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*

https://aetnet.aetna.com/mpa/cpb/300_399/0344.html 5/27/2021

https://aetnet.aetna.com/mpa/cpb/300_399/0344.html

https://www.aetna.com/


5/27/2021 https://aetnet.aetna.com/mpa/cpb/300_399/0344.html

◾ 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.


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).


experimental and investigational for the following (not an all-

inclusive list):




◾ 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:




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)




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.




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




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




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”




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.




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




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.




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




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.




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




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-




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




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).




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




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.




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




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




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




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




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 <




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




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




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-




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




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




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




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




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




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




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




(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




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-




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.




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




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




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,




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




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




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)




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




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




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




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




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




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




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




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




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




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




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




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;


https://rarediseases.info.nih.gov/diseases/12062/visual-snow-syndrome

https://rarediseases.info.nih.gov/diseases/12062/visual-snow-syndrome



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


5/27/2021https://aetnet.aetna.com/mpa/cpb/300_399/0344.html


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




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




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




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




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




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





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



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



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





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





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





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





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

The above policy is based on the following references:

1. Aetna Health Plans (AHP). Confocal Laser Scanning

Tomography. Technology Assessment No. 373.

Hartford, CT: AHP; 1996.

2. Aetna Health Plans (AHP). Stereophotogrammetry

(Glaucoma-Scope). Technology Assessment No. 377.

Hartford, CT: AHP; 1996.

3. Aggarwal K, Agarwal A, Mahajan S, et al. The role of

optical coherence tomography angiography in the

diagnosis and management of acute Vogt-Koyanagi-

Harada disease. Ocul Immunol Inflamm. 2018;26

(1):142-153.

4. Alberta Heritage Foundation for Medical Research

(AHFMR). Confocal scanning laser ophthalmoscopy

and scanning laser polarimetry for early diagnosis of

glaucoma. Technote TN 55. Edmonton, AB: AHFMR;

2006.





(AHFMR). Optical coherence tomography for

diagnosing retinal diseases. Technote. TN 41.

Edmonton, AB: AHFMR; August 2003.


(AHFMR). Scanning laser ophthalmoscope for

diagnosis and monitoring of glaucoma. Technote TN 5.

Edmonton, AB: Alberta Heritage Foundation for

Medical Research; 1996.

7. American Academy of Ophthalmology (AAO). Age-

related macular degeneration. Preferred Practice

Pattern. San Francisco, CA: AAO; 2006.

8. American Academy of Ophthalmology (AAO). Diabetic

retinopathy. Preferred Practice Pattern. San Francisco,

CA: AAO; 2003.

9. American Academy of Ophthalmology (AAO).

Idiopathic macular hole. Preferred Practice Pattern.

San Francisco, CA; AAO; 2003.

10. American Academy of Ophthalmology (AAO).

Noteworthies. Washington Report. News for the

Academy’s Government Affairs Division. Washington,

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Amendment to Aetna Clinical Policy Bulletin Number: 0344 Optic Nerve

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