Brain & Development 20 (1998) 209–221

Review article

CT and MR imaging of cerebral tuberous sclerosis

Yuichi Inoue a ,*, Yutaka Nemoto a, Ryuusuke Murata b, Takahiko Tashiro a, Miyuki Shakudo a,
Kinuko Kohno a, Osamu Matsuoka c, Kunizo Mochizuki a
a
Department of Radiology, Osaka City University Medical School, 1-5-7 Asahimachi, Abeno, Osaka, 545 Japan
b
Department of Pediatrics, Osaka City General Hospital, 2-13-22 Miyakojima-Hondori, Miyakojirna, Osaka, 534 Japan
c
Department of Pediatrics, Osaka City University Medical School, 1-5-7 Asahimachi, Abeno, Osaka 545, Japan

Received 14 October 1997; revised version received 3 March 1998; accepted 3 March 1998

Abstract

Tuberous sclerosis is a heredofamilial neurocutaneous syndrome, or phakomatosis, with multisystem involvement including the brain,
kidney, skin, retina, heart, lung, and bone. The brain is the most frequently affected organ in tuberous sclerosis. Brain lesions in tuberous
sclerosis are of three kinds; cortical tubers, white matter abnormalities, and subependymal nodules. We review the computed tomography
(CT) and magnetic resonance (MR) features of the brain lesions in patients with tuberous sclerosis. CT clearly demonstrates calcified
subependymal nodules. MR imaging demonstrates more clearly cortical, and white matter lesions than CT, since MR imaging shows
excellent image contrast between various normal structures and high sensitivity in detecting pathological states due to intrinsic differences
in proton density and in particular, in proton relaxation times of tissues. Possible pathogenesis of this disorder is also discussed  1998
Elsevier Science B.V. All rights reserved

Keywords: Tuberous sclerosis; Subependymal nodule; Cortical tuber; White matter tuber; Subependymal giant cell tumor; Seizures; Mental
retardation

1. Introduction 1.1. Incidence and genetics

Tuberous sclerosis is a heredofamilial neurocutaneous
syndrome, or phakomatosis, with multisystem involvement
including the brain, kidney, skin, retina, heart, lung and
bone. The brain is the most frequently affected organ in
tuberous sclerosis. Although the earliest report of a patient
with tuberous sclerosis is said to have been by von Reck-
linghausen (1862) in a neonate with cardiac rhabdomyo-
mata, the name tuberous sclerosis was introduced by
Bourneville (1880) in a 3-year-old girl with mental retarda-
tion, seizures and facial angiofibromas (cited in Ref. [1]). In
1890, Pringle described the facial nevi of adenoma seba-
ceum. Vogt later emphasized the classic triad of seizures,
mental retardation, and sebaceous adenoma. The eponym
Pringle disease is used when there are only dermatological
findings, and Bonneville disease when the nervous system is
affected.
* Corresponding author. Tel.: +81 6 645 2141; fax: +81 6 646 6655.
A recent Swedish study found the prevalence to be at
least one in 6800 among children aged 11–15 years and
one in 12 900 in a population aged 0–20 years [7]. No racial
or sexual predilection has been detected. Familial cases are
inherited in an autosomal dominant fashion, but most cases
probably arise sporadically; the rate of spontaneous muta-
tion approaches 60–75% [2–5]. The tumor-like growth in
different organs may include cells of more than one type,
and examples of these are fibroblasts, cardiac myoblasts and
angioblasts or glioblasts and neuroblasts [2,3].
Due to multiple organ involvement and genetic hetero-
geneity, the disorder is called ‘tuberous sclerosis complex’
(TSC). Linkage of tuberous sclerosis to markers on chromo-
some 9q was first reported in 1987 [8] and in further details
in the recent literature [9]. It soon became clear that there is
genetic heterogeneity. The gene on chromosome 9 is called
TSC1. Another group has revealed an important tuberous
sclerosis locus on chromosome 16p13 [10,11], which was

0387-7604/98/$19.00  1998 Elsevier Science B.V. All rights reserved

PII S0387-7604 (98 )0 0022-9
210 Y. Inoue et al. / Brain & Development 20 (1998) 209–221
confirmed later on and designated as TSC2. No significant
phenotypical differences have been discovered between
TSC1 and TSC2.
1.2. Clinical manifestations
The traditional clinical triad of adenoma sebaceum, sei-
zures, and mental retardation has been refined with appre-
ciation of the complexity of the disorder. Recently,
diagnostic criteria have been established by the National
Tuberous Sclerosis Association (Table 1). A definitive diag-
nosis is established when one of the following are present:
(1) cortical tubers or subependymal nodules, (2) multiple
retinal astrocytomas, (3) facial or truncal adenoma seba-
ceum (angofibromas) or ungual angiofibromas, or (4) sub-
ependymal giant cell astrocytomas. In the absence of a
primary finding, the diagnosis can be made if any two of
the following are present: hypopigmented macules, sha-
green patches, a single retinal tuber, multiple renal hamar-
tomas (angiomyolipomas), cardiac rhabdomyoma, and
tuberous sclerosis in a first-degree relative. Many of the
clinical manifestations such as facial angiofibromas, ungual
fibromas, and subependymal nodules, may not be apparent
in infancy and childhood. Mental retardation and seizures
are common in this disorder, but because of the lack of
specificity they are not included in the diagnostic criteria.
1.3. The role of radiology
As described earlier, the diagnosis of tuberous sclerosis
has been based on the classic triad of characteristic cuta-
neous lesions, seizures, and mental retardation. Because
intellectual deficits are seen in only 40% of patients and
the cutaneous and intellectual deficits are not clinically
apparent in the first 2–3 years of life, the radiologic mani-
festations of tuberous sclerosis have taken on considerable
clinical importance in the diagnosis of this disorder in
infants and young children.
Plain radiographs of the skull demonstrate periventricular
calcification infrequently (Fig. 1). Historically, pneumoen-
cephalography demonstrated the characteristic ‘candle gut-
tering’ appearance of nodular subependymal masses. The
cortical tubers that dominate the gross pathologic appear-
ance of this disorder, however, were generally not discern-
ible on these plain radiography and pneumoencephalo-
graphy. Computed tomography (CT) and magnetic reso-
nance (MR) imaging revolutionized the role of radiologic
evaluation of this disorder. CT clearly demonstrates calci-
fied nodules, but it fails to demonstrate cortical tubers in
spite of the presumed presence of such lesions in most
patients. MR imaging demonstrates cortical tubers and
white matter lesions above a certain size, but it frequently
fails to depict subependymal nodules.
MR imaging utilizes programmed sequences of pulses to
produce different kinds of images such as T1-weighted, T2-
weighted, and proton-weighted images. In this article,
unless stated otherwise, T1-weighted images indicate
spin-echo T1-weighted images (TR: 500–600 ms, TE:
15–20 ms), and T2-weighted images indicate either spin-
echo T2-weighted images (TR: 2000–3000 ms. TE: 90–100
ms) or fast spin-echo T2-weighted images (TR: 4000–6000
ms, Teff: 80–100 ms).
1.4. Brain lesions
The cerebral lesions in tuberous sclerosis are of three
kinds: cortical tubers, white matter abnormalities, and sub-
ependymal nodules. They are almost always benign hamar-
Table 1
Diagnostic criteria for tuberous sclerosis complex (TSC)
Primary features
Facial angiofibromasa
Multiple ungual fibromasa
Cortical tuber (histologically confirmed)
Subependymal nodule or giant cell astrocytoma
(histologically confirmed)
Multiple calcified subependymal nodules protruding into the ventricle
(radiographic evidence)
Multiple retinal astrocytomasa
Secondary features
Affected first-degree relative
Cardiac rhabdomyoma (histologic or radiographic confirmation)
Other retinal hamartoma or achromic patcha
Cerebral tubers radiographic confirmation)
Non-calcified subependymal nodules (radiographic confirmation)
Shagreen patcha
Forehead plaquea
Pulmonary lymphangiomyomatosis (histologic confirmation)
Renal angiomyolipoma (radiographic or histologic confirmation)
Renal cysts (histologic confirmation)
Tertiary features
Hypomelanotic maculesa
‘Confetti’ skin lesionsa
Renal cysts (radiographic evidence)
Randomly distributed enamel pits in deciduous and/or permanent teeth
Hamartomatous rectal polyps (histologic confirmation)
Bone cysts (radiographic evidence)
Pulmonary lympllangiomyomatosis (radiographic evidence)
Cerebral white-matter ‘migration tracts’ orheterotopias
(radiographic evidence)
Gingival fibromasa
Hamartoma of other organs (histologic confirmation)
Infantile spasms
Definite TSC
One primary feature, two secondary features, or, one secondary
plus two tertiary features
Probable TSC
Either one secondary plus one tertiary feature or three tertiary features
Suspect TSC
Either one secondary feature or, two tertiary features
a
Histologic confirmation is not required if the lesion is clinically obvious.
Developed by the National Tuberous Sclerosis Association Professional
Advisory Board from Ref. [10].
 Y. Inoue et al. / Brain & Development 20 (1998) 209–221 211

Fig. 1. Calcified subependymal nodule in a 16- year-old boy with tuberous
sclerosis. The lateral skull radiograph shows calcification in the brain (in
conjunction with anteroposterior skull radiograph) which was confirmed to
be a calcified subependymal nodule by CT.
tomas. Bender and Yunis [12] have suggested that the same
cellular components are present in all the brain lesions in
tuberous sclerosis, and that they represent a combination of
both neuronal and astrocytic features.
1.4.1. Cortical tubers
Cortical tubers are the most characteristic lesions of
tuberous sclerosis at pathologic examination. Varying in
size from millimeters to several centimeters, tubers are
rounded or wart-like protrusions of single or adjacent gyri,
very firm to touch and pale in color [1,5,13]. They may be
wide and flat or dimpled. Tubers expand the gyri and blur
the margin between the gray and white matter [1,13]. They
may be present in the depths of sulci. Histologically, tubers
are characterized as atypical giant astrocytes, abnormal mal-
orientated neurons or many indeterminate cells, and lack the
normal six-layered lamination of the cortical gray matter.
Numerous glial processes and fibers, especially in the sub-
pial layers, make the tissue abnormally firm or sclerotic on
palpation [5,6]. They also have gliosis and abnormal mye-
lination. The gliosis and absence of myelin in cortical tubers
may extend into the underlying subcortical white matter.
Tubers are occasionally present in the cerebellum; disorga-
nized cortex, abnormal astrocytes and Purkinje cells, and
calcification are the main features [1,13].
On MR imaging, tubers are found in 95% of patients with
tuberous sclerosis [14,15]. They show somewhat thick cor-
tical gray matter and a less distinctive gray-white matter
junction compared with the normal cortex [15–17] (Fig.
2). The peripheral component of tubers is isointense to
mildly hyperintense to normal gray matter on both T1-
and T2-weighted images, and the inner core of tubers is
isointense to hypointense to gray matter on T1-weighted
images and hyperintense on T2-weighted images [15–18]
(Figs. 2 and 3). These signal intensity changes reflect
increased interstitial water in the subcortical area due to
absence of myelin and looseness of tissue structures. The
inner core of tubers may show a signal that is isointense to
cerebrospinal fluid on both T1- and T2-weighted images
[18,19] (Fig. 3). Although uncommon, part of the inner

Fig. 2. Cortical tuber and subependymal nodules in a 17-year-old girl with tuberous sclerosis. (a) T1-weighted image: (b) T2-weighted image. A cortical tuber
is seen in the left temporal lobe (arrows). The tuber expands the gyrus and has thickened cortical gray matter and less distinctive gray-white matter junction
compared with normal cortex. On the T2-weighted image (b), the peripheral component of the tuber is mildly hyperintense and the inner core of the tuber is
moderately hyperintense. In each lateral ventricular wall there are subependymal nodules which are mildly hyperintense on the T1-weighted image and
hypointense on the T2-weighted image.
212 Y. Inoue et al. / Brain & Development 20 (1998) 209–221

Fig. 3. Cortical tubers, white matter lesions, and subependymal nodules in a 2-year-old boy with tuberous sclerosis. (a) Non-enhanced CT (the scan angle is
somewhat different from that of the MR study shown in (b–d); (b) T1-weighted image; (c) T2-weighted image; (d) FLAIR (fluid attenuated inversion
recovery) image at the same level as the T1- and T2-weighted images. On CT, a calcified subependymal nodule is present in the wall of the right frontal horn
and at the left foramen of Monro. Several cortical tubers are seen in the right frontal and left temporal lobes (arrows). The right frontal lobe tuber expands the
gyri and shows heterogeneous hypodensity. A hypodense white matter lesion is seen beneath the cortical tuber (a). On MR, the calcified nodule in the right
frontal horn is hyperintense on the T1-weighted image (b), and isointense on the T2-weighted image (c). The subependymal nodule near the left foramen of
Monro shows ring-like hyperintensity on the T1-weighted image and hypointensity on the T2-weighted image. Cortical tubers in the right temporal lobe
expand the gyri and show a less distinct gray-white matter junction (arrows). The inner core of the tuber is nearly isointense to cerebrospinal fluid, markedly
hypointense on the T1-weighted image, and hyperintense on the T2-weighted image. Another cortical tuber is seen in the left medial frontal lobe just anterior
to the genu of the corpus callosum (small arrow). Several other white matter lesions and the inner core of the tubers are better defined on the FLAIR image
because cerebrospinal fluid in the cerebral sulci and ventricles is rendered hypointense (d).

core may be hyperintense to gray matter on T1-weighted
images [18,19].
Cerebrospinal fluid in cerebral sulci or over the brain
surface shows a hyperintense signal on T2-weighted images
and may produce a partial volume effect, which may
obscure small cortical tubers. Recently developed pulse
sequence, fluid attenuated inversion recovery (FLAIR)
sequence, which produces T2-weighted images with cere-
brospinal fluid appearing hypointense [20], appears to
delineate cortical lesions as well as small white matter
 Y. Inoue et al. / Brain & Development 20 (1998) 209–221
Fig. 4. Cortical tubers in a 5-month-old boy with tuberous sclerosis. (a)
Inversion recovery of T1-weighted image; (b) T2-weighted image. A cor-
tical tuber in the left frontal lobe appears hyperintense on the T1-weighted
image and hypointense on the T2-weighted image (arrow) because the
premyelinated white matter is relatively hypointense on the T1-weighted
images and hyperintense on the T2-weighted images compared with the
cortical tuber.
lesions clearly, and may be helpful occasionally [21,22]
(Fig. 3). Magnetic transfer imaging, another new technique
to suppress signals from protein-bound water protons, seems
an effective modality improving the detectability and signal
noise ratio for all intracranial lesions of tuberous sclerosis
[23].
In infants less than 1 year old, and particularly in those
less than 6 months old, the appearance of cortical tubers is
different compared with the children older than 2 years,
when myelination of white matter comes close to the adult
pattern [14]. In the brain of young infants, there is less
myelination, and a high water content in white matter is
present, which results in hyperintensity on T2-weighted
images [24]. Thus, the inner core of cortical tubers in very
young children is hyperintense to premyelinated white mat-
ter on T1-weighted images and is hypointense to premyeli-
nated white matter on T2-weighted images [14,25,26] (Fig.
4).
In adult patients with tuberous sclerosis, high signal
intensity in tubers on T2-weighted images is less often
213
seen than in children. In our patients who had follow-up
MR studies, the high signal on T2-weighted images seen
at a younger age became less distinct and often disappeared
(Fig. 5). These suggest that dysmyelinated white matter
subjacent to tubers may gain myelination with increasing
age. Enhancement of tubers following intravenous admin-
istration of gadopentate meglumine (GdDTPA) has been
reported to occur in less than 5% of patients [15]. Some
cortical tubers may distort the adjacent gyrus but do not
demonstrate high signal intensity on T2-weighted images
(Figs. 2 and 8). Visual inspection of the cortical areas on
T2-weighted images only fails to identify tubers that do not
show hyperintensity. Therefore, it is important to look for
gyral deformity (usually expanded), abnormal thickening of
the cortical gray matter, and/or blurring of the gray-white
matter junction. When only the latter findings are observed,
cortical dysplasia must be considered [27,28]. It should be
kept in mind that formes frustes of tuberous sclerosis are not
uncommon; a solitary cortical tuber unassociated with other
features of tuberous sclerosis should not be misdiagnosed as
a brain tumor [28,29].
On CT scans, cortical tubers can occasionally be detected
as a localized low-density area [30,31], which probably
reflects the inner core of the tuber (Fig. 3). Calcification in
cortical tubers has been reported as high as 54% [14]. The
cortical calcification may be gyriform, simulating the
appearance of Sturge–Weber syndrome [32]. In young
infants, cortical tubers may be radiologically occult (Fig.
6). With increasing age, the low-density area of the inner
core of tubers diminishes and becomes less distinctive, and
calcifications may appear [26].
1.4.2. Subependyrnal nodules
Subependymal nodules are found in 95% of patients with
tuberous sclerosis [14,15]. Subependymal nodules may
occur in the third and fourth ventricular walls, but most
are found in the lateral ventricular walls, near the sulcus
terminalis, with their deeper parts embedded in the caudate
or thalamus. They are firm, or stony hard due to calcifica-
tion, and form round or elongated protrusions into the ven-
tricles [1,13]. Calcification is common with increasing age.
Multiple adjacent subependymal nodules resemble dripping
wax, hence the nickname ‘candle guttering’ for the pneu-
moencephalographic appearance of these lesions. Histolo-
gically the nodules are composed of giant cells with glial
and neural features and may have many vascular elements to
account for the tumor stain, while in neonates there may be
scattered neuroblasts [1,4]. They are covered by an intact
layer of ependyma.
On CT scans, subependymal nodules are easily detected
because of calcification. They are rarely calcified in the first
year of life; the number of calcifications increases with the
age of the patient [33]. Calcification may be globular, par-
tial, or ring-like in appearance [17,19] (Figs. 3 and 7). MR
imaging is less sensitive in depicting calcified nodules com-
pared with CT. Gradient echo pulse sequences are known to
214 Y. Inoue et al. / Brain & Development 20 (1998) 209–221

Fig. 5. Changing intensities of white matter lesions on follow-up study in a 9-year-old girl with tuberous sclerosis. (a) T1-weighted image at 4 years of age;
(b) T2-weighted image at 4 years of age; (c) T1-weighted image at 9 years of age; (d) T2-weighted image at 9 years of age Irregular-shaped white matter
lesions are demonstrated between the cortical tuber and the lateral ventricular wall lateral to and posterior to the trigone of the lateral ventricles (arrow) as
mildly hypointense to gray matter on the T1-weighted image (a) and as heterogeneously hyperintense on the T2-weighted image (b). This is a typical, wedge-
shaped white matter lesion. On a follow-up MR study, 5 years later, the lesion shows less prominent intensity on both T1- and T2-weighted images, which
suggests that myelination has possibly occurred during this interval. Hyperintensity of the inner core of the tuber is also less prominent.

Fig. 6. Cortical tuber in a male infant with tuberous sclerosis. (a) Initial CT at 3 months (after contrast administration); (b) the second CT at 12 months. The
initial contrast CT at 3 months demonstrates periventricular hypodensity in the bilateral frontal periventricular white matter, and a questionable hyperdense
area in the left frontal pole (a). Non-enhanced CT at 12 months shows many cortical tubers seen as hypodense areas in the subcortical white matter (small
arrows). These lesions have been confirmed with MR (not shown).
 Y. Inoue et al. / Brain & Development 20 (1998) 209–221 215

Fig. 7. Subependymal giant cell astrocytoma, cortical tubers and white matter lesion in a 4-year-old girl with tuberous sclerosis. (a) Non-enhanced CT; (b)
T1-weighted image; (c) T2-weighted image; (d) T1-weighted image with gadolinium-DTPA. CT shows a partially calcified, hyperdense subependymal giant
cell astrocytoma in the right frontal horn and a calcified subependymal nodule near the left foramen of Monro (a). The tumor is nearly isointense to the gray
matter on the T1-weighted image (b) and heterogeneously hyperintense on the T2-weighted image (c). Several flow voids which indicate blood vessels are
seen in the tumor (c) (arrow heads). After contrast administration, the tumor is homogeneously and markedly enhanced (d). There are cortical tubers in the
right frontal, right parietal, and left occipital lobes (arrows). The cortical tuber in the right parietal lobe expands the gyrus and shows thickened cortical gray
matter with a blurred gray-white matter junction. The inner core of the lesions is moderately to markedly hyperintense on the T2-weighted image and mildly
hypointense on the T1-weighted image.

be more sensitive for detection of calcium, iron, or other
metals. Gradient echo T2-weighted images (T2* images)
have been reported to be useful in detecting calcified
nodules in patients with tuberous sclerosis [34]. Routine
clinical use of T2* pulse sequences, we believe, is not
necessary to study patients with tuberous sclerosis because
CT is widely available. Subependymal nodules compared
with cortical gray matter, are commonly isointense to hyper-
intense on T1-weighted images and isointense to hypoin-
tense on T2-weighted images (Figs. 2 and 3 and 10) [16–
18]. Hypointensity on T2-weighted images is a reflection of
the calcification in nodules. Relative hyperintensity on T1-
weighted images seems characteristic of subependymal
nodules but may partly reflect mild calcification itself
216 Y. Inoue et al. / Brain & Development 20 (1998) 209–221

Fig. 8. Cystic subependymal giant cell tumor and cortical tuber in a 16-year-old boy with tuberous sclerosis. (a) CT without contrast material; (b) CT with
contrast material; (c) T1-weighted image; (d) T2-weighted image; (e) T1-weighted image with gadolinium-DTPA. A partially calcified, mixed-density mass
is present near the foramen of Monro with bilateral hydrocephalus (a). The mass is heterogeneously enhanced on contrast CT (b). The mass has solid and
cystic portions. On MR, the solid portion is nearly isointense to the gray matter on both T1- and T2-weighted images, and markedly enhanced after
gadolinium-DTPA administration. Three cortical tubers are demonstrated on this section, one in the right insular cortex, one in the right frontal lobe (small
arrow), and one in the right posterior temporal lobe (arrows). In the first, thickening of gray matter is seen and the inner core of the tuber appears hyperintense
on the T2-weighted image, but in the latter two, the inner core of the tuber is not apparently hyperintense on the T2-weighted image.

[35]: calcification of less than 30% has been shown to cause
hyperintensity on T1-weighted images [33]. On Gd-DTPA
MR, 30–80% of subependymal nodules show enhancement
[15,36,37] with a nodular, heterogeneous, or ring-like
appearance. Enhancement of nodules does not necessarily
denote neoplastic transformation [35]. Periodic follow-up
studies of enhancing lesions near the foramen of Monro
are indicated because subependymal giant cell tumors
occur almost exclusively at this site.
1.4.3. Subependymal giant cell tumors
Grobus et al. were the first to report the association of
subependymal giant cell tumor with tuberous sclerosis
(cited in Ref. [15]). The average age at the time of diagnosis
is about 13 years old, and most commonly between 5 and 10
years. Subependymal giant cell tumors differ from the sub-
ependymal nodules by their size and tendency to enlarge.
Their incidence in tuberous sclerosis is approximately 10–
15% [4,15,33]. Prominent blood vessels are frequently pre-
 Y. Inoue et al. / Brain & Development 20 (1998) 209–221 217

sent in the tumors [38]. It is believed that subependymal

giant cell tumors originate from subependymal nodules of
tuberous sclerosis [39,40].
On CT scans, subependymal giant cell tumors are identi-
fied near the foramen of Monro as a partially calcified, solid
mass with either ipsilateral or bilateral ventricular enlarge-
ment, and they enhance to various degrees after intravenous
contrast injection (Figs. 7 and 8). On MR imaging, those
tumors are usually heterogeneous but can be homogeneous
and are isointense to slightly hypointense on T1-weighted
images and hyperintense on T2-weighted images, and show
marked enhancement with Gd-DTPA [15]. On rare occa-
sions, they may have a cystic internal component (Fig. 8).
Serpentine signal voids which represent dilated vessels are
occasionally seen in the tumors [15] (Figs. 7 and 8). Cere-
bral angiography may demonstrate tumor vessels as well as
a tumor stain [41]. Although uncommon, subependymal
giant cell tumors may bleed, resulting in intraventricular
hemorrhage [42] (Fig. 9). Why subependymal giant cell
tumors develop only in the area of the foramen of Monro
has not been determined. Uncommonly, other cerebral
tumors also occur in patients with tuberous sclerosis.
These tumors seem to be an incidental occurrence and not
specific to tuberous sclerosis. These include pilocytic astro-
cytoma, fibrillary astrocytoma, and diffuse gliomatosis of
the cerebral hemispheres [38].
Fig. 9. Subependymal giant cell tumor with hemorrhage in an 8-year-old
1.4.4. White matter lesions boy with tuberous sclerosis. CT without contrast material demonstrates
Islets consisting of a group of heterotopic clustered cells extensive intraventricular hemorrhage from the subependymal giant cell
are invariably present in the white matter of patients with tumor on the left. Note calcified subependymal nodules at the body of the
right lateral ventricle and a calcification in the right parietooccipital white
tuberous sclerosis [1,13]. Histologically the cells are often
matter which is probably a tuber in the white matter.
bizarre and gigantic, with characteristics of both neurons
and glia [12]. They are associated with areas of hypomye-
lination similar to those seen in the cortical tubers. Many of or curvilinear bands which may reflect a possible pathogen-
these lesions are microscopic and therefore do not appear on esis of tuberous sclerosis, which will be discussed later.
imaging studies [24]. Low power microscopic examination The other type of abnormal signal intensity in the white
of heterotopic clusters suggests that they are distributed matter is a hyperintense linear band on both T1-weighted
along the most direct line between the ependymal wall and T2-weighted images, which has been reported pre-
and the tubers [13]. This distribution corresponds to the viously [35] but not widely discussed, to our knowledge.
normal migratory path of spongioblasts during embryogen- These lesions are uncommon and some of them appear to
esis, and it is during this migration that they differentiate enhance after contrast administration (Figs. 10 and 11). On
[13,43]. CT, these lesions are not visualized. Corresponding histolo-
On CT, those lesions large enough to be seen demonstrate gic investigation has not been done, but the band appears to
decreased density in the white matter without enhancement correspond to lesions described by Donegami et al. have
after intravenous contrast administration. Calcification may described heterotopic clusters in white matter, some of
occur in white matter lesions (Fig. 9). On MR, these show which were distributed in a pattern similar to the normal
similar signal intensity to the cortical tubers: isointense to migratory path of primitive neuroepithelial cells during
hypointense on T1-weighted images and hyperintense on embryogenesis [13]. The reason why these lesions are
T2-weighted images. They demonstrate three distinctive hyperintense on T1-weighted images is not understood
patterns: straight or curvilinear bands [44,15] that extend and microcalcification has been suggested [35]. Hypermye-
from the ventricular wall through the cerebrum toward the lination is another possible cause for the T1 hyperintensity,
cortex (Fig. 10); wedge-shaped lesions; non-specific con- but pathologically has not been proven. Abnormal enhance-
glomerate foci (Figs. 3 and 5); and cerebellar radial bands ment is probably related to the absence or incompleteness of
[15]. Approximately 12% of these white matter lesions have the blood brain barrier in these lesions. To maintain an intact
been reported to show enhancement after contrast adminis- blood brain barrier, astrocytes require normal structure and
tration [15]. The most interesting among those are straight function [45]. Abnormal enhancement on contrast MR
218 Y. Inoue et al. / Brain & Development 20 (1998) 209–221

Fig. 10. Cortical tuber, white matter linear lesion and subependymal nodules in an 11-year-old girl with tuberous sclerosis. (a) T1-weighted image; (b) T2-
weighted image; (c) T1-weighted image with gadolinium-DTPA. The left lateral ventricle is dilated due to an obstructing subependymal giant cell
astrocytoma (not shown). A cortical tuber is demonstrated in the right frontal lobe without gyral deformity (arrow). The peripheral component of the
tuber is isointense on both T1- and T2-weighted images and the inner core of the tuber is hyperintense on the T2-weighted image (b) and moderately
hyperintense on the T1-weighted image (a). There is a short, band-like lesion between the cortical tuber and the right lateral ventricular wall. This linear
lesion is minimally hyperintense on the T1-weighted image as well as on the T2-weighted image (arrow), and is enhanced after administration of contrast
material (arrow) (c). Several subependymal nodules are depicted and some of them are hyperintense on the T1-weighted image (a) and enhanced after
gadolinium-DTPA administration (c).

images reflects the presence of abnormal astrocytes
(bizarre-shaped astrocytes), which may not function as nor-
mal astrocytes or may not produce the necessary protein to
maintain tight junctions (cited in Ref. [45]).
In neonates or young infants, white matter lesions look
somewhat different, and are hyperintense to premyelinated
white matter on T1-weighted images and hypointense to
premyelinated white matter on T2-weighted images.
1.4.5. Cerebellar lesions
Cerebellar lesions have been described in tuberous
sclerosis, but they are uncommon, occurring in approxi-

Fig. 11. Hyperintense white matter lesion on T1-weighted image in a 20-year-old woman with tuberous sclerosis. (a) T1-weighted image; (b) T1-weighted
image after gadolinium-DTPA injection. Several hyperintense lines are seen between the cortical area and the lateral ventricular wall (arrows) (a).
Hyperintense lines are moderately enhanced on the post-contrast T1-weighted image. On T2-weighted images (not shown), some of these lines were
hyperintense and some of them were not visible.
 Y. Inoue et al. / Brain & Development 20 (1998) 209–221
mately 10% of patients [33,46]. Lesions of the cerebellum
are similar to those seen in the cerebral hemispheres, con-
sisting of cortical tubers, heterotopic clusters in the white
matter and subependymal nodules [1,4,12].
1.4.6. Possible pathogenesis of cerebral lesions
On microscopic examination, bizarre giant cell clusters
are the main feature of cortical tubers, white matter lesions,
and subependymal nodules. Much discussion has focused on
the ontogenesis of these bizarre giant cells in tuberous
sclerosis. Classic morphologic studies by light microscopy
and electron microscopy have demonstrated astrocytic fea-
tures [47]. Immunohistochemical studies have shown neu-
ronal features [48]. Investigations using light microscopy,
electron microscopy, and immunohistochemical studies,
when considered together, have indicated that these bizarre
giant cells have both astrocytic and neuronal features in
cortical tubers, subependymal nodules, white matter lesions,
and even subependymal giant cell tumors [12]. These find-
ings suggest that the giant cell in tuberous sclerosis is the
product of a dysgenetic event in early development, result-
ing in incomplete expression of astrocyte or neuronal differ-
entiation in that cell [12,49]. At histologic examination, the
white matter lesions of tuberous sclerosis show clusters of
giant cells that characteristically align in rows that appear to
follow the path of neuronal migration, streaming radially
along the most direct line from the ependyma to the cortical
tuber [12,13]. Although straight or curvilinear lines that
extend from the ventricular wall toward the cortex seen on
MR seem to represent a migration anomaly, it may not be
the primary abnormality of tuberous sclerosis but the sec-
ondary change due to the presence of bizarre-shaped giant
cells. At present, it is reasonable to speculate as follows
concerning brain lesions of tuberous sclerosis. The primary
brain abnormality in tuberous sclerosis appears to be in
some of the germ cells in the germinal matrix [50,24], prob-
ably controlled by genes. Some dysgenetic giant cells in the
ventricular wall may completely migrate to the cortex, pro-
ducing cortical tubers; some may incompletely migrate,
producing white matter lesions; some may not migrate at
all, producing subependymal nodules [12,15,24].
1.4.7. Seizures and mental retardation
There has been much attention paid to types of seizures in
tuberous sclerosis patients, particularly infantile spasms,
and their possible relation to the anatomic location of tubers.
A statistical analysis by Shephard et al. has shown that the
occurrence of infantile spasms rather than any other type of
seizure was related to the total number of tubers and was not
related to the number in any one area of the brain [51].
Several investigations have been unable to demonstrate a
link between intelligence and the number of subependymal
nodules [18,52]. In our experience with a limited number of
patients, severely mentally retarded patients tended to have
a higher number of tubers; no correlation was noted between
the severity of mental retardation and either the number of
219
subependymal nodules or the degree of ventricular dilata-
tion [18,52]. Shephard et al. [51] have reported that all
tuberous sclerosis patients with mental retardation had or
have been had some type of seizure, usually generalized and
very often infantile spasms. and that none of the patients
who never had seizures were mentally disabled. Seizure-
free tuberous sclerosis patients had a larger number of cor-
tical tubers than the patients with partial seizures.
1.5. Ocular lesions
Ocular findings are common and present in approxi-
mately 50% of patients with tuberous sclerosis [13,53].
The most common of these is retinal hamartoma, an astro-
cytic proliferation without necrosis, hemorrhage, or disse-
mination [13,54,55]. Retinal hamartomas are usually
present in both eyes and are often multiple [13,54]. They
may present in children as leukocoria. They must be differ-
entiated from non-neoplastic causes of leukocoria as well as
from neoplastic masses, notably retinoblastoma [4]. When
retinal hamartomas calcify, they can be seen on CT images
as small calcifications in the region of the optic nerve head
[55]. When they do not calcify, they are difficult to detect on
either CT or MRI, even after contrast administration.
1.6. Vascular abnormalities
There have been several case reports of patients with
tuberous sclerosis associated with intracranial aneurysms
[56,57,19]. Although these intracranial aneurysms may be
merely a coincidental finding, these reports suggest some
association of intracranial aneurysms with tuberous sclero-
sis.
2. Conclusion
This article presents CT and MR findings of cortical
tubers, white matter lesions, subependymal tubers, and sub-
ependymal giant cell tumors. New findings on MR images
are particularly emphasized. Many of cortical tubers expand
cerebral gyri, and demonstrate thickening of the cortex and
blurring of the gray and white matter junction. The inner
core of cortical tubers is hypointense to nearly isointense to
the gray matter on T1-weighted images, and nearly isoin-
tense to hyperintense on T2-weighted images. White matter
lesions demonstrate three distinctive patterns: straight or
curvilinear bands that extend from ventricular wall through
the cerebrum toward the cortex: wedge-shaped lesions: non-
specific conglomerate foci. The most white matter lesions
show similar signal intensity to the cortical tubers: isoin-
tense to hypointense on T1-weighted images and hyperin-
tense on T2-weighted images. Some white matter lesions
show hyperintense on T1-weighted images and may be
enhanced after contrast administration. Subependymal
giant cell tumors develop from the subependyma of the
220 Y. Inoue et al. / Brain & Development 20 (1998) 209–221
lateral ventricle almost always adjacent to and on the cua-
date nucleus. Those tumors usually show heterogeneous
intensity and are isointense to slightly hypointense on T1-
weighted images and hyperintense on T2-weighted images,
and show marked enhancement after contrast administra-
tion. Possible pathogenesis is discussed. The primary
brain abnormality in tuberous sclerosis appears to be in
some of the germ cells in the germinal matrix.
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