Correlations between neurophysiological, behavioral, and cognitive function in Rett syndrome Aglaia Vignoli a, * , Rosa Angela Fabio b , Francesca La Briola a , Samantha Giannatiempo c , Alessandro Antonietti c , Silvia Maggiolini d , Maria Paola Canevini a a Centro Epilessia, Azienda Ospedaliera San Paolo, Università degli Studi di Milano, Milan, Italy b Dipartimento di Psicologia e Scienze dell’Educazione, Università di Messina, Messina, Italy c Dipartimento di Psicologia, Università Cattolica Sacro Cuore, Milan, Italy d Scienze dell’Educazione, Università Cattolica Sacro Cuore, Milan, Italy article info Article history: Received 13 November 2009 Revised 21 January 2010 Accepted 24 January 2010 Available online 16 March 2010 Keywords: Rett syndrome Epilepsy Electroencephalography Cognitive performance Eye tracking abstract Rett syndrome, a neurodevelopmental disorder affecting mainly females, is caused by a mutation of the MeCP2 gene. Girls with Rett syndrome manifest diverse behavioral and cognitive phenotypes, and the reasons for this variability remain unknown. In addition, girls with Rett syndrome often have epileptic seizures and abnormal EEGs, the characteristics of which differ with the patient. The aim of the study was to verify if neurophysiological and epileptological characteristics could be correlated with cognitive measures, obtained using eye tracker technology, and behavioral scores (Vineland Adaptive Behavior Scales and Rett Assessment Rating Scale) in 18 patients with Rett syndrome (mean age 13.7 years) at clin- ical stages III and IV. Age at epilepsy onset and seizure frequency were strictly correlated with neuropsy- chological outcome, as were EEG stage and distribution of paroxysmal abnormalities. Our findings demonstrate that neurophysiological features should be considered prognostic of cognitive and behav- ioral outcome in the clinical management of Rett syndrome. Ó 2010 Elsevier Inc. All rights reserved. 1. Introduction Rett syndrome (RS) is an X-linked dominant neurodevelopmen- tal disorder, affecting almost exclusively females, with an inci- dence ranging from 1/10,000 to 1/15,000. Clinical diagnosis of the classic form relies on a battery of obligatory criteria such as normal pre-/perinatal period and normal head circumference at birth, followed by loss of acquired skills such as communication and purposeful hand use associated with onset of stereotypies. Additional characteristic features include deceleration of head growth, gait posture ataxia, breathing dysfunction, and epilepsy [1]. About 80% of females with classic RS and 25 to 75% of those with variant forms, depending on the criteria used for diagnosis and size and age of sampled population, have mutations in MeCP2 (methyl CpG binding protein2), a transcriptional repressor gene located on Xq28 [2]. Several studies have reported a relationship between some characteristics of the phenotype and the genotype, but patients with the same MeCP2 mutation can vary greatly in phenotype, so there may be other mechanisms modulating the clinical presenta- tion [3]. With respect to neurodevelopmental and behavioral phe- notypes, girls affected by RS vary, and the reason(s) for the differences is not well understood. Moreover, the clinical and elec- troencephalographic picture of girls with RS follows different stages correlated with age [4,5], and electroencephalographic pat- terns vary not only between patients, but also between stages of the disease [6,7]. Epilepsy is very frequent in patients with RS, occurring in about 80% of subjects; seizures are often difficult to treat, and in several patients, antiepileptic drug polytherapy is needed [8]. It is well known that refractory epileptic seizures can be associated with neuropsychological impairment involving different cognitive func- tions, such as memory, attention, and mental speed [9]. The aim of our study was to delineate if and how neurological and neuro- physiological impairment reflects behavioral and neuropsycholog- ical functions, to identify prognostic factors that could be important in the clinical management of girls with RS. 2. Methods 2.1. Subjects Eighteen girls with RS (mean age = 13.7 years, range = 7–21) were classified as clinical stage III (characterized by prominent 1525-5050/$ - see front matter Ó 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2010.01.024 * Corresponding author. Address: Centro Epilessia, Ospedale San Paolo, Università degli Studi di Milano, Via di Rudinì, 8, 20142 Milan, Italy. Fax: +39 02 50323159. E-mail address: aglaia.vignoli@ao-sanpaolo.it (A. Vignoli). Epilepsy & Behavior 17 (2010) 489–496 Contents lists available at ScienceDirect Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh