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Neurology. May 3, 2011; 76(18): 1602–1604.
PMCID: PMC3100129
Metaplastic bone in a cortical tuber of a young patient with tuberous sclerosis complex
A. Gallagher, PhD,* A. Kovach, MD,* A. Stemmer-Rachamimov, MD, A.E. Rosenberg, MD, E. Eskandar, MD, and E.A. Thiele, MD, PhDcorresponding author
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 Neurosurgery (E.E.), Massachusetts General Hospital, Harvard Medical School, Boston.
corresponding authorCorresponding author.
Study funding: Supported by the CIHR (A.G.), the Carol and James Herscot Center for Tuberous Sclerosis Complex, and the NIH/NINDS1P01NS24279.
*These authors contributed equally to this work.
Address correspondence and reprint requests to Dr. Elizabeth A. Thiele, Carol and James Herscot Center for Tuberous Sclerosis Complex, 175 Cambridge Street, Suite 340, Boston, MA 02114; ethiele/at/partners.org
Received July 8, 2010; Accepted December 3, 2010.
Cortical tubers are the most common brain lesions of the tuberous sclerosis complex (TSC).1 They vary widely in size, location, and appearance, may have a cystic or a calcified component, and are often epileptogenic.2,3 Histologically, tubers are hypomyelinated hamartomas, which are characterized by abnormal cortical lamination and are typically composed of giant or balloon cells, dysplastic neurons, and reactive astrocytes.4 We report the radiologic and pathologic findings of a resected calcified tuber identified as an epileptogenic focus.
The patient is a 19-year-old right-handed woman with a known spontaneous TSC1 mutation. She was the product of a normal pregnancy. Seizure onset occurred at the age of 9 months and led to a diagnosis of TSC. Neuropathologic features include numerous cortical tubers and subependymal giant cell tumors (SGCT). The patient has experienced daily seizures since their onset. Multiple antiepileptic medications 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 neurosurgical intervention, an MRI showed SGCT, multiple tubers located in bilateral frontal, parietal, and occipital lobes, and a large (22 mm) T2 hypointense calcified lesion deep to the left superior frontal sulcus (figure). Review of prior scans revealed that the calcified component of this lesion was not visible when the patient was 2 years 4 months old and was first visible on MRI when the patient was 4 years old (figure). Fluorodeoxyglucose PET revealed numerous bilateral frontal and parietal foci of cortical hypometabolism corresponding 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 underwent a left frontal craniotomy and intraoperative electrocorticography, which demonstrated frequent interictal epileptiform abnormalities in the tissue surrounding the large frontal lobe calcified tuber that had been suspected to be the source of her more problematic partial seizures. The tuber and its immediately surrounding tissue were excised. Subsequently, she has had a significant improvement in both the number and severity of seizures.
Figure
Figure
Radiologic and histopathologic findings
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 matter, which was diffusely gliotic, suggesting that the adjacent tuber tissue had chronically compressed the white matter. The area of mineralization corresponded to a 0.5 × 0.3 × 0.3 cm fragment of mature cortical-like bone surrounded by punctuate calcifications. 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, IIC). In limited areas, small foci of woven bone extended from the surface into and encompassed some of the microscopic calcifications (IID).
A calcified component of tubers has been reported to contribute to epileptogenicity,5,6 but this relationship has not been consistently observed.7 In the present case, the significant improvement in seizure frequency after the surgery suggests that the lesion was involved in the epileptogenic zone. However, the relationship of the calcification to the epileptogenicity is unclear, particularly since the patient's seizure onset occurred years before the tuber appeared calcified. The calcification of tubers in TSC is poorly understood, and it is not known if seizure activity perhaps promotes an inflammatory response in tubers, which leads to calcification, or if instead some other process leads to calcification, which then by unknown mechanisms contributes to epileptogenicity.
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 frequency and possible relationships to dystrophic calcifications 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.
ACKNOWLEDGMENT
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 General Hospital.
Footnotes
Disclosure: Dr. Gallagher receives scholarship support from the CIHR. Dr. Kovach reports no disclosures. Dr. Stemmer-Rachamimov receives research support from the NIH/NINDS. Dr. Rosenberg and Dr. Eskandar report no disclosures. Dr. Thiele serves on scientific advisory boards for the Tuberous Sclerosis Alliance, the Angelman Syndrome Foundation, 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.
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