Publications by authors named "Elisabetta Cesaroni"

20 Publications

  • Page 1 of 1

Temporal lobe epilepsy surgery in children and adults: A multicenter study.

Epilepsia 2021 01 1;62(1):128-142. Epub 2020 Dec 1.

Department of Neuroscience, Imaging and Clinical Sciences, "G. D'Annunzio" University, Chieti, Italy.

Objective: To assess seizure and cognitive outcomes and their predictors in children (<16 years at surgery) and adults undergoing temporal lobe epilepsy (TLE) surgery in eight Italian centers.

Methods: This is a retrospective multicenter study. We performed a descriptive analysis and subsequently carried out multivariable mixed-effect models corrected for multiple comparisons.

Results: We analyzed data from 511 patients (114 children) and observed significant differences in several clinical features between adults and children. The possibility of achieving Engel class IA outcome and discontinuing antiepileptic drugs (AEDs) at last follow-up (FU) was significantly higher in children (P = .006 and < .0001). However, percentages of children and adults in Engel class I at last FU (mean ± SD, 45.9 ± 17 months in children; 45.9 ± 20.6 months in adults) did not differ significantly. We identified different predictors of seizure outcome in children vs adults and at short- vs long-term FU. The only variables consistently associated with class I outcome over time were postoperative electroencephalography (EEG) in adults (abnormal, improved,odds ratio [OR] = 0.414, P = .023, Q = 0.046 vs normal, at 2-year FU and abnormal, improved, OR = 0.301, P = .001, Q = 0.002 vs normal, at last FU) and the completeness of resection of temporal magnetic resonance (MR) abnormalities other than hippocampal sclerosis in children (OR = 7.93, P = .001, Q = 0.003, at 2-year FU and OR = 45.03, P < .0001, Q < 0.0001, at last FU). Cognitive outcome was best predicted by preoperative performances in either age group.

Significance: Clinical differences between adult and pediatric patients undergoing TLE surgery are reflected in differences in long-term outcomes and predictors of failures. Children are more likely to achieve sustained seizure freedom and withdraw AEDs after TLE surgery. Earlier referral should be encouraged as it can improve surgical outcome.
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http://dx.doi.org/10.1111/epi.16772DOI Listing
January 2021

Health Technology Assessment Report on Vagus Nerve Stimulation in Drug-Resistant Epilepsy.

Int J Environ Res Public Health 2020 08 24;17(17). Epub 2020 Aug 24.

Pediatric Neurology Unit, Salesi Children Hospital, 60123 Ancona, Italy.

: Vagus nerve stimulation (VNS) is a palliative treatment for medical intractable epileptic syndromes not eligible for resective surgery. Health technology assessment (HTA) represents a modern approach to the analysis of technologies used for healthcare. The purpose of this study is to assess the clinical, organizational, financial, and economic impact of VNS therapy in drug-resistant epilepsies and to establish the congruity between costs incurred and health service reimbursement. : The present study used an HTA approach. It is based on an extensive detailed bibliographic search on databases (Medline, Pubmed, Embase and Cochrane, sites of scientific societies and institutional sites). The HTA study includes the following issues: (a) social impact and costs of the disease; (b) VNS eligibility and clinical results; (c) quality of life (QoL) after VNS therapy; (d) economic impact and productivity regained after VNS; and (e) costs of VNS. Results: Literature data indicate VNS as an effective treatment with a potential positive impact on social aspects and on quality of life. The diagnosis-related group (DRG) financing, both on national and regional levels, does not cover the cost of the medical device. There was an evident insufficient coverage of the DRG compared to the full cost of implanting the device. : VNS is a palliative treatment for reducing seizure frequency and intensity. Despite its economic cost, VNS should improve patients' quality of life and reduce care needs.
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http://dx.doi.org/10.3390/ijerph17176150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504285PMC
August 2020

Trends in pediatric epilepsy surgery in Europe between 2008 and 2015: Country-, center-, and age-specific variation.

Epilepsia 2020 02 26;61(2):216-227. Epub 2019 Dec 26.

Claudio Munari Epilepsy Surgery Center, Niguarda Hospital, Milan, Italy.

Objective: To profile European trends in pediatric epilepsy surgery (<16 years of age) between 2008 and 2015.

Methods: We collected information on volumes and types of surgery, pathology, and seizure outcome from 20 recognized epilepsy surgery reference centers in 10 European countries.

Results: We analyzed retrospective aggregate data on 1859 operations. The proportion of surgeries significantly increased over time (P < .0001). Engel class I outcome was achieved in 69.3% of children, with no significant improvement between 2008 and 2015. The proportion of histopathological findings consistent with glial scars significantly increased between the ages of 7 and 16 years (P for trend = .0033), whereas that of the remaining pathologies did not vary across ages. A significant increase in unilobar extratemporal surgeries (P for trend = .0047) and a significant decrease in unilobar temporal surgeries (P for trend = .0030) were observed between 2008 and 2015. Conversely, the proportion of multilobar surgeries and unrevealing magnetic resonance imaging cases remained unchanged. Invasive investigations significantly increased, especially stereo-electroencephalography. We found different trends comparing centers starting their activity in the 1990s to those whose programs were developed in the past decade. Multivariate analysis revealed a significant variability of the proportion of the different pathologies and surgical approaches across countries, centers, and age groups between 2008 and 2015.

Significance: Between 2008 and 2015, we observed a significant increase in the volume of pediatric epilepsy surgeries, stability in the proportion of Engel class I outcomes, and a modest increment in complexity of the procedures.
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http://dx.doi.org/10.1111/epi.16414DOI Listing
February 2020

d-Glycerate kinase deficiency in a neuropediatric patient.

Brain Dev 2020 Feb 11;42(2):226-230. Epub 2019 Dec 11.

Research Group Inborn Errors of Metabolism, Department of Natural Sciences and Institute for Functional Gene Analytics (IFGA), Bonn-Rhein-Sieg University of Applied Sciences, von-Liebig-Str. 20, 53359 Rheinbach, Germany.

d-Glyceric aciduria (DGA) due to d-glycerate kinase deficiency (DGKD) is a rare autosomal-recessive inborn error of metabolism that is usually linked to the metabolism of fructose and serine. We describe a Moroccan patient with DGKD whose metabolic defect has been characterized by metabolite studies, sequencing of genomic DNA and by studies on the RNA level. Since birth the index patient presented with severe muscular hypotonia, joint hypermobility and tremor. Enantioselective analysis showed elevated d-glyceric acid in the urine of the patient, but not in that of his parents. DNA analysis revealed homozygosity in the GLYCTK gene for c.517G>T [p.(Val173Leu)], the first mutation reported for exon 3 of this gene, as well as for the c.530-4A>G polymorphism. RNA studies suggest that none of these sequence variants affects splicing. The mother was heterozygous for both sequence variants, the father heterozygous for the first one and homozygous for the polymorphism, which further supports that c.517G>T is the functionally relevant nucleotide change. The conservation of GLYCTK throughout evolution suggests an important biological role of this enzyme, although it is not known yet how mutations are linked to clinical features. Future studies should investigate the molecular defect in a more general way and search for additional roles of GLYCTK beyond its established role in catabolism of serine and fructose.
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http://dx.doi.org/10.1016/j.braindev.2019.11.008DOI Listing
February 2020

Defining the electroclinical phenotype and outcome of PCDH19-related epilepsy: A multicenter study.

Epilepsia 2018 12 19;59(12):2260-2271. Epub 2018 Nov 19.

Epilepsy Center, San Paolo Hospital, Milan, Italy.

Objective: PCDH19-related epilepsy is an epileptic syndrome with infantile onset, characterized by clustered and fever-induced seizures, often associated with intellectual disability (ID) and autistic features. The aim of this study was to analyze a large cohort of patients with PCDH19-related epilepsy and better define the epileptic phenotype, genotype-phenotype correlations, and related outcome-predicting factors.

Methods: We retrospectively collected genetic, clinical, and electroencephalogram (EEG) data of 61 patients with PCDH19-related epilepsy followed at 15 epilepsy centers. All consecutively performed EEGs were analyzed, totaling 551. We considered as outcome measures the development of ID, autistic spectrum disorder (ASD), and seizure persistence. The analyzed variables were the following: gender, age at onset, age at study, genetic variant, fever sensitivity, seizure type, cluster occurrence, status epilepticus, EEG abnormalities, and cognitive and behavioral disorders. Receiver operating characteristic curve analysis was performed to evaluate the age at which seizures might decrease in frequency.

Results: At last follow-up (median = 12 years, range = 1.9-42.1 years), 48 patients (78.7%) had annual seizures/clusters, 13 patients (21.3%) had monthly to weekly seizures, and 12 patients (19.7%) were seizure-free for ≥2 years. Receiver operating characteristic analysis showed a significant decrease of seizure frequency after the age of 10.5 years (sensitivity = 81.0%, specificity = 70.0%). Thirty-six patients (59.0%) had ID and behavioral disturbances. ASD was present in 31 patients. An earlier age at epilepsy onset emerged as the only predictive factor for ID (P = 0.047) and ASD (P = 0.014). Conversely, age at onset was not a predictive factor for seizure outcome (P = 0.124).

Significance: We found that earlier age at epilepsy onset is related to a significant risk for ID and ASD. Furthermore, long-term follow-up showed that after the age of 10 years, seizures decrease in frequency and cognitive and behavioral disturbances remain the primary clinical problems.
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http://dx.doi.org/10.1111/epi.14600DOI Listing
December 2018

Increasing volume and complexity of pediatric epilepsy surgery with stable seizure outcome between 2008 and 2014: A nationwide multicenter study.

Epilepsy Behav 2017 10 15;75:151-157. Epub 2017 Sep 15.

"Claudio Munari" Epilepsy Surgery Center, Niguarda Hospital, Milan, Italy.

Objective: The objective of the study was to assess common practice in pediatric epilepsy surgery in Italy between 2008 and 2014.

Methods: A survey was conducted among nine Italian epilepsy surgery centers to collect information on presurgical and postsurgical evaluation protocols, volumes and types of surgical interventions, and etiologies and seizure outcomes in pediatric epilepsy surgery between 2008 and 2014.

Results: Retrospective data on 527 surgical procedures were collected. The most frequent surgical approaches were temporal lobe resections and disconnections (133, 25.2%) and extratemporal lesionectomies (128, 24.3%); the most frequent etiologies were FCD II (107, 20.3%) and glioneuronal tumors (105, 19.9%). Volumes of surgeries increased over time independently from the age at surgery and the epilepsy surgery center. Engel class I was achieved in 73.6% of patients (range: 54.8 to 91.7%), with no significant changes between 2008 and 2014. Univariate analyses showed a decrease in the proportion of temporal resections and tumors and an increase in the proportion of FCDII, while multivariate analyses revealed an increase in the proportion of extratemporal surgeries over time. A higher proportion of temporal surgeries and tumors and a lower proportion of extratemporal and multilobar surgeries and of FCD were observed in low (<50surgeries/year) versus high-volume centers. There was a high variability across centers concerning pre- and postsurgical evaluation protocols, depending on local expertise and facilities.

Significance: This survey reveals an increase in volume and complexity of pediatric epilepsy surgery in Italy between 2008 and 2014, associated with a stable seizure outcome.
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http://dx.doi.org/10.1016/j.yebeh.2017.08.010DOI Listing
October 2017

Symptomatic and presumed symptomatic focal epilepsies in childhood: An observational, prospective multicentre study.

Epilepsia 2016 11 20;57(11):1808-1816. Epub 2016 Oct 20.

Pediatric Neurology Unit, V. Buzzi Hospital, A.O. ICP, Milan, Italy.

Objective: To describe the clinical, neuropsychological, and psychopathologic features of a cohort of children with a new diagnosis of symptomatic or presumed symptomatic focal epilepsy at time of recruitment and through the first month. The selected population will be followed for 2-5 years after enrollment to investigate the epilepsy course and identify early predictors of drug resistance.

Methods: In this observational, multicenter, nationwide study, children (age 1 month-12.9 years) with a new diagnosis of symptomatic or presumed symptomatic focal epilepsy were consecutively enrolled in 15 Italian tertiary childhood epilepsy centers. Inclusion criteria were as follows: (1) diagnosis of symptomatic focal epilepsy due to acquired and developmental etiologies, and presumed symptomatic focal epilepsy; (2) age at diagnosis older than 1 month and <13 years; and (3) written informed consent. Children were subdivided into three groups: ≤3 years, >3 to 6 years, and >6 years. Clinical, electroencephalography (EEG), neuroimaging, and neuropsychological variables were identified for statistical analyses.

Results: Two hundred fifty-nine children were enrolled (116 female and 143 male). Median age: 4.4 years (range 1 month-12.9 years); 46.0% (n = 119) of children were younger than 3 years, 24% (61) from 3 to 6 years of age, and 30% (79) older than 6 years. Neurologic examination findings were normal in 71.8%. Brain magnetic resonance imaging (MRI) was abnormal in 59.9%. Children age ≤3 years experienced the highest seizure frequency in the first month after recruitment (p < 0.0001). Monotherapy in the first month was used in 67.2%. Cognitive tests at baseline revealed abnormal scores in 30%; behavioral problems were present in 21%. At multivariate analysis, higher chances to exhibit more than five seizures in the first month after epilepsy onset was confirmed for younger children and those with temporal lobe epilepsy.

Significance: In this prospective cohort study, an extensive characterization of epilepsy onset in children with symptomatic or presumed symptomatic focal epilepsies is reported in relation to the age group and the localization of the epileptogenic zone.
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http://dx.doi.org/10.1111/epi.13574DOI Listing
November 2016

Efficacy of ketamine in refractory convulsive status epilepticus in children: a protocol for a sequential design, multicentre, randomised, controlled, open-label, non-profit trial (KETASER01).

BMJ Open 2016 06 15;6(6):e011565. Epub 2016 Jun 15.

Neurology Unit, Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Introduction: Status epilepticus (SE) is a life-threatening neurological emergency. SE lasting longer than 120 min and not responding to first-line and second-line antiepileptic drugs is defined as 'refractory' (RCSE) and requires intensive care unit treatment. There is currently neither evidence nor consensus to guide either the optimal choice of therapy or treatment goals for RCSE, which is generally treated with coma induction using conventional anaesthetics (high dose midazolam, thiopental and/or propofol). Increasing evidence indicates that ketamine (KE), a strong N-methyl-d-aspartate glutamate receptor antagonist, may be effective in treating RCSE. We hypothesised that intravenous KE is more efficacious and safer than conventional anaesthetics in treating RCSE.

Methods And Analysis: A multicentre, randomised, controlled, open-label, non-profit, sequentially designed study will be conducted to assess the efficacy of KE compared with conventional anaesthetics in the treatment of RCSE in children. 10 Italian centres/hospitals are involved in enrolling 57 patients aged 1 month to 18 years with RCSE. Primary outcome is the resolution of SE up to 24 hours after withdrawal of therapy and is updated for each patient treated according to the sequential method.

Ethics And Dissemination: The study received ethical approval from the Tuscan Paediatric Ethics Committee (12/2015). The results of this study will be published in peer-reviewed journals and presented at international conferences.

Trial Registration Number: NCT02431663; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2016-011565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916612PMC
June 2016

Paediatric anti-N-methyl-D-aspartate receptor encephalitis: The first Italian multicenter case series.

Eur J Paediatr Neurol 2015 Jul 3;19(4):453-63. Epub 2015 Mar 3.

Paediatric Neurology Unit, Department of Woman's and Child's Health, University Hospital of Padua, Padua, Italy. Electronic address:

Background: Given the rarity of this condition, especially in children, there is a paucity of large reported paediatric case series of anti-N-methyl-d-aspartate receptor encephalitis.

Methods: To contribute to define the features of this condition, we describe retrospectively a new nationwide case series of 20 children (50% females), referred by 13 Italian centres.

Results: Mean age at onset was 8 years (range 3-17). Prodromal symptoms were reported in 31.6%; onset was with neurological symptoms in 70%, and with behavioural/psychiatric disturbances in 30%. Most patients developed a severe clinical picture (90%), and 41% experienced medical complications; children 12-18 years old seemed to be more severe and symptomatic than younger patients. All children received first-line immune therapy; second-line treatment was administered to 45%. Relapses occurred in 15%. At last follow-up (mean 23.9 months, range 5-82), 85% patients had mRS 0-1; this rate was higher among older patients, and in those receiving first immune therapy within 1 month.

Conclusions: Our case series confirms a symptomatologic core of paediatric anti-N-methyl-d-aspartate receptor encephalitis, even though displaying some distinctive features that may be explained by a specific genetic background or by the limited number of patients. The growing incidence of this condition, the relative age-dependent variability of its manifestations, the availability of immunotherapy and the possible better outcome with early treatment impose a high index of clinical suspicion be maintained. In the absence of data suggesting other specific etiologies, paediatricians should consider this diagnosis for children presenting with neurological and/or behavioural or psychiatric disturbances, regardless of age and gender.
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http://dx.doi.org/10.1016/j.ejpn.2015.02.006DOI Listing
July 2015

An educational campaign about epilepsy among Italian primary school teachers. 2. The results of a focused training program.

Epilepsy Behav 2015 Jan 12;42:93-7. Epub 2014 Dec 12.

IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Dipartimento di Neuroscienze, Milano, Italy. Electronic address:

A cohort of 582 Italian primary school teachers underwent a questionnaire survey to test their knowledge and attitudes toward epilepsy and verify whether an intensive and focused educational program could result in improvement of knowledge and attitudes. The program consisted of a presentation of the clinical manifestations of epilepsy and the distribution of informative brochures and an educational kit on the disease and its management to be used with their students. After several months, 317 teachers were retested using the same questions. Upon retest, the number of "don't know" answers decreased significantly for almost all questions. This was not the case for negative attitudes. The same holds true for teachers believing that epilepsy is a source of learning disability and social disadvantage. These findings support the beliefs that education on epilepsy is more likely to affect ignorance than prejudice and that stronger interventions are needed to counteract stigmatizing behaviors.
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http://dx.doi.org/10.1016/j.yebeh.2014.07.022DOI Listing
January 2015

Long-term seizure and behavioral outcomes after corpus callosotomy.

Epilepsy Behav 2014 Dec 29;41:23-9. Epub 2014 Sep 29.

Neurosurgery, Polytechnic University of Marche, Ancona, Italy.

Outcomes of corpus callosotomy (CC) have been mainly focused on seizures. The present study aimed to evaluate the long-term effects of CC on adaptive behaviors and caregivers' satisfaction in addition to seizures and to identify clinical predictors of postsurgical outcomes. Medical records of 26 patients (mean age at study time: 40 years, mean follow-up: 14 years) with childhood-onset epilepsy who underwent anterior or 2-stage complete CC were reviewed. A structured questionnaire was submitted to caregivers asking about relative changes in different seizure types, behavioral functions, and satisfaction with the postoperative outcomes. Formal neuropsychological assessment was carried out in a subgroup of patients. Selected clinical variables including age at surgery, extent of callosal section, length of follow-up, epilepsy syndrome, and presurgical cognitive level were submitted to multiple regression analysis. At the last follow-up visit, a reduction greater than 50% was observed mainly for drop attacks (65% of patients), followed by generalized tonic-clonic seizures (53%), and complex partial seizures (50%). No presurgical variables were significantly associated with seizure outcome. After surgery, more than half of patients showed attention enhancement, which was related to drop seizure improvement. Early age at surgery was associated with better behavioral regulation; complete CC slightly worsened language abilities. Satisfaction with surgery outcomes was expressed by 73% of caregivers and was dependent on drop seizure reduction and improvements in activities of daily living. A long-term positive psychosocial outcome is likely after CC also in severely disabled patients, especially if surgery is performed early.
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http://dx.doi.org/10.1016/j.yebeh.2014.08.130DOI Listing
December 2014

Lacosamide in children with refractory status epilepticus. A multicenter Italian experience.

Eur J Paediatr Neurol 2014 Sep 24;18(5):604-8. Epub 2014 Apr 24.

Department of Pediatrics, University of Siena, Italy.

Objective: Status epilepticus (SE) is considered a life-threatening medical emergency. First-line treatment with antiepileptic drugs (AEDs) consists of intravenous benzodiazepines followed by phenytoin. SE is considered refractory (RSE) when unresponsive to standard doses of the first two AEDs. Scarce evidence is available to support specific guidelines for the management of RSE in either adults or children. This study aimed to assess the efficacy and tolerability of intravenous (iv) lacosamide (LCM) in children affected by RSE.

Method: Children with RSE who were treated with ivLCM were included in the study. Efficacy was defined as the cessation of seizures after administration of ivLCM, with no need for any further antiepileptic drug. All patients had been unsuccessfully treated following standard protocols before ivLCM was administered.

Results: Eleven children entered the study (mean age: 9.4 years). Etiology was symptomatic in 7 patients (63%). RSE was convulsive (focal or generalized) in 6 patients and nonconvulsive in 5. The mean initial bolus dose of LCM was 8.6 mg/kg. The drug, which was used as a fourth or later option, was effective in stopping RSE in 45% of patients, with seizures terminating within 12 h in three children. No serious adverse events attributable to LCM were reported.

Conclusions: LCM might be an effective and well-tolerated AED in children with RSE.
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http://dx.doi.org/10.1016/j.ejpn.2014.04.013DOI Listing
September 2014

Electroclinical features and long-term outcome of cryptogenic epilepsy in children with Down syndrome.

J Pediatr 2013 Dec 27;163(6):1754-8. Epub 2013 Aug 27.

Department of Pediatrics, University of Perugia, Perugia, Italy.

Objective: To describe the electroclinical features and the long-term outcomes of epilepsy in a large cohort of males and females with Down syndrome who developed epilepsy in childhood.

Study Design: Subjects with Down syndrome and cryptogenic epilepsy with onset in childhood were identified retrospectively from the databases of 16 Italian epilepsy centers over a 40-year period. For each subject, age at onset of seizures, seizure semiology and frequency, electroencephalography characteristics, treatment with antiepileptic drugs, and long-term clinical and electroencephalography outcomes were analyzed.

Results: A total of 104 subjects (64 males [61.5%], 40 females [38.5%]) were identified. Seizure onset occurred within 1 year of birth in 54 subjects (51.9%), between 1 and 12 years in 42 subjects (40.4%), and after 12 years in 8 subjects (7.7%). Males had a younger age of seizure onset than females. Of the 104 subjects, 51 (49.0%) had infantile spasms (IS), 35 (33.7%) had partial seizures (PS), and 18 (17.3%) had generalized seizures (GS). Febrile seizures were recorded in 5 (4.8%) subjects. Intractable seizures were observed in 23 (22.1%) subjects, including 5 (9.8%) with IS, 8 (44.4%) with PS, and 10 (31.3%) with GS.

Conclusion: Cryptogenic epilepsy in Down syndrome may develop during the first year of life in the form of IS or, successively, as PS or GS. Electroclinical features of IS resemble those of idiopathic West syndrome, with a favorable response to treatment with adrenocorticotropic hormone seen. Patients experiencing PS and GS may be resistant to therapy with antiepileptic drugs.
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http://dx.doi.org/10.1016/j.jpeds.2013.07.022DOI Listing
December 2013

Focal seizures with affective symptoms are a major feature of PCDH19 gene-related epilepsy.

Epilepsia 2012 Dec 4;53(12):2111-9. Epub 2012 Sep 4.

Pediatric Neurology Unit, A. Meyer Children's Hospital-University of Florence, Florence, Italy.

Purpose: Mutations of the protocadherin19 gene (PCDH19) cause a female-related epilepsy of variable severity, with or without mental retardation and autistic features. Despite the increasing number of patients and mutations reported, the epilepsy phenotype associated with PCDH19 mutations is still unclear. We analyzed seizure semiology through ictal video-electroencephalography (EEG) recordings in a large series of patients.

Methods: We studied 35 patients with PCDH19 gene-related epilepsy and analyzed clinical history and ictal video-EEG recordings obtained in 34 of them.

Key Findings: Clusters of focal febrile and afebrile seizures had occurred in 34 patients, at a mean age of 10 months. The predominant and more consistent ictal sign was fearful screaming, occurring in 24 patients (70.5%); it was present since epilepsy onset in 12 and appeared later on, during the course in the remaining 12 patients. In infancy, fearful screaming mainly appeared within the context of seizures with prominent hypomotor semiology, whereas during follow-up it was associated with prominent early motor manifestations. In 16 patients, seizures were video-EEG recorded both at onset and during follow-up: in five patients (31%) seizure semiology remained identical, in 7 (44%) semiology varied and in four patients it was unclear whether ictal semiology changed with age. Three patients (9%) had both focal and generalized seizures, the latter consisting of absences and myoclonus. Ictal EEG during focal seizures showed a prominent involvement of the frontotemporal regions (22 patients). About 45% of patients had an alternating EEG pattern, with the ictal discharge migrating from one hemisphere to the contralateral during the same ictal event. Status epilepticus occurred in 30% of patients. Cognitive impairment occurred in 70%, ranging from mild (42%) to moderate (54%) and severe (4%); autistic features occurred in 28.5%. Direct sequencing detected 33 different heterozygous candidate mutations, 8 of which were novel. Mutations were missense substitutions (48.5%), premature termination (10 frameshift, 4 nonsense, and 2 splice-site mutations; 48.5%), and one in-frame deletion. Thirty candidate mutations (91%) were de novo. No specific genotype-phenotype correlation could be established, as missense and truncating mutations were associated with phenotypes of comparable severity.

Significance: Most patients with PCDH19 mutations exhibit a distinctive electroclinical pattern of focal seizures with affective symptoms, suggesting an epileptogenic dysfunction involving the frontotemporal limbic system. Awareness of this distinctive phenotype will likely enhance recognition of this disorder.
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http://dx.doi.org/10.1111/j.1528-1167.2012.03649.xDOI Listing
December 2012

Early clinical features in Dravet syndrome patients with and without SCN1A mutations.

Epilepsy Res 2012 Mar 8;99(1-2):21-7. Epub 2011 Nov 8.

Neurology Clinic, Polytechnic University of Marche, Ancona, Italy.

Background: SCN1A is the most clinically relevant epilepsy gene, most mutations causing Dravet syndrome (also known as severe myoclonic epilepsy of infancy or SMEI). We evaluated clinical differences, if any, between young patients with and without a SCN1A mutations and a definite clinical diagnosis of Dravet syndrome.

Methods: Twenty-five patients with a diagnosis of Dravet Syndrome (7 males, 18 females; mean age at inclusion: 10.3; median: 9±7; range: 18 months-30 years) were retrospectively studied. A clinical and genetic study focusing on SCN1A was performed, using DHPLC, gene sequencing and MLPA to detect genomic deletions/duplications. A formal cognitive and behavioral assessment was available for all patients.

Results: Analysis revealed SCN1A mutations comprising missense, truncating mutations and genomic deletions/duplications in eighteen patients and no mutation in seven. The phenotype of mutation positive patients was characterized by a higher number of seizures/month in the first year of life, an earlier seizure onset and a higher frequency of episodes of status epilepticus. The cognitive and behavioral profile was slightly worst in mutation positive patients.

Conclusions: These findings confirm that SCN1A gene mutations are strongly associated to a more severe phenotype in patients with Dravet syndrome.
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http://dx.doi.org/10.1016/j.eplepsyres.2011.10.010DOI Listing
March 2012

Vagal nerve stimulation for drug-resistant epilepsies in different age, aetiology and duration.

Childs Nerv Syst 2010 Jun 21;26(6):811-9. Epub 2010 Jan 21.

Neurosurgery, Catholic University, Largo Agostino Gemelli 1, 00168, Rome, Italy.

Purpose: The aim of the study was to compare the outcome with respect to age of implant, aetiology and duration of epilepsy.

Methods: One hundred thirty-five drug-resistant epileptic patients, excluded from ablative surgery, were submitted to vagal nerve stimulation (1995-2007). Aetiology was cryptogenic in 57 and symptomatic in 78 patients. Ages of implant were 0.5-6 years (18 patients), 7-12 years (32 patients), 13-18 years (31 patients) and more than 18 years (54 patients). Epilepsy types were Lennox-Gastaut (18 patients), severe multifocal epilepsy (33 patients) and partial (84 patients). Duration of epilepsy is 3 months to 57 years. Clinical outcome was determined by comparing the seizure frequency after stimulation at 3-6-12-18-24-36 months with the previous 3 months. 'Responders' were the patients experiencing a seizure frequency reduction of 50% or more during follow-up. In statistical analysis, Wilcoxon and McNemar tests, general linear model for repeated measures, logistic regression and survival analysis were used.

Results: The seizure frequency reduction was significant in the group as a whole between baseline and the first follow-up (Wilcoxon test). The percentage of responder increases with time (McNemar test p = 0.04). Univariate analysis showed a significant effect of the age of implant on seizure frequency reduction: Adult patient had worst clinical outcome than children (p < 0.001) and adolescents (p = 0.08). Patients with severe multifocal epilepsy had better percentage seizure reduction compared with Lennox-Gastaut and partial (p = 0.03). Lesser duration of epilepsy had positive influence on outcome. Multivariate analysis confirmed age of implant to be the strongest factor influencing prognosis. Furthermore, positive is the association between lesional aetiology and young age.

Conclusions: The best responder could be a young lesional epileptic patient; after 3 years of follow-up, the percentage of responders is still in progress.
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http://dx.doi.org/10.1007/s00381-009-1069-2DOI Listing
June 2010

Mitochondrial encephalomyopathy lactic acidosis and strokelike episodes mimicking occipital idiopathic epilepsy.

Pediatr Neurol 2009 Aug;41(2):131-4

Child Neuropsychiatry Unit, Polytechnic University of the Marche, Ancona, Italy.

We report on a 19-year-old man with a 9-year history of occipital seizures characterized by deviation of the eyes and tonic ipsilateral turning of the head during sleep, initially diagnosed as idiopathic childhood occipital epilepsy, Gastaut type. The eventual development of status epilepticus, associated with a T(1) hypointense as well as T(2), fluid-attenuated inversion recovery, and diffusion-weighted hyperintense brain lesion led to pathologic and genetic testing that identified a A3243G mitochondrial DNA point mutation associated with mitochondrial, encephalomyopathy, lactic acidosis, and strokelike episodes. This case emphasizes that occipital epileptic seizures can be the only presenting and long-lasting sign in patients with mitochondrial, encephalomyopathy, lactic acidosis, and strokelike episodes.
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http://dx.doi.org/10.1016/j.pediatrneurol.2009.02.018DOI Listing
August 2009

Vagus nerve stimulation (VNS) is effective in treating catastrophic 1 epilepsy in very young children.

Neurosurg Rev 2008 Jul 30;31(3):291-7. Epub 2008 Apr 30.

Pediatric Neurology Department, Azienda Ospedaliera-Universitaria, Ospedali Riuniti, Presidio G Salesi, Ancona, Italy.

The objective of this study is to evaluate the safety and efficacy of vagus nerve stimulation (VNS) in very young children suffering from catastrophic epilepsy and status epilepticus. We reviewed files of 60 VNS-implanted children at our institution and we selected six very young patients, less than 3 years old (mean age at implant 1.6 years). All patients suffered from severe cognitive impairment and catastrophic epilepsy with underlying diagnosis of hemimegalencephaly (1), hypoxic-ischemic encephalopathy (1), tuberous sclerosis complex (1), and malignant migrating partial epilepsy of infancy (3). Three patients were VNS-implanted during admission at intensive care unit (ICU) after developing life-threatening status epilepticus. The mean follow-up time was 41.6 months. The VNS was implanted using a single cervical incision. No surgery-related complications were observed. Four of six children have shown a significant, persistent improvement in seizure control (range, 60-90%). In patients with status, insertion of the vagal nerve stimulator allowed early cessation of status and discharge from ICU. Quality of life and parental satisfaction improved and for three children there was some milestone evolution. Catastrophic epilepsy in infancy can be devastating and difficult to treat with drugs and surgery. If resective surgery is inappropriate or refused, VNS can be considered as a well-tolerated and effective procedure even in toddlers affected by severe epilepsy and multiple developmental disabilities.
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http://dx.doi.org/10.1007/s10143-008-0134-8DOI Listing
July 2008

Bobble head doll syndrome in a child with a third ventricular cyst and hydrocephalus.

Childs Nerv Syst 2005 May 21;21(5):350-4. Epub 2004 Sep 21.

Pediatric Neurology Department, Children's Hospital G. Salesi, Ancona, Italy.

Introduction: The bobble head doll syndrome, mainly affecting children under 10 years of age, is a rare and surgically treatable movement disorder characterized by head bobbing occurring at a rate of 2-3 times/s. Its pathophysiological mechanism is not well known but two main factors are commonly associated with the condition: a dilatation of the third ventricle and, more frequently, a cystic lesion rather than a solid mass in the region of the third ventricle.

Illustrative Case: The illustrative case concerns a child with a third ventricular cystic lesion and hydrocephalus who had experienced abnormal head movements since the age of 1 year as well as ataxia and tremor of the arms. Contrast cranial MRI, at the age of 3, demonstrated enlargement of the third and lateral ventricles, a ballooned cyst inside the third ventricle with compression of all the diencephalic structures, a funnel dilation of the cranial part of the aqueduct, and a cyst in the septum pellucidum. A ventriculoperitoneal shunt (Hakim-Cordis) was placed and the head bobbing, tremor of the arms, and ataxia disappeared immediately.

Conclusion: The good and immediate clinical result in our case emphasizes the opinion that the reduction of CSF pressure is the best therapeutical option in the bobble head doll syndrome.
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http://dx.doi.org/10.1007/s00381-004-1030-3DOI Listing
May 2005