REVIEW ARTICLE
Neurofibromatosis Type 1:
Review and Update on Emerging Therapies
Tanya Karaconji, FRANZCO,*† Eline Whist, BMed, MPHTM, FRANZCO,*‡
Robyn V. Jamieson, PhD, FRACP,§¶ǁ** Maree P. Flaherty, FRANZCO, FRACS, FRCOphth,*†† and
John R.B. Grigg, MD, FRANZCO*¶ǁ‡‡
Abstract: Neurofibromatosis type 1 is an autosomal dominant
neurocutaneous disorder affecting 1 in 3000 births. This familial tumor
predisposition syndrome is diagnosed clinically and affects the skin,
bones, and nervous system. Malignant tumors can arise in childhood or
adulthood and are the most common cause of mortality in this population.
Early diagnosis and management led by a multidisciplinary team remains
the standard of care, particularly in the management of optic pathway
glioma. Emerging concepts in the genetic patterns of this condition
have led to the introduction of new treatment modalities that target the
mitogen-activated protein kinase and the mammalian target of rapamycin
pathways. In this review, the role of the ophthalmologist and approach
to screening for optic pathway glioma are outlined based on previous
recommendations. Updates on choroidal involvement, as a diagnostic
criterion, will also be discussed, further highlighting the pivotal role of
the ophthalmologist in the diagnosis and management of this complex
condition.
Key Words: choroidal nodules, neurofibromatosis 1, optic pathway
glioma, phakomatoses
(Asia Pac J Ophthalmol (Phila) 2019;8:62–72)
N eurofibromatosis 1 (NF1) is an inherited neurocutaneous
disorder. It is characterized by the presence of multisystem
tumors throughout the skin and central nervous system (CNS),
which carries a risk of malignant transformation.1 The hallmark
clinical features of NF1 include multiple café au lait macules,
neurofibromas, intertriginous freckling, osseous lesions, Lisch
nodules, and optic pathway gliomas (OPGs).2 An evolving
understanding of both the genetic and newly recognized
From the *Discipline of Ophthalmology, Save Sight Institute, Sydney Medical
School, University of Sydney, Australia; †Manchester Royal Eye Hospital,
Manchester, United Kingdom; ‡Royal Darwin Hospital, Darwin, Australia;
§Disciplines of Paediatrics, Genomic Medicine and Ophthalmology, Sydney
Medical School, University of Sydney, Australia; ¶Eye Genetics Research
Unit, Children’s Medical Research Institute, University of Sydney, Australia;
ǁSave Sight Institute and Eye Genetics Clinics, The Children’s Hospital at
Westmead, Australia; **Westmead Hospital, Sydney, Australia; ††Department
of Ophthalmology, The Children’s Hospital at Westmead, Australia; and
‡‡Sydney Eye Hospital, Sydney, Australia.
Submitted May 1, 2018; accepted August 23, 2018.
J.R.B.G. and R.V.J. are supported in part by NHMRC Centre for Research
Excellence APP1116360. E.W. is supported in part by Sydney Eye Hospital
Foundation.
The other authors have no funding or conflicts of interest to declare.
Reprints: Tanya Karaconji, Discipline of Ophthalmology, Save Sight Institute,
Sydney Medical School, University of Sydney, NSW 2006, Australia. E-mail:
tkaraconji.@gmail.com.
Copyright © 2019 by Asia Pacific Academy of Ophthalmology
ISSN: 2162-0989
DOI: 10.22608/APO.2018182
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ophthalmic features of this complex disorder are discussed in this
review.
EPIDEMIOLOGY
Neurofibromatosis 1 is one of the most common genetic
disorders with no sex or racial predilection. It occurs in
approximately 1 in 3000 people.3 Estimates of the prevalence
of NF1 range from 1:21904 to 1:7800.5 Some of the difficulties
with accurate prevalence data for this condition may be due to
ascertainment bias6 partly because of the wide variability in the
expression of the condition, whereby mild cases may escape
study inclusion particularly in studies dependent on an affected
individual coming to medical attention.7 Reduced prevalence
in later adulthood may be due to increased mortality seen in
individuals with NF1 or to underascertainment of adult patients.8
The physician Mark Akenside first recognized the disorder in
1768. Robert Smith, an Irish surgeon, published further details
on the disease in 1849. However, it was the German pathologist
Friedrich von Recklinghausen who is credited with its recognition
in 1882.1
GENETICS AND PATHOPHYSIOLOGY
The inheritance of NF1 is autosomal dominant with 100%
penetrance but highly variable expressivity.1,3,9 Importantly, a high
spontaneous mutation rate of up to 42% exists.3 The NF1 gene is
located on chromosome 17q11.2 and was cloned in 1990. It was
originally cloned by the Wallace group10 along with the Cawthon
and Viskochil group.11 It is an important tumor suppressor gene
found throughout the nervous system.12
The NF1 gene encodes the protein neurofibromin, which
influences multiple signaling pathways affecting many cellular
processes throughout the body. Importantly, it acts as a negative
regulator of cell growth and proliferation.2 Several pathways are
thought to be involved in the development of tumors associated
with NF1. Loss of neurofibromin increases rat sarcoma viral
oncogene homolog (RAS) activity. This increased RAS activity
causes unopposed cell growth and activation of important
downstream intermediates such as the mitogen-activated protein
kinase (MAPK) and the mammalian target of rapamycin (mTOR)
pathways.2,9
Neurofibromin is also involved in the regulation of cyclic
adenosine monophosphate levels, which has been shown to affect
the CNS in animal models, and importantly in OPG formation.12–14
Although NF1 may result in a combination of benign and
malignant tumors of the central and peripheral nervous system,
the initial event in tumor formation is the germline mutation in
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Asia-Pacific Journal of Ophthalmology • Volume 8, Number 1, January/February 2019 Neurofibromatosis Type 1

the NF1 tumor-suppressor gene. The “second hit” in this “2-
hit hypothesis” pathway is a somatic mutation, causing loss of
heterozygosity of the NF1 gene, and consequently leading to
Schwann cell neurofibromas along with other tumors.9
CLINICAL PRESENTATION
Neurofibromatosis 1 is a neurocutaneous disorder with an
age-dependent, variable clinical presentation. This often leads
to difficulty in establishing an early diagnosis. Despite this, NF1
has well-recognized diagnostic criteria as outlined in Table 1.15
Although these “classical” criteria are widely used and agreed
upon, additional new cutaneous and extracutaneous features
have been described in recent years (Table 1). An example of
this is the presence of unidentified bright objects on imaging.
These are seen as hyperintense lesions on T2-weighted brain
magnetic resonance imaging (MRI) scans, which may represent
aberrant gliosis pathognomonic of NF1.16 Additionally, advanced
molecular analysis is now available, refining our knowledge of
the NF1 gene mutation.17
A small subset of patients present with a somatic mutation or
“segmental” NF1 where the clinical features only affect a specific
area of the body and neither parent is affected.18 Other phenotypic
presentations in patients with an NF1 gene mutation include
neurofibromatosis-Noonan syndrome, which may occur in up to
12% of these patients. Clinical features are an overlap between
the 2 named syndromes and include the Noonan features of short
stature, ocular hypertelorism, low-set ears, and downslanting
palpebral fissures.19
Lisch Nodules
Austrian ophthalmologist Karl Lisch was the first to
emphasize what are now called Lisch nodules and their association
with NF1 in 1937.20 Histologically Lisch nodules are melanocytic
hamartomas, consisting of a condensation of spindle cells on the
anterior iris surface. Stromal iris nevi underlie the pigmented
nodules.21 They are present on the anterior iris surface or in the
anterior chamber angle. They are well-defined yellow-brown
dome-shaped elevated lesions and can range in size from pinpoint
to large (Fig. 1).20,22 Although Lisch nodules do not cause ocular
morbidity or disability, they are important because they are one of
the diagnostic criteria for NF1. Their presence is age-dependent.
Although their presence is unusual before the age of 2 years, they
are seen in half of 5-year-olds, 75% of 15-year-olds, and almost
100% of adults older than 30 years.2
Skin
Café au lait macules and skin fold freckling do not usually
cause complications and have no malignant potential.23 They are
an important component of the diagnostic criteria of NF1. Café au
lait patches are usually the first identified clinical manifestation in
NF1.24 They are usually present within the first 2 years of life.18
They present as well-defined hyperpigmented macular lesions
that are generally absent from the scalp and eyebrows along with
the palms and soles (Fig. 2).18 Histologically these lesions are due
to increased proliferation of epidermal melanocytes with basal
hyperpigmentation of the epidermis.
Axillary and inguinal freckling usually presents after the
development of café au lait macules by the age of 5 to 8 years.24

TABLE 1. National Institutes of Health (NIH) Diagnostic Criteria for Neurofibromatosis 1 (NF1) and Other Common Findings2,6,9,14,15

The NIH Diagnostic Criteria are Met if 2 or More of the Following are Found
1. Six or more café au lait macules of over 5 mm in greatest diameter in prepubertal individuals and over 15 mm in greatest diameter in
postpubertal individuals
2. Two or more neurofibromas of any type or 1 plexiform neurofibroma
3. Freckling in the axillary or inguinal regions
4. Optic glioma
5. Two or more Lisch nodules (iris hamartomas)
6. A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex
7. A first-degree relative with NF1 by the above criteria
Nondiagnostic Cutaneous and Extracutaneous Signs to Consider in Addition to the “Classical” Diagnostic Criteria When Evaluating
Patients with NF1
Genetic analysis Molecular analysis of the NF1 gene
Cutaneous signs Anemic nevus
Juvenile xanthogranuloma
Mixed vascular hamartomas and cherry angiomas
Hypochromic macules
“Soft-touch” skin
Hyperpigmentation
Extracutaneous Choroidal hamartomas
Large head circumference and hypertelorism
Unidentified bright objects on neuroimaging
Cerebrovascular dysplasia, moyamoya
Learning, speech and behavioral disabilities, headache and seizures
Neoplasms

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Karaconji et al Asia-Pacific Journal of Ophthalmology • Volume 8, Number 1, January/February 2019

Typically, they present as small freckles less than 5 mm in size in

the axillary or inguinal area.18,24,25 They may also present in areas
where skin folds are in apposition, including the neck and under
the breasts in women.7 These are given the eponymous name,
Crowe sign, after the physician Frank Crowe who first described
their association with café au lait macules in the diagnosis of NF1
in 1964.26

FIGURE 1. Slit-lamp photograph showing multiple Lisch nodules.
FIGURE 2. Café au lait macules.
Neurofibromas
Neurofibromas are a hallmark feature of NF1, present in
almost all patients older than 30 years.25 They are benign soft tissue
tumors of Schwann cell origin that arise on peripheral nerves.27 In
addition to neoplastic Schwann cells, they also contain fibroblasts,
macrophages, and mast cells.28 Clinically, neurofibromas can be
further classified as cutaneous, subcutaneous, or plexiform which
can be further divided into nodular or diffuse. The features of
each are outlined in Table 2.17–19,24 Although they typically present
symptomatically on the skin, they can also develop deep within
the body and may remain largely asymptomatic.24
Like most features in NF1, the presence of neurofibromas
is age-dependent. Although neurofibromas tend to increase with
age, the presence of plexiform neurofibromas may manifest at
birth and are most active during the first decade of life, developing
in 25% to 50% of individuals with NF1.29
The morbidity associated with plexiform neurofibromas is
2-fold. In addition to the disfigurement, bony destruction, and
pain associated with these lesions, they also carry an 8% to 13%
lifetime risk of malignant transformation [malignant peripheral
nerve sheath tumor (MPNSTs)].23,24 This rate of malignant
transformation is higher than previously thought.30
Unlike cutaneous neurofibromas, plexiform neurofibromas
can infiltrate surrounding soft tissue and arise from multiple
nerve fascicles, with multiple discrete tumors forming along
nerve trunks.23 Growth of these tumors is often unpredictable
and is usually rapid during the first decade of life, resulting in
significant disfigurement and functional impairment.25 Palpebral
plexiform neurofibromas typically affect the upper eyelid
unilaterally appearing in infancy or early childhood and may
result in significant functional impairment including amblyopia.25
This may be due to a mechanical ptosis causing astigmatism.
As always in pediatric patients, regular refraction, dilated
examination, and amblyopia treatment are of utmost importance,
particularly in NF1 patients presenting with eyelid plexiform
neurofibromas.
Unfortunately, MPNSTs have a poor prognosis with a 5-year
survival of up to 60%, warranting ongoing careful surveillance
with a low threshold for investigation.31 Poor prognosis is

TABLE 2. Clinical Features of Established Neurofibroma Subtypes17–19,24

Neurofibroma Types Location Clinical Signs Presentation

Cutaneous Epidermis and dermis
Subcutaneous Deep to dermis
Nodular plexiform Localized interdigitation
with normal tissues
Diffuse plexiform Infiltrate widely and deeply
Moves with skin, bluish tinge, local pruritus.
Size: ~2 mm to 3 cm
Skin moves over, firm and rounded feel, located
along peripheral nerves. Size: 3 to 4 cm
“Bag of worms” feel
Smooth slightly irregular skin thickening
Asymptomatic; most common type;
presents in late teens
Tenderness on palpation; tingling in
distribution of affected nerve
May be present from birth, enlarges
during first decade of life
−

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Asia-Pacific Journal of Ophthalmology • Volume 8, Number 1, January/February 2019
associated with early metastasis and poor response to systemic
chemotherapy. Delayed diagnosis remains an issue. Features
including increased growth rate, irregular contour, and pain in
existing neurofibromas are symptoms and signs that may indicate
malignant transformation. These symptoms may also be present
in benign lesions.31,32
Although a histological diagnosis remains the gold standard
in differentiating benign from malignant lesions, imaging with
positron emission tomography and computed tomography
combined with a flurodeoxyglucose tracer provides a noninvasive
technique to identify malignant transformation based on in-vivo
glucose metabolism.31 Definitive diagnosis of a MPNST requires
pathological identification.
Neurofibroma Treatment
Plexiform neurofibromas are notoriously difficult to treat
surgically due to their infiltration of adjacent normal tissue and
the commonly reported risk of regrowth after excision.33 Targeted
chemotherapeutic agents such as imatinib (tyrosine kinase
inhibitor) have also been studied but have only demonstrated a
modest reduction in tumor volume size in a phase 2 trial in affected
patients with clinically significant plexiform neurofibromas
due to NF1.34 Interferons exert antitumor activity via a number
of mechanisms including antiproliferative, antiangiogenesis,
and cytotoxic effects. A phase 1 trial of pegylated interferon-
alpha-1beta in young patients with progressive and unresectable
plexiform neurofibromas has demonstrated a promising reduction
and stabilization of plexiform neurofibroma size.35
Clinical trials with biologic agents including mTOR and
MAPK (MEK) inhibitors are underway.36 Studies looking
at MEK inhibitors in mouse models have demonstrated that
blocking MEK signaling was sufficient to profoundly shrink
existing neurofibromas.37 Clinical trials with MEK inhibitors
for plexiform neurofibromas are ongoing or in development and
will allow further evaluation of the utility of the mouse model in
FIGURE 3. The near-infrared reflectance images of the right and left eyes of a patient with neurofibromatosis type 1 demonstrating bright patchy
areas localized to the posterior pole and vascular arcade. White arrows indicate 2 of multiple lesions in each eye (images courtesy of Francesco Viola
Università degli Studi di Milano).
© 2019 Asia-Pacific Academy of Ophthalmology
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Neurofibromatosis Type 1
predicting response in humans.
Although these studies have shown promising results
in plexiform neurofibromas, unfortunately they have only
demonstrated a transient benefit in the treatment of MPNST in
mice models.36,38 In contrast, mTOR pathway inhibitors such as
rapamycin suppress the growth of these MPNST but have not
demonstrated tumor regression.39 The mTOR pathway is critically
deregulated in NF1-mutant MPNST, hence the role of mTOR
inhibitors.39 However, when combined with heat shock protein 90
inhibitors, potent tumor regression is observed.40
Anterior Segment and Uvea
The presence of choroidal abnormalities in neurofibromatosis
was reported in as early as the 1930s.41 These lesions were
identified on enucleated specimens and attributed to proliferating
Schwann cells arranged as concentric rings around axons.42,43
More recently, a number of case series have used confocal near-
infrared reflectance (NIR) imaging as a means of identifying
these choroidal lesions in NF1 patients.44–47 In each of these
studies, the choroidal abnormalities identified were not visualized
by simple ophthalmoscopic examination or fundus fluorescein
angiography.46 Further studies have found that these choroidal
abnormalities tend to increase with age and are particularly
localized around the posterior pole.45
Near-infrared reflectance imaging at 815 nm and optical
coherence tomography have further elucidated the presence of
these choroidal bright patchy nodules in patients with NF1.46
Viola et al46 found choroidal bright patches in 82% of NF1
patients compared with only 7% of normal controls with a
diagnostic sensitivity of 83% and specificity of 96%. These
choroidal abnormalities have been further categorized as either
“domeshaped” or “placoid-like”.48 These lesions are also reported
at a high frequency in pediatric NF1 patients.47 The appearance of
these lesions on NIR imaging is demonstrated in Figure 3.
These studies highlight the potential importance of choroidal
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Karaconji et al
involvement as a new diagnostic criterion for NF1. In particular,
the use of NIR imaging to detect these choroidal abnormalities is
gaining increasing interest particularly among ophthalmologists
as a possible screening tool, as it is noninvasive and can be
applied to the pediatric population, at least in older children.46,47
Additional choroidal changes that have also been described
include a reduction in mean choroidal thickness, which may be
related to altered choroidal circulation in the presence of choroidal
nodules (Fig. 4).48 Another case report has identified increased
subfoveal choroidal thickness in a case of NF1.49 Pigmentary
hamartomas (choroidal nevi) may also involve the posterior uveal
tract in up to 30% of affected patients.50
Although the association of glaucoma and neurofibromatosis
has been described in the literature as a rare association, the
mechanism is not well understood and is most likely related
to angle closure.25,51,52 A retrospective histological study by
Edward et al51 analyzed the eyes from 5 patients with NF1
and glaucoma, ranging in age from birth to 13 years. They
identified endothelialization of the anterior chamber angle,
which they hypothesized might be related to overexpression of
the RAS-MAPK genes in these eyes.51 Clinically, infiltration of
the iris and angle with neurofibromas may obstruct the angle
resulting in secondary angle closure.25 Other anterior segment
features include congenital ectropion uvea, iris heterochromia,
developmental anomaly of the angle, and posterior embryotoxon,
FIGURE 4. Choroidal changes (arrows) are shown in a patient with neurofibromatosis type 1 as seen on near-infrared reflectance imaging, with
corresponding optical coherence tomography through the choroidal lesions in the right (A) and left (B) eye.
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Asia-Pacific Journal of Ophthalmology • Volume 8, Number 1, January/February 2019
which may all predispose to glaucoma.51 Interestingly, Morales et
al53 found ipsilateral glaucoma and increased axial length in 23%
of 95 patients with orbitofacial involvement.
Skeletal Anomalies
A number of skeletal manifestations are recognized in NF1
patients. These may present as either generalized or focal bony
abnormalities. Generalized bony changes include osteopenia,
short stature, and macrocephaly.36 In NF1 patients older than 40
years, a 5-fold increase in fracture risk has been reported, with a
3-fold risk in children younger than 16 years.54
Focal bony abnormalities include tibial dysplasia/
pseudarthrosis (2%), sphenoid wing dysplasia (1–6%), scoliosis
(10–15%), nonossifying fibrosis, pectus deformities of the chest,
and rarely, defects in the occipital bone.24,36,55 Of particular
significance to the ophthalmologists is the presence of sphenoid
wing dysplasia that may present with asymmetric orbits,
proptosis, or enophthalmos.24 More specifically, these patients
usually present with pulsatile proptosis due to herniation of the
temporal lobe into the orbit.23 Importantly, absence or thinning
of the sphenoid wing may be due to the presence of an orbital
plexiform neurofibroma.24
Although the mechanisms underlying these osseous
manifestations remain poorly understood, studies have
demonstrated that neurofibromin plays a critical role in
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Asia-Pacific Journal of Ophthalmology • Volume 8, Number 1, January/February 2019
regulating mesenchymal stem/progenitor cell differentiation into
osteoblasts, affecting collagen synthesis and mineralization.36,56
A defect in this process is likely to contribute in part to some of
these clinical features. Ideally, specialized pediatric orthopedic
surgeons should manage these children.
Optic Pathway Gliomas
Optic pathway gliomas account for 5% of pediatric
intracranial tumors.57 Traditional figures suggest that 15% to 20%
of children with NF1 will develop a low-grade glial neoplasm.58,59
A large retrospective review of 861 patients seen at the tertiary
referral neurofibromatosis clinic at the Children’s Hospital
at Westmead in Sydney found a prevalence of 6.6% in their
population.60
Optic pathway gliomas can occur anywhere in the brain or
spine in children with NF1. They are, however, most common
in the optic pathway, hypothalamus, and (to a lesser extent)
brainstem.24,61 The traditional Dodge classification (DC) of OPGs
proposed in 195862 defines tumors anatomically as involving the
optic nerves alone (stage 1), the chiasm with or without nerve
involvement (stage 2), and the hypothalamus or other adjacent
structures (stage 3). The DC has long been used to select patients
for resection of optic nerve tumors and to provide an important
indicator of prognosis with tumors at the optic chiasm having a
poorer outcome. More recently, a modified DC has introduced
an imaging-based method using MRI scans and is referred to as
the PLAN score.63 This updated score provides a more detailed
anatomical description that can help to categorize and select tumors
at a higher risk of visual morbidity to better guide treatment and
detect change. Taylor et al63 found that NF1-positive cases more
commonly involved both optic nerves and multiple locations
at other sites whereas NF1-negative tumors more commonly
involved the central chiasm and the hypothalamus. Most patients
will be diagnosed before 6 years of age,61 although other series
have found that up to 30% of children presented with OPGs after
the age of 6.60,64 Table 3 outlines the features of the most common
subtype, pilocytic astrocytoma. Although pilocytic astrocytomas
are common in NF1 patients and usually follow an indolent
course, they may spontaneously resolve without intervention.36,65
Pilomyxoid astrocytoma, another subtype, is less common in
the context of NF1.2 It is found that NF1-associated OPGs have
active MAPK signaling and rarely transform into high-grade
tumors with no malignant potential.2
These tumors may have a wide range of clinical presentations.
Many OPGs are asymptomatic. They may become evident either
as a result of patient signs or symptoms or as an incidental finding
on “ baseline” neuroimaging studies.66 A study by Listernick et
al67 in 1989 demonstrated that, if all children with NF1 undergo
screening neuroimaging, 15% of them will have radiographic
evidence of OPG with only half of these children developing
TABLE 3. Characteristic Features of the Most Common Subtype of Optic Pathway Glioma (OPG) in Neurofibromatosis 1 (NF1): Pilocytic Astrocytoma13,54
Histological features GFAP-staining in cell cytoplasm and presence of Rosenthal fibers; contains piloid cells and astrocytes
Incidence (per 100,000 per year) 0.48
Association with NF1 Mainly OPG (50%)
Age 5–19 y
World Health Organization grade I
Location Cerebellum/brainstem/optic pathway
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Neurofibromatosis Type 1
symptoms or signs related to the OPG.60,67,68 Symptomatic
OPG in children with NF1 generally results in decreased visual
acuity, diminished visual fields, abnormal pupillary function,
or proptosis. It is important to note that young children rarely
complain of vision loss, necessitating the use of reliable,
reproducible measures to detect visual changes.58 Reduction in
visual acuity is the most common finding on screening.61 Other
less common ocular presentations include strabismus, proptosis,
nystagmus, afferent pupil defect, and abnormal color vision.61
Clinically, the optic discs usually appear pale. Low-grade glial
tumors may also present with systemic manifestations such as
precocious puberty or rarely, diencephalic syndrome.68 Although
it is extremely rare, the latter may occur in cases with tumor
involvement of the thalamus or hypothalamus and presents with
failure to thrive, vomiting, headaches, and vision abnormalities.69
Minimum requirements for cranial MRI at diagnosis include
T2-weighted, T1-weighted, and gadolinium contrast-enhanced
T1-weighted sequences and fluid-attenuated inversion recovery.
This is used to diagnose and monitor progression of these tumors.
Typical features include fusiform enlargement, tortuosity, and
kinking of the optic nerves. There may also be involvement of the
chiasm (best visualized on coronal sections), optic tract, or optic
radiation with diffuse enlargement.70 Optic pathway gliomas are
isointense or slightly hypointense to normal optic nerve on T1
imaging and hyperintense on T2 imaging71,72 (Fig. 5). Although
they may demonstrate gadolinium enhancement, not all OPGs do.
Abnormal perineural tissue within the nerve sheath may also be
present.71,72 The screening guidelines and management pathways
of patients with NF1 are outlined in Figure 6.60,61
Treatment
Current imaging is virtually always diagnostic, so biopsy of
suspected tumors is no longer necessary.70 Surgery is recommended
for OPG cases with severe vision loss and disfiguring proptosis
only when assessed by a multidisciplinary team, as surgery in
NF1 OPG is rarely useful and will often sacrifice whatever vision
remains.73
A combination of carboplatin-based chemotherapy, often
in conjunction with vincristine, remains the gold standard for
NF1-associated low-grade gliomas requiring treatment.74 The
5-year progression-free survival in these patients has been shown
to be as high as 69%.74 This regimen also has lower toxicity
and side-effect profile than other comparable agents.74 Other
traditional chemotherapeutic agents have also been associated
with a worrisome risk of secondary malignancies.36 In recurrent,
refractory tumors, alternative agents such as vinblastine have
proven to be efficacious, although it is poorly tolerated due
to extensive bone marrow suppression in many patients.36
Pretreatment vision is an important prognostic indicator of final
visual acuity after chemotherapy.36
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A B

FIGURE 5. Magnetic resonance imaging (MRI): A, Coronal T2 of the brain: bilateral optic nerve enlargement with tortuosity. B, axial T2 of the brain and
orbits demonstrating enlargement and tortuosity of both optic nerves, consistent with an optic pathway glioma.

Screening  guidelines   Management  Pathways  

Screening   3  Monthly  
Annual  ophthalmic   children  with   follow-­‐up  with  
assessment  (VA,  VF,   suspected  OPG   MRI  +   MRI  in  the  1st  
0  −  8  y   or  abnormal   MDT   year.  May  be  
pupils,  eyelids,  OMS,  iris,  
fundi,  refrac0onC   ophthalmic   extended  in  
examina0on   the  following  
year  if  clinically  
stable  

Second  yearly  
Screening  
ophthalmic  assessment  
asymptoma0c   >8  −  18  y  
(VA,  VF,  pupils,  eyelids,  
1F1  pa0ents  
OMS,  iris,  fundi,   During  chemotherapy:    
refrac0onC   3  monthly  ophthalmic  
Monitoring   assessment  +  OCT  +  MRI  
children  with  
confirmed  OPG  
Rou0ne  eye  care  only,   undergoing   Post  chemotherapy:    
>18  y  
no  screening   treatment   3-­‐6  monthly  ophthalmic  
assessment  +  OCT  +  MRI.  
Increase  intervals  if  
clinically  improved/stable  

FIGURE 6. Proposed screening guidelines and management pathways of patients with NF1. If unable to accurately assess a child clinically, there may be
a role for neuroimaging. Some centers do perform baseline neuroimaging in new diagnosis of NF1. MDT indicates multidisciplinary team (pediatrician,
neurologist, oncologist, neurosurgeons, geneticist); MRI, magnetic resonance imaging; NF1, neurofibromatosis 1; OCT, optical coherence tomography;
OMS, ocular motor score; OPG, optic pathway glioma; VA, visual acuity; VF, visual field (age-appropriate).

Newer therapies targeting MEK inhibitors and mTOR based therapy.76 Although further studies are required, this
pathways are currently under trial.70 Drugs targeting tumor presents a promising treatment in addition to standard therapies.
angiogenesis, such as bevacizumab, have shown objective The Pediatric Brain Tumour Consortium study is currently
responses radiologically and on vision testing in cases of evaluating the use of selumetinib, an MEK inhibitor, in children
refractory OPG.75 A study by Avery et al76 in 2014 looked at the with recurrent or refractory low-grade gliomas with promising
use of intravenous bevacizumab in 4 cases of pediatric OPGs who results.77
demonstrated progressive visual acuity or visual field loss despite
prior treatment with chemotherapy or proton-beam radiotherapy. Screening for Optic Pathway Tumors in NF1
All 4 subjects demonstrated a marked improvement in their One of the critical roles that ophthalmology plays in the
visual acuity, visual field, or both while receiving bevacizumab- management of children with NF1 is the regular monitoring

68 | www.apjo.org © 2019 Asia-Pacific Academy of Ophthalmology

Copyright © 2019 Asia-Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
Asia-Pacific Journal of Ophthalmology • Volume 8, Number 1, January/February 2019
and screening for OPGs. Given the high frequency of learning
and behavioral problems in NF1 children, this regular screening
should be in the context of a multidisciplinary team.23
Routine screening remains the commonest means to identify
OPGs.61 The neuro-ophthalmic examination is a key component
in the diagnosis and management of OPGs. In children with
NF1, examination guidelines have been developed by expert
consensus58 and are outlined in Figure 6. The Response Evaluation
in Neurofibromatosis and Schwannomatosis Visual Outcomes
Committee recommends that visual acuity should be the primary
outcome measure to assess for tumor progression, guide treatment
decisions, and evaluate treatment effect.61
Pattern visual evoked potentials are performed in some
centers at the same frequency as neuroimaging. These provide
additional objective evidence for visual pathway dysfunction
when performed in laboratories experienced with visual
electrophysiology in children. Multifocal visual evoked potentials
offer a method for assessing the topographic optic nerve function,
providing an objective measure of visual field function.78,79 Optical
coherence tomography of the optic nerve has also proved to be an
effective, noninvasive tool to assess for progressive retinal nerve
fiber layer thinning secondary to OPGs in NF1 patients; although
it is not considered standard surveillance, it has proved a potential
biomarker of vision in NF1 OPGs.59,80
The decision on when to treat children with OPGs remains
controversial and relies on input from a multidisciplinary team.
Treatment is reserved for progressive disease, which may
include either reduced vision or radiographic tumor growth, or a
combination of the 2.59,70
Central Nervous System and Other Systems
Other CNS Tumors
Gliomas can present throughout the CNS in individuals with
NF1.73 It is important to recognize that among patients with NF1
who are older than 10 years, the relative risk of a brain tumor is
100 times higher than those without NF1.81 Most brain tumors
in children with NF1 are low-grade gliomas [World Health
Organization (WHO) grade I–II], and the majority of those are
WHO grade I.9 These tumors do have malignant potential and can
infiltrate the brain.9
Brainstem gliomas associated with NF1 have been described
and, in contrast to the general population, they tend to have a
more indolent course and may not require treatment.82
Non-CNS Tumors
A range of other non-CNS tumors has also been reported
in patients with NF1 including pheochromocytomas, which may
initially present with hypertension.9 Gastrointestinal fibromas
have also been described.9
The lifetime breast cancer risk is 4 times higher in women
with NF1 who are younger than 50 years compared with the
general population.83 Women with NF1 also have an increased
risk for invasive breast cancer across all age groups.83
Learning Difficulties; Speech, Language, and Cognitive
Impairment
Learning difficulties and cognitive impairment remain
the commonest neurological complication of NF1 in children.
The mean full-scale intelligence quotient is in the low-to-
© 2019 Asia-Pacific Academy of Ophthalmology
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Neurofibromatosis Type 1
average range.23 The incidence of true cognitive delay in NF1
is, however, lower than expected.84 There are increased rates of
autism spectrum disorder, attention-deficit hyperactivity, and
sleep disturbances in these patients.85 Language difficulties,
particularly receptive language and language structure, have
been identified as issues in children with NF1.86 In view of
these findings, early neuropsychological screening assessment
to help evaluate and support these children as they enter school
should be considered.24 This also supports the need for ongoing
routine screening, which is best performed in dedicated NF
multidisciplinary clinics.
Vascular Complications
A number of cardiovascular abnormalities have also been
described in NF1 patients. Congenital heart disease, particularly
pulmonary stenosis, accounts for as many as 50% of these
abnormalities.87 Other NF1-related vascular abnormalities
include renal and cerebral artery stenosis, moyamoya, aneurysmal
lesions, and arteriovenous fistula malformations.36
Interestingly, both adult and pediatric patients with NF1
have a significantly increased risk of stroke when compared with
the general population.88 Although the risk is most notable for
hemorrhagic strokes, it is also increased for ischemic strokes
in children due to a number of underlying vascular lesions.88,89
Various associations have included moyamoya arteriopathy,90
cerebral aneurysms, and ectatic cerebral vessels.89
Prognosis
In children with NF1-associated OPG after chemotherapy,
approximately a third will regain some vision with treatment.91
Unlike vision, which will largely remain stable or may even
improve, NF1 reduces average life expectancy by 10 to 15 years,
and malignant tumors are the most common cause of death in
individuals with this syndrome.7 It is important to remember that
NF1 patients have a 5-fold risk for cancer and more than a 2000-
fold risk for neurogenic malignancies compared with the general
population.92
CONCLUSIONS
As NF1 remains a multisystem disease with life-threatening
complications, a multidisciplinary approach with close
collaboration among NF1 clinicians will facilitate a uniform
method for diagnosis and management of this condition.
Ophthalmologists have a crucial role in diagnosis and in
monitoring visual function. The recent characterization of the
choroidal hamartomas emphasizes this role.
Despite the recent and exciting new advances in NF1
research, including MEK and mTOR inhibitors, there still remain
many questions about the disease. The continuing challenge
for clinicians is the detection of progression of OPG as early as
possible so that effective treatment can be instigated to maximize
the preservation of vision.
ACKNOWLEDGMENT
The authors would like to thank Dr. Francesco Viola,
Università degli Studi di Milano, UO Oculistica, Fondazione
IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy,
who contributed optical coherence tomography images.
www.apjo.org | 69
Karaconji et al
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