorder, schizophrenia, and substance use disorder)
- Diagnosis of suicidal ideation
- Differentiation of hypersomnia subtypes
- Evaluation of autism spectrum disorder
- Evaluation of childhood brain tumor survivors
- Evaluation of rhegmatogenous retinal detachment
- Screening for chloroquine and hydroxychloroquine retinopathy/toxicity;
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Multi-focal ERG for the following indications (not an all-inclusive list):
- Anti-depressant selection in individuals with depression
- Diagnosis/evaluation of glaucoma
- Evaluation of idiopathic epiretinal membrane
- Evaluation of poppers maculopathy
- Prediction of visual acuity decline in age-related macular degeneration.
Background
The retina is composed of rod and cone cells in the photoreceptive layer of tissue at the back of the inner eye. It acts like the film in a camera -- images come through the eye's lens and are focused on the retina. The retina then converts these images to electric signals and sends them via the optic nerve to the brain. The macula, composed mainly of cones, is used primarily for central and color vision (photopic vision) while the remaining retina, composed mainly of rod photoreceptors, is utilized primarily for peripheral and night (scotopic) vision.
The electroretinogram or electroretinography (ERG) records the electrical response evoked from the entire retina by a brief flash of light and consists of an “A” wave, a photoreceptor response, and a “B” wave that emanates from the Muller and bipolar cells. The ERG provides information about the performance of the rods and cones. The ERG helps to distinguish retinal degeneration and dystrophies. Multi-focal electroretinography (mfERG) measures the photoreceptors’ activity. It is an advanced form of ERG in that it produces images with higher resolution than ERG. It involves stimulating areas of the retina using an electrical signal and mapping the response. Multi-focal ERG also allows the stimulation of multiple spots simultaneously, producing a changing pattern that is supposed to give more diagnostic information.
An assessment conducted by the Australian Medical Services Advisory Committee (MSAC, 2001; Johnston et al, 2003) concluded that mfERG is experimental. The report reached the following conclusions regarding mfERG: “All the studies of multifocal ERG were classified as level IV evidence. They did not present diagnostic characteristics or sufficient data to compute them. Although the studies showed that the multifocal ERG was able to discriminate between some visual parameters of patients with disease and controls with normal vision, they had little consistency and comparability. It is apparent from the available studies that much of the attention is focused on the mechanics of the technique and issues concerned with averaging signals and presentation of results. Thus, the clinical benefits of this technique are not yet apparent”,
Feigl et al (2005) investigated the cone- and rod-mediated mfERG in early age-related maculopathy (early ARM). A total of 17 eyes of 17 subjects with early ARM and 16 eyes of 16 age-matched control subjects with normal fundi were examined. These researchers concluded that their findings show a functional impairment of the rods in early ARM subjects. As there is histopathological evidence showing earlier rod than cone impairment in early ARM, following the rod function with the mfERG might be helpful in diagnosis or for monitoring the progression of early ARM.
In a prospective cohort study, Lai and colleagues (2005) assessed the longitudinal changes in mfERG in patients receiving hydroxychloroquine (HCQ) and examined the effects of cumulative HCQ dose on mfERG. A total of 24 eyes in 12 patients receiving HCQ underwent mfERG recordings at baseline and 1 to 2 years later. The first negative (N1) and first positive (P1) response amplitudes and peak latencies were compared with normal controls. Serial changes in the pattern of mfERG abnormalities and in response amplitudes and peak latencies were also compared between eyes in which HCQ therapy was continued or stopped. Correlation analyses were performed to assess the effects of a cumulative dose of HCQ on mfERG. These investigators concluded that patients receiving HCQ showed a longitudinal decline in retinal function; patients who stopped HCQ therapy showed improvement. Although these data are insufficient to demonstrate the sensitivity of mfERG for evaluating early HCQ toxicity, the results suggested that serial mfERG assessment may help detect early retinal changes associated with HCQ therapy. they stated that further studies with long-term results will be useful in clarifying the value of mfERG in evaluating early retinal toxicity due to HCQ.
Lai et al (2007) stated that mfERG is an investigation that can simultaneously measure multiple electroretinographic responses at different retinal locations by cross-correlation techniques. Thus, mfERG allows topographic mapping of retinal function in the central 40 to 50 degrees of the retina. The strength of mfERG lies in its ability to provide objective assessment of the central retinal function at different retinal areas within a short duration of time. Since the introduction of mfERG in 1992, mfERG has been applied in a large variety of clinical settings. Multi-focal ERG has been found to be useful in the assessment of localized retinal dysfunction caused by various acquired or hereditary retinal disorders. The use of mfERG also enabled clinicians to objectively monitor the treatment outcomes as the changes in visual functions might not be reflected by subjective methods of assessment. By changing the stimulus, recording, and analysis parameters, investigation of specific retinal electrophysiological components can be performed topographically. Further developments and consolidations of these parameters will likely broaden the use of mfERG in the clinical setting.
Moon et al (2012) conducted a study to investigate the association between automated perimetry, mfERG, and optical coherence tomography (OCT) measurements in patients with advanced retinitis pigmentosa (RP). In 25 patients with advanced RP central visual field sensitivity (VFS) was evaluated using an average of visual sensitivity value at central four test points during central 30-2 static automated perimetry. When OCT imaging was conducted the inner and outer segment (IS/OS) line was classified into three groups: Group 1, absence; Group 2, partially intact; and Group 3, intact. Central retinal thickness (CRT), defined as the retinal thickness of central 3.0 mm, was also evaluated. Average amplitude and implicit time of N1 and P1 in ring 1 and 2 were measured on mfERG and comparisons of VFS, mfERG and OCT among the three subgroups were performed following IS/OS integrity. The relationship between VFS, mfERG and CRT was evaluated by regression analysis. The authors reported that group 3 patients with an intact IS/OS line showed a better VFS, and amplitude of mfERG response than those of Group 1 and 2. VFS and amplitudes of mfERG were correlated significantly with CRT in linear regression analysis. The authors concluded that disrupted IS/OS integrity was associated with visual dysfunction which was shown by decreased amplitude of mfERG response and reduced central VFS. CRT was significantly correlated with amplitude of mfERG response and central VFS and an eye with the more reduced CRT was associated with the worse amplitude of mfERG response and central VFS.
Narayanan et al (2013) conducted a prospective study of mfERG in patients with type 2 MacTel to characterize the electroretinography response of the macula by mfERG. The study was conducted from April 2009 to November 2009 and mfERGs were recorded using a visual evoked response imaging system (MonElec2, Metrovision, Perenchies, France). The International Society for Clinical Electrophysiology of Vision (ISCEV) guidelines were followed and the study included patients with type 2 MacTel confirmed by fundus fluorescein angiography without sub-retinal neo-vascularization. Individual mfERG responses for the hexagons were grouped into concentric rings centered on the fovea for analysis (less than 2, 5 to 10, 10 to 15 and greater than 15°). A total of 28 eyes of 14 patients and 20 eyes of 10 normal controls were included in the study. The authors reported that the mean logMAR visual acuity of the patients was 0.51 (Snellen equivalent 20/63)and the mean N1 amplitude (nv/deg(2)) of patients were significantly reduced compared to controls as follows: 8.91 ± 14.00 versus 43.44 ± 9.55 (p < 0.0001) in less than 2°, 9.24 ± 10.47 versus 22.00 ± 3.87 (p < 0.0001) in 5-10°, 8.57 ± 10.02 versus 15.24 ± 1.89 (p < 0.0001) in 10-15°, and 7.03 ± 6.52 versus 12.47 ± 2.62 in > 15° (p < 0.001). The mean P1 amplitude (nv/deg(2)) was also significantly reduced in patients compared to controls. The results specified 27.66 ± 37.44 versus 96.20 ± 12.41 (p < 0.0001) in less than 2°, 22.61 ± 19.38 versus 53.78 ± 9.79 (p < 0.0001) in 5-10°, 18.75 ± 20.21 versus 35.22 ± 4.16 (p < 0.001) in 10-15°, and 17.10 ± 12.54 versus 25.71 ± 3.93 (p < 0.001). The implicit time of N1 and P1 were also delayed significantly in all the rings. The mean central foveal thickness assessed by OCT scan was 84.78 ± 45.12 μm. There was poor correlation between mfERG amplitudes or implicit times with either the visual acuity or OCT central thickness. The authors concluded that mfERG showed significant reduction in amplitudes and implicit times of the waveforms in patients with type 2 MacTel in all the rings, suggesting a more generalized affection of the macula. The maximum reductions were seen in the <2(o) rings. Although there was poor correlation between the visual acuity and the amplitudes a of the waveforms, mfERG is a useful investigative modality for functional assessment of macula in type 2 MacTel patients. However, this study by Narayanan et al. was limited by the sample size of 28 eyes in 14 patients.
In a review on “Hydroxychloroquine-induced retinal toxicity”, Hansen and Schuman (2011) stated that at the initiation of treatment with HCQ, the prescribing physician should refer the patient to an ophthalmologist. During the initial examination, it is recommended that the patient receive:
- A thorough ocular examination documenting any pre-existing conditions; and
- A Humphrey visual field central 10-2 white-on-white pattern; and
- At least 1 of the following objective tests, if available:
- Fundus auto-fluorescence (FAF) test; or
- mfERG; or
- Spectral domain OCT (SD-OCT).
Moreover, these investigators noted that mfERG, a test that is typically available in large clinical centers, objectively evaluates function and can be used in place of visual fields. They also stated that it is also worth considering the use of color fundus photographs to assist in documenting changes over time, especially if there is pre-existing retinal pathology. However, the dilated fundus examination should not be considered a screening tool, as it only picks up relatively late toxic changes.
Costedoat-Chalumeau et al (2012) stated that new recommendations for screening of HCQ retinopathy, updating those of 2002, have been recently published by the American Academy of Ophthalmology (AAO). These recommendations have been necessary because of new knowledge about the prevalence of toxicity and because of improved screening tools. Amsler grid testing, color vision testing, fluorescein angiography, full-field ERG, and electro-oculogram are no longer recommended. It is now recommended to perform fundus examinations with 10-2 automated fields, and whenever possible, at least 1 objective test including mfERG, FAF or SD-OCT. A baseline examination is advised as a reference and then, annual screening should be initiated no later than 5 years after starting HCQ therapy.
An eMedicine review on “Chloroquine and Hydroxychloroquine Toxicity” (Roque, 2017) listed full-field ERG or electro-oculogram as one of the ancillary tests, although not recommended for toxicity screening because of sensitivity, specificity and reliability issues, may also be used in diagnosing toxicity. Moreover, the author also indicated that the ophthalmic examination should also include a Humphrey visual field central 10-2 white-on-white pattern, and at least one of the following objective tests, if available:
- SD-OCT
- FAF test
- mfERG.
Browning and Lee (2014) determined the relative sensitivity and specificity of 10-2 visual fields (10-2 VFs), mfERG, and SD-OCT in detecting HCQ retinopathy. A total of 121 patients taking HCQ (n = 119) or chloroquine (CQ; n = 2) with 10-2 VF, mfERG, and SD-OCT tests were retrospectively reviewed. Rates of test abnormality were determined. Retinopathy was present in 14 and absent in 107; 11 of 14 (78.6 %) patients with retinopathy were over-dosed; 12 (85.7 %) had cumulative dosing greater than 1,000 g. The sensitivities of 10-2 VF, mfERG, and SD-OCT in detecting retinopathy were 85.7 %, 92.9 %, and 78.6 %, respectively. The specificities of 10-2 VF, mfERG, and SD-OCT in detecting retinopathy were 92.5 %, 86.9 %, and 98.1 %, respectively. Positive-predictive values (PPVs) of 10-2 VF, mfERG, and SD-OCT in detecting retinopathy were less than 30 % for all estimates of HCQ retinopathy prevalence; negative-predictive values (NPVs) were greater than 99 % for all tests. The authors concluded that based on published estimates of HCQ retinopathy prevalence, all 3 tests are most reliable when negative, allowing confident exclusion of retinopathy in patients taking less than or equal to 6.5 mg/kg/day. Each test is less useful in allowing a confident diagnosis of retinopathy when positive, especially in patients taking less than or equal to 6.5 mg/kg/day.
An UpToDate review on “Antimalarial drugs in the treatment of rheumatic disease” (Wallace, 2014) sates that “The earliest retinal abnormalities are asymptomatic and can only be detected by ophthalmologic examination. These “pre-maculopathy” changes consist of macular edema, increased pigmentation, increased granularity, and loss of the foveal reflex. Subtle functional loss in the paracentral retina can occur before biomicroscopic changes in the retinal pigment epithelium. Detection of changes at this stage, using techniques such as multifocal electroretinography, is desirable since they may be completely reversible upon discontinuation of the medication”.
Guidelines from the AAO(Marmor et al, 2011) on screening for CQ and HCQ toxicity stated that newer objective tests, such as mfERG, SD-OCT, and FAF, can be more sensitive than visual fields. The guidelines recommended that along with 10-2 automated fields, at least 1of these procedures be used for routine screening where available. The guidelines stated that, because mfERG testing is an objective test that evaluates function, it may be used in place of visual fields.
Tsang et al (2015) determined the validity of mfERG as a screening tool for detecting CQ and HCQ retinal toxicity in patients using these medications. To evaluate the sensitivity and specificity of mfERG when compared with automated visual fields (AVFs), FAF, and OCT. The 2011 AAO recommendations on screening for CQ/HCQ retinopathy recommended a shift toward more objective testing modalities. Multi-focal ERG may be effective in detecting functional change before irreversible structural damage from CQ/HCQ toxicity. These investigators performed a search for records reporting the use of mfERG for screening CQ/HCQ retinopathy in MEDLINE (PubMed and OVID), EMBASE, and Web of Science, and assessed these using the QUADAS-2 risk of bias tool. They conducted an analysis of 23 individual studies and their reported individual patient data (449 eyes of 243 patients) published from January 2000 to December 2014. Multi-focal ERG had the greatest proportion of positive test results, followed by AVF. The pooled sensitivity and specificity of mfERG were 90 % (95 % confidence interval [CI]: 0.62 to 0.98) and 52 % (CI: 0.29 to 0.74), respectively, with AVF as reference standard (13 studies). Sensitivity was high, but specificity was variable when OCT, FAF, and the positivity of 2 of 3 tests was used as the reference standard. When verified against AVF as the reference test, patients with a false-positive mfERG result received higher HCQ cumulative doses (1,068 g) than patients with true-negative (658 g, p < 0.01) and false-negative (482 g, p < 0.01) results. The authors concluded that mfERG was shown to have a high sensitivity but variable specificity when verified against AVF, OCT, FAF, and a combination of tests. The greater average cumulative dose in the false-positive group compared with the true-negative group when mfERG was verified against AVF suggested that mfERG may have the ability to detect cases of toxicity earlier than other modalities. Moreover, they state that there is an unclear risk of bias in the available evidence, and future studies should adhere to Standards for Reporting of Diagnostic Accuracy reporting guidelines.
Multi-Focal Electroretinography (mfERG) for Prediction of Visual Acuity Decline in Age-Related Macular Degeneration
In a prospective study, Ambrosio et al (2015) examined the role of mfERG for predicting visual acuity (VA) decline in early age-related macular degeneration (ARMD) with time. A total of 26 early ARMD patients (12 males and 14 females, mean age of 66.9 ± 9.8; range of 46 to 82 years) were included in the study. A complete ophthalmic examination and mfERG (Retiscan, Roland Germany, ISCEV standard protocol) were performed at the study entry (baseline), after 20 and 24 months. The first-order kernel mfERG responses were analyzed by ring analysis. The amplitude density (AD) of the first positive peak (P1, nV/deg2), the P1 amplitude (µV) and P1 implicit time (ms) for Rings 1 (central) to 6 (most peripheral) were evaluated. Data were statistically analyzed by analysis of variance and receiver operating characteristic (ROC) curves. The loss in the mfERG Ring 1 AD from normal control values, recorded at baseline, was correlated with the decrease in ETDRS VA with time (p = 0.004); ROC analysis showed that, after 24 months, the average decline in VA was greater (3 letters versus 0.4 letters, p = 0.0021) in patients whose Ring 1 P1 AD at baseline was equal to or less than 65.9 nV/deg2, compared to those with higher AD values. Both P1 amplitude and AD of Ring 1 had an area under the curve of 0.702 (95 % CI: 0.50 to 0.92) with a sensitivity of 64.3 % (35.14 to 87.24 %) and a specificity of 91.7 % (61.52 to 99.79 %). The authors concluded that these findings indicated that mfERG P1 amplitude and AD of Ring 1 may be highly specific to predict VA decline in early ARMD. These preliminary findings need to be validated by well-designed studies.
Guidelines from the American Academy of Ophthalmology (AAO, 2015) on age-related macular degeneration have no recommendation for mfERG.
ERG / mfERG for Diagnosis / Evaluation of Glaucoma
In a report by the AAO on “Assessment of visual function in glaucoma”, Jampel and colleagues (2011) reviewed the published literature to summarize and evaluate the effectiveness of visual function tests in diagnosing glaucoma and in monitoring progression. Literature searches of the PubMed and Cochrane Library databases were conducted last on May 7, 2010, and were restricted to citations published on or after January 1, 1994. The search yielded 1,063 unique citations. The first author reviewed the titles and abstracts of these articles and selected 185 of possible clinical relevance for further review. The panel members reviewed the full text of these articles and determined that 85 met inclusion criteria. They conducted data abstraction of the 85 studies, and the panel methodologist assigned a level of evidence to each of the selected articles. One study was rated as level I evidence. The remaining articles were classified broadly as providing level II evidence. Studies deemed to provide level III evidence were not included in the assessment. Standard white-on-white automated perimetry remains the most commonly performed test for assessing the visual field, with the Swedish interactive threshold algorithm (SITA) largely replacing full-threshold testing strategies. Frequency-doubling technology and its refinement into Matrix perimetry, as well as short-wavelength automated perimetry, now available with SITA, have been evaluated extensively. Machine learning classifiers seem to be ready for incorporation into software to help distinguish glaucomatous from non-glaucomatous fields. Other technologies, such as multi-focal visual-evoked potential (VEP) and ERG, which were designed as objective measures of visual function, provided testing free of patient input, but issues prevent their adoption for glaucoma management. The authors concluded that advances in technology and analytic tools over the past decade had provided them with more rapid and varied ways of assessing visual function in glaucoma, but they have yet to produce definitive guidance on the diagnosis of glaucoma or its progression over time. They stated that further research on an objective measure of visual function is needed.
Nouri-Mahdavi (2014) stated that testing the peripheral field of vision is the mainstay for detection of glaucoma deterioration. Various methods and algorithms are currently available for detection of early glaucoma or establishing disease progression. Alternative testing strategies such as frequency doubling technology perimetry or short-wavelength automated perimetry have been extensively explored over the last 2 decades. The former has been found most promising for detection of earliest evidence of functional glaucoma damage when the standard achromatic perimetry results are still within the normal range. However, standard achromatic perimetry remains the standard technique for establishing deterioration of the disease. Both trend and event analyses were used for establishing change within series of visual fields. Trend analyses provided the clinician with rates of progression, putting the speed of glaucoma progression in the context of patient longevity, whereas event analyses demonstrated a "step" change regardless of the length of time it took for this amount of change to occur. The 2 techniques are complementary and should be used concurrently; ERG/mfERG was not mentioned as a management tool.
Furthermore, guidelines from the American Academy of Ophthalmology (2010) and UpToDate reviews on “Open-angle glaucoma: Epidemiology, clinical presentation, and diagnosis” (Jacobs, 2015), “Angle-closure glaucoma” (Weizer, 2015), and “Overview of glaucoma in infants and children” (Olitsky and Reynolds, 2015) do not mention ERG/mfERG as diagnostic tools.
In a prospective, case-series study, Gupta and colleagues (2015) evaluated the use of mfERG in diagnosing retinal toxicity from siderosis with normal ERG. A total of 6 patients with retained intra-ocular foreign body were recruited. The affected eye of the patients had no clinical evidence of siderosis, had similar full-field photopic 3.0 ERG compared with the fellow eye, and had subnormal VA. Group averages in each mfERG ring for implicit time and amplitude at P1 wave were compared between affected and fellow eye to look for latent siderosis. On mfERG, no statistical difference in group averaged amplitude was observed; however, a significant difference (p < 0.05) was found in group averaged latency between fellow and affected eye at most tested rings (less than 2 degree, 2 to 5 degree, and greater than 15 degree rings). Average latency for overall retinal area mapped also showed significant difference (p = 0.010). The authors concluded that increased mfERG latency may serve as an early predictor of retinal damage from siderosis when full-field ERG is normal.
ERG for Diagnosis of Birdshot Chorioretinopathy
Tzekov and Madow (2015) stated that birdshot chorioretinopathy (BSCR) is a rare form of autoimmune posterior uveitis that can affect the visual function and, if left untreated, can lead to sight-threatening complications and loss of central vision. These investigators performed a systematic search of the literature focused on visual electrophysiology studies, including ERG, electrooculography (EOG), and VEP, used to monitor the progression of BSCR and estimate treatment effectiveness. Many reports were identified, including using a variety of methodologies and patient populations, which made a direct comparison of the results difficult, especially with some of the earlier studies using non-standardized methodology. Several different electrophysiological parameters, like EOG Arden's ratio and the mfERG response densities, were reported to be widely affected. However, informal consensus emerged in the past decade that the full-field ERG light-adapted 30-Hz flicker peak time is one of the most sensitive electrophysiological parameters. As such, it has been used widely in clinical trials to evaluate drug safety and effectiveness and to guide therapeutic decisions in clinical practice. The authors concluded that despite its wide use, a well-designed longitudinal multi-center study to systematically evaluate and compare different electrophysiological methods or parameters in BSCR is still lacking; but would benefit both diagnostic and therapeutic decisions. The authors stated that, "u]ntil then, there is enough evidence to recommend the use of photopic 30 Hz flicker in the clinical management of BSCR."
ERG for Evaluation of Childhood Brain Tumor Survivors
In a population-based, cross-sectional study, Pietila and colleagues (2016) evaluated the clinical value of ERG and VEP in childhood brain tumor survivors. A flash ERG and a checker-board reversal pattern VEP (or alternatively a flash VEP) were done for 51 survivors (age of 3.8 to 28.7 years) after a mean follow-up time of 7.6 (1.5 to 15.1) years. Abnormal ERG was obtained in 1 case (2 %), bilaterally delayed abnormal VEPs in 22/51 (43 %) cases; 9 of 25 patients with infra-tentorial tumor location, and altogether 12 out of 31 (39 %) patients who did not have tumors involving the visual pathways, had abnormal VEPs. Abnormal ERGs are rarely observed, but abnormal VEPs are common even without evident anatomic lesions in the visual pathway. Bilateral changes suggested a general and possibly multi-factorial toxic/adverse effect on the visual pathway. The authors concluded that ERG and VEP may have clinical and scientific value while evaluating long-term effects of childhood brain tumors and tumor treatment.
ERG for Evaluation of Achromatopsia
Schallhorn and colleagues (2018) reported novel ERG findings in a genetically confirmed case of achromatopsia. A patient with a history of childhood nystagmus, photo-aversion, and absent color vision was examined. Electroretinography and fundus examination were performed under anesthesia at the time of corrective surgery for nystagmus. Genomic DNA isolated from peripheral blood was directly sequenced for variations in the CNGA3 and CNGB3 genes. Ophthalmoscopic examination revealed no distinct abnormalities; ERG obtained under anesthesia at age 3 years revealed absent photopic responses. The dark-adapted (DA) combined responses had reduced b-wave amplitudes resulting in an electro-negative configuration. Genetic testing revealed 2 heterozygous sequence variations present in the coding sequence of the CNGA3 gene (Arg223Trp and Pro372Ser), which have been previously described in the setting of achromatopsia. Sequencing of the patient's parents confirmed that these 2 variations lie on separate alleles. The authors concluded that novel ERG findings in a patient with genetically confirmed achromatopsia were reported; the electro-negative configuration in this clinical setting is of unclear etiology; however, it may suggest some component of inner retinal dysfunction. The clinical value of ERG in the evaluation of achromatopsia has to be further investigated.
ERG for Evaluation of Autism Spectrum Disorder
- a high-functioning ASD group (n = 11), and
- a control group (n = 15) for DA and n = 14 for LA ERGs who were matched for mean age and range.
Flash strengths ranged from DA -4.0 to 2.3 log phot cd s m(-2) and LA -0.5 to 1.0 log phot cd s m(-2), and Naka-Rushton curves were fitted to DA b-wave amplitude over the first growth limb (-4.0 to -1.0 log phot cd s m(-2)). The derived parameters (V max, K m and n) were compared between groups. Scotopic 15-Hz flicker ERGs (14.93 Hz) were recorded to 10 flash strengths presented in ascending order from -3.0 to 0.5 log Td s to assess the slow and fast rod pathways, respectively. LA 30-Hz flicker ERGs, oscillatory potentials (OPs) and the responses to prolonged 120-ms ON-OFF stimuli were also recorded. The ISCEV LA b-wave amplitude produced by 0.5 log phot cd s m(-2) was lower in the ASD group (p < 0.001). Repeated measures ANOVA for the LA b-wave amplitude series forming the photopic hill was significantly (p = 0.01) different between groups. No group differences were observed for the distributions of the time to peaks of LA a-wave, b-wave or the photopic negative responses (phNR) (p > 0.08) to the single flash stimuli, but there was a significant difference in the distribution for the LA b-wave amplitudes (corrected p = 0.006). The prolonged 120-ms ON responses were smaller in the ASD group (corrected p = 0.003), but the OFF response amplitude (p > 0.6) and ON and OFF times to peaks (p > 0.4) were similar between groups. The LA OPs showed an earlier bifurcation of OP2 in the younger ASD participants; however, no other differences were apparent in the OPs or 30-Hz flicker waveforms. DA b-wave amplitudes fell below the control 5th percentile of the controls for some individuals including 4 ASD participants (36 %) at the 1.5 log phot cd s m(-2) flash strength and 2 (18 %) ASD participants at the lower -2 log phot cd s m(-2) flash strength. However, across the 13 flash strengths, there were no significant group differences for b-wave amplitude's growth (repeated measures ANOVA p = 0.83). Nor were there any significant differences between the groups for the Naka-Rushton parameters (p > 0.09). No group differences were observed in the 15-Hz scotopic flicker phase or amplitude (p > 0.1), DA ERG a-wave amplitude or time to peak (p > 26). The DA b-wave time to peak at 0.5 log phot cd s m(-2) was longer in the ASD group (p = 0.04). The authors concluded that under LA conditions, the b-wave was reduced across the ASD group, along with the ON response of the prolonged flash ERG. They noted that some ASD individuals also showed subnormal DA ERG b-wave amplitudes. The authors stated that these exploratory findings suggested there is altered cone-ON bipolar signaling in ASD.
Furthermore, an UpToDate review on “Autism spectrum disorder: Diagnosis” (Augustyn, 2017) does not mention electroretinography as a diagnostic tool.
ERG for Evaluation of Non-Glaucomatous Optic Neuropathies
Bach and Kay (2017) presented 3 cases of inflammatory optic neuritis that was followed to resolution using PERG. They noted that these cases represented the first report in which a relatively new office-based PERG technology has been demonstrated to be useful in monitoring recovery of visual function in the setting of inflammatory optic neuropathies. Two patients demonstrated normalization of their PERG paralleling their full recovery of optic nerve function as assessed via other standard measures such as VA and Humphrey visual field (HVF), while the third demonstrated improvement, albeit still reduced in amplitude, consistent with the incomplete recovery of optic nerve function, at most recent follow-up. Furthermore, in 1 of the patients, use of this technology provided an objective means of following recovery of ganglion cell function in an individual who could not be reliably monitored with serial HVFs secondary to poor field testing technique. Moreover, these investigators stated that whether this technology is applicable to the evaluation of non-glaucomatous optic neuropathies has not been well established, although a recent report did demonstrate recovery of ganglion cell function as assessed by PERG in 3 patients who underwent resection of a pituitary tumor abutting the optic chiasm. PERG has also been shown to be a useful diagnostic tool in experimental models for optic neuritis as well as having potential for other types of optic neuropathies. These researchers have now applied this technology to 3 patients with inflammatory optic neuropathies, and have performed serial PERG studies as their optic neuropathy resolved demonstrating progressive improvement on PERG studies. The authors concluded that the PERG technique may prove useful as an adjunctive objective measure for monitoring progression and/or resolution of glaucoma and other optic neuropathies in patients who are consistently unreliable when performing HVF. They stated that further studies are needed to determine if this new testing paradigm will be of benefit in monitoring for progression or recovery of ganglion cell function in other non-glaucomatous optic neuropathies including compressive lesions of the optic apparatus, ischemic optic neuropathy, papilledema, and toxic optic neuropathies.
ERG for Evaluation of Sickle Cell Retinopathy
- HbSS or
- HbSC (homozygous or heterozygous mutations, respectively).
Patients affected by non-proliferative SC retinopathy were included from November 2014 to April 2016. They were separated into 1 of the following 3 groups:
- HbSS,
- HbSC, and
- control.
All groups underwent full ophthalmologic examination (fundus examination) and ffERG. For SC patients, additional imaging testing was also performed (fluorescein angiography and spectral domain OCT). A total of 24 eyes from 12 patients (6 HbSS and 6 HbSC) and 12 eyes from 6 controls were included. The HbSS group exhibited a dramatic decrease of the b-wave amplitudes for all DA ffERG responses when compared with the control group (p = 0.02, p = 0.003, p = 0.005, respectively, after DA 0.01, DA 3.0, and DA 10.0 cd.s.m-2 stimulations) and decreased a-wave amplitudes for LA responses (p = 0.03 after LA 3.0 cd.s.m-2 stimulations). The a-Wave amplitudes were significantly reduced for all DA and LA responses in HbSC group compared to the control group (p = 0.03, p = 0.01, p = 0.03, respectively, after DA 3.0, DA 10.0, and LA 3.0 cd.s.m-2 stimulations). The HbSS+HbSC groups presented decreased a-wave amplitudes for DA and LA responses and decreased b-wave amplitude after DA 0.01 and 10.0 cd.s.m-2 stimulations when compared to the control group. The authors concluded that these findings could suggest an early involvement of the inner retinal cells in the disease process in HbSS patients and of the outer retinal cells in HbSC patients. This could provide new insights on the pathophysiology of the retinal affection in HbSS/HbSC SC disease. The authors stated that it would also be of interest to compare ffERG data to OCT-angiography findings; however, current systems mostly cover the area of the central retina, whereas ffERG collects responses from the whole retina. Moreover, they stated that the main drawback of this study was its small sample size (n = 12 for the experimental group); larger studies are needed to support this hypothesis.
Furthermore, an UpToDate review on “Overview of the clinical manifestations of sickle cell disease” (Vichinsky, 2017) does not mention electroretinography as a diagnostic tool.
ERG for Evaluation of Rhegmatogenous Retinal Detachment
Parvaresh (2018) noted that few studies have evaluated the role of retinal electrophysiology testing in patients with retinal detachment and after retinal re-attachment surgery using ffERG and mfERG. Both animal as well as human studies have shown that retinal detachment causes the loss of the outer segments of photoreceptor cells. Both cone and rod photoreceptors are affected in retinal detachment. However, the magnitude of the damage and its likely location in the retina are not clearly known. This investigator stated that current knowledge of electrophysiological changes in rhegmatogenous retinal detachment (RRD) is limited and future studies regarding the application of ERG studies in eyes with RRD are needed; and that although some studies have reported the prognostic value of ERG testing in eyes with RRD, the potential clinical applications of this technique are not clear. The author concluded that future large-scale studies may be helpful to examine the use of ERG testing for various aspects of retinal detachment, such as determination of the optimal time of intervention, the outcomes of different types of surgery, and effects of pharmacotherapies on surgery.
ERG for Diagnosis of Psychiatric Disorders
In a systematic review, Youssef and colleagues (2019) examined the available information on use of ERG as a diagnostic tool in psychiatry. The ERG has been found to have diagnostic utility in cocaine withdrawal (reduced light-adapted b-wave response), major depressive disorder (reduced contrast gain in pattern ERG), and schizophrenia (reduced a- and b-wave amplitudes). These researchers evaluated these findings as well as the applicability of ERG to substance use disorder, Alzheimer's disease, autism spectrum disorder (ASD), panic disorder, eating disorders, attention deficit hyperactivity disorder (ADHD), and medication use. The authors concluded that while there have been promising results, current research suffers from a lack of specificity. These researchers stated that further research that quantifies anomalies in ERG present in psychiatric illness is needed.
ERG for Screening for Chloroquine and Hydroxychloroquine Retinopathy/Toxicity
Marmor et al (2016) reported that the AAO’s recommendations on screening for CQ and HCQ retinopathy are revised in light of new information regarding the prevalence of toxicity, risk factors, fundus distribution, and effectiveness of screening tools. These investigators noted that although the locus of toxic damage is para-foveal in many eyes, Asian patients often show an extra-macular pattern of damage. They recommended a maximum daily HCQ use of 5.0 mg/kg or less real weight, which correlated better with risk than ideal weight. There were no similar demographic data for CQ; however, dose comparisons in older literature suggested using 2.3 mg/kg or less real weight. These researchers stated that the risk of toxicity is dependent on daily dose and duration of use. At recommended doses, the risk of toxicity up to 5 years is under 1 % and up to 10 years is under 2 %; however, it rose to almost 20 % after 20 years. Moreover, even after 20 years, a patient without toxicity had only a 4 % risk of converting in the subsequent year. High dose and long duration of use were the most significant risks. Other major factors were concomitant renal disease; or use of tamoxifen. The authors noted that a baseline fundus examination should be carried out to rule out pre-existing maculopathy; and annual screening should commence after 5 years for patients on acceptable doses and without major risk factors. The primary screening tests are automated visual fields plus SD-OCT. These should look beyond the central macula in Asian patients; mfERG could provide objective corroboration for visual fields, and FAF could show damage topographically. Modern screening should detect retinopathy before it is visible in the fundus. Moreover, the AAO did not recommend the use of full-filed ERG (standard ERG) for screening for CQ and HCQ retinopathy/toxicity.
Furthermore, AAO’s EyeWiki on “Hydroxychloroquine Toxicity” (Weng, 2022) stated that color testing, Amsler grid, time-domain OCT, fluorescein angiography, and full-field ERG are no longer recommended for hydroxychloroquine toxicity screening purposes.
mfERG for Evaluation of Idiopathic Epiretinal Membrane / Poppers Maculopathy
Gao and colleagues (2017) evaluated the macular function changes in patients with idiopathic macular epiretinal membrane (ERM) by mfERG and their correlations with VA and central macular thickness (CMT) by OCT. A total of 20 eyes of 20 patients with ERM underwent OCT and mfERG examinations. The response amplitude densities and implicit times of mfERG were compared to the control fellow eyes. Correlation analyses among VA, CMT and mfERG values in the central 2 concentric rings were performed. The mfERG P1 response amplitude densities in ring 1 to 2 and P1 implicit time in ring1 were significantly changed in epiretinal membrane eyes compared with controls (p < 0.05). Multi-variate step-wise linear regression analyses showed LogMAR VA was significantly correlated with CMT (p = 0.004), and also with the P1 amplitude density in ring 1 (p = 0.002); CMT showed significant correlation with P1 implicit time in ring 2 (p = 0.013). The authors concluded that these findings showed mfERG abnormalities appeared to demonstrate subtle macular function changes and correlated with VA and CMT in eyes with ERM. They stated that in first-order mfERG responses, P1 wave changes may be a sensitive functional measurement for ERM patients.
The authors stated that the drawbacks of this study included a small sample size (n = 20). This might have limited the power in detecting photoreceptor statues and other influence factors, which may have an impact on ERG values and statistical analysis. These researchers noted that the mechanism of mfERG impairment related to ERM may not be straight-forward; the mfERG abnormalities as described in this report need further investigation.
Pahlitzsch and associates (2019) noted that maculopathy is a potential side effect of amyl nitrite or "poppers" abuse. It is characterized by a sudden, painless decrease in VA. While the funduscopic changes are subtle, OCT showed alterations of the outer retinal layers in the fovea. However, the extent of retinal dysfunction remains poorly understood. These investigators compared the mfERG of 6 patients with poppers maculopathy to that of a control group consisting of 6 healthy subjects. Response densities and implicit times of N1 and P1 were analyzed. Response densities and implicit times of both N1 and P1 were lower in the patients with poppers maculopathy than in the control group, particularly in ring 1 and rings 4 and 5. The only statistically significant finding, however, was a reduced N1 response density of 1 hexagon in the patient group. No significant differences were found considering the sum response or the averaged rings 1 to 5. The authors concluded that compared to a healthy control group, mfERG of patients with poppers maculopathy showed no relevant impairment contrasting the marked effect of the disease on VA. These investigators stated that in clinical practice, poppers maculopathy could not be diagnosed by mfERG.
Pattern Electroretinography
Wilsey and colleagues (2017) compared diagnostic performance and structure-function correlations of mfERG, full-field flash ERG (ffERG) photopic negative response (PhNR) and transient pattern-reversal ERG (PERG) in a non-human primate (NHP) model of experimental glaucoma (EG). At baseline and after induction of chronic unilateral intra-ocular pressure (IOP) elevation, 43 NHP had alternating weekly recordings of retinal nerve fiber layer thickness (RNFLT) by spectral domain OCT (Spectralis) and retinal function by mfERG (7F slow-sequence stimulus, VERIS), ffERG (red 0.42 log cd-s/m2 flashes on blue 30 scotopic cd/m2 background, LKC UTAS-E3000), and PERG (0.8° checks, 99 % contrast, 100 cd/m2 mean, 5 reversals/s, VERIS). All NHP were followed at least until HRT-confirmed optic nerve head posterior deformation, most to later stages. mfERG responses were filtered into low- and high-frequency components (LFC, HFC, greater than 75-Hz). Peak-to-trough amplitudes of LFC features (N1, P1, N2) and HFC RMS amplitudes were measured and ratios calculated for HFC:P1 and N2:P1. ffERG parameters included A-wave (at 10 ms), B-wave (trough-to-peak) and PhNR (baseline-to-trough) amplitudes as well as PhNR:B-wave ratio. PERG parameters included P50 and N95 amplitudes as well as N95:P50 ratio and N95 slope. Diagnostic performance of retinal function parameters was compared using the area under the receiver operating characteristic curve (A-ROC) to discriminate between EG and control eyes. Correlations to RNFLT were compared using Steiger's test. Study duration was 15 ± 8 months. At final follow-up, structural damage in EG eyes measured by RNFLT ranged from 9 % above baseline (BL) to 58 % below BL; 29/43 EG eyes (67 %) and 0/43 of the fellow control eyes exhibited significant (greater than 7 %) loss of RNFLT from BL. Using raw parameter values, the largest A-ROC findings for mfERG were: HFC (0.82) and HFC:P1 (0.90); for ffERG: PhNR (0.90) and PhNR:B-wave (0.88) and for PERG: P50 (0.64) and N95 (0.61). A-ROC increased when data were expressed as % change from BL, but the pattern of results persisted. At 95 % specificity, the diagnostic sensitivity of mfERG HFC:P1 ratio was best, followed by PhNR and PERG. The correlation to RNFLT was stronger for mfERG HFC (R = 0.65) than for PhNR (R = 0.59) or PERG N95 (R = 0.36), (p = 0.20, p = 0.0006, respectively). The PhNR flagged a few EG eyes at the final time-point that had not been flagged by mfERG HFC or PERG. The authors noted that among the ERG modes evaluated in this study, the mfERG HFC had the highest diagnostic sensitivity and strongest correlation to structure in this cohort of NHP with experimental glaucoma. Consistent with numerous other reports, accounting for inter-eye differences by normalization to baseline amplitudes and/or by normalization to other features of the same ERG response less sensitive to glaucomatous damage improved both diagnostic performance and correlation to a structural measure of damage severity for the best parameters of all 3 ERG modes. After normalization, the mfERG HFC had the highest diagnostic sensitivity and strongest correlation to RNFL thickness and missed only a few EG eyes flagged by PhNR or PERG. The mfERG also offered an opportunity to evaluate focal loss, unlike the ffERG; future studies are planned to evaluate whether any benefit can be realized from this potential advantage, even in this EG model, which tends to manifest as more diffuse progressive damage rather than as sequential focal loss. Moreover, these researchers stated that further research is needed to examine if these observations will successfully translate to clinical management of human glaucoma.
Cvenkel et al (2017) examined discrimination ability of PERG and PhNR between early glaucoma and healthy controls, and their relationship with structural measurements using SD-OCT. These researchers carried out a cross-sectional study with 34 patients with ocular hypertension (n = 7), suspect glaucoma (n = 17), and early glaucoma (n = 10), plus 24 age-matched controls. The following parameters were analyzed: P50 and N95 amplitude of the PERG, PhNR amplitude and PhNR/b-wave ratio, peripapillary retinal and macular nerve fiber layer (NFL) thicknesses, and ganglion cell complex (GCC) thickness. Data from only 1 eye per individual were included in the statistical analysis. Descriptive statistics, ANOVA, ROC curves, and correlation tests were used for analysis of the variables. PERG N95 and PhNR amplitudes were significantly reduced in suspect and early glaucoma eyes versus controls. Significant differences across ocular hypertensive, suspect, and early glaucoma eyes were found for macular NFL and GCC thickness, but not for any of the ERG parameters. The mean PhNR amplitude did not differ across these groups and was already reduced on average by 46 % in ocular hypertensive and early glaucoma eyes and by 52 % in suspect glaucoma eyes. The P50 and N95 amplitudes showed similar reduction in suspect and early glaucoma eyes on average by 15 % and 26 %, respectively. Of the ERG parameters, PhNR amplitude distinguished best between glaucoma and control groups, with an area under ROC curve of 0.90 for suspect glaucoma, and 0.86 for early glaucoma. PhNR/b-wave ratio showed strongest association in suspect glaucoma eyes with peripapillary retinal (r = 0.61) and macular NFL (r = 0.76) thicknesses. In eyes with early glaucoma, peripapillary retinal NFL thickness correlated best with PhNR amplitude (r = 0.71) and PERG P50 amplitude (r = 0.67). The authors concluded that in eyes with suspect glaucoma, important decrease in PhNR amplitude was associated with small changes in peripapillary retinal and macular NFL thicknesses. These researchers stated that these findings suggested that PhNR may be a useful and sensitive test in eyes with diagnostic dilemma, although further follow-up of such eyes is needed for definitive confirmation.
Jeon et al (2019) examined the relationship between PERG and optic disc morphology in glaucoma suspect and glaucoma. A total of 86 eyes of glaucoma suspect and 145 eyes of manifest glaucoma subjects were included in this study. Average peripapillary RNFLT was obtained with SD-OCT, and optic disc imaging was performed using the Heidelberg Retinal Tomograph (HRT). Visual function was evaluated with perimetry (SITA and frequency doubling technology) and PERG. Scatter plots and correlation coefficients were evaluated between visual function and RNFLT or optic disc structure. Scatter plots of PERG and perimetry according to RNFLT change showed that PERG started to decrease earlier than did perimetry. The differences between linear and logarithmic R2 were largest for the scatter plot of SITA 24-2 (linear R2 = 0.415; logarithmic R2 = 0.443) and the smallest for P50 amplitude of PERG (linear R2 = 0.136, logarithmic R2 = 0.138). In glaucoma suspect, HRT parameters such as cup shape measure (CSM) and linear cup-disc ratio (CDR) had significant correlations with PERG amplitudes (p = 0.016 for P50 and 0.049 for N95 in CSM, p = 0.012 for P50 in CDR). However, in glaucoma patients, mean RNFLT was associated with PERG amplitude (p = 0.011 for P50 and 0.002 for N95). The authors concluded that PERG deterioration occurred earlier than did perimetry according to RNFLT decrease; PERG amplitudes were significantly correlated with disc morphology in glaucoma suspect. These researchers stated that these findings suggested that PERG can detect ganglion cell dysfunction before the cells die.
The authors stated that this study has the intrinsic limitation of a cross-sectional design, and as such, it was difficult to predict the progression probability or prognosis of study subjects. In future study, a longitudinal prospective study that could examine serial change of structure and functional parameters should be performed for clinical application of electrophysiologic test. In addition, this study excluded patients with increased IOP and it could make the results of this study not including all type of glaucoma.
Fernandes et al (2022) noted that PERG is a highly sensitive electrophysiological technique used as an indicator of changes in retinal macular area. Amblyopia appears to result from a cortical visual imbalance; however, changes at the retinal level may also be present. In a systematic review, these investigators examined if there are any consistent changes described in the literature in PERG responses of amblyopic eyes. These researchers carried out searches in PubMed and Embase databases, using the keywords "electroretinography" and "amblyopia", combined with MeSH or Emtree terms "pattern electroretinography", "amblyopia", "PERG" and "amblyopia". PERG P50-N95 amplitude and P50 latency were analyzed as well as the methodology used. A total of 234 articles were found and 6 articles were included for review – 1 article reported results in adults and 5 articles reported results in children. One of the articles in children reported no changes in either P50-N95 amplitude or P50 latency. All articles that described differences between the amblyopic eye and the normal eye found a decrease in P50-N95 amplitude and/or a delay in P50 latency. The authors concluded that this review showed promising findings for the use of PERG in amblyopia as an aid in the diagnostic protocol, since this technique may be able to detect an apparent functional impairment of the amblyopic eye.
Schwitzer et al (2022a) stated that major depressive disorder (MDD) is a major public health problem. The retina is a relevant site to indirectly study brain functioning. Alterations in retinal processing were demonstrated in MDD with PERG. These researchers examined the relevance of signal processing and machine learning tools applied on PERG. PERG -- whose stimulation is reversible checkerboards -- was carried out according to the International Society for Clinical Electrophysiology of Vision (ISCEV) standards in 24 MDD patients and 29 controls at the inclusion. PERG was recorded every 4 weeks for 3 months in patients. Amplitude and implicit time of P50 and N95 were evaluated. Then, time/frequency features were extracted from the PERG time series based on wavelet analysis. A statistical model has been learned in this feature space and a metric aiming at quantifying the state of the MDD patient has been derived, based on minimum co-variance determinant (MCD) mahalanobis distance. MDD patients showed significant increase in P50 and N95 implicit time (p = 0.006 and p = 0.0004, respectively, Mann-Whitney U test) at the inclusion. The proposed metric extracted from the raw PERG provided discrimination between patients and controls at the inclusion (p = 0.0001). At the end of the follow-up at week 12, the difference between the metrics extracted on controls and patients was not significant (p = 0.07), reflecting the effectiveness of the treatment. The authors concluded that signal processing and machine learning tools applied on PERG could aid in clinical decision-making in the diagnosis and the follow-up of MDD in measuring treatment response. These preliminary findings need to be validated by well-designed studies.
In a review on “A reflection upon the contribution of retinal and cortical electrophysiology to time of information processing in psychiatric disorders”, Schwitzer et al (2022b) concluded that future studies using electrophysiological techniques in psychiatric disorders and substance uses will include combined and synchronized measures of retinal and cortical electrophysiology by ERG and visual evoked potentials (VEP) as well as the retinocortical time. These researchers stated that studying visual electrophysiology from the retina to the brain is promising for a better understanding of pathophysiological mechanisms underlying psychiatric disorders and could also provide additional electrophysiological markers for precision medicine in psychiatry.
Global Flash Electroretinography for Evaluation of Refractive Errors
Zahra et al (2023) noted that refractive errors (e.g., myopia and hyperopia) are the most common visual disorders and are severe risk factors for secondary ocular pathologies. The development of refractive errors has been reported to be associated with changes in ocular axial length, suggested to be induced by outer retinal elements. In a systematic review, these investigators examined the available evidence on the use of global flash ERG (gfERG) for evaluating retinal function in human clinical refractive error populations. Electronic database searching via Medline, PubMed, Web of Science, Embase, Psych INFO, and CINAHL retrieved 981 unique records (last searched on the May 29, 2022). Single-case studies, samples with ocular co-morbidities, drug trials, and reviews were excluded. Demographic characteristics, refractive state, gfERG protocol details, and waveform characteristics were extracted for the 8 studies that met the inclusion criteria for the review and were judged to have acceptable risk of bias using the OHAT tool (total n = 552 subjects; age of 7 to 50 years). The authors concluded that study synthesis suggested that myopia in humans entailed attenuation of gfERG photo-receptor (a-wave) and bi-polar cell (b-wave) function, consistent with the animal literature. Meaningful interpretation of the overall findings for hyperopia was limited by inconsistent reporting, highlighting the need for future studies to report key aspects of gfERG research design and outcomes more consistently for myopic and hyperopic refractive errors. Moreover, these researchers stated that higher quality studies consistently and explicitly reporting on gfERG outcomes are needed to further clarify the evidence.
The authors stated that this review had several drawbacks were common across the included studies. First, some early studies did not follow ISCEV standards for testing, as they were carried out prior to the standards were established. Thus, methods of gfERG testing varied in these studies considerably. Studies that followed the ISCEV protocol for gfERG stimuli often failed to adhere to the durations outlined for dark-adaptation and light-adaptation. The current ISCEV standard specifies a minimum of 20 mins for dark-adaptation and 10 mins for light-adaptation. Failure to adhere to the duration of adaptation means the rod systems isolated by dark-adaptation and cone systems isolated by light-adaptation may have been inadequately assessed. Second, in some cases, reporting of the results did not provide clear indications regarding the direction of change for the outcomes measured. Reporting of the outcomes was too general in these instances to determine which aspects of the ERG waveform were affected and to what degree this effect was detected. Third, the included studies covered a wide age range, and few studies reported whether the comparison groups were age-matched. Therefore, age-matching remains a crucial factor to consider, given that age-related changes in the ERG have long been recognized, and the stability of refractive state and likelihood of secondary associated pathology vary across the life span.
Full-Field Electroretinography for Evaluation of Vogt-Koyanagi-Harada Disease and Exudative Retinal Detachment
Moschos et al (2014) stated that uveitis is the inflammation of the uveal tract, which usually also affects the retina and vitreous humor. The electrophysiological examination is an objective ocular examination that includes the ERG, visual evoked potentials (VEPs), the EOG, the mfERG, and mfVEPs. In a systematic review, these investigators examined the literature on the use of the electrophysiological examination in cases of uveitis. They carried out a systematic search of the literature of published papers until October 2012 using the PubMed search engine. The key terms that were used were “uveitis”, “electrophysiological examination”, “electroretinogram”, “visual evoked potentials”, “electrooculogram”, “multifocal electroretinogram”, and “multifocal visual evoked potentials” in multiple combinations. To the best of the authors’ knowledge, this was the 1st review concerning the assessment of electrophysiology in uveitis. The search of the literature revealed that the electrophysiological examination, mainly by means of ERG, mfERG, and VEPs, is carried out in several cases of uveitis for many purposes, including diagnosis and monitoring of disease progression and treatment effectiveness. The electrophysiological examination is more useful in patients with multiple evanescent white dot syndrome, acute posterior multi-focal placoid pigment epitheliopathy, birdshot chorioretinopathy, Vogt–Koyanagi-Harada (VKD) disease, Adamantiades-Behcet disease (ABD), ocular syphilis, and Fuchs heterochromic cyclitis. The authors concluded that this review summarized the use of the electrophysiological examination in uveitic patients and underlined its value as a useful tool in the objective assessment and the monitoring of the disease.
Furthermore, American Academy of Ophthalmology EyeWiki on “Vogt-Koyanagi-Harada disease” (Feldman et al, 2023) noted that full-field ERG analysis demonstrated diffusely diminished amplitudes in both scotopic and photopic phases in patients in the chronic stage.
Full-Field Flash Electroretinography Monitoring During Endoscopic Trans-Sphenoidal Pituitary Mass Resection
StatPearls’ webpage on “Full-field electroretinogram” (Asanad and Karanjia, 2022 ) does not mention endoscopic trans-sphenoidal pituitary mass resection as an indication for full-field ERG.
Furthermore, an UpToDate review on “Transsphenoidal surgery for pituitary adenomas and other sellar masses” (Swearingen, 2023) does not mention full-field flash ERG as a management option.
Pattern Electroretinography for the Management of Patients with Macular Drusen
Tanner et al (2021) reported on the case of a 35-year-old woman with acquired partial lipodystrophy (PLD) and features of type 2 membranoproliferative glomerulonephritis (MPGN-II), who presented with difficulty in her fine detailed vision over the past year. She had right amblyopia from a hypermetropic anisometropia with astigmatism, displaying a best-corrected visual acuity (BCVA) of 0.50 and 0.00 LogMAR, in the right and left eye, respectively. Fundoscopy showed bilateral symmetrical drusenoid deposits most prominent in the temporal macula with clusters in the superior and inferior retina, outside the temporal vascular arcades. Multi-modal retinal imaging was performed, which confirmed hyper-auto-fluorescent drusen located between the retinal pigment epithelium and Bruch's membrane. Electroretinography (ERG) showed bilateral mild peripheral macular dysfunction, but normal central macular function on the pattern electroretinogram. Both PLD and macular drusen, are rare as distinct disease entities, but an association does exist and may be linked to MPGN-II.
Furthermore, an UpToDate review on “Congenital and acquired abnormalities of the optic nerve” (Golnik, 2023) does not mention pattern electroretinogram as a management / therapeutic option.
Electroretinography for Identification of Biomarkers of Idiopathic Hypersomnia and Narcolepsy Type 1
Rach et al (2024) stated that hypersomnia spectrum disorders are under-diagnosed and poorly treated due to their heterogeneity and absence of biomarkers; ERG has been proposed as a proxy of central dysfunction and has proved to be valuable to differentiate certain psychiatric disorders. Hyper-somnolence is a shared core feature in central hypersomnia and psychiatric disorders. These researchers attempted to identify biomarkers by examining ERG profile in patients with narcolepsy type 1 (NT1), idiopathic hypersomnia (IH), and in healthy controls (HCs). Cone, rod, and retinal ganglion cells electrical activity were recorded with flash-ERG in non-dilated eye of 31 patients with IH (women 84 %, 26.6 ± 5.9 years), 19 patients with NT1 (women 63 %, 36.6 ± 12.7 years), and 43 HCs (women 58 %, 30.6 ± 9.3 years). Reduced cone a-wave amplitude (p = 0.039) and prolonged cone (p = 0.022) and rod b-wave (p = 0.009) latencies were observed in patients with NT1 as compared with HCs, while prolonged photopic negative response-wave latency (retinal ganglion cells activity) was observed in patients with IH as compared with HCs (p = 0.033). The rod and cone b-wave latency clearly distinguished NT1 from IH and HCs (area under the curve [AUC] greater than 0.70), and the photopic negative response-wave latency distinguished IH and NT1 from HCs with an AUC of greater than 0.68. This 1st original study revealed ERG anomalies observed in patients with hypersomnia; NT1 was associated with impaired cone and rod responses, whereas IH was associated with impaired retinal ganglion cells response, suggesting different photo-transduction alterations in both hypersomnia. The authors concluded that although these preliminary findings need to be confirmed with a larger sample size, ERG may be a promising tool for clinicians to differentiate hypersomnia subtypes. These investigators stated that further investigations should compare retinal response of IH with long sleep time and NT1 with other central hypersomnia subtypes such as IH without long sleep time and narcolepsy type 2 (NT2), their distinction being one of the major diagnostic pitfalls. Furthermore, retinal markers should be combined with other markers, such as pupillometry or polysomnographic markers, and may aid in increasing the prediction values to diagnose central hypersomnia subtypes.
The authors stated that his study had several drawbacks. First, whereas this was the 1st study examining ERG biomarkers between IH and NT1, the sample size of 93 individuals may be considered as small as several co-variates were added to the statistical models. However, adjusting on age, sex, and pupil diameter was necessary to ensure that the differences in ERG responses found between groups were not explained by these factors. Second, analyses of diagnostic accuracy (sensitivity, specificity, and AUC) did not take confounding factors into account, which could result in an over-estimation of the discriminative properties of the ERG. Third, the absence of artificially induced mydriasis. Indeed, it is recommended to maximize the amount of ERG response; however, mydriasis has side-effects, such as blurred vision, high eye sensitivity to light and headaches. Pupil diameter was added as a co-variate in the analysis to counter the potential effect of non-dilated eyes, and these researchers used an adapted luminance to at least partially compensate for the absence of pupil dilation. Fourth, latency has been described in the art as a robust and highly reproducible parameter, poorly influenced by acquisition technique, and the presence or absence of mydriasis. Fifth, medication may affect ERG response; thus, it would be interesting for future studies to take this aspect into account (e.g., by using subgroup analyses within a larger sample or by performing a prospective analysis, before patients are treated for their hypersomnia).
Electroretinography / Multi-Focal Electroretinography for Major Depressive Disorder
de Deus et al (2024) noted that MDD is characterized by at least one major depressive episode. It requires medical attention typically involving the prescription of anti-depressants. Remission in MDD patients is often difficult to achieve because of the limited effectiveness of these drugs. To-date, many patients receiving various anti-depressant treatments, with subjective changes in their personal experiences being regularly monitored thus, it is important to find clinical and objective tools that offer a more tailored approach to anti-depressant selection. These researchers stated that since the neurochemistry of the retina is similar to the brain, one promising method would be to use ERG measurements on MDD patients requiring anti-depressant treatment. In a scoping review, these investigators highlighted the effects of different classes of anti-depressants on retinal function examined by ffERG, PERG and mfERG waveforms in MDD patients. The authors concluded that these ERG measurements could serve as pivotal indicators in defining patient profiles, facilitating a more objective and personalized approach to therapeutic interventions; thus, advancing precision psychiatry. Moreover, these researchers stated that the number of studies on anti-depressants and ERGs remains insufficient. They stated that even if more studies are needed on the topic of this review in the near future, ERG could be one of tomorrow's tools to improve MDD patients' care. Indeed, thanks to ERG patient’s profiles, potential responders and non-responders to anti-depressants could be distinguished. Therapeutic decisions would thus be facilitated for clinicians, in particular for the 1st-line anti-depressant choice and the monitoring of the response to this treatment. These researchers stated that ERG tests are a real hope to improve the daily lives of MDD patients thanks to a quickly appropriate anti-depressant treatment. By combining it with other clinical examinations, the long-term objective would be to integrate them into everyday practice. This multi-modal approach associated with ERG could contribute to the development of precision medicine in the field of psychiatry.
The authors stated that his study had several drawbacks. First, the limited number of included studies could be attributed to the novelty of the subject. Indeed, 9 of the 12 studies included were published between 2010 and 2022; therefore, antidepressant effects on ERG results are an innovative subject where a lot of knowledge is still to be discovered. For example, studies on the subjects were mainly based on ffERG results whereas interesting results could be found with PERG and mfERG. Indeed, mfERG and PERG are complementary and could complete the ffERG results since these techniques enable the study of different anatomical zones. PERG waves allow the study of the macula, mfERG measurements allow the study of the fovea, whereas ffERG allows recording the electrical potentials of the peripheral retina. Second, these 3 types of ERG record different functional properties. PERG waves represent all retinal cells layers; mfERG measurements represent cone bipolar cells with cone participation; whereas ffERG waves record photo-receptors and associated bipolar cells; therefore, another review should be written when new studies will be released, notably with PERG and mfERG results. In this case, more studies should examine the role of neurotransmitters or other mechanisms for mfERG and PERG results with anti-depressants. This would validate potential mfERG and PERG results in these future studies. Indeed, no studies have examined the biological mechanisms underlying mfERG results and only 2 studies have examined it for PERG. Third, there aren't any human or mice studies on the noradrenaline action on ERG results; however, it’s essential to carry out studies on the topic, noradrenaline being a monoamine implicated in anti-depressant actions.
Multi-Focal Electroretinography for Diagnosis of Stargardt Disease
Tosha et al (2010) examined test-retest reliability and inter-ocular symmetry of mfERG recordings in Stargardt disease (STGD) and in patients without retinal pathology. mfERG were recorded with continuous fundus monitoring using the VERIS multi-focal recording system using an array of 103 hexagons spanning 50 degrees of central retina. Recordings were made sequentially from one eye (test-retest) followed by recordings from the fellow eye. A departure score, expressed as a percentage difference from the 1st recording (or from the fellow eye), was calculated for each comparison and parameter. mfERG response topographies were similar within and between eyes for a particular individual and parameter; however, local response variability within and between eyes was significantly higher in STGD than in patients without retinal pathology for both amplitude and timing parameters. Amplitude variability in STGD decreased with more peripheral targets and with larger stimuli but never to the levels achieved with normal observers. The authors concluded that both test-retest reliability and inter-ocular symmetry of mfERG responses were significantly lower in STGD compared to normal eyes, a finding attributable primarily to unsteady fixation. The greater variability between eyes in STGD may also reflect pathological differences in the topography of retinal function. This inherent variability must be taken into consideration if the mfERG is to be sufficiently sensitive to reliably detect small differences in retinal function. Moreover, these researchers noted that mfERG reliability can be relatively poor in STGD and likely also in any other patient population with pathology involving the central retina. This finding would make mfERG a relatively insensitive measure to be used to examine the effectiveness of a therapeutic intervention in a clinical trial. In addition, while mfERG is a very useful tool to evaluate the status of central retinal function in disease, the weak reliability would preclude its use as a measure of serial change unless methods can be developed to better stabilize the retinal image much like what has been performed for visual field testing. For example, it would be difficult to interpret the meaning of a decrease in average amplitude of 20 % over the course of 1 year in a patient with a test-retest variability rate on the order of 20 % to 25 %. However, these investigators found that reliability could be enhanced substantially, at least for amplitude variations, if the “effective” stimulus size was increased. These researchers reported that when response amplitudes were averaged over larger areas, either rings concentric with the fovea, or for disks of progressively larger angular diameters, the variation between test sessions could be reduced significantly, although never to the levels observed in subjects without macular pathology. Moreover, while the authors found consistent delays in the implicit time of P1 amplitude in STGD, the test-retest reliability for this parameter was much better than that for amplitude, suggesting that changes in timing may, in fact, be a better and a more sensitive index of serial change. This hypothesis is consistent with previous research showing that the implicit time of mfERG, not amplitude, is the more sensitive measure of damage in degenerative diseases involving loss of photoreceptor cells. Furthermore, these investigators examined the symmetry of responses between eyes in both normal and in patients with STGD. The difference in response amplitude at any location between eyes for both normal and STGD subjects was significantly larger than that observed within an eye on test-retest, although the magnitude of the difference between eyes was approximately the same for both groups of individuals. Nevertheless, the agreement between eyes was weaker for STGD subjects, although the difference between the inter-class correlation coefficient (ICC) for normal and STGD did not reach statistical significance. The larger difference between eyes could simply be due to procedural differences (i.e., the contact lens electrode was not removed for test-retest recordings but was, of course, removed and inserted into the fellow eye for inter-ocular comparisons). However, these researchers could not preclude the possibility that the greater variability between eyes in STGD may also reflect pathological differences in the topography of retinal function in affected eyes.
In a study entitled “Test-retest variability of functional and structural parameters in patients with Stargardt disease participating in the SAR422459 gene therapy trial”, Parker et al (2019) stated that ”To our knowledge, there is currently limited information regarding the test-retest variability in STGD patients in the late stages of their disease. These previous studies have examined repeatability of microperimetry and multifocal ERG, but there is currently no published test-retest information regarding visual acuity, visual fields, and structural measures acquired by spectral-domain optical coherence tomography (SD-OCT) for STGD patients … These data can be useful for designing future clinical trials and show the challenges and importance of performing repeat testing prior to treatment. Similar analyses should be performed for patients with different stages of disease”.
Full-Field Electroretinography for Diagnosis of Congenital Stationary Night Blindness
Miraldi Utz et al (2018) noted that congenital stationary night blindness (CSNB) denoted a stable condition, with the major symptom being nyctalopia present at birth. Pediatric clinical presentation and the course of different genetic subtypes of CSNB have not been well-described in the era of molecular genetic diagnosis. In a retrospective, longitudinal, case-series study, these researchers described the presentation and longitudinal clinical characteristics of pediatric patients with molecularly confirmed TRPM1-associated complete CSNB (cCSNB). This study was carried out at the University of Iowa from January 1, 1990, to July 1, 2015, and included 7 children (5 [71.4 %] female) with TRPM1-associated cCSNB followed-up for a mean (SD) of 11.1 (2.8) years. History, ophthalmologic examination findings, ffERG results, full-field stimulus threshold testing results, Goldmann visual field results, OCT results, and molecular genetic results were evaluated. Presenting symptoms and signs, the correlation of refractive error with ERG, and clinical evolution were analyzed. A total of 7 patients presented early in childhood with strabismus (n = 6 [86 %]), myopia (n = 5 [71 %]), and/or nystagmus (n = 3 [43 %]) were included in this study. The mean (SD) age at presentation was 8 (4) months and for receiving a diagnosis by ffERG was 7.3 years, with molecular diagnosis at 9.7 years. The mean (SD) length of follow-up was 11 (2.8) years. The BCVA at the most recent visit averaged 20/30 in the better-seeing eye (range of 20/20 to 20/60). The mean (SD) initial refraction was -2.80 (4.42) diopters (D) and the mean refraction at the most recent visit was -8.75 (3.53) D (range of -4.00 to -13.75 D), with the greatest rate of myopic shift before age 5 years. Full-field electroretinogram results were electro-negative, consistent with cCSNB, without a significant change in amplitude over time. No patient or parent noted night blindness at presentation; however, subjective nyctalopia was eventually reported in 5 of 7 patients (71 %). The full-field stimulus threshold testing results were moderately subnormal (-29.7 [3.8] dB; normal -59.8 [4.0] dB). Goldmann visual field results were significant for full I-4e, but constricted I-2e isopter. A total of 8 different mutations or rare variants in TRPM1 predicted to be pathogenic were detected, with 3 novel variants. The authors concluded that children with TRPM1-associated cCSNB presented before school age with progressive myopia as well as strabismus and nystagmus (but not nyctalopia), with stable, electro-negative ffERG results, mildly subnormal full-field stimulus threshold testing results, and a constricted I2e isopter on perimetry. These findings suggested that ffERG and cCSNB genetic testing should be considered for children who present with early-onset myopia, especially in the presence of strabismus and/or nystagmus, and that TRPM1-associated cCSNB is a channelopathy that may present without complaints of night blindness in childhood.
Almutairi et al (2021) stated that CSNB is a group of rare, mainly stationary disorders of the retina, resulting from dysfunction of several specific and essential visual processing mechanisms. The inheritance is often recessive and as such, CSNB may be more common among populations with a high degree of consanguinity. These investigators presented a topic update and a review of the clinical and molecular genetic spectrum of CSNB in Saudi Arabia. They noted that since a 2015 major review article on CSNB described 17 genes underlying CSNB, an additional 4 genes have been incriminated in autosomal recessive CSNB: RIMS2, GNB3, GUCY2D and ABCA4. These have been associated with syndromic cone-rod synaptic disease, ON-center bipolar cell dysfunction with reduced cone sensitivity, CSNB with dysfunction of the photo-transduction (Riggs type) and CSNB with cone-rod dystrophy, respectively. In Saudi Arabia, a total of 24 patients with CSNB were identified, using a combination of literature search and retrospective study of previously unpublished cases. Recessive mutations in TRPM1 and CABP4 accounted for the majority of cases (5 and 13 for each gene, respectively). These genes were associated with cCSNB and incomplete CSNB (icCSNB), respectively, and were associated with high myopia in the former and hyperopia in the latter; 4 novel mutations were identified. The authors concluded that for the 1st time, they described the fundus albipunctatus in 2 patients from Saudi Arabia, caused by recessive mutation in RDH5 and RPE65, where the former in addition featured findings compatible with cone dystrophy. No cases were identified with any dominantly inherited CSNB. These investigators noted that assessment of patients with CSNB included multi-modal retinal imaging entailing cross-sectional OCT; color fundus photography; and Optos PLC. Visual acuity was measured in Snellen format; and retinal function was examined by means of ffERG ERG, in dark-adapted and light-adapted state according to ISCEV guidelines with a few modifications.
Bai et al (2024) noted that CSNB is a group of clinically and genetically heterogeneous, mainly non-progressive hereditary retinal disorders, which are characterized by dysfunction of the photo-transduction cascade, signal transmission defect from the photo-receptors to the bipolar cells or defective retinoid recycling in the retinal pigment epithelium (RPE). Clinical symptoms of CSNB are mainly impaired night vision or poor adaption to darkness, and other manifestations, such as poor VA, myopia, photophobia, nystagmus, strabismus, and fundus abnormalities can also occur. Based on ffERG, patients of CSNB with normal fundi can be distinguished into 2 types, the Riggs type, and the Schubert-Bornschein type. The former, which is infrequent, features decreased a-wave amplitude in the scotopic bright flash ERG, indicating a defect in the rod photo-receptor. Usually, the phenotype of Riggs type is relatively mild, including night blindness but no high myopia, no nystagmus and normal photopic VA. The Schubert-Bornschein type is further divided into cCSNB and icCSNB). cCSNB is caused by dysfunction in the ON bipolar pathway. There is no detectable ERG to a scotopic dim flash and there is an electro-negative scotopic bright flash ERG with a normal a-wave and severely reduced b-wave in cCSNB. Patients with cCSNB usually have a history of congenital night blindness, decreased VA, moderate-to-high myopia, strabismus, and nystagmus. Color vision and visual fields are usually not affected and the fundus appearance is usually normal other than myopic changes. icCSNB is associated with dysfunction in both ON and OFF pathways. The scotopic dim flash ERG is present in icCSNB but of subnormal amplitude and there is a normal a-wave in the scotopic bright flash ERG. The phenotype of icCSNB is more heterogeneous than cCSNB. The patients with icCSNB may present with little or no light vision disturbances, variable degree of refractive error from myopia to hyperopia, various degree of nystagmus and strabismus. Visual fields and fundus appearance are normal in icCSNB while color vision may show variable defects and VA is lower than in cCSNB. Cone responses are typically less affected than the rod responses, in all forms of CSNB.
Huang et al (2024) stated that CSNB is an inherited retinal disorder; and most of patients have myopia. It is generally characterized by impaired night vision, decreased VA, nystagmus, myopia, and strabismus. Based on the ERG recordings, CSNB can be classified into 2 groups of the Schubert-Bornschein type and Riggs type. The Schubert-Bornschein type is characterized by a selectively reduced ERG b-wave at the scotopic light flash, indicating dysfunction at the level of bipolar cells. The Riggs type is characterized by a proportional reduction of the a- and b-waves, indicating dysfunction at the level of the photo-receptor and bipolar cells. Moreover, the Schubert-Bornschein type can be subdivided into complete and incomplete forms -- cCSNB is characterized by a severely reduced b-wave with a normal a-wave under photopic conditions indicating ON bipolar dysfunction; and icCSNB) is characterized by a reduced rod b-wave and substantially reduced cone responses indicating dysfunction of both ON and OFF bipolar cells These investigators described the clinical and genetic characteristics of 59 patients with CSNB and examined myopic progression under genetic cause. A total of 65 variants were detected in the 59 CSNB patients, including 32 novel and 33 reported variants. The most frequently involved genes were NYX, CACNA1F, and TRPM1. Myopia (96.61 %, 57/59) was the most common clinical finding, followed by nystagmus (62.71 %, 37/59), strabismus (52.54 %, 31/59), and nyctalopia (49.15 %, 29/59). An average SE of -7.73 ± 3.37 D progressed to -9.14 ± 2.09 D in NYX patients with myopia, from - 2.24 ± 1.53 D to -4.42 ± 1.43 D in those with CACNA1F, and from - 5.21 ± 2.89 D to -9.24 ± 3.16 D in those with TRPM1 during the 3-year follow-up; the TRPM1 group showed the most rapid progression. The authors concluded that high myopia and strabismus are distinct clinical features of CSNB that are helpful for diagnosis. The novel variants identified in this study will further expand the knowledge of variants in CSNB and aid in examining the molecular mechanisms of CSNB.
An UpToDate review on “Pendular nystagmus” (Barton, 2024) states that “Clinical features distinguish spasmus nutans from congenital nystagmus. A positive family history and infantile myopia are clues to congenital stationary night blindness; the diagnosis is made with electroretinogram (ERG)”.
Furthermore, an EyeWiki review on “Congenital stationary night blindness (CSNB)” (Tang et al, 2024) states that “ERG plays a critical role in the diagnosis of CSNB. As previously described the ERG is crucial to distinguish the four subtypes of CSNB and also assists in distinguishing between cCSNB and iCSNB”.
Electroretinography for Diagnosis of Suicidal Ideation
Kaggwa et al (2023) stated that ERG is one of the tools used to examine the electrophysiological underpinnings of mental illnesses and major clinical phenomena (e.g., suicide) to improve their diagnosis and care. While multiple studies have reported specific ERG changes among individuals with suicidal behaviors, these investigators were unaware of any review that has been carried out to characterize their findings to inform future research. This review included available literature concerning ERG and suicidal behaviors. This article's 1st section briefly provided an overview on the theoretical basis of ERG and neurotransmitters involved in suicidal behaviors. The 2nd section described the findings of a review of studies reporting ERG findings among individuals with suicidal behaviors. Most reviewed studies reported normal amplitude and implicit time of the a-waves; however, the latency in individuals with suicidal behaviors was lower than normal. Furthermore, the b-waves amplitude was reduced; however, the implicit time and latency were increased. The b-a amplitude ratio and oscillatory potential were decreased. The authors concluded that despite identifying certain ERG correlates with suicidal behaviors in the existing studies, there is a need for adequately powered and methodologically robust studies to advance the potential utility of ERG findings as biomarker in suicidology. Notably, further studies are needed to examine the relationship between ERG waves, retinal neurotransmitters, and suicidal behaviors.
The authors stated that this review had several drawbacks. First, the majority of the studies were case reports and lacked sufficient statistical power to confirm the actual effect or changes in the ERG waves caused by suicidal behaviors. It also made it difficult to distinguish the effects of cofounders to clarify whether the effect on ERG wave is due to medications, suicidal behaviors, or psychiatric illness. Second, there was no actual link between neurotransmitters in the retina and specific regions responsible for suicidal behaviors in the brain, rendering the conclusions on the findings regarding ERG correlates of suicidal behaviors difficult since no study has examined such results to implicate specific brain regions. These researchers recommended that future studies examine this possible link. Third, the OP waves are not specific to retinal neurotransmitters and may not be specific to inhibitory or excitatory cells in the amacrine cells, which have many neurotransmitters that are correlated with suicidal behaviors. The lack of specificity of the waves to distinguish between the neurotransmitters made detecting suicidal behaviors difficult. These investigators recommended that future researchers examine the effect of individual neurotransmitters on the OP waves and other waves of the ERG. This will advance the knowledge of eliciting potential biomarker that is more specific and reliable. Fourth, only few studies had examined ERG use among individuals with suicidal behaviors. These studies were limited because of cross-sectional design and small sample size; therefore, causality could not be inferred. The authors recommended future studies should be prospective, and with larger sample sizes to allow the detection of the small changes in the different wave measurements, such as latency, and amplitude, among others. Fifth, distinguishing between the severity of suicide from depression is complex using ERG because of the high level of similarities between the neurotransmitters involved in the 2 conditions. Future researchers should examine suicidal behaviors among individuals with and without depression to detect the ERG differences in the 2 conditions using a control. Sixth, many studies were conducted months after the suicidal attempt, and it was hard to determine the effect or correlates of suicidal behavior on the ERG. A follow-up study proximal to the suicidal attempt may yield better results for at least 6 months following the suicidal attempt since ERG changes related to suicide were observed at 6 months. Seventh, most studies involved females, and significant differences between genders may need to be examined. Furthermore, the extreme of ages were not studied; thus, future studies should consider matching the populations studied and controlling for variables that may confound, such as gender, age, and medication use, among others. Eighth, the ISCEV standards for ERG use are updated regularly, making ERG comparisons difficult as the case studies used for this review span decades, including before the 1st ISCEV standards were published.
Furthermore, an UpToDate review on “Suicidal ideation and behavior in children and adolescents: Evaluation and disposition” (Kennebeck and Bonin, 2024) does not mention electroretinography/ERG as a management tool.
References
The above policy is based on the following references:
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