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Infantile spasm–associated microencephaly in tuberous sclerosis complex and cortical dysplasia

From the Divisions of Neurosurgery (P.S.C., S.T.N., J.W.C., M.N.H., G.W.M.), Neuroradiology (N.S.), Neuropathology (H.V.V.), and Pediatric Neurology (S.K.), and Department of Neurology (H.V.V.), Brain Research Institute (H.V.V., G.W.M.), and Mental Retardation Research Center (C.C., G.W.M.), David Geffen School of Medicine, University of California, Los Angeles; Departments of Pathology (L.N.) and Neurology (J.P.L.), Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto, Brazil; and Department of Neurosurgery (P.S.C.), All India Institute of Medical Sciences, New Delhi.

Address correspondence and reprint requests to Dr Mathern, Reed Neurological Research Center, 710 Westwood Plaza, Rm. 2123, Los Angeles, CA 90095-1769; e-mail: gmathern{at}ucla.edu

Objective: In children with and without infantile spasms, this study determined brain volumes and cell densities in epilepsy surgery patients with tuberous sclerosis complex (TSC) and cortical dysplasia with balloon cells (CD).

Methods: We compared TSC (n = 18) and CD (n = 17) patients with normal/autopsy controls (n = 20) for MRI gray and white matter volumes and neuronal nuclei (NeuN) cell densities.

Results: In patients without a history of infantile spasms, TSC cases showed decreased gray and white matter volumes (–16%). In cases with a history of infantile spasms, both CD (–25%) and TSC (–35%) patients showed microencephaly. This was confirmed in monozygotic twins with TSC, where the twin with a history of spasms had cerebral volumes less (–16%) than the twin without a history of seizures. Regardless of seizure history, TSC patients showed decreased NeuN cell densities in lower gray matter (–36%), whereas CD patients had increased densities in upper cortical (+52%) and white matter regions (+65%). For TSC patients, decreased lower gray matter NeuN densities correlated with reduced MRI volumes.

Conclusions: Patients with tuberous sclerosis without spasms showed microencephaly associated with decreased cortical neuronal densities. In contrast, cortical dysplasia patients without spasms were normocephalic with increased cell densities. This supports the concept that tuberous sclerosis and cortical dysplasia have different pathogenetic mechanisms despite similarities in refractory epilepsy and postnatal histopathology. Furthermore, a history of infantile spasms was associated with reduced cerebral volumes in both cortical dysplasia and tuberous sclerosis patients, suggesting that spasms or their treatment may contribute to microencephaly independent of etiology.

Supported by the NIH grants R01 NS38992 and P05 NS02808 to G.W.M., the International Brain Research Organization (IBRO) and Boyscast Fellowship from the Ministry of Science and Technology of India to S.P.C., and FAPESP (CInAPCe-Project-04/14004-9) to J.P.L.

Disclosure: The authors report no conflicts of interest.

Received June 26, 2006. Accepted in final form October 19, 2006.

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