J Neurosurg Pediatrics 11:268–273, 2013
©AANS, 2013

The ability of high field strength 7-T magnetic resonance
imaging to reveal previously uncharacterized brain lesions in
patients with tuberous sclerosis complex
Clinical article
Jason R. Chalifoux, Ph.D.,1,2 Nissa Perry, M.A., 2 Joel S. Katz, D.O.,1
Graham C. Wiggins, D.Phil., 2 Jonathan Roth, M.D.,1 Daniel Miles, M.D., 3
Orrin Devinsky, M.D., 3 Howard L. Weiner, M.D.,1,3 and Sarah S. Milla, M.D. 2
Department of Neurosurgery, Division of Pediatric Neurosurgery, 2Department of Radiology, and
The Comprehensive Epilepsy Center, New York University Langone Medical Center, New York, New York

1
3

Object. Tuberous sclerosis complex (TSC) brain pathology is characterized on MRI by cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas. Seizures, the prominent feature of TSC, are frequently
intractable to medical therapy and, in many patients, resection of tubers results in seizure control. However, in approximately 40% of patients, resection of tubers does not control seizures. This fact, as well as evidence from invasive electrophysiological recordings and experimental animal models, suggests that in patients with TSC, there may
be extratuberal epileptogenic brain that does not display any apparent abnormality on conventional MRI. The authors
hypothesized that high field strength MRI might uncover lesions not seen on conventional MRI in these patients.
Methods. Institutional review board approval was obtained to scan 4 patients with TSC (ages 18–26 years)
in a 7-T MR unit. Optimized 7-T sequences, including T1- and T2-weighted, FLAIR, SPACE FLAIR, T2*, and
MPRAGE studies, were performed. Imaging studies were compared with identical sequences performed using a
conventional 1.5-T MR scanner.
Results. In all 4 patients, there was improved visualization of the findings demonstrated on conventional imaging. Importantly, new lesions were detected in all 4 patients, which were not well visualized with conventional MRI.
Newly detected lesions included microtubers, radial glial signal abnormalities, subependymal nodules arising from
the caudate nucleus, and caudate nucleus lesions.
Conclusions. High field strength MRI detects previously uncharacterized lesions in patients with TSC and allows better detection and delineation of subtle abnormalities. In addition, the data demonstrate a compelling relationship between intraventricular lesions and the caudate nucleus. These data support previous electrophysiological and
animal-model findings that demonstrate neurological pathology beyond the conventionally detected lesions in TSC.
(http://thejns.org/doi/abs/10.3171/2012.12.PEDS12338)

Key Words
•
tuberous sclerosis complex
•
seizure
•
magnetic resonance imaging
•
cortical tuber •
subependymal nodule
subependymal giant cell astrocytoma
•
oncology

T

uberous sclerosis complex is an autosomal dominant genetic disease that frequently (in about 75%
of cases) arises from de novo mutations in 1 of 2
tumor suppressor genes: TSC1 or TSC2. These encode
hamartin and tuberin proteins, respectively.8 Tuberous
sclerosis complex results in hamartoma formation in
multiple organs including the brain, heart, kidneys, skin,
and lungs. Although this is a multisystem disease, the ma-

Abbreviations used in this paper: SEGA = subependymal giant
cell astrocytoma; SEN = subependymal nodule; TSC = tuberous
sclerosis complex.

268

•

jor morbidity results from brain dysfunction, manifesting as frequent seizures, autism, and mental retardation.
Seizures occur in about 85% of patients9 and frequently
require surgical intervention because of failed medical
therapy with antiepileptic drugs.
Classically, cortical tubers are thought to be the origin
of seizure activity in patients with TSC. This hypothesis
has been supported by electroencephalographic recordings, which have localized interictal and ictal discharges
to tubers seen on MRI.3,13,18,28 Similarly, studies using
magnetoencephalography17,19,38,41,48 and PET1,4,20,21,34,46,47
have localized epileptogenic foci to tubers. Finally, cases
J Neurosurg: Pediatrics / Volume 11 / March 2013

Tuberous sclerosis complex lesions imaged at 7 T
of seizure relief after resection of tubers further supports
the hypothesis that tubers initiate seizure activity in patients with TSC.16,25,27,33,47
Although seizure freedom may occur after resection
of tubers, it is estimated from a number of publications
that, after surgery, approximately 40% of patients will
still suffer from medically intractable seizures. To better
localize seizure foci, surgeons have employed subdural
grid and depth electrode recordings to examine cortical
activity with higher spatiotemporal resolution. These recordings have shown that, in certain cases, epileptiform
activity is confined to perituberal regions and not to the
tuber itself.30,33 Interestingly, most rodent models of TSC
do not develop cortical tubers; however, in such animals
the cortex is hyperexcitable, has a decreased seizure
threshold, and demonstrates areas of abnormal neuronal
cytoskeleton.12,15,42,45,49 Together, these data suggest that
the epileptogenic brain in TSC may extend beyond the
borders of radiographically defined cortical tubers and
that our current imaging techniques may lack the resolution to visualize pathological abnormalities. We hypothesized that increasing the resolution of MR images by using a 7-T magnet may reveal previously uncharacterized
lesions that correlate with extratuberal epileptogenic foci.

Methods

Institutional review board approval was obtained
from New York University Langone Medical Center to
scan 4 patients in a 7-T MR scanner. We had previously
acquired 1.5-T sequences, which were used for comparison. The intervals between the 1.5-T and 7-T scans were
28 months in Case 1; 3 months in Case 2; 3 months in
Case 3; and 2 months in Case 4. Patients were recruited
from the New York University Comprehensive Epilepsy
Center. To decrease the influence of movement artifact,
patients older than 16 years were recruited. Written informed consent was obtained. The results from Case 3
were included in a previously published study.23

lobes, with significant calcification in the parietooccipital
lesion. Calcified subependymal nodules were noted bilaterally along the bodies of the lateral ventricles with no
evidence of SEGA. Sequences obtained at 7 T revealed
previously unseen SENs and small areas of T2 abnormality with the radiographic characteristics of cortical tubers
(“microtubers”) in the right hemisphere (Fig. 1).

Case 2. This patient is an 18-year-old male diagnosed with TSC at 18 months. At this time, the patient
developed focal motor seizures involving the face, which
were resistant to numerous antiepileptic drugs. Complete
seizure control was achieved with vigabatrin, carbamazepine, and lamotrigine. Magnetic resonance imaging at 1.5
T demonstrated right frontal and left parietal tubers and a
right peritrigonal white matter tuber with no evidence of
SENs or SEGAs. Scanning at 7 T revealed a previously
unappreciated subtle radial glial abnormality in the parietal cortex and a tuber in the insular cortex that was also
not seen on the previous scan (Fig. 2).
Case 3. This patient is a 21-year-old male diagnosed
with TSC at 22 months. He initially presented with staring and blinking episodes at 2 months of age. The clinical presentation was remarkable for medically controlled
complex partial seizures, SEGA without hydrocephalus,
and neuropsychiatric symptoms of decreased executive
function and attention. Electroencepalographic analysis
showed left temporal spikes. The patient underwent epilepsy surgery at 10 years to resect left frontal and temporal epileptogenic tubers with good effect. He was seizure
free for 7 years and then developed complex partial seizures. At the time of the 7-T scan, his seizures were well
controlled. The 7-T scan revealed additional complexity
in a hyperintense lesion adjacent to the right caudate that
had been previously defined on T2-weighted images. In
addition, a previously uncharacterized hyperintense lesion, radiographically consistent with a tuber, was identified in the head of the right caudate23 (Fig. 3).

Seven-Tesla MRI

The individuals were scanned on a Siemens 7-T
whole-body MR scanner. Coronal, sagittal, and axial optimized 7-T sequences, including T1- and T2-weighted,
FLAIR, SPACE FLAIR, T2*, and MPRAGE, were performed. Imaging studies were reviewed by a pediatric
neuroradiologist and compared with identical sequences
obtained with a conventional 1.5-T MR scanner.

Results
Case 1. This patient is a 28-year-old female in whom
TSC was diagnosed at age 16, when she developed episodes of déjà vu sensations, periods of out-of-body dissociation, and somatic paresthesias. Since then, she has
suffered from partial epilepsy with impairment of consciousness, anxiety disorder, and major depressive disorder. Electroencephalography showed frequent right anterior temporal sharp waves, and 1.5-T MRI revealed linear
subcortical white matter areas of FLAIR signal hyperintensity within the left mesial parietooccipital and parietal
J Neurosurg: Pediatrics / Volume 11 / March 2013

Fig. 1. Case 1. Comparison of corresponding T2* and T2 axial slices
obtained through the body of the lateral ventricles on 7-T (left) and
1.5-T (right) MR images. The 7-T image demonstrates multiple calcified SENs along the ventricular surface of the lateral ventricles (arrow)
that are not well visualized on the 1.5-T image. Small hyperintense lesions (microtubers, arrowhead) in the subcortical white matter seen
on the T2-weighted image are better defined on the 7-T image due to
increased signal from high field strength.

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J. R. Chalifoux et al.

Fig. 2. Case 2. Comparison between corresponding T2 axial slices
obtained through the level of the striatum on 7-T (left) and 1.5-T (right)
MR images. The 7-T image demonstrates improved visualization of a
cortical tuber along the right insula (arrow), which was not initially detected on the original clinical 1.5-T examination.

Case 4. This patient is a 20-year-old female diagnosed with TSC at age 14, who suffers from complex
partial epilepsy, controlled by levetiracetam and oxcarbazepine. Examination at 1.5 T revealed several small hyperintense, enhancing subependymal nodules along the
borders of the lateral ventricles on T2-weighted images.
Cortical tubers were visualized as FLAIR hyperintensities in the left frontal and parietal lobes. In addition, there
were small, scattered foci of increased FLAIR signal visualized in the subcortical white matter. There was no
hydrocephalus. A previously uncharacterized radial glial
abnormality in the left frontal lobe was detected on images obtained at 7 T (Fig. 4).

Discussion

Increasing evidence suggests that the full spectrum
of pathological abnormalities and involvement in TSC
may not be completely detected by conventional imaging.

Fig. 3. Case 3. Comparison between corresponding T2* and T2
axial slices obtained through the body of the lateral ventricles on 7-T
(left) and 1.5-T (right) MR images. Higher resolution and improved
gray-white delineation on the 7-T examination demonstrate complexity
of a cystic area adjacent to the right caudate (white arrow) and illustrate
an abnormal hyperintense lesion in the head of the right caudate (black
arrow) as well as a microtuber (arrowhead) that was poorly visualized
on the T2-weighted image.

270

Fig. 4. Case 4. Comparison between corresponding MPRAGE axial
slices obtained through the level of the striatum on 7-T (left) and 1.5-T
(right) MR images. Improved signal and gray-white differentiation at 7
T allows new visualization of a radial-glial abnormality in the left frontal lobe (arrow). The corresponding image from the 1.5-T clinical scan
does not demonstrate this abnormality.

We used high field strength MRI (7 T) to further evaluate
the brain parenchyma in patients with TSC. To the best of
our knowledge, this is the first report specifically analyzing 7-T imaging of TSC lesions of the brain. Although
new lesions were found in all patients, 7-T imaging was
also important in highlighting lesions that were missed
on 1.5-T studies. For example, the tuber seen on the 1.5-T
scan in Case 2 was missed on the first reading, but was
seen clearly on the 7-T scan. Our results suggest that high
field strength imaging can improve the detection of brain
lesions in patients with TSC.
Seizure Etiology in TSC

Theories on the origin of seizures in TSC have, for a
long time, focused on the importance of cortical tubers,
partly because of the known association between focal
cortical dysplasia, a malformative brain lesion with many
apparent similarities to tubers, and epileptogenesis.36,37
In a number of ways, tubers resemble focal cortical dysplasia, with dysplastic neurons, disorganized nonlaminar cortex, giant cells, balloon cells, and areas of gliosis. Clinical findings supported this theory: researchers
uncovered a correlation between seizure frequency and
tuber number,14,40 suggesting that tubers may be independent foci of seizures. In addition, noninvasive localization
of interictal spike discharges showed close correlations
between functional spike onset and localization of tubers
on MRI.4,10 Finally, surgical data lent further support to
this theory: resection of an epileptogenic tuber was often
successful in rendering a patient seizure free.16,25,27 These
findings all supported the hypothesis that tubers are the
primary source of seizures in TSC.
In contrast, other observations are not consistent with
tubers being the sole epileptogenic focus in TSC. Firstly,
in many patients with numerous tubers, only a few are
found to be truly epileptogenic. Similarly, some patients
who have cortical tubers do not suffer from seizures at
all, are neurologically normal, and may come to medical
attention because of a symptomatic brain tumor, a SEGA.
Secondly, patients are not always rendered seizure free
J Neurosurg: Pediatrics / Volume 11 / March 2013

Tuberous sclerosis complex lesions imaged at 7 T
from removal of an apparently epileptogenic tuber, and
this fact raises the possibility that the epileptogenic zone
may extend beyond the margin of the tuber visualized on
MRI and into apparently normal brain.16,25,27 Thirdly, animal models with mutations in the TSC genes have no apparent tubers in the brain.15,42,49 Finally, there are patients
with medically refractory seizures who do not have any
tubers on conventional imaging, and data have shown that
some seizure foci do not localize to tubers identified on
conventional MRI.10 These studies call into question the
causal relationship between tubers and seizure onset.
Recently, some studies have provided evidence that
seizure activity arises outside of the tuber.22,29,30 Madhavan et al.29 reported that analysis of ictal spike generation consistently localized seizure foci around cortical
tubers, suggesting that the cortex around tubers may be
responsible for epileptiform activity. Interestingly, they
found that in all patients, ictal spiking began in previously silent distant cortical regions after tuber resection.
These regions did not correspond to tubers on MR images. Kamimura et al.22 used magnetoencephalography to
investigate the spatial relationship between the location
of interictal spike discharges and visible cortical tubers
on MRI. They found that in 6 of 15 patients, discharges
were associated with a visualized tuber. However, in all
of these cases, the discharges were only found adjacent to
the tuber. These data support a hypothesis of widespread
cortical dysfunction, in which seizure foci cannot be predicted reliably using current imaging techniques.
The use of intracranial electrodes to localize seizure
foci in patients with TSC has further challenged the idea
of epileptogenesis solely residing within tubers.30 Major
et al.30 showed that in all 3 patients they examined, the
perituberal cortex was epileptogenic. Surprisingly, they
found that, in all 3 cases, the tuber was electrically silent.
This work provides further support for the belief that cortical regions outside of tubers are epileptogenic.
Evidence for Widespread Neuronal Dysfunction in TSC

Postmortem pathological examinations of TSC brains
have found widespread cortical microscopic pathology. In
addition to cortical tubers seen radiographically, “microtubers” were described, which were composed of giant
cells not seen on conventional MRI.31 In addition, in all
patients, there were areas of cortex that had defects in
lamination. Interestingly, these areas of structural deficits
were found in close proximity to cortical tubers, which
lends support to electrophysiology studies of perituberal abnormalities. Moreover, whole-cell recordings from
cortical pyramidal neurons of a patient with TSC showed
enhanced excitation in nontuberous brain regions.45 Using
MRI techniques, Ridler et al.39 found widespread deficits
in gray and white matter volume in cortical and subcortical structures. Together, the evidence suggests that perituberal cortex is abnormal in patients with TSC.
Animal models have provided insight into the etiology of brain dysfunction in TSC. For unknown reasons,
most rodent models of TSC do not develop cortical tubers. Supporting the hypothesis of neuronal dysfunction
independent of tubers or seizures, Goorden et al.15 showed
that mice heterozygous for Tsc1 had cognitive and social
J Neurosurg: Pediatrics / Volume 11 / March 2013

defects in the absence of seizures or microscopically detected pathology. At the cellular level, many studies have
revealed deficits of neuronal structure and function. One
study used viral knockdown to show that loss of either
TSC gene results in decreased dendritic spine density, increased dendritic spine head width, and an increase in
synaptic AMPA/NMDA current ratio.43
Research into mTOR (mammalian target of rapamycin) signaling in the brain has also shed light on neuronal
dysfunction in TSC. Tuberin and hamartin proteins are
downstream of mTOR and regulate protein translation
in neurons. Because new proteins are required for longterm synaptic plasticity and activity-dependent structural
changes, it is posited that patients with TSC suffer from
widespread dysfunction in neuronal plasticity. Recently,
a group has hypothesized that TSC lies on the opposite
end of the same spectrum as fragile X syndrome.2 Because metabotropic glutamate receptor 5 (mGluR5) signaling modulates protein translation, this group has used
an mGluR5 positive allosteric modulator (PAM) to show
improvement in synaptic plasticity in neurons heterozygous for Tsc2 and has shown that heterozygous Tsc2 mice
treated with an mGluR PAM perform as well as wildtype mice in a test of cognitive ability. This is compelling evidence that, similar to patients with fragile X syndrome, patients with TSC suffer from impaired neuronal
function that disrupts cognitive/behavioral function, independent of pathological lesions or seizures.
The Use of 7-T MRI for Surgical Planning in Patients With
TSC

Imaging at 7 T offers many advantages over conventional, lower field strength MRI. Increasing magnetic
field strength allows higher resolution of brain structures.
Previous studies have shown that images obtained with
a 7-T scanner uncover brain lesions not previously seen
on lower field strength MRI.24,26,32 Interestingly, new
studies have shown that quantitative T2* mapping at 7 T
can reveal patterns of cytoarchitecture and the orientation of gray matter fiber tracts in the cortex,7 suggesting
even better visualization of deficits in patients with TSC.
Although not currently approved for clinical use, studies
on long-term side effects of 7-T MRI have not yielded
any results.44 Future studies should focus on using 7-T sequences during preoperative planning to uncover lesions
beyond the resolution of lower field strength MRI. In addition, studies should correlate new 7-T MRI findings and
clinical factors such as seizure frequency and cognitive/
behavioral outcome.
Future surgical planning should consider the use of
7-T MRI to localize abnormalities and correlate them
with discharges detected on electroencephalography and
electrocortigraphy.11 In addition to allowing better demarcation of previously detected lesions, the identification
of new lesions made possible by 7-T imaging may help
guide surgical planning and placement of subdural grids
and depth electrodes to better achieve seizure-free status
in patients. Finally, in cases requiring resection of tissue,
it should be noted that 7-T imaging is superior at visualizing vasculature and will aid in operative management.5,35
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J. R. Chalifoux et al.
Limitations of the Current Study

Magnetic resonance imaging at 7 T is limited by sensitivity to air and artifacts, as well as by the long sequence
durations required for high resolution. Currently, 7-T
MRI has not received approval for clinical use and is intended for research purposes only. In this study, it should
be noted that all individuals were high-functioning adults
because the 7-T scanner did not have the anesthesia capability required for children. Therefore, it is possible that
the inclusion of more severely affected, younger patients
may reveal different radiographic abnormalities. As these
patients did not undergo surgery, pathological comparisons were not made. In addition, electrophysiological
recordings were not performed to correlate seizure foci
with lesions. Finally, it should be noted that there was a
long delay between scans (28 months) in the patient in
Case 1. Although there are limited data on the dynamics of tuber formation, recent studies have shown that
changes are rare and usually result in cystlike changes in
tubers.6 Future studies should address these issues to further our understanding of the role of high field strength
MRI in epilepsy surgery planning.

Conclusions

This is the first report exclusively investigating the
use of 7-T MRI in TSC. In all cases, there was improved
visualization of findings reported on conventional imaging, and lesions were detected that were not well seen on
conventional imaging. Higher-resolution 7-T images allowed the detection of microtubers and radial glial abnormalities and provided better characterization of the
margins of established lesions. High field strength MRI
detects previously uncharacterized lesions in patients
with TSC and allows better delineation of subtle abnormalities. As suggested by electrophysiological and pathological data, 7-T MRI demonstrates that pathology in
TSC extends beyond the conventionally apparent lesions.
Disclosure
The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this
paper.
Author contributions to the study and manuscript preparation
include the following. Conception and design: Milla, Wiggins, Katz,
Roth, Miles, Devinsky, Weiner. Acquisition of data: Milla, Wiggins,
Perry, Katz, Roth. Analysis and interpretation of data: Milla, Wig­
gins, Weiner. Drafting the article: Chalifoux, Wiggins, Weiner.
Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the
manuscript on behalf of all authors: Milla. Administrative/technical/
material support: Perry. Study supervision: Milla.
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Manuscript submitted June 27, 2012.
Accepted December 3, 2012.
Portions of this work were presented in lecture form at the
39th Annual Meeting of the AANS/CNS Section on Pediatric
Neurological Surgery, Cleveland, Ohio, December 2010, and at the
American Society of Pediatric Neurosurgeons Meeting in Lanai,
Hawaii, February 2011.
Please include this information when citing this paper: published
online January 4, 2013; DOI: 10.3171/2012.12.PEDS12338.
Address correspondence to: Sarah S. Milla, M.D., Department
of Radiology, New York University Langone Medical Center, 560
First Avenue, IRM 234, New York, New York 10016. email: sarah.
milla@nyumc.org.

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