0344 Optic Nerve and Retinal Imaging Methods (1)...papilledema secondary to intra-cranial...
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Optic Nerve and Retinal ImagingMethods
Policy History
Last Review
05/25/2021
Effective: 07/23/1999
Next
Review: 03/24/2022
Review History
Definitions
Additional Information
Clinical Policy Bulletin
Notes
Number: 0344
Policy *Please see amendment for Pennsylvania Medicaid at the end of this CPB.
Aetna considers optic nerve and retinal imaging methods
medically necessary for documenting the appearance of the
optic nerve head and retina in the following
diagnoses/individuals:
◾ Age-related macular degeneration
◾ Cystoid macular edema following cataract surgery
◾ Diabetic retinopathy
◾ Ethambutol-induced optic neuropathy
◾ Glaucoma suspects
◾ Macular edema
◾ Macular hole
◾ Persons with glaucoma
◾ Posterior vitreous detachment
◾ Pseudotumor cerebri
◾ Screening and monitoring for chloroquine (Aralen),
ethambutol (Myambutol), ezogabine (Potiga),
hydroxychloroquine (Plaquenil), ponatinib (Iclusig),
siponimod (Mayzent), and vigabatrin (Sabril) toxicity*
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◾ Sudden onset vitreous hemorrhage
◾ Vitreomacular traction and vitreomacular adhesion
◾ Vogt-Koyanagi-Haradas (to quantify subretinal fluid and
to follow individuals during treatment)
◾ Other diseases where the optic nerve head and retina
have been affected.
Note: Optic nerve imaging for glaucoma more frequently than
once per year is considered not medically necessary.
Note: Accepted optic nerve and retinal imaging methods
include the following:
◾ Confocal laser scanning ophthalmoscopy
◾ Nerve fiber layer testing or analysis (confocal laser
scanning tomography with polarimetry)
◾ Optical coherence tomography (OCT)
◾ Stereophotogrammetry.
Aetna considers optic nerve and retinal imaging methods
experimental and investigational as a screening test for the
following (not an all-inclusive list):
◾ Decision on the need for surgery
◾ Glaucoma and other retinal diseases and for all other
indications (e.g., cataracts, dry eye diseases, ocular
histoplasmosis, posterior capsule opacification)
◾ Imaging of the retina as a biomarker for
neurodegeneration in frontotemporal degeneration,
multiple sclerosis and optic neuritis
◾ Screening/monitoring persons on fingolimod (Gilenya).
Aetna considers optic nerve and retinal imaging methods
experimental and investigational for the following (not an all-
inclusive list):
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◾ Evaluation of the neurodegeneration pattern in
individuals with intra-cranial tumors
◾ Evaluation of Parinaud oculoglandular syndrome (cat
scratch disease)
◾ Evaluation of visual snow syndrome
◾ Imaging following intra-ocular lens (IOL) exchange
following IOL dislocation.
Aetna considers the use of patient-initiated image capture and
transmission to a remote surveillance center via the optical
coherence tomography (OCT) device experimental and
investigational because the effectiveness of this approach has
not been established.
* In addition to annual screening that should begin after 5
years of use (or sooner it there are unusual risk factors), a
baseline study of optic nerve and retinal imaging is
considered medically necessary before initiation of
chloroquine, hydroxychloroquine, or vigabatrin therapy.
See also CPB 0563 - Retinopathy Telescreening Systems
(../500_599/0563.html).
Background
The appearance of the optic nerve head (the disc) and the
nerve fiber layer is evaluated in the diagnosis and follow-up of
glaucoma. The standard methods of detecting glaucoma
include ophthalmoscopy, tonometry, perimetry, and
gonioscopy. These procedures are considered part of the
comprehensive ophthalmologic examination. Recently, other
methods of measuring the optic disc and the nerve fiber layer
have been developed in an attempt to create more accurate
and reproducible methods of screening, detecting, and
following structural parameters related to glaucoma. These
methods include the following:
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Confocal Laser Scanning Opthalmoscopy
Confocal laser scanning ophthalmoscopy, also known as
scanning laser ophthalmoscopy (SLO), is a method of
examining the eye using confocal laser scanning microscopy
(stereoscopic videographic digitized imaging) to make
quantitative topographic measurements of the optic nerve
head and surrounding retina. This may be done with either
reflection or fluorescence. Targeted tissues can be viewed in
3-dimensional (3D) high-resolution planes running parallel to
the line of sight.
The confocal laser scanning tomographic ophthalmoscope
scans layers of the retina to make quantitative measurements
of the surface features of the optic nerve head and fundus. It
has been used as an alternative to standard ophthalmologic
methods of evaluating the optic nerve head and fundus in
patients with glaucoma, papilledema, and other disorders
affecting the retina. Other terms for confocal laser scanning
tomography include: laser scanning topography, confocal
scanning laser topography, confocal laser scanning
tomography, scanning laser opthalmoscopy (SLO), and
electro-fundus imaging. Types of confocal laser scanning
ophthalmoscopes include:
◾ Heidelberg Laser Tomographic Scanner or Heidelberg
Retina Tomograph (HRT) (Heidelberg Engineering,
Dossenheim, Germany),
◾ TopSS Topographic Scanning System (Laser Diagnostic
Technologies, San Diego, CA); and the
◾ ZeissTM Confocal Laser Scanning Ophthalmoscope. (Zeiss
Humphrey Systems, Dublin, CA).
Nerve Fiber Layer Testing or Analysis (Laser Scanning Polarimetry)
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Thinning of the nerve fiber layer is associated with
glaucomatous damage and has been shown to be correlated
with visual field loss. Scanning laser polarimetry, also called
confocal scanning laser polarimetry, measures change in the
linear polarization (retardation) of light. It uses both a scanning
laser ophthalmoscope and a polarimeter (an optical device to
measure linear polarization change) to measure the thickness
of the nerve fiber layer of the retina. The confocal scanning
laser polarimeter is essentially a confocal scanning laser
ophthalmoscope with an additional polarization modulator, a
cornea polarization compensator and a polarization detection
unit.
The GDx Nerve Fiber Analysis System (Laser Diagnostic
Technologies, Inc., San Diego, CA) is a confocal laser
scanning ophthalmoscope with an integrated polarimeter.
Instead of measuring topography, or height of the retina, like
other confocal laser scanners, GDx measures the thickness of
the retinal nerve fiber layer and then analyzes the results and
compares them to a database of normative values.
The Retinal Thickness Analyzer (RTA) Digital Fundus Imaging
(Talia Technology, Inc., Tampa, FL) uses a scanning laser
biomicroscope that uses a laser to create a series of slit
images of the retina that are digitalized and converted into a
topographic map that quantifies retinal thickness.
Optical Coherence Tomography
Optical coherence tomography (OCT) is a noninvasive,
transpupillary, retinal imaging technology, which uses near-
infrared light to produce high-resolution cross-sectional
images. It is suggested for diagnostic use as an alternative to
standard excisional biopsy and to guide interventional
procedures.
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OCT (e.g., Humphrey OCT Scanner (Zeiss Humphrey, Dublin,
CA)) has also been used for screening, diagnosis, and
management of glaucoma and other retinal diseases. In OCT,
low coherence near-infrared light is split into a probe and a
reference beam. The probe beam is directed at the retina
while the reference beam is sent to a moving reference mirror
(AHFMR, 2003). The probe light beam is reflected from
tissues according to their distance, thickness, and refractive
index, and is then combined with the beam reflected from the
moving reference mirror. When the path lengths of the two
light beams coincide (known as constructive interference) this
provides a measure of the depth and reflectivity of the tissue
that is analogous to an ultrasound A scan at a single point. A
computer then corrects for axial eye movement artifacts and
constructs a two dimensional B mode image from successive
longitudinal scans in the transverse direction. A map of the
tissue is then generated based on the different reflective
properties of its components, resulting in a real-time cross-
sectional histological view of the tissue.
Barella et al (2013) examined the diagnostic accuracy of
machine learning classifiers (MLCs) using retinal nerve fiber
layer (RNFL) and optic nerve (ON) parameters obtained with
spectral-domain optical coherence tomography (SD-OCT). A
total of 57 patients with early-to-moderate POAG and 46
healthy patients were recruited. All 103 patients underwent a
complete ophthalmological examination, achromatic standard
automated perimetry, and imaging with SD-OCT. Receiver
operating characteristic curves were built for RNFL and ON
parameters. Ten MLCs were tested. Areas under ROC
curves (aROCs) obtained for each SD-OCT parameter and
MLC were compared. The mean age was 56.5 ± 8.9 years for
healthy individuals and 59.9 ± 9.0 years for glaucoma patients
(p = 0.054). Mean deviation values were -1.4 dB for healthy
individuals and -4.0 dB for glaucoma patients (p < 0.001).
Spectral domain-OCT parameters with the greatest aROCs
were cup/disc area ratio (0.846) and average cup/disc (0.843).
Areas under ROC curves obtained with classifiers varied from
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0.687 (CTREE) to 0.877 (RAN). The aROC obtained with
RAN (0.877) was not significantly different from the aROC
obtained with the best single SD-OCT parameter (0.846) (p =
0.542). The authors concluded that MLCs showed good
accuracy, but did not improve the sensitivity and specificity of
SD-OCT for the diagnosis of glaucoma.
Bidot et al (2013) noted that OCT is used primarily in neuro-
ophthalmology to measure thinning of the RNFL in optic
neuropathies and to rule out a subtle maculopathy in patients
complaining of blurred vision with a "normal" fundoscopic
appearance. Only a few studies address the role of OCT in
papilledema secondary to intra-cranial hypertension. Optical
coherence tomography has been proposed as a diagnostic
tool for mild papilledema, assisting the clinician in
differentiating papilledema from optic nerve head drusen
(ONHD), and for following the RNFL thickening from
papilledema. However, the contribution of OCT in intra-cranial
hypertension management is still unclear with the exception of
its role in detecting associated maculopathy. Currently, OCT
does not replace visual field testing and fundus examination.
In a comparative case-series study, Kulkarni et al (2014)
evaluated the clinical utility of SD-OCT in differentiating mild
papilledema from buried ONHD. A total of 16 eyes of 9
patients with ultrasound-proven buried ONHD, 12 eyes of 6
patients with less than or equal to Frisen grade 2 papilledema
owing to idiopathic intra-cranial hypertension were included in
this study. Two normal fellow eyes of patients with buried
ONHD were included. A raster scan of the ON and analysis of
the RNFL thickness was performed on each eye using SD-
OCT. Eight eyes underwent enhanced depth imaging SD-
OCT. Images were assessed qualitatively and quantitatively to
identify differentiating features between buried ONHD and
papilledema. Five clinicians trained with a tutorial and masked
to the underlying diagnosis independently reviewed the SD-
OCT images of each eye to determine the diagnosis. Main
outcome measures were differences in RNFL thickness in
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each quadrant between the 2 groups and diagnostic accuracy
of 5 independent clinicians based on the SD-OCT images
alone. These investigators found no difference in RNFL
thickness between buried ONHD and papilledema in any of
the 4 quadrants. Diagnostic accuracy among the readers was
low and ranged from 50 % to 64 %. The kappa coefficient of
agreement among the readers was 0.35 (95 % confidence
interval [CI]: 0.19 to 0.54). The authors concluded that SD-
OCT is not clinically reliable in differentiating buried ONHD and
mild papilledema.
Stereophotogrammetry
Stereophotogrammetry, (Glaucoma-Scope (OIS, Sacramento,
CA)) measures the dimensions of the optic disc in three-
dimensional space using stereophotography.
Stereophotographs are taken from two camera positions with
parallel optical axes. Stereoanalysis of these photographs are
used to determine the three-dimensional characteristics of the
optic nerve head, and for following glaucomatous change of
the optic nerve head over time. Stereoplotters and digital
computer processing of scanned images have been used in an
attempt to provide more quantitative, objective, and
reproducible methods of measuring optic nerve disc changes.
Each of these methods has been used to image the optic
nerve head in glaucoma patients. According to available
guidelines, these methods may be used for documenting the
appearance of the optic nerve head and retina in persons with
glaucoma and other retinal diseases. But these devices have
not been proven to be of value for screening of asymptomatic
persons.
Available methods of optic nerve imaging (e.g., Heidelberg
Retinal Tomograph, GDx confocal laser scanning polarimeter,
Humphrey OCT Scanner, Glaucoma-Scope) were cleared by
the U.S. Food and Drug Administration (FDA) based on a 510
(k) premarket notification due to their “substantial equivalence”
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to other devices on the market. Thus, the manufacturers were
not required to submit to the FDA the evidence that would be
required to support a premarket approval application (PMA).
An American Academy of Ophthalmology (AAO)'s Preferred
Practice Pattern on Primary Open Angle Glaucoma Suspect
(2005) focuses on the management of persons with ocular
hypertension or findings suggestive of ocular damage but
without established glaucoma. The AAO guidelines define a
glaucoma suspect as having one or more of the following
characteristics: (i) visual fields suspicious for early
glaucomatous damage; or (ii) intraocular pressure
consistently above 21 mm Hg by applanation tonometry; or
(iii) appearance of the optic disc or retinal nerve fiber layer
that is suggestive of glaucomatous damage. Glaucomatous
damage may be suggested by findings such as nerve fiber
layer disc hemorrhage, asymmetric appearance of the optic
disc or rim between fellow eyes that suggests loss of neural
tissue, diffuse or focal narrowing or notching of the disc rim
(especially at the inferior or superior poles), or diffuse or
localized abnormalities of the retinal nerve fiber layer
(especially at the inferior or superior poles). The AAO
guidelines conclude that "[c]olor stereophotography or
computer-based image analysis of the optic nerve head and
retinal nerve fiber layer are the best currently available
methods to document optic disc morphology and should be
performed."
An AAO Preferred Practice Pattern on Primary Open-Angle
Glaucoma (2005), which focuses on management of patients
with evidence of glaucomatous damage as manifested by
acquired optic nerve or nerve fiber layer abnormalities or
typical visual field loss, states that optic nerve head and retinal
nerve fiber layer analysis should be performed to document
optic nerve head morphology.
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Finnish evidence-based guidelines on open-angle glaucoma
(Tuulonen et al, 2003) state: “High technology instruments (the
Heidelberg retina tomograph, retinal nerve fibre analyser and
optical coherence tomography), developed for nerve fibre layer
and optic disc imaging and measurements, are not yet ready
for routine glaucoma diagnostics. Due to their sensitivity and
specificity, some instruments may be used for the follow-up of
glaucoma.”
Aetna’s position on optic nerve and retinal imaging devices is
based on the use of these devices as standard of care for
documenting the appearance of the optic nerve head and
retina, in place of retinal drawings or fundus photographs. In
addition, optic nerve head imaging methods have been used
as a noninvasive alternative to fluorescein angiography and
slit-lamp biomicroscopy in assessing the retinal nerve fiber
layer, although fluorescein angiography is also a sensitive test
to detect leakage of incompetent retinal vessels. Because of
the slow rate of progression of glaucoma, repeated optic nerve
head imaging is not necessary more frequently than once
every year.
Although optic nerve and retinal imaging devices have been
used to document the appearance of the optic nerve head and
retina, there is a lack of evidence from prospective clinical
studies demonstrating that clinical outcomes are improved by
incorporating this technology into glaucoma screening. A
number of structured evidence reviews have concurred that
there is limited evidence of the clinical utility of optic nerve
head imaging methods in these situations (AHP, 1996;
AHFMR, 1996; Lee, et al., 1996; TEC, 2001; AHFMR, 2003:
TEC, 2003; IECS, 2003; AHFMR, 2006). A BlueCross
BlueShield Association Technology Evaluation Center (2003)
assessment of optic nerve imaging devices (termed RNFL
analysis (RNFLA) in the report) in the diagnosis and
management of glaucoma and concluded that they do not
meet TEC criteria. Using data from the Ocular Hypertension
Treatment Study, the assessment found that RNFLA would not
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be useful in deciding whether to initiate early treatment of
glaucoma or change treatment regimens, as the vast majority
of patients with abnormal RNFLA test results would not be
expected to go on to develop glaucoma. The assessment
concluded: "The scientific evidence is insufficient to permit
conclusions concerning the effects of RNFLA for the diagnosis
or management of POAG [primary open angle glaucoma];
therefore, it is not possible to determine whether the procedure
improves net health outcome."
The TEC assessment (BCBSA, 2003) focused on the best
available evidence for retinal nerve fiber layer analysis.
Although there are many published studies of RNFLA, almost
all of them are cross-sectional studies that evaluate the
sensitivity and specificity of RNFA by comparing RNFA
measurements of normal persons to persons with glaucoma or
ocular hypertension. The assessment explains, however, that
cross-sectional studies do not follow persons over time and
are not designed to assess the relationship between a test
result and subsequent development of disease. Studies that
follow persons over time (longitudinal studies) are necessary
to evaluate the ability of a test to predict which persons will
develop disease and need treatment from those that will not
develop disease.
Another limitation of published cross-sectional studies of
RNFA is that they only compare normal persons to persons
with glaucoma or ocular hypertension. Because these studies
do not include persons with other ocular conditions, they do
not provide information on the ability of RNFLA to distinguish
patients with glaucoma or ocular hypertension from other
ocular conditions. The subjects of these cross-sectional
studies do not accurately reflect the spectrum of conditions
that one would expect to see in the usual clinical practice
setting (BCBSA, 2001). The external validity of these studies
could be strengthened by selecting study subjects from a
representative sample of the population of patients suspected
of having the disease.
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Cross-sectional studies cannot determine whether
abnormalities that are detected by RNFA but not by any other
standard method are early disease that might benefit from
treatment (BCBSA, 2003). The most reliable evidence for
assessing the clinical impact of RNFLA would be direct
evidence from randomized trials comparing the impact on
visual field defects of treatment initiated by different thresholds
of RNFLA test results. As no such studies are available,
technology assessments of RNFLA have had to rely on
indirect evidence.
The most reliable indirect evidence to estimate diagnostic
performance of RNFLA comes from longitudinal studies with a
clinical population of patients suspected of having glaucoma,
using follow-up for visual loss as a reference standard
(BCBSA, 2003). The key issue in the early detection of
glaucoma is how well test results predict the future
development of visual loss. Thus, it is critical that the
diagnostic performance of an early test be measured against
follow-up for visual changes as the reference standard, in a
longitudinal study.
The TEC assessment noted that no longitudinal study has yet
appeared that selected subjects for whom RNFLA results are
most likely to influence management decisions, that is,
persons who have normal intraocular pressure and who do not
meet conventional diagnostic criteria for glaucoma (BCBSA,
2003). The report identified only two published longitudinal
studies that present data showing whether RNFLA changes
precede development of visual field defects, on an individual
patient basis. The most useful longitudinal evidence for the
indication concerning detection of glaucoma comes from a
subset of the Ocular Hypertension Treatment Study (Kamal et
al, 2000). In this study, 21 patients progressed from ocular
hypertension to glaucoma (converters) and 164 patients did
not progress (nonconverters). Of the 21 converters, 13 had
abnormal RNFLA results and in 11 of these the tests were
positive prior to development of visual field defects (average
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lead time was 5.4 months). Of the 164 nonconverters, 47 had
abnormal RNFLA results. Using this study’s results to
estimate diagnostic performance, the positive predictive value
of RNFLA, which is the most relevant index for early detection
of glaucoma, is 22 % (13/60), so that 78 % of persons with
signs of progression of glaucoma on RNFLA would not go on
to develop visual field changes within the 6-year follow-up
period of this study. The TEC assessment concluded that "a
positive predictive value at this level does not appear to be
sufficiently high for use in deciding to initiate early treatment or
to change treatment regimens" (BCBSA, 2003). In addition,
this study only included persons with ocular hypertension, and
may not accurately reflect the performance of RNFLA in a
cohort of glaucoma suspects without ocular hypertension.
Given that the predictive values are dependent on the
prevalence of the target condition in the population, the
predictive value RNFLA in a population that includes
individuals without ocular hypertension is likely to be even
lower than the estimate from this study of ocular
hypertensives, given that persons with ocular hypertension, an
established glaucoma risk factor, are more likely to develop
glaucoma than persons without ocular hypertension.
Chauhan et al (2001) reported on the results of a longitudinal
study of RNFLA and visual field testing (perimetry) in patients
with glaucoma who were followed for a median of 5.5 years.
In 29 percent of cases, progression was detected by both
perimetry and RNFLA; when progression was detected by
both tests, it was just as common for perimetry to detect it first
as it is for RNFLA to detect it first. Although progression was
observed by RNFLA alone in 40 % of patients, it is unclear
from this study how often such patients experience visual
progression (true positives versus false positives). The TEC
assessment (2003) emphasizes that the key issue in the early
detection of glaucoma is how well test results predict the future
development of visual loss, as loss of vision is an endpoint that
patients experience in terms of quality of life and ability to
function.
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A report on glaucoma screening prepared for the UK National
Screening Committee (Spry and Sparrow, 2003) stated that
methods of assessing optic nerve head appearance using
images acquired by digital scanning laser instrumentation are
quantitative and rapid to perform. The report concluded,
however, that “[t]o date, however, scant longitudinal
information is available on individuals who exhibit apparent
structural abnormalities with these techniques but no
glaucomatous loss of visual function.” The ability to utilize
optic nerve head appearance in assessing glaucoma risk is
limited by the fact that “considerable overlap exists between
the distribution of relevant parameters found in patients with
glaucoma and normal individuals.”
The AAO and the American Glaucoma Society prepared a
work group report to provide a “rationale for [insurance]
coverage” of optic nerve head imaging (Remey 2002; AAO,
2003; AAO/AGS, 2003). The AAO/AGS Work Group
statement (2003) on the clinical utility of optic nerve scanning
devices in screening focused exclusively on comparisons with
automated perimetry or photography used alone. However,
the standard methods of detecting and monitoring glaucoma
include ophthalmoscopy (to inspect the optic disk and nerve
fiber layer), drawings of the optic nerve head and stereoscopic
disc photographs (to document the status of the optic nerve
head), tonometry (to measure intraocular pressure), perimetry
(to measure visual fields), and gonioscopy (to measure the
angle of the anterior chamber).
None of the studies cited in the AAO/AGS Work Group
statement (2003) represented prospective clinical outcome
studies. The need for prospective clinical outcome studies
comparing optic nerve scanning devices to standard methods
of evaluation is especially critical given that there is no
established gold standard comparison test for predicting the
risk of glaucoma development prior to the onset of visual field
defects. Although RNFLA devices have been in commercial
use for more than a decade, the quality of evidence supporting
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their use remains limited, and the best available evidence
indicates that the ability of RNFLA to predict progression to
glaucoma is limited.
The monograph from the AAO/AGS Work Group (2003)
commented on the limited quality of evidence supporting the
use of optic nerve scanning devices. The monograph stated:
"In clinical practice, many patients now are tested with more
advanced visual field techniques designed to detect glaucoma
earlier. Yet these variations on visual field testing have not
required rigorous TEC assessment to determine if they are
useful. Clinical experience, cross-sectional studies, and a few
longitudinal cohort studies have shown that they are useful
improvements in our ability to detect glaucoma and/or
progression. The case is similar to RNFLA, where clinicians
and researchers have determined that this newer technology
surpasses or equals the current clinical assessment of the
optic nerve and nerve fiber layer."
Assessment of the evidence supporting the use of optic nerve
scanning devices is required because these techniques have
been presented as a new technology rather than as an
incremental advance over an existing technology such as
ophthalmoscopy or other established methods of evaluating
the retina and optic nerve head.
The Center for Medicare and Medicaid Services (CMS) has
not established a national coverage position on optic nerve
imaging devices; CMS has left coverage of optic nerve
imaging devices to the discretion of local Medicare carriers.
Optical coherence tomography (OCT) (e.g., Humphrey OCT
Scanner (Zeiss Humphrey Systems, Dublin, CA) has also
been used for screening, diagnosis, and management of
glaucoma and other retinal diseases. Optical coherence
tomography (OCT) is a relatively new non-invasive imaging
modality that uses reflected light in a manner analogous to the
use of sound waves in ultrasonography to create high-
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resolution (10 micron) cross-sectional images of the
vitreoretinal interface, retina and subretinal space, analogous
to histological sections seen through a light microscope. OCT
also gives quantitative information about the peripapillary
retinal nerve fiber layer thickness.
The Alberta Heritage Foundation for Medical Research (2003)
assessed the value of optical coherence tomography (OCT) in
the diagnosis of retinal diseases. It stated that “OCT appears
promising for diagnosing patients with cystoid macular edema
and moderate glaucoma.”
OCT can determine the presence of cystoid macular edema
(CME) by visualizing the fluid-filled spaces in the retina. The
amount of CME can be monitored over time by quantifying the
area of cystoid spaces on a cross-sectional image through the
macula. Studies have reported OCT to be comparable to
fluorescein angiography in the evaluation of CME. However,
fluorescein angiography may be a more sensitive study for
leakage of incompetent retinal vessels (Roth, 2001).
OCT, scanning laser ophthalmoscope, and confocal laser
tomography may also be useful in macular holes, in
establishing the status of the vitreomacular interface and
distinguishing full-thickness holes from lamellar holes and
macular cystic lesions (Valero and Atebara, 2001). According
to the American Academy of Ophthalmology (2003), “[i]n most
cases the diagnosis [of macular hole] is made by clinical
evaluation. Optical coherence tomography provides
information on the anatomy of the macular hole and may aid in
the diagnosis and staging.”
OCT has also been used in a variety of other retinal diseases.
In diabetic retinopathy, OCT has been used to evaluate retinal
swelling and serous retinal detachment. OCT has been able
to demonstrate a moderate correlation between retinal
thickness and best-corrected visual acuity, and it has been
able to demonstrate three basic structural changes of the
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retina from diabetic retinal edema, i.e., retinal swelling, cystoid
edema, and serous retinal detachment (Khan and Lam,
2004). There is, however, a lack of prospective clinical studies
demonstrating that clinical outcomes are improved by
incorporating OCT into screening of persons with diabetes for
retinopathy. Current guidelines from the American Diabetes
Association do not incorporate OCT into diabetic retinopathy
screening algorithms. Optical coherence tomography can be
useful for quantifying retinal thickness, monitoring partial
resolution of macular edema, and identifying vitreomacular
traction in selected patients with diabetic macular edema
caused by a taut posterior hyaloid face (AAO, 2003).
The AAO (2003) states that this test might be considered in
diabetic retinopathy patients unresponsive to laser treatment
for macular edema for whom the ophthalmologist is
considering vitrectomy with removal of the posterior hyaloid
face.
OCT has also been used to determine the presence of
subretinal fluid and in documenting the degree of retinal
thickening in age-related macular degeneration (AMD). This
study has shown decreased reflectance at the level of the rod-
cone layer indicating that atrophy is present in this layer
(Maturi, 2005). According to guidelines from the AAO (2003),
“the value of this test in evaluating and treating AMD remains
unknown.”
OCT is also being investigated in evaluating choroidal
neovascularization (CNV). Well-defined and diffuse CNV have
characteristic appearances on OCT, as do subretinal
hemorrhages and retinal detachments. Despite the many
advantages of OCT, fluorescein angiography remains the
imaging modality of choice in the management of CNV.
Currently, OCT cannot replace fluorescein angiography in the
management of CNV (Wu, 2005).
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Alberta Heritage Foundation for Medical Research (2003)
stated that “while OCT appears promising for diagnosing
patients with cystoid macular edema and moderate glaucoma,
it still has a number of practical and theoretical limitations. Its
ability to detect any other of the myriad retinal diseases is
unknown. It is clear that OCT in its current state of
development is ineffective as a stand alone diagnostic test, but
a study has not yet been conducted to assess its value as part
of a serial testing strategy. The position of OCT in the scheme
of testing needs to be established so that an optimal testing
strategy can be identified that is both highly accurate and
clinically practical. Randomized controlled trials are also
needed to establish the clinical impact of OCT diagnostic
imaging on the management, treatment options, and outcomes
of patients”. The AHFMR reasoned that “[w]hile OCT appears
promising as a tool for diagnosing retinal disease, there are
many questions relating to its clinical utility that are not likely to
be answered by a cross-sectional study. Longitudinal studies
are needed to determine the temporal relationship between
OCT RNFL thickness measurements and visual field defects,
and to identify any changes in RNFL thickness that could
predict future visual deterioration.”
A more recent assessment by the Alberta Heritage Foundation
for Medical Reseach (AHFMR, 2006) summarized the current
status of ophthalmic scanning devices in glaucoma. The
assessment concluded: "B ased on results from three
systematic reviews, the value of CSLO [confocal scanning
laser ophthalmoscopy] and SLP [scanning laser polarimetry]
as diagnostic tools for the detection of early glaucoma remains
unclear, although the HRT and GDx methods hold
considerable promise for the detection of glaucoma-associated
structural change. The available evidence showed that HRT
and GDx are able to differentiate between normal individuals
and those with glaucoma. However, whether these devices
have the sensitivity and specificity to detect the early onset of
glaucoma, before the onset of visual field loss, remains to be
determined. The available CSLO and SLP devicesstill await
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prospective validation against accepted measures of structural
and functional change in terms of whether the use of a test
results improves patient outcomes and is helpful in patient
management and obviates unnecessary treatment."
The United Kingdom National Health Service National
Coordinating Centre for Healthcare Technology Assessment
(NCCHTA) conducted primary research and a comprehensive
systemic review of the ophthalmic scanning devices in
glaucoma screening (Kwartz et al, 2005). The assessment
concluded "[t]he findings of the glaucoma imaging study
suggest that, although optic nerve head tomography and
scanning laser polarimetry provide good-quality digital images,
their data may contribute little to a patient's clinical diagnosis
but would add significantly to the cost of their assessment."
Hickman (2007) reviewed the last 10 years of progress in the
imaging of the optic nerve with a particular focus on
applications to multiple sclerosis (MS). Development of
magnetic resonance imaging (MRI) of the optic nerve has
lagged behind imaging of other parts of the CNS. These
limitations are due to technical challenges related to the small
size and mobility of the optic nerves and artefacts caused by
surrounding cerebrospinal fluid, orbital fat, and air-bone
interfaces. Nonetheless, the last 10 years has seen significant
progress with regard to detecting optic nerve atrophy following
optic neuritis, the use of fat- and CSF-suppressed high
resolution imaging, the ability to measure magnetization
transfer ratio and diffusivity in the optic nerve, and the
emergence of SPIR-FLAIR for increasing sensitivity to
inflammatory demyelination. Remaining challenges include
further reduction of movement artifacts, testing ultra-high field
MRI systems and dedicated surface coils, and developing
automated segmentation techniques to improve the
reproducibility of quantitative measurements. Finally the role
of OCT as a marker of retinal damage needs to be clarified
further through correlations with MRI, clinical, and
electrophysiologic data.
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In a report on optic nerve head and retinal nerve fiber layer
analysis by the American Academy of Ophthalmology, Lin and
associates (2007) evaluated the current published literature on
the use of optic nerve head (ONH) and retinal nerve fiber layer
(RNFL) measurement devices in diagnosing open-angle
glaucoma and detecting progression. The authors concluded
that ONH and RNFL imaging devices provide quantitative
information for the clinician. Based on studies that have
compared the various available technologies directly, there is
no single imaging device that outperforms the others in
distinguishing patients with glaucoma from controls.
In a report on laser scanning imaging for macular disease by
the American Academy of Ophthalmology, McDonald and
colleagues (2007) examined if laser scanning imaging is a
sensitive and specific tool for detecting macular disease when
compared with the current standard technique of slit-lamp
biomicroscopy or stereoscopic fundus photography. Literature
searches conducted in December 2004 and in August 2006
retrieved 370 citations. The Retina Panel members selected
65 articles for the panel methodologist to review and rate
according to the strength of the evidence. Of the 65 articles
reviewed, 6 provided level I evidence, 9 provided level II
evidence, and 50 provided level III evidence. A level I rating
was assigned to studies that reported an independent masked
comparison of an appropriate spectrum of consecutive
patients, all of whom had undergone both the diagnostic test
and the reference standard. A level II rating was assigned to
an independent masked or objective comparison; a study
performed in a set of non-consecutive patients or confined to a
narrow spectrum of study individuals (or both), all of whom had
undergone both the diagnostic test and the reference
standard; or an independent masked comparison of an
appropriate spectrum, but the reference standard had not
been applied to all study patients. A level III rating was
assigned when the reference standard was unobjective,
unmasked, or not independent; positive and negative tests
were verified using separate reference standards; or the study
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was performed in an inappropriate spectrum of patients.
There are high-level studies of the use of laser scanning
imaging to quantify macular thickness and, thereby, macular
edema in patients with diabetic retinopathy and to examine
patients with a macular hole. There is lower-quality evidence
on the use of laser scanning imaging for other diseases of the
macula. There is insufficient evidence to compare the different
instruments. The authors concluded that there is level I
evidence that laser scanning imaging can accurately and
reliably quantify macular thickness in patients with diabetic
retinopathy. There is level I evidence that OCT provides
additional information to clinical examination when used in
patients with a macular hole. Laser scanning imaging
provides important information that is helpful in patient
management by allowing objective serial quantitative
measurements. Although further studies are needed to
develop an optimal testing strategy using these imaging
modalities, laser scanning imaging is a sensitive, specific,
reproducible tool for diagnosing macular edema and,
therefore, is likely to be useful for managing diseases that
result in macular edema.
In a prospective, controlled, single-center study, Ibrahim and
colleagues (2010) examined the applicability of tear meniscus
height (TMH) measurement using Visante OCT in the
diagnosis of dry eye disease. A total of 24 right eyes of 24
patients (6 males, 18 females; mean age of 63.14 +/- 13.4
years) with definite dry eye according to the Japanese dry eye
diagnostic criteria and 27 right eyes of 27 control subjects (12
males, 15 females; mean age of 56.04 +/- 14.22 years) were
recruited. All subjects underwent slit-lamp TMH measurement,
OCT upper and lower TMH measurements, tear film breakup
time (BUT) measurements, vital stainings, and Schirmer test.
The results were compared between the 2 groups by Mann-
Whitney test. Main outcome measures were the correlation
between the clinical findings of slit-lamp TMH, strip
meniscometry examination, tear functions, vital staining
scores, and the OCT upper and lower TMH parameters were
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tested by Spearman's correlation test. Receiver operating
characteristic (ROC) curve technique was used to evaluate the
sensitivity, specificity and cut-off values of OCT TMH
examination in the diagnosis of dry eye. The OCT upper and
lower TMH values, slit-lamp TMH, strip meniscometry, tear film
BUT, and vital staining scores were significantly lower in the
dry eye patients compared with controls (p < 0.001). A
significant correlation between the OCT upper and lower TMH
measurements as well as slit-lamp TMH, strip meniscometry,
tear functions, vital staining scores, and the Schirmer test was
found. The ROC curve technique analysis of the OCT lower
TMH showed that, when the cut-off value was set at less than
0.30 mm, the sensitivity and specificity of the testing were 67
% and 81 %, respectively. The authors concluded that Visante
OCT is a quick, non-invasive method for assessing the TMH,
with acceptable sensitivity, specificity, and repeatability, and
may have potential applications for the diagnosis and
evaluation of dry eye disease. They also stated that further
studies on OCT TMH should determine age- and gender-
specific cut-off values, sensitivity, specificity of the test in the
diagnosis of dry eye disease when performed alone or in
conjunction with other dry eye tests.
In a prospective, cross-sectional study, Jeoung et al (2010)
evaluated quantitatively the degree of diffuse retinal nerve
fiber layer (RNFL) atrophy using Stratus optical OCT. A total
of 102 eyes of 102 patients with diffuse RNFL atrophy and 102
healthy eyes of 102 age-matched subjects were enrolled in the
Diffuse Atrophy Imaging Study. Two experienced observers
graded RNFL photographs of diffuse RNFL atrophy eyes using
a previously reported standardized protocol with a 4-level
grading system. Readings were taken from the superior and
inferior RNFL areas. The OCT-measured RNFL thickness
parameters were compared among normal eyes and diffuse
atrophy subgroups. Area under the ROCs (AROCs) was
calculated for various OCT RNFL parameters. Main outcome
measures were average and segmental (4 quadrants and 12
clock-hours) OCT-measured RNFL thicknesses and AROCs
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for various OCT parameters. For superior and inferior RNFL
areas, diffuse atrophy grading by 2 observers agreed in 82.5
% and 83.3 % of cases, respectively, with a substantial
agreement (kappa value = 0.760 [p < 0.001] and 0.777 [p <
0.001]). Significant differences were observed in RNFL
thickness among normal and all diffuse atrophy subgroups,
especially in the 7 and 11 o'clock sectors (p < 0.0001). The
OCT RNFL thickness measurements decreased with
increasing severity of RNFL damage. The 7 and 11 o'clock
sectors showed the highest AROCs for discrimination of mild
RNFL atrophy from normal eyes (0.972 and 0.979,
respectively). The authors concluded that the OCT RNFL
thickness parameters showed excellent quantitative correlation
with the degree of diffuse RNFL atrophy. These findings
suggested that Stratus OCT may serve as a useful adjunct in
accurately and objectively assessing the degree of diffuse
RNFL atrophy. Moreover, the authors noted that further
studies are needed to assess the diagnostic ability of the
Stratus OCT with its internal normative database to detect
diffuse RNFL atrophy.
Cettomai and associates (2010) performed clinical and OCT
examinations on 240 patients attending a neurology clinic.
Using OCT 5th percentile to define abnormal RNFL
thickness, these investigators compared eyes classified by
neurologists as having optic atrophy to RNFL thickness, and
afferent pupillary defect (APD) to RNFL thickness ratios of eye
pairs. Mean RNFL thickness was less in eyes classified by
neurologists as having optic atrophy (79.4 +/- 21 μm; n = 63)
versus those without (97.0 +/- 15 μm; n = 417; p < 0.001,
t-test) and in eyes with an APD (84.1 +/- 16 μm; n = 44) than
without an APD (95.8 +/- 17 μm; n = 436; p < 0.001).
Physicians' diagnostic accuracy for detecting pallor in eyes
with an abnormal RNFL thickness was 79 % (sensitivity =
0.56; specificity = 0.82). Accuracy for detecting a retinal APD
in patients with mean RNFL ratio (affected eye to unaffected
eye) less than 0.90 was 73 % (sensitivity = 0.30; specificity =
0.86). Ability to detect visual pathway injury via assessment of
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atrophy and APD differed between neurologists. The authors
concluded that OCT reveals RNFL abnormality in many
patients in whom eyes are not classified by neurologic
examiners as having optic atrophy. They stated that further
study is needed to define the role of OCT measures in the
context of examinations for optic atrophy and APD by
neuroophthalmologists.
In a retrospective chart review, Ota et al (2010) studied
morphologic changes of serous retinal detachment (SRD) and
hyper-reflective dots, which have been reported to be
precursors of hard exudates, detectable in SRD using OCT to
assess whether or not the OCT findings are correlated with the
subfoveal deposition of hard exudates in patients with diabetic
macular edema (DME) accompanied by SRD. A total of 28
eyes of 19 patients with DME accompanied by SRD were
included in this analysis. These researchers imaged SRD and
the hyper-reflective dots in SRD using spectral domain OCT
(SD-OCT). The number and distribution of the hyper-reflective
dots in SRD were evaluated before the initial treatment at the
authors' hospital for DME accompanied by SRD. Based on a
difference in the SD-OCT findings, the study eyes were divided
into 2 groups: (i) eyes with a few dots and (ii) those with
many dots. These investigators studied the clinical course of
these 2 groups to assess whether or not the findings of SRD
and hyper-reflective dots on the SD-OCT images were
correlated with deposition of hard exudates in the subfoveal
space during follow-up. Main outcome measures were
correlation of the SD-OCT findings of SRD and hyper-reflective
dots with deposition of hard exudates in the subfovea of
patients with DME accompanied by SRD. Subfoveal
deposition of hard exudates was seen in 11 of the 28 eyes at
the final examination. Before initial treatment at the
authors' hospital, 14 eyes had a few hyper-reflective dots SRD
and 14 eyes had many hyper-reflective dots. Whereas no
deposition of hard exudates in the subfoveal space was seen
in the former eyes, it was seen in 11 of the latter 14 eyes (p <
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0.0001). In addition, using SD-OCT, these researchers found
discontinuity of the outer border of detached neurosensory
retina in 9 of the 28 eyes. Of these 9 eyes, 1 was in the group
with few hyper-reflective dots and 8 were in the group with
many hyperreflective dots (p = 0.0046). The authors
concldued that in patients with DME accompanied by SRD, SD
OCT revealed that hyper-reflective dots may be associated with
the subfoveal deposition of hard exudates during follow- up.
Furthermore, they noted that further prospective studies with a
larger sample size are needed to elucidate these details of
SRDand the reason(s) why foveal deposition of hard exudates
occurs in eyes with DME.
Marmor et al (2011) stated that the AAO recommendations for
screening of chloroquine (CQ) and hydroxychloroquine (HCQ)
retinopathy were published in 2002, but improved screening
tools and new knowledge about the prevalence of toxicity have
appeared in the ensuing years. No treatment exists as yet for
this disorder, so it is imperative that patients and their
physicians be aware of the best practices for minimizing toxic
damage. New data have shown that the risk of toxicity
increases sharply toward 1 % after 5 to 7 years of use, or a
cumulative dose of 1000 g of HCQ. The risk increases further
with continued use of the drug. The prior recommendation
emphasized dosing by weight. However, most patients are
routinely given 400 mg of HCQ daily (or 250 mg CQ). This
dose is now considered acceptable, except for individuals of
short stature, for whom the dose should be determined on the
basis of ideal body weight to avoid overdosage. A baseline
examination is advised for patients starting these drugs to
serve as a reference point and to rule out maculopathy, which
might be a contraindication to their use. Annual screening
should begin after 5 years (or sooner if there are unusual risk
factors). Newer objective tests, such as multi-focal electro-
retinogram (mfERG), spectral domain-OCT(SD-OCT), and
fundus auto-fluorescence (FAF), can be more sensitive than
visual fields. It is now recommended that along with 10-2
automated fields, at least one of these procedures be used for
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routine screening where available. When fields are performed
independently, even the most subtle 10-2 field changes should
be taken seriously and are an indication for evaluation by
objective testing. Because mfERG testing is an objective test
that evaluates function, it may be used in place of visual
fields. Amsler grid testing is no longer recommended. Fundus
examinations are advised for documentation, but visible bull's-
eye maculopathy is a late change, and the goal of screening is
to recognize toxicity at an earlier stage. Patients should be
aware of the risk of toxicity and the rationale for screening (to
detect early changes and minimize visual loss, not necessarily
to prevent it). The drugs should be stopped if possible when
toxicity is recognized or strongly suspected, but this is a
decision to be made in conjunction with patients and their
medical physicians.
Scanning Computerized Ophthalmic Diagnostic Imaging (OCT) for Patients with Multiple Sclerosis
Saidha et al (2015) examined if atrophy of specific retinal
layers and brain substructures are associated over time, in
order to further validate the utility of OCT as an indicator of
neuronal tissue damage in patients with MS. Cirrus high-
definition OCT (including automated macular segmentation)
was performed in 107 MS patients biannually (median follow-
up of 46 months). Three-Tesla magnetic resonance imaging
brain scans (including brain-substructure volumetrics) were
performed annually. Individual-specific rates of change in
retinal and brain measures (estimated with linear regression)
were correlated, adjusting for age, sex, disease duration, and
optic neuritis (ON) history. Rates of ganglion cell + inner
plexiform layer (GCIP) and whole-brain (r = 0.45; p < 0.001),
gray matter (GM; r = 0.37; p < 0.001), white matter (WM; r =
0.28; p = 0.007), and thalamic (r = 0.38; p < 0.001) atrophy
were associated. GCIP and whole-brain (as well as GM and
WM) atrophy rates were more strongly associated in
progressive MS (r = 0.67; p < 0.001) than relapsing-remitting
MS (RRMS; r = 0.33; p = 0.007). However, correlation
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between rates of GCIP and whole-brain (and additionally GM
and WM) atrophy in RRMS increased incrementally with step-
wise refinement to exclude ON effects; excluding eyes and
then patients (to account for a phenotype effect), the
correlation increased to 0.45 and 0.60, respectively, consistent
with effect modification. In RRMS, lesion accumulation rate
was associated with GCIP (r = −0.30; p = 0.02) and inner
nuclear layer (r = −0.25; p = 0.04) atrophy rates. The authors
concluded that over time GCIP atrophy appeared to mirror
whole-brain, and particularly GM, atrophy, especially in
progressive MS, thereby reflecting underlying disease
progression. They stated that these findings supported OCT
for clinical monitoring and as an outcome in investigative trials.
This study had several major drawbacks: (i) because the
majority of included patients had RRMS, more accurate
characterization of the associations between retinal and
brain atrophy by MS subtype is needed, requiring the
enrollment of greater numbers of progressive MS patients,
of both the secondary-progressive (SPMS) and primary-
progressive MS (PPMS) subtypes. Larger and longer
longitudinal studies would help address these limitations
and establish the validity of these findings, (ii) the cohort
included in this study is a heterogeneous cohort, both in
terms of clinical characteristics and disease-modifying
therapies. Thus, it is necessary to exercise caution when
extrapolating results from the current study for the
purpose of designing future clinical trials, which would
more likely be structured toward recruitment of
homogenous MS cohorts, (iii) virtually all RRMS patients in
the current study cohort were on disease-modifying
therapies, and, as a result, it is likely that these results
under-estimated true rates of retinal atrophy; retinal rates
of atrophy might be hypothetically higher in untreated MS
populations. Furthermore, there was variability in terms of the
classes of disease-modifying therapies patients were receiving
not only at baseline, but also for the duration of study follow-
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up. This mix in disease-modifying therapies throughout the
study duration precluded assessment of the effects of MS
treatments on these results. Future investigations including
more homogenously treated MS subgroups would allow for
more accurate assessment of the effects of disease modifying
therapies on the relationships between rates of retinal and
brain atrophy. Such information would be of great utility and
assist in guiding future clinical trial designs that incorporate
OCT as an outcome measure.
The authors stated that the results of this study indicated that
GCIP and brain atrophy in MS closely parallel each other over
time, suggesting a role for OCT as a valuable biomarker not
only for the purpose of tracking patients clinically, but also in
clinical trials for objective investigation of putative neuro-
protective and/or neuro-restorative therapies. Although GCIP
and brain atrophy are associated in RRMS (especially after
refinement for ON history; a factor that should be borne in
mind in the interpretation of GCIP measures longitudinally),
the associations between GCIP and brain atrophy in
progressive MS appeared to be exceptional. These
researchers noted that although their findings require
independent verification, and should be replicated across
larger MS cohorts.
Behbehani and colleagues (2017) stated that OCT with retinal
segmentation analysis is used in assessing axonal loss and
neuro-degeneration in MS by in-vivo imaging, delineation and
quantification of retinal layers. There is evidence of deep
retinal involvement in MS beyond the inner retinal layers. The
ultra-structural retinal changes in MS in different MS
phenotypes can reflect differences in the pathophysiologic
mechanisms. There is limited data on the pattern of deeper
retinal layer involvement in progressive MS (PMS) versus
relapsing remitting MS (RRMS). In a cross-sectional study,
these researchers compared the OCT segmentation analysis
in patients with RRMS and PMS. A total of 113 MS patients
(226 eyes) (29 PMS, 84 RRMS) and 38 healthy controls (72
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eyes) were included in this trial; SD-OCT using the macular
cube acquisition protocol and segmentation of the retinal
layers for quantifying the thicknesses of the retinal layers were
carried out. Segmentation of the retinal layers was performed
utilizing Orion software for quantifying the thicknesses of
individual retinal layers. The retinal nerve finer layer (RNFL) (p
= 0.023), the ganglion-cell/inner plexiform layer (GCIPL) (p =
0.006) and the outer plexiform layer (OPL) (p = 0.033) were
significantly thinner in PMS compared to RRMS. There was
significant negative correlation between the outer nuclear layer
(ONL) and EDSS (r = -0.554, p = 0.02) in PMS patients. In
RRMS patients with prior optic neuritis, the GCIPL correlated
negatively (r = -0.317; p = 0.046), while the photoreceptor
layer (PR) correlated positively with EDSS (r = 0.478; p =
0.003). The authors concluded that patients with PMS
exhibited more atrophy of both the inner and outer retinal
layers than RRMS. The ONL in PMS and the GCIPL and PR
in RRMS can serve as potential surrogate of disease burden
and progression (EDSS). The specific retinal layer predilection
and its correlation with disability may reflect different
pathophysiologic mechanisms and various stages of
progression in MS. Moreover, they stated that longitudinal
studies using OCT segmentation analysis can better define the
significance and the dynamics of the changes in retinal layers
in different MS phenotypes and how they relate to disease
progression.
The authors noted that this study was limited by its cross-
sectional design and its relatively small sample size. Most of
the PMS cohort were composed of secondary progressive MS
(SPMS) with under-representation of primary progressive MS
(PPMS) due to rarity of the latter phenotype. In addition, these
investigators combined the primary and secondary progressive
cohort as a single group, which may have influenced their
findings. However, there is increasing evidence of the
phenotypic similarities between PPMS and SPMS and,
common genetic susceptibility to MS are similar between and
measures of global brain tissue damage and magnetization
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transfer imaging. Despite that, the OCT findings in this study
in the progressive cohort did not strictly apply to PPMS, which
had its unique aspects of indolent course with less frequent
visual pathway involvement and thus relative preservation of
the inner retinal layers.
Scanning Computerized Ophthalmic Diagnostic Imaging (OCT) for Patients with Vogt-Koyanagi-Haradas
Sakata et al (2014) noted that Vogt-Koyanagi-Harada (VKH)
disease is a systemic autoimmune disorder that affects
pigmented tissues of the body, with its most dire
manifestations affecting the eyes. This review focused on the
diagnostic criteria of VKH disease, including some information
on history, epidemiology, appropriate clinical and classification
criteria, etiopathogenesis, treatment and outcomes. Expert
review of most relevant literature from the disease's first
description to 2013 and correlation with the experience in the
care of VKH disease patients at a tertiary Uveitis Service in
Brazil gathered over the past 40 years. The clinical
manifestations and ancillary assessment of VKH disease have
been summarized in the Revised Diagnostic Criteria proposed
in 2001 in a manner that allows systematic diagnosis of both
acute and chronic patients. It includes the early acute uveitic
manifestations (bilateral diffuse choroiditis with bullous serous
retinal detachment and optic disk hyperemia), the late ocular
manifestations (diffuse fundus depigmentation, nummular
depigmented scars, retinal pigment epithelium clumping and/or
migration, recurrent or chronic anterior uveitis), besides the
extra-ocular manifestations (neurological/auditory and
integumentary). There are 2 exclusion criteria, i.e., absence of
previous ocular penetrating trauma or surgery and any other
ocular disease that could be confounded with VKH disease.
HLA-DRB1*0405 plays an important role in pathogenesis,
rendering carriers more susceptible to disease. The primary
ocular pathological feature is a diffuse thickening of the uveal
tract in the acute phase. Later on, there may be a
compromise of choriocapillaris, retinal pigment epithelium and
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outer retina, mostly due to an "upstream" effect, with clinical
correlates as fundus derangements. Functional tests (ERG
and visual field testing) as well as imaging modalities
(retinography, fluorescein/indocyanine green angiography
(FA/ICGA), OCT and ultrasound) play an important role in
diagnosis, severity grading as well as disease monitoring.
Though high-dose systemic corticosteroids remain gold-
standard therapy, refractory cases may need other agents
(cyclosporine A, anti-metabolites and biological agents). In
spite of good visual outcomes in the majority of patients,
knowledge about disease progression even after the acute
phase and its impact on visual function warrant further
investigation.
Komuku et al (2015) stated that VKH disease and central
serous chorio-retinopathy (CSCR) develop serous retinal
detachment; however, the treatment of each disease is totally
different. Steroids treat VKH but worsen CSC; therefore, it is
important to distinguish these diseases. These investigators
reported a case with CSCR, which was diagnosed by en face
OCT imaging during the course of VKH disease. A 50-year old
man was referred with blurring of vision in his right eye.
Fundus examination showed bilateral optic disc swelling and
macular fluid in the right eye; OCT showed thick choroid, and
en face OCT images depicted blurry choroid without clear
delineation of choroidal vessels. Combined with angiography
findings, this patient was diagnosed with VKH disease and
treated with steroids. Promptly, fundus abnormalities resolved
with the reduction of the choroidal thickness and the choroidal
vessels became visible on the en face images. During the
tapering of the steroid, serous macular detachment in the right
eye recurred several times. Steroid treatment was effective at
first; however, at the 4th appearance of sub-macular fluid, the
patient did not respond. At that time, the choroidal vessels on
the en face OCT images were clear, which significantly
differed from the images at the time of recurrence of VKH.
Angiography also suggested CSCR-like leakage. The tapering
of the steroids was effective in resolving the fluid. Secondary
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CSCR may develop in the eye with VKH after steroid
treatment. The authors concluded that en face OCT
observation of the choroid may be helpful to distinguish each
condition.
Tsuboi et al (2015) characterized patients with (VKH disease
with choroidal folds (CFs) and determine how the foveal
choroidal thickness changes after initial treatment using high-
penetration OCT (HP-OCT). In this retrospective
observational study, these researchers analyzed 42 eyes of 21
patients with new-onset VKH disease to determine the
demographic and clinical differences between patients with
and without CFs; 24 eyes (57.1 %) of 13 patients with VKH
disease had CFs. The mean age (p = 0.0009) of patients with
CFs was significantly higher than that of those without CFs
(49.1 versus 39.4 years, respectively). The frequency of disc
swelling (p = 0.0001) was significantly higher in eyes with CFs
than in those without CFs (95.8 % versus 38.9 %). The
choroidal thickness at the first visit (p = 0.0011) was
significantly greater in eyes with CFs than in those without CFs
(794 ± 144 μm versus 649 ± 113 μm). The choroid 6 months
after the initial treatment (p = 0.0118) was significantly thinner
in eyes with CFs than in those without CFs (270 ± 92 μm
versus 340 ± 80 μm). The frequency of sunset glow fundus at
6 months (p = 0.0334) in eyes with CFs was significantly higher
than in those without CFs (62.5 % versus 27.8 %). The
authors concluded that the development of CFs in patients
with VKH disease was significantly correlated with age, disc
swelling, and choroidal thickness. The eyes with CFs
frequently developed a sunset glow fundus. They stated that
these findings suggested that patients with CFs might have
severe and longstanding inflammation of the choroidal tissues.
Lee et al (2016) investigated morphologic features of choroid
in the choroidal thickening diseases, including CSCR,
polypoidal choroidal vasculopathy (PCV), and VKH, by a novel
tomographic classification system of the choroid. This cross-
sectional study involved 30 patients with active CSC, 30
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patients with active PCV, and 27 patients with active VKH, and
30 normal controls. Utilizing enhanced depth imaging OCT
(EDI-OCT), these researchers classified the morphology of the
choroid into 5 categories: (i) Standard (S), (ii) Dilated outer
layer and attenuated inner layer (DA), (iii) Darkened (D), (iv)
Marbled (M), and (v) Pauci-vascular (PV) types. Additional
tomographic characteristics of the choroid such as choroidal
vascular dilation, convolution, scleral invisibility, and choroidal
hyper- or hypo-thickening were identified as well. The
distribution of 5 choroidal tomographic morphology and
additional tomographic characteristics in each group were
analyzed. The DA type was observed in the CSCR group
more frequently than in the normal control group (53.3 %
versus 3.3 %, p < 0.001). Additional tomographic
characteristics, such as choroidal vascular dilation (76.7 %),
and choroidal hyper-thickening (36.7 %), were more prevalent
in the CSCR group than in the control group. The PCV group
showed higher prevalence of DA type (33.3 % versus 3.3 %, p
= 0.006) than the control group. The VKH group showed a
significantly higher frequency of the D type (63.0 %),
convolution (40.7 %), and scleral invisibility (70.4 %) than
controls (0 % for all 3 findings). The authors concluded that
CSCR and PCV shared common morphologic characteristics
of choroid, including dilated outer vascular layer and focally
attenuated innermost layer. Dense hypo-reflectivity and
convolution of choroid were the specific tomographic markers
for acute VKH. They stated that a new tomographic
classification system of choroid may provide discrimination
ability and insight into major pachychoroidopathies.
Hashizume et al (2016) determined the clinical significance of
retinal pigment epithelium (RPE) undulations in the acute
stage of VKH disease. Retinal pigment epithelium undulations
were detected and classified into 3 grades: Grade 1, slight;
Grade 2, moderate; and Grade 3, severe undulations, in the
EDI-OCT images. The relationship between the clinical
characteristics and the presence of RPE undulations was
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investigated. Among the 61 eyes of 31 patients with VKH
disease, 40 eyes had some degree of RPE undulations (Grade
1 = 12, Grade 2 = 15, and Grade 3 = 13). The patients with
RPE undulations in both eyes were significantly older at the
onset (p = 0.0002). The eyes with RPE undulations were
more likely to develop posterior recurrences (p = 0.032) and
have worse vision at 12 months (p = 0.043). Multiple
regression analysis revealed that RPE undulations were an
independent predictor of posterior recurrences (p = 0.009) and
poor visual outcomes (p = 0.035). The authors concluded that
retinal pigment epithelium undulations detected by EDI-OCT
were relatively frequent occurrences at the acute stage of
VKH, and their presence is a predictor of posterior recurrences
and poor visual outcomes after high-dose steroid therapy.
Bae et al (2017) examined if the inflammatory composition of
sub-retinal fluid in VKH serous retinal detachments is
predictive of photoreceptor injury, and quantified photoreceptor
recovery, following resolution of these detachments. Optical
density (OD) measurements of spectral-domain OCT (SD-
OCT) scans were used to derive the fibrinous index, a
measure of the inflammatory composition of sub-retinal fluid. In
order to assess photoreceptor status, photoreceptor outer
segment (PROS) volume was measured from SD-OCT scans.
The fibrinous index of sub-retinal fluid in VKH uveitis was
strongly correlated with the PROS volume following resolution
of sub-retinal fluid (r = -0.70, p = 0.006). Following fluid
resolution, both PROS volume (p < 0.0001) and visual acuity
(p = 0.0015) improved. The authors concluded that the
fibrinous index of sub-retinal fluid during the acute stage of
VKH can predict photoreceptor status following resolution of
sub-retinal fluid; PROS volume is a useful measure of
photoreceptor recovery in VKH.
Aggarwal et al (2018) reported the imaging characteristics of
acute VKH disease using OCT angiography (OCTA). In this
prospective study, patients with acute VKH (n = 10; mean age
of 30.5 ± 13.43 years) underwent multi-modal imaging
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(baseline and follow-up) using fundus photography, FA, ICGA,
OCT, and OCTA. The OCTA images were analyzed to assess
the retino-choroidal vasculature and compared with other
imaging techniques. During the active stage, all eyes showed
multiple foci of choriocapillaris flow void that correlated with
ICGA. These foci decreased in number and size after initiation
of therapy. In 1 patient, flow void areas re-appeared after
cessation of therapy without any detectable change on ICGA.
This patient soon developed clinical recurrence requiring re-
initiation of immunosuppression. The authors concluded that
OCTA allowed high-resolution imaging of inflammatory foci
suggestive of choriocapillaris hypo-perfusion in acute VKH
disease non-invasively. They stated that OCTA may be very
helpful in the follow-up of such patients.
Liu et al (2016) examined the diagnostic value of OCT for the
detection of acute VKH disease. Clinical charts and OCT
images were retrospectively reviewed for patients
consecutively diagnosed with acute VKH, sub-acute VKH,
multi-focal CSCR, and posterior scleritis. All patients
underwent OCT, fundus photography, and FA before
treatment. The characteristics of OCT and FA were analyzed
and recorded. The study included 80 eyes with acute VKH, 32
eyes with sub-acute VKH, 33 eyes with CSCR, and 13 eyes
with posterior scleritis. The most common OCT features of
VKH disease were hyper-reflective dots (70/80; 88 %), sub-
retinal membranous structures (64/80; 80 %), retinal
detachment higher than 450 μm (63/80; 79 %), and retinal
pigment epithelium (RPE) folds (44/80; 55 %). For the
detection of VKH disease, sensitivity and specificity were for
sub-retinal membranous structures 80 % and 95.6 %,
respectively, for high retinal detachment 78.8 % and 76.1 %,
respectively, for sub-retinal hyper-reflective dots, 87.5 and
60.9 %, respectively, and for RPE folds 55 % and 80.4 %
respectively. Sub-retinal membranous structures showed the
highest positive predictive value (97.3 %) and negative
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predictive value (65.7 %) of all OCT assessed features. The
authors concluded that OCT-related morphological signs had a
relatively high predictive value for the diagnosis of acute VKH.
Chee et al (2017) compared EDI-OCT and swept source OCT
(SS-OCT) in assessment of VKH disease. All consecutive
VKH patients seen at Singapore National Eye Centre during
2012 to 2013 were imaged using both modalities. Sub-foveal
choroidal thickness (SFCT) was measured by one masked
trained observer. A total of 137 pairs of scans were obtained
from 48 patients. SFCT was more likely to be measurable on
SS-OCT than EDI-OCT (112, 81.8 %; 84, 61.3 %; p < 0.001
Fisher's Exact test). There was good inter-OCT correlation of
SFCT when both scans were measureable (mean of the
difference in SFCT ± 2 standard deviations (SD) of -14.5 ±
21.0 μm). The authors concluded that SS-OCT images were
superior to EDI-OCT; but the SFCT measurements are
comparable when both are readable.
Furthermore, the American Academy of Ophthalmology (2016)
states that “The diagnosis of VKH syndrome is essentially
clinical; exudative retinal detachment during the acute disease
and sunset glow fundus during the chronic phase are highly
specific to this entity. In patients presenting without extra-
ocular changes, FA, ICG angiography, OCT, FAF imaging,
lumbar puncture, and ultrasonography may be useful
confirmatory tests. During the acute uveitic stage, FA typically
reveals numerous punctate hyper-fluorescent foci at the level
of the RPE in the early stage of the study followed by pooling
of dye in the sub-retinal space in areas of neurosensory
detachment. The vast majority of patients show disc leakage,
but CME and retinal vascular leakage are uncommon. In the
convalescent and chronic recurrent stages, focal RPE loss and
atrophy produce multiple hyper-fluorescent window defects
without progressive staining … OCT may be useful in the
diagnosis and monitoring of serous macular detachments,
CME, and choroidal neovascular membranes. More recently,
the combined use of FAF imaging and SD-OCT offers a non-
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invasive assessment of RPE and outer retina changes in
patients with chronic VKH syndrome that may not be apparent
on clinical examination”.
Frontotemporal Degeneration
Kim and colleagues (2017) noted that whereas Alzheimer
disease (AD) is associated with inner retina thinning visualized
by SD-OCT, these researchers sought to determine if the
retina has a distinguishing biomarker for frontotemporal
degeneration (FTD). Using a cross-sectional design, these
investigators examined retinal structure in 38 consecutively
enrolled patients with FTD and 44 controls using a standard
SD-OCT protocol. Retinal layers were segmented with the
Iowa Reference Algorithm. Subgroups of highly predictive
molecular pathology (tauopathy, TAR DNA-binding protein 43,
unknown) were determined by clinical criteria, genetic
markers, and a CSF biomarker (total tau: β-amyloid) to
exclude presumed AD. These researchers excluded eyes with
poor image quality or confounding diseases; SD-OCT
measures of patients (n = 46 eyes) and controls (n = 69 eyes)
were compared using a generalized linear model accounting
for inter-eye correlation, and correlations between retinal layer
thicknesses and Mini-Mental State Examination (MMSE) were
evaluated. Adjusting for age, sex, and race, patients with FTD
had a thinner outer retina than controls (132 versus 142 μm, p
= 0.004). Patients with FTD also had a thinner outer nuclear
layer (ONL) (88.5 versus 97.9 μm, p = 0.003) and ellipsoid
zone (EZ) (14.5 versus 15.1 μm, p = 0.009) than controls, but
had similar thicknesses for inner retinal layers. The outer
retina thickness of patients correlated with MMSE (Spearman r
= 0.44, p = 0.03). The highly predictive tauopathy subgroup (n
= 31 eyes) also had a thinner ONL (88.7 versus 97.4 μm, p =
0.01) and EZ (14.4 versus 15.1 μm, p = 0.01) than controls.
The authors concluded that FTD was associated with outer
retina thinning, and this thinning correlated with disease
severity.
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The authors stated that one drawback of this study was the
different demographics of controls and patients. While all
patients were recruited consecutively, differences reflected the
different populations of FTD versus controls recruited during a
routine eye examination. Another drawback of these findings
was the limited number of patients in the non-tauopathy
subgroups; this must be considered before generalizing the
results to all patients with FTD. These investigators stated that
the findings of this study suggested that measurements of
retinal thickness have the potential to serve as biomarkers for
FTD and may relate to disease severity; future work should
focus on direct comparison of AD patients with FTD patients
and comparison of the different subgroups of FTD using
similar methods and longitudinal studies with autopsy
confirmation.
Diagnosis of Optic Neuritis
In a retrospective, observational study, Xu and colleagues
(2019) examined the sensitivity of OCT in detecting prior
unilateral optic neuritis. Patients who presented from January
1, 2014, to January 6, 2017, with unilateral optic neuritis and
OCT available at least 3 months after the attack were enrolled
in this trial. These investigators compared OCT RNFL and
GCIPL thicknesses between affected and unaffected
contralateral eyes. They excluded patients with concomitant
glaucoma or other optic neuropathies. Based on analysis of
normal controls, thinning was considered significant if RNFL
was at least 9 µm or GCIPL was at least 6 µm less in the
affected eye compared to the unaffected eye. A total of 51
patients (18 male and 33 female) were included in the study;
RNFL and GCIPL thicknesses were significantly lower in eyes
with optic neuritis compared to unaffected eyes (p < 0.001);
RNFL was thinner by greater than or equal to 9 µm in 73 % of
optic neuritis eyes compared to the unaffected eye; GCIPL
was thinner by greater than or equal to 6 µm in 96 % of optic
neuritis eyes, which was more sensitive than using RNFL (p <
0.001). When using a threshold less than or equal to 1st
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percentile of age-matched controls, sensitivities were 37 % for
RNFL and 76 % for GCIPL, each of which was lower than
those calculated using the inter-eye difference as the threshold
(p < 0.01). The authors concluded that these findings
supported the use of OCT in the diagnosis of prior optic
neuritis, especially in those with unilateral presentation. There
were no patients who had optic neuritis with complaints of
vision loss who did not have thinning of the GCIPL on OCT.
These researchers stated that although larger prospective
studies are needed to confirm the optimal criteria for
identifying pathologic thinning of the inner retina by OCT, it is a
highly sensitive method of detecting a history of unilateral optic
neuritis. This study provided Class III evidence that OCT
accurately identified patients with prior unilateral optic neuritis.
The authors stated that this study had several drawbacks.
Because this patient cohort consisted of unilateral optic
neuritis, these findings were not directly applicable to patients
with bilateral optic neuritis or patients with prior episodes of
optic neuritis in the concomitant eye. This study excluded any
patients with optic nerve pathology in the fellow eye. In
patients with bilateral optic neuritis or any other optic
neuropathy in the fellow eye, the 1st percentile threshold may
be a more sensitive method than the inter-eye difference
threshold for detecting optic neuritis, given that inter-eye
difference decreases with any bilateral process. Furthermore,
depending on the provider's preference or patient's schedule,
not all unilateral chronic optic neuritis patients seen during the
time period of the study had OCT data (3/54 patients or 5.6 %
were excluded due to this). Thus, this could have introduced
sampling bias in this retrospective, observational study. The
follow-up period for OCT was variable and was as short as 3
months. This could have contributed to the decreased
sensitivity in RNFL because continued thinning is expected for
at least 6 months after an initial optic neuritis. Nonetheless,
these investigators found similar sensitivities when they
examined a subset of patients who had follow-up OCT images
beyond 6 months and, subsequently, the sensitivities were
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valid in this cohort. Another drawback of the study was that
patients with optic neuritis had a variety of causes, including
MS, neuromyelitis optica spectrum disorder (NMOSD), and
idiopathic. The cause of optic neuritis can influence the
expected degree of RNFL and GCIPL thinning. However,
even after excluding patients with myelin oligodendrocyte
glycoprotein (MOG)-IgG and aquaporin-4 (AQP4)-IgG-NMOSD
associated optic neuritis, the sensitivity using the proposed
99th percentile cut-offs for inter-eye variability was still 70 %
and 96 % for RNFL and GCIPL, respectively; therefore, OCT
remained sensitive for detecting prior optic neuritis for typical
demyelinating optic neuritis patients. Lastly, the control group
had a higher percentage of male participants than this cohort
of optic neuritis. However, male and female participants had
the same inter-eye RNFL or GCIPL difference in both the
control group and the cohort of patients with optic neuritis
(unpublished data). Although traumatic brain injury (TBI) could
be a potential confounder in OCT measurements, the control
cohort excluded any veterans with TBI. Also, no difference
between the 1st-season OCT measurements of the football
players and track team players was found in the healthy
controls.
In an editorial that accompanied the afore-mentioned study,
Saidha and Naismith (2019) states that “The current study is
an excellent start, but more work is required before fully
recommending OCT as a routine tool for diagnosing ON and
subclinical optic neuropathy. Larger studies should be
performed within specific disease states such as MS, with
subset analyses to evaluate patients at older age or many
years from their suspected demyelinating event. Longitudinal
studies can help clarify whether inter-eye differences change
during the course of disease. The identification of inter-eye
asymmetry in an individual patient may be an uncertain basis
upon which to conclude that there is definitive evidence of
prior ON, especially if asymmetry in both measures are
incongruent (e.g., fulfilled by RNFL but not GCIPL). Despite
the limitations noted, and the need for further, larger,
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longitudinal studies, the results of this study are promising.
Potentially, OCT could fulfill multiple roles towards diagnosis,
prognosis, and treatment monitoring in ON, MS, and related
disorders”.
Evaluation and Screening for Ethambutol Toxicity
The American Academy of Ophthalmology’s guideline on
“Drug-related adverse effects of clinical importance to the
ophthalmologist” (Fraunfelder, 2014) stated that “Ethambutol
optic neuropathy is usually retrobulbar and bilateral, though
sometimes asymmetric. Ethambutol toxicity may affect only
the small caliber papillo-macular bundle axons, which are hard
to visualize, and optic atrophy will not develop for months after
the fibers are lost. This means objective findings on the
fundus exam are frequently unrecognized. Optic neuropathy
may occur, on average, at 2 to 5 months after starting therapy.
The earliest ophthalmologic findings in toxic optic neuropathy
from ethambutol may be loss of visual acuity, color vision loss
or central scotomas. Ethambutol also has an affinity for the
optic chiasm with bi-temporal visual field defects manifesting
with toxicity … Consider optical coherence tomography or
contrast sensitivity testing as these tests could pick up early
ethambutol toxicity not detected with the baseline examination.
Optical coherence tomography (OCT) may be the future for
following toxic optic neuropathies as subtle retinal nerve fiber
layer (NFL) swellings can be visualized with the acute insult
and NFL thinning can be visualized from chronic toxicity”.
Furthermore, the Royal College of Ophthalmologists’ RCOphth
statement on ethambutol toxicity (2017) stated that
“Ethambutol is an effective antibiotic used to treat tuberculosis
but optic neuropathy is a potentially serious side effect of the
drug, thought to be due to zinc chelation causing mitochondrial
dysfunction. Ethambutol toxicity in adults is rare, occurring in
less than 2 % of patients on the standard dosage of 15
mg/kg/day, but impaired renal function and smoking may
increase the risk. Onset of optic neuropathy is typically 2to 5
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months after starting therapy, but may occur within days.
Symptoms can be highly variable and may initially be
unilateral. Loss of visual acuity, color vision impairment and
central/paracentral scotomata may occur; bi-temporal field
defects have also been reported due to an affinity of
ethambutol for the chiasm. Although optic atrophy will
subsequently develop, signs may be absent in early stages of
toxicity, but visual evoked potentials and optical coherence
tomography show promise in detecting subclinical optic
neuropathy”.
In a review on “Ethambutol optic neuropathy”, Chamberlaina
and colleagues (2017) provided a summary of the
epidemiology, clinical findings, management and outcomes of
ethambutol-induced optic neuropathy (EON). Ethambutol-
induced optic neuropathy is a well-known, potentially
irreversible, blinding but largely preventable disease.
Clinicians should be aware of the importance of patient and
physician education as well as timely and appropriate
screening. Two of the largest epidemiologic studies
investigating EON to-date showed the prevalence of EON in
all patients taking ethambutol to be between 0.7 and 1.29 %, a
value consistent with previous reports of patients taking the
doses recommended by the World Health Organization
(WHO). Several studies evaluated the utility of OCT in
screening for EON. These showed decreased RNFL thickness
in patients with clinically significant EON, but mixed results in
their ability to detect such changes in patients taking
ethambutol without visual symptoms. The authors concluded
that ethambutol-induced optic neuropathy is a well-known and
devastating complication of ethambutol therapy. It may occur
in approximately 1 % of patients taking ethambutol at the WHO
recommended doses, although the risk increases substantially
with increased dose. All patients on ethambutol should
receive regular screening by an ophthalmologist including
formal visual field testing. Visual evoked potentials and OCT
may be helpful for EON screening, but more research is
needed to clarify their clinical usefulness. Patients who
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develop signs or symptoms of EON should be referred to the
ethambutol-prescribing physician immediately for
discontinuation or a reduction in ethambutol dosing.
Evaluation of the Neurodegeneration Pattern in Individuals with Intra-Cranial Tumors
Banc and colleagues (2018) noted that OCT is a non-invasive,
high-resolution imaging technique that was suggested to be a
powerful biomarker of neurodegeneration. These researchers
examined the pattern of retinal OCT changes in patients with
visual pathway tumors. A prospective clinical study was
conducted and patients with single cerebral tumors with
potential of compression on the visual pathway were included.
Patients with multiple and/or metastatic tumors were
excluded. Each patient underwent a neurosurgical and
ophthalmologic evaluation, cranial-cerebral MRI, and ocular
OCT in both eyes. The OCT parameters included
circumpapillary RNFL thickness (average and sector
thickness) and retinal thickness in the macular area (average
and sector thickness). A total of 50 patients were examined
clinically and by MRI, and 18 patients were excluded; 32
patients were eligible for the study and completed the retinal
OCT; 18 patients had tumors with compressive potential on
the optic chiasm, 11 patients had tumors close to the optic
radiations, and 3 patients had tumors in the occipital lobe. A
specific pattern of OCT changes was found for each site.
Regional parameters of both optic nerve and macula were
altered. The authors concluded that retinal OCT is a promising
tool for the in-vivo assessment of the neurodegeneration
pattern in patients with intra-cranial tumors. They stated that
the evaluation of single intra-cranial tumors with compressive
potential on the visual pathway is a good candidate for the
study of neurodegeneration.
Evaluation of Parinaud Oculoglandular Syndrome (Cat Scratch Disease)
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Perez and colleagues (2010) noted that cat scratch disease
(CSD) is the main clinical presentation of Bartonella henselae
infection. However, ocular manifestations of bartonellosis
occur in about 5 to 10 % of the patients, mainly presenting as
neuroretinitis, choroiditis or oculoglandular syndrome of
Parinaud. The authors described 2 patients with documented
B. henselae infection and typical ocular compromise. Both
patients were treated and had a favorable visual outcome.
An UpToDate review on “Microbiology, epidemiology, clinical
manifestations, and diagnosis of cat scratch disease” (Spach
and Kaplan, 2019) states that “Parinaud oculoglandular
syndrome is an atypical form of CSD, which is reported in 2 to
8 % of patients with CSD. Parinaud oculoglandular syndrome
is characterized by tender regional lymphadenopathy of the
preauricular, submandibular, or cervical lymph nodes
associated with infection of the conjunctiva, eyelid, or adjacent
skin surface. Usual complaints include unilateral red eye,
foreign body sensation, and excessive watering of the eyes.
Discharge may be serous or purulent and copious in some
patients. The inoculation of the organism occurs via a cat bite
or lick near (or in) the eye, as well as by self-inoculation from
another site … Some patients develop a stellate macular
exudate (known as a "macular star"). Macular stars are due to
vascular leakage from the optic nerve head, and can be seen
on fluorescein angiography or optical coherence tomography
angiography. Patients with B. henselae-induced neuroretinitis
may not develop a macular star until 1 to 4 weeks after initial
presentation, and the exudate may persist for months, despite
resolution of the neuroretinitis”. However, there is no
mentioning of OCT in the “Summary and Recommendations”
of this review.
Monitoring of Plaquenil (Hydroxychloroquine) Toxicity
In a retrospective, observational cohort study, Browning (2013)
determined the impact of the revised American Academy of
Ophthalmology (AAO) guidelines on screening for
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hydroxychloroquine retinopathy. The setting was a private
practice of 29 doctors; study population entailed a total of 183
patients for follow-up and 36 patients for baseline screening.
Review of charts, 10-2 visual fields (VFs), multi-focal
electroretinograms (mfERG), and spectral-domain optical
coherence tomography (SD-OCT) images before and after the
revised guidelines. Main outcome measure was rates of use
of ancillary tests and clinical intervention, costs of screening,
follow-up schedules, and comparative sensitivity of tests. New
hydroxychloroquine toxicity was found in 2 of 183 returning
patients (1.1 %). Dosing above 6.5 mg/kg/day was found in 28
of 219 patients (12.8 %), an under-estimate because patient
height, weight, and daily dose were not determined in 77 (35.1
%), 84 (38.4 %), and 59 (26.9 %), respectively. In 10 of the 28
(35.7 %), the dose was reduced, in 2 (7.1 %)
hydroxychloroquine was stopped, but in 16 (57.1 %) no action
was taken. The cost of screening rose 40 %/patient after the
revised guidelines. Fundus autofluorescence (FAF) imaging
was not used. No toxicity was detected by adding mfERG or
SD-OCT. In no case was a 5-year period free of follow-up
recommended after baseline screening in a low-risk patient.
The author concluded that detection of toxic daily dosing was
a cost-effective way to reduce hydroxychloroquine toxicity, but
height, weight, and daily dose were commonly not checked.
The revised guidelines, emphasizing mfERG, SD-OCT, or
FAF, raised screening cost without improving case detection.
The recommended 5-year screening-free interval for low-risk
patients after baseline examination was ignored.
In a retrospective, observational, case-series study, Leung et
al (2015) reported rapid onset of retinal toxicity in a series of
patients followed on high-dose (1,000 mg daily)
hydroxychloroquine during an oncologic clinical trial studying
hydroxychloroquine with erlotinib for non-small cell lung cancer
(NSCLC). Ophthalmic surveillance was performed on patients
in a multi-center clinical trial testing high-dose (1,000 mg daily)
hydroxychloroquine for advanced NSCLC. The Food & Drug
Administration (FDA)-recommended screening protocol
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included only visual acuity testing, dilated fundus examination,
Amsler grid testing, and color vision testing. In patients seen
at Stanford, additional sensitive screening procedures were
added at the discretion of the retinal physician: high-resolution
SD-OCT, FAF imaging, Humphrey visual field (HVF) testing,
and mfERG. Out of the 7 patients having exposure of at least
6 months, 2 developed retinal toxicity (at 11 and 17 months of
exposure). Damage was identified by OCT imaging, mfERG
testing, and, in 1 case, visual field testing. Fundus
autofluorescence imaging remained normal. Neither patient
had symptomatic visual acuity loss. The authors concluded
that these cases showed that high doses of
hydroxychloroquine could initiate the development of retinal
toxicity within 1 to 2 years. Although synergy with erlotinib is
theoretically possible, there are no prior reports of erlotinib-
associated retinal toxicity despite over a decade of use in
oncology. These results also suggested that sensitive retinal
screening tests should be added to ongoing and future clinical
trials involving high-dose hydroxychloroquine to improve safety
monitoring and preservation of vision.
In a case-series study, Latasiewicz et al (2017) raised
awareness of the emerging issue of serious retinal damage
caused by the prolonged use of hydroxychloroquine (HCQ)
and the importance of adequate and appropriate monitoring of
visual function during treatment. This was a small
retrospective case series of 3 patients on long-term HCQ who
developed serious symptomatic retinal toxicity confirmed on
imaging and functional testing. All 3 patients were treated with
HCQ for over 15 years; 2 for rheumatoid arthritis (RA), and the
3rd for systemic lupus erythematosus (SLE). All 3 patients
had macular involvement varying in severity confirmed with
characteristic features on imaging and functional testing (OCT,
autofluorescence (AF) and Humphrey 10-2 visual fields). The
authors concluded that HCQ is widely used to treat
autoimmune conditions with a proven survival benefit in
patients with SLE. However, long-term use can be associated
with irreversible retinal toxicity. These cases highlighted that
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HCQ, like chloroquine, could also cause visual loss in
susceptible individuals. These researchers stated that early
detection of pre-symptomatic retinal changes by the
introduction of appropriate screening and monitoring is
mandatory to limit the extent of irreversible visual loss due to
HCQ retinal toxicity.
Kowalski et al (2018) reported the findings of 2 patients with
dermatological conditions who developed retinal toxicity after
treatment with HCQ that exceeded dosing recommendations.
There was no treatment for HCQ retinal toxicity and associated
visual loss, so appropriate monitoring is imperative. All
members of a patient's multi-disciplinary team should be
aware of the ocular risks of HCQ, the importance of dosing
within recommended guidelines and appropriate monitoring in
reducing the risk of visual loss.
Furthermore, an UpToDate review on “Antimalarial drugs in
the treatment of rheumatic disease” (Wallace, 2020) states
that “We advise assessment of ocular health within 1 year of
starting long-term antimalarial drug therapy. The baseline
examination should include a fundus examination of the
macula to rule out any underlying disease that may interfere
with the interpretation of screening tests. The frequency of
subsequent screening during the first 5 years of treatment may
be individualized based upon assessment of risk. We prefer
annual screening exams for all patients, but the AAO has
suggested that for patients with a normal baseline exam who
do not have major risk factors for toxic retinopathy, follow-up
examinations may be deferred until there have been 5 years of
exposure . Major risk factors for toxic retinopathy include a
daily dose of HCQ greater than 5 mg/kg real body weight or a
daily dose of chloroquine greater than 2.3 mg/kg real body
weight, antimalarial use for greater than 5 years, the presence
of renal disease, concomitant tamoxifen use, and/or the
presence of macular disease. Patients should be alert for any
change in visual acuity and should seek medical attention
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promptly if any visual loss is noted. Antimalarials should be
discontinued immediately if there is any suspicion of
retinopathy”.
Screening and Monitoring of Ethambutol (Myambutol) Toxicity
Menon et al (2009) evaluated various visual parameters for
early detection of ethambutol toxicity. This was a prospective
study of 104 eyes of 52 patients being treated with ethambutol
in the Directly Observed Treatment Strategy Centre (Dr R P
Centre for Opthalmic Sciences, New Delhi, India). Visual
acuity (VA), visual fields, visual evoked responses (VER),
stereo-acuity and retinal nerve fiber layer (RNFL) thickness on
optical coherence tomography (OCT) were assessed.
Examinations were done before the start of therapy, after 1
and 2 months of treatment, and 1 month after stopping
ethambutol. No visual functional defect was noted at
baseline. On follow-up, VA, color vision, contrast sensitivity,
fundus and stereo-acuity were not affected in any patient.
Visual field defects developed in 7.69 % (8/104) of the eyes.
Pattern-VER showed an increased mean latency of the P(100)
wave after 1 and 2 months of therapy (p < 0.001 for both) with
14.42 % (15/104) of eyes showing more than 10 ms increase
in latency. On OCT, significant loss of mean temporal RNFL
thickness was detected in 2.88 % (3/104) of eyes individually.
Overall, 19.23 % (20/104) of the studied eyes showed sub-
clinical toxicity. Reversal of this observed toxicity on pattern-
VER and visual fields was observed in 80 % of eyes after 1
month of stoppage of ethambutol; however, mean VER latency
remained delayed (p = 0.002). The authors concluded that
pattern-VER and visual field examinations were sensitive tests
to detect early toxicity. Together with OCT, they may help to
identify patients who are likely to develop clinical toxicity.
Gumus and Oner (2015) examined the effect of anti-tubercular
treatment on RNFL thickness and the efficiency of OCT on
early diagnosis of optic neuropathy. A total of 20 patients
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diagnosed with either pulmonary or extra-pulmonary
tuberculosis that were treated with anti-tubercular treatment
(isoniazid (INH), rifampicin, ethambutol (ETM), and
pyrazinamide) were enrolled in the study. RNFL thicknesses
of the patients were measured via OCT, at baseline (before
starting anti-tubercular treatment) and after the 2-month
treatment period. Standard ophthalmologic examinations were
also performed. Compared to baseline values, after the
2-month treatment period, thinning was detected in the right
eye's average and superior quadrant RNFLs (p = 0.024 and p
= 0.006 respectively) and in the left eye's average, superior
quadrant, and inferior quadrant RNFLs (p = 0.001, p = 0.008, p
< 0.001, respectively). The authors reported that patients
receiving INH and ETM, which were the basic medicines of
anti-tubercular treatment, experienced thinning in RNFL after
the 2-month treatment period. These researchers stated that
patients receiving these drugs can be followed via OCT in
terms of reduction in RNFL thicknesses for early diagnose of
INH and ETM toxicity.
Kim and Park (2016) noted that tuberculosis in developed
countries is on the rise, and the main treatment ethambutol is
known to induce ocular toxicity. However, to-date, there are
unknown tests or protocols for detecting sub-clinical
ethambutol-induced ocular toxicity, which is important as early
detection is related to symptom reversibility. These
researchers defined ethambutol-induced ocular toxicity as
statistically significant change of visual function that was
induced by ethambutol. They identified a visual function test
for the early detection of sub-clinical ethambutol-induced
ocular toxicity. Furthermore, these investigators examined the
continuity or reversibility of early sub-clinical changes that
were observed during the visual function tests after stopping
ethambutol treatment. The age range of 31 patients was from
13 to 72 years. The range of dosage was 15 to 19 mg/kg/day.
The average period of dosage was 5 months. These
researchers performed a VA test, visual field test, color vision
test, contrast sensitivity test, fundus examination, RNFL OCT
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per month and pattern visual evoked potential test (pattern
VEP) every 2 months before and during ethambutol treatment
in 62 eyes of 31 patients. Among these patients, selected 21
patients were re-examined by these tests at the 3, 6 and 12
months after stopping ethambutol treatment. These
investigators compared the test results from the last follow-up
during ethambutol treatment and after ethambutol stoppage
with those obtained before ethambutol treatment (baseline).
RNFL OCT showed that average RNFL thickness increased 5
months after ethambutol treatment (p = 0.032), and pattern
VEP showed that P100 latency was delayed in 2 and 4 months
after ethambutol treatment (p = 0.001; p < 0.001, respectively).
These early changes observed on RNFL OCT and pattern
VEP progressed 6 months after ethambutol stoppage in 21
patients. Twelve months after ethambutol stoppage, these
early changes returned to baseline levels. During the study,
no changes in VA, color vision, fundus, contrast sensitivity or
visual field were observed. The authors concluded that
pattern VEP and RNFL OCT were suitable tests for the early
detection of sub-clinical ethambutol-induced ocular toxicity.
These tests should be performed until 12 months after
ethambutol stoppage.
Pavan Taffner et al (2018) evaluated, through OCT, alterations
in retinal thickness, secondary to use of ethambutol in the
treatment of patients with tuberculosis, in addition to studying
the use of simpler semiological tools, such as Amsler and
Ishihara, in the screening of these cases. A total of 30
patients with ethambutol were recruited from the reference
service of tuberculosis treatment at the Federal University of
Espírito Santo from May 2015 to July 2016. After clinical
history, the following parameters were analyzed; best
corrected visual acuity (BCVA), biomicroscopy, tonometry,
photo-motor reflex testing, Ishihara test, Amsler's grid test,
color digital retinography and OCT with CIRRUS HD-OCT
(Humphrey-Zeiss) every 2 months during treatment with
ethambutol. They were divided into 2 groups according to the
treatment: standard group, 2 months of ethambutol; extended
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group, 9 to 12 months of ethambutol. There was a significant
reduction in OCT thickness between the pre- and post-
treatment times in 10 eyes of the extended group, mean
reduction of 7.8 microns and in 7 eyes of the standard group,
with an average of 5.57 microns. During the study, a
significant reduction of retinal thickness was observed in both
groups at 2 months of treatment, and the delta percentage
was higher in those patients who presented reduction of VA
and / or change in the Ishihara test. The authors concluded
that there was a significant reduction in the thickness of the
nerve fiber layer by OCT in the patients studied, being more
pronounced in those submitted to the extended treatment
regimen. This reduction was observed 2 months after the start
of therapy, and was more significant in the cases that
presented changes in the Ishihara test. Moreover, these
researchers stated that further studies are needed to elucidate
the risk factors and intervals required between OCT screening
tests for early signs of ethambutol optic neuropathy.
Jin et al (2019) longitudinally evaluated the visual function and
structure of patients taking ethambutol by various modalities
and identified useful tests for detection of sub-clinical
ethambutol-induced optic toxicity. This retrospective study
enrolled 84 patients with newly diagnosed tuberculosis treated
with ethambutol; BCVA, color vision, contrast sensitivity,
fundus and RNFL photography, automated visual field (VF)
test, and OCT were performed: prior to starting; every month
during administration, and 1 month after stoppage. These
researchers longitudinally compared visual function and
structure with the baseline and identified the occurrence of
sub-clinical toxicity. BCVA, color vision, and contrast
sensitivity showed no change from the baseline. Mean
temporal RNFL thickness was significantly increased at 6
months (p = 0.014). Sub-clinical toxicity was found in 22 eyes
of 14 patients (i.e., 13 % of 168 eyes), in the forms of VFI
decrease (VF index, 9 eyes of 6 patients), quadrant RNFL
thickness increase (5 eyes of 4 patients), and VF pattern
defect (12 eyes of 6 patients); 73 % of the patients showed
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recovery to the baseline at 1 month post-stoppage. The risk
factors for occurrence of sub-clinical toxicity were age,
cumulative dose, and medication duration. The authors
concluded that mean temporal RNFL thickness increased after
administration. The VFI, quadrant RNFL thickness, and VF
pattern defect could prove useful in assessment of sub-clinical
toxicity; medication duration was shown to be a strong risk
factor for occurrence of sub-clinical toxicity.
These investigators noted that in this study, the incidence of
clinical toxicity could not be rated, because no patient
complained of clinical symptoms. However, they could
assume that the incidence would be lower than 1.2 % (1/84),
which is compatible with the results of previous studies. The
authors stated that this study had several drawbacks. First,
none of the participants experienced clinical symptoms, and
therefore, incidence of clinical optic neuropathy after sub-
clinical change could not be ruled out. They did not stop
administration of ethambutol in the sub-clinical cases, and
none of these patients developed clinical ethambutol-induced
optic neuropathy until 1 month after administration. Thus, the
implications of sub-clinical ethambutol-induced toxicity for
actual occurrence of clinical toxicity remain to be elucidated in
another long-term, prospective studies. Second, these
researchers could not evaluate the patients for a sufficient
span of time after stoppage of drug administration. Given the
retrospective study design, they were unable to control the
follow-up visitation, and so 50 % of subjects with sub-clinical
changes failed to visit after stoppage of administration (7 of 14
patients), and these investigators were also were unable to
collect data beyond 1 month after stoppage. In reversible
cases, the resolution of ethambutol-induced optic toxicity
typically occurred 3 months after cessation. With a longer
follow-up period, sub-clinical changes in VF pattern and RNFL
thickness, which remained at 1 month after stoppage in this
study, might have been shown to have recovered to the
baseline. Furthermore, although GCC analysis was possible
with up-graded Cirrus HD-OCT software, the up-graded
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software was not available at the authors’ institute at the time
of the study. Changes in GCC thickness might be more
dramatic than changes in RNFL thickness, but they might also
be less specific, as they involved 3 different innermost retinal
layers instead of just one. These researchers stated that
future study including foveal GCC or GC-IPL should be
conducted with more advanced modalities. Finally, the
concurrent effect of isoniazid could not be ruled out.
Furthermore, an UpToDate review on “Ethambutol: An
overview” (Drew, 2020) states that “Monitoring -- It is generally
recommended that patients receiving ethambutol as part of
combination therapy for treatment of a mycobacterial infection
undergo baseline Snellen visual acuity and red-green color
perception testing. All patients should be advised of the side
effects associated with ethambutol, most notably those
associated with the development of optic neuritis. The need
for routine periodic visual acuity testing during therapy is
controversial, especially if a dose of 15 mg/kg is chosen, but
patients noting changes in their vision should be referred to an
ophthalmologist for careful monitoring. In all patients receiving
combination therapy for tuberculosis or MAC infections,
baseline laboratory studies should be obtained and repeated
in the event of suspected drug-related toxicity. Although
serum concentration monitoring of ethambutol is not routinely
performed, it may be useful in cases of severe renal
insufficiency or suspected malabsorption (as demonstrated in
some HIV-infected patients receiving anti-tuberculous
therapy). If serum drug concentration monitoring is performed,
the proposed therapeutic range 2 hours post-dose is 2 to 6
mcg/mL”.
Screening and Monitoring of Ponatinib (Iclusig) Toxicity
An UpToDate review on “Ocular side effects of systemically
administered chemotherapy” (Liu et al, 2020) states that
“Fibroblast growth factor receptor (FGFR) inhibitors -- Several
inhibitors of FGFR (including ponatinib, dovitinib, and
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erdafitinib) are in clinical trials for a variety of malignancies.
Erdafitinib has now been approved for the treatment of
advanced urothelial cancers that harbor certain FGFR
mutations. All of these drugs appear to be associated with a
similar type of serous retinopathy (foci of subretinal fluid) to
that seen with the MEK inhibitors, possibly because the FGFR
pathway intersects with the MEK pathway. In the phase II
BLC2001 trial, which included 87 patients with locally
advanced or metastatic urothelial cancer that had susceptible
FGFR2 or FGFR3 mutations, ocular toxicity resulting in a
visual field defect was reported in 25 %, with a median time to
first onset of 50 days. Grade 3 symptoms, defined as involving
the central field of vision causing vision worse than 20/40 or >3
lines of worsening from baseline, were reported in 3 % of
patients. Dry eye symptoms occurred in 28 % of patients
during treatment and were grade 3 in 6 %. Ocular symptoms
resolved in 13 % and were ongoing at the study cutoff in 13 %
… The United States prescribing information for erdafitinib
recommends that all patients receive dry eye prophylaxis with
ocular lubricants as needed. Monthly ophthalmologic
examinations (including an assessment of visual acuity, slit
lamp examination, fundus examination, and optical coherence
tomography) are recommended during the first 4 months of
treatment and every 3 months thereafter, with urgent
reevaluation at any time for visual symptoms. It is
recommended that the drug be withheld when serous retinal
toxicity occurs, regardless of vision, and permanently
discontinued if it does not resolve in 4 weeks or if it is grade 4
in severity (i.e., visual acuity 20/200 or worse in the affected
eye). However, there were no data provided on the
percentage of patients whose symptoms resolved within 4
weeks. There are also recommended dose modification
guidelines for patients who develop ocular adverse reactions”.
Evaluation of Visual Snow Syndrome
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According to NIH’s Genetic and Rare Diseases Information
Center (GARD) webpage, visual snow syndrome is diagnosed
based on the symptoms and a specific set of criteria. In order
for a person to be diagnosed with visual snow syndrome, other
potential causes of the symptoms must be ruled out. Most
people with visual snow syndrome have normal vision tests
and normal brain structure on imaging studies. Symptoms of
visual snow syndrome may include:
◾ Tiny, snow-like dots across the visual field
◾ Sensitivity to light (photophobia)
◾ Continuing to see an image after it is no longer in the
field of vision (palinopsia)
◾ Difficulty seeing at night (nyctalopia)
◾ Seeing images from within the eye itself (entoptic
phenomena).
Less common symptoms may include migraines, tinnitus, and
fatigue. In general, the symptoms of visual snow syndrome
don't change with time. Some people with visual snow
syndrome have depression or anxiety related to their
symptoms. The symptoms of visual snow syndrome can start
at any age, but usually occur in early adulthood. The
underlying cause of visual snow syndrome is unknown. It is
thought to be due to a problem with how the brain processes
visual images. There is no mentioning on “fundus
photography” or “scanning computerized ophthalmic
diagnostic imaging, posterior segment”. Visual Snow
Syndrome
(https://rarediseases.info.nih.gov/diseases/12062/visual-
snow-syndrome)
Puledda et al (2020) validated the current criteria of visual
snow and described its common phenotype using a substantial
clinical data-base. These investigators carried out a web-
based survey of patients with self-assessed visual snow (n =
1,104), with either the complete visual snow syndrome ( VSS;
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n = 1,061) or visual snow without the syndrome (n = 43). They
also described a population of patients (n = 70) with possible
hallucinogen persisting perception disorder who presented
clinically with visual snow syndrome. The visual snow
population had an average age of 29 years and had no sex
prevalence. The disorder usually started in early life, and
approximately 40 % of patients had symptoms for as long as
they could remember. The most commonly experienced static
was black and white. Floaters, after-images, and photophobia
were the most reported additional visual symptoms. A latent
class analysis showed that visual snow does not present with
specific clinical endophenotypes. Severity can be classified by
the amount of visual symptoms experienced. Migraine and
tinnitus had a very high prevalence and were independently
associated with a more severe presentation of the syndrome.
The authors concluded that clinical characteristics of visual
snow did not differ from the previous cohort in the literature,
supporting validity of the current criteria. Visual snow likely
represents a clinical continuum, with different degrees of
severity. On the severe end of the spectrum, it is more likely
to present with its common co-morbid conditions, migraine and
tinnitus. Visual snow does not depend on the effect of
psychotropic substances on the brain. This study does not
mention fundus photography or scanning computerized
ophthalmic diagnostic imaging as diagnostic/management
tools.
Traber et al (2020) noted that visual snow is considered a
disorder of central visual processing resulting in a perturbed
perception of constant bilateral whole-visual field flickering or
pixelation. When associated with additional visual symptoms,
it is referred to as VSS. Its pathophysiology remains elusive.
These researchers highlighted the visual snow literature
focusing on recent clinical studies that add to the
understanding of its clinical picture, pathophysiology, and
treatment. Clinical characterization of VSS is evolving,
including a suggested modification of diagnostic criteria.
Regarding pathophysiology, 2 recent studies tested the
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hypothesis of dysfunctional visual processing and occipital
cortex hyper-excitability using electrophysiology. Likewise,
advanced functional imaging shows promise to allow further
insights into disease mechanisms. A retrospective study
provided Class IV evidence for a possible benefit of
lamotrigine in a minority of patients. The authors concluded
that scientific understanding of VSS is growing. Major
challenges remain the subjective nature of the disease, its
overlap with migraine, and the lack of quantifiable outcome
measures, which are necessary for clinical trials. In that
context, refined perceptual assessment, objective
electrophysiological parameters, as well as advanced
functional brain imaging studies, are promising tools in the
pipeline.
Eren and Schankin (2020) stated that VSS is a debilitating
disorder characterized by tiny flickering dots (like TV static) in
the entire visual field and a set of accompanying visual
(palinopsia, enhanced entoptic phenomena, photophobia,
nyctalopia), non-visual (e.g., tinnitus) and non-perceptional
(e.g., concentration problems, irritability) symptoms. Its
pathophysiology is enigmatic and therapy is often frustrating.
These researchers summarized the current understanding of
pathophysiology and treatment of VSS. They carried out a
systematic search of PubMed data-base using the key word
"visual snow" and pre-defined inclusion and exclusion criteria.
The results were stratified into "treatment" and
"pathophysiology". In additional, these investigators
performed a search with the key words "persistent migraine
aura" and "persistent visual aura" and screened for mis-
diagnosed patients actually fulfilling the criteria for visual snow
syndrome. The reference lists of most publications and any
other relevant articles known to the authors were also
reviewed and added if applicable. From the 50 original papers
found by searching for "visual snow, 21 were included
according to the inclusion and exclusion criteria. An additional
4 publications came searching for "persistent migraine aura" or
"persistent visual aura". Further publications derived from
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literature references resulting in a total of 20 articles for
pathophysiology and 15 for treatment with some overlaps.
Regarding pathophysiology, hyper-excitability of the visual
cortex and a processing problem of higher order visual
function were assumed; however, the location is still being
debated. In particular, it is unclear if the primary visual cortex,
the visual association cortex or the thalamo-cortical pathway is
involved. Regarding treatment, data are available on a total of
153 VSS patients with medication mentioned for 54 resulting in
a total of 136 trials. From the 44 different medications tried,
only 8 were effective at least once. The best data are
available for lamotrigine being effective in 8/36 (22.2 %,
including 1 total response and no worsening), followed by
topiramate being effective in 2/13 (15.4 %, no total response
and 1 worsening). The only other medication resulting in
worsening of VSS was amitriptyline according to the literature
review. The others reported to be effective at least once were
valproate, propranolol, verapamil, baclofen, naproxen and
sertraline. The non-pharmacological approach using color
filters of the yellow-blue color spectrum might also be helpful in
some patients. The authors concluded that VSS is still far
from being fully understood. In respect of pathophysiology, a
disorder of visual processing is likely. The best
pharmacological evidence exists for lamotrigine, which can be
discussed off-label. As non-pharmacological option, patients
might benefit from tinted glasses for everyday use.
Yoo et al (2020) noted that the findings of ophthalmic
examinations have not been systematically investigated in
VSS. These researchers examined the abnormal neuro-
ophthalmologic findings in a patient cohort with symptoms of
VSS. They retrospectively reviewed 28 patients who were
referred for symptoms of visual snow to a tertiary referral
hospital from November 2016 to October 2019. These
investigators defined the findings of best corrected visual
acuity (BCVA), visual field testing, pupillary light reflex,
contrast sensitivity, full-field and multi-focal electroretinography
(mf-ERG), and optical coherence tomography (OCT). A total
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of 20 patients (71 %) were finally diagnosed as VSS. Their
additional visual symptoms included illusionary palinopsia (61
%), enhanced entoptic phenomenon (65 %), disturbance of
night vision (44 %), and photophobia (65 %). A history of
migraine was identified in 10 patients (50 %). The mean
BCVA was less than 0.1 logarithm of the minimum angle of
resolution, and electrophysiology showed normal retinal
function in all patients. Contrast sensitivity was decreased in 2
of the 7 patients tested. Medical treatment was administered
to 5 patients which all turned out to be ineffective. Among the
8 patients who were excluded, 1 was diagnosed with rod-cone
dystrophy and another with idiopathic intra-cranial
hypertension. The authors concluded that neuro-
ophthalmologic findings were mostly normal in patients with
VSS; retinal or neurological diseases must be excluded as
possible causes of visual snow.
Patient-Initiated Optical Coherence Tomography (OCT) with Mobile Devices
Mehta et al (2017) noted that OCT is widely used in
ophthalmology clinics and has potential for more general
medical settings and remote diagnostics. In anticipation of
remote applications, these researchers developed wireless
interactive control of an OCT system using mobile devices. A
web-based user interface (WebUI) was developed to interact
with a hand-held OCT system. The WebUI consisted of key
OCT displays and controls ported to a webpage using HTML
and JavaScript. Client–server relationships were created
between the WebUI and the OCT system computer. The
WebUI was accessed on a cellular phone mounted to the
hand-held OCT probe to wirelessly control the OCT system. A
total of 20 subjects were imaged using the WebUI to assess
the system. System latency was measured using different
connection types (wireless 802.11n only, wireless to remote
virtual private network [VPN], and cellular). Using a cellular
phone, the WebUI was successfully used to capture posterior
eye OCT images in all subjects. Simultaneous interactivity by
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a remote user on a laptop was also demonstrated. On
average, use of the WebUI added only 58, 95, and 170 ms to
the system latency using wireless only, wireless to VPN, and
cellular connections, respectively. Qualitatively, operator
usage was not affected. The authors concluded that using a
WebUI, they demonstrated wireless and remote control of an
OCT system with mobile devices. These researchers stated
that by enabling wireless viewing and control of an OCT
imaging session by multiple users, the WebUI provides a
promising platform to develop remote OCT applications. This
is particularly important for eye care delivery in acute or
general care settings, which may have limited access to
specialty ophthalmic care. The WebUI has the potential to
enable primary, non-ophthalmologist providers to receive real-
time feedback and input from remotely located specialists
simultaneously during OCT imaging sessions (or
asynchronously for stored OCT data); and ultimately improve
eye care for those patients with ocular pathology who present
to non-specialty acute care settings. They noted that although
there have been prior works in store-and-forward tele-
ophthalmology using OCT, the presented work is, to the best
of the authors’ knowledge, the 1st demonstration of live,
remote interactivity and control of ocular imaging with an OCT
system.
Malone et al (2019) stated that OCT is the gold standard for
quantitative ophthalmic imaging. The majority of commercial
and research systems require patients to fixate and be imaged
in a seated upright position, which limits the ability to perform
ophthalmic imaging in bedridden or pediatric patients. Hand-
held OCT devices overcome this limitation; however, image
quality often suffers due to a lack of real-time aiming and
patient eye and photographer motion. These researchers
described a hand-held spectrally encoded coherence
tomography and reflectometry (SECTR) system, which
enabled simultaneous en face reflectance and cross-sectional
OCT imaging. The hand-held probe employs a custom
double-pass scan lens for fully telecentric OCT scanning with a
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compact optomechanical design and a rapid-prototyped
enclosure to reduce the overall system size and weight.
These researchers also introduced a variable velocity scan
waveform that allowed for simultaneous acquisition of densely
sampled OCT angiography (OCTA) volumes and wide-field
reflectance images, which enabled high-resolution vascular
imaging with precision motion-tracking for volumetric motion
correction and multi-volumetric mosaicking. Finally, these
investigators demonstrated in-vivo human retinal OCT and
OCTA imaging using hand-held SECTR on a healthy
volunteer. Clinical translation of hand-held SECTR will allow
for high-speed, motion-corrected wide-field OCT and OCTA
imaging in bedridden and pediatric patients who may benefit
ophthalmic disease diagnosis and monitoring. The authors
concluded that while further work is needed to overcome
limitations associated with this new technology, they have
demonstrated the feasibility of wide-field ophthalmic OCTA
using a hand-held probe.
Chopra et al (2021) stated that OCT is a paragon of success in
the translation of biophotonics science to clinical practice.
OCT systems have become ubiquitous in eye clinics; however,
access beyond this is limited by their cost, size and the skill
needed to operate the devices. Remarkable progress has
been made in the development of OCT technology to improve
the speed of acquisition, the quality of images and into
functional extensions of OCT such as OCT angiography.
However, more works to be carried out to radically improve the
access to OCT by addressing its limitations and enable
penetration outside of typical clinical settings and into under-
served populations. Beyond high-income countries, there are
6.5 billion people with similar eye-care needs, which could not
be met by the current generation of bulky, expensive and
complex OCT systems. These investigators noted that recent
regulatory approvals and feasibility studies highlighted the
emerging spread of miniaturized, portable and hand-held OCT
systems, lending their use as a point-of-care diagnostic tool in
non-traditional settings such as intensive care, as well as in
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the home environment for remote monitoring of chronic
conditions such as AMD. The latter in particular could be
analogous to continuous monitoring; thus, providing
opportunities for personalized treatment plans for conditions
such as wet AMD that benefit from close monitoring and often
require indefinite follow-up.
Hillmann (2021) noted that OCT has become one of the most
important techniques in ophthalmic diagnostics, as it is the
only way to provide a 3D visualization of morphological
changes in the layered structure of the retina at a high
resolution. Furthermore, OCT is applied for countless medical
and technical purposes. Recent developments pave the way
for small-footprint OCT systems at significantly reduced costs,
thereby extending possible use cases. The author stated that
it appears increasingly likely that, in the near future, OCT will
find its way into many more industrial and medical
applications, including disease monitoring at home.
Well-designed studies are needed to determine whether
patient-initiated OCT would improve health outcomes of
patients with ophthalmic diseases.
CPT Codes / HCPCS Codes / ICD-10 Codes
Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+":
Code Code Description
CPT codes covered if selection criteria are met:
92133 Scanning computerized ophthalmic diagnostic
imaging, posterior segment, with interpretation
and report, unilateral or bilateral; optic nerve
92134 retina
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Code Code Description
CPT codes not covered for indications listed in the CPB:
0469T Retinal polarization scan, ocular screening with
on-site automated results, bilateral
0604T Optical coherence tomography (OCT) of retina,
remote, patient-initiated image capture and
transmission to a remote surveillance center
unilateral or bilateral; initial device provision,
set-up and patient education on use of
equipment
0605T Optical coherence tomography (OCT) of retina,
remote, patient-initiated image capture and
transmission to a remote surveillance center
unilateral or bilateral; remote surveillance
center technical support, data analyses and
reports, with a minimum of 8 daily recordings,
each 30 days
0606T Optical coherence tomography (OCT) of retina,
remote, patient-initiated image capture and
transmission to a remote surveillance cent er
unilateral or bilateral; review, interpretation and
report by the prescribing physician or other
qualified health care professional of remote
surveillance center data analyses, each 30
days
ICD-10 codes covered if selection criteria are met:
B39.4
[H32 also
required]
Infection by Histoplasma capsulati, unspecified
[retinitis caused by histoplasma capsulati]
B50.0 -
B54
Malaria
B58.01 Toxoplasma chorioretinitis
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Code Code Description
C69.20 -
C69.32
Malignant neoplasm of the retina and choroid
D18.09 Hemangioma of other sites [retina]
D31.20 -
D31.32
Benign neoplasm of the retina and choroid
E08.311
E08.3599,
E09.311
E09.3599,
E10.311
E10.3599,
E11.311
E11.3599,
E13.311
E13.3599
Diabetes mellitus due to underlying condition
with ophthalmic complications
G35 Multiple sclerosis [screening and monitoring for
siponimod (Mayzent) toxicity]
G40.201 -
G40.219
Localization-related (focal)(partial) symptomatic
epilepsy and epileptic syndromes with complex
partial seizures, not intractable and intractable
[screening for vigabatrin (Sabril) toxicity]
G40.401 -
G40.419
Other generalized epilepsy and epileptic
syndromes, not intractable and intractable, with
and without status epilepticus [screening for
vigabatrin (Sabril) toxicity]
G40.821 -
G40.824
Epileptic spasms
G93.2 Benign intracranial hypertension [pseudotumor
cerebri]
H01.121 -
H01.129
Discoid lupus erythematosus of eyelid
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Code Code Description
H20.821 -
H20.829
Vogt-Koyanagi Syndrome
H30.001 -
H31.9
Chorioretinal inflammations, scars, and other
disorders of choroid
H32
[B39.4
also
required]
Chorioretinal disorders in diseases classified
elsewhere [retinitis]
H33.001 -
H36
Retinal detachments and defects and other
retinal disorders
H40.001 -
H40.9
Glaucoma
H43.10 –
H43.13
Vitreous hemorrhage
H43.811 -
H43.819
Vitreous degeneration [posterior vitreal
detachment] [not covered for vitreous
degeneration]
H43.821 -
H43.829
Vitreomacular adhesion
H46.00 -
H47.399
Disorders of optic nerve
H47.9 Unspecified disorder of visual pathways
H53.40 -
H53.489
Visual field defects
H59.031 -
H59.039
Cystoid macular edema following cataract
surgery
L93.0 -
L93.2
Lupus erythematosus
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Code Code Description
M05.0 -
M06.9
Rheumatoid arthritis
M32.0 -
M32.9
Systemic lupus erythematosus (SLE)
Q14.0 -
Q14.9
Congenital malformations of posterior segment
of eye
Q15.0 Congenital glaucoma [buphthalmos]
Q85.00 -
Q85.01
Neurofibromatosis, unspecified or type 1
T37.2x1+
-
T37.2x4+
Poisoning by antimalarials and drugs acting on
other blood protozoa
ICD-10 codes not covered for indications listed in the CPB:
A28.1 Cat-scratch disease
C71.0 -
C71.9
Malignant neoplasm of brain [intra-cranial
tumors]
G31.01 -
G31.09
Frontotemporal dementia
G31.9 Degenerative disease of nervous system,
unspecified [neurodegeneration pattern]
H04.121 -
H04.129
Dry eye syndrome
H04.561 -
H04.569
Stenosis of lacrimal punctum
H11.141 -
H11.149
Conjunctival xerosis, unspecified
H16.221 -
H16.239
Keratoconjunctivitis sicca, not specified as
Sjogren's
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Code Code Description
H25.011 -
H28
Cataracts
H53.8 Other visual disturbances [visual snow
syndrome]
M35.00 -
M35.09
Sicca syndrome [Sjogren]
Q12.0 -
Q12.9
Congenital lens malformations
T85.22x+ Displacement of intraocular lens
Z13.5 Encounter for screening for eye and ear
disorders
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AETNA BETTER HEALTH® OF PENNSYLVANIA
Amendment to Aetna Clinical Policy Bulletin Number: 0344 Optic Nerve
and Retinal Imaging Methods
There are no amendments for Medicaid.
revised 05/24/2021