Electroretinography (ERG) is considered reasonable and medically necessary
for:

  1. Detection of loss of retinal function, **OR**
  2. To distinguish retinal from optic nerve lesions, **OR**
  3. Detecting chloroquine and hydroxychloroquine toxicity

ERG is investigational for all other indications, including glaucoma.

_Background:_

The full-field electroretinogram (ERG) is used to detect loss of retinal
function or distinguish between retinal and optic nerve lesions. ERG measures
the electrical activity generated by neural and non-neuronal cells in the
retina in response to a light stimulus. ERGs are usually obtained using
electrodes embedded in a corneal contact lens or a thin wire inside the lower
eyelid, which measures a summation of retinal electrical activity at the
corneal surface. The ERG provides information about the macula, composed
mainly of cones and used for primary central and color vision, and the rest of
the retina is mainly composed of rod photoreceptors, used in peripheral and
night (scotopic) vision. By providing information about the rods and cones,
ERG helps distinguish retinal degeneration and dystrophies.1 The International
Society for Clinical Electrophysiology of Vision (ISCEV) introduced minimum
ERG standards in 1989. The ERG helps to distinguish retinal degeneration and
dystrophies.2 The widespread use of electrophysiological measurements has been
hindered by limitations associated with its widespread clinical implication
and large magnitude of measurement variability.3

_Definitions:_

Full-Field ERG (ffERG)- measures mass response for the retina in response to
flashing lights and is valuable for conditions with widespread retinal
dysfunction but not useful for small retinal lesions.4

Focal ERG (fERG)- also called foveal ERG, measures the functional integrity of
the central macula.4

Multifocal ERG (mfERG)- higher resolution form of ERG, enabling assessment of
ERG activity in small areas of the retina by measuring local ERG responses and
providing spatial information. It measures the photoreceptors and aids in the
detection of localized abnormalities within the macula.2,4

Pattern electroretinography (PERG) (also called reversal pattern ERG) uses
pattern-reversal stimuli to elicit electrical activity in the retina and
monitor retinal ganglion cell activity, and used to detect subtle optic
neuropathies.2,5

Photopic Negative Response ERG (PhNR) is a slow ERG wave recorded under
photopic conditions and accesses ganglion cells on cones and bipolar cells.6

**ERG for Retinal Dysfunction**

ERG has played a role as a diagnostic tool for retinal disease since its
inception in the 1940s. It has become a standard tool for the assessment of
retinal function. It plays a role in the early detection of diabetic
retinopathy, and there are treatments if detected early. ERG, in various
forms, provides an objective assessment of retinal function and can aid in
assessment and monitoring in treatment outcomes for acquired and hereditary
retinal disorders. There is robust literature composed of hundreds of articles
to support ERG and mfERG for retinal evaluation.7 Full-field ERG is limited as
the recording is massed potential from the whole retina. Unless 20% or more of
the retina is affected, the ffERG may be normal. Multi-focal ERG produces
higher resolution images than ffERG, allowing assessment of a smaller area of
the retina.8 The International Society for Clinical Electrophysiology of
Vision (ISCEV) established a guideline for ERG testing.9-12 Literature for
PERG is limited.

The American Academy of Ophthalmology (AOA) Clinical Assessment of Patients
with Inherited Retinal Degenerations13 includes ERG. The guidelines state:
"The full-field electroretinogram (ERG) is important for diagnosis and staging
of disease and is useful for many patients with diffuse photoreceptor disease
to evaluate the retina-wide function of rods and cones. Multifocal ERG testing
can be useful for detection and monitoring disease progression for diseases
that primarily affect the macula. However, its accuracy can be limited in
those patients with a notable loss of central vision who are unable to
maintain steady foveal fixation." They also recommend following ISCEV
standards so recordings can be compared between institutions and examiners.

The supporting literature includes support for the use of ERG for the
following indications:4,7

Toxic retinopathies, including those caused by intraocular metallic foreign
bodies, Vigabatrin, Chlorpromazine, and Amiodarone

  * Diabetic retinopathy
  * Retinal vascular disease [e.g., Central Retinal Artery Occlusion (CRAO), Central Retinal Vein

Occlusion (CRVO), Branch Vein Occlusion (BVO), and sickle cell retinopathy]

  * Autoimmune retinopathies [e.g., Cancer Associated Retinopathy (CAR), Melanoma Associated

Retinopathy (MAR), and Acute Zonal Occult Outer Retinopathy (AZOOR)]

  * Retinal detachment
  * Retinal transplantation
  * Assessment of retinal function after trauma [e.g., vitreous hemorrhage, dense cataracts, and other conditions where the fundus cannot be visualized]
  * Retinitis pigmentosa and related hereditary degenerations
  * Retinitis punctata albescens
  * Leber's congenital amaurosis
  * Choroideremia
  * Gyrate atrophy of the retina and choroid
  * Goldman-Favre syndrome
  * Congenital stationary night blindness
  * X-linked juvenile retinoschisis
  * Achromatopsia
  * Cone dystrophy
  * Disorders mimicking retinitis pigmentosa
  * Usher Syndrome
  * Retinal Dystrophies (e.g., Stargardt's disease, Fundus Flavimaculata, North Carolina macular dystrophy, Best's Vitelliform dystrophy, Sorsby's macular dystrophy)
  * Phototoxic Retinopathy

**ERG for Glaucoma**

Reports of using ERG for glaucoma management began to emerge in the 1950s, but
clear normative values and standards have limited uptake of glaucoma
technology. A 2011 report by the AAO summarized the literature through 2010.
In this review, 185 papers were evaluated, and the quality of literature was
rated with the Centre for Evidence-Based Medicine rating scale. The results of
this analysis, "Assessment of Visual Function in Glaucoma," reported that
while ERG, as objective measures of visual function, provided testing free of
patient input, issues prevent their adoption for glaucoma management. It
concluded that advances in technology have yet to produce definitive guidance
on the diagnosis of glaucoma or its progression over time and that further
research on an objective measure of visual function is needed.14 The 2011 APP
report stated that while there was emerging evidence on the role of ERG in
glaucoma, they concluded that the test was "not ready for widespread clinical
use".14

Researchers have been interested in the early detection of glaucoma and the
detection of potential converters to help reserve preventive treatment for
those who need it. PERG has been explored as a potential modality to
accomplish this. Bach et al. (2006) conducted a prospective study on 95 eyes
of 54 patients with elevated intraocular pressure >25mg Hg. PERG was performed
every six months over 8.2 years. This accumulated previous reported outcomes
from the same cohort, so results were for findings over 12 years. They
conclude that PERG can help predict the stability of progression to glaucoma
at least one year ahead of conversion based on 8/95 eyes (5 patients) who
converted to glaucoma.15 Limitations of the study include that treatment was
allowed, and all converting eyes received treatment before conversion. They
report a sensitivity of 80% and specificity of 71%, with only 1-2% of those
with ocular hypertension at risk for conversion to glaucoma; this low
specificity would not offer strong predictive value, and at best, would serve
as an adjunct measurement. There were not clinical recommendations as to the
benefit of early detection, and the treatment used at that time did not
prevent the conversion to glaucoma. Finally, as refractive errors can
interfere with PERG testing, they only included patients with good visual
acuity, reducing the applicability of findings to the general population.

Between 2010-2013 additional longitudinal studies have shown the potential
benefit of ERG, specifically PERG, in glaucoma management; still, these
studies are challenged by longitudinal design, different methods used for the
PERG test, and the actual analysis of the longitudinal studies. Bode et al.
(2011) conducted a longitudinal study including 120 eyes (64 subjects) with
elevated intraocular pressure >25mm HG over a mean period of 10.3 years. A
PERG study was conducted at enrollment and every six months over the study
period. 13/120 eyes converted to glaucoma according to visual field
definition. The authors reported amplitude and PERG ratio predicted conversion
to glaucoma four years ahead with sensitivity/specificity of 67%/64% and
75%/76%, respectively. They also compared the trends of converters and non-
converters are and reported that while there were significant differences in
the PERG ratio, the trends did not predict conversion as successfully as
single-visit measures. They suggest a PERG ratio <1, based on 13/120 eyes
converting over ten years, may have clinical value regarding when to initiate
treatment. However, there is no analysis of how many non-converters would
receive treatment using this threshold and if it resulted in clinical
benefits.16 Ventura et al. (2013) enrolled 59 patients as glaucoma suspects
and observed them untreated over an average of 5.7 years, during which PERG
and Standard Automated Perimetry (SAP) was conducted twice per year. They
reported that the PERG displayed clear longitudinal loss of signal, but the
finding's pathophysiological significance was not determined. They conclude
that additional investigation would be necessary to determine if PERG losses
will have served as predictors of future visual field loss.17 Additional small
studies reported similar findings, but these findings have yet to be confirmed
in larger trials.18-20

A 2019 systematic review included thirty English language studies published
after 2013. All studies were cohort or case-controlled, and there was no Level
I studies included in the body of literature. The studies' quality score was
based on the Newcastle-Ottawa Scale (NOS) for nonrandomized studies and case
series graded using a modification of NOS and was listed as 6-10 in this
series. Each study was assessed to determine if they used a standardized
protocol, specifically the ISCEV protocol. The studies reviewed multiple types
of electrophysiological tests, including ERG. They report nine papers on
mfERG, largely comparing to optical coherence tomography (OCT). These reports
showed relatively good spatial correlation with visual field defects and OCT
scans, but most studies performed protocols modified from traditional mfERG.
In evaluating mfPERG, they determined that results are not usually homogenous,
and there was uncertainty in how it could contribute to the early diagnosis of
glaucoma. PERG was described in seven studies and reported some accuracy in
localized glaucomatous defects. PnHR was reported in three studies, and while
it did have some promising preliminary findings, there is little research on
its utility in glaucoma. Criticism for the electrophysiologic tests includes
difficulties in performing a good exam, cost, some tests are invasive and
require sensors in the patient's eye for up to 50 minutes, technical concerns,
extensive data evaluation requiring experts for interpretation, and
inconsistent protocols. The authors conclude a correlation between
electrophysiological test and current standards in the visual field and
optical coherence tomography testing and growing evidence the technology may
play a role in glaucoma. However, they acknowledge that definitive indications
of these tests are needed and have not been established for early detection or
follow-up of glaucoma; there is a need for more straightforward protocols and
better correspondence with current glaucoma tests for their routine use.6

A small 2019 retrospective analysis of thirty-eight patients showed
progressively decreased PERG amplitude overtime in a proportion of glaucoma
suspects suggesting PERG progression can independently contribute to the
prediction of visual field progression.21 In a 2020 comparative analysis
between forty patients (eighty eyes) with open-angle glaucoma to 23 healthy
patients (46 eyes) measured PERG, steady-state PERG (sspERG), computerized
visual field screening, examination of retinal nerve fiber layer, and macular
thickness on optical coherence tomography (OCT) were compared. They reported
significantly lower amplitudes for both PERG and ssPERG in patients with the
delay in patients with open-angle glaucoma than those with healthy eyes, with
results of ssPERG being more pronounced. They conclude there may be a value of
the addition of SSpERG to OCT parameters.22 This study distributed patients
into the group to achieve a balanced demographic, but this introduced
selection bias and was not sufficiently powered. A 2019 observational study
was done with three groups: a control, primary open-angle glaucoma, and ocular
hypertension with 30 eyes in each group measured visual fields, OCT and PERG.
They concluded PERG can detect dysfunctional but still live retinal ganglion
cells earlier than OCT in ocular hypertension cases, allowing an opportunity
for earlier treatment and potential restoration of function before
irreversible damage occurs.23 The study is limited by the small number of
cases, observational design, and there was no evaluation of the potential
impact on the disease but rather a hypothesis.

The International Society for Clinical Electrophysiology of Vision guidelines
provides standards for electrodiagnostic procedures and common clinical
indications. They state there may be a value in the evaluation of "glaucoma
suspects." They state that there may be a reduction in components of transient
recordings, but the emerging ssPERG are more affected. They also stated there
is an increasing interest in photopic negative response (PHNR). They also
report that standard mfERG may play a role in glaucoma, but standardization
and clinical utility has not yet been established.24

In a 2017 review paper, the authors conclude that PERG may be altered at the
earlier stages of glaucoma preceding losses of visual field and optic nerve
tissue which, could be potentially reversible with lowering the intraocular
pressure. Despite this potential, the paper also reviews several limitations
of the PERG technique in early glaucoma, including the presence of cataracts
and diabetes that may impair the PERG signal. Additional comorbidities that
could potentially reduce the specificity of PERG alterations for early
detection of glaucoma include high myopia, macular degeneration, and
neurological conditions such as Parkinson's disease, Alzheimer's disease, and
multiple sclerosis.25

Contractor Advisory Committee (CAC) Meeting

CGS Administrators hosted a CAC meeting to review the evidence for
electroretinography with J15 CAC members for ophthalmology and optometry. The
meeting was held on 11/18/2020, and transcription voting results are published
on the CGS website at
[https://www.cgsmedicare.com/partb/medicalpolicy/lcd_discussion_recordings.html](https://www.cgsmedicare.com/partb/medicalpolicy/lcd_discussion_recordings.html).
The panel was in support of the use of ERG and the management of retinal
disease and the important role that it plays in the treatment of these
conditions. The one area of controversy was the role of the ERG in the
diagnosis and management of glaucoma. The panel felt there was robust clinical
evidence to support the use of PERG in the diagnosis and management of
glaucoma with a voting score of 4/5. The discussion stated that there is value
in equivocal cases where visual fields and OCT are not congruent or
definitive. The panel had a consensus that it is used mainly as an adjunct
test and not a standalone test and felt that it could help prevent patients'
overtreatment with equivocal findings. The type of system used was discussed,
and that the corneal electrodes are more sensitive than skin electrodes which
can impact the interpretation of the test. There was no standardization for
patient selection, frequency of test, and role in follow-up/management. The
panel felt there was clinical evidence to support the role of other forms of
ERG in glaucoma management with a score of 4/5, and the various types of ERG
and applications were discussed. The panel did not feel there was evidence to
support the role of PERG in retinal disease with a score of 1.6/5. Literature
was submitted by the panel and included in the literature review conducted for
this topic.26

Literature was submitted regarding the question of the sensitivity of skin
electrodes compared to corneal electrodes. The placement of corneal or
conjunctive electrodes typically used for recordings requires highly skilled
technicians and compliant patients. The amplitude measured by the corneal
electrodes is much lower and more accurate than skin electrodes. The 2013
ISCEV standards for PERG states, "Skin (surface) active electrodes should not
routinely be used for recording the standard PERG, because skin electrodes
positioned on the lower eyelid will record PERGs of lower amplitudes than
those recorded from an electrode in contact with the eye."9 Some literature
has emerged documenting comparability between the skin and the conjunctive
electrodes for PhNR. This literature seems to apply to PhNR rather than PERG
recordings.3,27,28

_Evidence Tables_

The CAC panel voted for robust clinical evidence in support of ERG for
glaucoma; however, our literature search could not identify any high-quality
studies to support this use. Due to this discrepancy, a formal evidence
analysis was conducted. A literature search was conducted using PubMed, EBSCO,
and Medline. English language articles were identified that addressed the role
of PERG, MFERG, and phNR for glaucoma evaluation. Articles already assessed in
the 2019 SR were excluded. Retrospective studies and case series were excluded
due to low quality. Studies with less than thirty eyes evaluated were
excluded. All literature submitted by the CAC panel was reviewed. Individual
studies were rated with the Scottish Intercollegiate Guideline Network (SIGN),
which is used by AAO in their Preferred Practice Guidelines.

There were no high-quality randomized controlled trials. There were no trials
with a direct comparison of ERG to the current standard test. No trials on
clinical utility were identified.

**Table 1. Pattern Electroretinography (PERG) for glaucoma**

|  
---|---  
  
Study

|

Study Type

|

Protocol

|

Results

|

SIGN Rating  
  
Bach (2006)15 Pattern ERG as an early glaucoma indicator in ocular
hypertension: a long-term, prospective study

|

observational, long-term, prospective  
study

|

95 eyes (54 patients) with intraocular pressure _>_ 25 mm Hg (or _>_ 23 mm Hg
with additional risk factors), normal visual fields, normal optic disc
cupping, and visual acuity _>_ 0.8 were evaluated to assess the pattern
electroretinogram (PERG) as an early indicator of dysfunction preceding
glaucoma.

|

Eight eyes developed glaucomatous visual field defects. Analysis of the
receiver-operating characteristic (ROC) yielded steadily increasing ROC areas
before conversion for the PERG to 0.8 checks and the PERG ratio. One year
before conversion, the ROC area of the PERG ratio was 0.78, at a threshold of
1.06 with a sensitivity of 80% and a specificity of 71%.

|

II+  
  
Bode (2011)16 Pattern electroretinogram in glaucoma suspects: new findings
from a longitudinal study

|

longitudinal study

|

120 eyes (64 patients) with intraocular pressure greater than 25 mm Hg (or _>_
23 mm Hg with additional risk factors), normal visual fields, normal optic
disc appearance, and visual acuity _>_ 0.8 were included in the study to
compare PERG measures from eyes that converted to glaucoma with eyes that did
not convert.

|

13 eyes converted to glaucoma throughout the duration of the study according
to a visual field definition. Amplitude to 0.8 check size, PERG ratio, and
peak time was significantly lower in converters. Amplitude and PERG ratio
predicted conversion 4 years ahead with a sensitivity and specificity of
67%/64% and 75%/76%, respectively. Converters and non converters trend
comparisons revealed significant differences in the PERG ratio. However,
trends did not predict conversion as successfully as single-visit measures.
The PERG, especially the PERG ratio, detected glaucoma patients 4 years before
visual field changes occurred, with a sensitivity of 75% and specificity of
76%. Slope analysis provided little information in detecting converters.

|

II+  
  
Demir (2015)18 Comparison of Pattern Electroretinography and Optical Coherence
Tomography Parameters in Patients with Primary Open-Angle Glaucoma and Ocular
Hypertension

|

observational cohort study

|

72 eyes (37 patients) with early POAG, 76 eyes (38 patients) with OHT, and 60
eyes (30 controls) were enrolled to assess the correlation of visual field
(VF), pattern electroretinography (PERG), and Fourier domain optical coherence
tomography (FD-OCT) results in patients with ocular hypertension (OHT) and
early primary open-angle glaucoma (POAG).

|

All GCC parameters and RNFL results were significantly lower in the POAG group
compared to the OHT and control groups, except the nasal quadrant. There was
no statistically significant difference between the OHT and control group.
PERG amplitudes were lower in the POAG and OHT groups than in the control
group. Reduction in N95 amplitude was greater than that of P50 amplitude.
There was no difference detected in PERG latencies among groups. GCC was
significantly correlated with VF and RNFL in the POAG groups.

|

II+  
  
Ganekal (2013)29 Pattern Electroretinography Changes in Patients with
Established or Suspected Primary Open Angle Glaucoma

|

observational cohort study

|

76 normal, 32 glaucomatous and 22 glaucoma suspect eyes were enrolled to
assess pattern electroretinogram (PERG) changes in patients with established
or suspected primary open-angle glaucoma (POAG).

|

The P50 and N95 amplitude of the POAG and glaucoma suspect groups were
significantly reduced. Significant shortening in the P50 latency in the POAG
and glaucoma suspect groups was observed. DFA using the P50 amplitude, N95
amplitude, and P50 latency waveform parameters yielded a sensitivity and
specificity of 76.67% and 88.57%, respectively.

|

II+  
  
Jeon (2019)30 Relationship Between Pattern Electroretinogram and Optic disc
Morphology in Glaucoma

|

cross-sectional study

|

86 eyes (54 patients) glaucoma suspect and 145 eyes (84 patients) normal-
tension glaucoma (NTG)

|



PERG decrease earlier than perimetry according to scatter plots of changes of
RNFL thickness. The linear and logarithmic R2 differences 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). glaucoma suspect patients, HRT parameters such as cup shape measure
(CSM) and linear cup-disc ratio (CDR) yielded significant correlations with
PERG amplitudes (P= 0.016 for P50 and 0.049 for N95 in CSM, P= 0.012 for P50
in CDR). Mean RNFL thickness in glaucoma patients was associated with PERG
amplitude (P= 0.011 for P50 and 0.002 for N95). Authors conclude that RNFL
thickness change showed that purge started to decrease earlier than did
perimetry and purge amplitudes were significantly correlated with
dysmorphology in glaucoma suspects suggesting herb can detect ganglion cell
dysfunction before cells die. Authors acknowledge the need for future studies
to assess the effect of neuroprotective strategies for identifying RG C
function restoration and dysfunctional but reversible ganglion cell with
intact structure.

|

II+  
  
Karaca (2020)22 Comparison of structural and functional tests in primary open-
angle glaucoma

|

observational cohort study

|

80 eyes (40 patients) with primary open-angle glaucoma (POAG) and 46 eyes (23
healthy individuals) were enrolled to comparatively analyze the structural and
functional tests used in the diagnosis and follow-up of glaucoma.

|

80 eyes (40 patients) with a diagnosis of POAG (18 mild 22 moderate POAG) and
46 eyes (23 healthy individuals) were enrolled. PERG P50 and N95 and ssPERG
latency revealed a significant delay in the POAG group. Wave amplitudes were
significantly lower in both PERG and sSPERG tests for the POAG group, with
more pronounced results in ssPERG. The latency values of PERG and ssPERG tests
were not significantly correlated with any of the parameters of the remaining
tests. However, the amplitude values of these tests had a positive correlation
with the mean deviation value and a negative correlation with the pattern
standard deviation value of VF. All associated parameters were significant for
the amplitude value of the ssPERG test.

|

II-  
  
Mutolo (2016)31 Oral Administration of Forskolin, Homotaurine, Carnosine, and
Folic Acid in Patients with Primary Open Angle Glaucoma: Changes in
Intraocular Pressure, Pattern Electroretinogram Amplitude, and Foveal
Sensitivity

|

short-term (12 months) randomized control clinical pilot study

|

44 eyes (22 patients) with POAG were enrolled and randomly assigned to the
food supplement or control treatment group to evaluate the effects of a food
supplement containing forskolin, homotaurine, carnosine, folic acid, vitamins
B1, B2, B6, and magnesium in patients with primary open-angle glaucoma (POAG)
already in treatment and compensated by intraocular pressure (IOP)-lowering
drugs.

|

IOP response in the treated and the control: A decrease of IOP was observed in
treated patients, starting at 6 months of treatment and becoming statistically
significant at 9 (P< 0.05) and 12 months (P< 0.01). After 12 months, the
average decrease for both eyes (on top of the topical treatment, which was not
interrupted) was 1.9mmHg on the enrollment value. The control group resulted
in no significant reductions of IOP values throughout the observation period.
A significant improvement of PERG amplitude after 6 months (P< 0.05) was
observed in treated patients. A trend of improvement was observed treated
patients, which was significant after 12 months (P< 0.05). At this time, the
average increase over enrollment values was 4.3 and 5.3 dB respectively for
the right and the left eye. No adverse events were reported.

|

II-  
  
Pfeiffer (1992)32 The pattern-electroretinogram in glaucoma and ocular
hypertension. A cross-sectional and longitudinal study

|

cross-sectional, longitudinal study

|

65 eyes (44 patients) with normal eyes, 52 eyes (31 patients) in early stages
of glaucoma, and 28 eyes (17 patients) with ocular hypertensive (OHT) eyes.

|

PERG was recorded using steady-state high contrast (98%) counterphasing
checkerboard patterns at check sizes of 0.8 degrees and 15 degrees at 16
reversals/s and 98% contrast. Stimulation area was 27 degrees x 30 degrees.
Compared to normals, in glaucoma eyes PERG amplitudes are reduced to 56 +/-
3.6%, (P < 0.0001) for 0.8 degrees and to 79 +/- 4.0% (P < 0.001) for 15
degrees check sizes. Preferential reduction for the small check size allows
classification of patients on an individually. Discriminant analysis revealed
normal, and glaucoma eyes were classified with a sensitivity of 82.7% and a
specificity of 90.8%. Nineteen of 28 OHT eyes were classified as pathological.
Eyes with OHT were tested to determine whether the PERG can be used to predict
visual field damage. At the repeat visit 5 to 35 months later (mean follow-up
20.2 +/- 8.2 months), in eyes with normal PERGs the average loss in mean
sensitivity was -0.61 +/- 0.5 dB, while in eyes with pathological PERGs it was
-2.6 +/- 0.7 dB (P = 0.05).

|

II+  
  
Sehi (2011)33 The impact of intraocular pressure reduction on retinal ganglion
cell function measured using pattern electroretinogram in eyes receiving
latanoprost 0.005% versus placebo

|

prospective, placebo-controlled, double masked, cross-over

|

68 eyes (68 patients) 35 glaucoma, and 33 glaucoma suspect were enrolled to
assess the impact of intraocular (IOP) reduction on retinal ganglion cell
(RGC) function measured using pattern electroretinogram optimized for glaucoma
(PERGLA) in glaucoma suspect and glaucomatous eyes receiving latanoprost
0.005% versus placebo.

|

68 eyes (68 patients) were included in the analysis. 35 eyes with perimetric
glaucoma (PG) and 33 glaucoma suspect (GS) eyes, comprised of nine pre-
perimetric glaucoma (glaucomatous optic neuropathy and normal SAP) and 24
ocular hypertensive (OHT, no optic neuropathy, normal SAP) eyes. 46 patients
(23 glaucoma, 18 OHT, five preperimetric glaucoma) were using topical anti-
glaucomatous treatment prior to the initiation of this study. The mean IOP (mm
Hg) after latanoprost 0.005% therapy (14.9  3.8) was significantly lower than
baseline (18.8  4.7, p < 0.001) or placebo (18.0  4.3), with a mean
reduction of -20  13%. Mean PERGLA amplitude (lV) and phase (p-radian) using
latanoprost (0.49  0.22 and 1.71  0.22, respectively) were similar (p >
0.05) to baseline (0.49  0.24 and 1.69  0.19) and placebo (0.50  0.24 and
1.72  0.23). No significant (p > 0.05) diurnal variation in PERGLA amplitude
was observed at baseline, or using latanoprost or placebo. Treatment with
latanoprost, time of day, and IOP were not significantly (p > 0.05) associated
with PERGLA amplitude or phase.

|

II-  
  
Ventura (2013)17 Pattern electroretinogram progression in glaucoma suspects

|

observational, longitudinal cohort study

|

Fifty-nine (59) glaucoma suspects (GS) patients were enrolled to prospectively
monitor progressive changes of retinal ganglion cell (RGC) function in early
glaucoma using the pattern electroretinogram (PERG).

|

"On average, progression slopes of PERG amplitude/phase were skewed toward
negative values, and mean being significantly (P<0.01) different from zero.
Mean slopes of SAP-MD and PSD were not significantly different from zero. SNRs
were higher for PERG than SAP (P<0.01). A substantial number of eyes resulted
in a significant (P < 0.05) progression of PERG amplitude (15-20%) or PERG
phase (16-25%). Fewer eyes resulted in a significant progression of SAP-MD
(0-2%) or SAP-PSD (4-8%)."

|

II+  
  
**Table 2. Photopic Negative Response (PhNR) and glaucoma**

|  
  
Study

|

Study Type

|

Protocol

|

Results

|

SIGN Rating  
  
Turno-Krecicka (1998)34 Flash electroretinography and pattern-type visual
evoked potentials in early glaucoma

|

prospective observational study

|

416 eyes - primary open-angle glaucoma (120 eyes), normal tension glaucoma
(137), ocular hypertension (74), glaucoma-like discs (86)

|

No statistically significant difference between parameters of flash-erg and
pVEP of examined population and control group. There was a significant
reduction in OPs amplitude in NTG patients.

|

II+ *  
  
  |   |   |

*Based on abstract only. Full-Text article not available.  
  
  |   |   |   |  
  
**Table 3. Multifocal Electroretinography (mfERG) and glaucoma**

|  
  
Study

|

Study Type

|

Protocol

|

Results

|

SIGN Rating  
  
Golemez (2016)35 Is multifocal electroretinography an early predictor of
glaucoma?

|

observational, cohort study

|

126 patients were included. There were 30 healthy (Group 1), 28 glaucoma
suspect (Group 2), 48 early glaucoma (Group 3), and 20 advanced glaucoma cases
(Group 4) patients enrolled to investigate the potential use of mfERG as an
objective functional test that can express inner and outer retinal changes
during the early stages of glaucoma. Subjects were divided into four groups
according to their disease state (healthy control, glaucoma suspect, early
glaucoma, and advanced glaucoma).

|

A one-way ANOVA revealed no statistically significant differences in patient
age between groups (p = 0.126). Statistically significant differences were
detected for the mean implicit time (latency) of the N1, P1, and N2 components
between the advanced glaucoma and control subjects and between the advanced
glaucoma and glaucoma suspects for all rings. Compared to control subjects,
the N2 amplitudes were significantly decreased in all rings in the advanced
glaucoma patients. The N2 amplitude was significantly different when compared
to healthy subjects (Group 1) and early glaucoma subjects (Group 3) in the
central 2 and 2-5 rings. MedClac ROC curve analysis was utilized to
identify parameters for discriminating between control subjects (Group 1) and
early glaucoma patients (Group 3). The N2 implicit time for the central 2
ring (p\0.0001), N2 amplitude for the central 2 ring (p = 0.0001), P1
implicit time for the 2-5 ring (p = 0.0001), N2 implicit time for the 2- 5
ring (p = 0.0003), and N2 amplitude for the 2-5 ring (p = 0.001) had C0.7
AUC values and were the best parameters in the ROC curve analyses that
included the VFA parameters.

|

II+  
  
  |   |   |   |  
  
**To rate individual studies, a scale based on SIGN is used. The definitions
and levels of evidence to rate individual studies are as follows:**

|  
  
I++

|

High-quality meta-analyses, systematic reviews of randomized controlled trials
(RCTs), or RCTs with a very low risk of bias  
  
I+

|

Well-conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low
risk of bias Meta-analyses, systematic reviews of RCTs, or RCTs with a high
risk of bias  
  
I-

|

Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of bias

|  
  
II++

|

High-quality systematic reviews of case-control or cohort studies High-quality
case-control or cohort studies with a very low risk of confounding or bias and
a high probability that the relationship is causal  
  
II+

|

Well-conducted case-control or cohort studies with a low risk of confounding
or bias and a moderate probability that the relationship is causal  
  
II-

|

Case-control or cohort studies with a high risk of confounding or bias and a
significant risk that the relationship is not causal  
  
III

|

Nonanalytic studies (e.g., case reports, case series)

|  
  
The highest quality of literature identified was II+ per SIGN scale which is a
well-conducted case control or cohort studies with low risk of bias and
moderate probability that  the relationship is causal. This body of literature
contributed further knowledge to defining abnormalities found with ERG in
glaucoma but collectively do not define the objective measure of visual
function with ERG for glaucoma or clinical utility of the test.36-40

These findings are consistent with a recent technical assessment.

  * A 2020 ECRI report concludes that the evidence is "inconclusive" for PERG for detecting central retinal damage from glaucoma. This report included one systematic review and five case-controlled studies (not included in the systematic review) that suggested changes in PERG waveform may indicate retinal ganglion cell damage in individuals with glaucoma. However, no evidence was found to determine if these findings correlated with earlier interventions or improved patient outcomes.5
  * UpToDate does not include any electroretinography in the newer technology section for glaucoma diagnosis.41

_Societal Guidance and Recommendations_

  * The 2015 AAO Primary Open-Angle Glaucoma Preferred Practice Pattern Guideline recommends comprehensive eye examinations for patients with risk factors for glaucoma and screening but does not address ERG as a diagnostic tool.42
  * The 2015 AAO Preferred Practice Guidelines, "Primary Open-Angle Glaucoma Suspect also omits ERG as a diagnostic tool.43
  * The 2016 AAO Comprehensive Adult Medical Eye Evaluation Guideline states, "electrophysiologic testing" is not part of a routine comprehensive medical eye evaluation but does acknowledge it as an "additional option for diagnostic testing." Furthermore, the guideline does not explicitly address ERG or offer any grade of evidence specific to electrophysiologic testing.44
  * The 2016 AAO POAG Preferred Practice Pattern Guidelines42, the 2017 AAO for Diabetic Retinopathy45, and the 2018 AAO summary benchmarks for preferred practice pattern guidelines46 do not specifically mention PERG as a diagnostic tool.
  * The American Optometric Association Care of the Patient with Open Angle Glaucoma omits ERG.47
  * The 2019 Canadian Agency for Drugs and Technologies in Health: Automated Perimetry or Electroretinography for Visual Field Testing in Eye Examinations: Guideline did not include PERG.48
  * The 2019 Royal Australian College of General Practitioners, Ophthalmology Clinical Committee. Medicare Benefits Schedule Review Taskforce: Ophthalmology Report states Electroretinography helps diagnose disease of the retina, including retinitis and hereditary conditions as well as diabetic retinopathy. They state that it requires specialized training and equipment to conduct and interpret the test. It does not include a role in glaucoma management or evaluation.49
  * International Society for Clinical Electrophysiology of Vision (ISCEV). ISCEV Standard for Clinical Pattern Electroretinography (PERG): updated 2013 report States the role of PERG for both neurological and ophthalmological practice, including glaucoma, optic neuropathy, and primary ganglion cell disease.9

**Other indications**

_Childhood Brain Tumors_

ERG has been investigated as a tool for clinical evaluation in childhood brain
tumor survivors. A small cross-sectional study did not show the value of EMG
for this population.50

_Chloroquine and Hydroxychloroquine Toxicity_

Multiple studies have shown the benefit of ERG in evaluation for Chloroquine
and Hydroxychloroquine toxicity. A 2015 systematic review reported mfERG for
retinal toxicity has a high sensitivity of 90% (95% confidence interval [CI],
0.62-0.98) and 52% (CI, 0.29-0.74), respectively, with automated visual fields
(AVF) testing as a reference standard (13 studies), but specificity was
variable when compared to other testing modalities.41 In 2016 AAO revised
recommendations for screening of Chloroquine and Hydroxychloroquine Toxicity
retinopathy, stating the preliminary screening tests are automated visual
fields plus spectral-domain optical coherence tomography (SD-OCT).42 The
multifocal electroretinogram (mfERG) can provide objective corroboration for
visual fields, and fundus autofluorescence (FAF) can show damage
topographically. The guidance stated that mfERG is similar in sensitivity to
visual field testing and can provide objective information about suspected
visual field loss52. Using the definition of toxicity from AAO Guidelines, a
2019 study of 120 eyes reported a sensitivity of 1.00 (95% CI 0.79-1.00) and a
specificity of 0.78 (95% CI 0.69-0.85) of MFErG for detection of toxicity.53

_Evaluation of autism spectrum disorder_

A 2016 paper explored a relationship between reduced scotopic ERG b-wave
amplitudes and early findings of autism. ERG was performed on 11 patients with
autism spectrum disorder (ASD) and 15 typically developing controls. They
noted that some ASD patients showed subnormal dark adaptive ERG b-wave
amplitudes. They conclude that the exploratory findings suggest there is
altered cone-ON bipolar signaling in ASD.54



**ERG and Glaucoma**

The current literature on the use of ERG for the early detection of glaucoma
is limited. There were no studies that compare ERG to a diagnostic gold
standard test for retinal ganglion cell damage. The current body of literature
is limited to case-controlled studies, which are at risk of inflating
estimates of sensitivity and specificity of the test.5 Most studies did not
have an adequate sample size, protocols were not standardized, and normal and
abnormal values were unclear. While glaucoma is included in the ISCEV
guidelines, but the clinical application is still not clearly defined.

While we appreciate that there may be an emerging role for the use of ERG in
glaucoma, there are many challenges. There is a lack of standardized
protocols, including the best form of ERG (PERG, ssPERG, phRG), type, and
placement of electrodes, and standardized reference range. The appropriate
patient selection is uncertain, and the impact of co-morbidities such as
cataracts, diabetes and other underlying conditions which may impact PERG
specificity is not clear. Timing and frequency of the test, and how to use the
results are still under investigation. There is a lack of evidence on how to
use ERG for clinical glaucoma management or improve outcomes. There is a lack
of support for this technology as part of the routine evaluation of glaucoma
by AAO. Therefore, CGS Administrators considers the use of ERG for glaucoma
diagnosis or management investigational.

**Other indications**

There is strong evidence in support of ERG (ffERG and MFERG) as part of the
evaluation and for treatment monitoring of retinal function and distinguishing
retinal from optic nerve lesions. There is also sufficient evidence of the
role of mfERG in the assessment of the detection of chloroquine and
hydroxychloroquine toxicity. There is not sufficient evidence for other
indications since there is little supporting data in other populations.