Epilepsia, 47(1):86–97, 2006 Blackwell Publishing, Inc. C  2006 International League Against Epilepsy Periventricular Nodular Heterotopia: Classification, Epileptic History, and Genesis of Epileptic Discharges ∗ Giorgio Battaglia, †Luisa Chiapparini, ‡Silvana Franceschetti, §Elena Freri, ‖ Laura Tassi, ∗ Stefania Bassanini, ∗ Flavio Villani, ∗ Roberto Spreafico, †Ludovico D’Incerti, and §Tiziana Granata Divisions of ∗ Experimental Neurophysiology and Epileptology, †Neuroradiology, ‡Clinical Neurophysiology, and §Child Neurology, Neurological Institute “C. Besta”; and ‖Epilepsy Surgery Center “Claudio Munari,” Niguarda General Hospital, Milan, Italy Summary: Purpose. Periventricular nodular heterotopia (PNH) is among the most common malformations of cortical develop- ment, and affected patients are frequently characterized by focal drug-resistant epilepsy. Here we analyzed clinical, MRI, and electrophysiologic findings in 54 PNH patients to reevaluate the classification of PNH, relate the anatomic features to epileptic outcome, and ascertain the contribution of PNH nodules to the onset of epileptic discharges. Methods: The patients were followed up for a prolonged pe- riod at the Epilepsy Center of our Institute. In all cases, we related MRI findings to clinical and epileptic outcome and analyzed in- terictal and ictal EEG abnormalities. In one patient, EEG and stereo-EEG (SEEG) recordings of seizures were compared. Results: We included cases with periventricular nodules, also extending to white matter and cortex, provided that anatomic continuity was present between nodules and malformed cortex. Based on imaging and clinical data, patients were subdivided into five PNH groups: (a) bilateral and symmetrical; (b) bilateral single-noduled; (c) bilateral and asymmetrical; (d) unilateral; and (e) unilateral with extension to neocortex. The latter three groups were characterized by worse epileptic outcome. No dif- ferences in outcome were found between unilateral PNH patients regardless the presence of cortical involvement. Interictal as well as ictal EEG abnormalities were always related to PNH location. Conclusions: The distinctive clinical features and epilep- tic outcomes in each group of patients confirm the relia- bility of the proposed classification. Ictal EEG and SEEG recordings suggest that seizures are generated by abnormal anatomic circuitries including the heterotopic nodules and ad- jacent cortical areas. Key Words: Subependymal nodular heterotopia—Cerebral malformation—Cortical development— Neuronal migration—Epilepsy outcome. Periventricular nodular heterotopia (PNH) is among the most frequent malformations of cortical development in most clinical series based on magnetic resonance imag- ing (1,2). PNH is made up of round nodular masses of normal neurons and glial cells with no laminar organiza- tion, located close to the periventricular germinal matrix, and hence called periventricular or subependymal nodu- lar heterotopia (3,4). For this particular location within the brain and the normal features of the heterotopic cells, it has been considered the result of a primary failure of neuronal migration (5). Previous articles already addressed the clinical and imaging features of PNH, which may involve both sides of the brain or be restricted to a single hemisphere (6– Accepted July 30, 2005. Address correspondence and reprint requests to Dr. G. Battaglia at Molecular Neuroanatomy Lab, Department of Experimental Neurophys- iology and Epileptology, Istituto Neurologico “C. Besta,” Via Celoria 11, 20133 Milano, Italy. E-mail: battaglia@istituto-besta.it 10). Bilateral and symmetrical PNH occurs mostly in fe- male subjects; it may be familial and causally related to point mutations of the FLN1 gene (11–15). In addition to these cases, familial patients with bilateral PNH not related to FLN1 mutations (16,17), and sporadic female patients with bilateral but clearly asymmetrical PNH have been reported (8). Unilateral PNH is frequently located in the posterior paratrigonal region of the lateral ventricles and may ex- tend into the white matter to involve adjacent neocortical and archicortical areas (18). Large PNH extending from the subependymal region to involve overlying malformed cortical areas in different lobes has been termed subcor- tical heterotopia, but it is not yet clear whether periven- tricular and subcortical heterotopia are separate entities or different extensions of the same brain dysgenesis (19). Regardless the different MRI features, the main clini- cal problem in most PNH patients is the presence of focal drug-resistant epilepsy (6–8), but few data are available 86