Childs Nerv Syst
DOI 10.1007/s00381-017-3578-8
REVIEW ARTICLE
Optical coherence tomography as a marker of vision
in children with optic pathway gliomas
Ana Banc 1 & Cristina Stan 1,2 & Ioan Stefan Florian 3,4
Received: 21 October 2016 / Accepted: 16 August 2017
# Springer-Verlag GmbH Germany 2017
Abstract
Purpose Optic pathway gliomas (OPG) represent an impor-
tant cause of visual loss in pediatric population. The indication
of treatment is based on clinical or neuroimaging progression.
Visual acuity loss is the most important symptom of disease
progression, but children with OPG are frequently unable to
complete the testing of visual function. Optical coherence to-
mography (OCT) was suggested as an objective tool for visual
assessment. A literature review was performed in order to
determine the role of retinal OCT as a surrogate marker of
vision in children with OPG.
Methods The search was performed using PubMed, Embase,
and Web of Science databases and was restricted to articles
published in English between 2000 and 2016, with a mini-
mum of ten participants enrolled.
Results Eleven studies met the eligibility criteria and were
included in the present review. Both neurofibromatosis-1 as-
sociated and sporadic OPG were investigated.
Conclusions Retinal OCT is a promising tool to be considered
as a screening or follow-up test in children with OPG, and
further multicenter research is encouraged.
* Ana Banc
Ana.Banc@umfcluj.ro
1
Department of Ophthalmology, Iuliu Hatieganu University of
Medicine and Pharmacy, Clinicilor Street no 3-5,
400006 Cluj-Napoca, Romania
2
Ophthalmology Clinic, Emergency County Hospital Cluj,
Cluj-Napoca, Romania
3
Department of Neurosurgery, Iuliu Hatieganu University of Medicine
and Pharmacy, Cluj-Napoca, Romania
4
Neurosurgery Clinic, Emergency County Hospital Cluj,
Cluj-Napoca, Romania
Keywords Optic pathway glioma . Children . Optical
coherence tomography . Retinal nerve fiber layer . Review
Introduction
Optic pathway gliomas (OPG) are low-grade pilocytic astro-
cytomas intrinsic to the precortical visual pathway and repre-
sent 3–5% of brain tumors in children [8, 33]. Approximately
65% of OPG are diagnosed before the age of 5 and represent
an important cause of vision loss in pediatric population [33].
OPG are also detected in 13–20% of patients with neurofibro-
matosis type 1 (NF1), an autosomal dominant disorder with an
incidence of 1:3.500–1:4.000 births [14]. Children with OPG
require frequent and long-term monitoring for ophthalmolog-
ical abnormalities [31].
In 1997, the OPG task force established a set of guidelines
for the diagnosis and treatment of OPG associated to NF1
[32], and the recommendations were revised a decade later
[31]. According to the OPG task force, the indication to initi-
ate treatment is based on clinical or neuroimaging progres-
sion. The main symptom of clinical progression is considered
the visual acuity loss [31]. However, young children with
OPG are frequently unable to complete visual function testing
due to lack of cooperation. This inability is more pronounced
in children with NF1, who often have developmental delay
and attention-deficit disorder [32]. Although the diagnosis of
OPG is confirmed with neuroimaging and MRI is the exam-
ination of choice for monitoring progression or treatment re-
sponse [13, 31], neuroimaging results were found to be a poor
predictor of visual outcome [19, 43]. MRI of the brain and
orbits is not recommended as a screening tool in patients with
NF1, but it is indicated in cases with documented abnormal
ophthalmological examination [31, 41].

In this context, a surrogate marker of vision is needed in
order to objectively identify children with visual loss and to
monitor the possible clinical progression. Optical coherence
tomography (OCT) of the retina has been suggested as such a
tool [15]. OCT is a non-invasive high-resolution imaging
technique which provides an in vivo optical biopsy of the
retinal layers [20]. OPG may induce damage to the axons of
retinal ganglion cells, which form the retinal nerve fiber layer
(RNFL). The RNFL thickness is assessed by OCT and de-
creased values represent retinal ganglion cell loss, which oc-
curs through Wallerian degeneration if the lesion is located in
the anterior visual pathway and through retrograde trans-
synaptic degeneration in posterior visual pathway lesions
[28, 29]. OCT proved to be useful in the diagnosis and
follow-up of adult patients with tumors of visual pathway
[18, 45].
The objective of this review is to determine the role of
retinal OCT as a potential marker of vision in children with
OPG.
Methods
A literature review was performed using the PubMed,
Embase, and Web of Science databases, and it included the
original studies conducted on children diagnosed with OPG,
either NF1-associated or sporadic. The search was restricted to
humans, age birth—18 years, and articles published in English
between 2000 and 2016. A manual search was also performed
in order to identify additional articles.
The preliminary search was based on the following MeSH
terms: Boptical coherence tomography,^ Bretinal nerve fiber
layer,^ and Boptic pathway glioma.^ Inclusion criteria were
as follows: documented OPG, use of retinal OCT, and a min-
imum of ten participants enrolled in the study. Exclusion
criteria were as follows: associated glaucoma, intraocular tu-
mors, or the presence of other neurological conditions.
All the results were screened for relevance by one reviewer
(AB) based on title and abstract. The articles considered rele-
vant were included into full-text assessment, which was per-
formed independently by two reviewers (AB, CS). The inclu-
sion and exclusion criteria were used to determine the eligi-
bility of each study. The date of our last search was September
20, 2016. Eleven articles were assessed in the full-text format,
and none was excluded.
The following data was collected from the studies: study
design, number of participants, demographic characteristics,
tumor type, mean follow-up time, OCT device type, OCT
parameters, and conclusions.
Consecutiveness of patients’ inclusion, representativeness
of the samples, the comparison with the reference standard test
(i.e., brain and orbit contrast-enhanced MRI), and blinding
Childs Nerv Syst
were also investigated in order to establish the level of evi-
dence of each study.
To avoid the bias as much as possible, we established the
inclusion and exclusion criteria before performing the search,
and the eligibility evaluation was made by two independent
reviewers based only on inclusion and exclusion criteria. We
did not use the type of OCT equipment as a criterion for
selecting the studies for the present analysis. We declare no
conflict of interest for this research.
Discussion
All the eligible studies had a prospective design, and each was
conducted in a single institution. Table 1 contains details about
design of studies, demographic characteristics, and level of
evidence according to the Oxford Centre for Evidence-
Based Medicine 2011 [26]. All the studies used MRI as refer-
ence standard test, but the research of Parrozzani et al. [36]
was the only stating both the consecutiveness of patients’
inclusion and blinding for MRI, OCT, and clinical examina-
tion. Gu et al. [23] used blinding only for OCT layer segmen-
tation. All the other articles are lacking information about
inclusion of consecutive patients, or blinding for interpretation
of MRI or OCT.
Assessment of visual function in children with OPG
Visual decline represents an indication of treatment in children
with OPG. Ophthalmological assessment includes evaluation
of visual acuity, visual field, color vision, and other neuro-
ophthalmological tests, but visual acuity loss is considered
the most reliable and important clinical symptom of OPG
[31].
Visual acuity assessment is a psychophysical measure and
relies on the cooperation and attention of the patient [7]. The
examination includes age-adapted visual acuity tests, and dif-
ferent testing methods are used depending on the child’s age
and cognitive abilities: preferential looking test is used in in-
fants (e.g., Teller acuity test), Lea figure or HOTV matching in
preliterate children, and Snellen charts in literate children [7,
31]. Moreover, normal visual acuities improve with age and
different age-related norms must be used in young children
[31]. Since the visual acuity of children with OPG is long-term
monitored, the same child may complete more complex visual
acuity tests as his/her cognitive capacity is developed [3, 7].
As the visual acuity scores are not equivalent between the
tests and because there is a great variability in terms of cogni-
tive status between the children of the same age, Avery et al.
[7] recommended the use of a standardized visual acuity as-
sessment in all the future OPG clinical trials: the authors sug-
gested that Teller acuity test should be used across all age
groups and, when capable, children would complete the
Table 1 Demographic features of the studies included in review

Authors and year Study design No. of patients/no. No. of females (%) Mean age (yrs) No. of No. of Mean age (yrs) Mean follow- Level of
of eyes controls/ females up (mos) evidencea
no. of eyes
Childs Nerv Syst

Chang L et al. 2010 [16] Prospective case-series 15/NA 5 (55%); NA (range 6–17; 7–20) 15/NA NA NA (age- and 0 4
3 (50%) race-matched)
Avery RA et al. 2011 [10] Prospective cross-sectional 58/109 40 (68%) 11.6 14/28 65% 11.3 0 3
Fard MA et al. 2013 [21] Prospective cohort 23/38 12 (53%) 5.8 0 – – 24 3
Parrozzani R et al. 2013 [36] Prospective case-controlled 57/114 23 (40%) 7.2 0 – – 0 2
Topcu-Yilmaz P et al. 2014 [41] Prospective case-series 27/NA 15 (55%) 14.5 (NF1 without 17/NA 6 (35%) 12.35 0 4
OPG); 12.6
(NF1 with OPG)
Gu S et al. 2014 [23] Prospective cross-sectional 26/47 NA 5.3; 6.1 0 – – 0 3
Avery RA et al. 2014 [9] Prospective cross-sectional 33/64 18 (54%) 4.8 20/31 7 (35%) 8.7 0 3
Avery RA et al. 2014 [4] Prospective cross-sectional Intra-visit cohort: 61%; 58.6% Intra-visit cohort, 4.6; 0 – – 6 3
and longitudinal inter-visit cohort, 5.7
59/NA; inter-visit
cohort: 29/NA
Avery RA et al. 2014 [5] Prospective cohort Intra-visit cohort: 27 (64%); NA 5.3; NA 0 – – 6 3
42/45; inter-visit
cohort: 21/25
Rajjoub RD et al. 2015 [39] Prospective cohort 42/62 Abnormal vision, 14 Abnormal vision, 0 – – 4.2 3
(64%); normal 10.7; normal
vision, 16 (67%) vision, 8.5
Avery RA et al. 2015 [6] Prospective cohort New vision loss, 5 (50%); 30 (67%) 6.9; 6.5 0 – – 16.5; 13.4 3
7/10; stable
vision, 39/45

NA information not available, NF1 neurofibromatosis-1, OPG optic pathway glioma

a
Level of evidence according to Oxford Centre for Evidence-Based Medicine 2011 [26]

computer-based HOTV testing in addition to the Teller acuity
test. Both tests have been validated in pediatric clinical trials,
and the results can be converted in logMAR units [7, 32].
The need of standardized visual acuity testing is also
sustained by the observation we made during the analysis of
the 11 studies: the methods of visual acuity assessment were
highly variable—Teller acuity test [4], HOTV test [9, 10], Lea
fig. [36], Sloan low-contrast acuity chart [10], E-game [21], or
Snellen chart [36]. Some papers did not specify the employed
methods for visual acuity testing, although it was stated that
age-adapted tests were used [4–6, 23]. However, an observa-
tion we consider worth mentioning is that low-contrast acuity
measures may be more sensitive to visual pathway damage
from OPG in comparison with high-contrast visual acuity
measures [10].
Visual field examination also requires patient’s collabora-
tion, and the results are highly variable [31]. Confrontation
test, Goldmann kinetic perimetry, or static automated
perimetry can be used depending on the child’s age.
However, there is high test-retest variability, and the results
are hard to quantify [31]. Although the visual field was tested
by the majority of the studies included in review, the results
were not interpreted alone, but in association with concurrent
visual acuity deficits.
Color vision loss usually accompanies visual acuity decline
in NF1-associated OPG, and the presence of visual acuity loss
without color vision loss is indicative of refractive error, am-
blyopia, a functional disorder, or lack of cooperation [31].
None of the 11 studies investigated the possible correlation
between color vision and visual acuity, visual field, or OCT
parameters in children with OPG.
In a study investigating the post-treatment functional
changes in 21 children with OPG, Magli et al. [33] assessed
the changes of contrast sensitivity. According to the presented
data, in patients with normal visual acuity at diagnosis, con-
trast sensitivity seemed to be a better indicator of tumor pro-
gression than visual acuity [33]. Contrast sensitivity was not
evaluated in the articles included in the present review.
Visual evoked potentials (VEP) have been suggested as
a screening or follow-up method in children with NF1,
but there was not enough evidence to recommend it
[31]. A review on the role of VEP in the assessment of
OPG [42] demonstrated that the use of VEP as a routine
screening test in OPG is not indicated. The studies includ-
ed in the cited review presented limitations regarding the
sample sizes, differences in VEP protocol, variability in
interpretation of the VEP results, and the absence of ap-
propriate control groups in some studies [42]. Iannaccone
et al. [27] demonstrated that VEP abnormalities were also
present in children with NF1 even in the absence of OPG
or other brain tumors. These findings prove that VEP
interpretation in children with NF1 can be particularly
challenging.
Childs Nerv Syst
The Response Evaluation in Neurofibromatosis and
Schwannomatosis (REiNS) International Collaboration was
established in 2011 to achieve consensus about the methodol-
ogy of clinical trials regarding NF [38]. One of the seven
working groups of the REiNS Collaboration focuses on visual
outcomes. According to this committee (2013) [22], visual
acuity should be the main functional outcome measure in clin-
ical trials of children with NF1-associated OPG. The recom-
mended tests are Teller acuity charts and HOTV, and the re-
sults should be reported in logMAR, considering the age-
specific norms [22]. The other recommended outcomes are
the presence of optic disc pallor and Children’s Visual
Function Questionnaire—given the importance of including
patient-reported outcomes in clinical trials. Assessment of vi-
sual field, color vision, strabismus, nystagmus, optic disc
swelling, proptosis, or visual evoked potentials are not recom-
mended [22]. OCT was not included among the recommended
investigations due to lack of data [22].
OCT technology
Retinal OCT is an imaging technique analogous to ultrasound
as it is based on low-coherence interferometry and measures
the intensity of the back-scattered light from the tissue. Time-
domain was the first generation of OCT technology, and the
first in vivo OCT studies of the human retina were performed
in 1993 [20]. Time-domain OCT offers an axial resolution of
10 μm and acquires 400 A-scans/s. The second generation of
OCT is called spectral-domain (or Fourier-domain) OCT and
became commercially available in 2006. Spectral-domain
OCT permits an axial resolution of 1–5 μm and the acquisition
of up to 52,000 A-scans/s, with tridimensional reconstruction
of the examined tissue [1, 20].
Retinal OCT was primarily used in ophthalmological con-
ditions, and after a period of clinical employment, studies
investigating neurological diseases (e.g., multiple sclerosis,
Parkinson’s disease) were conducted. Moreover, the majority
of OCT devices are table-mounted and are being used in adult
patients. Therefore, it is not surprising that we found only 11
eligible papers using retinal OCT in children with OPG. The
first reported study we identified was published in 2010 [16].
Different types of OCT devices were utilized in the studies
included in our review. The majority were table-mounted,
either time-domain or Spectral-domain OCT. A handheld
spectral-domain OCT equipment (Bioptigen, Durham, NC)
was also successfully used in young children [4–6, 9, 23,
39]. For all OCT devices, the duration of retinal scan was of
a few seconds for each eye and the main examination proto-
cols included the assessment of the retinal nerve fiber layer
(RNFL) thickness around the optic nerve papilla and the ret-
inal thickness in the macular area [4–6, 9, 10, 16, 23, 36, 39,
41]. Retinal ganglion cell loss was expressed as RNFL thin-
ning and/or decreased macular thickness.
Childs Nerv Syst
Particularities of OCT use in children
One aspect to be considered in the interpretation of OCT re-
sults in children is the normative reference for the young pop-
ulation. Unlike in the case of adult patients, for the commer-
cially available OCT devices, the results are not automatically
compared with normal age-matched population and the inter-
pretation must be done either by follow-up (comparing the
results with the baseline), by creating a normative database
or by using one which it has already been published.
The studies included in the present review used the follow-
up method and/or included small-sized samples of controls,
equivalent to a mini normative database (Tables 1, 2). Fard
et al. [21] used the follow-up method and suggested that age-
related RNFL thickness decline should be considered when
discriminating between the physiologic and the pathologic
process. To the best of our knowledge, there is only one
OCT study investigating the age-related RNFL decline in
which both children and adults were enrolled [35]; the results
suggest that the RNFL loss is maximum after the age of 50
[35]. The other studies were conducted on adults only, and the
results were extrapolated to pediatric population: the presence
of a linear decrease of average RNFL thickness with age was
documented [25, 30], with a decline range between − 0.16 and
− 0.44 μm/year [30]. Age-related RNFL loss was not uniform
in all the quadrants [30, 35].
Nevertheless, several normative OCT reference values for
the pediatric population are now available and no correlation
between RNFL thickness and age was found, as seen in the
following recently published results:
– Gürağaç et al. (2016) examined 318 Turkish children
aged between 3 and 17 using Cirrus Spectral-domain
OCT (Carl Zeiss Meditec, Dublin, CA) and the strongest
predictors of RNFL thickness were ocular axial length,
refraction, and optic nerve rim area [24].
– Pawar et al. (2014) examined 120 Indian children aged
between 5 and 17 using stratus time-domain OCT (Carl
Zeiss Meditec, Dublin, CA), and age had no statistical
significant effect on RNFL thickness, unlike ocular re-
fraction which it had a significant effect on RNFL thick-
ness [37].
– Al-Haddad et al. (2014) examined 108 Middle East chil-
dren aged between 6 and 17 using Cirrus spectral-domain
OCT, and RNFL measurements did not correlate with
age, but it did show a positive correlation with refraction
[2].
– Zhu et al. (2013) evaluated 1955 Chinese children aged
12 using iVue-100 spectral-domain OCT (Optovue,
Fremont, CA), and the RNFL thickness had no significant
correlation with age [46].
– Rao et al. (2013) examined 74 Indian children aged be-
tween 4 and 17 using Cirrus spectral-domain OCT, and
the RNFL thickness was influenced mostly by ocular ax-
ial length and refractive error while it was independent of
age [40].
– Barrio-Barrio et al. (2013) conducted a multicenter study
in which 283 Spanish children aged between 4 and 17
were enrolled; the examination was performed with
Cirrus spectral-domain OCT, and a positive correlation
was found between RNFL thickness and ocular refraction
only [11].
– Yanni et al. (2013) examined 83 North American children
aged between 5 and 15 using Spectralis spectral-domain
OCT (Heidelberg Engineering GmbH, Heidelberg,
Germany), and the only parameter significantly correlated
with age was central subfield macular thickness [44]. Other
studies also reported a statistically significant correlation
between OCT macular parameters and age [2, 11, 24].
The reproducibility of OCT parameters was investigated by
three of the 11 studies included in our review [4, 5, 39].
Rajjoub et al. [39] reported the use of BEye-Tracking^ OCT
feature (Spectralis OCT) in children with OPG. The authors
observed that adding BEye-Tracking^ feature to the scanning
protocol offered excellent reproducibility of RNFL measures
[39], although the studies using the handheld OCT device also
reported a good reproducibility of the measures [4, 5].
Another element to be considered in young children is
performing the OCT scan during general anesthesia. The au-
thors who reported the use of handheld OCT device per-
formed the examination during the sedation indicated for
MRI evaluation [4–6, 9, 23]. The ability to acquire high-
resolution spectral-domain OCT in young children with
OPG who cannot cooperate with vision testing or table-
mounted OCT imaging is highly relevant because most pa-
tients become symptomatic and require treatment during early
childhood [9]. However, Avery et al. [4] brought into question
whether exposure to additional anesthesia for obtaining a thor-
ough OCT evaluation would be ethically acceptable or not.
Although the handheld OCT device offers the advantage of
portability, there are also some limitations: the variability of
ocular axial lengths in children may influence the OCT sam-
pling [9], and the assessment of the image/signal quality and
retinal segmentation cannot be performed until the end of the
imaging session [5].
Chemotherapy was also incriminated as a possible cause of
RNFL loss in children with OPG [5, 8], but further research is
needed to address this issue.
The role of OCT in OPG assessment
Table 2 reveals clinical features of the studies. Taking into
consideration the fact that the OCT devices and scanning pro-
tocols were variable between the studies, and there were also
differences regarding sampling (Tables 1, 2) and methods of
Table 2 Clinical features of the studies included in review
Authors and year Tumor type
Chang L et al. 2010 [16] 9 pts.: NF1 with OPG
6 pts.: NF1 without OPG
Avery RA et al. 2011 [10] 48 pts.: sporadic +
NF1-associated OPG
10 pts.: NF1 without OPG
Fard MA et al. 2013 [21] 9 pts.: sporadic OPG
14 pts.: NF1 with OPG
Parrozzani R et al. 2013 [36] 15 pts.: NF1 with OPG
42 pts.: NF1 without OPG
Topcu-Yilmaz P et al. 2014 [41] 17 pts.: NF1 with OPG
10 pts.: NF1 without OPG
Gu S et al. 2014 [23] 26 pts.: sporadic +
NF1-associated OPG
Avery RA et al. 2014 [9] 25 pts.: NF1 with OPG
8 pts.: sporadic OPG
Avery RA et al. 2014 [4] 35 pts.: NF1 with OPG
10 pts.: NF1 without OPG
14 pts.: sporadic OPG
Type of OCT OCT protocol OCT parameters Comparison Conclusion of study
equipment
TD-OCT (Stratus/Carl Fast macular Macular thickness, RNFL patients vs controls OCT can be used to detect RNFL
Zeiss Meditec) thickness, fast thinning secondary to OPG in NF1
RNFL thickness subjects. This objective tool shows
promise as a useful adjunct to
routine clinical ophthalmologic
evaluation in children with NF1.
TD-OCT (Stratus/Carl Fast RNFL thickness RNFL High-contrast Eyes of most children with OPG and
Zeiss Meditec) visual acuity, decreased RNFL thickness had
low-contrast let- abnormal visual acuity or visual
ter acuity field loss.
SD–OCT Posterior pole Grid retinal thickness, Baseline vs RNFL and posterior pole retinal
(Spectralis/Heidelb- thickness map, RNFL 24-months data thickness may be helpful in
erg Engineering) RNFL map monitoring OPG.
SD–OCT RNFL thickness RNFL Visual acuity, RNFL is superior to visual function
(Spectralis/Heidelb- ophthalmoscopic assessment and optic disc
erg Engineering) optic disc evaluation as a clinical screening
evaluation tool for OPG.
TD–OCT RNFL thickness, RNFL, macular thickness Patients vs controls RNFL thinning can be a helpful
(Stratus/Carl Zeiss retinal macular marker for the detection of OPG in
Meditec) thickness NF1 patients.
Handheld SD-OCT Macular scan, RNFL Ganglion cell—inner Normal vs Ganglion cell layer—inner plexiform
(HH OCT/Bioptigen) thickness plexiform layer abnormal vision layer thickness could be used as a
thickness, RNFL surrogate marker of vision in
children with OPG.
Handheld SD-OCT 6 mm × 6 mm optic RNFL (obtained using a Visual acuity, Measures of RNFL thickness acquired
(HH OCT/Bioptigen) nerve head scan, en custom-made soft- visual field with handheld OCT during
face volume ware) sedation can differentiate between
young children with and without
vision loss from OPG. For young
children who do not cooperate with
vision testing, handheld OCT
measures may be a surrogate
marker of vision.
Handheld SD-OCT 6 × 6 × 2 mm RNFL (obtained using a Intra- vs inter-visit RNFL measures acquired with
(HH OCT/Bioptigen) volumes acquired custom-made soft- cohort handheld OCT during sedation
over the optic nerve ware) demonstrate good intra- and
head inter-visit reproducibility.
Handheld OCT has the potential to
monitor progressive optic neuropa-
thies in young children who have
difficulty cooperating with tradi-
tional OCT devices.
Childs Nerv Syst
Table 2 (continued)
Authors and year
Avery RA et al. 2014 [5]
Rajjoub RD et al. 2015 [39]
Avery RA et al. 2015 [6]
NF1 neurofibromatosis-1, OPG optic pathway glioma, RNFL circumpapillary retinal nerve fiber layer, SD-OCT spectral-domain optical coherence tomography, TD-OCT time-domain optical coherence
tomography
Tumor type Type of OCT OCT protocol OCT parameters Comparison Conclusion of study
equipment
Childs Nerv Syst
25 pts.: NF1 with OPG Handheld SD-OCT Macular volume Total macular thickness, Intra- vs inter-visit Macular volumes acquired with
5 pts.: NF1 without OPG (HH OCT/Bioptigen) ganglion cell—inner cohort handheld OCT demonstrated
12 pts.: sporadic OPG plexiform layer excellent reproducibility of total
thickness retinal thickness and ganglion
cell—inner plexiform layer
thickness measures.
28 pts.: sporadic + SD-OCT RNFL thickness + eye RNFL Normal vs SD-OCT with eye tracking
NF-associated OPG (Spectralis/Heidelberg tracking feature abnormal vision demonstrates highly reproducible
2 pts.: craniopharyngioma Engineering) RNFL thickness measures in
1 pt.: prolactinoma children with non-glaucomatous
1 pt.: Langerhans cell optic neuropathy.
histiocytosis
1 pt.: demyelination
46 pts.: sporadic + Handheld SD-OCT Optic nerve head cube; RNFL Visual acuity, Children experiencing vision loss
NF1-associated OPG (HH RNFL measure visual field from their OPG frequently
OCT/Bioptigen) or using Nsite demonstrate a ≥ 10% decline of
table-mounted analytics and RNFL thickness in 1 or more
SD-OCT TruTrack anatomic sectors. Global average
(Spectralis/Heidelb- and the inferior quadrant
erg Engineering) demonstrated the best positive and
negative predictive values. RNFL is
a surrogate marker of vision and
could be helpful in making
treatment decisions for children
with OPG.

testing visual acuity, a reliable statistical comparison between
the studies was not possible.
The studies tested the hypothesis that retinal OCT could be
a surrogate marker of vision in children with OPG and, con-
sequently, a screening [6, 9, 10, 23, 36, 41] or follow-up tool
[4–6, 16, 21, 39].
The results of the studies investigating OCT as a screening
tool for the detection of OPG [6, 8, 9, 23, 36, 41] indicated
thinner OCT measures in patients with OPG compared to
controls and also a correlation between visual acuity status
and RNFL or macular thickness. All the studies included in
review showed that OCT may be a useful instrument to detect
the presence of OPG in children with or without NF1 and to
identify visual decline (Table 2). Patients with OPG who had
thinner RNFL even in the presence of normal visual function
were also identified [10, 16, 41]. Avery et al. [9] reported an
average RNFL thickness of approximately 80 μm as threshold
value for visual loss: RNFL thickness of > 80 μm was asso-
ciated with normal visual acuity, whereas lower RNFL thick-
ness was associated with worse visual acuity. For the children
who did not cooperate to perform the examination at a table-
mounted OCT device, the retinal scan with a handheld OCT
during sedation was also considered a marker of vision [9].
Parrozzani et al. [36] demonstrated that RNFL is superior to
visual function assessment and optic disc evaluation as a clin-
ical screening tool for OPG in children with NF1.
Other studies investigated the role of retinal OCT scan for
follow-up evaluation. The results indicate that RNFL may be a
surrogate marker of vision [4–6, 16, 39] and could be helpful
in making treatment decisions for children with OPG [6]. A
RNFL thickness decline of 10 to 15% in comparison with the
baseline thickness was considered clinically significant and
regarded as disease progression [4]; whereas for the macular
parameters, a change of > 10% in the ganglion cell-inner plex-
iform layer thickness was also considered clinically signifi-
cant [5]. Avery et al. [6] noticed that a greater amount of
RNFL loss may need to occur in patients with normal RNFL
thickness compared to patients with already reduced RNFL
thickness, who may require less of a decline to experience
visual loss.
We mention the exceptional situation of two patients with
sporadic glioma isolated to the optic nerve who demonstrated
increases of RNFL thickness of less than 20 μm in the absence
of optic disc edema [6]. The authors considered that axonal
stasis may be responsible of this small increase in RNFL
thickness, especially in these two patients with preexisting
optic nerve pallor [6].
The majority of studies included RNFL thickness evalua-
tion, but there was a variety of the macular scanning protocols
(Table 2). Studies conducted on adult patients with optic path-
way tumors showed that the results provided by different OCT
devices or using different macular scanning protocols were
not comparable [17, 34]. Moreover, Rajjoub et al. [39]
Childs Nerv Syst
reported that the papillomacular bundle measures were highly
variable between examinations, probably due to it being the
thinnest area and the most susceptible to segmentation or mo-
tion artifacts. The authors advise clinicians to be cautious
when interpreting small changes in the thickness of the
papillomacular bundle [39].
Although OCT imaging may be limited by subject cooper-
ation, it is less limited than the evaluation of visual function,
requiring only seconds of cooperation instead of minutes as in
the latter [16, 36].
The major limitations of the studies are the small number of
patients and the short follow-up time (Table 1). Other limita-
tions are as follows: incomplete MRI data (either baseline or
concurrent MRI) [16], undilated refraction to determine best
corrected visual acuity [10], lack of OCT data for healthy
control children [21], or variable frequency of study visits [6].
OCT use in other types of visual pathway tumors
in pediatric population
Bialer et al. [12] investigated the use of OCT for monitoring
optic neuropathy in children with craniopharyngioma. The
authors conducted a retrospective study in which RNFL thick-
ness was assessed in 20 children treated in the same pediatric
medical center. The results demonstrated that thinner RNFL
on OCT was associated with poorer visual acuity and visual
field loss [12]. These findings were congruent with the results
of the studies investigating the use of OCT in OPG.
Conclusion
Retinal OCT is a promising tool to be considered as a screen-
ing or monitoring test for OPG in children, and further re-
search is encouraged. Multicenter clinical research using stan-
dardized protocols of both visual function assessment and
retinal OCT scanning is needed.
MRI of the brain and orbits remains the gold standard for
OPG diagnosis, and the presence of clinical or neuroimaging
progression represents an indication for therapy.
Compliance with ethical standards
Conflicts of interest/disclosures The authors declare that they have no
financial or other conflicts of interest in relation to this research and its
publication.
Ethical approval For this type of study, formal consent is not required.
This article does not contain any studies with human participants or an-
imals performed by any of the authors.
Childs Nerv Syst
References
1. Adhi M, Duker JS (2013) Optical coherence tomography—current
and future applications. Curr Opin Ophthalmol 24(3):213–221
2. Al-Haddad C, Barikian A, Jaroudi M, Massoud V, Tamim H,
Noureddin B (2014) Spectral domain optical coherence tomogra-
phy in children: normative data and biometric correlations. BMC
Ophthalmol. https://doi.org/10.1186/1471-2415-14-53
3. Avery RA, Bouffet E, Packer RJ, Reginald A (2013) Feasibility and
comparison of visual acuity testing methods in children with neu-
rofibromatosis type 1 and/or optic pathway gliomas. Invest
Ophthalmol Vis Sci 54:1034–1038
4. Avery RA, Cnaan A, Schuman JS, Chen CL, Glaug NC, Packer RJ
et al (2014) Reproducibility of circumpapillary retinal nerve fiber
layer measurements using handheld optical coherence tomography
in sedated children. Am J Ophthalmol 158(4):780–787
5. Avery RA, Cnaan A, Schuman JS, Chen CL, Glaug NC, Packer RJ
et al (2014) Intra- and inter-visit reproducibility of ganglion cell—
inner plexiform layer measurements using handheld optical coher-
ence tomography in children with optic pathway gliomas. Am J
Ophthalmol 158(5):916–923
6. Avery RA, Cnaan A, Schuman JS, Trimboli-Heidler C, Chen CL,
Packer RJ et al (2015) Longitudinal change of circumpapillary ret-
inal nerve fiber layer thickness in children with optic pathway gli-
omas. Am J Ophthalmol 160(5):944–952
7. Avery RA, Ferner RE, Listernick R, Fisher MJ, Gutmann DH, Liu
GT (2012) Visual acuity in children with low grade gliomas of the
visual pathway: implications for patient care and clinical research. J
Neuro-Oncol 110:1–7
8. Avery RA, Fisher MJ, Liu GT (2011) Optic pathway gliomas. J
Neuroophthalmol 31:269–278
9. Avery RA, Hwang EI, Ishikawa H, Acosta MT, Hutcheson KA,
Santos D et al (2014) Handheld optical coherence tomography dur-
ing sedation in young children with optic pathway gliomas. JAMA
Ophthalmol 132(3):265–271
10. Avery RA, Liu GT, Fisher MJ, Quinn GE, Belasco JB, Phillips PC
et al (2011) Retinal nerve fiber layer thickness in children with optic
pathway gliomas. Am J Ophthalmol 151(3):542–549
11. Barrio-Barrio J, Noval S, Galdos M, Ruiz-Canela M, Bonet E,
Capote M et al (2013) Multicenter Spanish study of spectral-
domain optical coherence tomography in normal children. Acta
Ophthalmol 91(1):e56–e63
12. Bialer OY, Goldenberg-Cohen N, Toledano H, Snir M, Michowiz S
(2013) Retinal NFL thinning on OCT correlates with visual loss in
pediatric craniopharyngioma. Can J Ophthalmol 48:494–499
13. Binning MJ, Liu JK, Kestle JRW, Brockmeyer DL, Walker ML
(2007) Optic pathway gliomas: a review. Neurosurg Focus 23(5):E2
14. Caen S, Cassiman C, Legius E, Casteels I (2015) Comparative
study of the ophthalmological examinations in neurofibromatosis
type 1. Proposal for a new screening algorithm. Eur J Paedriatr
Neurol 19:415–422
15. Cassiman C, Legius E, Spileers W, Casteels I (2013)
Ophthalmological assessment of children with neurofibromatosis
type 1. Eur J Pediatr 172:1327–1333
16. Chang L, El-Dairi MA, Frempong TA, Burner EL, Bhatti MT,
Young TL et al (2010) Optical coherence tomography in the eval-
uation of neurofibromatosis type-1 subjects with optic pathway
gliomas. J AAPOS 14:511–517
17. Costa-Cunha LVF, Cunha LP, Malta RFS, Monteiro MLR (2009)
Comparison of fourier-domain and time-domain optical coherence
tomography in the detection of band atrophy of the optic nerve. Am
J Ophthalmol 147:56–63
18. Danesh-Meyer HV, Wong A, Papchenko T, Matheos K, Stylli S,
Nichols A et al (2015) Optical coherence tomography predicts vi-
sual outcome for pituitary tumors. J Clin Neurosci 22:1098–1104
19. Dodgshun AJ, Elder JE, Hansford JR, Sullivan MJ (2015) Long-
term visual outcome after chemotherapy for optic pathway glioma
in children: site and age are strongly predictive. Cancer 121:4190–
4196
20. Drexler W, Fujimoto JG (2008) State-of-the-art retinal optical co-
herence tomography. Prog Retin Eye Res 27(1):45–88
21. Fard MA, Fakhree S, Eshraghi B (2013) Correlation of optical
coherence tomography parameters with clinical and radiological
progression in patients with symptomatic optic pathway gliomas.
Graefes Arch Clin Exp Ophthalmol 251:2429–2436
22. Fisher MJ, Avery RA, Allen JC, Ardern-Holmes SL, Bilaniuk LT,
Ferner RE et al (2013) Functional outcome measures for NF1-
associated optic pathway glioma clinical trials. Neurology
81(Suppl 1):S15–S24
23. Gu S, Glaug N, Cnaan A, Packer RJ, Avery RA (2014) Ganglion
cell layer-inner plexiform layer thickness and vision loss in young
children with optic pathway gliomas. Invest Ophthalmol Vis Sci 55:
1402–1408
24. Gürağaç FB, Totan Y, Güler E, Tenlik A, Ertuğrul IG (2016)
Normative spectral domain optical coherence tomography data in
healthy Turkish children. Semin Ophthalmol. https://doi.org/10.
3109/08820538.2015.1053625
25. Harwerth RS, Wheat JL (2008) Modeling the effects of aging on
retinal ganglion cell density and nerve fiber layer thickness. Graefes
Arch Clin Exp Ophthalmol 246:305–314
26. Howick J, Chalmers I, Glasziou P, Greenhalgh T, Heneghan C,
Liberati A, et al. The Oxford 2011 levels of evidence. Oxford
Centre for Evidence-Based Medicine. http://www.cebm.net/index.
aspx?o=5653. Accessed July 2016
27. Iannaccone A, McCluney RA, Brewer VR, Spiegel PH, Taylor JS,
Kerr NC et al (2002) Visual evoked potentials in children with
neurofibromatosis type 1. Doc Ophthalmol 105:63–81
28. Jindahra P, Petrie A, Plant GT (2009) Retrograde trans-synaptic
retinal ganglion cell loss identified by optical coherence tomogra-
phy. Brain 132:628–634
29. Keller J, Sanchez-Dalmau BF, Villoslada P (2014) Lesions in the
posterior visual pathway promote trans-synaptic degeneration of
retinal ganglion cells. PLoS One 9(5):e97444. https://doi.org/10.
1371/journal.pone.0097444
30. Leung CKS, Yu M, Weinreb RN, Ye C, Liu S, Lai G et al (2012)
Retinal nerve fiber layer imaging with spectral-domain optical co-
herence tomography. Ophthalmology 119:731–737
31. Listernick R, Ferner RE, Liu GT, Gutmann DH (2007) Optic path-
way gliomas in neurofibromatosis-1: controversies and recommen-
dations. Ann Neurol 61:189–198
32. Listernick R, Louis DN, Packer RJ, Gutmann DH (1997) Optic
pathway gliomas in children with neurofibromatosis-1: consensus
statement from the NF1 optic pathway glioma task force. Ann
Neurol 41(2):143–149
33. Magli A, Forte R, Cinalli G, Esposito F, Parisi S, Capasso M et al
(2013) Functional changes after treatment of optic pathway paedi-
atric low-grade gliomas. Eye 27:1288–1292
34. Monteiro MLR, Cunha LP, Vessani RM (2008) Comparison of
retinal nerve fiber layer measurements using stratus OCT fast and
regular scan protocols in eyes with band atrophy of the optic nerve
and normal controls. Arq Bras Oftalmol 71(4):534–539
35. Parikh RS, Parikh SR, Sekhar GC, Prabakaran S, Babu JG, Thomas
R (2007) Normal age-related decay of retinal nerve fiber layer
thickness. Ophthalmology 114:921–926
36. Parrozzani R, Clementi M, Kotsafti O, Miglionico G, Trevisson E,
Orlando G et al (2013) Optical coherence tomography in the diag-
nosis of optic pathway gliomas. Invest Ophthalmol Vis Sci 54:
8112–8118
37. Pawar N, Maheshwari D, Ravindran M, Ramakrishnan R (2014)
Retinal nerve fiber layer thickness in normal Indian pediatric

population measured with optical coherence tomography. Indian J
Ophthalmol 62(4):412–418
38. Plotkin SR, Blakeley JO, Dombi E, Fisher MJ, Hanemann CO,
Walsh KS et al (2013) Achieving consensus for clinical trials. The
REiNS international collaboration. Neurology 81(Suppl 1):S1–S5
39. Rajjoub RD, Trimboli-Heidler C, Packer RJ, Avery RA (2015)
Reproducibility of retinal nerve fiber layer thickness measures
using eye-tracking with spectral-domain optical coherence tomog-
raphy in children with non-glaucomatous optic neuropathy. Am J
Ophthalmol 159(1):71–77
40. Rao A, Sahoo B, Kumar M, Varshney G, Kumar R (2013) Retinal
nerve fiber layer thickness in children <18 years by spectral-domain
optical coherence tomography. Semin Ophthalmol 28(2):97–102
41. Topcu-Yilmaz P, Kasim B, Kiratli H (2014) Investigation of retinal
nerve fiber layer thickness in patients with neurofibromatosis-1. Jpn
J Ophthalmol 58:172–176
42. Van Mierlo C, Spileers W, Legius E, Casteels I, Cassiman C (2013)
Role of visual evoked potentials in the assessment and management
of optic pathway gliomas in children. Doc Ophthalmol 127:177–190
Childs Nerv Syst
43. Wan MJ, Ulrich NJ, Manley PE, Kieran MW, Goumnerova LC,
Heidary G (2016) Long-term visual outcomes of optic pathway
gliomas in pediatric patients without neurofibromatosis type 1. J
Neurooncol doi. https://doi.org/10.1007/s11060-016-2163-4
44. Yanni SE, Wang J, Cheng CS, Locke KI, Wen Y, Birch DG et al
(2013) Normative reference ranges for the retinal nerve fiber layer,
macula, and retinal layer thickness in children. Am J Ophthalmol
155(2):354–360
45. Yoneoka Y, Hatase T, Watanabe N, Jinguji S, Okada M, Takagi M
et al (2015) Early morphological recovery of the optic chiasm is
associated with excellent visual outcome in patients with compres-
sive chiasmal syndrome caused by pituitary tumors. Neurol Res
37(1):1–8
46. Zhu BD, Li SM, Li H, Liu LR, Wang Y, Yang Z, Anyang
Childhood Eye Study Group et al (2013) Retinal nerve fiber layer
thickness in a population of 12-year-old children in central China
measured by iVue-100 spectral-domain optical coherence tomog-
raphy: the Anyang childhood eye study. Invest Ophthalmol Vis Sci
54(13):8104–8111