- Email: [email protected]
P.7.b.002 Epilepsy and EEG paroxysmal abnormalities associated with autism spectrum disorders
P.7.b. Child and adolescent disorders and treatment − Disorders (clinical)
P.7.b. Child and adolescent disorders and treatment − Disorders (clinical) P.7.b.001 Assessment of theory of mind and empathy skills of typically developing siblings of children diagnosed with autism spectrum disorder
S635
Conclusion: Typically developing siblings of children diagnosed with DSM IV Autism Spectrum Disorders might experience some difficulties in their social life and in understanding what others think and might have limited empathy skills, even though they had no psychiatric diagnosis. Meanwhile, in our study it was assumed that higher scores of Social Communication Questionnaire in case group was consistent with broad autism phenotype [1]. References
M. Eyuboglu1 ° , B. Baykara2 , D. Eyuboglu1 1 Mardin State Hospital, Child and Adolescent Psychiatry, mardin, Turkey; 2 Dokuz Eyl¨ ul University Hospital, Child and Adolescent Psychiatry, izmir, Turkey Aim: The aim of this study was to compare typically developing siblings of children, that were diagnosed with Autism Spectrum Disorders according to DSM IV-TR criteria, in terms of theory of mind, social communication and empathy skills with typically developing children matched by sociodemographic features such as age and sex. Method: 41 typically developing siblings of 41 cases that were diagnosed with Autistic Disorder, Asperger’s Disorder and Pervasive Developmental Disorder-not otherwise specified according to DSM IV-TR criteria and referred to the Child and Adolescent Psychiatry Clinic in Dokuz Eylul University Hospital between September 2013 and March 2014 and 43 controls as typically developing children who had no history of any psychiatic disorders in their family were included. Psychiatric diagnostic interview (Schedule for Affective Disorders and Schizophrenia for School Age Children Lifetime Version − K-SADS-PL) were applied to all children and adolescents who were included in the study. False belief tests were applied to case and control group to assess theory of mind skills and comprehension test and unexpected outcomes test which were among the parts of emotion recognition tests were applied to case and control groups to assess empathy skills. Social Communication Questionnaire, Childhood Autism Rating Scale were applied to parents of case and control groups. Data collected from the study were analysed by using The Statistical Package for Social Sciences 15.0 (SPSS 15.0) package programme. For quantitative variables, student t test was used to compare the mean between two groups with normal distribution while a nonparametric test, Mann Whitney U test, was used for the comparison of groups with skewed distribution. Categorical variables were measured with Pearson’s chi-square test and Fisher’s Exact test. Statistical significance was set as p < 0.05. Pearson correlation test was used for those showing normal distribution and Spearman correlation test for those who did not show normal distribution in order to identify the direction and level of the relationship between numeric variables. Results: The mean scores of Social Communication Questionnaire in case and control groups were 4.82±2.84 and 0.67±0.86 respectively, and there was a significant difference between two groups (Z = −6.446, p < 0.001). Total scores of theory of mind tests were significantly lower in case group (Z = −3.751, p < 0.001). Comprehension test and unexpected outcomes test scores were significantly lower in the case group (p < 0.001). There was a significant negative correlation between Social Communication Questionnaire and comprehension test scores (rho: −0.500, p < 0.001) and also a negative correlation between Social Communication Questionnaire and unexpected outcomes test (rho: −0.519, p < 0.001) scores was observed.
[1] Volkmar, F., Klin, A., 2000. Pervasive developmental disorders, Kaplan and Sadocks comprehensive textbook of psychiatry, 7th edition Lippincott Williams and Wilkins, Philadelphia.
P.7.b.002 Epilepsy and EEG paroxysmal abnormalities associated with autism spectrum disorders N.J. Jovic1 ° , B.D. Cekic1 1 Clinic of Neurology and Psychiatry for Children and Youth, Neurology, Belgrade, Serbia Purpose: Autism spectrum disorders (ASD) and epilepsies are heterogeneous, often linked disorders, that have diverse etiologies and pathophysiologies [1]. The relationship among ASD, EEG paroxysmal abnormalities (PA) and epilepsy remains unclear and could refer to cerebral dysfunction independent of lesions [2]. There is no recommended treatment protocol for ASD and epilepsy. We analyzed our clinical data on epilepsy and EEG abnormalities in children and adolescents with ASD. Patients and Methods: This retrospective study includes 27 patients (11 male, 16 female) with epilepsy and symptomatic ASD, associated with: tuberous sclerosis-TSC (16 patients), neurofibromatosis type 1 (2), fragile X syndrome (4), Angelman syndrome (3) and ARX gene mutation (2). Patients affected by Rett disorder were ruled out. The diagnosis of ASD was based on medical history, physical and psychological examination including the Child Behavior Checklist and according to the DSM-IV [1]. For TS patients TAND (Tuberous Sclerosis Associated Neuropsychiatric Disorders) Checklist was used [3]. The mean age of our subjects was 14.7 years (range: 3−21y); the mean follow-up was 6.8 years. The mean age of seizure onset was 5.1 years (range: 3 month to 14y). Familial antecedents for epilepsy were present in 25.9% of all cases. Written informed consent was provided. Results: Focal seizures were predominant seizure type (74.1%). Infantile spasms(IS) previously or concurrently with partial seizures occurred in 11/16 patients with TSC and ASD. Primary generalized seizures were observed in 25.9% cases. The mental retardation was moderate to severe in 70.4% of cases. Severe mental deficiency (IQ<35), language deficit and autistic features were observed in 6/7 children with late and in 1/4 with early IS therapy (vigabatrin). The current study showed 55.6% of all patients were seizurefree for more than two years. Contrary to the literature [2,3], in 10/16 (62.5%) children with TSC and ASD, long-term favorable seizure control was achieved. Duo-therapy of valproate with lamotrigine (7), levetiracetam (2), vigabatrin (1), topiramate (2) or oxcarbazepine (2) was effective and well tolerated. Antiepileptic drug (AED) was withdrawn in two patients. Levetiracetam in two, phenobarbital and peramapanel each in one case induced aggressive behavior and irritability. Except in two cases, no severe intractable epilepsy developed in remaining 10 patients. Psychotropic agents were used in 51.8%.
S636
P.7.b. Child and adolescent disorders and treatment − Disorders (clinical)
Improvement in ASD symptoms after therapy with AEDs was noted in 14.8%, while the majority of cases did not show any amelioration. EEG PA were focal/multifocal in 40.7%, diffuse in 22.2%, focal/generalized in 37.0%. Focal EEG PA were mainly localized in temporal and frontal regions. The suppression of clinical seizures was accompanied with an EEG improvement in 53.3%. EEG PA are recorded in 7 patients with ASD despite seizure freedom achieved with AEDs. In 4/7, EEG paroxysms were activated only during sleep. Conclusions: Intellectual disability, ASD and early-life seizures are clinically overlapped in some neurogenetic syndromes. Stable, favorable seizure control could be achieved by current AEDs. No pharmacological agents influenced the core symptoms of ASD, despite the seizure freedom. Suppression of clinical seizures was accompanied with an EEG improvement in only half of cases. References [1] Johnson, C.P., Myers, S.M., 2007 Identification and Evaluation of Children With Autism Spectrum Disorders. Pediatrics 120(5), 1183– 1215. [2] Parmeggiani, A., Barcia, G., Posar, A., Raimondi, E., Santucci, M., Scaduto, M.C., 2010 Epilepsy and EEG paroxysmal abnormalities in autism spectrum disorders. Brain Dev 32, 783–789. [3] de Vries, P.J., Whittemore, V.H., Leclezio, L., et al., 2015 Tuberous Sclerosis Associated Neuropsychiatric Disorders (TAND) and the TAND Checklist. Pediatr Neurol 52, 25−35.
P.7.b.003 Incorporating a clinical staging model to a sample of children and adolescent offspring of schizophrenia, bipolar and community control V. Sanchez-Gistau1 ° , S. Romero1 , D. Moreno2 , E. De la Serna1 , G. Sugranyes1 , I. Baeza1 , C. Moreno2 , E. Rodriguez-Toscano2 , J. Castro-Fornieles1 1 Hospital Clinic, Child and adolescent psychiatry and psychology department, Barcelona, Spain; 2 Gregorio Mara˜ non, adolescent unit, Madrid, Spain Background: The substantial overlap of symptoms in the earlier phases suggests that early identification programs should be aimed at detecting both the pre-psychotic and the pre-manic phases of schizophrenia (SZ) and bipolar disorder (BP) [1]. A positive first-degree family history remains the most robust predictor of developing SZ or BP [2]. Therefore, the study of genetic high-risk children prevails as a powerful approach towards understanding the ethiopathogenesis and clinical course of the disease from its earliest stages. As a result, offspring studies hold the potential to help towards the development of clinical staging models for major psychiatric disorders aimed at reducing morbidity associated with delayed diagnosis [3]. Purpose: We aim to compare prevalence of DSM-IV Axis I disorders between BP, SZ and community control (CC) offspring. Additionally we attempt to incorporate a clinical staging model for assessing the less specific initial clinical features of these offspring. Methods: SZ and BP patients with children between 7 and 17 years were recruited through adult mental health services of two tertiary Hospitals of Spain.CC parents were recruited from the same geographical area. Psychopathology and prodromal psychotic symptoms of BP-offspring (BpO) (n = 90), Sz-offspring (SzO) (n = 41) and CC-offspring (CcO) (n = 107) were assessed by child psychiatrists blinded to parental status using the K-SADS-PL and SOPS respectively. We define Stage 0 (no psychopathological
symptoms) as positive family history of SZ or BP and/or developmental impairments. Stage 1 (unspecific psychopathological symptoms). 1a: sub-threshold symptoms of ADHD, mood or anxiety disorder; 1b: threshold symptoms (diagnosis) of ADHD, anxiety or mood disorder (non-major depressive disorder) Stage 2 (ultra-high clinical risk): sub-threshold psychotic symptoms and/ or genetic risk + diagnosis of major depressive disorder). Results: 58.5% of SZ-offspring, 36.7% of BP-offspring and 17.8% of CC-offspring had experienced a lifetime Axis I DSM-IV psychiatric disorder. When comparing groups SZ and BPoffspring presented significantly higher rates of Attention Deficit Hyperactivity Disorder (ADHD) than CC-offspring. ADHD was significantly more prevalent in SZ than BP-offspring and BPoffspring presented significantly higher prevalence of depression than CC-offspring. Prevalence of SzO, BpO and CcO in each stage: – Stage 0 (no symptoms): 22.5% of SzO and 40% of BpO (genetic risk +/− developmental impairment) and 11.2% of CcO with developmental impairment. – Stage 1 (unspecific symptoms): – stage 1a (sub-threshold): 22.5% of SzO, 23.4% of BpO and 20.2% of CcO – stage 1b (threshold): 55% of SzO, 30% BpO and 17.5% CcO – Stage 2 (ultra-high risk): 7.3% of BpO presenting MDD, any subject fulfilled SOPS criteria for prodromal symptoms Conclusions: We find a gradient of clinical severity between SzO, BpO and CcO. SzO presented the highest rate of psychopathology being ADHD the most common clinical phenotype. BpO presented the highest rate of mood disorders but any case of mania or hypomania was detected. SzO presented more prodromal psychotic symptoms than BpO and CcO however any of them fulfilled criteria for an attenuated psychotic syndrome. The longitudinal follow-up of these children from a developmental approach might help to distinguish illness trajectories [4]. References [1] Correll, C.U., Penzner, J.B., Frederickson, A.M., Richter, J.J., Auther, A.M., Smith, C.W., Kane, J.M., Cornblatt, B.A., 2007. Differentiation in the preonset phases of schizophrenia and mood disorders: evidence in support of a bipolar mania prodrome. Schizophr Bull. 33, 703–714. [2] Gottesman, I.I., Laursen, T.M., Bertelsen, A., Mortensen, P.B., 2010. Severe mental disorders in offspring with 2 psychiatrically ill parents. Arch Gen Psychiatry. 67, 252–257. [3] Hickie, I.B., Scott, E.M., Hermens, D.F., Naismith, S.L., Guastella, A.J., Kaur, M., Sidis, A., Whitwell, B., Glozier, N., Davenport, T., Pantelis, C., Wood, S.J., McGorry, P.D., 2013. Applying clinical staging to young people who present for mental health care. Early Interv Psychiatry. 7(1), 31−43. [4] Duffy, A., 2015. Early identification of recurrent mood disorders in youth: the importance of a developmental approach. Evid Based Ment Health. 18(1), 7−9. Disclosure statement: This work was supported by the Spanish Ministry of Health, Instituto de Salud Carlos III (FIS PI 07/0066, PI 11/00683), European Regional Development Fund (ERDF), Marato TV3 foundation (091630), Catalonia Government (2009SGR1119) and Madrid Regional Government (S2010/BMD-2422 AGES)
P.7.b. Child and adolescent disorders and treatment − Disorders (clinical) P.7.b.001 Assessment of theory of mind and empathy skills of typically developing siblings of children diagnosed with autism spectrum disorder
S635
Conclusion: Typically developing siblings of children diagnosed with DSM IV Autism Spectrum Disorders might experience some difficulties in their social life and in understanding what others think and might have limited empathy skills, even though they had no psychiatric diagnosis. Meanwhile, in our study it was assumed that higher scores of Social Communication Questionnaire in case group was consistent with broad autism phenotype [1]. References
M. Eyuboglu1 ° , B. Baykara2 , D. Eyuboglu1 1 Mardin State Hospital, Child and Adolescent Psychiatry, mardin, Turkey; 2 Dokuz Eyl¨ ul University Hospital, Child and Adolescent Psychiatry, izmir, Turkey Aim: The aim of this study was to compare typically developing siblings of children, that were diagnosed with Autism Spectrum Disorders according to DSM IV-TR criteria, in terms of theory of mind, social communication and empathy skills with typically developing children matched by sociodemographic features such as age and sex. Method: 41 typically developing siblings of 41 cases that were diagnosed with Autistic Disorder, Asperger’s Disorder and Pervasive Developmental Disorder-not otherwise specified according to DSM IV-TR criteria and referred to the Child and Adolescent Psychiatry Clinic in Dokuz Eylul University Hospital between September 2013 and March 2014 and 43 controls as typically developing children who had no history of any psychiatic disorders in their family were included. Psychiatric diagnostic interview (Schedule for Affective Disorders and Schizophrenia for School Age Children Lifetime Version − K-SADS-PL) were applied to all children and adolescents who were included in the study. False belief tests were applied to case and control group to assess theory of mind skills and comprehension test and unexpected outcomes test which were among the parts of emotion recognition tests were applied to case and control groups to assess empathy skills. Social Communication Questionnaire, Childhood Autism Rating Scale were applied to parents of case and control groups. Data collected from the study were analysed by using The Statistical Package for Social Sciences 15.0 (SPSS 15.0) package programme. For quantitative variables, student t test was used to compare the mean between two groups with normal distribution while a nonparametric test, Mann Whitney U test, was used for the comparison of groups with skewed distribution. Categorical variables were measured with Pearson’s chi-square test and Fisher’s Exact test. Statistical significance was set as p < 0.05. Pearson correlation test was used for those showing normal distribution and Spearman correlation test for those who did not show normal distribution in order to identify the direction and level of the relationship between numeric variables. Results: The mean scores of Social Communication Questionnaire in case and control groups were 4.82±2.84 and 0.67±0.86 respectively, and there was a significant difference between two groups (Z = −6.446, p < 0.001). Total scores of theory of mind tests were significantly lower in case group (Z = −3.751, p < 0.001). Comprehension test and unexpected outcomes test scores were significantly lower in the case group (p < 0.001). There was a significant negative correlation between Social Communication Questionnaire and comprehension test scores (rho: −0.500, p < 0.001) and also a negative correlation between Social Communication Questionnaire and unexpected outcomes test (rho: −0.519, p < 0.001) scores was observed.
[1] Volkmar, F., Klin, A., 2000. Pervasive developmental disorders, Kaplan and Sadocks comprehensive textbook of psychiatry, 7th edition Lippincott Williams and Wilkins, Philadelphia.
P.7.b.002 Epilepsy and EEG paroxysmal abnormalities associated with autism spectrum disorders N.J. Jovic1 ° , B.D. Cekic1 1 Clinic of Neurology and Psychiatry for Children and Youth, Neurology, Belgrade, Serbia Purpose: Autism spectrum disorders (ASD) and epilepsies are heterogeneous, often linked disorders, that have diverse etiologies and pathophysiologies [1]. The relationship among ASD, EEG paroxysmal abnormalities (PA) and epilepsy remains unclear and could refer to cerebral dysfunction independent of lesions [2]. There is no recommended treatment protocol for ASD and epilepsy. We analyzed our clinical data on epilepsy and EEG abnormalities in children and adolescents with ASD. Patients and Methods: This retrospective study includes 27 patients (11 male, 16 female) with epilepsy and symptomatic ASD, associated with: tuberous sclerosis-TSC (16 patients), neurofibromatosis type 1 (2), fragile X syndrome (4), Angelman syndrome (3) and ARX gene mutation (2). Patients affected by Rett disorder were ruled out. The diagnosis of ASD was based on medical history, physical and psychological examination including the Child Behavior Checklist and according to the DSM-IV [1]. For TS patients TAND (Tuberous Sclerosis Associated Neuropsychiatric Disorders) Checklist was used [3]. The mean age of our subjects was 14.7 years (range: 3−21y); the mean follow-up was 6.8 years. The mean age of seizure onset was 5.1 years (range: 3 month to 14y). Familial antecedents for epilepsy were present in 25.9% of all cases. Written informed consent was provided. Results: Focal seizures were predominant seizure type (74.1%). Infantile spasms(IS) previously or concurrently with partial seizures occurred in 11/16 patients with TSC and ASD. Primary generalized seizures were observed in 25.9% cases. The mental retardation was moderate to severe in 70.4% of cases. Severe mental deficiency (IQ<35), language deficit and autistic features were observed in 6/7 children with late and in 1/4 with early IS therapy (vigabatrin). The current study showed 55.6% of all patients were seizurefree for more than two years. Contrary to the literature [2,3], in 10/16 (62.5%) children with TSC and ASD, long-term favorable seizure control was achieved. Duo-therapy of valproate with lamotrigine (7), levetiracetam (2), vigabatrin (1), topiramate (2) or oxcarbazepine (2) was effective and well tolerated. Antiepileptic drug (AED) was withdrawn in two patients. Levetiracetam in two, phenobarbital and peramapanel each in one case induced aggressive behavior and irritability. Except in two cases, no severe intractable epilepsy developed in remaining 10 patients. Psychotropic agents were used in 51.8%.
S636
P.7.b. Child and adolescent disorders and treatment − Disorders (clinical)
Improvement in ASD symptoms after therapy with AEDs was noted in 14.8%, while the majority of cases did not show any amelioration. EEG PA were focal/multifocal in 40.7%, diffuse in 22.2%, focal/generalized in 37.0%. Focal EEG PA were mainly localized in temporal and frontal regions. The suppression of clinical seizures was accompanied with an EEG improvement in 53.3%. EEG PA are recorded in 7 patients with ASD despite seizure freedom achieved with AEDs. In 4/7, EEG paroxysms were activated only during sleep. Conclusions: Intellectual disability, ASD and early-life seizures are clinically overlapped in some neurogenetic syndromes. Stable, favorable seizure control could be achieved by current AEDs. No pharmacological agents influenced the core symptoms of ASD, despite the seizure freedom. Suppression of clinical seizures was accompanied with an EEG improvement in only half of cases. References [1] Johnson, C.P., Myers, S.M., 2007 Identification and Evaluation of Children With Autism Spectrum Disorders. Pediatrics 120(5), 1183– 1215. [2] Parmeggiani, A., Barcia, G., Posar, A., Raimondi, E., Santucci, M., Scaduto, M.C., 2010 Epilepsy and EEG paroxysmal abnormalities in autism spectrum disorders. Brain Dev 32, 783–789. [3] de Vries, P.J., Whittemore, V.H., Leclezio, L., et al., 2015 Tuberous Sclerosis Associated Neuropsychiatric Disorders (TAND) and the TAND Checklist. Pediatr Neurol 52, 25−35.
P.7.b.003 Incorporating a clinical staging model to a sample of children and adolescent offspring of schizophrenia, bipolar and community control V. Sanchez-Gistau1 ° , S. Romero1 , D. Moreno2 , E. De la Serna1 , G. Sugranyes1 , I. Baeza1 , C. Moreno2 , E. Rodriguez-Toscano2 , J. Castro-Fornieles1 1 Hospital Clinic, Child and adolescent psychiatry and psychology department, Barcelona, Spain; 2 Gregorio Mara˜ non, adolescent unit, Madrid, Spain Background: The substantial overlap of symptoms in the earlier phases suggests that early identification programs should be aimed at detecting both the pre-psychotic and the pre-manic phases of schizophrenia (SZ) and bipolar disorder (BP) [1]. A positive first-degree family history remains the most robust predictor of developing SZ or BP [2]. Therefore, the study of genetic high-risk children prevails as a powerful approach towards understanding the ethiopathogenesis and clinical course of the disease from its earliest stages. As a result, offspring studies hold the potential to help towards the development of clinical staging models for major psychiatric disorders aimed at reducing morbidity associated with delayed diagnosis [3]. Purpose: We aim to compare prevalence of DSM-IV Axis I disorders between BP, SZ and community control (CC) offspring. Additionally we attempt to incorporate a clinical staging model for assessing the less specific initial clinical features of these offspring. Methods: SZ and BP patients with children between 7 and 17 years were recruited through adult mental health services of two tertiary Hospitals of Spain.CC parents were recruited from the same geographical area. Psychopathology and prodromal psychotic symptoms of BP-offspring (BpO) (n = 90), Sz-offspring (SzO) (n = 41) and CC-offspring (CcO) (n = 107) were assessed by child psychiatrists blinded to parental status using the K-SADS-PL and SOPS respectively. We define Stage 0 (no psychopathological
symptoms) as positive family history of SZ or BP and/or developmental impairments. Stage 1 (unspecific psychopathological symptoms). 1a: sub-threshold symptoms of ADHD, mood or anxiety disorder; 1b: threshold symptoms (diagnosis) of ADHD, anxiety or mood disorder (non-major depressive disorder) Stage 2 (ultra-high clinical risk): sub-threshold psychotic symptoms and/ or genetic risk + diagnosis of major depressive disorder). Results: 58.5% of SZ-offspring, 36.7% of BP-offspring and 17.8% of CC-offspring had experienced a lifetime Axis I DSM-IV psychiatric disorder. When comparing groups SZ and BPoffspring presented significantly higher rates of Attention Deficit Hyperactivity Disorder (ADHD) than CC-offspring. ADHD was significantly more prevalent in SZ than BP-offspring and BPoffspring presented significantly higher prevalence of depression than CC-offspring. Prevalence of SzO, BpO and CcO in each stage: – Stage 0 (no symptoms): 22.5% of SzO and 40% of BpO (genetic risk +/− developmental impairment) and 11.2% of CcO with developmental impairment. – Stage 1 (unspecific symptoms): – stage 1a (sub-threshold): 22.5% of SzO, 23.4% of BpO and 20.2% of CcO – stage 1b (threshold): 55% of SzO, 30% BpO and 17.5% CcO – Stage 2 (ultra-high risk): 7.3% of BpO presenting MDD, any subject fulfilled SOPS criteria for prodromal symptoms Conclusions: We find a gradient of clinical severity between SzO, BpO and CcO. SzO presented the highest rate of psychopathology being ADHD the most common clinical phenotype. BpO presented the highest rate of mood disorders but any case of mania or hypomania was detected. SzO presented more prodromal psychotic symptoms than BpO and CcO however any of them fulfilled criteria for an attenuated psychotic syndrome. The longitudinal follow-up of these children from a developmental approach might help to distinguish illness trajectories [4]. References [1] Correll, C.U., Penzner, J.B., Frederickson, A.M., Richter, J.J., Auther, A.M., Smith, C.W., Kane, J.M., Cornblatt, B.A., 2007. Differentiation in the preonset phases of schizophrenia and mood disorders: evidence in support of a bipolar mania prodrome. Schizophr Bull. 33, 703–714. [2] Gottesman, I.I., Laursen, T.M., Bertelsen, A., Mortensen, P.B., 2010. Severe mental disorders in offspring with 2 psychiatrically ill parents. Arch Gen Psychiatry. 67, 252–257. [3] Hickie, I.B., Scott, E.M., Hermens, D.F., Naismith, S.L., Guastella, A.J., Kaur, M., Sidis, A., Whitwell, B., Glozier, N., Davenport, T., Pantelis, C., Wood, S.J., McGorry, P.D., 2013. Applying clinical staging to young people who present for mental health care. Early Interv Psychiatry. 7(1), 31−43. [4] Duffy, A., 2015. Early identification of recurrent mood disorders in youth: the importance of a developmental approach. Evid Based Ment Health. 18(1), 7−9. Disclosure statement: This work was supported by the Spanish Ministry of Health, Instituto de Salud Carlos III (FIS PI 07/0066, PI 11/00683), European Regional Development Fund (ERDF), Marato TV3 foundation (091630), Catalonia Government (2009SGR1119) and Madrid Regional Government (S2010/BMD-2422 AGES)