Original Investigation

Optic Nerve Glioma: Case Series With Review of Clinical,

Radiologic, Molecular, and Histopathologic Characteristics
Lora R. Dagi Glass, M.D.*, Peter Canoll, M.D., Ph.D.†, Angela Lignelli, M.D.‡,
Azra H. Ligon, Ph.D.§¶║, Michael Kazim, M.D.*
*Department of Ophthalmology, †Department of NeuroPathology, and ‡Department of NeuroRadiology, Columbia
University Medical Center, New York-Presbyterian Hospital, New York, New York, U.S.A.; and §Department of
Pathology, Brigham and Women’s Hospital, ¶Center for Molecular Oncologic Pathology, Dana Farber Cancer Institute,
and ║Harvard Medical School, Boston, Massachusetts, U.S.A.

There is a long-standing debate regarding the etiology

Purpose: This study was designed to better understand the
biologic nature of optic nerve gliomas (ONGs) and to investigate
staining techniques that might improve the pathologic
interpretation of surgical margins.
Methods: In this retrospective case series, clinical data on
patient presentation, MRI, surgical visualization, and initial
pathologic interpretation were gathered. Specimens were then
reexamined using analysis of p53, isocitrate dehydrogenase
1 (IDH1), MIB-1, and B-rapidly accelerated fibrosarcoma
(BRAF) duplication.
Results: Six patients were studied. All were diagnosed
with World Health Organization grade 1 ONGs on original
pathology. On reexamination, BRAF tandem duplication was
found in 2 patients with neurofibromatosis Type 1 association.
P53 immunoreactivity was noted in a third case. No cases had
IDH1 immunoreactivity. Focal elevations of MIB-1 up to 7.5%
were noted in 2 cases.
Conclusions: ONGs are neoplasms with variable degrees of
aggressiveness. As more is understood regarding their varied
genetic underpinnings, improved pathologic classification and
individualized treatment regimens may be achieved. The authors
hope that this study helps guide the oculoplastic community
toward a multi-institutional, prospective study of ONG genomic
sequencing.
(Ophthal Plast Reconstr Surg 2014;30:372–376)
of optic pathway gliomas (OPGs). Some have emphasized the
hamartoma-like, site-appropriate nature of the disorganized
tissue, which grows at an appropriate pace (if at all), has a low
mitotic index, generally lacks metastases, and can regress;5
others point to examples of more rapidly growing, destructive
and symptomatic lesions, with published cases of metastases
and pathology consistent with cerebral astrocytoma.6 This
discussion is mired in difficulty with terminology because
ONGs represent a subset of OPGs, but the clinical behavior
of the 2 is not identical. In addition, pilocytic astrocytoma
has been used interchangeably with ONG, but ONGs (and
OPGs) are not always pilocytic astrocytomas or World Health
Organization (WHO) grade I neoplasms.4 This is further com-
plicated by cases such as 1 reported from the authors’ clinic
in which an otherwise healthy 5-year-old child demonstrated
MRI-documented progressive growth of an ONG, spreading
from the right optic nerve to the chiasm and ultimately to the
left optic nerve, both internal capsules, and likely the bilateral
optic tracts and radiations.7 Pathology of the partially resected
glioma was consistent with WHO grade I pilocytic astrocy-
toma, yet the MIB-1 index was focally elevated up to 7%, con-
sistent with its more aggressive behavior.7 Despite advances in
the sensitivity of MRI, a multi-institutional study noted 38%
(5/13) discordance between preoperative MRI and gross and
microscopic tumor margins on resection.8
The current study was designed to better understand the
biologic nature of ONGs and to investigate staining techniques
that might improve the pathologic interpretation of surgical mar-

O ptic nerve gliomas (ONGs) are generally low-grade pilo-
cytic astrocytomas, representing 66% of optic nerve
tumors.1 Most—up to 75%—are identified in those younger
than 10 years.2 Higher grade ONGs are more common in older
adults.3 ONGs are highly associated with neurofibromatosis
Type I (NF1).1 Between 8% and 31% of patients with NF1 have
ONGs; anywhere from 10% to 70% of patients with glioma of
the optic nerve or chiasm have NF1.4
gins. These include fluorescence in situ hybridization (FISH)
analysis for tandem duplication involving B-rapidly accelerated
fibrosarcoma (BRAF), which in turn causes mitogen-activated
protein kinase (MAPK) activation and has been found in 61%
of pediatric OPGs and between 23% and 78.6% of ONGs,9–11
immunostaining for p53 and isocitrate dehydrogenase 1 (IDH1)
mutations, both of which are oncogenic in nature but generally
found in higher grade gliomas, and MIB-1 labeling indices,
which are measures of cellular proliferation.12,13

Accepted for publication December 17, 2013.
This material has been presented, in part, at the Orbital Society Symposium
on September 2012 in Buenos Aires, Argentina, and at the ASOPRS Annual
Meeting November 2012, in Chicago, IL.
Supported by Orbital Disease Education and Research Foundation.
The authors have no financial or conflicts of interest to disclose.
Address correspondence and reprint requests to Lora R. Dagi Glass, MD
Edward S. Harkness Eye Institute, 635 West 165th Street, New York, NY
10032. E-mail: loradglass@gmail.com
DOI: 10.1097/IOP.0000000000000106
METHODS
Institutional review board approval was obtained with waiver
of informed consent, and the study was HIPAA-compliant. The au-
thors reviewed all surgical records of 1 author (M.K.) to identify pa-
tients with ONGs who had undergone surgical resection or biopsy. Six
patients were identified. Patient records were reviewed for gender, age
of diagnosis, age of presentation to the office, presenting visual acu-
ity, proptosis, pupillary defects, and optic nerve findings. In addition,
NF1 status, comorbidities, and any preoperative treatments were noted.

372 Ophthal Plast Reconstr Surg, Vol. 30, No. 5, 2014

Ophthal Plast Reconstr Surg, Vol. 30, No. 5, 2014 Optic Nerve Glioma Case Series

Preoperative MRI was reviewed with a single neuroradiologist (A.L.)
for confirmation of radiologic tumor margin.
Surgical and pathology reports were reviewed, with special at-
tention paid to original pathologic diagnosis and margins. The origi-
nal tissue was reexamined using 4 diagnostic assays: FISH evaluation
for BRAF tandem duplication and immunostaining for p53, IDH1, and
MIB-1. Both central tumor and tumor margins were examined.
BRAF Tandem Duplication: FISH. FISH analysis to detect BRAF dupli-
cation was performed and results interpreted by a Cytogeneticist (A.H.L.).
Four-micron tissue sections were mounted on standard glass slides and
baked at 60°C for at least 2 hours, then deparaffinized and digested for 5
minutes, as described previously.14 The following DNA probes were cohy-
bridized: RP11-767F15 (SpectrumGreen), which maps to 7q34, upstream
(5′) of BRAF; RP11-60F17 (SpectrumOrange), which maps to 7q34,
downstream (3′) of BRAF; and the D7Z1 control probe (SpectrumAqua),
which maps to 7p11.11-q11.11. The D7Z1 probe was purchased prela-
beled from Abbott Molecular (Abbott Park, IL). The BRAF-flanking bac-
terial ­artificial chromosome (BAC) clones were obtained from ­Children's
­Hospital Oakland Research Institute (CHORI) (www.chori.org). DNA
probes were direct-labeled using nick translation and precipitated using
standard protocols. Final probe concentration was 100 ng/μl. The final
concentration used for the D7Z1 probe followed manufacturer’s recom-
mendations. The tissue sections and probes were codenatured at 80°C for
5 minutes, hybridized at least 16 hours at 37°C in a darkened humid cham-
ber, washed in 2× SSC at 70°C for 10 minutes, rinsed in room temperature
2× SSC, and counterstained with 4’,6-diamidino-2-phenylindole (Abbott
Molecular/Vysis, Inc.). Slides were imaged using an Olympus BX51 fluo-
rescence microscope. Individual images were captured using an applied
imaging system running CytoVision Genus version 3.92.
p53 and IDH1: Immunohistochemistry. Formalin-fixed p­araffin-­
embedded tissue was cut at 5 microns. All immunohistochemistry was
performed on a Ventana benchmark Ultra using the ultraview dab detec-
tion system. Antibodies used were mouse anti-IDH1 ­(anti-IDH1-R132H/
DIAH09; Dianova, Miami Beach, FL; distributed by HistoBioTec; di-
lution, 1:30); mouse anti-p53 (Ventana, Tucson, AZ; Catalog number,
760–2542; dilution, ready-to-use); and rabbit anti-Ki67 (Ventana; Cata-
log number, 790–4286; dilution, ready-to-use). Slides were pretreated
with ULTRA Conditioner no. 1 and ULTRA CC1 (Ventana).
Determination of Ki67-Proliferation Index. A representative slide
containing tumor was selected and stained for Ki67 (as above). The
slide was initially scanned at low power, and an area with relatively
high staining was selected for counting. Four additional, randomly se-
lected, adjacent fields were counted. Fields were counted at 400× us-
ing an Olympus BH-2 light microscope and an ocular containing a grid
reticle yielding a counting area of 0.0784 mm2. All mononuclear cells
in a given grid were counted. Cells scored as positive for Ki67 showed
distinct nuclear staining with at least moderate positivity relative to the
positive control lymphoid tissue on the same slide (only rare cells were
discounted due to very weak staining). Counting 5 fields yielded a mini-
mum of 1,138 total cells and a maximum of 2,093.
RESULTS
Men and women were equally represented (3:3, respectively).
Average age at diagnosis was 6.75 years (3–16); average age at pre-
sentation to the authors’ office was 8.8 years (3–23). One patient was
positive for NF1 by genetic testing; another had a negative screening but
had a cousin who had screened positively. One patient’s family refused
screening. None had comorbidities. On clinical examination, visual acu-
ity ranged from no light perception to 20/200 in the affected eye(s). All
patients were found to have relative afferent pupillary defects and pro-
ptosis on the side of the lesion. Of five patients with disc pallor, 2 had
edematous pallor. One patient was unable to cooperate for disc visual-
ization in the office. One patient had been treated with radiation therapy
prior to presentation. Another was treated emergently with intravenous
dexamethasone and radiation therapy just prior to surgery.

Characteristics of patient cases

Case 1 Case 2 Case 3 Case 4 Case 5 Case 6

Age at presentation 3 7 (6.5) 8 (6) 5 (3) 23 (16) 7 (6)

(diagnosis)
Gender F M M F F M
NF1 status (+) (−) But (+) FH in (−) (−) (−) Refused testing
cousin
MRI Prechiasmal, Intracanalicular Prechiasmal, Bilateral nerves, Prechiasmal, Intracanalicular
>5 mm from >5 mm from chiasm, <5 mm from
chiasm chiasm bilateral internal chiasm
capsules, likely
optic tracts and
radiations
Preoperative None None None Radiation, IV Radiation None
treatment steroids
Pathology WHO grade I WHO grade WHO grade WHO grade WHO grade WHO grade
pilocytic I pilocytic I pilocytic I pilocytic I pilocytic I pilocytic
astrocytoma, astrocytoma, astrocytoma, astrocytoma, astrocytoma, astrocytoma,
clear margin clear margin margins not margin not margin not intracranial
labeled attempted attempted inferior margin (+)
BRAF (+) Fusion, (+) Fusion, not (−) (−) Trisomy 7 (−)
involving margin involving margin
IDH1 (−) (−) (−) (−) (−) (−)
TP53 (−) (−) (−) (−) (−) Mild-to-moderate
positivity
Highest MIB-1 7.5 4.3 3.6 7 2 2.5 (Up to 3.3 in
(%) dura)
Recurrence (−) (−) (−) Stable Stable (−)
Age, gender, neurofibromatosis Type I (NF1) status, MRI findings, preoperative treatments, original pathology, newer pathology stains, and recurrence are reported.
Dx, diagnosed; F, female; FH, family history; M, male; WHO, World Health Organization.

© 2014 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc. 373
L. R. Dagi Glass et al. Ophthal Plast Reconstr Surg, Vol. 30, No. 5, 2014

On review of preoperative MRI, no ONG was found to be solely
intraconal; 2 were intracanalicular, 3 were prechiasmal, and 1 extended
beyond the chiasm bilaterally to both internal capsules and likely both
optic radiations. Of those that were prechiasmal, only 1 was located less
than 5 mm from the chiasm.
Intraoperatively, all resections spared the chiasm. Four of the 6
resections were planned to produce clear margins. Pathologic investiga-
tion diagnosed WHO grade I pilocytic astrocytoma in all cases.
BRAF tandem duplication was identified in the resected ONGs
of both the patient with a positive NF1 screening (Case 1) and the
patient with negative screening but a positive family history of NF1
(Case 2; Table; Figs. 1 and 2). In the subject with positive NF1 screen-
ing, the margin was thought to be clear in initial pathology; however, it
was noted to have nuclei with BRAF duplication. Trisomy of chromo-
some 7 was found in the eldest of the patients (Case 5). All others were
negative for BRAF tandem duplication and chromosome 7 polysomy
by FISH.
On immunostaining, 1 case (Case 6) was found to have
­mild-to-moderate p53 immunostaining in a subset of cells; all cases
were found to be negative for IDH1 mutations. MIB-1 immunostaining
overall was low but showed focal elevations of up to 7.5%.
Follow up has spanned 6.5 to 96 months, with an average of
48.9 months. For cases in which clear margins were anticipated (1, 2, 3,
and 6), follow up has spanned 4 to 96 months, with an average of 43.6
months; there is no evidence of recurrent disease in any of these cases.
For reference to individual cases, please see the Table.
DISCUSSION
BRAF fusion to KIAA1549 typically occurs due to a tan-
dem duplication event at 7q34.15 The BRAF-KIAA1549 fusion
is theorized to create an oncogene of double-edged function.
Although its activation of the MAPK pathway appears to
induce neoplastic activity,16 the subsequent DNA damage that
it ultimately causes results in cell growth arrest.10 This may
account for the increased incidence of progression-free survival
in patients with pediatric low-grade astrocytomas, including
OPGs, with BRAF activation.10
In this case series, a BRAF tandem duplication was
limited to the ONGs of 2 patients (33.3%), both with an NF1
association. In another case series of 14 cases of ONGs, 1 of 4
patients with NF1 appears to have a similar BRAF aberration.11
In the same study, 11 of the 14 (78.6%) demonstrated BRAF
duplication and 2 of the 14 (14.3%) demonstrated polysomy of
chromosome 7.11 As described above, BRAF fusion activates
the MAPK pathway, which includes the “rat sarcoma” protein,

FIG. 1. Imaging, original pathology, and fluorescence in situ hybridization assay for BRAF duplication in Case 1, a patient with neu-
rofibromatosis Type I. A, Preoperative MRI with prechiasmal involvement. B, The original hematoxylin and eosin stained section with
moderately cellular glial neoplasm, course fibrillar processes, and scattered Rosenthal fibers (white arrow; micrograph taken with ×400
objective). C and D, BRAF duplication in the tumor center (C) and margin (D). Two adjacent red probes indicate tandem duplication
(micrograph taken with ×60 objective).

374 © 2014 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.
Ophthal Plast Reconstr Surg, Vol. 30, No. 5, 2014 Optic Nerve Glioma Case Series

FIG. 2. Imaging, original pathology, and fluorescence in situ hybridization assay for BRAF duplication in Case 2, a patient with nega-
tive neurofibromatosis screening but a positive family history. A, Preoperative MRI with intracanalicular involvement. B, The original
hematoxylin and eosin stained section with moderately cellular glial neoplasm, course fibrillar processes, and scattered Rosenthal fibers
(white arrow; micrograph taken with ×400 objective). C and D, BRAF duplication in the tumor center (C) but not the tumor margin (D).
Two adjacent red probes indicate tandem duplication (micrograph taken with ×60 objective).

or RAS. Because the genetic implication of NF1 is that of a
mutated tumor suppressor gene activating RAS,17,18 the addi-
tion of a second recognizable genetic mutation in the ONGs
of the NF1-associated cases might be recognized as a second
genetic “hit” causing neoplasm. This description is limited, in
that one of the cases did not test positively for NF1; however,
given his cousin with positive testing and his ONG, the suspi-
cion remains high that this patient may have an unrecognized
NF1-associated mutation.
In the NF1 case, the margin was thought to be clear on
initial pathologic assessment; however, the margin was noted to
have nuclei containing BRAF duplication. This case was 1 of
4 in which clear margins were surgically attempted; a second
case showed intracranial margin positivity on original pathol-
ogy. The presence of a positive margin via BRAF FISH shows
25% failure of our current pathology system in accurately inter-
preting margins. Should later research demonstrate changes in
clinical outcome based on findings of BRAF duplication, it may
be prudent to start testing for this phenomenon at tumor mar-
gins on a regular basis. Though the number of cases is small, 2
cases of 4 suggest 50% failure of MRI to identify correct gross
or microscopic margins. A previously published report showing
38% failure of concordance did not assess BRAF duplication.8
The case with trisomy 7 is also of interest as BRAF maps
to this chromosome. In this case series, extra copies of chromo-
some 7 were found in the patient who was oldest at diagnosis and
presentation. Trisomy 7 has been identified in malignant gliomas
across the age spectrum and in a small number of ­lower-grade
gliomas and is not specific for any particular subtype of primary
brain tumor.15 The patient has not shown progression in 7 years.
None of the ONGs in the series showed IDH1 immu-
nostaining. This is not surprising as the IDH1 mutation gener-
ally is not found in WHO grade I gliomas but rather is highly
associated with higher grade diffusely infiltrating gliomas.12
Immunoreactivity for p53 was found in 1 of the 6 cases. TP53
is a tumor suppressor gene, and labeling indices of greater than
2% are associated with diffuse astrocytoma of the optic nerve,13
which is considered a WHO grade II neoplasm. Despite p53
staining in a subset of cells in Case 6, the overall appearance of
the glioma was consistent with WHO grade I, given the pres-
ence of Rosenthal fibers, eosinophilic granular bodies, and only
rare mitotic figures. However, the clinical aspects of the case—
discordance between preoperative imaging and tumor margin
and aggressive progress over a 6-month period leading to sur-
gery—are of particular interest given the p53 positivity. Future
studies incorporating genomic sequencing may allow for better

© 2014 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc. 375
L. R. Dagi Glass et al. Ophthal Plast Reconstr Surg, Vol. 30, No. 5, 2014
identification of key genomic changes in ONGs as they relate to
variable degrees of aggressive behavior.
MIB-1 labeling indices refer to antibody recognition of
Ki-67 protein, a marker for cellular proliferation. In general,
the MIB-1 labeling indices are higher than those of Cummings
et al.,13 who examined 22 cases of ONGs and found the 19 WHO
grade I pilocytic astrocytomas to have MIB-1 indices less than
1%, whereas more aggressive pathology was correlated with indi-
ces of 2% to 3%; it was also higher than Reis et al.,9 who found
all Ki-67 indices to be <1% in their study of 13 cases of pilocytic
astrocytoma of the optic nerve. An earlier article by Dirven et al.19
showed up to 15% MIB-1 labeling indices in optic nerve pilocytic
astrocytomas, though it is unclear if chemotherapy was given
prior to or following resection. The indices correlate with the up
to 6% MIB-1 indices noted by Yeung et al.20 in their examination
of 12 WHO grade I ONGs. However, in 2 of the cases—both the
genetics-proven NF1 case and the most aggressive case—MIB-1
labeling indices were focally elevated (≥7%).
This article supports the notion that there is a diversity of
behavior among ONGs. As of yet, neither this study nor those in
the literature have been able to identify pathologic features that
clearly segregate ONGs by expected degree of aggressiveness.
In their recent discussion of OPGs, Liu et al.21 note that an accu-
mulation of evidence points toward OPGs as neoplasms with
variable tumor behaviors. As a subset of OPGs, ONGs are con-
sidered neoplastic as well. The next major research effort at this
point should be the creation of genetically tailored treatment
regimens suitable for variable tumor entities grouped under the
same pathologic diagnosis. For example, in a recently published
retrospective review of 21 patients with OPGs, of which 9 had
optic nerve involvement, tumor volume decreased after che-
motherapy or radiation treatment in 53% of patients, whereas
it increased in 20%.22 Tumor response to treatment may well
depend on specific genetic alterations, and current studies are
already starting to identify cellular pathway differences between
OPGs in patients with and without NF1.21 The authors speculate
that future individualized regimens might allow for improved
outcomes in ONGs and hope to contribute to this through a pro-
spective study of ONG genomic sequencing.
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