Handbook of Pediatric Neurosurgery

9 Spinal Cord Tracts and Development
Micol Babini, Francesco Sala
9.1 Introduction
The spinal cord extends from the foramen mag-
num to the space between the first and second
lumbar vertebrae. It is 40 to 50 cm long and 1 to
1.5 cm in diameter.
The spinal cord is divided into four di erent
regions:
● Cervical.
● Thoracic.
● Lumbar.
● Sacral.
Two enlargements of the spinal cord can be identi-
fied:
● The cervical enlargement (from C3 to T1).
● The lumbar enlargement (from L1 to S2).
The cord is segmentally organized in 31 segments,
defined by 31 pairs of nerves exiting the cord:
● Eight cervical.
● Twelve thoracic.
● Five lumbar.
● Five sacral.
● One coccygeal.
A transverse section of the spinal cord shows
white matter in the periphery, gray matter inside,
and a central canal filled with cerebrospinal fluid.
The gray matter mainly contains the cell bodies
of neurons and glia, and is divided into four main
columns:
● Dorsal horn comprises sensory nuclei that
receive and process incoming somatosensory
information. From there, ascending projections
transmit the sensory information to brain.
● Interm ediate colum n and lateral horn
comprise autonomic neurons innervating
visceral and pelvic organs.
● Ventral horn comprises motor neurons that
innervate skeletal muscle.
Surrounding the gray matter is white matter
containing nerve fibers that conduct information
up (ascending) or down (descending) the cord
(Fig. 9.1).
The white matter is divided into:
● The dorsal column.
● The lateral column.
● The ventral column.
Fig. 9.1 Major ascending and descending tracts in a cross section of the spinal cord. (Reproduced with permission from
Luka T. Ahčin, )
58

The spinal cord white matter contains ascending
and descending tracts.
9.2 Ascending Tracts
The ascending tracts transmit sensory information
from the sensory receptors to higher levels of the
central nervous system (CNS).
The three major sensory tracts involve chains of
neurons:
● First-order neuron: Delivers sensations to the
CNS. The cell body is in the dorsal or cranial root
ganglion.
● Second-order neuron: An interneuron with the
cell body in the spinal cord or brain.
● Third-order neuron: Transmits information from
the thalamus to the cerebral cortex.
Neurons in the sensory tracts are arranged accord-
ing to three anatomical principles:
● Sensory modality: Fine touch sensations are
carried in one sensory tract.
● Somatotopic: Ascending tracts are arranged
according to the site of origin.
● Medial-lateral rule:
– Sensory neurons that enter a low level of the
spinal cord are more medial within the spinal
cord.
– Sensory neurons that enter at a higher level of
the spinal cord are more lateral within the
spinal cord.
The dorsal colum n (m edial lem niscal pathway)
is occupied by the gracile and cuneate fasciculi
that carry information related to tactile, two-point
discrimination of simultaneously applied pressure,
vibration, position, and movement sense, and con-
scious proprioception. Within the medial lemnis-
cal pathway, the a erents carrying discriminative
touch information are kept separate from those
carrying proprioceptive information up to the level
of the cerebral cortex.
In the lateral colum n, the following are located:
● The neospinothalamic tract that carries pain,
temperature, and crude touch information from
somatic and visceral structures.
● The spinocerebellar tracts that carry
unconscious proprioception information from
muscles and joints of the lower extremity to the
cerebellum.
In the ventral colum n, there are four prominent
tracts:
● The paleospinothalamic tract (or anterior
spinothalamic tract) carry pain, temperature,
and information associated with touch.
● The spino-olivary tract carries information from
Golgi tendon organs to the cerebellum.
● The spinoreticular tract.
● The spinotectal tract.
9.2.1 Posterior Column Tracts
It consists of:
● Fascicu lus gracilis: Transmits information
coming from areas inferior to T6.
● Fascicu lus cuneatus: Transmits information
coming from areas superior to T6.
First-order Neuron
● It arises from the sensory receptors of the body.
● Fibers enter the dorsal column and ascend to the
medulla oblongata.
● It enters medulla oblongata.
● It ends in the gracile and cuneate nucleus.
Second-order Neuron
● It starts at the gracile and cuneate nucleus of the
medulla oblongata.
● These fibers cross to the opposite side of the
medulla oblongata.
● It ascends through the brainstem as flattened
bundle medial lemniscus.
● It ends in the ventral posterolateral nucleus of
the thalamus.
Third-order Neuron
● It arises from the thalamus.
● It passes through the internal capsule (medial
aspect of the posterior limb of internal capsule).
● It reaches the postcentral gyrus and ends there.
9.2.2 Spinothalamic Tracts
● The neospinothalam ic tract (or lateral
spinothalam ic tract) carries and processes
sharp, pricking pain and dropping temperature
(cool/cold) information from the body. The
neospinothalamic pathway is also characterized
Spinal Cord Tracts and Development
59

by somatotopic representation, which allows for
accurate localization of the painful stimulus.
● The anterior spinothalam ic tract.
First-order Neuron
● It arise from sensory receptors of the body.
● The fibers enter the white matter and end at the
substantia gelatinosa.
Second-order Neuron
● The fibers of first-order neuron synapse with the
second-order neuron at the substantia
gelatinosa.
● These fibers then cross to the opposite side. Pain
and temperature fibers enter the lateral
spinothalamic tract. Light touch and pressure
fibers enter the anterior spinothalamic tract.
● These tracts ascend to brainstem.
● It reaches the ventral posterolateral nucleus of
the thalamus.
● It ends there.
Third-order Neuron
● The third-order neurons arise from the thalamus
and pass through the internal capsule.
● Thalamocortical fibers pass through the medial
part of the posterior limb of the internal capsule.
● They enter the postcentral gyrus.
9.2.3 Spinocerebellar Tracts
● The posterior spinocerebellar tract.
● The anterior spinocerebellar tract.
9.3 Descending Tracts
The descending tracts originate from di erent
cortical areas and from brainstem nuclei. They
carry information associated with maintenance of
motor activities such as posture, balance, muscle
tone, and visceral and somatic reflex activity.
Descending pathways are organized into two
major groups:
● Lateral pathways control both proximal and
distal muscles, and are responsible for most
voluntary movements of arms and legs. They
include:
– The lateral corticospinal tract.
– The rubrospinal tract.
● Medial pathways control axial muscles and are
responsible for posture, balance, and coarse
control of axial and proximal muscles. They
include:
– The vestibulospinal tracts (both lateral and
medial).
– The reticulospinal tracts (both pontine and
medullary).
– The tectospinal tract.
– The anterior corticospinal tract.
9.3.1 Corticospinal Tracts
The corticospinal tract originates in the motor cor-
tex: the axons collect in the internal capsule, and
then course through the crus cerebri (cerebral
peduncle) in the midbrain.1
At the level of the caudal medulla, the cortico-
spinal tract splits into two tracts:
● Approximately 90% of the axons cross over to the
contralateral side at the pyramidal decussation,
forming the lateral corticospinal tract. These
axons continue to course through the lateral
funiculus of the spinal cord, before synapsing
either directly onto alpha motor neurons or onto
interneurons in the ventral horn.
● The remaining 10% of the axons do not cross the
anterior corticospinal tract, as they continue
down the spinal cord in the anterior funiculus.
When they reach the spinal segment at which
they terminate, they cross over to the
contralateral side through the anterior white
commissure and innervate alpha motor neurons
or interneurons in the anterior horn. Thus, both
are crossed pathways.
The corticospinal tract is the primary pathway that
carries the motor commands that underlie volun-
tary movement.
The lateral corticospinal tract is responsible for
the control of the distal musculature and the ante-
rior corticospinal tract is responsible for the con-
trol of the proximal musculature. A particularly
important function of the lateral corticospinal
tract is the fine control of the digits of the hand. In
addition to the fine control of distal muscles, the
corticospinal tract also plays a role in the volun-
tary control of axial muscles.
9.3.2 Rubrospinal Tract
The rubrospinal tract originates in the red nucleus
of the midbrain: the axons immediately cross to
the contralateral side of the brain, and they course
through the brainstem and the lateral funiculus of
the spinal cord.
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60

The rubrospinal tract is an alternative by which
voluntary motor commands can be sent to the spi-
nal cord. Although it is a major pathway in many
animals, it is relatively minor in humans. Activa-
tion of this tract causes excitation of flexor
muscles and inhibition of extensor muscles.
9.3.3 Vestibulospinal Tracts
The two vestibulospinal tracts originate in two of
the four vestibular nuclei.
● The lateral vestibulospinal tract originates in the
lateral vestibular nucleus. It courses through the
brainstem and through the anterior funiculus of
the spinal cord on the ipsilateral side, before
exiting ipsilaterally at all levels of the spinal cord.
● The m edial vestibulospinal tract originates in
the medial vestibular nucleus, splits immediately,
and courses bilaterally through the brainstem via
the medial longitudinal fasciculus and through
the anterior funiculus of the spinal cord, before
exiting at or above the T6 vertebra.
The vestibulospinal tracts mediate postural adjust-
ments and head movements. They also help the
body to maintain balance. The lateral vestibulospi-
nal tract excites antigravity muscles in order to
exert control over postural changes necessary to
compensate for tilts and movements of the body.
The medial vestibulospinal tract innervates neck
muscles in order to stabilize head position. It is
also important for the coordination of head and
eye movements.
9.3.4 Reticulospinal Tracts
The two reticulospinal tracts originate in the
brainstem reticular formation:
● The pontine reticulospinal tract originates in
the pontine reticular formation, courses
ipsilaterally through the medial longitudinal
fasciculus and through the anterior funiculus of
the spinal cord, and exits ipsilaterally at all
spinal levels.
● The m edullary reticulospinal tract originates
in the medullary reticular formation, courses
mainly ipsilaterally (although some fibers cross
the midline) through the anterior funiculus of
the spinal cord, and exits at all spinal levels.
The reticulospinal tracts are a m ajor alternative
to the corticospinal tract, by w hich cortical neu-
rons can control m otor function by their inputs
onto reticular neurons. These tracts regulate the
sensitivity of flexor responses to ensure that only
noxious stim uli elicit these responses. The reticu-
lospinal tracts are involved in m any aspects of
m otor control, including the integration of sen-
sory input to guide m otor output.
9.3.5 Tectospinal Tract
The tectospinal tract originates in the deep layers
of the superior colliculus and crosses the midline
im mediately. It then courses through the pons
and medulla, just anterior to the medial longitu-
dinal fasciculus. It courses through the anterior
funiculus of the spinal cord, where the majority
of the fibers terminate in the upper cervical
levels.
9.4 Development
The nervous system develops from an area of
embryonic ectoderm, called the neural plate which
appears during the third week of gestational age.
This area gives rise to
● The neural tube: that gives rise to the CNS.
● The neural crest: that gives rise to the peripheral
nervous system.
The form ation of the neural tube begins during
the early part of week 4 (22–23 days) in the re-
gion of the fourth to sixth pairs of som ites. The
spinal cord is form ed from the neural tube caudal
to som ites 4.
Once neurons have been generated, they move
from their place of origin to their final place of des-
tination in two di erent forms of migration. The
migration peaks between the third and the fifth
month of gestation and stops around 30-week
postmenstrual age. The grow th cones of the devel-
oping axon pathways navigate to their intermedi-
ate and final targets by responding to a variety of
substrate-bound or di usible molecular targets at
near or long distance.
The development of the cerebral cortex can be
divided into three periods:
● The embryonic.
● The fetal.
● The perinatal.
The corticospinal tract is the last of the major
descending fiber systems to enter the spinal cord.2
Layer V neurons are among the first cortical
neurons that reach their place in the cortical
plate.3,4 The first corticofugal projections originate
Spinal Cord Tracts and Development
61

in the embryonic period. They reach the pyramidal
decussation at the end of the embryonic period.
The pyramidal decussation is complete by 17
weeks’ postconceptional age (PCA).
Corticospinal axons reach the lower cervical spi-
nal cord by 24 weeks PCA.5,6 In a few weeks, they
progressively innervate the gray matter, so before
birth there is extensive innervation of spinal neu-
rons, including motoneurons. By 40 weeks’ PCA,
corticospinal axons have begun to express neurofi-
laments and to undergo myelination.6 Myelination
of the pyramidal tract starts at the end of the sec-
ond or the beginning of the third trimester, and it
is not completed until the age of 2 to 3 years7; the
cranial part is myelinated much earlier that its spi-
nal part. Motor latencies decrease with age; in
particular, a rapid decrease of the central motor
conduction time happens during the first decade
of life: and this corresponds to the maturation
processes as myelination and axon grow th.
In human, di erently from subhuman primates,
there is a prenatal establishment of functional cor-
ticospinal innervation.
During the final trimester of pregnancy, func-
tional synaptic corticospinal projections to moto-
neurons and to interneurons are established.
At birth, the corticospinal tract is the least mature
of the various tracts and undergoes dramatic
changes during the first postnatal months. At birth,
there is a significant bilateral innervation of spinal
motoneuronal pool from each motor cortex. How-
ever, in the first 15 to 18 months after birth, there is
greater withdrawal of ipsilateral corticomotoneuro-
nal projections than contralateral.6,8,9
References
[1] George TM, Adamson DC. Normal and abnormal development
of the nervous system. In: Albright AL, Pollack IF, Adelson PD,
eds. Principles and Practice of Pediatric Neurosurgery. 2nd ed.
New York, NY: Thieme Medical Publishers; 2007:12–30
[2] Amiel-Tison C, Maillard F, Lebrun F, Bréart G, Papiernik E.
Neurological and physical maturation in normal growth
singletons from 37 to 41 weeks’ gestation. Early Hum Dev.
1999; 54(2):145–156
[3] Martin JH, Friel KM, Salimi I, Chakrabarty S. Corticospinal
development. In: Squire LR, ed. Encyclopedia of Neuroscience.
Oxford: Academic Press; 2009:203–214
[4] ten Donkelaar HJ, Lammens M, Wesseling P, Hori A, Keyser A,
Rotteveel J. Development and malformations of the human
pyramidal tract. J Neurol. 2004; 251(12):1429–1442
[5] Eyre JA. Corticospinal tract development and its plasticity
after perinatal injury. Neurosci Biobehav Rev. 2007; 31(8):
1136–1149
[6] Eyre JA. Development and plasticity of the corticospinal
system in man. Neural Plast. 2003; 10(1–2):93–106
[7] Tanaka S, Mito T, Takashima S. Progress of myelination in the
human fetal spinal nerve roots, spinal cord and brainstem
with myelin basic protein immunohistochemistry. Early Hum
Dev. 1995; 41(1):49–59
[8] Eyre JA, Taylor JP, Villagra F, Smith M, Miller S. Evidence of
activity-dependent withdrawal of corticospinal projections
during human development. Neurology. 2001; 57(9):1543–
1554
[9] Müller K, Kass-Iliyya F, Reitz M. Ontogeny of ipsilateral
corticospinal projections: a developmental study with
transcranial magnetic stimulation. Ann Neurol. 1997; 42(5):
705–711
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62

10 Migration Disorders
Gary Hsich
10.1 Introduction
The migrational disorders refers to a heterogenous
group of disorders that share a similar pathogene-
sis. The neurons and glial cells are generated
around the ventricles, the proliferative neuroepi-
thelium. The first was of migrations results in
the formation of the provisional cortex, the pre-
plate. This is replaced by the permanent cortical
plate. Migrating neurons are guided by adhesion
molecules that are present on their membranes
and are also neuronal and glial precursors.
These malformations are organized according to
the underlying mechanism:
1. Abnormal cell proliferation
2. Abnormal neuronal migration
3. Abnormal cortical organization
10.2 Malformations
The following malformations are organized
according to the timing of the insult during fetal
central nervous system development, leading to
the respective cortical migration disorders.
10.2.1 Anencephaly
Anencephaly is a condition in which major por-
tions of the brain, skull, and scalp are absent. It
occurs when the rostral (anterior) neuropore fails
to close, which usually occurs between days 23
and 26 of gestation. About 1 in 1,000 pregnancies
is a ected by anencephaly, although most of the
pregnancies result in miscarriage.1 For fetuses that
reach live birth, the rate is about 1 in 5,000 to
10,000; however, these infants do not survive lon-
ger than a few days. There is no treatment or sur-
gical intervention indicated, except for comfort
care and palliative measures. Management, there-
fore, has focused on preventive measures—folic
acid supplementation has been shown to reduce
the frequency of anencephaly by about 38%.2
10.2.2 Holoprosencephaly
Holoprosencephaly (Fig. 10.1) is caused by fail-
ure of the prosencephalon to divide fully into two
hemispheres during the third to fourth week of
gestation. Definitive diagnosis is made by brain
magnetic resonance imaging (MRI), and can show
a spectrum of severity (in decreasing order of
severity)3:
● Alobar: Single monoventricle, no separation of
cerebral hemispheres.
● Sem ilobar: Left and right frontal and parietal
lobes are fused, and the interhemispheric fissure
is present only posteriorly.
● Lobar: Most of the right and left cerebral
hemispheres and lateral ventricles are
separated; but the frontal lobes are fused,
especially ventrally.
● Middle interhem ispheric variant: Posterior
frontal and parietal lobes fail to separate, with
varying lack of cleavage of the basal ganglia and
Fig. 10.1 Brain magnetic resonance imaging (MRI) of a 4-year-old child with holoprosencephaly. (a) Coronal,
T1-weighted image. (b) Midline sagittal, T1-weighted image. (c) Axial, T2-weighted image. Note the fused thalami
and single lateral ventricle.
63

thalami; absence of the body of the corpus
callosum, but presence of the genu (anterior)
and splenium (posterior) of the corpus callosum.
Likewise, clinically, there is a range of develop-
mental disabilities; and a ected children may have
various craniofacial anomalies, such as cyclopia
(one eye), proboscis (a noselike structure which
may be located on the forehead), or cleft palate, or
even normal facies. Seizures and pituitary dysfunc-
tion are common. Long-term prognosis depends
on the severity of the malformation, with severely
a ected individuals surviving only a few years or
less.
Approximately 25 to 50% of individuals have
various causative chromosomal abnormalities;
environmental causes, such as maternal diabetes,
are also possible.4
Management is symptomatic, and may include
shunting for hydrocephalus, anticonvulsant medi-
cation for seizures, hormone replacement for
pituitary deficiencies, and interventions for feed-
ing di culties (gastrostomy tube, cleft palate
repair).
10.2.3 Schizencephaly
Schizencephaly ( Fig. 10.2) is characterized by a
cleft in the cerebral hemisphere, and this cleft is
lined by gray matter. It is distinguished from por-
encephaly by the fact that porencephalic cysts are
lined by white matter, while the disrupted cerebral
cortex in schizencephaly is lined by gray matter.
Schizencephaly can be classified as type I, in which
the cleft is closed, or type II, in which the cleft is
open and extends from the ventricle to the pia
peripherally. Hydrocephalus is associated with
about 50% of type II lesions.5
Schizencephaly is thought to be caused by a dis-
ruption in gray matter migration during the first
trimester. The disruptive insult may be infarction,
infection, a toxin, or genetic. Individuals with clefts
in both hemispheres are typically quite impaired
developmentally, while those with unilateral clefts
may be of normal intelligence with unilateral
weakness. Because of the presence of the hetero-
topic gray matter which lines the clefts, seizures
are quite common.
10.2.4 Hydranencephaly
Hydranencephaly (“water brain”) refers to a condi-
tion in which the cerebral hemispheres are
replaced by cerebrospinal fluid (Fig. 10.3). This
malformation is thought to occur due to an insult
(such as vascular or infection) during the late first
or early second trimester, possibly in an anterior
circulation distribution. The only remaining parts
of the brain generally are the brainstem and the
cerebellum. Because the brainstem is still intact,
infants can appear and act normally for the first
few months of life. They may have normal infant
reflexes and behavior, such as sucking, swallowing,
and crying. However, after a few weeks or months,
these infants become irritable and spastic, and
may develop hydrocephalus, seizures, and/or vis-
ual impairment. They do not achieve any signifi-
cant developmental milestones, such as sitting,
Fig. 10.2 Schizencephaly: brain MRI of
newborn infant with schizencephaly,
showing a gray matter–lined cleft in
the right cerebral hemisphere. This
cleft communicates with the right
lateral ventricle. (a) Axial, T2-weighted
image. (b) Coronal, T1-weighted
image.
Neurology
64

rolling, or speech production. Many children with
this disorder die within the first few years of life,
although some can live for several years or more
with attentive care.
Di erential diagnoses include severe hydroce-
phalus, alobar holoprosencephaly, and bilateral
schizencephaly.
Treatment is symptomatic, and may include a
palliative shunt for hydrocephalus. Gabapentin
may be helpful for irritability, and baclofen is often
used for spasticity.
10.2.5 Lissencephaly and
Pachygyria
Lissencephaly (“smooth brain”) and pachygyria
(“thick brain”) are often considered variations along
the same spectrum. The timing of the defect is
thought to occur during the third to fourth month of
gestation.5 This cortical malformation is character-
ized by a lack of the normally folded gyri, such that
the cerebral cortex is smooth with no folds (lissence-
phaly) or that the few existing folds are thickened
and broad (Fig. 10.4). A ected children have signif-
icant developmental impairments, do not learn to
walk or speak, and almost always have seizures.
Lissencephaly can be classified into two di er-
ent types.5 In type I (“classic”) lissencephaly, the
cortex is smooth and underdeveloped, similar in
appearance to that of a 12-week-old fetus. In type
II lissencephaly, the meninges are thickened and
adherent to the cortical surface. The resulting
radiographic appearance has been described as
“cobblestone lissencephaly,” in which the cortex is
composed of clusters and circular arrays of neu-
rons. Type II lissencephaly is associated with a few
specific syndromes, including Walker–Warburg,
Fukuyama, and muscle-eye-brain disease.
A few notable syndromes and genes are associ-
ated with lissencephaly. Miller–Dieker syndrome is
caused by microdeletions of chromosome 17p13.3,
which includes the LIS1 gene and additional telo-
meric genes.6 The LIS1 gene is also responsible for
up to 50% of isolated lissencephaly sequence (ILS)
cases, in which there is a smaller submicroscopic
deletion, duplication, or mutation of LIS1. Neuropa-
thological findings in LIS1 gene mutations include
not only lissencephaly but also subcortical band
Fig. 10.3 Hydranencephaly: computed tomography
(CT) scan of a newborn infant with hydranencephaly.
The cerebral cortex has been almost entirely replaced
with cerebrospinal fluid. The thalami, brainstem, and
cerebellum are still present.
Fig. 10.4 Lissencephaly: brain MRI of 6-month-old child with lissencephaly due to LIS1 gene mutation. (a) Midline
sagittal, T1-weighted image. (b) Axial, T2-weighted image. (c) Coronal, T2-weighted image.
Migration Disorders
65

heterotopia (SBH). SBH refers to a band of hetero-
topic gray matter separated from overlying cortex
by a thin zone of normal white matter. Subcortical
bands restricted to the posterior lobes are more typ-
ically associated with LIS1 mutations.
The DCX gene is responsible for about 10% of ILS
cases.7 DCX is inherited on the X chromosome.
Males with DCX mutations have classic type I lis-
sencephaly and severe global developmental
impairment. Females with DCX mutations, how-
ever, are a ected less severely, and tend to have an
SBH pattern of neuropathology, rather than classic
type I lissencephaly. Subcortical bands restricted
to the frontal lobes are more typically associated
with DCX mutations.
10.2.6 Corpus Callosum
Abnormalities
Corpus callosum abnormalities can range from par-
tial to complete absence, or manifest as various
states of dysgenesis or hypoplasia. Disruption of cal-
losal formation can occur anytime between the 5th
and 16th week of gestation.8 These abnormalities
are best diagnosed by brain MRI, although head
ultrasound or computed tomography (CT) of the
head can also show the commonly associated paral-
lel lateral ventricles. Callosal abnormalities may
occur in isolation or in association with other CNS
malformations, such as holoprosencephaly (dis-
cussed earlier), schizencephaly, or lissencephaly.9
Some syndromes, such as Aicardi’s syndrome, are
defined by the presence of callosal abnormalities.
Generally, most patients with callosal abnormalities
have varying degrees of learning disabilities or
developmental delays, including hypotonia, seizures,
or autism. Rarely, an individual may be develop-
mentally normal. No surgical intervention is indi-
cated for the abnormality of the corpus callosum
itself, although associated abnormalities, such as
hydrocephalus, may need to be shunted.
10.2.7 Polymicrogyria
In polymicrogyria (“many small gyria”), the clinical
severity is correlated with the extent and distribu-
tion of the malformation.10 Mild, focal polymicrogy-
ria may have minimal neurologic manifestations,
whereas widespread, bilateral polymicrogyria invar-
iably causes severe developmental impairment and
refractory seizures.
The timing of the defect is thought to occur in
the second trimester or later.5 An insult during the
stage of neuronal migration causes disruption of
formation of the six cortical layers, resulting in
overfolded and aberrant gyri (Fig. 10.5).
Polymicrogyria can be caused by either genetic
or environmental causes. Genetic causes include
Zellweger’s/peroxisomal disorders or GPR56 gene
mutations. GPR56 mutations are inherited in an
autosomal recessive manner, and tend to cause a
bilateral frontoparietal polymicrogyria.
Management is symptomatic. However, neuro-
surgery may be indicated if refractory seizures
originate from a focal region of polymicrogyria.
10.2.8 Heterotopias
Heterotopias are foci of gray matter that are not
located in their proper locations. Neuronal migra-
tion typically happens between 6 and 24 weeks of
gestation.11 In normal brain development, neural
precursor cells originate in the subventricular
zone, and then migrate peripherally toward the
cortical surface to form the six cortical layers.
However, when this process is disrupted, these
neuronal precursors fail to migrate, and subse-
quently form aberrant clumps in the periventricu-
lar area. This heterotopic gray matter is then often
an etiologic foci for seizures. Individuals may have
normal intelligence or significant developmental
disabilities, depending on the number and location
of the heterotopic gray matter.
Many cases of periventricular heterotopia are
caused by mutations in FLNA, an X-linked gene.12
Fig. 10.5 Polymicrogyria: coronal, T1-weighted brain
MRI of a 13-month-old boy with polymicrogyria.
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66

Mutations are usually lethal in males, so most
known a ected individuals are female.
Neurosurgical intervention may be indicated if
refractory seizures are isolated to certain hetero-
topic foci.
References
[1] Genetics Home Reference. Available at:
gov/condition/anencephaly. Published November 4, 2013.
Accessed November 11, 2013
[2] De Wals P, Tairou F, Van Allen MI, et al. Reduction in neural-
tube defects after folic acid fortification in Canada. N Engl J
Med. 2007; 357(2):135–142
[3] Hahn JS, Barnes PD. Neuroimaging advances in
holoprosencephaly: Refining the spectrum of the midline
malformation. Am J Med Genet C Semin Med Genet. 2010; 154C
(1):120–132
[4] Solomon BD, Gropman A, Muenke M. Holoprosencephaly
overview. In: Pagon RA, Adam MP, Bird TD, et al., eds.
GeneReviews® [Internet]. Seattle, WA: University of
Washington; 1993–2013. Available at:
nih.gov/books/NBK1530/. Accessed November 12, 2013
[5] Volpe JJ. Neurology of the Newborn. Philadelphia, PA: W.B.
Saunders Company; 2001:62–68
[6] Dobyns WB, Das S. LIS1-associated lissencephaly/subcortical
band heterotopia. In: Pagon RA, Adam MP, Bird TD, et al., eds.
GeneReviews® [Internet]. Seattle, WA: University of
Washington; 1993–2013. Available at:
nih.gov/books/NBK5189/. Accessed November 12, 2013
[7] Hehr U, Uyanik G, Aigner L, Couillard-Despres S, Winkler J.
DCX-related disorders. In: Pagon RA, Adam MP, Bird TD, et al.,
eds. GeneReviews® [Internet]. Seattle, WA: University of
Washington; 1993–2013. Available at:
nih.gov/books/NBK1185/. Accessed November 12, 2013
[8] Corpus Callosum Disorders. Available at:
org/index.php?option=com_content&task=view&id=12&
Itemid=27. Retrieved November 13, 2013
[9] Medscape. Available at:
article/407730-overview. Published June 20, 2013. Accessed
November 13, 2013
[10] Chang B, Walsh CA, Apse K, et al. Polymicrogyria overview.
In: Pagon RA, Adam MP, Bird TD, et al., eds. GeneReviews®
[Internet]. Seattle, WA: University of Washington; 1993–
2013. Available at:
NBK1329/. Accessed November 12, 2013
[11] Genetics Home Reference. Available at:
condition/periventricular-heterotopia. Published November
12, 2013. Accessed November 12, 2013
[12] Sheen VL, Bodell A, Walsh CA. X–linked periventricular
heterotopia. In: Pagon RA, Adam MP, Bird TD, et al., eds.
GeneReviews® [Internet]. Seattle, WA: University of
Washington; 1993–2013. Available at:
nih.gov/books/NBK1213/. Accessed November 12, 2013
Migration Disorders
67

11 Neurofibromatosis Type 1
Ben Shofty, Liat Ben-Sira, Hagit Toledano-Alhadef, Felix Bokstein, Shlomi Constantini
11.1 Introduction
Neurofibromatosis type 1 (NF1) is a neurocutane-
ous, autosomal dominant disorder. Historically
named von Recklinghausen’s disease, it is now con-
sidered a “RASopathy” based on the intracellular
signaling pathway that is hyperactivated. Because of
the plethora of systems a ected by the lack of neu-
rofibromin, and the diversity of the clinical manifes-
tations, NF1 patients should optimally be managed
by a multidisciplinary team, including neurosur-
gical input, which is often required. NF1 a ects
approximately 1/2,700 newborns,1 with variable
presentation and disease severity. The main, dis-
ease-defining manifestations are café-au-lait mac-
ules (CALMs), neurofibromas, skin-fold freckling, iris
hamartomas (Lisch’s nodules), optic pathway glio-
mas (OPGs), and skeletal deformities. In addition,
cognitive and behavioral impairments are noted in
50% of patients. Although considered benign,
plexiform neurofibromas (PNs) and OPGs are a sig-
nificant source of concern, and may cause disfigure-
ment and blindness. Susceptibility to malignancies
is the main reason for close, prolonged follow-up, as
patients may develop malignant peripheral nerve
sheath tumors (MPNSTs) and rarely high-grade
gliomas.
11.2 Genetics and
Cellular Biology
Neurofibromin is a giant intracellular protein (~320
kDa) that is encoded by the NF1 tumor suppressor
gene (chromosome 17q) and is nonfunctional in
NF1 patients because of genetic alterations.2,3 Nor-
mal neurofibromin acts as Ras-negative regulator
(among its other, mostly unknown functions) by
accelerating hydrolysis of Ras-bound GTP. When
there is a lack of neurofibromin, Ras is constantly
attached to GTP and the pathway is hyperactivated,
leading to deregulated cellular proliferation and
survival.4 Upregulation of Ras triggers many down-
stream signaling pathways, including the mitogen-
activated protein kinase (MAPK), RAF/MEK/ERK
pathway, mammalian target of rapamycin (mTOR),
and phosphatidylinositol 3-kinase (PI3K).5
NF1 is an autosomal dominant disease with
100% penetrance and highly variable clinical
presentation.6 Approximately 50% of NF1 patients
have a familial disease,7 and more than 80% of
identified germline mutations are of the truncat-
ing type.8,9 Deletion of the entire gene or large
deletions are seen in approximately 5% of patients
and are associated with a more severe pheno-
type.10,11 Because of the 50% chance of inheriting
the mutated gene, genetic counseling to known
NF1 families should be o ered. It is important to
inform the patients that prenatal diagnosis using
ultrasonography was reported for severe NF1 cases
only.12 For preimplementational diagnosis to be an
option, the specific familial mutation needs to be
mapped prior to pregnancy.13,14,15
11.3 Diagnosis and Clinical
Presentation
Diagnosis of NF1 is based on clinical criteria estab-
lished by the National Institutes of Health (NIH) in
1987 (Table 11.1).16 Two or more of these crite-
ria are required for diagnosis of NF1. The sensitiv-
ity and specificity of this system is high; it is
robust enough to diagnose 50% of a ected children
with no family history by the age of 1 year and
95% of a ected children by the age of 8 years.7,17,18
Because of the fact that some of major disease
manifestations present slowly, young children
with multiple (six or more) CALMs and no family
history, or other major symptoms, should be fol-
lowed carefully as 95% of them will eventually
meet the criteria for NF1.19 T2 hyperintensities
(T2Hs) on brain magnetic resonance imaging
(MRI) were suggested as a supplemental diagnos-
tic criterion, but are seldom used for initial diagno-
sis because of the complexity in acquiring MRI
data in young children and their lack of specific-
ity.20 CALMs and PNs may be present at birth, and
can be noticed by the age of 1 to 3 years. Tibial
dysplasias and skin-fold freckling typically present
around the age of 1 to 2 years. Other manifesta-
tions, such as Lisch’s nodules, OPGs, learning dis-
abilities, and precocious puberty, usually present
between the ages of 2 and 5 years. The last main
manifestation of the disease to appear is cutaneous
and subcutaneous neurofibromas, peaking at early
adolescence.21
68

11.4 Management
A multidisciplinary team at an NF1-dedicated center
should optimally manage these complex patients.
The team should include a pediatric neurologist,
pediatric neurosurgeon, neuro-ophthalmologist,
pediatric radiologist, social worker, neuropsycholo-
gist, geneticist, and a patient coordinator. Orth-
opedists, oncologists, head and neck surgeons,
reconstructive surgeons, dermatologists, and other
specialists should be consulted, depending on the
issue at hand. This multidisciplinary approach will
prevent management errors that may be made by
physicians who are not familiar with the complexities
and sensitivities of NF1 patients. Initial evaluation for
a newly diagnosed pediatric NF1 patient should
include a thorough physical and neurological exami-
nation with special emphasis on skin lesions, neuro-
ophthalmological examination including fundus and,
if available, optical coherence tomography (OCT)
for evaluation of retinal nerve fiber layer thick-
ness, cardiovascular baseline (blood pressure and
heart examination), neuropsychological test bat-
tery, and skeletal screening (yearly growth curves)
to direct further workup.
11.5 Imaging
Imaging regimes for NF1 patients are controversial,
and vary from center to center. MRI is the diagnos-
tic tool of choice because of the nature of most
of the pathologies involved. The high sensitivity of
NF1 children to radiation should make the use of
computed tomography (CT) minimal, reserved for
occasional use only, essentially for skeletal pathol-
ogies. Screening MRIs in an asymptomatic patient
at presentation are generally not recommended,
Table 11.1 Clinical diagnostic criteria for NF1,16 and accessory diagnostic and clinical findings
Diagnostic criteria

Expected age of presentation

Percentage of patients
CALMs (six or more, larger than 15 mm in
adults and 5 mm in children)
Birth to 2 y

>99%
Cutaneous neurofibromas (two or more)

5 + y

>99%
One plexiform neurofibroma

Birth to 3 y

30–50%
Axillary or inguinal freckling

3–5 y

90%
Lisch’s nodules (two or more)

5–10 y

90%
Optic pathway glioma

3–8 y

15–30%
Typical osseous lesion (SWD/long-bone
cortical thinning, with or without
pseudoarthrosis)
1–3 y

2% pseudoarthrosis
1% SWD
Family history of NF1 (first-degree relative) –

50%
Additional common clinical findings
(% of patients)
Required evaluation
ADHD/memory and learning difficulties
(50–75%)
Neuropsychological consultation

ADHD/memory and learning
difficulties (50–75%)
T2 hyperintensities (60–70%)

None

T2 hyperintensities (60–70%)
Cardiovascular abnormalities
(hypertension, renal artery stenosis,
pulmonary artery stenosis, 2% each)
Yearly blood pressure monitoring and
heart examination, echocardiography
as needed
Cardiovascular abnormalities
(hypertension, renal artery
stenosis, pulmonary artery
stenosis, 2% each)
Hormonal abnormalities/precocious puberty Growth curves at every routine
follow-up
Hormonal abnormalities/
precocious puberty
Progressive scoliosis

Skeletal/bone evaluation

Progressive scoliosis
Neuropathy (~ 1%, usually distal and
symmetrical)
Rule out other causes for neurological
changes in NF1 patients (PNs,
MPNSTs, etc.)
Neuropathy (~ 1%, usually distal
and symmetrical)
Pheochromocytoma (2%)

24-h urinary excretion of catechol-
amines and their metabolites
Pheochromocytoma (2%)
Abbreviations: ADHD, attention-deficit/hyperactivity disorder; CALMs, café-au-lait macules; MPNSTs, malignant peripheral
nerve sheath tumors; NF1, neurofibromatosis type 1; PNs, plexiform neurofibromas; SWD, sphenoid wing dysplasia.
Neurofibromatosis Type 1
69

but a high index of suspicion should nevertheless
be kept. In patients who cannot be reliably
assessed for functionality (visual exam, neurologi-
cal signs, orthop-edic examination, etc.) or who
cannot express complaints because of their young
age (usually less than 1 year) or cognitive status, a
baseline brain MRI at presentation should be con-
sidered.22
For patients presenting with a specific com-
plaint or developing a specific symptom, an MRI of
the relevant body part should be urgently
acquired. When planning an MRI study in NF1
patients, one must take into account the di erent
expected pathologies (cerebral, spinal, and periph-
eral) that correlate with the age of the patient and
the nature of the signs and symptoms. A prelimi-
nary consultation with a pediatric radiologist with
NF1 experience is advised in order to plan the
imaging regime and protocol. A comprehensive
study including pre- and postcontrast T1, T2, high-
resolution 3D anatomical sequence, and orbit-
oriented T1 and T2 with fat saturation is the
minimal evaluation required for cerebral exam. For
spinal and body imaging, a short T1 inversion
recovery with fat saturation (such as short tau
inversion recovery [STIR]) should be added in
order to characterize and di erentiate the PN from
the surrounding fat and subcutaneous tissues.
Whole-body MRI is a new, upcoming technique
that should be considered in patients with a large
disease burden.23,24,25 More advanced sequences
such as di usion tensor imaging (DTI) and di u-
sion should be considered when attempting to
assess functionality in OPG patients.26,27,28 For
long-term follow-up and monitoring of treatment
e cacy, volumetric measurements are considered
state of the art and are highly recommended for
both cerebral lesions and PNs.29,30,31,32,33
Nonneoplastic abnormalities on MRI are rela-
tively common in NF1, and should be carefully
interpreted. T2Hs are perhaps the most common
imaging abnormality, found in 60 to 70% of NF1
children. T2Hs are typically found in the basal gan-
glia, thalamus, cerebellum, brainstem, and cerebral
white matter. These lesions are thought to repre-
sent foci of fluid accumulation within decom-
pacted myelin sheath. T2Hs within the basal
ganglia, thalamus, and brainstem tend to disap-
pear with time, perhaps due to recycling of oligo-
dendrocytes.34 The presence of T2Hs, especially in
the thalamus, is associated with cognitive impair-
ment, although there is no clear-cut association
between the cognitive phenotype and the number
or size of the T2Hs.35,36
11.6 Cutaneous Manifestations
CALMs are the most common cutaneous manifes-
tation of NF1, and can be observed in 95% of
patients by the age of 3. Other common manifesta-
tions include freckling of skin folds (axillary and
inguinal), found in the majority of the patients
(Crowe’s sign), and hypopigmented macules. All of
the above findings are benign, and require no fol-
low-up or intervention.37
Lisch’s nodules are benign melanocytic iris
hamartomas that appear between the ages of 5
and 10 years, and are best diagnosed on slit-lamp
examination. They do not a ect vision, nor should
they be the cause for any clinical concern.
Cutaneous neurofibromas (CNs) are benign
nerve sheath tumors comprised of neoplastic
Schwann’s cells nested within mast cells and fibro-
blast stroma. CNs arise from a single terminal
nerve fascicle. These tumors can be sensed as sub-
cutaneous pealike masses or small exophytic
masses, and are not painful. The most common
complaint associated with CNs is pruritus, which is
unresponsive to antihistamines. CNs are not asso-
ciated with malignant transformation or growth.22
Cutaneous manifestations of NF1 may be treated
cosmetically if causing distress; it is recommended
to refer the patients to a plastic surgeon with NF1
experience or to a peripheral nerve surgeon in
order to avoid neurological damage that may
be associated with subcutaneous neurofibroma
excision.
11.6.1 Plexiform Neurofibromas
PNs are the hallmark of neurofibromatosis, and
one of the main causes of morbidity and mortality.
Thirty percent of NF1 patients have visible PNs
and 50% have PNs on imaging studies.17 Hyperpig-
mentation or hypertrophy of the overlaying skin
and patches of hair are often indicative of an
underlying PN. Unlike CNs, PNs are di use tumors,
which may involve multiple nerve branches or
trunks and are often clinically described as a “bag
of worms.” PNs vary from tiny millimeter-diame-
ter lesions to huge complex masses. PNs develop
around the age of 7 and are prone to progression
during pregnancy, since about 75% express proges-
terone receptors.38 These tumors, although benign
in nature, are infiltrative, often involving the
surrounding structures. Growth pattern and natu-
ral history are unpredictable; periods of rapid
growth (most common in early childhood or dur-
ing the hormonal changes of puberty or during
Neurology
70

pregnancy) may be followed by long-term
stability.
PNs have a typical MRI appearance: a hypoin-
tense T1 signal, high signal intensity in T2 with
central areas of low signal, and hyperintensity in
STIR sequences. No biopsy is needed in an NF1 pa-
tient with a typically appearing PN on MRI. The
most common complications associated with PNs
are local mass e ect, bone deformity, spontaneous
intratumoral bleed, and malignant transformation
into an MPNST. PNs may progress and cause signif-
icant morbidity even without malignant transfor-
mation. Local mass e ect or neurological deficits
are considered indications for treatment.
Managing progressive PNs is extremely di cult
because of the complexity of surgery and the lack of
e cient medical treatment options. Early surgery,
when possible, may spare complications later in
life.39 Radiotherapy is contraindicated because of the
significant risk of malignant transformation. Many
clinical trials for progressive PNs are being con-
ducted; nevertheless, data in the literature are insuf-
ficient to support the use of any specific agent.40
11.6.2 Malignant Peripheral Nerve
Sheath Tumor
MPNSTs are the most common malignant tumors
associated with NF1, with 5-year survival of 34 to
58%.41 These are highly aggressive tumors, occurring
in 2 to 10% of the NF1 population and only in
0.001% of the general population.42 MPNSTs occur
mainly during the second and third decades of life,
but diagnosis in patients as young as 5 years old has
been reported.43 MPNSTs often but do not exclu-
sively arise from PNs, and are often metastatic at
presentation. A high index of suspicion should be
maintained in any NF1 patient with a “red flag” com-
plaint. An NF1 patient with any of these complains
should be urgently referred to an NF1 clinic, even in
the absence of a known or visible PN, as MPNSTs
often arise from hidden, central PNs (Box 11.1).
Box 11.1 “Red flags” warrant
immediate workup for MPNSTs
Symptom
● Persistent pain that lasts more than a month/
awakes from sleep.
● New or unexplained neurological deficit.
● Rapid increase in size of existing PN.
● Change in existing PN consistency.
Conventional MRI or positron emission tomogra-
phy (PET; usually with FDG [fluorodeoxyglucose],
or experimentally with F-thymidine) is the method
of choice for evaluation of a de novo MPNST-
suspected lesion or a suspected malignant
transformation of an existing PN. Following multi-
disciplinary discussion, a Tru-Cut biopsy, prefera-
bly under imaging guidance, is recommended as
the initial diagnostic method, obtaining multiple
cores from the suspected area in the lesion. Exci-
sional biopsies should only be considered for
small superficial tumors, where clear margins are
obtainable.41 Aggressive surgical resection follow-
ing biopsy is the preferred treatment method for
nonmetastatic tumors, although because of the
associated functional impairment, this approach
should be thoroughly discussed with the patient
and their families. Gross total resection with clear
surgical margins significantly improves both over-
all survival and disease-free interval.44
Adjuvant radiation therapy and/or chemother-
apy is indicated for incomplete excision, nonclear
surgical margins, and large tumors.41 Chemother-
apy with either doxorubicin as a single agent or a
combination of doxorubicin and ifosfamide may be
considered in order to enable resection in nonre-
sectable tumors or for metastatic tumors.41
11.7 Optic Pathway Gliomas
OPGs are low-grade glial neoplasms (WHO grade I)
that originate from any location along the visual
system, such as the optic nerve (ON), optic chiasm,
optic tracts, and, rarely, the optic radiation. These
lesions tend to have an erratic natural history,
requiring careful follow-up and management by a
multidisciplinary team. Patient age at presenta-
tion, histology, and molecular markers (such as
BRAF fusion protein45,46) may be important factors
in clinical behavior and in the practical individual-
ized decision-making process. The subset of
patients seen by the pediatric neurosurgeon may
be biased toward the aggressive end of the spec-
trum, with a tendency to progress and require
multiple treatment lines.
OPGs are relatively rare neoplasms, comprising
approximately 1% of all central nervous system
(CNS) neoplasms in the general population and
approximately 5% of CNS neoplasms in children.47
Eighty percent of all diagnosed patients are in the
first decade of their lives, and 90% are in the
first two decades. The mean age at diagnosis is
8.8 years in older series, ranging between 2.7 and
Neurofibromatosis Type 1
71

5.4 years in more recent series.48,49,50 An estimated
37% of OPGs tend to progress.51 There is no gender
predisposition.
OPGs in NF1 patients tend to have a more
benign course as compared to opposing sporadic
OPGs.51,52 In a recent series comparing NF1 OPGs
to sporadic gliomas, children with NF1 had a sig-
nificantly better clinical status at diagnosis, with
less increase in intracranial pressure, less decrease
in visual acuity (VA), and fewer abnormalities of
fundus of the eye. Radiological progression, visual
deterioration, and endocrinological damage were
also less frequent in NF1 OPGs.53 Historically, NF1
OPGs were considered relatively indolent tumors
that do not tend to progress.
However, recently, several publications have
described a more active clinical course, with pro-
gression of the tumor noted in up to 75% of NF1
patients, even in children older than 11 years
old.54 Recently, macrocephaly was also correlated
with OPG incidence in NF1 patients.55 In addition,
in a genetic study targeting genotype–phenotype
correlation done by Sharif et al, for an NF1 patient
with OPG the odds ratio of a mutation being
present in the 5' tertile end of the gene was 6.05,
when compared to an NF1 patient with no OPG.56
Visual complaints are the mainstay of clinical
symptoms and signs, although they may be hard to
detect because of the young age of the patients.
These include decreased VA, nystagmus, and prop-
tosis, and are found at presentation in 46% of
patients. To maximize diagnostic yield, MR proto-
cols should be planned with the assistance of an
experienced neuroradiologist and should include
orbit-oriented scanning with fat suppression and
contrast injection. Tumors may di er in MR
appearance depending on their locations, but they
are usually isointense on T1, hyperintense on T2,
and receive variable enhancement patterns. Addi-
tional cystic as well as solid nonenhancing compo-
nents are often present.
Isolated tumors of the ON proper usually do not
have cystic changes, and are characterized by gross
thickening of the nerve itself, with or without
nerve sheath enlargement. The di erential diagno-
sis for ON enlargement is broad, including menin-
gioma, hemangioblastoma, and lymphoma.57 ON
sheath enlargement is also found in nonneoplastic
diseases such as increased intracranial pressure,
optic neuritis, Grave’s disease, sarcoidosis,
toxoplasmosis, central vein occlusion, idiopathic
intracranial hypertension, and tuberculosis.58,59
Posterior OPGs may appear as minimal chiasmal
thickening or as large masses protruding into the
third ventricle with apparent mass e ect. Cystic
changes are common in hypothalamic/chiasmatic
tumors, and are a part of the natural history of the
tumor. They may progress and enlarge with time,
requiring treatment due to mass e ect.
Neoplastic changes posteriorly to the lateral
geniculate nucleus are rare and are di cult to dif-
ferentiate from NF1 T2Hs. Because of the long
follow-up required in these patients and the
importance of early detection of changes in the
tumor bulk or in its internal components, we rec-
ommend the use of volumetric measurements.
These measurements, although time-consuming,
may improve patient care by enabling more accu-
rate decision-making.29,30
A decline in VA is often present at diagnosis and
sometimes may be the reason for initial testing,
even in the very young (e.g., an infant that starts
bumping into objects or sitting closer to the televi-
sion). In addition, color vision, visual field, eye
movements, relative a erent pupillary defect,
pupil size, and fundus should all be evaluated. Any
progressive change should be considered seriously
as a reason to initiate therapy. In very young chil-
dren, a normal ophthalmological examination
does not rule out visual impairment from an OPG.
OCT has been shown to detect loss of retinal nerve
fiber layer in children with OPG. This may prove to
be an auxiliary tool in the diagnosis of visual
damage in young children, as well as providing
evidence regarding visual reserve and need for
treatment.60,61
The follow-up and management of OPGs re-
quires an experienced multidisciplinary team that
provides individualized patient care. Only then can
adequate therapeutic decisions be made. The goal
of treatment is twofold: to prevent visual decline
and to achieve long-term tumor control. In the
presence of severe mass e ect or hydrocephalus,
immediate, life-saving neurosurgical procedures
may be indicated. In most cases, however, OPGs
are not a life-threatening tumor. The risk-to-bene-
fit ratio of treatment must therefore be considered
carefully for each patient.
The exact timing of treatment initiation is one of
the major open questions in OPG management. In
most cases, we recommend delaying treatment for
as long as possible, unless a clear-cut radiological
progression or visual decline is noted. Treating an
asymptomatic or minimally symptomatic stable
patient seems to o er no advantage over observa-
tion alone.48,62,63 Thus, current guidelines suggest
intervention only when there is a documented
decline in vision or radiological progression.51
Neurology
72

Treatment initiation dilemmas may be very rele-
vant to a child, especially an infant, who presents
for the first time with compromised vision. At the
moment of presentation, progression cannot be
defined. However, compromised reserve may be a
relevant reason to start treatment earlier, rather
than later.
We recommend imaging and neuro-ophthalmo-
logical examinations (including visual field and
OCT if available) every 6 months. Patients with
compromised reserve for whom a decision was
taken not to treat should be clinically examined
more frequently. If the tumor is chiasmatic/hypo-
thalamic, a detailed endocrinological evaluation
should be performed. If the patient has been stable
for a period of 1 year and has no adverse prognos-
tic factors, follow-ups may be scheduled on a
yearly basis.
Fig. 11.1 illustrates a suggested management
algorithm for OPG. For tumors with characteristic
MRI appearance that are epicentered on the optic
pathway, no biopsy is required.64 Biopsies are indi-
cated if the tumor has an atypical appearance on
MRI, for an unusual age group, or with unusual
clinical characteristics (rapidly progressing or
severe neurological deficits other than vision loss).
Surgery is controversial and is reserved for tumors
confined to the orbit in a blind or severely prop-
totic eye, and for shunt placement in patients with
tumor-associated hydrocephalus. Total resection
of hypothalamic/chiasmatic glioma in a patient
with viable eyesight is usually not recommended.
Chemotherapy with vincristine and carboplatin is
now considered an accepted first-line treatment.
Other options (vinblastine, temozolomide, mTOR
inhibitors) should be considered for second-line
treatment. Cerebral irradiation for OPGs is rela-
tively contraindicated in NF1 patients because of
unacceptable adverse e ects such as secondary
malignancies and cognitive decline.
11.8 Other NF1 Brain Tumors
Brainstem gliomas (BSGs) are the most common
CNS tumor seen in NF1 patients outside of the
optic pathway.65 These are usually low grade (pilo-
cytic astrocytomas), and have a relatively indolent
course. NF1-associated BSGs usually occur in
patients 7 to 10 years of age, and are most com-
monly found in the medulla (not in the pons, typi-
cal of sporadic BSGs). Di erentiating BSGs from
T2Hs can be challenging at times, although T2Hs
do not demonstrate mass e ect.22 Expectant ma-
nagement is recommended, as progression is usu-
ally rare and spontaneous regression has been
reported.66,67 Hydrocephalus is the main reason
for concern in NF1 patients with brainstem
(medullary or tectal) gliomas; endoscopic third
ventriculostomy is the recommended method of
treatment.68 NF1 patients are prone to su er from
cerebral high-grade gliomas, although, as they do
not di er genetically from sporadic high-grade
gliomas, the treatment is the same.22
Fig. 11.1 OPG management algorithm.
Neurofibromatosis Type 1
73

11.9 NF1 Brain Function
Neurofibromin has a crucial role in normal devel-
opment and function of the CNS. Besides being a
tumor suppressor gene, it has many functions hav-
ing to do with synaptic transmission, neuronal sig-
naling, myelination, blood–brain barrier forma-
tion, and more. NF1 patients have a characteristic
cognitive phenotype that is often a major cause for
morbidity for patients and their families. NF1
patients typically have IQ in the low average range.
Severe IQ deficit (<70) is rare. Approximately 50 to
75% of NF1 patients su er from learning and
memory di culties, attention-deficit/hyperactiv-
ity disorder, visuo-spatial coordination di culties,
and memory impairments.69,70 Each patient should
have an individualized treatment plan according
to his/her specific issues and needs.
11.10 NF1 Skeletal
Manifestations
Tibial or long-bone pseudoarthrosis and sphenoid
wing dysplasia (SWD) are the two hallmark
osseous lesions of NF1. Short stature occurs in
14% and scoliosis in approximately 20% of NF1
patients.71,72,73,74,75
SWD may be a cause for
enophthalmos and cerebral herniation into the
orbit. Decreased bone density, cortical thinning,
and dysplasias predispose NF1 patients to patho-
logical fractures, and may worsen scoliosis. Early
therapy with bisphosphonates is recommended in
such cases usually seen in adult patients, as correc-
tive surgery often has poor outcome and should be
saved for a last resort.73
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Neurology
76

12 Medical Management for Epilepsy
Sarah A. Kelley, Adam L. Hartman
12.1 Introduction
Antiseizure medicines are used in the acute treat-
ment of seizures and for seizure prophylaxis. Seiz-
ure prophylaxis is indicated when a patient has a
diagnosis of epilepsy. Antiseizure medicines may
be used for prophylaxis when a patient is at high
risk for seizures, such as after a traumatic brain
injury or after brain surgery.
In general, prophylactic medications to treat epi-
lepsy are started after the second unprovoked seiz-
ure or in patients with a single seizure at high risk
for further seizures (e.g., penetrating traumatic
brain injury). The goal of medical management of
epilepsy is to obtain good seizure control with as
few side e ects as possible, which operationally is a
single agent at the lowest tolerated dose. There are
now over 30 di erent antiseizure medications with
varying mechanisms of action. The choice of medi-
cation is based on the patient’s type of epilepsy
(because some medicines can exacerbate certain
types of seizures), comorbidities, and side e ect
profiles. However, even with trials of multiple medi-
cations, up to one-third of patients will not be seiz-
ure-free on medication.1 If this occurs, then other
treatment options including dietary therapy, seizure
surgery, and vagus nerve stimulation are consid-
ered. Because neurosurgeons frequently encounter
patients who are taking antiseizure medications,
this chapter will focus on these medications and
briefly discuss dietary therapy.
12.2 Treatment of Status
Epilepticus
Status epilepticus is a neurologic emergency.
Although the o cial definition is a seizure that
continues for longer than 30 minutes, in fact it is
thought that injury to the brain begins after
5 minutes of ongoing seizure activity.2 It is there-
fore important to treat status epilepticus as soon
as possible (Table 12.1). The first dose of intrave-
nous lorazepam, intravenous diazepam, or intra-
muscular midazolam should be given after
5 minutes of seizure activity. If seizure activity
continues for 20 minutes, then treatment options
include levetiracetam, valproate, or fosphenytoin.3
If these medications do not stop the seizures, then
subsequent medications can be tried and anes-
thetic agents used once the patient’s airway has
been protected (Table 12.2). While treating the
seizures, the etiology of the status epilepticus
should also be investigated (i.e., metabolic abnor-
malities, stroke, hemorrhage) and treated while
monitoring breathing and circulation. It is impor-
tant to note that in neonates, at the time of this
writing, phenobarbital (PB) is the first drug of
choice for treatment of status epilepticus followed
by fosphenytoin and then lorazepam.
12.3 Specific Anticonvulsant Uses
Medications that can be given intravenously and
therefore used for the treatment of status epilepti-
cus or when medications cannot be taken enterally
include lorazepam (or other benzodiazepines such
as midazolam), fosphenytoin, phenobarbital, val-
proate, levetiracetam, or lacosamide.
● Seizure prophylaxis with phenytoin after
traumatic brain injury has been studied and
demonstrates that immediate use of this
medicine prevents early (within the first 7 days)
posttraumatic seizures but not late (that is,
>7 days) posttraumatic seizures.4
Table 12.1 Treatment of status epilepticus
Times since
seizure onset
Intervention
0–5 min

ABC, ECG, IVaccess, blood for CBC, CMP,
AED levels, toxicology screen
5–20 min

Lorazepam IV 0.1 mg/kg (up to 4 mg)
or
Diazepam IV 0.2 mg/kg (up to 10 mg)
May repeat dosing one time if needed
or
Midazolam IM (5 mg for 13-40 kg, 10 mg
for >40 kg) given once
20–40 min

Fosphenytoin/phenytoin 20 mg/kg IV,
max 1500 mg/dose or Valproate
40 mg/kg IV, max 3000 mg/dose
or
Levetiracetam 60 mg/kg IV, max
4500 mg/dose
40–60 min

May repeat second-line therapy or
general anesthesia with continuous
EEG monitoring
Abbreviations: ABC, airway, breathing, and circulation;
AED, antiepileptic drug; CBC, complete blood count; CMP,
comprehensive metabolic panel; ECG, electrocardiogram;
EEG, electroencephalogram; IV, intravenous.
77

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Neurology

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79
Medical Management for Epilepsy

● Infantile spasms treatment: Adrenocorticotropic
hormone (ACTH), prednisolone, vigabatrin.
● Lennox–Gastaut syndrome: felbamate,
rufinamide, topiramate, clobazam, valproate,
lamotrigine, zonisamide.
● Medications used at home for repetitive seizures:
– Diazepam (Diastat): Rectal gel that can be used
to abort a seizure or cluster of seizures. Dose
per age and weight.
– LZP/Diazepam Intensol solutions: Oral solution
that can be placed in the side of the mouth
(buccal administration) to abort a seizure or
cluster of seizures. LZP Intensol needs to be
refrigerated. LZP 2 mg/1 mL liquid, diazepam
5 mg/5 mL liquid.
– LZP or clonazepam tablets may also be used for
clusters of seizures.
12.4 Brief Overview of the Most
Commonly Used Anticonvulsant
Medications
12.4.1 Lorazepam (Ativan; LZP)
LZP is used primarily for acute treatment of seiz-
ures and status epilepticus. It is relatively short-
acting and causes sedation. It is used first line in
status epilepiticus5 and the dose may be repeated
once if seizures do not subside prior to moving on
to a second agent. It also can be used orally as a
rescue agent for seizure clusters.
12.4.2 Phenytoin/Fosphenytoin
(Dilantin; PHT)
In children, these medications are used primarily
for the treatment of status epilepticus. Historically,
PHT was used widely for seizure prophylaxis after
traumatic brain injury. They are di cult to use as
seizure prophylaxis because of poor oral absorp-
tion (PHT), nonlinear kinetics requiring frequent
blood draws and poor side e ect profile leading to
gum hyperplasia, hirsutism, and central nervous
system side e ects. For IV administration, fosphe-
nytoin is preferred over PHT because of the less
caustic nature of the compound, making it signifi-
cantly less dangerous if it extravasates. Serum
esterases metabolize fosphenytoin to PHT, so the
onset of e ect for the former may be slightly
increased, compared to the latter.
12.4.3 Levetiracetam
(Keppra; LEV)
LEV is one of the most commonly prescribed seiz-
ure medications due to its short half-life, good side
e ect profile, and availability in multiple forms.
LEV may be used in focal or generalized epilepsy. It
can be given intravenously and is therefore tried in
status epilepticus. With chronic use, mood prob-
lems are the most common type of side e ect
and may be helped by B6 supplementation
(25–100 mg/day depending on weight).
12.4.4 Valproate (Depakote; VPA)
It is e ective in the treatment of all seizure types;
however, VPA is not recommended for patients
younger than 2 years due to the higher risk of liver
and hematologic side e ects. Rarely, it can cause
liver disorders or hemorrhagic pancreatitis. More
common side e ects include weight gain, hair loss
or thinning, abdominal pain, or sedation. VPA also
may also cause a decrease in the number and/or
function of platelets, leading to the potential for
increased bleeding during surgery. VPA is terato-
genic and can specifically cause neural tube mal-
formations in the fetus.
12.4.5 Phenobarbital
(Luminal; PB)
Used for treatment of focal and generalized seiz-
ures, PB is often the treatment of choice in neona-
tal seizures. PB is available in an IV formulation
and may be loaded in status epilepticus. Uncom-
monly, it is used for maintenance therapy in older
children or adults.
12.4.6 Lacosamide (Vimpat; LCM)
Generally used for treatment of focal seizures, LCM
is available in an IV formulation (loading dose is
200–300 mg in an adult-size patient) in status epi-
lepticus. The most common side e ects for LCM
include dizziness and loss of balance.
12.4.7 Carbamazepine
(Tegretol; CBZ)
CBZ is e ective in the treatment of focal seizures.
It cannot be given intravenously or loaded. It is
Neurology
80

used for prophylaxis. Side e ects include lowering
serum sodium levels, hepatotoxicity, dizziness,
and risk of Stevens–Johnson syndrom e in certain
populations. CBZ may exacerbate generalized seiz-
ure disorders.
12.4.8 Oxcarbazepine
(Trileptal; OXC)
OXC is a newer ketone derivative of CBZ. It is e ec-
tive in the treatment of focal seizures. It cannot be
given intravenously. It is used for prophylaxis. Side
e ects include lowering serum sodium levels and
dizziness. OXC may exacerbate generalized seizure
disorders. OXC doses can be titrated once every
3 days.
12.4.9 Lamotrigine (Lamictal; LTG)
LTG is e ective in the treatment of generalized
and focal seizures. It has a good side e ect profile,
particularly with cognition. The biggest risk is rash
that may evolve into Stevens–Johnson syndrom e.
This risk is greatly reduced by a slow titration
schedule. LTG is well tolerated in all age groups.
12.4.10 Topiramate (Topamax;
TPM)
TPM is used for generalized and focal seizures.
Most common side e ects include cognitive di -
culty (di culty thinking of words), acidosis, and
decreased sweating. TPM carries and increased
risk of kidney stones. Patients should stay well
hydrated on this medication.
12.4.11 Zonisamide (Zonegran;
ZNS)
ZNS is used for generalized and focal seizures. It
has a sim ilar side e ect profile to TPM (above).
One benefit is once daily dosing due to a long
half-life.
12.4.12 Clobazam (Onfi; CLB)
CLB is a 1,5-benzodiazipine that has a longer half-
life than other 1,4-benzodiazepines such as LZP
and therefore has fewer side e ects and less habit-
uation. CLB is indicated in the treatment of seiz-
ures associated with Lennox-Gastaut syndrome.
Recently, its manufacturer issued a warning about
the risk of Stevens–Johnson syndrome.
12.4.13 Ethosuximide (Zarontin;
ESM)
ESM is specifically used for the treatment of child-
hood absence epilepsy without generalized tonic–
clonic seizures. Its side e ects include abdominal
pain and possible white count suppression.
12.4.14 Rufinamide (Banzel; RUF)
RUF is a newer drug indicated initially for Lennox–
Gastaut syndrom e. It is not available in IV form.
Side e ects may include somnolence and QTc
shortening. It should not be stopped abruptly.
12.5 Medication Side E ects
All anticonvulsants virtually cause some central
nervous system side e ect, especially when first ini-
tiated. Most will cause sedation or fatigue. Some will
cause dizziness or di culty with balance and others
will cause problems with cognition. These side
e ects can be seen even if the patient is not toxic on
the medication. However, if a patient appears overly
sedated, it is important to determine if she/he just
had a seizure, is in subclinical status, or is sedated as
a result of the medication. Ask about recent changes
in medication, think about drug–drug interactions,
and consider getting an electroencephalogram
(EEG) if ongoing seizure activity is suspected. Levels
may be checked for many anticonvulsant medica-
tions and compared to therapeutic ranges; however,
there are some patients who tolerate high levels of
medication without side e ects.
12.6 Drug–Drug Interactions
Anticonvulsant medications that a ect the cyto-
chrome P450 (CYP) (cytochrome P450) system
may interact with each other or other medications
that the patient is taking. VPA and FBM are inhibi-
tors and can slow the excretion of other medica-
tions. CBZ, PHT, OXC, and PB are inducers and can
speed the metabolism of other medications includ-
ing oral contraceptives.
12.7 Discontinuation of
Anticonvulsant Therapy
Once a patient has been seizure-free on antisei-
zure medication for 2 years, it is reasonable to
consider weaning o the medication. Successful
discontinuation is more likely if seizures were easily
Medical Management for Epilepsy
81

controlled and the patient has a normal exam, a
normal EEG, and magnetic resonance imaging
(MRI), and in the setting of primary generalized epi-
lepsy (other than juvenile myoclonic epilepsy) or a
childhood epilepsy syndrome. Unsuccessful discon-
tinuation is more likely if the patient has had multi-
ple failed treatment attempts, previous unsuccessful
withdrawal attempts, abnormal EEG prior to with-
drawal, or a remote symptomatic epilepsy (e.g.,
known lesion).
After seizure surgery, most neurologists start
weaning medicine after 6 months of seizure free-
dom. Weaning medication prior to the 6-month
mark leads to an increased risk of recurrence.6
12.8 Treatment in the Setting
of Comorbidities
Antiseizure medicines are also used in the treat-
ment of other disorders. VPA and TPM are used in
the treatment of migraine headaches. VPA, LTG,
and CBZ are used for treatment of various mood
disorders and/or anxiety. TPM and ZNS may lead
to weight loss. Gabapentin, pregabalin, and CBZ
are used in the treatment of pain syndromes.
During pregnancy, LTG and LEV have the best
safety profile. VPA and PHT have known serious
teratogenic potential. Many of the other antisei-
zure medicines have known risk in the setting of
pregnancy as well.
12.9 Dietary Therapy
Diets, specifically the ketogenic diets and modified
Atkins diet, are often used in patients when medi-
cations fail. These are high-fat, low-carbohydrate,
and adequate-protein diets that are monitored
closely by neurologists and nutritionists. Patients
on these diets should not receive glucose in their
fluids or medications mixed with solutions con-
taining glucose unless this is medically necessary.
If it is necessary to discontinue the diet due to
another medical condition, it can be reinstituted
once the patient has recovered.
12.10 Common Clinical
Questions
1. In the treatment of a patient in status epilepticus,
what are the first three medications you would
use and what doses would you choose?
2. Which antiseizure medicine can cause
metabolic acidosis?
3. Which medications could potentially exacerbate
a generalized seizure disorder?
4. Why should valproate be avoided in young
women if possible?
12.11 Answers to Common
Clinical Questions
1. Lorazepam (0.1 mg/kg/dose up to 4 mg) can be
given first and m ay be redosed one tim e if the
patient continues to have seizures. Diazepam
and m idazolam are other options. Phenytoin/
fosphenytoin levetiracetam , or valproate
would be the next line of treatm ent.
Fosphenytoin is less likely to cause cutaneous
injury if it extravagates and is therefore
preferred.
2. Topiram ate can cause m etabolic acidosis as
well as di culty w ith word finding, tingling in
the extrem ities, anhydrosis, and kidney
stones.
3. Oxcarbazepine and carbamazepine, which are
used to treat focal seizure disorders, may
exacerbate generalized seizures.
4. Valproate is teratogenic and can cause spinal
dysraphism and decreased IQ in the fetus. It
can also cause weight gain, hair loss, and in
rare cases hem orrhagic pancreatitis or liver
failure.
References
[1] Kwan P, Brodie MJ. Early identification of refractory epilepsy.
N Engl J Med. 2000; 342(5):314–319
[2] Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J
Med. 1998; 338(14):970–976
[3] Glauser T, Shinnar S, Gloss D, et al. Evidence-based guideline:
treatment of convulsive status epilepticus in children and
adults: report of the Guideline Committee of the American
Epilepsy Society. Epilepsy Curr 2016;6(1):4861
[4] Temkin NR, Dikmen SS, Wilensky AJ, Keihm J, Chabal S, Winn
HR. A randomized, double-blind study of phenytoin for the
prevention of post-traumatic seizures. N Engl J Med. 1990;
323(8):497–502
[5] Brophy GM, Bell R, Claassen J, et al. Neurocritical Care Society
Status Epilepticus Guideline Writing Committee. Guidelines
for the evaluation and management of status epilepticus.
Neurocrit Care. 2012; 17(1):3–23
[6] Lachhwani DK, Loddenkemper T, Holland KD, et al.
Discontinuation of medications after successful epilepsy
surgery in children. Pediatr Neurol. 2008; 38(5):340–344
Neurology
82

IV
Section IV
Tumor
13 Pediatric Scalp and Skull
Lesions

84
14 Supratentorial Tumors

91
15 Hypothalamic and Optic
Pathway Tumors

107
16 Craniopharyngiomas and
Other Sellar Tumors

112
17 Germ Cell Tumors

125
18 Pineal Region Tumors

136
19 Intraventricular Tumors in
Children

145
20 Posterior Fossa Tumors

154
21 Brainstem Gliomas

169
22 Intramedullary Spinal Cord
Tumors

178
23 Tumors of the Spinal Column 188

13 Pediatric Scalp and Skull Lesions
Rajiv R. Iyer, Lee S. Hwang, Je rey P. Mullin, Violette M.R. Recinos
13.1 Introduction
Pediatric neurosurgeons are frequently asked to
evaluate children who present with various
“lumps” and “bumps” on the head that come to
attention in a multitude of ways. Often, such scalp
and skull lesions are asymptomatic and inciden-
tally discovered as general head swelling or a
discreet mass on the scalp during infancy and
childhood, identified by parents, teachers, or even
hairdressers. Some lesions are preceded by
trauma, while most are nontraumatic and idio-
pathic in nature. The majority of such lesions are
benign, and some can be managed expectantly
with serial monitoring. In other circumstances,
when a diagnosis is sought, if the lesion is painful
or bothersome to the patient, or for cosmetic rea-
sons, surgical intervention can be considered.
Broad heterogeneity exists in the types of scalp
and skull lesions found in children, and the extent
of soft tissue, calvarial, and intracranial involve-
ment is variable. In many cases, the natural history
of scalp and skull lesions is not well defined.
Therefore, it is no surprise that thresholds to inter-
vene surgically vary between surgeons. Nonethe-
less, when surgical intervention is pursued, it often
represents a safe, durable treatment option.
Given the wide pathological variability of scalp
and skull lesions, a structured diagnostic approach
is important in the evaluation of infants and chil-
dren. Frequently, a multidisciplinary approach
allows for comprehensive treatment of these dis-
orders, involving neurosurgeons, pediatricians,
plastic surgeons, and dermatologists. Recognition
of such lesions may begin with the general pedia-
trician or a dermatologist during general checkups.
For the neurosurgeon, history and physical exami-
nation are important in delineating a time course
for lesion growth or change, for determining head
circumference, and for characterization of the le-
sion itself. Many times, physical examination alone
can lead to a diagnosis. Imaging is obtained in
some instances, and often includes ultrasound,
plain radiographs, computed tomography (CT) and
magnetic resonance (MR) imaging. CT imaging
allows evaluation of the bony architecture sur-
rounding, and possibly comprising, particular
lesions. MR imaging allows for delineation of soft-
tissue structures and may aid in determining the
extent of intracranial and intradural involvement.
In some cases, vascular imaging can be helpful for
those lesions that have robust blood supply, those
that communicate with the dural venous sinuses,
or those with have unique venous drainage.
Reported incidences of each particular lesion vary
considerably and may in part be due to varying
referral patterns amongst institutions, in addition
to the variety of medical subspecialties to which
patients are referred.1,2,3 Surgical intervention fre-
quently involves a neurosurgeon and may also
involve a plastic surgeon in situations where par-
ticular attention to wound healing is needed and
in which primary scalp closure may pose a chal-
lenge.
In this chapter, we discuss som e of the com -
m on scalp and skull lesions found in the pediatric
population that com e to the attention of a neuro-
surgeon.
13.2 Cephalohematoma
With the advent of improved obstetrical care and a
decrease in the frequency of vacuum- and forceps-
assisted vaginal delivery of neonates, the develop-
ment of cephalohematoma is rare, occurring in
approximately 1% of births. Such lesions are typi-
cally identified in the first days of life after partic-
ularly challenging deliveries, especially those
involving abnormal fetal position, narrow birth
canal, and vacuum and forceps assistance. After
traumatic deliveries, a soft mass on the scalp, espe-
cially in the parietal regions, is suggestive of ceph-
alohematoma formation ( Fig. 13.1). Because
cephalohematomas arise between the skull and
the pericranium, they are contained by the suture
lines. This is in contrast to subgaleal hematomas,
in which blood distributes above the pericranial
space, and caput succedaneum, in which edema
tracks below the skin and above the galea. Unlike
cephalohematomas, both of these related phenom-
ena share the ability to cross suture lines. In unsta-
ble neonates with expanding hematomas, it is
essential to be aware that a large portion of the cir-
culating blood volume can be lost in such lesions
and that blood count monitoring may be neces-
sary. In rare instances, hyperbilirubinemia or
infection of the hematoma can also occur. The
majority of cephalohematomas are managed
expectantly with serial monitoring. Observation
84

alone is often su cient as these lesions frequently
exhibit self-resolution. Rarely, initially malleable
lesions ossify and can lead to morbidity from cos-
metic deformity. In those instances, surgical inter-
vention may be indicated and typically involves
drilling the hematoma to the appropriate shape, or
in severe cases, craniectomy and cranioplasty with
split-thickness calvarial grafting may be required.
13.3 Epidermoids/Dermoids
The most frequently occurring pediatric skull
lesions are dermoid and epidermoid cysts, which
occur due to a failure of dysjunction during devel-
opment, leading to intraosseous retention of epi-
thelial and dermal elements. While epidermoids
are often found in older children and adults in the
intracranial space (especially the cerebellopontine
angle and suprasellar region), dermoids have a
preponderance for the midline scalp and skull, fre-
quently located along the anterior fontanelle.4
Cystic cavities containing keratin accumulation
from desquamation is typical with epidermoids.
Dermoids, on the other hand, contain skin ele-
ments in addition to dermal structures such as
sebaceous glands and follicles. Physical examina-
tion typically reveals a firm, immobile lesion.
Imaging is not always necessary, but may reveal a
lytic skull lesion close to midline (Fig. 13.2).
Rarely, a dermoid sinus tract is associated and
communicates with the intracranial space and,
more unusually, the intradural space. These lesions
have the propensity of becoming infected, which
can thereby lead to infection of the subgaleal space
and, theoretically, the intracranial space in
Fig. 13.2 Dermoid. (a) Plain radiograph demonstrating a lucent skull lesion (arrowhead) consistent with a dermoid.
(b, c) A small scalp incision is utilized to visualize the raised dermoid attached to the calvarium (b) and its firm appearance
grossly following en bloc excision (c).
Fig. 13.1 Cephalohematoma. (a) Firm, expansile scalp lesion in the parietal region of an infant with a cephalohematoma at
birth. (b, c) Computed tomography (CT) imaging demonstrating evolution of a cephalohematoma with an ossified rim.
Pediatric Scalp and Skull Lesions
85

communicating lesions. Surgical treatment often
consists of excision using a curvilinear incision
around the lesion. Ideally, removal would occur en
bloc without lesion entry and potential seeding of
the surrounding space. However, in some instances
this is not possible and the resection cavity
should be thoroughly inspected and expunged of
suspected lesional tissue in order to prevent
recurrence. While bony involvement is certainly
possible, intradural exploration is typically
unnecessary. Care must be taken for midline
lesions, which may communicate with the sagittal
sinus. In such instances, a tract entering the bone
can be cauterized and ligated.
13.4 Langerhans Cell
Histiocytosis
Langerhans cell histiocytosis is an umbrella term
for a group of disorders that are characterized at
the cellular level by proliferation of immune cells
leading to a variety of clinical phenotypes, includ-
ing lesions of the skeletal system, skin, and other
organ systems. Some eponymous conditions such
as Hand-Schüller-Christian and Letterer-Siwe dis-
ease are examples of multifocal Langerhans cell
histiocytosis characterized by systemic features
including hepatosplenomegaly and pancytopenia.
In children, a common form of Langerhans cell
histiocytosis that may come to the attention of a
neurosurgeon is a solitary skull mass known as
eosinophilic granuloma.5 These lesions often present
in children prior to puberty as gradually expanding
skull masses that can be painful in nature. Imaging
studies typically demonstrate an osteolytic skull le-
sion ("punched-out" appearance) with rare intra-
cranial or intradural extension (Fig. 13.3).
While the natural history of eosinophilic granu-
lomas of the skull is not well defined, enlarging,
painful lesions and the need for biopsy make sur-
gical intervention the treatment of choice in many
cases. The goal of surgery is complete resection,
which can be performed with craniectomy sur-
rounding the margins of the lesion, or with piece-
meal curettage in cases when this is not feasible.
Extensive, large skull lesions may require calvarial
reconstruction following surgical excision. Thus, in
preparation for extirpation of such bony lesions,
calvarial donor sites may need to be prepped and
accounted for during incision planning.
Recurrence rates following total resection of
Langerhans cell histiocytosis of the skull are low.
After surgery, children should be followed for
some time by the neurosurgeon to monitor for
recurrence. Radiographic skeletal surveys and
radionuclide bone scans can be helpful in evaluat-
ing polyostotic disease. In lesions that are not sur-
gically amenable, or for recurrent, aggressive
lesions, alternative adjuvant therapy with chemo-
therapy or low-dose radiation is a possibility.
13.5 Fibrous Dysplasia
Fibrous dysplasia is a benign osseous condition
characterized by the slow, abnorm al deposition
of collagen and fibrous tissue am ongst a network
of im m ature woven bone. Single and m ultiple
areas of dysplasia are classified as m onostotic
and polyostotic, respectively. The underlying
pathophysiology of this disorder is related to
genetic m utations leading to constitutive activa-
tion of a G-protein-coupled receptor. McCune-
Albright syndrom e is a well-characterized syn-
drom e consisting of a com bination of polyostotic
fibrous dysplasia, café-au-lait hyperpigm entation
spots, and precocious puberty.
Because of the slow-growing nature of fibrous
dysplasia, serial clinical monitoring is important in
children and adolescents. Painless, progressive
skull deformity is a possible for clinical presenta-
tion. High-resolution CT imaging provides infor-
mation about the extent of bony involvement,
Fig. 13.3 Eosinophilic granuloma.
(a, b) CT imaging demonstrating a
punched out, lytic lesion consistent
with an eosinophilic granuloma.
Tumor
86

including structures of the skull base. A typical
appearance on CT imaging is of a ground-glass le-
sion that di erentiates this from normal bone
(Fig. 13.4). Lesions can involve various aspects of
the calvarium and skull base involvement can lead
to narrowing of the natural corridors and foramina
of the skull base, leading to cranial nerve dysfunc-
tion, vision loss from optic canal narrowing, prop-
tosis, tinnitus, and other issues. A low risk of
malignant transformation to osteosarcoma has
been described, underlining the importance of
clinical monitoring over time. Medical therapy
with bisphosphonates may help slow bone turn-
over and reduce pain. Surgical intervention typi-
cally involves a multidisciplinary approach with
skull base lesions in particular, often with com-
bined e orts from neurosurgical, otolaryngology,
and craniofacial experts, with the goal being
decompression of normal neural structures, resec-
tion of all dysplastic bone, and cosmetic and
functional reconstruction. In some cases, open cra-
niofacial approaches are preferred, while in others
endoscopic endonasal approaches can be used to
achieve excellent outcomes.
13.6 Hemangiomas
Hemangiomas of the scalp and skull are rare occur-
rences in children and are often asymptomatic and
incidentally found. Plain radiography in patients
with hemangiomas will reveal a characteristic
“honeycomb” appearance due to vascular channels
interspersed with bony trabeculations. Typically,
these lesions do not extend into the intracranial
space. Some vascular supply may, however, ema-
nate from the dura, although it is usually not
involved. A theoretical risk of hemorrhage from
trauma exists, but is unusual. Acceptable manage-
ment of hemangiomas includes serial monitoring,
but large or symptomatic lesions can be surgically
excised en bloc with appropriate skull reconstruc-
tion, if needed, and primary scalp closure.
13.7 Sinus Pericranii
Soft, expansile, midline, or paramedian scalp
lesions consisting of an abnormal communication
between intracranial and extracranial veins are
referred to as sinus pericranii. Typically in this con-
dition, a slow-flow anastomosis exists between
extracranial scalp veins and intracranial veins in
proximity to the sagittal sinus, which extends
through a calvarial defect to intercommunicate
(Fig. 13.5). While venous imaging can provide in-
formation regarding the abnormal venous net-
works associated with sinus pericranii, the diagno-
sis is usually clinically made. Soft, compressible
lesions that enlarge and increase in prominence
with recumbency or with Valsalva maneuvers dif-
ferentiate sinus pericranii from other scalp lesions.
Similar to hemangiomas, a theoretical risk of trau-
matic hemorrhage exists and thus, surgical inter-
vention is often recommended. Intraoperatively,
following induction with general anesthesia,
Fig. 13.4 Fibrous dysplasia. (a) CT imaging demonstrating ground-glass appearance of a left temporal lesion
(arrowhead) consistent with fibrous dysplasia. (b, c) Magnetic resonance (MR) imaging demonstrating left temporal
fibrous dysplasia on T1-weighted postcontrast imaging (b) T2-weighted imaging (c).
Pediatric Scalp and Skull Lesions
87

Valsalva maneuvers can allow the surgeon to map
out the pattern of scalp veins at the time of inci-
sion planning. This can be helpful in circumferen-
tially excising the lesion with minimal blood loss,
as each surrounding vein can be preemptively
identified and controlled. Once circumferential dis-
section of the lesion is accomplished, a tract extend-
ing through a calvarial defect is typically isolated,
ligated, and cut. Surgical intervention is well toler-
ated and often provides a durable solution.
13.8 Growing Skull Fracture
Growing skull fractures, also known as leptomenin-
geal cysts, are rare phenomena (~1%) in infants
and young children, typically less than 5 years of
age, who su er from skull fractures. An occult
dural tear occurring at the time of a skull fracture
is typically the basis for this occurrence.6,7 Weeks
to months following the initial injury, normal
brain growth can cause neural elements to herni-
ate through the dural defect at the site of the frac-
ture. This can lead to a soft, pulsatile lesion at the
site of injury and its growth can result in neurolog-
ical deficit or seizures.
Surgical intervention is the mainstay of therapy
for growing skull fractures to prevent or treat neu-
rological impairment or seizures. A wide-margin
craniectomy is typically utilized to adequately sur-
round the dural defect and herniating neural ele-
ments. This is necessary to encompass the entirety
of the dural tear, which may extend beyond the
elements of the skull fracture itself. Duraplasty
with synthetic graft or autologous pericranium
can be used to create a watertight dural closure,
and depending on the quality of the fractured
bone, it can be replaced and fixated, or cranio-
plasty can be performed, preferentially using
split-thickness autologous grafting from a donor
calvarial site.
13.9 Aneurysmal Bone Cyst
Aneurysmal bone cysts (ABCs) are osseous lesions
that tend to expand in the diploic space of chil-
dren, leading to the presentation of a variably
painful, enlarging mass.8
These lesions occur
throughout the body in the long bones and spine,
while only rarely involving the calvarium (3–6%).
ABCs can form primarily due to unclear mecha-
nisms and also secondarily due to the presence of
an associated bone tumor, such as osteoblastomas,
giant cell tumors, and others. Diagnostic imaging is
critical for identification of the lesion, as CT imag-
ing demonstrates expansion of cortical bone and
MR imaging demonstrates a heterogenous, expan-
sile lesion that may contain fluid–fluid levels and
cystic components (Fig. 13.6).
Treatm ent of ABCs is surgical resection, w ith
good outcom es when gross resection is achieved.
Due to the considerably vascular nature of these
lesions, preoperative angiography and neuroin-
terventional em bolization may aid in hem ostasis
during resection. Surgical intervention with
resection and curettage is the favored approach
for these lesions, w hile cryotherapy, em boliza-
tion, and radiation therapy serve as adjuvant
therapeutic options.
Fig. 13.5 Sinus pericranii. (a) Three-dimensional CT venogram reconstruction demonstrating scalp vein engorgement
due to sinus pericranii. (b) CT imaging demonstrating calvarial defect (arrowhead) and scalp vein engorgement in
communication with the superior sagittal sinus (c) in a patient with sinus pericranii.
Tumor
88

13.10 Osteoma,
Osteoblastoma, and
Osteoid Osteoma
Three generally benign skull lesions that are rare
in children include osteomas, osteoblastomas, and
osteoid osteomas. Osteomas are hyperostotic skull
lesions derived from mature cortical bone, arising
from the inner or outer table. These lesions are
rare in young children, occurring more commonly
in young adults. Many times, osteomas are asymp-
tomatic and without cosmetic significance. Their
appearance on CT imaging is expansile and hyper-
dense, generally without evidence of bony
destruction. Gardner's syndrome, an inheritable
form of colonic polyposis, also features the devel-
opment of osteomas throughout the body.
Osteoblastomas are comprised of immature
osteoid material laced with osteoblasts, a ecting
the skull in approximately 10 to 20% of cases.9
Their imaging appearance features more variable
calcification, and malignant features resembling
osteosarcoma are also possible.10 These lesions
may enlarge and become painful. Although benign,
recurrence rates of osteoblastomas are higher than
osteomas following resection, highlighting the
importance of complete surgical removal. Malig-
nant transformation has been reported, but is
uncommon. Osteoid osteomas rarely occur in the
skull and typically present with dull, throbbing
pain that is worse at nighttime. Pain relief can be
attained with aspirin and nonsteroidal anti-
inflammatory drugs. Surgical resection for medi-
cally refractory cases can also alleviate pain.
13.11 Sarcoma and
Neuroblastoma
Primary sarcomas of the skull are unusual, but can
a ect older children and young adults. Metastases
to the skull are possible, including fibrosarcoma,
osteosarcoma, or Ewing s sarcoma from the long
bones. Postradiation sarcomas in children with a
history of other tumors have also been described.
On imaging, sarcomas often appear as osteolytic
lesions with poorly defined margins on CT, and as
infiltrative lesions on MR imaging. MR imaging
plays an important role in determining intradural
involvement, which is critical for preoperative
planning. Preoperative angiography and emboliza-
tion can be useful for particularly vascular lesions.
Following resection, adjuvant radiation and che-
motherapy are often used. Postresection skull
reconstruction is often delayed until after chemo-
radiation in order to lessen the likelihood of
wound complications.
Neuroblastoma is the most common extracra-
nial solid tumor in children and is the most com-
mon tumor to metastasize to the skull in this age
group. Focal skull enlargement, with a hair-on-end
appearance with bony imaging, is common. The
most important prognostic factor is pathological
grade, with 5-year survival rates around 80% for
low-grade lesions and 40% for high-grade lesions.11
Maximal surgical resection is advocated if total or
near-total resection is feasible. Along these lines,
chemoradiation plays an important role in resid-
ual, recurrent, or inoperable disease.
References
[1] Yoon SH, Park SH. A study of 77 cases of surgically excised
scalp and skull masses in pediatric patients. Childs Nerv Syst.
2008; 24(4):459–465
[2] Gibson SE, Prayson RA. Primary skull lesions in the pediatric
population: a 25-year experience. Arch Pathol Lab Med.
2007; 131(5):761–766
[3] Ruge JR, Tomita T, Naidich TP, Hahn YS, McLone DG. Scalp
and calvarial masses of infants and children. Neurosurgery.
1988; 22(6, Pt 1):1037–1042
[4] Hashiguchi K, Morioka T, Yokoyama N, Mihara F, Sasaki T.
Subgaleal dermoid tum ors at the anterior fontanelle. Pediatr
Neurosurg. 2005; 41(1):54–57
Fig. 13.6 Aneurysmal bone cyst.
(a) CT and (b) MR imaging demon-
strating cortical bone expansion and
fluid–fluid levels in a posterior fossa
lesion consistent with an aneurysmal
bone cyst. Mass effect on the
underlying can be seen, but the dura
is typically not penetrated in such
lesions.
Pediatric Scalp and Skull Lesions
89

[5] Lam S, Reddy GD, Mayer R, Lin Y, Jea A. Eosinophilic
granuloma/Langerhans

cell

histiocytosis:

pediatric
neurosurgery update. Surg Neurol Int. 2015; 6 Suppl 17:
S435–S439
[6] Singh I, Rohilla S, Siddiqui SA, Kumar P. Growing skull
fractures: guidelines for early diagnosis and surgical
management. Childs Nerv Syst. 2016; 32(6):1117–1122
[7] Muhonen MG, Piper JG, Menezes AH. Pathogenesis and
treatment of growing skull fractures. Surg Neurol. 1995; 43
(4):367–372, discussion 372–373
[8] Gan YC, Hockley AD. Aneurysmal bone cysts of the cranium
in children. Report of three cases and brief review of the
literature. J Neurosurg. 2007; 106(5) Suppl:401–406
[9] McLeod RA, Dahlin DC, Beabout JW. The spectrum of
osteoblastoma. AJR Am J Roentgenol 1976;126(2):321–325
[10] Aziz TZ, Neal JW, Cole G. Malignant osteoblastoma of the
skull. Br J Neurosurg 1993;7(4):423–426
[11] Tsai EC, Santoreneos S, Rutka JT. Tumors of the skull base in
children: review of tumor types and management strategies.
Neurosurg Focus 2002;12(5):e1
Tumor
90

14 Supratentorial Tumors
Eveline T. Hidalgo, Nir Shimony, Karl F. Kothbauer
14.1 Introduction
Supratentorial hemispheric tumors account for
17% of all central nervous system (CNS) tumors in
children.1 They are more common in children
younger than 2 years; older children tend to have
more infratentorial tumors. In adolescence, tumors
of the sellar region are predominant.1 An interdis-
ciplinary approach and enrollment in studies is
essential to achieve the best possible long-term
outcome. Presentation at a tumor board is one of
the first steps in the management of a child with
this condition and should be planned before sur-
gery to complete the diagnostic workup and to
adjust the surgical approach if necessary. Surgical
gross total resection (GTR) is the most important
prognostic factor in most of these tumors; there-
fore, surgery should always be considered as the
first-line treatment. Surgery is performed to
obtain a diagnosis, to reverse neurologic deficit
due to mass e ect, to resect a seizure focus, and
for cytoreduction as an oncologic objective.
The variety of tumors that may be encountered
supratentorially range from benign types, which
may be managed with surveillance, to highly malig-
nant tumor types requiring adjuvant therapies.
14.2 Clinical Presentation
The clinical presentation depends on the location
and size of the tumor. Age also plays an important
role.
In children:
● Seizures—often first symptom, with and without
neurologic deficit.
● Neurologic deficit—depends on site, location,
and size of the lesion, often a late sign.
● Elevated intracranial pressure (ICP) manifests as:
– Headache, vomiting, drowsiness.
– Papilledema.
In infants:
● Developmental delay and failure to thrive.
● Elevated ICP manifests as:
– Vomiting, bulging fontanels, and sunset sign.
– Macrocephaly—head circumference curve
should be used.
– Ophthalmologic examination may reveal optic
atrophy or papilledema.
The decision whether the patient should be admit-
ted to the floor or the pediatric intensive care
unit (PICU) depends on the clinical presentation
(Box 14.1).
Box 14.1 Indications to admit the
patient to the PICU
● Signs of elevated ICP.
● Moderate to severe hydrocephalus.
● Intratumoral hemorrhage.
● First seizure.
● GCS<14.
14.2.1 Emergencies in Patients
with Supratentorial Brain Tumors
If the child presents with clinical signs of ele-
vated ICP, due to mass e ect, hydrocephalus with
trapped temporal horn, or trapped contralateral
ventricle, and/or if Glasgow Coma Scale (GCS) <13:
● Call anesthesiology and stabilize child (airways,
breathing, and cardio).
● Perform computed tomography (CT) scan or
preferably magnetic resonance imaging (MRI) if
immediately available.
● Type and screen and order blood.
● Give steroids or mannitol if immediate surgery is
considered.
● External ventricular drain (EVD) if
hydrocephalus and/or consider urgent
craniotomy for decompression and tumor
resection.
● Make sure that parents are informed in an
interdisciplinary fashion involving all required
pediatric caregivers.
14.3 Clinical Evaluation
Evaluation should always be interdisciplinary,
involving pediatricians, pediatric oncologists, and,
in select cases, pediatric neurologists and the
pediatric epilepsy team. Presentation at a multidis-
ciplinary tumor board is useful prior to surgery to
determine the strategy, including preoperative
diagnostic evaluations, early inclusion in trials,
surgical strategy, and, to a certain degree, anticipa-
tion of subsequent adjuvant treatment.
91

Potential inclusion in a clinical trial should be
considered early and ongoing clinical trials as well
as inclusion criteria may be found in:
● United States and worldwide: website of the
National Cancer Institute at the National
Institute of Health ().
● Europe:
If the presenting symptom is longstanding epi-
lepsy, it should be discussed prior to surgery with
the epilepsy team to tailor the size of the resec-
tion. Invasive monitoring with subdural or depth
electrodes before and/or after resection may be
necessary to determine the epileptogenic zone.
The epileptogenic zone may extend outside the
radiographic lesion. Particularly in benign tumors
(ganglioglioma, dysembryoplastic neuroepithelial
tumor [DNET]), postoperative long-term seizure
freedom is one of the goals of the surgery. Where
the clinical evaluation of the patient occurs
depends on the urgency of the presenting symp-
toms. It may be in an inpatient setting or in ambu-
latory care
The clinical evaluation includes:
● Thorough neurologic examination.
● Fundoscopy and/or ophthalmologic
examination; in older children, the visual field
should be examined with Goldmann
perimetry.
● Electroencephalogram (EEG) if seizures are
present or suspected and/or 24-hour video EEG
(VEEG) to evaluate epileptic focus.
● Endocrinologic workup.
● Neuropsychological assessment—in older
children and adolescents.
● Anesthesia consult—if the child su ers from any
other medical condition.
● If a lumbar puncture is required for staging
reasons, it should be performed only after
imaging. Be aware of possible brain herniation
due to mass e ect. Send samples of
cerebrospinal fluid (CSF) to cytology to evaluate
for CSF dissemination. A diagnostic lumbar
puncture is more often performed
postoperatively, and should be delayed at least
14 days post-operative to avoid false-positive
results.2
14.4 Imaging
The imaging of choice, if not in an emergency, is
always MRI with and without contrast agent,
including navigation, di usion, and fluid-attenu-
ated inversion recovery (FLAIR) images.
An MRI of the whole spine is necessary in
almost all cases for staging reasons. If it cannot be
obtained before surgery, it should be planned at
least 14 days after surgery to reduce false-positive
results.2
Functional MRI and di usion tensor imaging
(DTI), depending on location of tumor and age of
child, can provide functional and structural infor-
mation for surgical planning.
Positron emission tomography (PET) is a meta-
bolic imaging modality that can be helpful in dif-
ferentiating low-grade from high-grade lesions
and for further di erentiation of incidental supra-
tentorial lesions.3
CT has almost no role in the evaluation of supra-
tentorial hemispheric tumors, except in emer-
gency situations. There is a small cumulative abso-
lute risk reported for leukemia and brain tumors
from numerous CTscans.4
Preoperative digital subtraction angiography and
embolization may be useful in selected cases of
highly vascularized tumors (meningioma, heman-
gioblastoma).5
Ultrasound is only a screening tool in infants,
and it may be helpful in follow-up in CSF outflow
obstructions.
14.5 Preoperative Management
● Extensive and thorough communication with
parents/caregivers.
● The child should be informed in an age-
appropriate fashion.
● Preoperative blood work (hemoglobin,
electrolytes, coagulation, type and screen).
● Preoperative steroids plus omeprazole.
● Antiepileptic medication (AED) is indicated for
suspected or diagnosed seizures.
● Neuroanesthesiologic evaluation.
If hydrocephalus is present, an EVD placement
may be helpful to temporize until the time of sur-
gery and avoid placement of a definitive shunt.
Handling of an EVD needs special attention, partic-
ularly during transfers, as open drains may result
in overdrainage and clamped drains may result in
ICP elevation. There is generally no role for defini-
tive placement of ventriculoperitoneal shunts
prior to tumor surgery, as hydrocephalus often
resolves with the tumor resection.
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92

14.6 Perioperative
Management
● Adequate temperature in the operating room.
● Antibiotics 30 to 60 minutes before incision.
● Have blood in the room before incision
(especially in highly vascularized tumors such as
atypical teratoid rhabdoid tumor [ATRT],
meningiomas, and hemangioblastomas and in all
infants).
● Apply SCD (sequential compression device) for
children older than 12 years and/or beginning of
puberty.
● Head shaving is contraindicated. Only minimal
clipping on the site of incision is used; long hair
is combed and braided away.
● Head fixation: In very young children and infants,
headrests that do not require pins may be an
option. In children older than 2 years, the head is
fixed in a Sugita or Mayfield-type head holder.
Appropriate pins and pressure must be used,
depending on the patient’s age. The six-pin Sugita
head holder is optimal for smaller children.
● Neuronavigation is especially helpful in
determining the location and size of the
craniotomy and should be used in all cases.
Intraoperative brain shift reduces its reliability.
● Intraoperative neurophysiological
neuromonitoring—depending on the location of
the tumor, this can help in performing a safer
resection, for example, if the tumor is close to
the central region. Somatosensory evoked
potential and motor evoked potential as well as
cortical stimulation mapping may be used.
● If one of the aims of the surgery is to resect the
epileptogenic zone around the tumor, pre- or
postresection invasive monitoring or
intraoperative electrocorticography (ECoG) may
be required.
● Ultrasonic aspirator is a useful and essential tool
in the resection of supratentorial hem ispheric
tumors.
● Ultrasound is a real-time intraoperative imaging
that provides information quickly and safely.
● Intraoperative MRI is a relative real-time tool
only available in a few pediatric neurosurgery
centers and only little data about its e cacy
exist.
● Awake craniotomy with functional mapping can
be used in selected cases where tumors are close
to language areas and/or motor areas and only in
older children, as cooperation of the patient is
required.6
● Evaluate if 5-aminolevulinic acid (5-ALA) should
be given as a surgical aid, but be aware that at
the present time in most countries it is not
approved for children and could only be given in
the context of clinical trials. Convincing data
exist for adults,7 but little is known about its use
in pediatric brain tumors. However, it appears to
be useful in recurrent high-grade gliomas
(HGGs) in children.8
● Repeated informing of the parents via telephone
during surgery is very well received. It is an easy
way to reduce stress for the family.
● Collect tissue for frozen section and definitive
pathology in adequate container and storage
media; evaluate if frozen samples for molecular
analysis are necessary.
14.7 Postoperative
Management
After elective surgery of supratentorial hemispheric
tumors, all patients should be extubated in the ope-
ration room for immediate evaluation (Box 14.2).
Box 14.2 Management of postopera-
tive drains
● If epidural/subgaleal/CSF drains are used,
ensure that they are open and written orders
regarding volumes and alarm triggers exist and
are thoroughly communicated.
● Soft silicone-type drains are preferable to all
other types.
● Never use strong vacuum bottle suction, as
this carries a risk of low ICP and subsequent
epidural hemorrhage even far from the original
craniotomy site.
● If CSF drainage is used, make sure it is on the
correct drainage level and written orders about
maximum drainage volume are provided.
All patients should be admitted to the ICU postop-
eratively:
● Head of bed elevation: approximately 30 degrees.
● Check every 30 minutes for GCS, pain score,
neurologic deficits, and vital signs.
● Ensure su cient analgesia (often
underestimated).
● Continue steroids for 48 hours, then taper
usually in 5 days.
● Check labs (hemoglobin and electrolytes) and
fluid balance.
Supratentorial Tumors
93

● Continue AED.
● Management of postoperative drains.
● Post-operative MRI within 24 hours should be
considered a modern standard: it is essential to
document the rate of resection/extent of
residual tumor, hemorrhage, swelling, and
postsurgical ischemia (include di usion-
weighted sequences!).
● Mobilization should be under instruction of
physiotherapy as soon as possible, usually on the
first postoperative day.
● Evaluate if the patient requires inpatient
neurorehabilitation, physiotherapy, and speech
therapy.
● Neuropathologic workup should include
molecular diagnostics.
● Present the patient at the tumor board.
● Postoperative neuropsychological assessment—
important to keep up with the child’s school
performance.
An appointm ent should be scheduled in an inpa-
tient or outpatient setting to inform the parents/
caregivers about the neuropathologic results and
the recom m endations of the tum or board. With
a form al appointm ent, it can be ensured that all
caregivers of the patient can be present and that
su cient tim e is available to answer all the
questions.
If chemotherapy and radiation is indicated, it is
usually started as soon as the surgical incision is
healed. Patients should always be clinically seen by
the surgeon and the healing incision must be ins-
pected before starting radiation or chemotherapy.
14.8 Complications
14.8.1 Intraoperative
Complications
● Hemorrhage: The risk of intraoperative
hemorrhage can be reduced by careful planning,
surgical technique, and checking the
preoperative coagulation labs and evaluating the
bleeding history.
● Swelling: General perioperative neurosurgical
measures such as steroids at the beginning of
the operation, keeping the Pco2 at levels around
30 to 35 mm Hg, and making sure venous
outflow is not obstructed can help in reducing
swelling. Reverse Trendelenburg positioning and
mannitol administration 0.5 to 1 mg/kg can be
helpful as an acute measure.
● Seizures: Give AED the m orning of the surgery
and use cold ringer lactate irrigation. If
seizures occur, have ice-cold ringer lactate in
the room !
14.8.2 Postoperative
Complications
● Postoperative hemorrhage: Asymptomatic
hemorrhage in the resection cavity on
postoperative MRI may be tolerated. If the size of
the hemorrhage extends past the tumor size, or
a drop in GCS and/or new onset of seizures
occurs, consider reoperation. Epidural
hematoma evacuation is indicated if
symptomatic or if the width is greater than the
skull diameter, or 1 cm. If a reoperation to
evacuate hematoma is necessary, check for
disturbances of coagulation and substitute if
necessary. Evaluate if postoperative low-
molecular-weight heparin administration should
be postponed.
● Infection: Check wound and temperature daily;
patients m ay have m ildly increased
temperature the first few days, usually not
exceeding 37.9 °C. Check infection param eters
on the first, second, and fifth postoperative day.
An increase of C-reactive protein on the first
and second postoperative day is physiologic; on
the fifth day, it should have dropped to nearly
norm al levels. Leukocytosis can be expected
postoperatively and in patients on steroids. As
steroids are tapered, leucocyte counts decrease
gradually.
● Wound healing: Check the wound daily. It would
be preferable to leave the incision uncovered
after the third day; however, draping may be
required as children tend to scratch on the
incision!
● Seizures: If a new seizure occurs and continues
for more than 3 minutes, treat with
benzodiazepines and evaluate intubation.
Immediately perform CT to check for rebleeding
or venous infarction. Consult pediatric epilepsy
team for AED and start VEEG.
Tumor
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14.9 Low-Grade Gliomas
(Di use, Juvenile Pilocytic
Astrocytoma)
14.9.1 Key Features
● WHO classification I or II.
● Slow-growing tumors with comparatively
favorable outcome.
● Better prognosis than in adults.
● Complete neurosurgical resection without
adjuvant therapy is the treatment of choice.
14.9.2 Epidemiology
Gliomas account for approximately 53% of tumors
in children 0 to 14 years of age and 36% in children
15 to 19 years of age.1 Low-grade gliomas (LGGs)
of the cerebral hemispheres account for approxi-
mately 24 to 40% of all low cerebral LGGs.9,10
14.9.3 Clinical Presentation
Approximately 40% of the tumors presents with
seizures.10 Other presentations are focal neuro-
logic deficit and raised ICP.
14.9.4 Evaluation
EEG and epilepsy-surgery-specific evaluation are
indicated if longstanding epilepsy is reported. Pre-
operative neuropsychological assessment is indi-
cated in older children.
14.9.5 Imaging
● Di use astrocytomas are characterized by being
homogeneously hyperintense on FLAIR imaging,
hypointense on T1, and hyperintense on T2; also,
they show no enhancement. No peritumoral
edema; magnetic resonance spectroscopy (MRS)
findings are nonspecific.11
● Pilocytic astrocytoma (PA) has in most cases the
classic appearance of a cystic mass with an
enhancing mural nodule. Less common
appearances are quite nonspecific. Surrounding
vasogenic edema is rarely present, and this
feature provides a valuable clue to the correct
diagnosis.12
● MRI navigation: Sequences should be obtained,
and in nonenhancing tumors (LGGs excluding
PA) MRI FLAIR sequences are mandatory to
evaluate the size and margins of the tumor.
14.9.6 Pathology
LGGs encompass tumors of astrocytic, oligoden-
droglial, and mixed glial–neuronal histology. In
children, juvenile pilocytic and fibrillary astrocy-
toma are the most common glial histological
types.13,14 Germline polymorphisms have been
associated with high risk for gliomas.15 BRAF
duplications have been found in the majority of
PA.16 BRAF and CDKN2A alterations in childhood
gliomas have been detected in LGGs, which trans-
formed into secondary HGGs.17 Pleomorphic xan-
thoastrocytoma (PXA), ganglioglioma, and a small
subset of extracerebellar PA have BRAF V600E
mutations.18 Potential future treatment includes
inhibition of the MAP kinase pathway, which regu-
lates cell proliferation. Several signal transduction
inhibitors are of potential clinical activity.
14.9.7 Treatment
GTR should be the goal when it can be achieved
with an acceptable functional outcome.9
● Neuronavigation: If neuronavigation is used,
FLAIR sequences should be fused with the T1
navigation sequences, as particularly GTR of
di use LGGs means resection of the “FLAIRoma.”
● Intraoperative imaging: Only high-resolution
MRI would provide su cient image quality to
evaluate di use astrocytoma.
● Intraoperative neuromonitoring should be used
in tumors close to eloquent regions.
● Consider awake surgery in children older than
12 years, with tumors near language areas.
● If there is a risk for intraoperative seizure, have
cold irrigation in the operation room.
● Post-operative care: watch out for seizures and
continue seizure medication.
Postoperative MRI should be obtained in the first
24 hours. Be aware that systematic and substantial
overestimation of residual nonenhancing volume
on MRI within 48 hours of resection compared
with months postoperatively, in particular for
FLAIR imaging, has been observed.19
14.9.8 Adjuvant Therapy
There is no role for adjuvant chemo- or radiother-
apy if GTR was achieved in supratentorial hemi-
spheric LGGs.
Radiotherapy and particularly chemotherapy
may be indicated for unresectable or partially
resected tumors.
Supratentorial Tumors
95

Stereotactic radiotherapy or intensity-modu-
lated radiotherapy can be applied; both provide
local control for children with small, localized,
low-grade glial tumors.20,21 As always in children,
the risk and benefit of radiation therapy must be
strongly assessed vis-à-vis the risks of long-term
e ects of radiation in long-term tumor survivors.
14.9.9 Outcome
According to the data of the Children’s Oncology
Group, the overall 5-year progression-free survival
(PFS) is 78% and 8-year PFS is 75% in hemispheric
tumors. If GTR is achieved, 5-year PFS is 94%.
The 5- and 8-year overall survival (OS) rate is
96%.9
14.9.10 Follow-Up
Regular follow-up with sequential MRIs every 6
months for the first 2 years, and yearly thereafter.
14.10 High-Grade Gliomas
14.10.1 Key Features
● The most frequent entities in HGGs are
glioblastoma multiforme (GBM; WHO grade IV)
and anaplastic astrocytoma (AA; WHO grade III).
● As it is a relatively rare disease, enrollment in
ongoing trials is crucial.
● GTR should be attempted.
● Highly aggressive and always needs adjuvant
chemo- and radiotherapy.
14.10.2 Epidemiology
HGGs comprise approximately 17% of all brain and
CNS tumors reported among 0 to 14 years old and
8% in children 15 to 19 years old.1
14.10.3 Clinical Presentation
HGGs often present with signs of raised ICP, and
duration of symptoms is usually short as they are
fast-growing tumors.
14.10.4 Evaluation
CT scan if emergency imaging is necessary, but
MRI is the imaging of choice.
14.10.5 Imaging
MRI appearance: GBMs present as an aggressive-
appearing, ill-defined, heterogeneous enhancing
mass that may invade the corpus callosum.
Necrosis and hemorrhage are the hallmarks of
these tumors.11,22 AAs are usually heterogenic
hemispheric masses, with involvement and expan-
sion to the cortex. They typically do not enhance
and do not show necrosis or calcification. Anaplas-
tic oligodendrogliomas can be di erentiated from
AAs by their high rates of calcification. MRS
provides information about metabolic and bio-
chemical activity of HGGs and decreased N-acety-
laspartic acid (NAA), lactate peak, and elevated
choline/creatinine ratio.23
14.10.6 Risk Factors
Prior radiation, Li–Fraumeni syndrome,24 and neu-
rofibromatosis type 1 (NF1).25
14.10.7 Pathology
According to the WHO classification, supratento-
rial HGGs are divided into AAs (WHO grade III),
anaplastic oligodendrogliomas (WHO grade III),
mixed astrocytic tumors, and GBM (WHO grade
IV).14 A subentity is identified as giant cell glioblas-
toma, which is reported to have a slightly better
prognosis in the pediatric age group.26
14.10.8 Molecular Features
There are molecular di erences between adult and
pediatric HGGs; therefore, results from adult clini-
cal trials cannot be extrapolated to children.
Molecular markers overexpressed in pediatric
HGGs include Platelet derived growth factor recep-
tor alpha (PDGFRα) and p53. Amplification of epi-
dermal growth factor receptor alpha (EGFRα) is
observed, but to a lesser degree than in adult
HGGs.27 In pediatric GBM, broad chromosomal
gains and losses, such as gain of chromosome 1q
and broad losses of chromosome 10q, are com-
mon. The heterozygous K27 mutation on histone
tail 3.1 and 3.3 and the G34 R/V mutations on the
histone tail 3.3 have been found to be common in
HGGs. Mutations of the p53 tumor suppressor
gene play a key role in tumorigenesis in patients
with Li–Fraumeni syndrome.28
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96

14.10.9 Treatment
GTR should be achieved since the extent of tumor
resection is also the strongest predictor of survival
in pediatric glioblastoma.27,29 GTR is significantly
associated with OS in pediatric patients with glio-
blastoma excluding tumors located in the brain-
stem.30 5-ALA as o -label use for recurrent HGG is
reported to be useful8 and appears to be safe.
14.10.10 Chemotherapy
Chemotherapeutic agents such as temozolomide,
bevacizumab, cisplatin, etoposide, vincristine, and
ifosfamide are used, but there is no international
standard protocol for children. Survival was signif-
icantly improved for patients with completely
resected HGG when they were treated with the
HIT-GBM-C chemotherapy.31 The combination of
bevacizumab and CPT-11 was reported to be fairly
well tolerated, and most severe BVZ-related toxic-
ities were rare, self-limiting, and manageable.32
Molecular targeted therapies are not available yet,
but promising results of preclinical data will lead
to tailored therapies.
14.10.11 Radiation
Radiation therapy is the standard of care after sur-
gical resection for children older than 3 years.33
Treatment of children with glioblastoma with con-
formal radiation, temozolomide, and bevacizumab
as adjuncts to surgical resection has shown prom-
ising results.34
14.10.12 Outcome
Glioblastoma survival is somewhat higher for chil-
dren than adults; in children, the 5-year survival
rate is 19%.1 The higher survival rates may be due
to more intensive chemotherapy protocols or due
to the fact that pediatric HGGs di er biologically
from HGGs in adults.35 The prognosis is worse in
very young children; this may be due to delayed
radiotherapy.
14.10.13 Follow-Up
Follow-up should always be interdisciplinary and
the children should be under the surveillance of
the pediatric neuro-oncologists. If recurrence is
suspected, there is a role for FDG-PET and MRS to
distinguish between radiation necrosis and tumor
recurrence.
14.11 Pleomorphic
Xanthoastrocytomas
14.11.1 Key Features
● WHO grade II, but worse outcome than LGG.
● GTR is the primary goal; unclear role of adjuvant
therapy.
● PXAs with anaplastic features have been
described and tend to have worse outcome.
● Older children and seizures as first presentation.
14.11.2 Epidemiology
Very rare, approximately 1% of all pediatric brain
tumors.
14.11.3 Presentation
May present with a longstanding history of seiz-
ures.
14.11.4 Evaluation
MRI appearance: peripheral or cortical mass com-
posed of cystic and solid components and hetero-
geneous enhancement.11
Staging with MRI neuroaxis is mandatory, as
CSF dissemination has been reported.36,37
14.11.5 Pathology
PXAs demonstrate immunoreactivity for neuronal
markers like S100 and GFAP. P53 immunolabeling is
usually weak or negative, but CD34 labeling is fre-
quent. PXAs can have anaplastic features but little is
known regarding clinicopathologic and molecular
features.
14.11.6 Molecular
PXAs have been found to have the highest frequency
of BRAF V600E mutations out of all CNS neoplasms.18
14.11.7 Treatment
GTR is the primary goal as it is a strong predictor
of PFS. The role of adjuvant treatment is not well
established, and both chemotherapy and radiation
therapy have been used with reports of a good res-
ponse. However, since radiation has been reported
as a negative predictor for long-term OS in LGG,38
this therapy should be spared for tumors with ana-
plastic features.
Supratentorial Tumors
97

14.11.8 Outcome
PXAs have very variable outcome. Five-year PFS is
reported to be 40 to 68% and 5-year OS rate is 76
to 87%.39,40,41 Ten-year OS rate is reported to be
about 43%.38 There has been no di erence in
pediatric PXAwith and without anaplastic features
regarding outcome. Prognosis is overall worse in
children than in adults.41
14.12 Primitive
Neuroectodermal Tumors
14.12.1 Key Features
● Heterogeneous group of tumors.
● Young age, aggressive tumor.
● Histology similar to medulloblastomas, but
worse outcome.
● All patients should be treated on a clinical trial.
● Adjuvant chemo- and radiotherapy show
increased survival.42
14.12.2 Epidemiology
Supratentorial primitive neuroectodermal tumors
(SPNETs) account for approximately 2.5% of all
pediatric brain tumors.43
14.12.3 Clinical Presentation
As it is a rapidly growing tumor, it often presents
with increased ICP. Focal neurologic deficits and
seizures are described as well.
14.12.4 Clinical Evaluation
Patients should have a staging workup to assess
the extent of disease. Preoperative MRI of the brain,
MRI of the spinal axis, and lumbar CSF sampling for
cytological examination (lumbar and intraopera-
tively) is mandatory. Discordance between the
results of neuroaxis MRI imaging and lumbar and
intracranial CSF cytology in perioperative detection
of tumor dissemination has been reported for
pediatric SPNETs.44
14.12.5 Imaging
MRI appearance: SPNETs are heterogeneous; no
specific distinct pattern characterizes them. The
solid component of PNETs usually has avid hetero-
geneous enhancement with minimal surrounding
edema.22 Necrosis and hemorrhage are common
and are seen as restriction on di usion-weighted
imaging (DWI).11
14.12.6 Pathology
Definition of the WHO Working Group14: hetero-
geneous embryonal tumor composed of undi er-
entiated or poorly di erentiated neuroepithelial
cells which have the capacity for or display diver-
gent di erentiation along neuronal, astrocytic, and
ependymal lines.
● Cerebral neuroblastomas—only neuronal
di erentiation.
● Ganglioneuroblastomas—neuronal
di erentiation and ganglion cells.
● Medulloepitheliomas—features of neural tube
formation.
● Ependymoblastomas—ependymoblastic rosettes.
14.12.7 Molecular
CNS PNETs have complex genomic alterations.45
Oncogenes located on chromosome 2p are
involved in initiating and sustaining CNS PNET.
14.12.8 Treatment
Blood should be in the operation room before skin
incision. This tumor is often highly vascularized,
so hypervolemia due to blood loss is a common
complication.
Be aware of brain collapse; occasionally, a shunt
is needed due to hydrocephalus. Surgical resection
of tumor should be done only if additional perma-
nent neurologic deficits can be spared. The role of
GTR is controversial.
14.12.9 Chemotherapy
All patients are treated with chemotherapy. The
specific protocol should be discussed in tumor
board. Chemotherapy combined with radiation
therapy has been associated with a significant
increase in survival.42
14.12.10 Radiation Therapy
Radiation of neuroaxis w ith focal beam on
tum or location is included in m ost protocols.
Whole-spine radiation is indicated for spinal
m etastasis. There are prom ising data about
favorable local control and low rates of acute
radiation-induced toxicity for proton radiation
therapy.46
Tumor
98

14.12.11 Outcome
Despite adjuvant chemo- and radiotherapy, the
outcome is relatively poor. One-year survival rate
is 76.4% and 5-year survival is 49.5%.1 Children
younger than 2 years have a worse prognosis.47
The outcome for children with SPNET generally
has been reported to be poor and worse than
medulloblastomas.48,49
14.12.12 Follow-Up
Interdisciplinary follow-up under the lead of
pediatric neuro-oncology is indicated.
14.13 Atypical Teratoid
Rhabdoid Tumors
14.13.1 Key Features
● Highly malignant.
● Mostly in infants.
● SMARCB1 is a specific marker.
14.13.2 Epidemiology
Around 80% of the patients diagnosed with ATRT
are children younger than 3 years. There is a slight
male predominance of 58%.50 About 50% are supra-
tentorial and 50% infratentorial.51 Rhabdoid tumor
predisposition syndrom e is a risk factor for ATRT.
14.13.3 Clinical Presentation
As most of the tumors arise in infants, symptoms
of elevated ICP such as macrocephaly, bulging fon-
tanels, and vomiting are the presenting symptoms.
14.13.4 Evaluation
MRI: A supratentorial tumor with a thick, wavy
(irregular) heterogeneously enhancing wall sur-
rounding a central cystic region is suggestive of
ATRT,52 as it is a distinctive and unusual pattern. It
is present in approximately 40% of ATRT.53
MRI spectroscopy may be helpful to distinguish
them from other brain tumors. The combination of
prominent choline and lactate and lipid peaks and
generally absent NAA and myo-inositol peaks pro-
vide a metabolite profile typically distinct from
other malignant pediatric brain tumors.54
MRI of the neuroaxis for staging reasons is man-
datory, especially in young children, as 13% present
with metastatic disease.50 If possible, a lumbar
puncture should be done as well, but be aware of
the risks described in the introduction chapter.
14.13.5 Risk Factors
In older children, ATRT can occur as secondary
tumor after whole-brain irradiation.55
14.13.6 Pathology
ATRTs, Medulloblastom as, and cerebral PNETs
form the group of embryonal tum ors. The main
histologic characteristics of rhabdoid tumor cells
are abundant cytoplasm with juxtanuclear eosi-
nophilic inclusions and nuclei that display a sin-
gle, prominent nucleolus in clear, uncondensed
chrom atin.14 A defect in the INI 1 gene (SMARCB1)
leading to loss of expression is associated with
rhabdoid tumors and is used for diagnosis.
SMARCB1 gene abnormalities are found in 76 to
95% of ATRT patients.56,57
14.13.7 Treatment
Improved OS and PFS have been reported with
maximal primary tumor resection,58 but an associ-
ation between the extent of resection and OS is
still controversial.50
14.13.8 Chemotherapy
No standard therapeutic approach has been estab-
lished given the rarity of ATRTs and the variety of
treatment regimens used to date. High-dose chemo-
therapy regimens seem to provide good results and
increase survival.51 Intrathecal therapy is widely used
as it has shown significantly higher survival rates.59
14.13.9 Radiotherapy
In children younger than 3 years, the strategy is
usually to avoid or delay radiation. Given the poor
prognosis of ATRT, delayed risks of neurocognitive
developmental problems should be balanced with
potential survival benefit derived from adjuvant
radiotherapy.50
If radiotherapy is indicated, it
should be started as soon as the incision is well
healed. There has been a search for treatments
avoiding irradiation to healthy tissue. Initial clini-
cal outcomes with proton therapy show favorable
results. The advantages of proton therapy are par-
ticularly suited to the treatment of ATRT, since the
disease often requires radiation treatment at an
early age.60
Supratentorial Tumors
99

14.13.10 Outcome
One-year survival is 48% and 5-year survival is
28%.1 The median OS is about 10 months and
metastatic disease correlates with a worse progno-
sis.50 Age less than 2 years, metastasis at diagnosis,
and strong claudin-6 positivity appear to be inde-
pendent prognostic factors for outcome.61
14.13.11 Follow-Up
Interdisciplinary follow-up under the lead of
pediatric neuro-oncology is indicated, similar to
CNS PNET. Several long-term complications have
been reported, such as peritoneal metastasis from
seeding through a ventriculoperitoneal shunt in
pineal and ventricular ATRT62,63 and multifocal
necrotizing leukoencephalopathy as a treatment-
related morbidity.64
14.14 Desmoplastic
Neuroepithelial Tumors
14.14.1 Key Features
● The presenting symptom is often seizures;
characteristically, it causes intractable partial
seizures.
● First described in 1988, WHO classified in 1993.
14.14.2 Epidemiology
DNET belongs to the neuronal–glial tumors, which
together with the neuronal tumors comprise 6.5 to
7.9% of CNS tumors in children.1
14.14.3 Pathology
DNET is a grade I glioneuronal tumor in the WHO
classification 14 and shows no IDH1 mutations. The
genetic basis of DNET is not well known or well
defined. Somatic FGFRI alterations and MAP kinase
pathway activation are events that both cause
DNETs to develop. Gains of chromosomes 5 and 7
and loss of chromosomes 1p, 10q, and 19q have
been observed and are associated with DNETs.65
14.14.4 Clinical Evaluation
Preoperative evaluation must always include con-
sultation with the epilepsy service. Children with
epilepsy and AED may have coagulation abnormal-
ities, so preoperative hematology consultation
may be indicated.
14.14.5 Imaging
MRI appearance: DNETs are characterized as hav-
ing a “bubbly” appearance, are multilobulated, are
hypointense on T1 in a wedge-shaped configura-
tion, and hyperintense on T2-weighted images.
FLAIR imaging shows a characteristic bright rim.
DNETs have one of the highest apparent di usion
coe cient values among benign tumors. MRS is
nonspecific.11
14.14.6 Treatment
Surgery is curative if the tumor can be completely
resected. DNETs in the temporal lobe are often
resected by temporal lobectomy (with or without
hippocampectomy), and in select cases, intraope-
rative ECoG and pre- and/or postoperative invasive
monitoring may be indicated.
14.14.7 Outcome
DNETs have a very good outcome from an onco-
logic standpoint, similar to LGGs. Long-term seiz-
ure freedom can be achieved in 86%.66
14.14.8 Follow-Up
Interdisciplinary follow-up under the lead of the
pediatric epilepsy team is indicated.
14.15 Gangliogliomas
14.15.1 Key Features
● Seizures are the most common presentation.
● Two di erent cell types (combination of
neuronal and glial cell).
● WHO I, rarely anaplastic.
● Very good prognosis with GTR.
14.15.2 Epidemiology
The majority of gangliogliomas are localized in the
temporal lobe, but can occur throughout the
CNS.14 Most of the supratentorial cases are tempo-
ral and frontal.
14.15.3 Clinical Presentation
Seizures are the most frequent presentation, and
gangliogliomas are the most common tumor to
cause intractable, chronic pediatric epilepsy.67
Tumor
100

14.15.4 Imaging
MRI shows a circumscribed mass and enhance-
ment varies; a mural nodule with a cyst is also
described. In CT, calcifications may be visible.
14.15.5 Pathology
Well-di erentiated, slow-growing neuroepithelial
tumor composed of neoplastic, mature ganglion
cells alone (gangliocytoma) or in combination with
neoplastic glial cells (ganglioglioma). Polymor-
phisms of the TSC1 and TSC2 genes have been com-
mon in patients with gangliogliomas.68 Anaplastic
gangliogliomas are rare.
14.15.6 Treatment
It is very important to identify pre- and intraopera-
tively the epilepsy focus and to perform a complete
lesionectomy. The use of intraoperative neuromoni-
toring is indicated. GTR should be performed safely
whenever possible and does not require postopera-
tive irradiation. If only a subtotal resection is
achieved, then radio therapy may improve long-
term tumor control of both low-grade and high-
grade tumors and, thus, should be considered.69
14.15.7 Post-operative Care
Continue AED.
14.15.8 Outcome
Overall, outcome is favorable. Five-year PFS rate is
81.2% and the OS rate is 97.4%.70 The 15-year OS rate
is reported to be 94%. PFS is a ected by the extent of
initial resection, so GTR should be achieved.71
For tumors located in the cerebral hemispheres,
the achievement of total resection and seizures at
presentation were associated with prolonged PFS.70
14.15.9 Follow-Up
Interdisciplinary follow-up with the pediatric epi-
lepsy team and neuro-oncology is indicated.
14.16 Ependymomas
14.16.1 Key Features
● GTR is the most important prognostic factor.
● Recent molecular classification of ependymomas
identified nine di erent subgroups in the CNS,
two of which are in pediatric supratentorial
tumors.
14.16.2 Epidemiology
A total of 5.4% of all tumors in childhood are epen-
dymomas.1 One-third of all pediatric ependymo-
mas are supratentorial.72
14.16.3 Clinical Presentation
In most of the cases, they present with elevated
ICP.73
14.16.4 Imaging
MRI of the neuroaxis and CSF analysis for cytology
for staging are indicated.
14.16.5 Pathology
Ependymomas are classified according to the
WHO grading system. The WHO classification sys-
tem separates ependymomas into three groups
based on histopathological criteria14: grade I
(myxopapillary); grade II, which is further subdi-
vided into four subtypes (cellular, papillary, clear-
cell, and tanycytic); and grade III (anaplastic).
Germline mutations on the tumor suppressor gene
NF2 on chromosome 22q are associated with
ependymomas. Loss of chromosome 1p and gain
of chromosome 1q are genetic abnormalities
highly linked to ependymomas. Recent molecular
classification of ependymomas identified nine dif-
ferent subgroups in the CNS, with three subgroups
in the supratentorial location. Two supratentorial
subgroups are in the pediatric population and are
characterized by prototypic fusion genes involving
RELA and YAP1, respectively.74
14.16.6 Treatment
Ependymoma remains a “surgical disease.”75 Sur-
gical considerations aim for GTR, as it is the most
important prognostic factor. For supratentorial
pediatric tumors, the GTR and GTR combined with
external beam radiation therapy results in the lon-
gest time to recurrence/progression. Subtotal
resection is correlated with inferior outcome.72
Perioperative considerations are similar to those in
astrocytomas.
Young age at diagnosis and the proximity of crit-
ical structures in patients with ependymoma make
Supratentorial Tumors
101

proton radiation therapy a possible radiation
modality.76
14.16.7 Outcome
Favorable outcome is reported with a 5-year OS
rate of 72 to 85%.77,78
There are case reports of grade II ependymomas
with GTR without adjuvant therapy and long-term
survival.79
It is controversial if classical grading plays a con-
tributing role in predicting outcome. In a report of
40 pediatric patients, the Children’s Cancer Group
found no di erences in PFS across WHO grades.80
14.16.8 Follow-Up
Follow-up should be continued with MRI scans
after 3 and 6 months, and yearly in stable situa-
tions with or without residual disease.
14.17 Meningiomas
14.17.1 Key Features
● Meningiomas are much rarer in children than in
adults.
● Believed to be more aggressive than in adults,
but this may be just a matter of a larger variety
of outcomes.
● Strong association with prior radiation
treatment81 and with neurofibromatosis.82
14.17.2 Epidemiology
Only about 2.5% of all primary pediatric CNS
tumors are meningeal in origin. The incidence
rises with age.1
14.17.3 Evaluation
A history of prior radiation treatment should be
actively inquired. Approximately 40% of children
with meningiomas have NF2.83 After vestibular
schwannoma, the next most common tumor type
in NF2 is meningioma, which is encountered in
roughly half of the cases.84
14.17.4 Imaging
MRI is also the imaging modality of choice and
optimally shows extent and vascularity. Childhood
meningiomas may more frequently lack any dural
attachment.82
14.17.5 Pathology
A large fraction of pediatric meningiomas are
WHO grade II or III (60%) and commonly demon-
strate aggressive variant morphology, brain inva-
sion, an increased mitotic index, and frequent
deletions of 1p and 14q. About half of these chil-
dren have significantly shortened PFS and OS.85
Even metastatic meningioma is reported.86
14.17.6 Treatment
Preoperative embolization should be considered in
extensive, highly vascularized tumors, particularly
in small children. Blood in the room before inci-
sion is mandatory, since intraoperative mortality
due to blood loss has been reported.82
Because of very small numbers and lack of
standardized adjuvant treatment options, the ma-
nagement has to be tailored to the individual situ-
ation.
14.17.7 Outcome and Adjuvant
Treatment
The 5-year survival is 83.9%, suggesting that the
biological behavior of pediatric meningiomas is
more aggressive than that of its adult counter-
parts.87,88
14.17.8 Follow-Up
As children more frequently have higher grade
tumors, the clinical and imaging follow-up should
be in rather short intervals of initially 3 to 6 months.
14.18 Surgical Pearls
● Supratentorial tumors in children are less
common than posterior fossa tumors but occur
in a much greater variety.
● Each entity requires extensive resection.
● Outcomes vary from “cure” with surgery only to
very short intervals to recurrence and death in
spite of extensive adjuvant treatment.
● These tumors may be large and vascular, so
“have blood in the room.”
Tumor
102

14.19 Common Clinical
Questions
1. What is the best treatment for a supratentorial
LGG?
2. Is there a role for “watchful waiting” or for
stereotactic biopsy in supratentorial LGG?
3. What is the outcome of LGGs that underwent
GTR?
4. Is the outcome of pediatric PXAs similar to
LGGs?
5. What is the perioperative strategy in patients
with chronic epilepsy and suspected DNETs or
gangliogliomas?
14.20 Answers to Clinical
Questions
1. The aim of surgery in supratentorial
hemispheric LGGs is GTR. This can be achieved
with the aid of pre- and perioperative tools
such as navigation, neuromonitoring, and
awake craniotomy. If GTR cannot be achieved,
further surveillance is indicated, as residual
disease can be stable (progression-free disease)
in up to 55%.9
2. Wait and see has a role in asymptomatic small
tumors, but the risk of surgery and progression
of the tumor must be constantly evaluated.
Stereotactic biopsy usually has only a limited
role. GTR remains the goal and can be achieved
safely in the majority of cases. The role of
stereotactic biopsy is limited to the rare cases
where no oncologically meaningful, if still
partial, resection is possible due to localization
and/or di use nature of the tumor.
3. Outcome data from the Children's Cancer Group
(CCG) and Pediatric Oncology Group (POG)
study of primary surgery in LGGs indicate 5-
year PFS in 92% of children after GTR, ranging
from 95 to 100% for juvenile pilocytic
astrocytomas and gangliogliomas to 80% for
grade II di use astrocytomas in this age group.9
4. No, the outcome of pediatric PXA is more
variable and typically worse than LGGs. The 5-
year PFS in PXA is reported to be 40 to 68% and
the 5-year OS rate is 76 to 87%.39,40,41 The 5-year
PFS in LGG is 78% and the 5-year OS rate is 96%.9
5. The perioperative strategy of DNETs and
gangliogliomas is preoperative presentation at a
multidisciplinary epilepsy surgery conference.
The preoperative evaluation of the patient
should include VEEG and MRI in all cases, and
when indicated, fMRI (functional MRI), SPECT
(single-photon emission computed tomography),
PET, and neuropsychological testing. To detect
more precisely the extension of the epileptogenic
zone in order to achieve a more complete
resection and better outcome, pre- and/or
postoperative invasive monitoring may be
indicated. AED should be continued
postoperatively and should be reduced gradually
in collaboration with the epilepsy team.
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