Vagus Nerve Stimulation for Refractory Epilepsy in Tuberous Sclerosis Nelia Zamponi, MD*, Cristina Petrelli, MD*, Claudia Passamonti, MD*, Romina Moavero, MD † , and Paolo Curatolo, MD † The goal of the study was to assess the long-term seizure and neuropsychologic outcomes of patients with tuber- ous sclerosis and refractory epilepsy who received vagus nerve stimulator implantation. Eleven patients with a follow-up period of at least 12 months were stud- ied retrospectively. The mean age at the time of implan- tation was 14 years (range, 2-35). Seizure outcome was rated as class I (>80% seizure frequency reduction) in 1 (9%), class II (50-79% reduction) in 7 (63%), and class III (<50% reduction) in 3 (27%). No patient experi- enced permanent adverse effects after the procedure. A significant increase of adaptive behaviors and quality of life was observed. Patients who had implantation during childhood exhibited a greater improvement in cognitive and neuropsychologic functioning. Vagus nerve stimulation can be considered an effective and safe therapeutic option in patients with tuberous sclero- sis and refractory epilepsy who are not candidates for epilepsy surgery. Ó 2010 by Elsevier Inc. All rights re- served. Zamponi N, Petrelli C, Passamonti C, Moavero R, Curatolo P. Vagus nerve stimulation for refractory epilepsy in tuber- ous sclerosis. Pediatr Neurol 2010;43:29-34. Introduction Tuberous sclerosis complex is a genetic variably expressed multisystem disorder resulting from inactivating mutations in one of two genes: TSC1 on chromosome band 9q34, encoding for hamartin, and TSC2 on chromosome band 16p13, encoding for tuberin [1]. Mutation in the TSC genes influences neural precursors between weeks 7 and 20 of gestation, resulting in disrupted cell division, abnormal cell differentiation, dysregulated cell size control, and abnormal cellular migration [2]. Approximately 80-85% of all tuberous sclerosis patients have epilepsy. Seizures begin during infancy and are often refractory to antiepileptic treatment in the majority of patients [3,4]. Individuals with TSC2 mutations are more likely to present a history of infantile spasms and intractable epilepsy than are those with TSC1 mutations [5]. Patients who present with inadequately controlled epilepsy after a trial of two or three antiepileptic drugs should early be evaluated as possible candidates for epilepsy surgery. If antiepileptic medications fail and no single epileptogenic tuber is clearly identified, nonpharmacologic therapies such as ketogenic diet and vagus nerve stimulation can be considered [6]. The vagus nerve stimulator was approved by the U.S. Food and Drug Administration in 1997 as an adjunctive therapy for intractable partial epilepsy in patients over 12 years of age. A great body of evidence has subsequently reported that vagus nerve stimulation is an effective and safe treatment for intractable epilepsy [7]. In the present study, 11 patients with tuberous sclerosis and medically refractory epilepsy were retrospectively stud- ied to evaluate the long-term seizure and neuropsychologic outcomes after vagus nerve stimulator implantation. Method Subjects Between 2000 and 2008, 11 patients with tuberous sclerosis associated with intractable epilepsy had insertion of a vagus nerve stimulator at the Regional Epilepsy Center. Data were retrospectively collected by review- ing clinical and operative reports, imaging studies, and electrophysiologic studies. All patients had a clinically definite diagnosis of tuberous sclerosis according to the revised diagnostic criteria of 1998 [8]. Molecular diagno- sis revealed a TSC2 mutation in all the patients. Epilepsy intractability was defined as the failure of three or more antiepileptic drugs for seizure con- trol. Selection criteria for vagus nerve stimulator insertion included multi- focal or diffuse seizure onsets not amenable to surgical resection. Each From the *Pediatric Neurology Department, Ospedali Riuniti, Ancona, Italy; and † Neuroscience Department, Pediatric Neurology Unit, Univer- sity of Rome ‘‘Tor Vergata,’’ Rome, Italy. Communications should be addressed to: Dr. Zamponi; Pediatric Neurology Department; Ospedali Riuniti; via Corridoni 11, Ancona, Italy. E-mail: n.zamponi@tin.it Received December 23, 2009; accepted March 1, 2010. Ó 2010 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2010.03.003  0887-8994/$—see front matter Zamponi et al: VNS in Tuberous Sclerosis 29