Brain, Vol. 122, No. 2, 219-238,
February 1999
© 1999 Oxford University Press
Characterization of nodular neuronal heterotopia in children
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1 University Laboratory of Physiology, University of Oxford, 2 Departments of Neurology and 3 Neuropathology, Radcliffe Infirmary, Oxford, UK
Correspondence to:
Dr Zoltán Molnár, Institut de Biologie Cellulaire et de Morphologie, Rue du Bugnon 9, 1005 Lausanne, Switzerland E-mail: zoltan.molnar{at}ibcm.unil.ch or Dr Marian Squier, Department of Neuropathology, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, UK E-mail: waney.squier{at}clinical-neurology.oxford.ac.uk
Neuronal heterotopia are seen in various pathologies and are associated with intractable epilepsy. We examined brain tissue from four children with subcortical or periventricular nodular heterotopia of different aetiologies: one with severe epilepsy following focal brain trauma at 17 weeks gestation, one with hemimegalencephaly and intractable epilepsy, one with focal cortical dysplasia and intractable epilepsy, and one dysmorphic term infant with associated hydrocephalus and polymicrogyria. The connectivity of nodules was investigated using histological and carbocyanine dye (DiI) tracing techniques. DiI crystal placement adjacent to heterotopic nodules revealed numerous DiI-labelled fibres within a 2–3 mm radius of the crystals. Although we observed labelled fibres closely surrounding nodules, the majority did not penetrate them. Placement of DiI crystals within nodules also identified a limited number of projections out of the nodules and in one case there was evidence for connectivity between adjacent nodules. The cellular and neurochemical composition of nodules was also examined using immunohistochemistry for calretinin and neuropeptide Y (NPY), which are normally expressed in GABAergic cortical interneurons. Within heterotopic nodules from all cases, numerous calretinin-positive neurons were identified, along with a few cell bodies and many processes positive for NPY. Calretinin-positive neurons within nodules were less morphologically complex than those in the cortex, which may reflect incomplete differentiation into an inhibitory neuronal phenotype. There were also abnormal clusters of calretinin-positive cells in the overlying cortical plate, indicating that the migratory defect which produces heterotopic nodules also affects development of the cortex itself. Thus, heterotopic nodules consisting of multiple neuronal cell types are associated with malformation in the overlying cortical plate, and have limited connectivity with other brain regions. This abnormal development of connectivity may affect neuronal maturation and consequently the balance of excitation and inhibition in neuronal circuits, leading to their epileptogenic potential.
epilepsy; heterotopia; calretinin; neuropeptide Y; cortex
DiI = 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate; GABA = 
-aminobutyric acid; LBCV = luxol blue/cresyl violet; NPY = neuropeptide Y
* Present address: Epilepsy Research Group, Institute of Neurology, Queen Square, London WC1N 3BG, UK
Present address: Institut de Biologie Cellulaire et de Morphologie, Lausanne, Switzerland
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