Publications by authors named "Martina Balestri"

31 Publications

I stay at home with headache. A survey to investigate how the lockdown for COVID-19 impacted on headache in Italian children.

Cephalalgia 2020 11;40(13):1459-1473

Headache Center, Department of Neuroscience, Bambino Gesù Children's Hospital, Rome, Italy.

Objective: The present Italian multicenter study aimed at investigating whether the course of primary headache disorders in children and adolescents was changed during the lockdown necessary to contain the COVID-19 emergency in Italy.

Methods: During the lockdown, we submitted an online questionnaire to patients already diagnosed with primary headache disorders. Questions explored the course of headache, daily habits, psychological factors related to COVID-19, general mood and school stress. Answers were transformed into data for statistical analysis. Through a bivariate analysis, the main variables affecting the subjective trend of headache, and intensity and frequency of the attacks were selected. The significant variables were then used for the multivariate analysis.

Results: We collected the answers of 707 patients. In the multivariate analysis, we found that reduction of school effort and anxiety was the main factor explaining the improvement in the subjective trend of headache and the intensity and frequency of the attacks ( < 0.001). The greater the severity of headache, the larger was the clinical improvement ( < 0.001). Disease duration was negatively associated with the improvement ( < 0.001). It is noteworthy that clinical improvement was independent of prophylaxis ( > 0.05), presence of chronic headache disorders ( > 0.05) and geographical area ( > 0.05).

Conclusions: Our study showed that lifestyle modification represents the main factor impacting the course of primary headache disorders in children and adolescents. In particular, reduction in school-related stress during the lockdown was the main factor explaining the general headache improvement in our population.
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http://dx.doi.org/10.1177/0333102420965139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684684PMC
November 2020

Medication Overuse Withdrawal in Children and Adolescents Does Not Always Improve Headache: A Cross-Sectional Study.

Front Neurol 2020 19;11:823. Epub 2020 Aug 19.

Child Neurology Unit, Neuroscience and Neurorehabilitation Department, Headache Center, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

MOH can be diagnosed in subjects with headache occurring 15 days/month in association with a regular medication overuse, but its existence is not universally accepted. ICHD-3 redefined criteria for MOH, removing the criterion associating drug suspension with headache course. The aim of our study was to compare the rate of patients diagnosed with medication overuse headache (MOH) according to ICHD-2 and ICHD-3 criteria, to verify the degree of concordance. The secondary aim was to verify if drug withdrawal was really associated with pain relief. In this cross-sectional study, we retrospectively analyzed a sample of 400 patients followed for primary chronic headache at the Headache Center of Bambino Gesù Children's Hospital. We then selected those presenting with a history of medication overuse, and we applied both ICHD-2 and ICHD-3 criteria to verify in which patients the criteria would identify a clinical diagnosis of MOH. We identified 42 subjects (10.5%) with MOH; 23 of them (55%) presented a relief of headache withdrawing drug overuse. Regarding the applicability of the ICHD-2 criteria, 43% of patients (18/42) fulfilled all criteria, while all ICHD-3 diagnostic criteria were satisfied in 76% of patients (32/42). Eighteen patients (43%) satisfied both ICHD-2 and ICHD-3 criteria, while 10 patients (24%) did not satisfy either diagnostic criterion. Our study suggests that in children and adolescents, withdrawing medication overuse is not always associated with a clinical benefit. Therefore, though allowing a MOH diagnosis in a higher rate of patients as compared to ICHD-2, the application of ICHD-3 criteria does not guarantee a true a causal relationship between medication overuse and headache worsening.
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http://dx.doi.org/10.3389/fneur.2020.00823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466727PMC
August 2020

Temperament and character influence on depression treatment outcome.

J Affect Disord 2019 06 9;252:464-474. Epub 2019 Apr 9.

Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy, University Vita-Salute San Raffaele, Milan, Italy.

Background: personality features have been repeatedly associated with depression treatment outcome in Major Depressive Disorder (MDD), however conclusive results are still lacking. Moreover, as for Bipolar Disorder (BD), results are only few and preliminary.

Aim: the aim of the present study was to perform an exploratory investigation of the influence of personality traits as assessed by the Temperament and Character Inventory (TCI), on principal depression treatment outcomes (non remission, non response and resistance).

Methods: 743 mood disorders patients (455 MDD (61.24%) and 288 BD (38.76%)) were recruited in the context of 6 European studies. Generalized logit models were performed to test the effects of TCI dimensions on treatment outcomes, considering possible confounders such as age, gender and education. Positive results were controlled for comorbidities (anxiety and substance use disorders) as well.

Results: MDD Non-Remitters showed high Harm Avoidance (HA) and Self Transcendence (ST) (p = 0.0004, d = 0.40; p = 0.007, d = 0.36 respectively) and low Persistence (P) and Self Directedness (SD) (p = 0.05; d = 0.18; p = 0.002, d = 0.40, respectively); MDD Non-Responders showed a slightly different profile with high HA and low Reward Dependence (RD) and SD; finally, MDD Resistants showed low RD, P and Cooperativeness (C). In BD patients, only higher HA in non response was observed.

Limitations: the retrospective cross-sectional design, the TCI assessment regardless of the mood state and the small number of bipolar patients represent the main limitations.

Conclusion: specific TCI personality traits are associated with depression treatment outcome in MDD patients. The inclusion of such personality traits, together with other socio-demographic and clinical predictors, could ameliorate the accuracy of the prediction models available to date.
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http://dx.doi.org/10.1016/j.jad.2019.04.031DOI Listing
June 2019

Features of aura in paediatric migraine diagnosed using the ICHD 3 beta criteria.

Cephalalgia 2018 10 14;38(11):1742-1747. Epub 2017 Dec 14.

1 Headache Centre, Bambino Gesù Children Hospital, IRCCS, Rome, Italy.

Background In children and adolescents, the prevalence rate of migraine with aura is 1.6%. Few studies concerning migraine with aura features in paediatric population have been reported. Aim The aim of our study was to investigate clinical features of aura in a retrospective cohort of children with migraine with aura. Furthermore, we studied whether the International Classification of Headache Disorder (ICHD) 3 beta version criteria could efficiently detect migraine with aura in a paediatric population. Results We included 164 patients who experienced aura associated with headache (mean age 9.92 ± 2.64 years). When the ICHD-II criteria were used, a final diagnosis of migraine with typical aura was obtained in 15.3% of patients, probable migraine with typical aura in 13.4%, and typical aura with headache in 61.8%, while in in 9.5% of patients the diagnosis was undetermined. According to ICHD-3 beta, we diagnosed migraine with typical aura in 77.7% of patients, probable migraine with typical aura in 13.4%, and an undetermined diagnosis in 9.5% (less than two attacks). Conclusion Aura features did not depend on age and were similar to those of adults. However, the headache could be difficult to classify if headache duration was considered. In this view, the ICHD-3 beta offers the advantage of not considering headache features, including pain duration, for the diagnosis of migraine with typical aura, thus making this diagnosis easier in children and adolescents.
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http://dx.doi.org/10.1177/0333102417748571DOI Listing
October 2018

Features of aura in paediatric migraine diagnosed using the ICHD 3 beta criteria.

Cephalalgia 2018 10 14;38(11):1742-1747. Epub 2017 Dec 14.

1 Headache Centre, Bambino Gesù Children Hospital, IRCCS, Rome, Italy.

Background In children and adolescents, the prevalence rate of migraine with aura is 1.6%. Few studies concerning migraine with aura features in paediatric population have been reported. Aim The aim of our study was to investigate clinical features of aura in a retrospective cohort of children with migraine with aura. Furthermore, we studied whether the International Classification of Headache Disorder (ICHD) 3 beta version criteria could efficiently detect migraine with aura in a paediatric population. Results We included 164 patients who experienced aura associated with headache (mean age 9.92 ± 2.64 years). When the ICHD-II criteria were used, a final diagnosis of migraine with typical aura was obtained in 15.3% of patients, probable migraine with typical aura in 13.4%, and typical aura with headache in 61.8%, while in in 9.5% of patients the diagnosis was undetermined. According to ICHD-3 beta, we diagnosed migraine with typical aura in 77.7% of patients, probable migraine with typical aura in 13.4%, and an undetermined diagnosis in 9.5% (less than two attacks). Conclusion Aura features did not depend on age and were similar to those of adults. However, the headache could be difficult to classify if headache duration was considered. In this view, the ICHD-3 beta offers the advantage of not considering headache features, including pain duration, for the diagnosis of migraine with typical aura, thus making this diagnosis easier in children and adolescents.
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http://dx.doi.org/10.1177/0333102417748571DOI Listing
October 2018

Features of aura in paediatric migraine diagnosed using the ICHD 3 beta criteria.

Cephalalgia 2018 10 14;38(11):1742-1747. Epub 2017 Dec 14.

1 Headache Centre, Bambino Gesù Children Hospital, IRCCS, Rome, Italy.

Background In children and adolescents, the prevalence rate of migraine with aura is 1.6%. Few studies concerning migraine with aura features in paediatric population have been reported. Aim The aim of our study was to investigate clinical features of aura in a retrospective cohort of children with migraine with aura. Furthermore, we studied whether the International Classification of Headache Disorder (ICHD) 3 beta version criteria could efficiently detect migraine with aura in a paediatric population. Results We included 164 patients who experienced aura associated with headache (mean age 9.92 ± 2.64 years). When the ICHD-II criteria were used, a final diagnosis of migraine with typical aura was obtained in 15.3% of patients, probable migraine with typical aura in 13.4%, and typical aura with headache in 61.8%, while in in 9.5% of patients the diagnosis was undetermined. According to ICHD-3 beta, we diagnosed migraine with typical aura in 77.7% of patients, probable migraine with typical aura in 13.4%, and an undetermined diagnosis in 9.5% (less than two attacks). Conclusion Aura features did not depend on age and were similar to those of adults. However, the headache could be difficult to classify if headache duration was considered. In this view, the ICHD-3 beta offers the advantage of not considering headache features, including pain duration, for the diagnosis of migraine with typical aura, thus making this diagnosis easier in children and adolescents.
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http://dx.doi.org/10.1177/0333102417748571DOI Listing
October 2018

Role of the Attachment Style in Determining the Association Between Headache Features and Psychological Symptoms in Migraine Children and Adolescents. An Analytical Observational Case-Control Study.

Headache 2017 Feb 6;57(2):266-275. Epub 2017 Jan 6.

Headache Center, Division of Neurology, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.

Objective: We aimed to study the role of attachment style on headache severity and psychological symptoms in migraineurs children/adolescents. Moreover, we investigated the association between attachment style, migraine severity, and psychological symptoms.

Background: Attachment theory suggests that early interpersonal relationships may be important determinants of psychopathology and pain management. In particular, individuals with insecure attachment styles have been shown to experience more pain than people with secure attachment style. Few studies focused on headache and data on attachment style in pediatric headache are scarce.

Methods: We studied 90 migraineurs (mean age 12.2 ± 2.6 years; female: 54, male: 36). Patients were divided in two groups according to headache attack frequency: (1) high frequency (HF) patients, having from weekly to daily episodes and (2) low frequency (LF) patients, showing ≤3 episodes per month. According to headache attack intensity, patients were classified in two groups: (1) mild pain (MP), allowing the patient to continue his/her daily activities and (2) severe pain (SP), leading to interruption of patient activities or forcing the child to go to bed. The psychological screening was assessed by SAFA Anxiety, Depression, and Somatization questionnaires. Attachment style was measured by the semi-projective test Separation Anxiety Test. Patients were divided into "secure," "avoidant," "ambivalent," and "disorganized/confused" attachment patterns.

Results: We found a significant relationship between the attachment style and migraine features. The ambivalent attachment was the most common style among patients reporting high attack frequency (51%) and severe pain intensity (50%). Anxiety (SAFA-A Tot: F = 23.3, P < .001), depression (SAFA-D Tot: F = 11.8, P < .001), and somatization (SAFA-S Tot: F = 10.1, P < .001) were higher in patients with ambivalent attachment style. Moreover, our results showed an association between high attack frequency and high anxiety levels, in children with ambivalent attachment style (F = 6.7, P < .002).

Conclusions: Ambivalent attachment style may be a common vulnerability factor that impacts on pain severity, anxiety, depression, and somatization symptoms in young migraineurs. In particular, the present study provides the first evidence of the role of insecure attachment on the relationship between pain severity and psychological symptoms in migraine children.
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http://dx.doi.org/10.1111/head.13007DOI Listing
February 2017

Rapid and safe response to low-dose carbamazepine in neonatal epilepsy.

Epilepsia 2016 12 26;57(12):2019-2030. Epub 2016 Nov 26.

Department of Neurology, University of California San Francisco, San Francisco, California, U.S.A.

Objective: To evaluate treatment responses in benign familial neonatal epilepsy (BFNE).

Methods: We recruited patients with BFNE through a multicenter international collaboration and reviewed electroclinical and genetic details, and treatment response. All patients were tested at minimum for mutations/deletions in the KCNQ2, KCNQ3, and SCN2A genes.

Results: Nineteen patients were included in this study. A family history of neonatal seizures was positive in 16 patients, and one additional patient had a family history of infantile seizures. Mutations or deletions of KCNQ2 were found in 14, and of KCNQ3 in 2, of the 19 patients. In all patients, seizures began at 2-5 days of life and occurred multiple times per day. Four patients developed status epilepticus. Seizures were focal, alternating between hemispheres, and characterized by asymmetric tonic posturing associated with apnea and desaturation, followed by unilateral or bilateral asynchronous clonic jerking. Twelve of 19 patients were treated with multiple medications prior to seizure cessation. Seventeen of (88%) 19 patients were seizure-free within hours of receiving oral carbamazepine (CBZ) or oxcarbazepine (OXC). Earlier initiation of CBZ was associated with shorter hospitalization (p < 0.01). No side effects of CBZ were reported. All patients had normal development and remain seizure-free at a mean follow-up period of 7.8 years (6 months-16 years).

Significance: This study provides evidence that CBZ is safe and rapidly effective in neonates with BFNE, even in status epilepticus. We propose that CBZ should be the drug of choice in benign familial neonatal seizures.
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http://dx.doi.org/10.1111/epi.13596DOI Listing
December 2016

Socio-demographic and clinical predictors of treatment resistant depression: A prospective European multicenter study.

J Affect Disord 2016 Jan 30;189:224-32. Epub 2015 Sep 30.

Department of Biomedical and NeuroMotor Sciences, University of Bologna, Viale Carlo Pepoli 5, 40123 Bologna, Italy. Electronic address:

Background: Few studies investigated socio-demographic and clinical predictors of non response and remission in treatment resistant depression (TRD) in the case of failure of more than two adequate antidepressant (AD) trial. The primary aim of this study was to investigate socio-demographic and clinical predictors of TRD defined as the lack of response to at least three adequate AD treatments, two of which prospectively evaluated. As secondary aims, we also investigated predictors of non response and remission to: (1) at least two adequate AD treatment (one of which prospectively assessed); (2) at least one adequate and retrospectively assessed AD treatment.

Methods: In the context of a European multicenter project, 407 major depressive disorder (MDD) patients who failed to respond to a previous AD treatment were recruited for a 2 stage trial, firstly receiving venlafaxine and then escitalopram. MINI, HRSD, MADRS, UKU, CGI-S and CGI-I were administered.

Results: Ninety eight subjects (27.61%) were considered as resistant to three AD treatments. Clinical predictors were: longer duration and higher severity of the current episode (p=0.004; ES=0.24; p=0.01; RR=1.41, respectively), outpatient status (p=0.04; RR=1.58), higher suicidal risk level (p=0.02; RR=1.49), higher rate of the first/second degree psychiatric antecedents (MDD and others) (p=0.04; RR=1.31, p=0.03; RR=1.32 respectively) and side effects during treatments (p=0.002; RR=2.82). Multivariate analyses underlined the association between TRD and the severity of the current episode (p=0.04). As for secondary outcomes, predicting factors were partially overlapping.

Limitations: The limited sample size and specific drugs used limit present findings.

Conclusion: Subjects with a high degree of resistance to AD treatments show specific features which may guide the clinicians to the choice of more appropriate therapies at baseline.
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http://dx.doi.org/10.1016/j.jad.2015.09.033DOI Listing
January 2016

Mild hypothermia and hemorrhagic lesions in neonates with hypoxic-ischemic encephalopathy: experience in an outborn center.

J Matern Fetal Neonatal Med 2016 17;29(12):1963-6. Epub 2015 Aug 17.

a Neonatal Intensive Care Unit, Department of Medical and Surgical Neonatology .

Objective: Therapeutic hypothermia (TH) started within six hours from birth has been shown to improve neurodevelopmental outcomes in newborns with moderate-to-severe hypoxic-ischemic encephalopathy.

Methods: Twenty-nine consecutive newborns treated with whole body cooling at the Bambino Gesú Children's Hospital between March 2011 and December 2012 were included in this study. All infants were out-born neonates. Passive cooling was always started at the birth center and continued during transportation. Pre- and post-transport risk index of physiological stability (TRIPS) scores were calculated for each patient to evaluate the impact of the transportation. Magnetic resonance imaging (MRI) was performed within 10 days of life to investigate the presence of brain injury.

Results: Among the 26 survivors, 14 had no detectable lesions and 12 presented with brain injury on MRI. Four babies presented with cerebral bleeding. Babies with cerebral hemorrhage had a worse pre-transport TRIPS score, but among these neonates no worsening between pre and post-transport score was registered.

Conclusion: The presence of cerebral hemorrhagic lesions seemed to be related to the initial clinical conditions of the baby rather than to the transport itself. Our data confirm that TH performed in an out-born center is efficient and safe.
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http://dx.doi.org/10.3109/14767058.2015.1070138DOI Listing
January 2017

Structural focal temporal lobe seizures in a child with lipoproteinosis.

Pediatr Neurol 2015 Jan 4;52(1):104-6. Epub 2014 Sep 4.

Neurology Division, Bambino Gesù Children Hospital, IRCCS, Rome, Italy.

Background: Lipoproteinosis is a rare autosomal recessive disorder caused by a mutation in a gene (ECM1) on chromosome 1q21. Alterations of membrane and vessels in the dermal-epidermal junction represent the pathologic background of the disease. Calcification in the temporal lobes and hippocampi are common and may be associated with epileptic seizures.

Patient Description: We describe a 7-year-old girl with lipoproteinosis who presented with hoarseness, typical skin lesions, and seizures.

Results: Video electroencephalography demonstrated focal temporal lobe seizures. Intelligence quotient was normal, but psychologic tests revealed depressed mood. Neuroimaging revealed bilateral mesial temporal lobe calcifications.

Conclusions: The report reveals that the temporal lobe calcifications and the consequent epileptic seizures can appear even very early. The psychological signs may reflect limbic system dysfunction.
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http://dx.doi.org/10.1016/j.pediatrneurol.2014.08.023DOI Listing
January 2015

Structural focal temporal lobe seizures in a child with lipoproteinosis.

Pediatr Neurol 2015 Jan 4;52(1):104-6. Epub 2014 Sep 4.

Neurology Division, Bambino Gesù Children Hospital, IRCCS, Rome, Italy.

Background: Lipoproteinosis is a rare autosomal recessive disorder caused by a mutation in a gene (ECM1) on chromosome 1q21. Alterations of membrane and vessels in the dermal-epidermal junction represent the pathologic background of the disease. Calcification in the temporal lobes and hippocampi are common and may be associated with epileptic seizures.

Patient Description: We describe a 7-year-old girl with lipoproteinosis who presented with hoarseness, typical skin lesions, and seizures.

Results: Video electroencephalography demonstrated focal temporal lobe seizures. Intelligence quotient was normal, but psychologic tests revealed depressed mood. Neuroimaging revealed bilateral mesial temporal lobe calcifications.

Conclusions: The report reveals that the temporal lobe calcifications and the consequent epileptic seizures can appear even very early. The psychological signs may reflect limbic system dysfunction.
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http://dx.doi.org/10.1016/j.pediatrneurol.2014.08.023DOI Listing
January 2015

The 5-HTTLPR polymorphism and posttraumatic stress disorder: a meta-analysis.

J Trauma Stress 2013 Dec 12;26(6):645-53. Epub 2013 Nov 12.

InsermU669, Department of Psychiatry, Univ Paris Sud, Assistance Publique-Hôpitaux de Paris, Bicêtre University Hospital, Le Kremlin Bicêtre, France.

Environmental and genetic factors contribute to the development of posttraumatic stress disorder (PTSD). Variation in the 5-HTTLPR polymorphism of the serotonin transporter gene has been hypothesized to affect risk for PTSD. With the aim of investigating this association, we conducted a meta-analysis to shed light on prior controversial results and increase statistical power to detect smaller effect sizes. PubMed and ISI databases were searched for studies published until December 2012. Twelve studies have been included, all based on trauma-exposed samples. Data were analyzed with Cochrane Collaboration Review Manager Software (Version 5). Quality and publication bias were assessed. Metaregressions were performed using Comprehensive Meta-Analysis software, Version 2. Taking into account all studies, no association was found between 5-HTTLPR and PTSD (p = .10), with evidence of between-study heterogeneity, which could be partly explained by gender differences. In sensitivity analyses, we found an association between SS genotype and PTSD in high trauma-exposed participants (p < .001). To be a carrier of the SS genotype seems to represent a risk factor for PTSD in high trauma exposure. Further studies focusing on Gene × Environment interactions are needed to better understand the role of this polymorphism in PTSD.
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http://dx.doi.org/10.1002/jts.21855DOI Listing
December 2013

Genetic modulation of personality traits: a systematic review of the literature.

Int Clin Psychopharmacol 2014 Jan;29(1):1-15

aDepartment of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna bIRCCS Centro S. Giovanni di Dio, Fatebenefratelli, Brescia, Italy.

The heritability of human personality traits is by now well established. However, since the first reports on associations between specific genetic variants and personality traits, only modest progress has been made in identifying loci that robustly support these associations. The aim of this study was to provide a summary of literature data on association studies focused on the genetic modulation of personality, according to the Cloninger, Eysenck and Costa and McCrae models. PubMed was searched for papers investigating the association between any gene variant and personality traits, which were grouped into five clusters: (a) anxiety, (b) impulsivity, (c) determination-activity, (d) socialization and (e) spirituality, in healthy individuals, populations and psychiatric patients. A total of 369 studies were included. No clear consensus on the role of any individual gene variant in personality modulation emerged, although SLC6A4 haplotypes and the DRD4 rs1800955 promoter variant seemed to be more reliably related to anxiety and impulsivity-related traits, respectively. Because conflicting results emerged from the literature, plausibly as a result of the combined influence of many loci of small effects on personality, larger sample sizes and more narrow and specific phenotype will be the minimum requirements for future genetic studies on personality. Moreover, gene × gene and gene × environment interaction studies deserve further attention.
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http://dx.doi.org/10.1097/YIC.0b013e328364590bDOI Listing
January 2014

Impact of 5-HTTLPR polymorphism on alexithymia in alcoholic patients after detoxification treatment.

J Addict Med 2013 Sep-Oct;7(5):372-3

Department of Biomedical and Neuromotor Sciences (LM, CM, MB, DDR, AS), Institute of Psychiatry, University of Bologna, Bologna, Italy; Department of Psychiatry (IL, EOT), Eginition Hospital, and Laboratory of Biological Chemistry (CP, AZ, AK), University of Athens Medical School, Athens, Greece; and Neuroscience Department (DA, GF, SR, SB, GB), Istituto di ricerche Farmacologiche "Mario Negri," Milan, Italy.

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http://dx.doi.org/10.1097/ADM.0b013e31829c3049DOI Listing
April 2014

Genetic modulation of borderline personality disorder: systematic review and meta-analysis.

J Psychiatr Res 2013 Oct 27;47(10):1275-87. Epub 2013 Jun 27.

IRCCS Centro S. Giovanni di Dio, Fatebenefratelli, Brescia, Italy.

Borderline personality disorder (BPD) is a highly prevalent psychiatric disorder with high morbidity and mortality. Early theories ascribed an environmental etiology of BPD, but growing evidence supports a genetic vulnerability as well. The primary aim of this study was to systematically review genetic association studies focused on BPD. PubMed, ISI Web of Knowledge and PsycINFO databases were searched for studies published until December 2012. Meta-analyses were also performed when three or more studies reported genetic data on the same polymorphism. Data were analyzed with Cochrane Collaboration Review Manager Software (RevMan, version 5.0). Quality and publication bias were assessed. The systematic review of association studies examining genetic polymorphisms and BPD produced conflicting results. Meta-analyses were performed for three serotonergic polymorphisms: two common polymorphisms of the serotonin transporter gene (SLC6A4), the promoter insertion/deletion (5-HTTLPR) and the intron 2 VNTR (STin2 VNTR), and the rs1800532 (A218C) polymorphism of the tryptophan hydroxylase 1 gene (TPH1), all showing no association. No direct role of genetic polymorphisms was found in BPD. However, a few studies only are present in literature to draw definite conclusions. Further studies focusing on gene × gene and gene × environment interactions are needed to more deeply dissect the genetic role in the modulation of BPD.
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http://dx.doi.org/10.1016/j.jpsychires.2013.06.002DOI Listing
October 2013

Clinical features and drug induced side effects in early versus late antidepressant responders.

J Psychiatr Res 2013 Oct 22;47(10):1309-18. Epub 2013 Jun 22.

Department of Biomedical and NeuroMotor Sciences, University of Bologna, Italy.

Early antidepressant response (2nd week) has been reported as the result of a true antidepressant effect and a predictor of subsequent stable response. With the purpose to study the clinical profile of early response/remission (2nd week) compared to late response/remission (4th-6th weeks), two independent major depressive disorder (MDD) samples (the Sequenced Treatment Alternatives to Relieve Depression or STAR*D n=1922 and an Italian sample n=171) were investigated. Patients were treated with citalopram in the STAR*D while in a naturalistic setting in the Italian sample. Depressive symptomatology was assessed by the Hamilton Depressive Rating Scale weekly in the Italian sample and biweekly by the Quick Inventory of Depressive Symptomatology Clinician Rated in the STAR*D. Logistic regression was used to investigate possible predictors of early response and the Bonferroni correction was applied. In the STAR*D, higher levels of baseline core depressive symptoms (Bech subscale) were associated with early response (p=0.00017), as well as lower baseline insomnia (p=0.003) and higher work and social functioning (p=0.001). In the Italian sample none of these variables were associated with the phenotype, but a non significant trend of lower baseline quality of life (p=0.078) was observed in late remitters. In the STAR*D late responders reported higher levels of antidepressant induced side effects, especially difficulty in sleeping (p=5.68e-13), with a non significant trend in the same direction in the Italian sample (p=0.09). The identification of late versus early antidepressant responders at the beginning of the treatment may be useful to guide therapeutic choices in clinical settings.
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http://dx.doi.org/10.1016/j.jpsychires.2013.05.020DOI Listing
October 2013

Social adjustment among treatment responder patients with mood disorders.

J Affect Disord 2013 Sep 10;150(3):961-6. Epub 2013 Jun 10.

Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.

Background: Patients with major depression (MD) show reduced social adjustment when compared with healthy controls. However, even among treatment responders, significant differences in social adjustment occur. The main aim of the present work is to study several socio-demographic and clinical variables possibly influencing social adjustment in MD patients who responded to treatment.

Methods: Two hundred and eleven MD patients experiencing a depressive episode who responded to their current treatment were recruited within the context of a large European multicentre project. Our primary outcome measure was the association between 19 socio-demographic and clinical variables and total social adjustment scores, as measured with the Social Adjustment Scale (SAS). Secondary outcome measures included the associations between the same variables and SAS sub-scales, and the associations between these variables and self-esteem, as measured with the Rosenberg Self-Esteem Scale.

Results: A co-morbidity with anxiety disorders and the severity of residual depression symptoms were the strongest independent factors associated with poorer social adjustment, in terms of total and most sub-areas' SAS scores. Other variables associated with total and sub-areas' SAS scores were identified as well, although some variations across different areas were observed.

Limitations: The cross-sectional design, the retrospective assessment of data and the lack of a placebo control group.

Conclusions: Our results confirm that a co-morbidity with anxiety disorders and higher residual depression symptoms could reduce social adjustment among responder MD patients. Further longitudinal studies are needed to confirm our results.
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http://dx.doi.org/10.1016/j.jad.2013.05.021DOI Listing
September 2013

Association between Sirtuin 2 gene rs10410544 polymorphism and depression in Alzheimer's disease in two independent European samples.

J Neural Transm (Vienna) 2013 Dec 28;120(12):1709-15. Epub 2013 May 28.

Department of Biomedical and NeuroMotor Sciences, University of Bologna, Viale Carlo Pepoli 5, 40123, Bologna, Italy.

Among the several genes associated with late-onset Alzheimer's disease (LOAD), recently, Sirtuin genes have roused a growing interest because of their involvement in metabolic homeostasis and in brain aging. Particularly SIRT2 gene has been associated with Alzheimer's disease (AD) as well as with mood disorders. The aim of this study is to investigate the possible associations between Sirtuin 2 gene (SIRT2) rs10410544 polymorphism and AD as well as depression in AD. In addition, we performed some exploratory analyses to investigate possible associations between the rs10410544 genotype and clinical features. We investigated these associations in two independent samples: the first one was composed of 275 Greek inhabitants and 117 patients; the second sample counted 181 Italian people and 43 patients. All patients were affected by LOAD. We failed to find any association between rs10410544 genotype and AD in the two samples. On the other hand, we found an association between the single nucleotide polymorphism (SNP) and depressive symptomatology (in the total sample p = 0.002), which was modulated by the tumor necrosis factor (TNF) values. Particularly, TT genotype seems to be protective versus depression. Finally, in the exploratory analyses, we found that the TT genotype was associated with earlier AD onset and a longer duration of the illness. In conclusion, we confirmed the association between SIRT2 gene and mood disturbances, although in AD patients. Further, we provided evidence that the TT genotype may be protective versus depressive symptoms, allowing an easier and thus earlier diagnosis of AD. This awareness may lead to a more detailed approach to these patients concerning diagnosis and therapy.
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http://dx.doi.org/10.1007/s00702-013-1045-6DOI Listing
December 2013

Evaluation of the role of MAPK1 and CREB1 polymorphisms on treatment resistance, response and remission in mood disorder patients.

Prog Neuropsychopharmacol Biol Psychiatry 2013 Jul 26;44:271-8. Epub 2013 Mar 26.

IRCCS Centro S. Giovanni di Dio, Fatebenefratelli, Brescia, Italy.

Treatment resistant depression (TRD) is a significant clinical and public health problem. Among others, neuroplasticity and inflammatory pathways seem to play a crucial role in the pathomechanisms of antidepressant efficacy. The primary aim of this study was to investigate whether a set of single nucleotide polymorphisms (SNPs) within two genes implicated in neuroplasticity and inflammatory processes (the mitogen activated protein kinase 1, MAPK1 (rs3810608, rs6928, rs13515 and rs8136867), and the cyclic AMP responsive element binding protein 1, CREB1 (rs889895, rs6740584, rs2551922 and rs2254137)) was associated with antidepressant treatment resistance (according to two different definitions), in 285 Major Depressive Disorder (MDD) patients. As secondary aims, we investigated the genetic modulation of the same SNPs on response, remission and other clinical features both in MDD patients and in a larger sample including 82 Bipolar Disorder (BD) patients as well. All patients were screened in the context of a European multicenter project. No association between both the investigated genes and treatment resistance and response was found in MDD patients. However, considering remission, higher rates of CREB1 rs889895 GG genotype were reported in MDD patients. Moreover, MAPK1 rs8136867 AG genotype was found to be associated with remission in the whole sample (MDD and BD). Present results suggest that some genetic polymorphisms in both CREB1 and MAPK1 could be associated with treatment remission. Although further research is needed to draw more definitive conclusions, such results are intriguing since suggest a potential role of two genes implicated in neuroplasticity and inflammatory processes in symptom remission after antidepressant treatment.
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http://dx.doi.org/10.1016/j.pnpbp.2013.03.005DOI Listing
July 2013

Effects of SORL1 gene on Alzheimer's disease. Focus on gender, neuropsychiatric symptoms and pro-inflammatory cytokines.

Curr Alzheimer Res 2013 Feb;10(2):154-64

Institute of Psychiatry, University of Bologna, Bologna, Italy.

It was suggested that the gene encoding for sorLa, (SORL1) may affect Alzheimer's disease (LOAD) through a female-specific mechanism. The aims of this study were to confirm the role of gender in modulating the association between SORL1 and LOAD and to ascertain the influence of SORL1 on cognitive impairment, neuropsychiatric symptoms (BPSD) and secretion of pro-inflammatory cytokines. Ninety six outpatients with LOAD and 120 unrelated controls were genotyped for APOE and three SNPs at the 5' end of SORL1(intron 6): SNP 8 (rs668387); SNP 9 (rs68902); SNP 10 (rs641120). Clinical evaluation was made with the MMSE, Neuropsychiatric Inventory (NPI) and Cornell Scale for Depression in Dementia (CDDS). ELISPOT assays were used to measure pro-inflammatory cytokine (TNF-alpha; IL-6; IL-1beta; IFN-gamma) production in peripheral blood mononuclear cell (PBMC) supernatant from AD patients. SORL1 SNPs were not associated with LOAD in overall sample. Instead the G-alleles at SNPs 9 (p=0.015) and 10 (p=0.015) and the CGG haplotype (p=0.02) were associated with LOAD in the women subgroup. The TAA haplotype was marginally protective in AD patients being associated with lower BPSD scores (p=0.01). The same haplotype was also associated with higher IL-1beta (p=0.01) production. These genetic effects were not modified by APOE4 allele and controlled for illness duration and treatment. In conclusion, SORL1 does not appear to be a major risk factor for LOAD. Its contribution could be underestimated in our small sample. Sex-specific factors could modulate the association between SORL1 and AD. The influence of SORL1 variants on production of inflammatory cytokines warrants further investigation.
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http://dx.doi.org/10.2174/1567205011310020005DOI Listing
February 2013

Antidepressants in elderly: metaregression of double-blind, randomized clinical trials.

J Affect Disord 2013 May 11;147(1-3):1-8. Epub 2012 Dec 11.

IRCCS Centro S. Giovanni di Dio, Fatebenefratelli, Brescia, Italy.

Background: Depression is common in the elderly and in the last few years this led to a significant increase in antidepressant prescription rates. However, little is known about antidepressant efficacy profile in relation with socio-demographic and clinical features in this population. The aim of the present study was to define the most suitable socio-demographic and clinical profile for the use of antidepressant treatments in late-life depression.

Methods: MEDLINE, EMBASE and PsycINFO were searched for randomized controlled trials (RCTs) focused on efficacy of antidepressants of all classes in major depressed elderly subjects (>60 years old). Reviews and meta-analyses focusing on this topic have been considered as well. Thirty-four RCTs were included and socio-demographic and clinical features were investigated via meta-regression analysis as moderators of efficacy measures (standardized mean difference based on Hamilton Depressive Rating Scale and Montgomery-Asberg Depression Rating Scale).

Results: A lower rate of response to antidepressants of all classes was found in patients of male gender, of older age, and with a longer mean duration of the current episode. On the contrary, a higher rate of response was found in patients with a higher baseline severity and at their first episode of illness. Subsamples treated with selective serotonin reuptake inhibitors alone yielded similar results.

Limitations: RCTs only have been included.

Conclusions: A number of socio-demographic and clinical features have been found to moderate antidepressant efficacy in elderly population. Those variables could help clinicians for a more individualized treatment.
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http://dx.doi.org/10.1016/j.jad.2012.11.053DOI Listing
May 2013

Pontocerebellar hypoplasia type 6 caused by mutations in RARS2: definition of the clinical spectrum and molecular findings in five patients.

J Inherit Metab Dis 2013 Jan 8;36(1):43-53. Epub 2012 May 8.

IRCCS Fondazione Stella Maris, Pisa, Italy.

Recessive mutations in the mitochondrial arginyl-transfer RNA synthetase (RARS2) gene have been associated with early onset encephalopathy with signs of oxidative phosphorylation defects classified as pontocerebellar hypoplasia 6. We describe clinical, neuroimaging and molecular features on five patients from three unrelated families who displayed mutations in RARS2. All patients rapidly developed a neonatal or early-infantile epileptic encephalopathy with intractable seizures. The long-term follow-up revealed a virtual absence of psychomotor development, progressive microcephaly, and feeding difficulties. Mitochondrial respiratory chain enzymes in muscle and fibroblasts were normal in two. Blood and CSF lactate was abnormally elevated in all five patients at early stages while appearing only occasionally abnormal with the progression of the disease. Cerebellar vermis hypoplasia with normal aspect of the cerebral and cerebellar hemispheres appeared within the first months of life at brain MRI. In three patients follow-up neuroimaging revealed a progressive pontocerebellar and cerebral cortical atrophy. Molecular investigations of RARS2 disclosed the c.25A>G/p.I9V and the c.1586+3A>T in family A, the c.734G>A/p.R245Q and the c.1406G>A/p.R469H in family B, and the c.721T>A/p.W241R and c.35A>G/p.Q12R in family C. Functional complementation studies in Saccharomyces cerevisiae showed that mutation MSR1-R531H (equivalent to human p.R469H) abolished respiration whereas the MSR1-R306Q strain (corresponding to p.R245Q) displayed a reduced growth on non-fermentable YPG medium. Although mutations functionally disrupted yeast we found a relatively well preserved arginine aminoacylation of mitochondrial tRNA. Clinical and neuroimaging findings are important clues to raise suspicion and to reach diagnostic accuracy for RARS2 mutations considering that biochemical abnormalities may be absent in muscle biopsy.
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http://dx.doi.org/10.1007/s10545-012-9487-9DOI Listing
January 2013

Habituation to pain in "medication overuse headache": a CO2 laser-evoked potential study.

Headache 2012 May 18;52(5):792-807. Epub 2012 Apr 18.

Department of Neurosciences, Catholic University, Rome, Italy.

Objective: Our aim was to investigate CO(2) laser-evoked potential (LEP) habituation to experimental pain in a group of patients affected by medication-overuse headache, with a history of episodic migraine becoming chronic, before and after treatment, consisting in acute medication withdrawal and a preventive treatment cycle.

Background: One of the main features of LEPs in migraineurs is a lower habituation to repetitive noxious stimuli during the interictal phase.

Methods: LEPs were recorded to stimulation of both the right hand and the right perioral region in 14 patients and in 14 healthy subjects. The habituation of both the N1 and the vertex N2/P2 components was assessed by measuring the LEP amplitude changes across 3 consecutive repetitions of 30 trials each.

Results: In the 8 patients who had clinically improved after treatment, the N2/P2 amplitude habituation was significantly higher after treatment than before treatment following both hand (F = 43.2, P < .0001) and face stimulation (F = 6.9, P = .01). In these patients, the N2/P2 amplitude habituation after treatment was not different from that obtained in healthy controls (P = .18 and P = .73 for hand and face stimulation, respectively). On the contrary, in the patients who did not improve, the N2/P2 amplitude still showed reduced habituation after both hand (F = 3.1, P = .08) and face (F = 0.7, P = .4) stimulation.

Conclusion: The deficient habituation of the vertex N2/P2 complex was partly restored after successful treatment of medication-overuse headache, reflecting a modification in pain-processing pathways.
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http://dx.doi.org/10.1111/j.1526-4610.2012.02151.xDOI Listing
May 2012

Psychophysiological mechanisms underlying spatial attention in children with primary headache.

Brain Dev 2012 Sep 17;34(8):640-7. Epub 2011 Nov 17.

Headache Center, Division of Neurology, Ospedale Bambino Gesù, IRCCS, Rome, Italy.

Objective: Neurophysiological studies to evaluate spatial attention in children with primary headache are lacking. Tactile spatial attention modulates the N140 somatosensory evoked potential (SEP) amplitude. The aims of the study are: (1) to investigate the effect of spatial attention on the N140 amplitude in children with migraine and tension-type headache (TTH) and in healthy children, and (2) to correlate the neurophysiological results with a neuropsychological test for spatial attention.

Methods: We studied 16 patients with migraine without aura (MoA), 12 TTH children and 10 healthy subjects. "Deux Barrage" test for spatial attention was administered. SEPs were recorded in a neutral condition (NC) and in a spatial attention condition (SAC).

Results: No significant differences in neuropsychological measures were found between MoA, TTH and healthy subjects. The N140 amplitude increase during SAC, as compared to NC, was significantly higher in patients than in healthy controls. Migraineurs showed a positive correlation between the N140 amplitude increase during SAC and their neuropsychological performance.

Conclusions: Although spatial attention performances in children with headache are as good as in controls, the N140 amplitude increase during SAC in headache patients suggests that the psychophysiological mechanisms subtending spatial attention are different from those in healthy children.
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http://dx.doi.org/10.1016/j.braindev.2011.10.005DOI Listing
September 2012

Electroencephalographic features in dravet syndrome: five-year follow-up study in 22 patients.

J Child Neurol 2012 Apr 21;27(4):439-44. Epub 2011 Oct 21.

Division of Neurology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

The aim of the study was to evaluate interictal electroencephalogram features in 22 patients with Dravet syndrome from the onset of the disease through the next 5 years. Electroencephalogram was abnormal in 5 patients (22.7%) at onset, and in 17 (77.3%) at the end of the study. Epileptiform abnormalities (focal, multifocal, or generalized) were seen in 6 patients at the onset and in 14 (27% vs 64%) at the end of the study. Photoparoxysmal response was present in 41% of patients at the end of follow-up. No statistical differences were found between mutated and nonmutated groups regarding evolution of background activity, interictal abnormalities, and presence of photoparoxysmal response. Electroencephalogram findings seemed to be age dependent, variable among different patients, and not influenced by the presence of sodium channel, voltage-gated, type I, alpha subunit (SCN1A) mutation. The lack of specific epileptiform abnormalities contributes to the difficulty of patients' management in Dravet syndrome.
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http://dx.doi.org/10.1177/0883073811419262DOI Listing
April 2012

Infantile childhood onset of spinocerebellar ataxia type 2.

Cerebellum 2012 Jun;11(2):526-30

Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Via Francesco Faggiana 34, Latina, Italy.

Spinocerebellar ataxia type 2 (SCA2) is a late-onset autosomal dominant cerebellar ataxia caused by triplet CAG/CTG expansion in the ATX2 gene. The initial symptoms usually appear when subjects are in their 30s.Pediatric onset is less common and usually associated with larger triplet expansions. We here report the case of a 1-year-old girl who presented with facial dysmorphism,dystonic features, developmental delay, and retinitis pigmentosa.She was diagnosed as carrying an expanded CAG/CTG tract (92 repeats) before a molecular diagnosis of SCA2 was made in her father. Facial dysmorphism associated with developmental delay and retinitis pigmentosa in early childhood should prompt a careful family investigation for ataxia and study of ATX2.
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http://dx.doi.org/10.1007/s12311-011-0315-9DOI Listing
June 2012

A novel de novo SCN1A missense mutation in Severe Myoclonic Epilepsy Borderland.

Acta Neurol Belg 2010 Sep;110(3):281-3

Division of Neurology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

In this report we describe a novel missense SCN1A mutation in a patient affected by Severe Myoclonic Epilepsy Borderland (SMEB). This three and a half year-old female patient experienced prolonged febrile seizures at the age of 14 months, followed by generalized tonic-clonic seizures, atonic seizures, atypical absences almost in a cluster and triggered by fever. Cognitive and motor development was normal. The case was suggestive for SMEB. SCN1A analysis revealed an unknown de novo point mutation: a heterozygous replacement of nucleotide G with nucleotide T in position 4183 of the coding region of the gene (c.4183 G>T) in exon 21. This mutation causes the replacement of aspartic acid with tyrosine in 1395 (p.D1396Y). Even if other SCN1A missense mutations localized in the same region are associated to SMEB, a definite genotype-phenotype correlation has not yet been found, probably because other factors are involved in the pathogenesis of this type of epilepsy.
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September 2010

Efficacy of levetiracetam in the treatment of drug-resistant Rett syndrome.

Epilepsy Res 2010 Feb 14;88(2-3):112-7. Epub 2009 Nov 14.

Division of Neurology, Bambino Gesù Children's Hospital, IRCCS, P.zza S. Onofrio, Rome, Italy.

Rett syndrome (RTT) is a progressive neurological disorder characterized by a wide spectrum of phenotypes. Epilepsy is reported to occur in 50-90% of patients with RTT; some develop medically refractory epilepsy. The aim of this study is to investigate the efficacy of levetiracetam (LEV) in drug-resistant patients with RTT. This prospective, pragmatic, open-label study consisted of an 8-week baseline period and a 6-month evaluation period. Efficacy variable was the mean frequency of monthly seizures before, and after 3 and 6 months of treatment with LEV. Eight female patients, aged 7.5-19 years (M12.8+/-5) entered the study. Mean age at epilepsy onset was 25.8+/-14.1 months. All patients showed MeCP2 mutation. Patients had been treated with a mean of 3.4 AEDs (2-7) before LEV. The mean LEV dose was 44.84+/-18.02mg/kg/day. The mean monthly seizure frequency for all types of seizures during the baseline period was 21.3+/-8.1 (range 10-35); after 3 months it was 3.3+/-4.1 (range 0-9) and after 6 months of LEV treatment it was 1.5+/-2 (range 0-4), p<0.0001. The mean follow-up period was 20.2+/-13 months. Mild sleepiness occurred in two patients, one reported intermittent agitation. Levetiracetam appeared effective in our series of drug-resistant RTT patients. All reported a reduction in seizure frequency and consequently a better quality of life.
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http://dx.doi.org/10.1016/j.eplepsyres.2009.10.005DOI Listing
February 2010

Intravenous levetiracetam terminates refractory status epilepticus in two patients with migrating partial seizures in infancy.

Epilepsy Res 2009 Sep 10;86(1):66-71. Epub 2009 Jun 10.

Division of Neurology, Bambino Gesú Children's Hospital, Rome, Italy.

Objective: To evaluate the efficacy and tolerability of intravenous (IV) levetiracetam in refractory status epilepticus of migrating partial seizures in infancy (MPSI).

Methods: IV levetiracetam was infused in two infants, first as a loading dose of 60mg/kg in 30min, then at 30mg/kg twice a day. Both infants were continuously monitored with video-EEG before, during and after the drug trial. Blood count, liver enzymes, serum creatinine, ammonia and lactate blood levels were performed repeatedly before and after the IV levetiracetam administration. Follow-up was of 16 and 10 months.

Results: EEG monitoring allowed the diagnosis of MPSI, showing the typical seizures pattern in both patients. IV levetiracetam was effective in stopping status epilepticus in both infants. Levetiracetam also prevented the recurrence of status epilepticus during follow-up. No adverse reactions were observed during the infusion phase or during follow-up.

Conclusions: MPSI is a newly recognized epileptic syndrome characterized by early onset of intractable partial seizures arisingly independently and sequentially from both hemispheres, migrating from one region of the brain to another and from one hemisphere to another. We report the efficacy of intravenous levetiracetam in resolving refractory status epilepticus in two infants with this new epilepsy syndrome.
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http://dx.doi.org/10.1016/j.eplepsyres.2009.05.004DOI Listing
September 2009