Journal of Neuro-Oncology

https://doi.org/10.1007/s11060-020-03487-8

CLINICAL STUDY

The effect of mTOR inhibition on obstructive hydrocephalus in patients

with tuberous sclerosis complex (TSC) related subependymal giant cell
astrocytoma (SEGA)
Danielle R. Weidman1,5 · Sunitha Palasamudram2,5 · Maria Zak3 · Robyn Whitney3,5 · Blathnaid McCoy3,5 ·
Eric Bouffet1,5 · Michael Taylor4,5 · Manohar Shroff2,5 · Ute Bartels1,5

Received: 31 January 2020 / Accepted: 6 April 2020

© Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract
Purpose  Mammalian target of rapamycin inhibitors (mTORi) are known to effectively reduce the size of subependymal
giant cell astrocytomas (SEGAs), which are benign brain lesions associated with Tuberous Sclerosis Complex (TSC) that
commonly cause obstructive hydrocephalus (OH). This retrospective case series reviews an institutional experience of the
effect of mTORi on OH in patients with TSC-related SEGA.
Methods  Thirteen of 16 identified patients with TSC-related SEGA treated with mTORi from October 2007 to December
2018 were included. Serial magnetic resonance imaging (MRI) and clinical charts were reviewed to correlate symptoms
and signs of increased intracranial pressure (iICP) with ventriculomegaly on MRI. A proposed ventriculomegaly scale was
used: none (< 7 mm), mild (7–10 mm), moderate (11–30 mm), and severe (> 30 mm). OH was defined as moderate or severe
ventriculomegaly, based on the largest measurement.
Results  Patients’ median age at start of mTORi was 13 (6–17) years and five (38%) patients were female. Eight patients had
OH at the time of mTORi initiation, five of whom were asymptomatic. Six patients had improvement of hydrocephalus on
serial MRI imaging with mTORi therapy, while seven patients had no change based on the ventriculomegaly scale used. All
three patients who presented with symptoms of iICP and had OH also had papilledema. None had worsening of hydrocephalus
or required shunt placement. Out of five patients with symptoms of iICP, four avoided surgery.
Conclusion  Most patients had asymptomatic OH at the time of diagnosis, and ventricular enlargement was not correlated
with iICP symptoms. mTORi was successful for treatment of OH from TSC-related SEGA, even in the setting of acute
symptoms of iICP.

Keywords  mTOR inhibition · Hydrocephalus · SEGA · Tuberous sclerosis complex (TSC)

Abbreviations
CSF Cerebrospinal fluid
EI Evans’ index
iICP Increased intracranial pressure
* Ute Bartels MRI Magnetic resonance imaging
ute.bartels@sickkids.ca
mTOR Mammalian target of rapamycin
1
Division of Haematology/Oncology, Department mTORi Mammalian target of rapamycin inhibitor
of Paediatrics, The Hospital for Sick Children, 555 OH Obstructive hydrocephalus
University Avenue, Toronto M5G 1X8, Canada SEGA Subependymal giant cell astrocytoma
2
Department of Diagnostic Imaging, The Hospital for Sick TSC Tuberous sclerosis complex
Children, Toronto, Canada VPS Ventriculoperitoneal shunt
3
Division of Neurology, Department of Paediatrics, The
Hospital for Sick Children, Toronto, Canada
4
Division of Neurosurgery, Department of Surgery, The
Hospital for Sick Children, Toronto, Canada
5
University of Toronto, Toronto, Canada

13
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Introduction
Tuberous sclerosis complex (TSC) is an autosomal domi-
nant multisystem disease that has a wide spectrum of phe-
notypic variability. In the majority of cases, it is caused
by inherited or sporadic mutations that inactivate TSC1 or
TCS2 tumor suppressor genes [1]. The respective protein
products of these genes are hamartin and tuberin, which
suppress mammalian target of rapamycin (mTOR). This
important protein kinase controls cell growth and, when
upregulated in TSC, leads to the benign lesion formation
characteristic of this disease [2, 3]. These hamartomas can
affect multiple organ systems, most commonly the brain,
heart, lung, liver, kidney, retina, and skin [3, 4].
Subependymal giant cell astrocytomas (SEGAs) are
benign WHO grade I brain tumors that occur in up to
20% of patients with tuberous sclerosis complex (TSC)
[5]. Due to their typical location near the foramen of
Monro, growth of these lesions may lead to obstructive
hydrocephalus (OH) [6]. Once identified, serial magnetic
resonance imaging (MRI) every one to three years is the
recommended monitoring [3, 7].
OH, particularly when symptomatic, has been and
remains an indication for surgical intervention in patients
with TSC-related SEGA [8, 9]. Neurosurgery, however,
is not without risk. Rates of post-operative complications
after SEGA resection have been reported as high as 50%
[10]. In addition, patients with OH who undergo surgery are
more likely to require a ventriculoperitoneal shunt (VPS),
which also portends potential complications such as shunt
dysfunction and infection [9]. Hyperproteinorrhachia (high
cerebrospinal fluid (CSF) protein) has also been associated
with SEGA, which can lead to recurrent proteinaceous shunt
obstruction [11]. Surgical morbidity is especially high in
patients with symptoms of raised intracranial pressure [12].
While surgery has been the longstanding standard
therapy for SEGAs [8], more recently, mammalian target
of rapamycin inhibitors (mTORi) such as Everolimus and
Sirolimus have become known to effectively reduce the
size of SEGAs. Franz et al. first described mTORi as an
effective treatment of SEGAs in 2006 [2] and since then,
the effectiveness of mTORi has been shown in several
clinical trials [4, 13]. In addition, it has been demonstrated
that when the mTORi is weaned, the SEGA regrows [14].
While there is suggestion that mTORi treatment is a rea-
sonable alternative to surgery [15, 16], it remains unknown
whether mTORi can potentially substitute surgical inter-
vention for OH secondary to TSC-related SEGAs [16].
Thus, the objective of this institutional retrospective case
series was to determine whether treatment with mTORi
might serve as a successful alternative to neurosurgical
intervention in patients with SEGA-associated OH.
13
Journal of Neuro-Oncology
Methods
Sixteen children diagnosed with TSC-related SEGA were
consecutively treated with mTORi at the Hospital for Sick
Children from October 2007 to December 2018. Three
patients were excluded from this review due to the following
reasons: mTORi for an indication other than SEGA, which
prevented determination of symptoms of increased ICP
(iICP) (one patient), an mTORi course that was too short
(10 days) to evaluate effectiveness (one patient), and lack of
follow-up imaging due to only recent mTORi initiation (one
patient). Hence 13 of 16 patients are included in this review.
MRI studies at four time points were reviewed for each
of the 13 patients included in this study: (1) the start of
treatment with mTORi, (2) first subsequent MRI, (3)
second subsequent MRI, and (4) the most recent MRI.
Patient charts were concurrently reviewed from the time of
mTORi initiation to correlate classical clinical symptoms
of iICP such as headaches, nausea, and vomiting. Patients
were considered to be symptomatic if they had at least one
out of three symptoms. Signs of iICP reviewed included
papilledema, which was considered present if it was unilat-
eral or bilateral, acute or chronic. While increased seizure
frequency was not considered a symptom or sign of iICP,
seizure frequencies were recorded.
Institutional Research Ethics Board approval was
obtained. Statistical analysis was descriptive.
Radiologic review
A neuroradiologist blinded to the MRI report and all other
clinical information reviewed MRIs for the included patients.
Axial T2W FLAIR MRI images were selected from before
initiation of mTORi, and at least three subsequent MRIs,
including the most recent. The neuroradiologist adjusted the
window and level settings to demonstrate the lateral ven-
tricle margins. In a few cases where T2W FLAIR images
were suboptimal due to motion artifacts, measurements were
performed on axial T1W images. The image that best dem-
onstrated the maximum width of the frontal horns of lateral
ventricles was selected and in the same image, the maximum
width of frontal horns anterior and superior to SEGA at the
level of septum pellucidum was obtained. This measure-
ment was calculated on both sides at the same level and was
repeated on all subsequent follow-up images. In three cases
(Patient #2, #11, and #13), the SEGA was large and caused
obliteration of frontal horns of lateral ventricles at the level
of the septum pellucidum, so measurement was obtained at
the maximum width of occipital horns of lateral ventricles
at the level of atria and choroid plexus, and was repeated at
the same level in the respective follow-up images.
Journal of Neuro-Oncology

Hydrocephalus was initially measured using Evans’ index
(EI) for all included patients, by obtaining the ratio calcu-
lated from the maximum width of the frontal horns to the
maximum width of the inner diameter of the cranium [17,
18]. To evaluate inter-observer variability, a second neu-
roradiologist repeated the EI measurements by calculating
the ratio in all MRIs using the same technique [17]. EI was
assessed for validity by correlating EI measurements with
clinical findings and visual inspection of MRI.
After finding EI to be not reflective of hydrocephalus evo-
lution on MRI, ventriculomegaly was subsequently evalu-
ated on all MRIs based on ventricular width (right and left
measured separately) in order to adequately quantify the
hydrocephalus. A proposed scale was used: no ventriculo-
megaly (< 7 mm), mild (7–10 mm), moderate (11–30 mm),
and severe (> 30  mm). OH was defined as moderate or
severe ventriculomegaly, based on the largest measurement.
Results
Of the thirteen patients, eight (62%) were male and five
(38%) were female. All patients were equal to or greater
than six years of age (median 13 years, range 6–17 years) at
the time of starting mTORi, and the majority (7/13 = 54%)
were teenagers (Table 1). Five out of thirteen patients had
symptoms of iICP, but not necessarily ventriculomegaly that
correlated (Table 1). At the time of mTORi initiation, eight
patients had OH; five of them were asymptomatic. On serial
MRI imaging, six out of the thirteen patients had improve-
ment of hydrocephalus, while the other seven patients had
no change based on the ventriculomegaly scale used. No
patient had worsening of hydrocephalus. Median follow-
up time was 46 months (range 7 to 98 months). Dosing of
mTORi followed the principal of achieving therapeutic lev-
els (5–15 ng/ml) for all patients [14].
Of the five patients with symptoms of iICP (Table 1), four
had only headaches (Patient #2, #5, #10, and #13), and one
had both headaches and vomiting (Patient #11). All three
patients who presented with symptoms of iICP and OH also
had papilledema on examination (Patient #2, #11, and #13).
One patient (Patient #11) presented with several months
of headaches as well as vomiting, vision changes, and was
found to have bilateral papilledema. Hydrocephalus was
moderate on MRI (Fig. 1). The patient clinically improved
rapidly after initiation of Everolimus treatment. Surgical
intervention was avoided as hydrocephalus became mild
within twenty-six days, with resolution of periventricular
edema, and MRI after six months of mTORi documented
resolution of hydrocephalus with reduction in SEGA size
(Fig.  1). Ophthalmological exam revealed resolution of
papilledema within ten weeks. Another patient (Patient
#13) was treated with a three-month course of Sirolimus
before proceeding to a near-complete surgical SEGA resec-
tion due to worsening symptoms. Hydrocephalus was meas-
ured as moderate throughout on the serial MRIs. The third

Table 1  Clinical features of the cases included in this series (M male, F female, N/A not applicable)
Patient # Sex Age at Start of Clinical evidence of increased Presence of Measurement of ventriculomegaly on MRI
mTORi (Years) ICP at start of mTORi increased seizure
frequency
symptoms (head- Papilledemaa MRI at First subsequent Second Last ­MRIb
aches, nausea, Start of MRI subsequent
vomiting) mTORi MRI

1 M 11 Absent Absent No Moderate Moderate Moderate Mild

2 F 10 Present Present No Severe Moderate Moderate Moderate
3 M 9 Absent Absent No Moderate Moderate Moderate Moderate
4 M 10 Absent Unknown No None None None None
5 M 13 Present Absent No None None None None
6 M 13 Absent Absent Yes Moderate Mild Mild Mild
7 F 6 Absent Absent No Moderate Mild Mild Mild
8 M 16 Absent Absent No Mild Mild Mild Mild
9 F 17 Absent Absent No None None N/A None
10 M 14 Present Absent No Mild None None None
11 F 8 Present Present No Moderate Moderate Mild None
12 M 16 Absent Absent No Moderate Moderate N/A Moderate
13 F 15 Present Present No Moderate Moderate Moderate Moderate
a
 Papilledema was assessed by an ophthalmologist (Patient #1, #2, #6, #7, #9, #10, #11, #12, and #13) or by a neuro-oncologist (Patient #3, #5,
and #8). A fundoscopic exam was not documented for Patient #4
b
 Median follow-up of 46 months (range 7 to 98 months)

13

Fig. 1  Magnetic resonance FLAIR images of Patient #11 at a the start of mTORi, b the first subsequent MRI, and c the last MRI, demonstrating
improvement and subsequent resolution of OH
symptomatic patient with OH (Patient #2) presented with
severe ventriculomegaly on MRI as well as headaches and
chronic papilledema. Serial MRIs demonstrated improve-
ment to moderate ventriculomegaly, and papilledema
resolved within three months of mTORi therapy (Fig. 2).
Of the two remaining symptomatic patients, one (Patient
#10) had no OH and no papilledema but had symptoms
of weekly headaches. The mild ventriculomegaly on MRI
resolved after three months of mTORi therapy. The second
patient (Patient #5) had mild headaches with no papilledema,
and no OH or ventriculomegaly.
Charts were reviewed for seizure frequency for all
patients to elucidate whether an increased seizure frequency
or new onset of seizures was present at diagnosis of OH.
One patient (Patient #6), with a remote history of seizures
Fig. 2  Magnetic resonance FLAIR images of Patient #2 at a the start of mTORi, b the first subsequent MRI, and c the last MRI, demonstrating
improvement from severe to moderate OH
13
Journal of Neuro-Oncology
in childhood and off antiepileptics for more than five years,
re-presented with seizures but no symptoms of iICP. This
prompted his late diagnosis of TSC. Increased seizure fre-
quency was documented while on mTORi, although ven-
triculomegaly did not increase. Another patient (Patient #8)
had a longstanding refractory seizure history but seizure
frequency was unchanged at the time of diagnosis of mild
ventriculomegaly caused by growing SEGA.
Discussion
This case series demonstrates that patients with TSC-related
SEGA and OH are often asymptomatic. This is consistent
with previous reports that slowly progressive OH may be
Journal of Neuro-Oncology
recognized late due to lack of obvious clinical manifestations
[19], and that clinical features of iICP may be vague, vari-
able, or absent [20]. We found that neither measurement of
ventricular size on MRI at diagnosis nor at response is nec-
essarily correlated with symptoms of iICP or symptom con-
trol. This discrepancy is consistent with the fact that SEGAs
usually grow slowly and OH develops gradually, and that
ventriculomegaly often persists even after symptoms have
resolved [21]. Not surprisingly, two patients (Patient #5 and
#10) who were symptomatic in the absence of papilledema
and OH experienced only headaches, which are known to be
a common symptom of TSC patients in general [22].
The TSC surveillance and management recommenda-
tions [7] advise regular brain MRI to monitor for SEGA
and potential growth and obstruction of the CSF pathway.
Periventricular edema may be seen at the time of OH [23],
and is typically most extensive the more acutely obstruc-
tion occurs (i.e. in aggressive fast growing brain tumours).
Evans’ Index (EI) is a widely used quantitative measure for
ventricular volume, measured as a ratio of the transverse
diameter of the anterior horns of the lateral ventricles to
the greatest internal diameter of the skull [18]. A normal
EI in the absence of hydrocephalus is < 0.3 [17]. Although
EI changes with age, it can be used for early diagnosis of
hydrocephalus. EI was initially employed in this study as an
objective measurement to document hydrocephalus evolu-
tion on MRI; however, we found the numbers to be unhelpful
because they were neither accurately reflective of severity of
hydrocephalus, nor its improvement. Completing two meth-
ods for radiologic review allowed us to demonstrate that
EI is not the ideal method for documenting hydrocephalus
in TSC-related SEGA, rather measurement of ventriculo-
megaly as detailed above. In addition to EI, other proposed
hydrocephalus grading tools exist [24]; however, a need
remains for a standardized radiologic measurement tool for
hydrocephalus in this context.
In clinical practice, classical symptoms of OH and degree
of periventricular edema are used to determine the indica-
tion for surgical intervention to either resect the cause of
OH and/or the need for CSF diversion. Controversy may
arise regarding the resectability of a SEGA and the neces-
sity of a VPS [12]. However, neurosurgeons—as much as
patients—try to avoid VPS whenever feasible due to its risk
of infection and frequent need for revisions [10]. Hence
alternative options that prevent or avoid VPS insertions are
almost always favored.
Our retrospective review showed that in the context of
progressive SEGA and OH, neither new onset of seizures
nor increased seizure frequency occurs commonly. Only one
patient had increased seizure frequency but in the absence of
OH. However there are studies showing associations [25].
In general, but especially in the TSC population, frequency
or severity of seizures can be very difficult to quantify [26].
We found that six out of thirteen patients treated with
mTORi had objective improvement of OH on MRI by ven-
tricular measurements, while the remaining seven patients
demonstrated ventricular width stability. Importantly,
we demonstrate one patient with acute symptoms of OH
in whom mTORi was initiated and surgical intervention
was avoided as the patient demonstrated rapid clinical and
radiologic improvement. Consistent with this, a recent case
report demonstrated a similar rapid response of symptomatic
SEGA with Everolimus being used in the acute setting [27].
Another recent series suggests an expanding role for mTORi
in acute scenarios of TSC-related SEGA [16]. Most impor-
tantly, of the thirteen patients included here, none required
CSF diversion at a median follow-up of 46 (range 7 to 98)
months. This is in contrast to patients treated surgically for
SEGA, where one third of patients require VPS insertion
[9, 28].
Limitations of this study include small study population,
descriptive statistical evaluation only, and the use of a ven-
triculomegaly scale that has not yet been validated. In addi-
tion, mTORi side effect data was not collected, which would
be important to consider when treating long-term. However,
this review underscores the value of treatment with mTORi
in TSC patients with progressive SEGA causing OH, and
challenges previous recommendations for surgical interven-
tion to manage acute OH caused by TSC-related SEGA [3,
7]. In addition, while current existing recommendation is
limited to asymptomatic SEGA patients with chronic OH
[7], based on our data, we feel confident to recommend
including mTORi as a treatment option, even in sympto-
matic patients with acute OH.
Funding None.
Compliance with ethical standards 
Conflict of interest  The authors declare that they have no conflict of
interest.
Ethical approval  This research study was conducted retrospectively
from data obtained for clinical purposes. Institutional Research Ethics
Board approval was obtained at The Hospital for Sick Children (REB
number: 1000060201).
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