Optic Pathway and

Hypothalamic Glioma
1

D R P R AV E E N
K T R I PAT H I

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 DEFINITION
2

 The term ‘‘optic pathway glioma’’ is reserved for

those tumors confined to the precortical visual
pathway, sometimes with the involvement of the
hypothalamus.
 Their location makes them a surgical challenge.
 Controversy surrounds the optimal management.

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 Epidemiology
3
INCIDENCE
 1% of all intracranial tumours, 3–5% of paediatric brain tumours
and 6% of all orbital tumours.
 Gliomas account for two-thirds of all tumours in the optic nerve.
 About 25% of OPGs are in the optic nerve [Optic nerve glioma
(ONG)] and 60% involve the chiasm (Optic chiasm glioma).
 Nearly one-third of patients with OPG have neurofibromatosis-1
(NF-1).
 The mean age at diagnosis was 8.8 years.
 The male:female ratio is nearly equal but pure optic nerve
tumours are commoner in girls.
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 OPTIC NERVE TUMORS
4
 Optic nerve is actually a
tract of central
nervous system,so
primary tumors of the
optic nerve are more
similar
histopathologically to
brain tumors than to
peripheral nerve tumors.

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 PATHOLOGY
5

Macroscopic Appearance
 ONG can be purely intraorbital or purely intracranial.
 Often starts in one compartment and spreads to the other
through the optic foramen causing a dumb-bell pattern .
 The chiasmal variety may diffusely infiltrate the
hypothalamus and the floor of the third ventricle- dubbed
as hypothalamic-chiasmatic glioma.
 The non-NF-1 OPG in the chiasma may become a large
mass and show areas of cystic change.

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 Gross Pathology
6

Path images

Coronal brain slice through the hypothalamus. A large soft tissue

mass is shown expanding the hypothalamus. Histology exhibited
juvenile pilocytic astrocytoma. (Images courtesy of Roy H. Rhodes, MD, PhD. Robert
Wood Johnson University Hospital. Department of Pathology.)

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 Histology: Low-grade Gliomas
7
■ Pilocytic astrocytomas
– WHO grade I circumscribed astrocytomas
– Biphasic pattern
▪ Rosenthal fibersand eosinophilic granular bodies
are characteristic
▪ Loose-textured astrocytes and microcysts
▪ Frequently not cystic in the optic pathway
▪ The cells are positive for glial fibrillary acidic
protein.
▪ A higher microvessel density (as assessed by
immunostaining for factor VIII) is thought to
indicate progression
▪ Adult patients may harbour anaplastic astrocytoma or
glioblastoma multiforme rarely Ganglioglioma 23 May 2016
 8 The tumour cells in optic nerve
glioma have elongated or hair-
like
appearance (pilocystic).Hence the
name pilocystic astrocytoma.

Rosenthal fibres in optic nerve glioma.

These are degenerative
eosinophilic substances found within the
cytoplasm of astrocytes.
There are characteristic but not
diagnostic of optic nerve glioma

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9

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 Symptoms at Presentation
10

 Visual disturbances (85%)

 Headache (23%)
 Failure to thrive (20%)
 – Diencephalic syndrome
 Nausea and vomiting (14%)
 Abnormal eye movement (14%)
 Symptoms of endocrine dysfunction (14%)

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 Clinical Signs at Presentation
11
■ Decreased visual acuity (33%)- early
■ Visual field deficit (33%)- bitemporal himeanopia – chiasmal
involvement.
■ Optic atrophy (61%)
■ Proptosis
■ Painless axial proptosis is commoner in NF-1 patients with OPG, due to the
frequent location of the tumour in the orbit.
■ Painful proptosis is seen only with large tumours and may be due to
compression of branches of the ophthalmic div.
■ Abnormal extraocular muscle exam (21%)
■ Signs of endocrine abnormalities (21%)
■ Ataxia (12%)
■ Papilledema (9%) 23 May 2016
 12

 Central scotomata
 altitudinal field defects

 and hemianopias have all been reported.

 At ophthalmoscopy,
 the optic disk may be normal in appearance;
 alternatively, edema

 or atrophy of the optic disk may be present.

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 13

Face photo of a 5-year-old girl who developed noticeable

proptosis OD and found to harbor an optic nerve glioma.

(a) The right fundus of a 5-year-old girl with a right optic nerve glioma reveals an optic nerve with
mild edema. Her visual acuity was moderately to severely reduced. (b) The left nerve was normal.

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 14

 In rare cases, the optic glioma can resolve

spontaneously
 Survival is typically reduced when hydrocephalus is
present.
 Foster Kennedy syndrome due to optic glioma presents
with unilateral optic atrophy first followed by
contralateral papilloedema but no anosmia

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 Diencephalic Syndrome
15
 The symptoms of hypothalamic dysfunction in OPG are commoner in
non-NF-1 patients.
 Emaciation despite normal caloric intake in an alert child is known as
the “diencephalic syndrome of infancy”.
 Attributed to the dysfunction of the leptin-ghrelin system.
 The somatic growth rate is normal in spite of the emaciation
 Normal pituitary hormonal function.
 Overactivity and pleasantness
 Escalating to euphoria & Initial growth acceleration
 Autonomic disturbance
 Skin pallor, erratic temperature control, diaphoresis, heat intolerance
 Spasmus nutans consists of disconjugate nystagmus, torticollis and
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titubation.
 MALIGNANT GLIOMA OF ADULTHOOD
16

 Since the advent of CT and MRI, the exceedingly rare

malignant gliomas of the optic nerve and chiasm are
more frequently being diagnosed before death.
 Almost invariably, patients present with rapidly
progressive unilateral or bilateral visual loss.
 Eye pain or headache may accompany the visual loss
and blindness occurs within weeks of onset.

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 OCHGs and Neurofibromatosis type 1
17
■ Associated with neurofibromatosis
type 1 (NF-1)
– 14-40% of NF-1 patients will
develop OCHGs

■ Vast majority of tumors arise prior

to six years of age

■ Traditionally
– Tumors associated with NF-1 are
considered to behave less
aggressively
– Higher incidence of spontaneous
regression

■ NF-1 not necessarily protective

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18

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 Imaging Characteristics
19
■ General characteristics
– Solid, cystic, or combination
– Classically described as globular/ exophytic
suprasellar mass
■ CT
– Low-density to isodense
– Intense enhancement with contrast
■ MRI
– T1: Low-intensity with marked gadolinium
enhancement- tubular or fusiform nerve in axial
– T2: Hyperintense mass
■ Found to grow postero-superiorly with invagination
of the third ventricle
■ With lateral progression, may involve the Circle of
Willis
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20

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 21
•-(A and B)(CECT) of a 4-
year-old boy without C
neurofibromatosis-1 A B
•Note the non-uniform
enhancement in the suprasellar
mass, which fills the
thirdventricle.
•The boy underwent right
pterional craniotomy and
partial excision of chiasmal
pilocytic astrocytoma followed
bybilateral shunt placement. (C
and D) The CECT scans after E
surgery—note the residual D
tumour. He was given
chemotherapy initially.
Radiation was given after he
completed 7 years of age.
•(E and F) The CECT scans
obtained 5 years after
initialpresentation—note the
tumour shrinkage. The vision
remains stable in the left eye
and the growth is near normal

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 22

MRI
(A) Non-contrast
coronal magnetic
resonance (MR).
(B) Contrast
sagittal MR of a
20-year-old
female with
nonneurofibroma
tosis-1
hypothalamic-
chiasmal glioma.

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 23

Fat-suppressed T1 axial
MRI, without (A) and
with (B) gadolinium
showing bulbous
enlargement of the right
optic nerve (arrow),
consistent with an optic
nerve glioma.
The right eye is
proptotic. Enhancement
extended into the optic
canal (not shown), but
there was no
enhancement or
enlargement of the
chiasm.

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24

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 Differenial diagnosis
25

 Pituitary adenoma
 Craniopharyngioma
 Germ cell tumour
 Hypothalamic hamartoma

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 Natural History
26

■ Natural history of OCHGs is erratic and highly variable

■ Debate in the literature

▪ Congenital, non-neoplastic, self-limiting,
hamartomatous lesions
▪ Progressive, prone to recurrence, associated with significant
morbidity and mortality

■ Ambiguity and inconsistency in the literature

– Failure to classify tumors with a consistent/ reproducible
system

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 Problems in the Literature: Sources
27
■ The existing literature is derived from a wide range of
sources
– NF-1 clinics predominately see indolent tumors
– Neuro-oncologists and radiation oncologists see mostly
those children with progressive disease
– Neuro-ophthalmologists primarily see intra-orbital optic
nerve tumors
– Neurosurgeons
▪ Typically, patients present to neurosurgical service following
the first diagnostic CT or MRI
▪ Broad spectrum of disease prior to the evolution of the natural
course

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 Problems in the Literature: The Importance of
Anatomic Location
28
■ Tumors grouped together regardless of anatomic location
– Tumors of the optic apparatus
– Optic pathway gliomas

■ Survival in relation to involvement of the chiasm

– Gliomas confined to the optic nerve are amenable to
complete resection with limited morbidity and mortality
– Low-grade gliomas confined to the optic nerve
▪ 85% long-term survival
– Low-grade gliomas involving the optic chiasm
▪ 44% long-term survival
Rush et al
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 Problems in the Literature: The
Importance of Anatomic Location
29

Survival at 5 and 10 Years in Patients with Low-Grade Optic Pathway

Gliomas Initially Treated With Radical Resection

Survival

Tumor Location 5 years 10 years

Type I (Retrobulbar-prechiasmatic 100% 88.8%
lesions)
Type II (Optic tract lesions) 75% 41.6%
Type IIIa (Chiasmatic lesions) 87.5% 54.1%
Type IIIb (Chiasmatic-hypothalamic 22.2% 0%
lesions)

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The Dodge Classification Systems for Optic
Pathway30
Gliomas

The Dodge Classification

The Modified Dodge
System (DC), 1958
Classification (MDC)
System, 2008

■ The DC breaks down tumors into pre-chiasmatic, chiasmatic, and

post-chiasmatic

■ The MDC provides a more detailed anatomical description based

on the images obtained by modern-day MRI.
– Not currently in widespread usage
Taylor T, et al.,British Journal of
Radiology (2008) 81, 761-766.
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 MANAGEMENT
31

 The variables affecting management of OPG

 age

 Presence or absence of NF-1,

 Location in optic pathway,

 size and symptoms (visual acuity, proptosis, raised pressure).

 The available methods of management are observation,

surgery, chemotherapy and radiotherapy.

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 Observation
32

 Since the growth rate of most OPGs is low, mere watchful

expectancy is an acceptable choice of initial management.
 The wait-and-watch approach applies to
 Incidentally detected asymptomatic tumours,
 Small tumours,
 Patients who have well-preserved vision with little proptosis and
 Those with NF-1.
 The surgeon has to instruct the family about the signs of
progression and maintain a meticulous clinical,
neuroophthalmic and imaging follow-up.

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 Spontaneous Regression
33

Piccirilli et al., Childs Nerv Syst 2006;22:1332.

Parrazzini et al., Am J Neurorad 1995;16:711

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 Surgery
34
 In contrast to the cerebellar juvenile pilocytic astrocytoma, surgery
plays only a limited role in OPG
 Radical surgery has not been proved to increase the length or
quality of survival.
 Indications for surgery in optic pathway glioma
 Biopsy for tumours with atypical imaging findings
 Mass reduction by cyst drainage and tumour decompression for relieving
raised pressure symptoms or neighbourhood compression syndromes
 Disfiguring or painful proptosis
 Total excision for orbital optic nerve tumours with total visual loss, so as to
prevent intracranial extension and to provide cure without adjuvant therapies
 Excision of exophytic masses (mainly chiasmal)
 Ventricular shunt placement for hydrocephalus
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 intraorbital tumours
35

 Biopsy of intraorbital tumours can be performed by Lateral

orbitotomy or by fine needle aspiration.
 Resection of ONG requires transcranial superior
orbitotomy .
 Transcranial orbitotomy can be done through an eyebrow incision but the
traditional method is to raise a flap from behind the hairline.
 Removing the superior orbital rim allows a lower trajectory and
 reduces frontal lobe retraction.
 The orbital rim may be taken with the frontal bone flap or as a separate
osteotomy piece.
 Extradural approach is reserved for lesions that do not
extend to the optic canal.
 Intradural approach is done for gliomas that reach into
the canalicular or the intracranial portions of the optic
nerve.
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 Approaches for chiasmal hypothalamic glioma
36

• Subfrontal
– Lateral (pterional)
– Anterior
• Transventricular
– Interhemispheric transcallosal
– Anterior interhemispheric, trans-lamina terminalis
– Endoscopic transventricular

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37

Enucleation
specimen with
optic nerve glioma
from a
patient with NF1.

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 Chemotherapy
38

■ Attempt to delay or eliminate need for radiation

■ Trial results difficult to compare due to variability in:

– Indication to begin treatment
– Classification of response to treatment
– Evaluation of time to response

■ Multiple small studies of single agents in recurrent OCHGs

– Show limited rates of tumor regression
– Higher rates of disease stabilization
– Etoposide (VP16) as example
–27% regression rate
–54% disease stabilization

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 Chemotherapy
39

 The risks of irradiating young children have caused a swing

towards the “chemotherapy-first” approach.
 Carboplatin based regimes are the most studied.
 Packer regimen
 Concurrent carboplatin and vincristine in a 10-week induction phase,
followed by 48 weeks of maintenance carboplatin/vincristine
 Resulted in progression- free survival of 75% at 2 years and 50% at 5
years.
 Imaging evidence of tumour shrinkage was seen in 63% of patients .
 Children 5 years of age or younger had a more favourable rate of
response.
 Recently, single agent temozolomide therapy has also been
found to be successful.
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 Chemotherapy
40
■ Front-Line: Vincristine and Carboplatin
– Highest progression free survival
– Well-tolerated

■ Problems with chemotherapeutic regimens

– Carboplatin allergy
– Concerns for leukemia with multiple agents
▪ Lomustine (CCNU), Procarbazine,
Cyclophosphamide, or Etoposide
– High frequency hearing loss with CPPD
Lafay-Cousin et al., Cancer 2008;112:892
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 Recent Chemotherapeutic Protocols
41

■ Temozolomide (Temodar)
– Gururangan ’07: N=30, 54% disease stabilization,
5yr PFS = 30%
– Nicholson ’07: N=21, 57% disease stabilization

■ Vinblastine: N=51, 24% partial response or complete

remission, 74% disease stabilization (34/46)
– Some with initial minor progression, then response

Gururangan et al., Neuro-Oncol 22000077;99:116611.

Nicholson et al., Cancer 2007;110:1542.
Lafay-Cousin et al., Cancer 2005;103:2636
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 Future Potential Regimens
■ Target angiogenesis 42

■ Vascular prolif in PA, increased VEGF

■ Avastin/CPT11

■ Adult Phase II in Recurrent HGG: 63% resp rate

■ Open trial for HGG in PBTC
■ Packer et al.: 10 Recurrent LGG. 1CR, 5 PR
■ Thalidomide, Celebrex, Fenofibrate, Oral VP16

■ Target molecular abnormalities

■ Activity in H-ras mutants not K-ras defective
pathways (more common in NF1)
■ mTOR inhibitor - RAD001

■ Multi-institutional trial for Rec-LGG in non-NF1

pts
■ NF consortium considering for Rec-OPG

■ CXCR4 G-protein coupled receptor pathway

inhibitors – AMD3100, Rolipram (increases cAMP) 23 May 2016
43

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 Radiotherapy
44
■ Significant toxicity
– Vision worse in 7-14%
– Endocrine dysfunction: Panhypopituitarism, GH deficiency
– Cerebrovascular Disease
▪ Moya Moya in 3/5 (60%) NF+, 2/23 (9%) NF- (Kestle ’93 )
▪ Vascular disease in 11/37 (30%) NF+, 2/32 (6%) NF- (Grill ’99 )
■ Secondary tumors
■ Neurocognitive Deficits
▪ Cappelli ’98: 18/51 (35%), 12 with mental retardation, all had
received radiation
▪ Lacaze ’03: Mean IQ 19 points lower in the patients receiving
radiation
▪ Sutton ’95: N=33
– 43% in special education (all received RT, mean age 5.7 yrs, only
3 > 6yo)
– 57% in regular school (4 no RT) (12 RT, mean age 11yrs, 4 were
5-8yo)
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 Radiotherapy
45
 The recognition of endocrine and cognitive side effects of
radiotherapy in young children has made chemotherapy the choice
in this age.
 69% children below 10 years developed hypothalamic- pituitary
endocrine deficiency after radiation
 Initial modality in older children >10 year and adults.
 The standard prescription is 45–50 Gy in 2 Gy daily fractions to the
tumour and the surrounding 0.5–1 cm margin.
 Progression-free survival probabilities after radiotherapy were 82% at 5 years and
77% at 10 years after radiotherapy for OPG
 The visual acuity improved in 36%, remained stable in 52% and deteriorated in
12% after radiotherapy in a German series of 25 patients.
 The risk of developing a second (usually malignant and lethal) tumour after
radiotherapy is real and is more so for NF-1 patients.
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 Radiotherapy
46

 Fractionated stereotactic radiotherapy has been

recently reported to provide 90% survival at 5
years while reducing the endocrine side effects
and the possibility of a second tumour.
 There are case reports of gamma knife
radiosurgery for OPG.

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47

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48

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Classification of Optic Glioma by Factors
Influencing Prognosis
49

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 CONCLUSION
50

 Optic pathway gliomas are slow growing

tumours but may behave erratically.
 The treatment recommendation is to observe the
course and intervene only when one is forced to.
 Chemotherapy for younger children and
radiotherapy for older patients is effective in
achieving long-term tumour control.
 Surgery does little to alterthe natural course of
the tumour.
23 May 2016