physiology and Neurogenetics Unit, IRCCS Stella Maris Foun-
dation, Pisa, Italy.
Study funding: Supported by the Pierfranco and Luisa Mariani
Disclosure: The authors report no disclosures.
Address correspondence and reprint requests to Dr. Pasquale
Striano, Muscular and Neurodegenerative Diseases Unit, Institute
G. Gaslini, University of Genova, Genova, Italy; pstriano@e-mail.
it; or Dr. Federico Zara, Laboratory of Neurogenetics, Muscular
and Neurodegenerative Diseases Unit, Institute G. Gaslini, Genova,
Copyright © 2011 by AAN Enterprises, Inc.
Study concept or design: P.S., F.Z.; drafting/revising of manuscript: all
the authors; analysis of interpretation: all the authors.
The authors thank Collaborative Group on Genetics of the Italian League
against Epilepsy (LICE) for support and suggestions and the Galliera Ge-
netic Bank–Network of Telethon Genetic Biobanks (project GTB07001)
for providing samples of patients. Details have been removed from these
cases to ensure anonymity.
1. Dulac O, Tuxhorn I. Infantile spasms and West syndrome.
In: Roger J, Bureau M, Dravet C, Genton P, Tassinari CA,
Wolf P, eds. Epileptic Syndromes in Infancy, Childhood
and Adolescence, 3rd ed. London: John Libbey & Co Ltd.;
Pal DK, Pong AW, Chung WK. Genetic evaluation and
counseling for epilepsy. Nat Clin Pract Neurol 2010;6:
Marshall CR, Young EJ, Pani AM, et al. Infantile spasms is
associated with deletion of the MAGI2 gene on chromo-
some 7q11.23-q21.11. Am J Hum Genet 2008;83:106–
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plication in chromosome band 14q12 including FOXG1
in a girl with refractory epilepsy and intellectual impair-
ment. Eur J Med Genet 2009;52:440–442.
Brunetti-Pierri N, Paciorkowski AR, Ciccone R, et al. Du-
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impairment. Eur J Hum Genet 2011;19:102–107.
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METAPLASTIC BONE IN A CORTICAL TUBER
OF A YOUNG PATIENT WITH TUBEROUS
Cortical tubers are the most common brain lesions of
the tuberous sclerosis complex (TSC).1They vary
widely in size, location, and appearance, may have a
cystic or a calcified component, and are often epilep-
togenic.2,3Histologically, tubers are hypomyelinated
hamartomas, which are characterized by abnormal
cortical lamination and are typically composed of gi-
ant or balloon cells, dysplastic neurons, and reactive
astrocytes.4We report the radiologic and pathologic
findings of a resected calcified tuber identified as an
Case report. The patient is a 19-year-old right-
handed woman with a known spontaneous TSC1 mu-
tation. She was the product of a normal pregnancy.
a diagnosis of TSC. Neuropathologic features include
numerous cortical tubers and subependymal giant cell
tumors (SGCT). The patient has experienced daily sei-
zures since their onset. Multiple antiepileptic medica-
tions and other anticonvulsant treatments were tried
without significant seizure control. The patient has a
history of global developmental impairment.
As part of the presurgical evaluation for neurosur-
gical intervention, an MRI showed SGCT, multiple
tubers located in bilateral frontal, parietal, and occip-
ital lobes, and a large (22 mm) T2 hypointense calci-
fied lesion deep to the left superior frontal sulcus
component of this lesion was not visible when the pa-
tient was 2 years 4 months old and was first visible on
MRI when the patient was 4 years old (figure). Fluoro-
deoxyglucose PET revealed numerous bilateral frontal
and parietal foci of cortical hypometabolism corre-
sponding to cortical tubers on coregistered MRI. There
was also a single focus of asymmetric hypermetabolism
in the left middle frontal gyrus located deep to the large
calcified cortical tuber described. Although the EEG
was multifocal, discharges were more prominent over
the left frontocentral region. At age 19, the patient un-
derwent a left frontal craniotomy and intraoperative
electrocorticography, which demonstrated frequent in-
terictal epileptiform abnormalities in the tissue sur-
rounding the large frontal lobe calcified tuber that had
partial seizures. The tuber and its immediately sur-
a significant improvement in both the number and se-
verity of seizures.
The resection specimen consisted of a 5.4 ?
2.6 ? 1.7 cm aggregate of brain tissue. A dominant
fragment had a heterogenous cut surface and central
mineralization (figure, B.a). Histology demonstrated
a tuber clearly delineated from overlying white mat-
ter, which was diffusely gliotic, suggesting that the
adjacent tuber tissue had chronically compressed the
A. Gallagher, PhD*
A. Kovach, MD*
A.E. Rosenberg, MD
E. Eskandar, MD
E.A. Thiele, MD, PhD
Neurology 76May 3, 2011
white matter. The area of mineralization corre-
sponded to a 0.5 ? 0.3 ? 0.3 cm fragment of mature
cortical-like bone surrounded by punctuate calcifica-
tions. The bone had lamellar architecture, haversian-
like canals, which enclosed small capillaries, and
small osteocytes with delicate canaliculi. The bone
surface was sharply demarcated from adjacent gliotic
white matter by a rim of flattened osteoblasts (IIB,
Figure Radiologic and histopathologic findings
(A) Progression over years of the left frontal tuber on MRI scans. Axial T2 fast spin-echo (FSE) (a) and axial fluid-attenuated
inversion recovery (FLAIR) (b) are presented chronologically. MRI shows that the calcified left frontal tuber does not appear
on T2 FSE sequence at the age of 2 years and 4 months. FLAIR was not available for review at this age. The calcified lesion
remains stable over time as shown on T2 FSE and FLAIR images from age 9 years 11 months, 17 years 1 month, and 19
years 1 month. (B) Gross and histopathology of tuber resection specimen. (a) The largest fragment of the resection speci-
men is bisected and demonstrates a firm tan cut surface with a central area of mineralization (arrows) and the in situ
which contains numerous small calcifications (top of field). Architecturally, the bone is cortical-like and has scattered
haversian-like canals, which enclose blood vessels (hematoxylin & eosin [H&E], 10?). (c) The surface of the bone that bor-
ders the brain tissue is lined by flattened osteoblasts (arrowheads). The bone is lamellar in pattern with scattered small
ing lamellae and extend into and encompass some of the small calcifications (H&E, 40?).
Neurology 76May 3, 2011
IIC). In limited areas, small foci of woven bone ex- Download full-text
tended from the surface into and encompassed some
of the microscopic calcifications (IID).
Discussion. A calcified component of tubers has been
lationship has not been consistently observed.7In the
present case, the significant improvement in seizure fre-
quency after the surgery suggests that the lesion was in-
volved in the epileptogenic zone. However, the
unclear, particularly since the patient’s seizure onset oc-
curred years before the tuber appeared calcified. The
it is not known if seizure activity perhaps promotes an
inflammatory response in tubers, which leads to calcifi-
tion, which then by unknown mechanisms contributes
The pathophysiology leading to calcification of
tubers in TSC is also unclear, and has been thought
to be a form of dystrophic calcification. Prospective
and retrospective studies are currently underway to
better understand the etiology of bone formation in
the cortical tuber as well as to characterize its fre-
quency and possible relationships to dystrophic calci-
fications frequently seen in tubers. So far, tissue from
7 resected calcified tubers has been reviewed and all
show dystrophic calcification without the presence of
lamellar bone. The presence of lamellar bone in the
current case raises interesting questions regarding the
cell origin and biology of cortical tubers.
*These authors contributed equally to this work.
From the Carol and James Herscot Center for Tuberous Sclerosis
Complex, Department of Neurology (A.G., E.A.T.), Department of
Pathology (A.K., A.E.R.), CS Kubik Laboratory for Neuropathology
and Department of Pathology (A.S.-R.), and Department of Neuro-
surgery (E.E.), Massachusetts General Hospital, Harvard Medical
Study funding: Supported by the CIHR (A.G.), the Carol and James
Herscot Center for Tuberous Sclerosis Complex, and the NIH/
Disclosure: Dr. Gallagher receives scholarship support from the CIHR.
Dr. Kovach reports no disclosures. Dr. Stemmer-Rachamimov receives
dar report no disclosures. Dr. Thiele serves on scientific advisory boards
for the Tuberous Sclerosis Alliance, the Angelman Syndrome Founda-
tion, and the Charlie Foundation; serves on the speakers’ bureau of and
has received funding for travel and speaker honoraria from UCB; serves
as a consultant for Lundbeck Inc.; and receives research support from
Lundbeck Inc., the NIH/NCI, and the Tuberous Sclerosis Alliance.
Received July 8, 2010. Accepted in final form December 3, 2010.
Address correspondence and reprint requests to Dr. Elizabeth A.
Thiele, Carol and James Herscot Center for Tuberous Sclerosis Com-
plex, 175 Cambridge Street, Suite 340, Boston, MA 02114;
Copyright © 2011 by AAN Enterprises, Inc.
The authors thank Dr. E.T. Hedley-Whyte for discussions related to data
interpretation and help with manuscript revision, as well as Inna Shepsis
for technical assistance with histologic sections. Dr. Hedley-Whyte and I.
Shepsis are both from the Department of Pathology at the Massachusetts
1.Inoue Y, Nemoto Y, Murata R, et al. CT and MR imaging
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Gallagher A, Madan N, Stemmer-Rachamimov A, Thiele
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