Publications by authors named "Giuseppe Gobbi"

72 Publications

Electroclinical features of MEF2C haploinsufficiency-related epilepsy: A multicenter European study.

Seizure 2021 Mar 30;88:60-72. Epub 2021 Mar 30.

Maternal and Pediatric Department, Fondazione IRCCS Casa Sollievo della Sofferenza, Poliambulatorio "Giovanni Paolo II", Viale Padre Pio, snc, San Giovanni Rotondo (FG) 71013, Italy.

Purpose: Epilepsy is a main manifestation in the autosomal dominant mental retardation syndrome caused by heterozygous variants in MEF2C. We aimed to delineate the electro-clinical features and refine the genotype-phenotype correlations in patients with MEF2C haploinsufficiency.

Methods: We thoroughly investigated 25 patients with genetically confirmed MEF2C-syndrome across 12 different European Genetics and Epilepsy Centers, focusing on the epileptic phenotype. Clinical features (seizure types, onset, evolution, and response to therapy), EEG recordings during waking/sleep, and neuroimaging findings were analyzed. We also performed a detailed literature review using the terms "MEF2C", "seizures", and "epilepsy".

Results: Epilepsy was diagnosed in 19 out of 25 (~80%) subjects, with age at onset <30 months. Ten individuals (40%) presented with febrile seizures and myoclonic seizures occurred in ~50% of patients. Epileptiform abnormalities were observed in 20/25 patients (80%) and hypoplasia/partial agenesis of the corpus callosum was detected in 12/25 patients (~50%). Nine patients harbored a 5q14.3 deletion encompassing MEF2C and at least one other gene. In 7 out of 10 patients with myoclonic seizures, MIR9-2 and LINC00461 were also deleted, whereas ADGRV1 was involved in 3/4 patients with spasms.

Conclusion: The epileptic phenotype of MEF2C-syndrome is variable. Febrile and myoclonic seizures are the most frequent, usually associated with a slowing of the background activity and irregular diffuse discharges of frontally dominant, symmetric or asymmetric, slow theta waves with interposed spike-and-waves complexes. The haploinsufficiency of ADGRV1, MIR9-2, and LINC00461 likely contributes to myoclonic seizures and spasms in patients with MEF2C syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.seizure.2021.03.025DOI Listing
March 2021

Genotype-phenotype correlations in patients with de novo pathogenic variants.

Neurol Genet 2020 Dec 30;6(6):e528. Epub 2020 Nov 30.

Department of Neurosciences (F. Malerba, G.B., E.A., A. Riva, V.S., L.N., C. Minetti, F.Z., P.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università degli Studi di Genova; Pediatric Neurology and Muscular Diseases Unit (F. Malerba, G.B., F. Marchese, E.A., A. Riva, M.S.V., V.S., C. Minetti, P.S.), IRCCS Istituto G. Gaslini; Center for Synaptic Neuroscience and Technology (NSYN@UniGe) (G.A., L.M., F.B.), Istituto Italiano di Tecnologia; Department of Experimental Medicine (G.A.), Università degli Studi di Genova; Laboratory of Human Genetics (E.G.); Unit of Medical Genetics (F. Madia, F.Z.), IRCCS Istituto G. Gaslini, Genova, Italy; Child Neurology and Neurorehabilitation Unit (M.A.), Department of Pediatrics, Central Hospital of Bolzano, Bolzano; Child Neurology and Psychiatry Unit (L.G., P.A., P.M.), ASST Spedali Civili, Brescia; Neurology Unit (M. Trivisano, N.S.), Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS, Roma; Child Neurology Unit (A. Russo, G.G.), IRCCS, Institute of Neurological Sciences of Bologna; Child Neuropsychiatry Unit (F.R.), U.O.N.P.I.A. ASST-Rhodense, Rho, Milano; Neurology Unit and Laboratories (T.P.), A. Meyer Children's Hospital, Firenze; Child Neurology and Psychiatric Unit (C. Marini), Pediatric Hospital G. Salesi, United Hospital of Ancona; Child Neuropsychiatry Unit (M.M.M., L.N.), IRCCS Istituto G. Gaslini, Genova; Department of Pediatric Neuroscience (E.F.), Fondazione IRCCS Istituto Neurologico Carlo Besta; Unit of Genetics of Neurodegenerative and Metabolic Diseases (B. Castellotti), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano; Department of Child Neuropsychiatry (G.C.), Epilepsy Center, C. Poma Hospital, Mantova; Fondazione Poliambulanza Brescia (G.C.); Epilepsy Center (A.C.), Department of Neuroscience, Reproductive and Odontostomatological Sciences, Università degli Studi di Napoli Federico II, Napoli; Department of Pediatrics (A.V.), University of Perugia; Section of Pharmacology (F. Miceli, M. Taglialatela), Department of Neuroscience, Reproductive and Odontostomatological Sciences, Università degli Studi di Napoli Federico II, Napoli; IRCCS Ospedale Policlinico San Martino (L.M., F.B.), Genova, Italy; Division of Pediatric Neurology (M.R.C.), Saint-Luc University Hospital, and Institute of Experimental and Clinical Research (IREC), Université Catholique de Louvain, Brussels, Belgium; Department of Epilepsy Genetics and Personalized Treatment (K.M.J., R.S.M.), The Danish Epilepsy Center Filadelfia, Dianalund, Denmark; Institute for Regional Health Services (K.M.J., R.S.M.), University of Southern Denmark, Odense, Denmark; Department of Neurology (B. Ceulemans, S.W.), University Hospital Antwerp; Applied & Translational Neurogenomics Group (S.W.), VIB-Center for Molecular Neurology; Laboratory of Neurogenetics (S.W.), Institute Born-Bunge, University of Antwerp, Belgium; and Department of Life and Environmental Sciences (L.M.), Polytechnic University of Marche, Ancona, Italy.

Objective: Early identification of de novo variants in patients with epilepsy raises prognostic issues toward optimal management. We analyzed the clinical and genetic information from a cohort of patients with de novo pathogenic variants to dissect genotype-phenotype correlations.

Methods: Patients with de novo pathogenic variants were identified from Italy, Denmark, and Belgium. Atomic resolution Kv7.2 structures were also generated using homology modeling to map the variants.

Results: We included 34 patients with a mean age of 4.7 years. Median seizure onset was 2 days, mainly with focal seizures with autonomic signs. Twenty-two patients (65%) were seizure free at the mean age of 1.2 years. More than half of the patients (17/32) displayed severe/profound intellectual disability; however, 4 (13%) of them had a normal cognitive outcome.A total of 28 de novo pathogenic variants were identified, most missense (25/28), and clustered in conserved regions of the protein; 6 variants recurred, and 7 were novel. We did not identify a relationship between variant position and seizure offset or cognitive outcome in patients harboring missense variants. Besides, recurrent variants were associated with overlapping epilepsy features but also variable evolution regarding the intellectual outcome.

Conclusions: We highlight the complexity of variant interpretation to assess the impact of a class of de novo mutations. Genetic modifiers could be implicated, but the study paradigms to successfully address the impact of each single mutation need to be developed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXG.0000000000000528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803337PMC
December 2020

Encephalopathy related to status epilepticus during sleep due to a de novo KCNA1 variant in the Kv-specific Pro-Val-Pro motif: phenotypic description and remarkable electroclinical response to ACTH.

Epileptic Disord 2020 Dec;22(6):802-806

Danish Epilepsy Center, Dianalund, Denmark, University of Copenhagen, Copenhagen, Denmark.

Although the classic phenotype of episodic ataxia type 1 (EA1) caused by variants in KCNA1 includes episodic ataxia and myokymia, further genotype-phenotype correlations are difficult to establish due to highly heterogeneous clinical presentations associated with KCNA1 pathogenic variants. De novo variants in the paralogous Pro-Val-Pro motif (PVP) of KCNA2, an essential region for channel gating, have been reported to be associated with severe epilepsy phenotypes, including developmental and epileptic encephalopathies (DEE). Here, we describe the first patient with a DEE who developed an encephalopathy related to status epilepticus during sleep (ESES) and cerebellar signs, harbouring a variant in the Kv-specific PVP motif of the KCNA1 gene. Interestingly, he showed a remarkable long-term electroclinical response to IM ACTH therapy. This report extends the range of phenotypes associated with KCNA1 variants to include that of ESES, and suggests that ACTH therapy is likely to have a positive effect in patients with these variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1684/epd.2020.1222DOI Listing
December 2020

Chromosome 14 deletions, rings, and epilepsy genes: A riddle wrapped in a mystery inside an enigma.

Epilepsia 2021 01 17;62(1):25-40. Epub 2020 Nov 17.

Institute of Genomic Medicine, Catholic University School of Medicine, Rome, Italy.

The ring 14 syndrome is a rare condition caused by the rearrangement of one chromosome 14 into a ring-like structure. The formation of the ring requires two breakpoints and loss of material from the short and long arms of the chromosome. Like many other chromosome syndromes, it is characterized by multiple congenital anomalies and developmental delays. Typical of the condition are retinal anomalies and drug-resistant epilepsy. These latter manifestations are not found in individuals who are carriers of comparable 14q deletions without formation of a ring (linear deletions). To find an explanation for this apparent discrepancy and gain insight into the mechanisms leading to seizures, we reviewed and compared literature cases of both ring and linear deletion syndrome with respect to both their clinical manifestations and the role and function of potentially epileptogenic genes. Knowledge of the epilepsy-related genes in chromosome 14 is an important premise for the search of new and effective drugs to combat seizures. Current clinical and molecular evidence is not sufficient to explain the known discrepancies between ring and linear deletions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/epi.16754DOI Listing
January 2021

Mapping the Effect of Interictal Epileptic Activity Density During Wakefulness on Brain Functioning in Focal Childhood Epilepsies With Centrotemporal Spikes.

Front Neurol 2019 19;10:1316. Epub 2019 Dec 19.

Neurology Unit, OCB Hospital, AOU Modena, Modena, Italy.

Childhood epilepsy with centrotemporal spikes (CECTS) is the most common type of "self-limited focal epilepsies." In its typical presentation, CECTS is a condition reflecting non-lesional cortical hyperexcitability of rolandic regions. The benign evolution of this disorder is challenged by the frequent observation of associated neuropsychological deficits and behavioral impairment. The abundance (or frequency) of interictal centrotemporal spikes (CTS) in CECTS is considered a risk factor for deficits in cognition. Herein, we captured the hemodynamic changes triggered by the CTS density measure (i.e., the number of CTS for time bin) obtained in a cohort of CECTS, studied by means of video electroencephalophy/functional MRI during quite wakefulness. We aim to demonstrate a direct influence of the diurnal CTS frequency on epileptogenic and cognitive networks of children with CECTS. A total number of 8,950 CTS (range between 27 and 801) were recorded in 23 CECTS (21 male), with a mean number of 255 CTS/patient and a mean density of CTS/30 s equal to 10,866 ± 11.46. Two independent general linear model models were created for each patient based on the effect of interest: "individual CTS" in model 1 and "CTS density" in model 2. Hemodynamic correlates of CTS density revealed the involvement of a widespread cortical-subcortical network encompassing the sensory-motor cortex, the Broca's area, the premotor cortex, the thalamus, the putamen, and red nucleus, while in the CTS event-related model, changes were limited to blood-oxygen-level-dependent (BOLD) signal increases in the sensory-motor cortices. A linear relationship was observed between the CTS density hemodynamic changes and both disease duration (positive correlation) and age (negative correlation) within the language network and the bilateral insular cortices. Our results strongly support the critical role of the CTS frequency, even during wakefulness, to interfere with the normal functioning of language brain networks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2019.01316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930928PMC
December 2019

A reflection on the role of genetics in the concept of "epileptic encephalopathy", as emerged from the most recent ILEA classification of epilepsy.

Ital J Pediatr 2020 Jan 6;46(1). Epub 2020 Jan 6.

Modena and Reggio Emilia University, Modena, Italy.

The International League Against Epilepsy (ILAE) has been working to standardize the epilepsy classifications for over a hundred years.The latest epilepsy classification has been recently carried out with a careful overview on several topics including the "epileptic encephalopathies" concept and several constructive discussions on this topic have taken place in the international community of epileptologists.Here we wish to share our reflection on a statement of the ILAE commission on the "epileptic encephalopathy" concept, which in our opinion pays less attention to the "electroclinical syndromes" concept in favor of the new and very rapid genetic advances, thus generating confusion.Our aim is both to preserve the role of electroclinical syndromes, while allowing for the association of the phenotype with specific gene mutations, and to underline the importance of bringing electroclinical syndromes back to the forefront of epileptology.We believe the "match" is still open and for this reason we would like to share our considerations and to open a constructive debate on the "epileptic encephalopathy" concept.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13052-019-0765-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945479PMC
January 2020

The localizing value of epileptic auras: pitfalls in semiology and involved networks.

Epileptic Disord 2019 Dec;21(6):519-528

Department of Neurology and Comprehensive Epilepsy Program, Brain Institute, Nicklaus Children's Hospital, Miami, USA, Department of Neurology, University of Miami Miller School of Medicine, Miami, USA.

A more complete understanding of the epileptic aura represents an important challenge for localizing the epileptogenic zone and understanding brain networks. This review re-visits the localizing value of the epileptic aura, focusing on clinical pitfalls in epileptogenic zone detection and the importance of defining functional connectivity. We review the role of network node activation or alteration and its relationship to hub activation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1684/epd.2019.1106DOI Listing
December 2019

Epilepsy, cerebral calcifications, and gluten-related disorders: Are anti-transglutaminase 6 antibodies the missing link?

Seizure 2019 Dec 16;73:17-20. Epub 2019 Oct 16.

Regional Epilepsy Centre, Great Metropolitan Hospital "Bianchi-Melacrino-Morelli", Reggio Calabria, Italy; Department of Medicine, Surgery and Health Sciences, Magna Græcia University, Catanzaro, Italy. Electronic address:

Purpose: Gluten-related disorders (GRDs) are a group of immune-mediated diseases often associated to neurologic manifestations. Epilepsies with cerebral calcifications, with or without coeliac disease (CD), are rare neurological disorders characterized by childhood-onset focal seizures, often refractory to antiepileptic drugs. Transglutaminase 6 antibodies (anti-TG6) have been considered a biomarker for gluten-related ataxia and neuropathy, but their prevalence in epilepsies with cerebral calcifications is unknown. The aim of this study is to evaluate anti-TG6 prevalence in patients with epilepsies and cerebral calcifications.

Method: this was a cross-sectional study conducted at five Italian epilepsy centres. The following groups were included. Group 1: nine patients with CD, posterior cerebral calcifications and epilepsy (CEC); group 2: nine patients with epilepsy and posterior cerebral calcifications, without CD; group 3: twenty patients with focal epilepsy of unknown etiology; group 4: twenty-two healthy controls (HC). All subjects were tested for serological evidence of anti-TG6 IgA and IgG. Differences among groups were analysed using χ ² test.

Results: anti-TG6 were present in 1/9 subjects (11%) of group 1, 2/9 subjects (22%) of group 2, 0/20 subjects in group 3, 3/22 (13.6%) of HC. No significant difference was found among the 4 groups.

Conclusions: Anti-TG6 do not seem to be associated to epilepsies with cerebral calcifications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.seizure.2019.10.012DOI Listing
December 2019

"Minimal" holoprosencephaly in a 14q deletion syndrome patient.

Am J Med Genet A 2017 Dec;173(12):3216-3220

Institute of Medical Genetics, Catholic University School of Medicine, Rome, Italy.

We report on a patient with terminal deletion of the long arm of chromosome 14 displaying brain interhemispheric fusion limited to the midline anterior frontal cortex associated with hypoplastic corpus callosum and incomplete rotation of the left hippocampus in a clinical setting of motor and intellectual disability with poor language, and social behavior abnormalities with aggressiveness. Some possible correlations between clinical signs and symptoms and various aspects of the complex brain malformation are briefly discussed and compared with other known abnormalities of chromosome 14. The different neuropathology of the most common forms and the new forms of holoprosencephaly recently described is also discussed and leads us to suggest classifying the interhemispheric fusion of this case as a "minimal" form of holoprosencephaly. This appears to be the first description in a 14q deletion patient.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.38378DOI Listing
December 2017

West syndrome in three patients with brain injury and a benign course.

Epilepsy Behav Case Rep 2017 15;8:35-39. Epub 2017 Mar 15.

IRCCS, Institute of Neurological Sciences of Bologna, Child Neurology Unit, via Altura 3, Bologna, Italy.

Infants with West Syndrome and underlying structural pathology typically experience persistent symptomatic focal seizures and intellectual disability. We performed a retrospective case review of 84 patients with West Syndrome evaluated at one institution between 1990 and 2013. From this group we identified three patients with West syndrome and congenital hemiplegia who later developed genetic epilepsy features and had normal intellectual development. This outcome is highly unusual and raises important questions about the relationship and possible influence of genetic epilepsy in patients with pre-existent West Syndrome and brain injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebcr.2017.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542381PMC
March 2017

Guideline recommendations for diagnosis and clinical management of Ring14 syndrome-first report of an ad hoc task force.

Orphanet J Rare Dis 2017 04 11;12(1):69. Epub 2017 Apr 11.

Ring14 International, Scientific office, Via Flavio Gioia, 5-42124, Reggio Emilia, Italy.

Background: Ring chromosome 14 syndrome is a rare chromosomal disorder characterized by early onset refractory epilepsy, intellectual disability, autism spectrum disorder and a number of diverse health issues.

Results: The aim of this work is to provide recommendations for the diagnosis and management of persons affected by ring chromosome 14 syndrome based on evidence from literature and experience of health professionals from different medical backgrounds who have followed for several years subjects affected by ring chromosome 14 syndrome. The literature search was performed in 2016. Original papers, meta-analyses, reviews, books and guidelines were reviewed and final recommendations were reached by consensus.

Conclusion: Conventional cytogenetics is the primary tool to identify a ring chromosome. Children with a terminal deletion of chromosome 14q ascertained by molecular karyotyping (CGH/SNP array) should be tested secondarily by conventional cytogenetics for the presence of a ring chromosome. Early diagnosis should be pursued in order to provide medical and social assistance by a multidisciplinary team. Clinical investigations, including neurophysiology for epilepsy, should be performed at the diagnosis and within the follow-up. Following the diagnosis, patients and relatives/caregivers should receive regular care for health and social issues. Epilepsy should be treated from the onset with anticonvulsive therapy. Likewise, feeding difficulties should be treated according to need. Nutritional assessment is recommended for all patients and nutritional support for malnourishment can include gastrostomy feeding in selected cases. Presence of autistic traits should be carefully evaluated. Many patients with ring chromosome 14 syndrome are nonverbal and thus maintaining their ability to communicate is always essential; every effort should be made to preserve their autonomy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-017-0606-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5387247PMC
April 2017

Mismatch Negativity Recording in Children With Duchenne Muscular Dystrophy: A Preliminary Study Integrating Neurophysiological and Neuropsychological Results.

J Child Neurol 2016 11 15;31(13):1468-1474. Epub 2016 Jul 15.

Child Neurology Unit, IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy.

Many studies on Duchenne muscular dystrophy children support the hypothesis of a specific neuropsychological phenotype affecting mostly phonological skills. This prospective study aimed to shed light on the role of phonological abilities. Fourteen Duchenne muscular dystrophy children and 7 healthy children underwent mismatch negativity. Moreover, verbal intelligence, visuospatial attention, immediate verbal memory, working memory, grammar, vocabulary, visuomotor skills, reading, text comprehension, writing, and arithmetic were tested in Duchenne muscular dystrophy children. No significant difference between control and Duchenne muscular dystrophy children was found neither for mismatch negativity amplitude (P = .191 and .116, respectively) nor for latency (P = .135). Eight (57.14%) patients showed an impairment of immediate verbal memory and of visuomotor skills, 7 (63.64%) patients had a deficit in writing and arithmetic skills, even with a mean normal intelligence quotient. Taken together, the results put in evidence a heterogeneous neuropsychological profile not explainable on the basis of a phonological deficit.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0883073816656404DOI Listing
November 2016

Psychiatric and Behavioural Disorders in Children with Epilepsy (ILAE Task Force Report): Epilepsy and ADHD.

Epileptic Disord 2016 May 19. Epub 2016 May 19.

MD, Professor of Psychiatry and Neurology, Riley Hospital Child and Adolescent Psychiatry Clinics, Indiana University School of Medicine, Indianapolis IN 46202 USA.

ADHD occurs in about 30% of children with epilepsy. The causes of ADHD features include some antiepileptic drugs, the epilepsy itself and underlying brain dysfunction. Management of the ADHD will depend on the cause. Treatment with methylphenidate is effective in about 70% of cases; standard treatments with methylphenidate, dexamfetamine and atomoxetine are very unlikely to exacerbate seizures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1684/epd.2016.0811DOI Listing
May 2016

Psychiatric and Behavioural Disorders in Children with Epilepsy (ILAE Task Force Report): Epidemiology of psychiatric/behavioural disorder in children with epilepsy.

Epileptic Disord 2016 May 19. Epub 2016 May 19.

MD, IRCCS - Institute of Neurological Sciences of Bologna, Child Neurology Unit, Bologna, Italy.

Psychiatric/behavioural problems can have a major effect on quality of life. Epidemiological studies in Europe, Scandinavia and the USA have confirmed a high rate of psychiatric disorder in children with epilepsy, typically around 35 to 50%. In children with additional impairment, particularly those with intellectual disability, the rates are even higher, over 50%. Determining the causes of these high rates and deciding on the best strategies, either for prevention or for optimal management, remain major challenges.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1684/epd.2016.0810DOI Listing
May 2016

Psychiatric and Behavioural Disorders in Children with Epilepsy (ILAE Task Force Report): When should pharmacotherapy for psychiatric/behavioural disorders in children with epilepsy be prescribed?

Epileptic Disord 2016 May 16. Epub 2016 May 16.

MD PhD, Professor Dr. emer., Senior Research Scientist, Depts. Public Health and Child Neurology, University of Turku, Turku, Finland.

The most important factor in deciding whether psychotropic medication should be prescribed is a meticulous assessment of the possible causes of the behavioural/psychiatric disturbance. This assessment should include a consideration of the possible roles of the epilepsy itself, treatment of the epilepsy, associated brain damage or dysfunction, reactions to the epilepsy and causes that are unrelated to the epilepsy or its treatment. If the epilepsy itself or antiepileptic drug treatment are responsible for the disorder then a review of antiepileptic medication is required. Contrary to popular myth, most psychotropic medications are not contraindicated in children with epilepsy. Treatment with methylphenidate, dexamfetamine, atomoxetine, clonidine or low-dose risperidone are unlikely to precipitate seizures. The selective serotonin reuptake inhibitors might protect against seizures but some of these are powerful enzyme inhibitors, implying that careful monitoring to avoid antiepileptic drug toxicity is recommended. In many cases, the appropriate approach will be through other interventions such as behavioural management or providing the young person with empowering strategies, implying that psychotropic pharmacotherapy should not be the first-line treatment. However, if assessment indicates that psychotropic medication is necessary, it can be of great benefit.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1684/epd.2016.0819DOI Listing
May 2016

Psychiatric and Behavioural Disorders in Children with Epilepsy (ILAE Task Force Report): Behavioural effects of epilepsy surgery.

Epileptic Disord 2016 May 16. Epub 2016 May 16.

MD PhD, Professor Dr. emer., Senior Research Scientist, Depts. Public Health and Child Neurology, University of Turku, Turku, Finland.

There are relatively few studies of the behavioural outcome of epilepsy surgery in children that have used standardised behavioural measures before and after the procedure. Those investigations that have used such measures are often on mixed groups with mixed pathology, implying that the numbers, when stratified, are very small. They are also often retrospective. Furthermore, because placebo surgery is generally not an option, the studies have been open and they are usually uncontrolled. The few available data suggest that, although individual children may benefit or deteriorate, there is little overall group effect of temporal or extratemporal surgery on behavioural/psychiatric outcome. Hemispherectomy has traditionally been associated with the expectation of marked behavioural improvement but firm data are lacking. Multiple subpial transection performed for electrical status epilepticus of slow-wave sleep in the Landau-Kleffner syndrome can result in marked improvements in cognition and behaviour. Vagus nerve stimulation appears to improve quality of life and mood/behaviour but again the quality of the data has been questioned. There is a need for large, prospective, multicentre, collaborative studies using standardised cognitive and behavioural measures before and after surgery to provide an adequate database on the outcome of various categories of procedures, pathologies and patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1684/epd.2016.0818DOI Listing
May 2016

Psychiatric and Behavioural Disorders in Children with Epilepsy (ILAE Task Force Report): Adverse cognitive and behavioural effects of antiepileptic drugs in children.

Epileptic Disord 2016 May 16. Epub 2016 May 16.

MD PhD, Professor Dr. emer., Senior Research Scientist, Depts. Public Health and Child Neurology, University of Turku, Turku, Finland.

The literature was evaluated for cognitive and more general behavioural effects. We distinguished the older antiepileptic drugs (AEDs), from the newer and newest AEDs. The striking finding was the lack of information on children. From the available evidence it would appear that there may be negative cognitive effects with phenobarbital, phenytoin, topiramate and zonisamide, and adverse behavioural effects with phenobarbital, valproate, gabapentin, topiramate, levetiracetam and zonisamide. There is inconclusive data on ethosuximide, clobazam, vigabatrin, felbamate, pregabalin, stiripentol, rufinamide, lacosamide and retigabine. The following drugs appear to be neutral with regard to cognitive effects: valproate, carbamazepine, gabapentin and oxcarbazepine. Carbamazepine appears to be neutral with regard to behavioural effects. Positive cognitive effects have been reported with lamotrigine and levetiracetam. Positive behavioural effects have been reported with lamotrigine. Recommendations are provided.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1684/epd.2016.0817DOI Listing
May 2016

Psychiatric and Behavioural Disorders in Children with Epilepsy (ILAE Task Force Report): Subtle behavioural and cognitive manifestations of epilepsy in children.

Epileptic Disord 2016 May 16. Epub 2016 May 16.

MD PhD, Professor Dr. emer., Senior Research Scientist, Depts. Public Health and Child Neurology, University of Turku, Turku, Finland.

A subtle behavioural or cognitive manifestation of epilepsy can be defined in two ways. First, epileptiform discharges not presenting as obvious seizures may nevertheless affect cognition and/or behaviour. Second, the actual seizures may be obvious but the way they affect cognition or behaviour may not be. There is a growing body of evidence indicating that the epileptiform discharges in benign epilepsy with centrotemporal spikes can affect behaviour and cognition. The focal discharges in other forms of epilepsy can also be associated with behavioural change. The Landau-Kleffner syndrome, the CSWS syndrome, transitory cognitive impairment and transient epileptic amnesia provide further examples of cognitive and behavioural manifestations resulting from subtle manifestations of the epilepsy. Prompt, effective antiepileptic treatment with medication or surgery can improve behaviour and cognition in at least some cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1684/epd.2016.0816DOI Listing
May 2016

Psychiatric and Behavioural Disorders in Children with Epilepsy (ILAE Task Force Report): Behavioural and psychiatric disorders associated with childhood epilepsy syndromes.

Epileptic Disord 2016 May 16. Epub 2016 May 16.

MD PhD, Professor Dr. emer., Senior Research Scientist, Depts. Public Health and Child Neurology, University of Turku, Turku, Finland.

The categorisation of the childhood epilepsies into a number of different syndromes has allowed greater insight into the prognosis, not only with regard to seizure control but also in relation to cognitive and behavioural outcome. The role of genetics in determining both the syndrome and the behavioural outcome remains promising, although the promise is still largely unfulfilled. The behavioural/psychiatric outcome of a selection of the large number of childhood epilepsy syndromes is presented. The rate of autism in West syndrome, particularly in children who have tuberous sclerosis with temporal tubers, is high. In Dravet syndrome there is a loss of skills, with an associated increase in behavioural problems. The frequency of both subtle and overt seizures in the Lennox-Gastaut syndrome almost certainly accounts for the apparent poor motivation; however, a marked improvement in seizure control with treatment can also result in behavioural problems, probably as a result of the "release phenomenon". A number of cognitive problems can arise in the so-called "benign" syndrome of epilepsy with centrotemporal spikes (BECTS) and the rate of ADHD is high. Autistic features and ADHD have been described in the Landau-Kleffner syndrome and other syndromes associated with electrical status epilepticus of slow-wave sleep (ESES). Early effective treatment may reverse some of these features. There is clear evidence for a behavioural syndrome in relation to juvenile myoclonic epilepsy (JME), in which both clinical descriptions and functional neuroimaging indicate frontal lobe deficits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1684/epd.2016.0815DOI Listing
May 2016

Psychiatric and Behavioural Disorders in Children with Epilepsy (ILAE Task Force Report): Epilepsy and psychosis in children and teenagers.

Epileptic Disord 2016 May 16. Epub 2016 May 16.

MD PhD, Professor Dr. emer., Senior Research Scientist, Depts. Public Health and Child Neurology, University of Turku, Turku, Finland.

Psychosis related to epilepsy or antiepileptic treatment can occur in teenagers and very rarely in children. Postictal, interictal and antiepileptic-drug-induced psychosis have all been reported in young people. Whether ictal psychosis occurs in this age group remains open to debate. Neuronal antibody encephalitis such as anti-NMDA receptor encephalitis can present with seizures and psychosis, both of which can resolve with prompt, appropriate immunotherapy. In addition, there have been several reports in which the terms psychosis or psychotic features have been used loosely to describe behavioural disturbance in children with epilepsy; in these cases there have apparently been no diagnostic features of psychosis, implying that these terms should not have been used. The management of epilepsy-related psychosis in young people is similar to that in adults. Antipsychotic medication should not be withheld if it is needed on clinical grounds. If the psychosis has been induced by antiepileptic medication then a medication review is necessary.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1684/epd.2016.0814DOI Listing
May 2016

Psychiatric and Behavioural Disorders in Children with Epilepsy (ILAE Task Force Report): Anxiety, depression and childhood epilepsy.

Epileptic Disord 2016 May 16. Epub 2016 May 16.

MD PhD, Professor Dr. emer., Senior Research Scientist, Depts. Public Health and Child Neurology, University of Turku, Turku, Finland.

Anxiety and depression are relatively common in children with epilepsy: anxiety has been reported in 15-36% and depression in 8-35% of patients. In some cases these conditions may be related specifically to the epilepsy or its treatment. For example, some antiepileptic drugs are known to be associated with depression in adults and are likely to have a similar effect in young people. Emotional reactions to the epilepsy, for example anxieties and social phobia related specifically to the seizures, might be expected and require appropriate management. However, there is a growing recognition of the bidirectional relationship between epilepsy and psychiatric disorders, including depression, largely based on adult data. Cognitive behavioural therapy and serotonin reuptake inhibitors are used for treatment of both anxiety and depression in children with epilepsy. There is a need for greater understanding of the causes of these conditions in young people and there is also a need for better evidence for optimal treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1684/epd.2016.0813DOI Listing
May 2016

Psychiatric and Behavioural Disorders in Children with Epilepsy (ILAE Task Force Report): Epilepsy and autism.

Epileptic Disord 2016 May 16. Epub 2016 May 16.

MD PhD, Professor Dr. emer., Senior Research Scientist, Depts. Public Health and Child Neurology, University of Turku, Turku, Finland.

A high proportion of children with epilepsy have autism spectrum disorder. Although estimates vary, depending both on the population studied and the definitions used, a figure of around 20% has typically been reported. Autism can have a major impact on the life of the child and family. Despite the importance of this comorbidity and although many studies have been performed, a full understanding of the possible links between epilepsy and autism remains elusive. In a minority of cases, for example in the Landau-Kleffner syndrome, the autistic features can be the result of the epilepsy itself. However, there has been a failure to demonstrate that the epilepsy itself plays a major role in most cases. The current evidence seems to point to a common underlying predisposing factor. The discovery of a growing number of genetic defects leading to both conditions would support this explanation of the link.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1684/epd.2016.0812DOI Listing
May 2016

Extrastriate visual cortex in idiopathic occipital epilepsies: The contribution of retinotopic areas to spike generation.

Epilepsia 2016 06 19;57(6):896-906. Epub 2016 Apr 19.

Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.

Objectives: To provide insight into the pathophysiology of idiopathic childhood occipital epilepsies (ICOEs), by mapping the contribution of retinotopic visual areas to the generation and sustainment of epileptic activity.

Methods: Thirteen patients affected by ICOEs (mean age = 10.9 years) underwent a video electroencephalography-functional magnetic resonance imaging (EEG-fMRI) study. A flexible-related fMRI analysis was applied to estimate the shape of the blood oxygen level-dependent (BOLD) response in each patient. Second-level analysis was performed using the interictal EEG discharge (IED)-specific response shape for the ICOE group. The resulting fMRI t-maps were warped to the Population-Average, Landmark- and Surface-based (PALS)-B12 atlas in Caret. For localization purposes, functional results were plotted and compared against 19 retinotopic areas for each hemisphere. A correlation analysis was performed between the hemodynamic maps and electroclinical variables.

Results: The shape of the group-averaged hemodynamic response in ICOE patients showed an earlier time-to-peak and a more pronounced undershoot than the canonical hemodynamic response function (HRF). The random-effect analysis showed positive hemodynamic changes in the bilateral temporooccipital network. With regard to the retinotopic subdivision of the visual cortex, the primary visual area was consistently spared. Conversely, an extensive involvement of the occipitotemporal cortex, including the fusiform gyrus, and the occipitoparietal areas was observed. Moreover, a linear relationship was detected between the occipital spike-density and BOLD increases at the postcentral gyrus and temporooccipital cortex.

Significance: Our data indicate that both the ventral and dorsal visual pathways are involved in spike generation in ICOEs, to extents that vary between patients, and reinforce the concept of benign childhood seizure susceptibility syndrome as a substrate for ICOEs. Finally, these results underscore the need for appropriate neuropsychological testing in these children, aimed at revealing selective impairments in functions subserved by both visual pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/epi.13385DOI Listing
June 2016

Neuropsychological profile in new-onset benign epilepsy with centrotemporal spikes (BECTS): Focusing on executive functions.

Epilepsy Behav 2016 Jan 5;54:71-9. Epub 2015 Dec 5.

Health Medical Centre, via della Chiusetta 14, 17021 Alassio, Italy; DISFOR Psychology, University of Genoa, Polo M.T. Bozzo, vico S. Antonio 5/7, 16121 Genova, Italy.

Purpose: Increased evidence of subnormal neuropsychological functioning in new-onset childhood epilepsy has been obtained, although results are still rare and controversial. With a prospective study, we aimed to define the very early neuropsychological profile of children with benign epilepsy with centrotemporal spikes (BECTS), including executive functions (EF) because of their key role in learning. Additionally, we enrolled drug-naïve children, with a NREM sleep frequency of discharges <85% and with a Performance Intelligence Quotient equal or superior to 85, in order to exclude additional effects on the neuropsychological functioning.

Methods: Fifteen school-aged children with BECTS (mean age: 8.8years, standard deviation [SD]: 2.4years) and fifteen healthy children (mean age: 9.2years, [SD]: 2.5years) were enrolled and assessed with a comprehensive neuropsychological battery. The assessment included domain-specific standardized tests of language, EF, academic skills, visuomotor and visuospatial skills, and short-term memory. A p-value<0.05 was considered significant.

Results: Significant differences between patients and controls emerged with respect to 3 domains. Language was affected in color naming (p=.026), spoonerism (p=.003), and phonemic synthesis (p=.009). Executive functions appeared inadequate in the five point test with respect to the number of correct figures (p=.003) and errors (p=.008). In the domain of academic skills, significant differences between groups emerged regarding the number of mistakes in nonword writing (p=.001), nonword reading speed (p=.027), nonword reading number of mistakes (p=.019), and word reading errors (p=.023).

Discussion: Results showed that children with new-onset BECTS may demonstrate a range of neuropsychological dysfunctions, particularly affecting executive attention, despite a normal IQ, a low frequency of NREM sleep discharges, and the absence of drugs. These difficulties indicate a frontal dysfunction with cascading effects on language and academic skills. The inclusion of EF in the assessment battery and in the intervention since the very onset is warranted in order to avoid further and persistent academic difficulties.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yebeh.2015.11.010DOI Listing
January 2016

Refractory absence seizures: An Italian multicenter retrospective study.

Eur J Paediatr Neurol 2015 Nov 18;19(6):660-4. Epub 2015 Jul 18.

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

Background: To evaluate evidence and prognosis of refractory cases of absence seizures.

Methods: Subjects with refractory absence seizures were identified retrospectively in 17 Italian epilepsy pediatrics Centers. We analyzed age at onset, family history, presence of myoclonic components, seizure frequency, treatment with antiepileptic drugs (AEDs), interictal electroencephalography (EEG) and neuropsychological assessment. Two subgroups were identified: one with patients with current absence seizures and another with patients that had become seizure free with or without AED treatment. The chi-square test was applied.

Results: A total of 92 subjects with drug-resistant absence seizures were analyzed. 45 subjects still show absence seizures (49%) and the other 47 became seizure free (51%) after a period of drug-resistance. The statistical analysis between these two groups showed no correlation between age of onset, family history and abnormalities at interictal EEG. Statistically significant differences were observed with regard to the number of AEDs used and intellectual disability.

Conclusion: Typical absence epilepsy classifiable as Childhood Absence Epilepsy could not be considered so "benign", as suggested in literature. A longer duration of disease and a higher frequency of seizure seem to be correlated with a higher presence of cognitive impairment. No significant risk factor was observed to allow the faster and better recognition of patients with worse prognosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpn.2015.07.008DOI Listing
November 2015

Spinal muscular atrophy associated with progressive myoclonic epilepsy: A rare condition caused by mutations in ASAH1.

Epilepsia 2015 May 3;56(5):692-8. Epub 2015 Apr 3.

Neurology Unit, Bellaria Hospital, IRCCS Institute of Neurological Sciences, Bologna, Italy.

Objective: To present the clinical features and the results of laboratory investigations in three patients with spinal muscular atrophy associated with progressive myoclonic epilepsy (SMA-PME), a rare condition caused by mutations in the N-acylsphingosine amidohydrosilase 1 (ASAH1) gene.

Methods: The patients were submitted to clinical evaluation, neurophysiologic investigations (that included wakefulness and sleep electroencephalography [EEG], video-polygraphic recording with jerk-locked back-averaging, multimodal evoked potentials, and electromyography), brain magnetic resonance imaging (MRI), biochemical screening, muscle and skin biopsies, and molecular genetic analysis.

Results: The main clinical features were onset in childhood with proximal muscular weakness, generalized epilepsy with absences and myoclonic seizures, cognitive impairment of variable degree; the course was progressive with muscle wasting and uncontrolled epileptic seizures. In one patient, earlier onset before the age of 2 years was associated with a more complex clinical picture, with abnormal eye movements, progressive cognitive impairment, and a more rapid and severe course. EEG/polygraphic data were consistent with PME, demonstrating generalized spike-and-wave discharges, evidence of positive and negative myoclonia, and prominent photosensitivity. In one patient, transcranial magnetic stimulation showed a hyperexcitable motor cortex, whereas somatosensory evoked potentials were unaffected. Possible involvement of the central acoustic and visual pathways was suggested by abnormal auditory and visual evoked potentials. Muscle biopsies showed typical signs of neurogenic damage. Molecular genetic analysis showed mutations of the ASAH1 gene.

Significance: Our data indicate that SMA-PME associated with ASAH1 mutations is a genetically distinct condition with specific clinical and neurophysiologic features. Further studies are warranted to explore the role of the ASAH1 gene in muscle and brain function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/epi.12977DOI Listing
May 2015

Comparing cortical auditory processing in children with typical and atypical benign epilepsy with centrotemporal spikes: Electrophysiologic evidence of the role of non-rapid eye movement sleep abnormalities.

Epilepsia 2015 May 25;56(5):726-34. Epub 2015 Mar 25.

Child Neurology Unit, IRCCS Institute of Neurological Sciences, Bologna, Italy.

Objective: The mismatch negativity (MMN) is an objective measure of central auditory discrimination. MMN alterations have been shown in children with language and/or developmental disorders. In benign focal epilepsies, neuropsychological disorders are often reported and linked to interictal epileptic discharges (IEDs) during non-rapid eye movement (NREM) sleep. There are few studies reporting MMN in children with benign epilepsy with centrotemporal spikes (BECTS) and sleep IEDs. Moreover, no MMN recording has yet been reported in atypical BECTS children with continuous spike-and-wave during sleep (CSWS). We retrospectively compared MMN in typical and atypical BECTS children, particularly addressing the impact of NREM sleep IEDs on auditory discrimination. Moreover, we attempted a neuropsychological characterization of patients.

Methods: The MMN was recorded in 9 normal controls and 23 patients (14 typical BECTS and 9 atypical BECTS) in an oddball paradigm with syllable stimuli. MMN, sleep electroencephalography (EEG) and neuropsychological evaluation were realized in the same testing session.

Results: Measurable MMN responses to speech stimuli were identified in both the control and patient groups. A significant difference between control and atypical BECTS children was found with respect to amplitude (p = 0.0061). Atypical BECTS also showed a lower MMN amplitude with respect to typical BECTS, but this difference did not reach statistical significance (p = 0.0545). Statistical comparisons between groups revealed no differences in latency. Among the neuropsychological variables, academic difficulties were significantly more prominent in the patients with atypical BECTS (p = 0.04).

Significance: CSWS EEG pattern affects auditory discrimination and may have a long-lasting impact on academic skills acquisition, whereas in typical BECTS children with a lower degree of IED NREM sleep, plastic brain reorganization or the preservation of participating networks may prevent such difficulty. Early electrophysiologic identification of auditory discrimination deficits in epileptic children could be used in early rehabilitation, thereby reducing the risk of developing neuropsychological disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/epi.12959DOI Listing
May 2015

Do pure absence seizures occur in myoclonic epilepsy of infancy? A case series.

Seizure 2015 Jan 15;24:8-11. Epub 2014 Nov 15.

Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophtalmology, Genetics, Maternal and Child Health, University of Genoa, "G. Gaslini" Institute, Genova, Italy.

Purpose: To assess if absence seizures (ASs) occur in patients with myoclonic epilepsy of infancy (MEI).

Methods: A retrospective chart review was conducted in 37 patients with MEI followed at seven different paediatric epilepsy centres in Italy, between 2002 and 2014. To assess the possible occurrence of pure ASs or absences associated with myoclonias, ASs were defined according to the following criteria: (i) a sudden onset and interruption of ongoing activities; (ii) bilateral polyspikes or spike-and-wave (SW) complexes; spike SW complexes at 2-4Hz; (iii) duration of AS: 3-30seconds.

Results: Thirty-seven MEI patients (25 boys and 12 girls) were identified. Nine patients (24.3%) had a history of simple FS during the first year of life. Ten patients (27%) had a family history of epilepsy, and six patients (16.2%) had a family history of FS. In 7/37 (18.9%) patients, during the occurrence of MSs, a total of nineteen brief ASs were captured by video-EEG recordings. ASs occurred both during a brief cluster of rhythmic MSs than after single myoclonic jerks. The ictal EEG abnormalities observed in patients with ASs were similar to the ictal EEG patterns associated with only myoclonias. No differences in relation to gender, family history, ictal EEG discharge were found between patients with myoclonic seizures with ASs and myoclonias without ASs.

Conclusions: Absence seizures can occur in approximately 20% of MEI patients and the occurrence of ASs, though not essential to formulate the diagnosis, do not automatically exclude the diagnosis of MEI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.seizure.2014.11.002DOI Listing
January 2015

Efficacy and safety of rufinamide in children under four years of age with drug-resistant epilepsies.

Eur J Paediatr Neurol 2014 Sep 15;18(5):641-5. Epub 2014 May 15.

Department of Pediatrics, University of Siena, Siena, Italy.

Background: Studies on the efficacy and tolerability of rufinamide in infants and young children are scarce. Here we report on an open, retrospective, and pragmatic study about safety and efficacy of rufinamide in children aged less than four years, in terms of seizures types and epilepsy syndromes.

Methods: Forty children (mean age 39.5 months; range 22-48) were enrolled in the study. The mean follow-up period was 12.2 months (range 5-21). Rufinamide was initiated at a mean age of 26.7 months (range 12-42). Final rufinamide mean dosage was 31.5 mg/kg/day if associated with valproic acid and 44.2 mg/kg/day if not.

Results: The highest seizure reduction rate was observed in the epileptic spasms (46%) and drop attacks (42%) groups. Seizure reduction was also observed in tonic seizures (35%) and in the focal seizure (30%) groups. In terms of epilepsy syndrome, rufinamide was effective in Lennox-Gastaut syndrome. Results were very poor for those affected by Dravet's syndrome. Globally, responder rate was 27.5%, including two (5%) patients seizure-free. Adverse reactions occurred in 37.5% of children and were mainly represented by vomiting, drowsiness, irritability, and anorexia. Discontinuation rate due to treatment-emergent adverse events was 15%.

Conclusion: The present study concludes that rufinamide may be a safe and effective drug for a broad range of seizures and epilepsy syndromes in infants and young children and represents a valid therapeutic option in this population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpn.2014.05.001DOI Listing
September 2014