Publications by authors named "Raffaella Cusmai"

41 Publications

CASK related disorder: Epilepsy and developmental outcome.

Eur J Paediatr Neurol 2021 Mar 19;31:61-69. Epub 2021 Feb 19.

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health, University of Genoa, Genova, Italy; Unit of Child Neuropsychiatry, ASST Fatebenefratelli Sacco, Milano, Italy.

Objective: CASK pathogenic variants are associated with variable features, as intellectual disability, optic atrophy, brainstem/cerebellar hypoplasia, and epileptic encephalopathy. Few studies describe the electroclinical features of epilepsy in patients with CASK pathogenic variants and their relationship with developmental delay.

Methods: this national multicentre cohort included genetically confirmed patients with different CASK pathogenic variants. Our findings were compared with cohorts reported in the literature.

Results: we collected 34 patients (29 females) showing from moderate (4 patients) to severe (22) and profound (8) developmental delay; all showed pontine and cerebellar hypoplasia, all except three with microcephaly. Seventeen out of 34 patients (50%) suffered from epileptic seizures, including spasms (11 patients, 32.3%), generalized (5) or focal seizures (1). In 8/17 individuals (47.1%), epilepsy started at or beyond the age of 24 months. Seven (3 males) out of the 11 children with spasms showed EEG features and a course supporting the diagnosis of a developmental and epileptic encephalopathy (DEE). Drug resistance was frequent in our cohort (52.9% of patients with epilepsy). EEG abnormalities included poorly organized background activity with diffuse or multifocal epileptiform abnormalities and sleep-activation, with possible appearance over the follow-up period. Developmental delay degree was not statistically different among patients with or without seizures but feeding difficulties were more frequent in patients with epilepsy.

Conclusions: epilepsy is a frequent comorbidity with a high incidence of spasms and drug resistance. Overall developmental disability does not seem to be more severe in the group of patients with epilepsy nor to be linked to specific epilepsy/EEG characteristics. A childhood onset of epilepsy is frequent, with possible worsening over time, so that serial and systematic monitoring is mandatory.
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http://dx.doi.org/10.1016/j.ejpn.2021.02.006DOI Listing
March 2021

The Ketogenic Diet Increases In Vivo Glutathione Levels in Patients with Epilepsy.

Metabolites 2020 Dec 10;10(12). Epub 2020 Dec 10.

Child Neurology Unit, Bambino Gesù Children's Hospital IRCCS, 00165 Rome, Italy.

The Ketogenic Diet (KD) is a high-fat, low-carbohydrate diet that has been utilized as the first line treatment for contrasting intractable epilepsy. It is responsible for the presence of ketone bodies in blood, whose neuroprotective effect has been widely shown in recent years but remains unclear. Since glutathione (GSH) is implicated in oxidation-reduction reactions, our aim was to monitor the effects of KD on GSH brain levels by means of magnetic resonance spectroscopy (MRS). MRS was acquired from 16 KD patients and seven age-matched Healthy Controls (HC). We estimated metabolite concentrations with linear combination model (LCModel), assessing differences between KD and HC with -test. Pearson was used to investigate GHS correlations with blood serum 3-B-Hydroxybutyrate (3HB) concentrations and with number of weekly epileptic seizures. The results have shown higher levels of brain GSH for KD patients (2.5 ± 0.5 mM) compared to HC (2.0 ± 0.5 mM). Both blood serum 3HB and number of seizures did not correlate with GSH concentration. The present study showed a significant increase in GSH in the brain of epileptic children treated with KD, reproducing for the first time in humans what was previously observed in animal studies. Our results may suggest a pivotal role of GSH in the antioxidant neuroprotective effect of KD in the human brain.
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http://dx.doi.org/10.3390/metabo10120504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763157PMC
December 2020

Novel congenital disorder of O-linked glycosylation caused by GALNT2 loss of function.

Brain 2020 04;143(4):1114-1126

Department of Pediatrics, Division of Human Genetics, Section of Biochemical Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

Congenital disorders of glycosylation are a growing group of rare genetic disorders caused by deficient protein and lipid glycosylation. Here, we report the clinical, biochemical, and molecular features of seven patients from four families with GALNT2-congenital disorder of glycosylation (GALNT2-CDG), an O-linked glycosylation disorder. GALNT2 encodes the Golgi-localized polypeptide N-acetyl-d-galactosamine-transferase 2 isoenzyme. GALNT2 is widely expressed in most cell types and directs initiation of mucin-type protein O-glycosylation. All patients showed loss of O-glycosylation of apolipoprotein C-III, a non-redundant substrate for GALNT2. Patients with GALNT2-CDG generally exhibit a syndrome characterized by global developmental delay, intellectual disability with language deficit, autistic features, behavioural abnormalities, epilepsy, chronic insomnia, white matter changes on brain MRI, dysmorphic features, decreased stature, and decreased high density lipoprotein cholesterol levels. Rodent (mouse and rat) models of GALNT2-CDG recapitulated much of the human phenotype, including poor growth and neurodevelopmental abnormalities. In behavioural studies, GALNT2-CDG mice demonstrated cerebellar motor deficits, decreased sociability, and impaired sensory integration and processing. The multisystem nature of phenotypes in patients and rodent models of GALNT2-CDG suggest that there are multiple non-redundant protein substrates of GALNT2 in various tissues, including brain, which are critical to normal growth and development.
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http://dx.doi.org/10.1093/brain/awaa063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534148PMC
April 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

ATP1A3-related epileptic encephalopathy responding to ketogenic diet.

Brain Dev 2018 May 1;40(5):433-438. Epub 2018 Feb 1.

Dept. of Neuroscience, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. Electronic address:

Background: Alternating Hemiplegia of Childhood (AHC) is a rare neurological disease caused by mutations in ATP1A3 gene codifying for alpha3 subunit of Na-K ATPase pump. Repeated and transient attacks of hemiplegia, usually affecting one side of the body or the other, or both sides of the body at once, are the core features of AHC. Monocular nystagmus, other abnormalities in ocular movements, dystonic posturing and epilepsy are commonly associated to AHC. However, the spectrum of ATP1A3 related diseases is still expanding and new phenotypes have been reported.

Case Report: Here, we described a patient who developed a severe early onset drug-resistant epileptic encephalopathy and months later, he presented episodes of hemiplegic attacks and monocular nystagmus. Thus, AHC was hypothesized and a novel mutation in ATP1A3 gene was found. Interestingly, ketogenic diet (KD) was started and both epileptic seizures and classical AHC paroxysmal episodes stopped. Long-term follow-up shows a global improvement of neurological development.

Conclusions: Our case reinforces the role of KD as a novel therapeutic option for ATP1A3-related conditions. However, proper dedicated confirmatory trials on KD are necessary.
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http://dx.doi.org/10.1016/j.braindev.2018.01.002DOI Listing
May 2018

Tubulin-related cerebellar dysplasia: definition of a distinct pattern of cerebellar malformation.

Eur Radiol 2017 Dec 4;27(12):5080-5092. Epub 2017 Jul 4.

Neuropsychiatry and Neurorehabilitation Unit, Scientific Institute, IRCCS Eugenio Medea, Via D. L. Monza 20, 23842, Bosisio Parini, Lecco, Italy.

Objective: To determine the neuroimaging pattern of cerebellar dysplasia (CD) and other posterior fossa morphological anomalies associated with mutations in tubulin genes and to perform clinical and genetic correlations.

Methods: Twenty-eight patients harbouring 23 heterozygous pathogenic variants (ten novel) in tubulin genes TUBA1A (n = 10), TUBB2B (n = 8) or TUBB3 (n = 5) were studied by a brain MRI scan performed either on a 1.5 T (n = 10) or 3 T (n = 18) MR scanner with focus on the posterior fossa.

Results: Cerebellar anomalies were detected in 24/28 patients (86%). CD was recognised in 19/28 (68%) including cortical cerebellar dysplasia (CCD) in 18/28, either involving only the cerebellar hemispheres (12/28) or associated with vermis dysplasia (6/28). CCD was located only in the right hemisphere in 13/18 (72%), including four TUBB2B-, four TUBB3- and five TUBA1A-mutated patients, while in the other five TUBA1A cases it was located only in the left hemisphere or in both hemispheres. The postero-superior region of the cerebellar hemispheres was most frequently affected.

Conclusions: The cerebellar involvement in tubulinopathies shows specific features that may be labelled as 'tubulin-related CD'. This pattern is unique and differs from other genetic causes of cerebellar dysplasia.

Key Points: • Cortical cerebellar dysplasia without cysts is suggestive of tubulin-related disorder. • Cerebellar dysplasia in tubulinopathies shows specific features labelled as 'tubulin-related CD'. • Focal and unilateral involvement of cerebellar hemispheres has important implications for counselling.
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http://dx.doi.org/10.1007/s00330-017-4945-2DOI Listing
December 2017

Current role of perampanel in pediatric epilepsy.

Ital J Pediatr 2017 Jun 2;43(1):51. Epub 2017 Jun 2.

Department of Pediatrics, University of L'Aquila, L'Aquila, Italy.

Perampanel is among the latest AEDs approved, indicated for the treatment of partial-onset seizures with or without secondary generalization, and for primary generalized tonic-clonic seizures, in patients aged 12 years and older. This paper summarizes the clinical recommendations on the current role of perampanel in the treatment of pediatric epilepsies and future directions for research. The optimal dosage should be comprised between 4 and 12 mg/day, with 8 mg/day being the most common dosage used. The rate and severity of adverse events, including psychiatric symptoms, can be decreased by starting at low doses, and titrating slowly. Overall, perampanel presents an acceptable risk/benefit ratio, but special caution should be made to the risk of seizure aggravation and behavioral problems. The favorable cognitive profile, the ease of use of the titration scheme and the once-daily formulation offer advantage over other AEDs and make this drug particularly suitable for adolescent population. Perampanel is a welcome addition to the armamentarium of the existing AEDs, as it represents a new approach in the management of epilepsy, with a novel mechanism of action and a potential to have a considerable impact on the treatment of adolescents with epilepsy.
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http://dx.doi.org/10.1186/s13052-017-0368-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457730PMC
June 2017

Reduced steroidogenesis in patients with PCDH19-female limited epilepsy.

Epilepsia 2017 06 4;58(6):e91-e95. Epub 2017 May 4.

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

Patients affected by protocadherin 19 (PCDH19)-female limited epilepsy (PCDH19-FE) present a remarkable reduction in allopregnanolone blood levels. However, no information is available on other neuroactive steroids and the steroidogenic response to hormonal stimulation. For this reason, we evaluated allopregnanolone, pregnanolone, and pregnenolone sulfate by liquid chromatographic procedures coupled with electrospray tandem mass spectrometry in 12 unrelated patients and 15 age-matched controls. We also tested cortisol, estradiol, progesterone, and 17OH-progesterone using standard immunoassays. Apart from estradiol and progesterone, all the considered hormones were evaluated in basal condition and after stimulation with adrenocorticotropic hormone (ACTH). A generalized decrease in blood levels of almost all measured neuroactive steroids was found. When considering sexual development, cortisol and pregnenolone sulfate basal levels were significantly reduced in postpubertal girls affected by PCDH19-FE. Of interest, ACTH administration did not recover pregnenolone sulfate serum levels but restored cortisol to control levels. In prepubertal girls with PCDH19-FE, by challenging adrenal function with ACTH we disclosed defects in the production of cortisol, pregnenolone sulfate, and 17OH-progesterone, which were not apparent in basal condition. These findings point to multiple defects in peripheral steroidogenesis associated with and potentially relevant to PCDH19-FE. Some of these defects could be addressed by stimulating adrenocortical activity.
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http://dx.doi.org/10.1111/epi.13772DOI Listing
June 2017

Missense mutations of CACNA1A are a frequent cause of autosomal dominant nonprogressive congenital ataxia.

Eur J Paediatr Neurol 2017 May 30;21(3):450-456. Epub 2016 Nov 30.

Department of Neurosciences, Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. Electronic address:

Background: Mutations in the CACNA1A gene, encoding the pore-forming CaV2.1 (P/Q-type) channel α1A subunit, localized at presynaptic terminals of brain and cerebellar neurons, result in clinically variable neurological disorders including hemiplegic migraine (HM) and episodic or progressive adult-onset ataxia (EA2, SCA6). Most recently, CACNA1A mutations have been identified in patients with nonprogressive congenital ataxia (NPCA).

Methods: We performed targeted resequencing of known genes involved in cerebellar dysfunction, in 48 patients with congenital or early onset ataxia associated with cerebellar and/or vermis atrophy.

Results: De novo missense mutations of CACNA1A were found in four patients (4/48, ∼8.3%). Three of them developed migraine before or after the onset of ataxia. Seizures were present in half of the cases.

Conclusion: Our results expand the clinical and mutational spectrum of CACNA1A-related phenotype in childhood and suggest that CACNA1A screening should be implemented in this subgroup of ataxias.
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http://dx.doi.org/10.1016/j.ejpn.2016.11.005DOI Listing
May 2017

Epilepsy in the setting of full trisomy 18: A multicenter study on 18 affected children with and without structural brain abnormalities.

Am J Med Genet C Semin Med Genet 2016 09 13;172(3):288-95. Epub 2016 Aug 13.

This paper reports on the clinical aspects, electroencephalographic (EEG) features, and neuroimaging findings in children with full trisomy 18 and associated epilepsy, and compares the evolution and outcome of their neurological phenotype. We retrospectively studied 18 patients (10 males and 8 females; aged 14 months to 9 years) with full trisomy 18 and epilepsy. All patients underwent comprehensive assessment including neuroimaging studies of the brain. We divided patients into two groups according to neuroimaging findings: (Group 1) 10 patients harboring structural brain malformations, and (Group 2) 8 patients with normal brain images. Group 1 had a significantly earlier age at seizure onset (2 months) compared to Group 2 (21 months). The seizure semiology was more severe in Group 1, who presented multiple seizure types, need for polytherapy (80% of patients), multifocal EEG abnormalities and poorer outcome (drug resistant epilepsy in 90% of patients) than Group 2 who presented a single seizure type, generalized or focal, and non-specific EEG pattern; these patients were successfully treated with monotherapy with good outcome. Imaging revealed a wide and complex spectrum of structural brain abnormalities including anomalies of the commissures, cerebellar malformations, cortical abnormalities, and various degrees of cortical atrophy. Epilepsy in full trisomy 18 may develop during the first months of life and can be associated with structural brain malformations. Patients with brain malformations can show multiple seizure types and can frequently be resistant to therapy with antiepileptic drugs. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.c.31513DOI Listing
September 2016

White matter disruption is associated with persistent seizures in tuberous sclerosis complex.

Epilepsy Behav 2016 07 11;60:63-67. Epub 2016 May 11.

Neuroradiology Unit, Imaging Department, "Bambino Gesù" Children's Hospital, IRCCS, Piazza S. Onofrio 4, 00165 Rome, Italy.

Background And Aims: White matter is diffusely altered in tuberous sclerosis complex (TSC), and these alterations appear to be more evident in subjects with a more severe neurologic phenotype. However, little is known on the correlation between white matter alterations and epilepsy in TSC. The aims of this study were to evaluate the effects of early onset and refractory seizures on white matter by using diffusion tensor imaging (DTI).

Methods: We enrolled 20 children with TSC and epilepsy onset in the first 3years of life and grouped them according to seizure persistence or freedom. All patients underwent brain MRI with DTI. Specific ROIs have were placed to generate tracks to calculate fractional anisotropy (FA) and apparent diffusion coefficient (ADC). Statistical analysis was performed by ANOVA.

Results: Children with persistent seizures presented an overall reduced FA, with statistically significant differences on the cingulum (right p=0.003, left p=0.016), the left cerebral peduncle (p=0.020), the superior cerebellar peduncles (right p=0.008, left p=0.002), the posterior limbs of internal capsule (right p=0.037, left p=0.015), the external capsule (right p=0.018, left p=0.031), the inferior frontooccipital fasciculus (right p=0.010, left p=0.026), and the temporal trunk (right p=0.017, left p=0.001).

Conclusions: Our study demonstrated that children with persistent seizures present more significant alterations of brain connectivity in areas crucial for global cognitive maturation, executive functions, and verbal abilities, implying a higher risk of cognitive impairment, attention-deficit hyperactivity disorder, and autism.
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http://dx.doi.org/10.1016/j.yebeh.2016.04.026DOI Listing
July 2016

Congenital disorders of glycosylation presenting as epileptic encephalopathy with migrating partial seizures in infancy.

Dev Med Child Neurol 2016 10 13;58(10):1085-91. Epub 2016 May 13.

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

Aim: Epilepsy is commonly observed in congenital disorders of glycosylation (CDG), but no distinctive electroclinical pattern has been recognized. We aimed at identifying a characteristic clinical presentation that might help targeted diagnostic work-up.

Method: Based on the initial observation of an index case with CDG and migrating partial seizures, we evaluated 16 additional children with CDG and analysed their clinical course, biochemical, genetic, electrographic, and imaging findings.

Results: Four of 17 consecutively observed children with CDG (three females, one male) were first referred between the first and fourth month of life, after early onset of migrating partial seizures. All four patients manifested developmental delay, microcephaly, and multi-organ involvement. Magnetic resonance imaging disclosed cerebral and cerebellar atrophy. Isoelectrofocusing of transferrin, enzymatic studies, and lipid-linked oligosaccharide analysis indicated CDG-I. Genetic testing demonstrated either homozygous or compound heterozygous variants involving the ALG3 gene in patients 1 and 3, the RFT1 gene in patient 2, and the ALG1 gene in patient 4. At last follow-up, patients 1 and 2 were 5 and 3(1/2) years old. Patients 3 and 4 had died due to respiratory failure during pneumonia and refractory status epilepticus respectively.

Interpretation: Children with migrating partial seizures and concomitant multisystem involvement should be investigated for CDG.
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http://dx.doi.org/10.1111/dmcn.13141DOI Listing
October 2016

PCDH19-related epilepsy in two mosaic male patients.

Epilepsia 2016 Mar 14;57(3):e51-5. Epub 2016 Jan 14.

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

PCDH19 gene mutations have been recently associated with an epileptic syndrome characterized by focal and generalized seizures. The PCDH19 gene (Xq22.1) has an unusual X-linked inheritance with a selective involvement for female subjects. A cellular interference mechanism has been hypothesized and male patients can manifest epilepsy only in the case of a mosaicism. So far about 100 female patients, and only one symptomatic male have been described. Using targeted next generation sequencing (NGS) approach we found a PCDH19 point mutation in two male patients with a clinical picture suggestive of PCDH19-related epilepsy. The system allowed us to verify that the two c.1352 C>T; p.(Pro451Leu) and c.918C>G; p.(Tyr306*) variants occurred in mosaic status. Mutations were confirmed by Sanger sequencing and quantified by real-time polymerase chain reaction (PCR). Up to now, the traditional molecular screening for PCDH19-related epilepsy has been targeted to all females with early onset epilepsy with or without cognitive impairment. Male patients were generally excluded. We describe for the first time two mosaic PCDH19 point mutations in two male patients with a clinical picture suggestive of PCDH19-related epilepsy. This finding opens new opportunities for the molecular diagnoses in patients with a peculiar type of epilepsy that remains undiagnosed in male patients.
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http://dx.doi.org/10.1111/epi.13295DOI Listing
March 2016

Ketogenic diet in a patient with congenital hyperinsulinism: a novel approach to prevent brain damage.

Orphanet J Rare Dis 2015 Sep 24;10:120. Epub 2015 Sep 24.

Metabolic Unit, Department of Pediatric Medicine, Bambino Gesù Children's Hospital, piazza S. Onofrio 4, 00165, Rome, Italy.

Background: Congenital hyperinsulinism (CHI) is the most frequent cause of hypoglycemia in children. In addition to increased peripheral glucose utilization, dysregulated insulin secretion induces profound hypoglycemia and neuroglycopenia by inhibiting glycogenolysis, gluconeogenesis and lipolysis. This results in the shortage of all cerebral energy substrates (glucose, lactate and ketones), and can lead to severe neurological sequelae. Patients with CHI unresponsive to medical treatment can be subjected to near-total pancreatectomy with increased risk of secondary diabetes. Ketogenic diet (KD), by reproducing a fasting-like condition in which body fuel mainly derives from beta-oxidation, is intended to provide alternative cerebral substrates such ketone bodies. We took advantage of known protective effect of KD on neuronal damage associated with GLUT1 deficiency, a disorder of impaired glucose transport across the blood-brain barrier, and administered KD in a patient with drug-unresponsive CHI, with the aim of providing to neurons an energy source alternative to glucose.

Methods: A child with drug-resistant, long-standing CHI caused by a spontaneous GCK activating mutation (p.Val455Met) suffered from epilepsy and showed neurodevelopmental abnormalities. After attempting various therapeutic regimes without success, near-total pancreatectomy was suggested to parents, who asked for other options. Therefore, we proposed KD in combination with insulin-suppressing drugs.

Results: We administered KD for 2 years. Soon after the first six months, the patient was free of epileptic crises, presented normalization of EEG, and showed a marked recover in psychological development and quality of life.

Conclusions: KD could represent an effective treatment to support brain function in selected cases of CHI.
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http://dx.doi.org/10.1186/s13023-015-0342-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4581011PMC
September 2015

Cognitive development in females with PCDH19 gene-related epilepsy.

Epilepsy Behav 2015 Jan 11;42:36-40. Epub 2014 Dec 11.

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

Mutations in the PCDH19 gene are now recognized to cause epilepsy in females and are claiming increasing interest in the scientific world. Clinical features and seizure semiology have been described as heterogeneous. Intellectual disability might be present, ranging from mild to severe; behavioral and psychiatric problems are a common feature of the disorder, including aggressiveness, depressed mood, and psychotic traits. The purpose of our study was to describe the cognitive development in 11 girls with a de novo mutation in PCDH19 and early-onset epilepsy. Six patients had average mental development or mild intellectual disability regardless of persistence of seizures in clusters. Five patients presented moderate or severe intellectual disability and autistic features. In younger patients, we found that despite an average developmental quotient, they all presented a delay of expressive language acquisition and lower scores at follow-up testing completed at older ages, underlining that subtle dysfunctions might be present. Larger cohort and long-term follow-up might be useful in defining cognitive features and in improving the care of patients with PCDH19.
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http://dx.doi.org/10.1016/j.yebeh.2014.10.019DOI Listing
January 2015

Long-term outcome of epilepsy in patients with Prader-Willi syndrome.

J Neurol 2015 Jan 18;262(1):116-23. Epub 2014 Oct 18.

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

Prader-Willi syndrome is a multisystemic genetic disorder that can be associated with epilepsy. There is insufficient information concerning the clinical and electroencephalographic characteristics of epilepsy and the long-term outcome of these patients. The aim of this study is to describe seizure types, electroencephalographic patterns and long-term seizure outcome in Prader-Willi syndrome patients suffering from epilepsy. We retrospectively studied 38 patients with Prader-Willi syndrome and seizures. Results of neuroimaging studies were obtained for 35 individuals. We subdivided these patients into two groups: group A, 24 patients, without brain lesions; and group B, 11 patients, with brain abnormalities. All patients were re-evaluated after a period of at least 10 years. Twenty-one patients (55.2 %) were affected by generalized epilepsy and 17 patients (44.8 %) presented focal epilepsy. The most common seizure type was generalized tonic-clonic seizure. The mean age at seizure onset was 4.5 years (ranged from 1 month to 14 years). In the follow-up period, seizure freedom was achieved in 32 patients (84.2 %). Seizure freedom was associated with electroencephalographic normalization, while the six children presenting drug-resistant epilepsy showed persistence of electroencephalographic abnormalities. Group B patients showed a higher prevalence of drug-resistant epilepsy. Patients with Prader-Willi syndrome were frequently affected by generalized seizures. Most of the patients had a favorable evolution, although, patients with brain abnormalities presented a worse outcome, suggesting that the presence of these lesions can influence the response to antiepileptic therapy.
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http://dx.doi.org/10.1007/s00415-014-7542-1DOI Listing
January 2015

Epilepsy in Menkes disease: an electroclinical long-term study of 28 patients.

Epilepsy Res 2014 Nov 30;108(9):1597-603. Epub 2014 Aug 30.

Child Neuropsychiatry, Regional Epilepsy Center, Brescia, Italy.

Background: Epilepsy is a frequent and severe feature of Menkes disease (MD) but only few studies described the long-term evolution of these children. We report a series of 28 epileptic MD patients, with clinical characteristics, EEG abnormalities, brain malformations and long-term outcome.

Methods: EEG, clinical characteristics and neuroimaging features in 28 MD patients were analyzed at the onset of epilepsy and after long-term follow-up (at least 4 years). We subdivided the patients into two groups: Group 1, 16 patients who received a subcutaneous copper-histidine treatment, and Group 2 including 12 patients who did not get any therapies.

Results: The large majority of our patients presented at the onset of epilepsy focal seizures (FS) and infantile spasms (IS). Five patients had recurrent status epilepticus (SE). During the follow-up, patients showed multiple seizure types: 6 patients had generalized tonic clonic seizures (GCT), 6 patients presented IS, 10 children had FS, 11 had myoclonic jerks and 3 had SE. Therapy with various antiepileptic drugs had poor efficacy, except in three patients who showed seizure disappearance with consequent discontinuation of antiepileptic therapy. There was no difference of neurological outcome among the two groups analyzed.

Conclusions: Epilepsy in MD is a difficult to treat problem. At the onset, the most frequent type of seizures are FC and IS; in the next months, other kinds of seizures can appear. Many children are drug resistant. Institution of replacement therapy with copper-histidine seems to be not beneficial for epilepsy.
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http://dx.doi.org/10.1016/j.eplepsyres.2014.08.006DOI Listing
November 2014

Current role of rufinamide in the treatment of childhood epilepsy: literature review and treatment guidelines.

Eur J Paediatr Neurol 2014 Nov 28;18(6):685-90. Epub 2014 May 28.

Department of Systems Medicine, Child Neurology and Psychiatry Unit, Tor Vergata University Hospital of Rome, Italy. Electronic address:

Purpose: The literature on the efficacy and safety of rufinamide in childhood-onset epilepsy syndromes currently includes approximately 600 paediatric patients. This paper summarizes the views of a panel of experienced European epileptologists with regard to the current role of rufinamide in the treatment of childhood epilepsies.

Results: Rufinamide is effective in decreasing the seizure frequency in the Lennox-Gastaut syndrome (LGS), especially tonic and atonic seizures. It might consequently be preferred to other drugs as a second-line treatment for LGS when drop-attacks are frequent. The mean responder rate in the published studies is 38% with seizure freedom achieved in 2.4% of patients. Rufinamide has shown some efficacy in epileptic encephalopathies other than LGS. It can be also effective as adjunctive therapy in children and adolescents with drug-resistant partial seizures. The available data suggest that rufinamide has an acceptable risk/benefit ratio with quite a low risk of aggravating seizures. Common adverse effects (somnolence, nausea and vomiting) are usually mild and self-limiting; they are more frequently observed during titration than in the maintenance phase, suggesting that low escalation rates might be associated with fewer adverse effects. Rufinamide appears to have a favourable cognitive profile compared with other antiepileptic drugs.

Conclusion: Rufinamide is only approved for adjunctive treatment of seizures associated with LGS in children 4 years of age and older. There are very few data on rufinamide treatment at the onset of LGS or early in the course of the disorder; whether early treatment will improve outcome has yet to be determined.
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http://dx.doi.org/10.1016/j.ejpn.2014.05.008DOI Listing
November 2014

Long-term follow-up in children with benign convulsions associated with gastroenteritis.

Eur J Paediatr Neurol 2014 Sep 14;18(5):572-7. Epub 2014 Apr 14.

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

Background: The outcome of benign convulsions associated with gastroenteritis (CwG) has generally been reported as being excellent. However, these data need to be confirmed in studies with longer follow-up evaluations.

Aim: To assess the long-term neurological outcome of a large sample of children presenting with CwG.

Methods: We reviewed clinical features of 81 subjects presenting with CwG (1994-2010) from three different Italian centers with a follow-up period of at least 3 years.

Results: Follow-up period ranged from 39 months to 15 years (mean 9.8 years). Neurological examination and cognitive level at the last evaluation were normal in all the patients. A mild attention deficit was detected in three cases (3.7%). Fourteen children (17.3%) received chronic anti-epileptic therapy. Interictal EEG abnormalities detected at onset in 20 patients (24.7%) reverted to normal. Transient EEG epileptiform abnormalities were detected in other three cases (3.7%), and a transient photosensitivity in one (1.2%). No recurrence of CwG was observed. Three patients (3.7%) presented with a febrile seizure and two (2.5%) with an unprovoked seizure, but none developed epilepsy.

Conclusions: The long-term evaluation of children with CwG confirms the excellent prognosis of this condition, with normal psychomotor development and low risk of relapse and of subsequent epilepsy.
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http://dx.doi.org/10.1016/j.ejpn.2014.04.006DOI Listing
September 2014

Rufinamide for the treatment of refractory epilepsy secondary to neuronal migration disorders.

Epilepsy Res 2014 Mar 30;108(3):542-6. Epub 2014 Jan 30.

Child and Adolescent Neuropsychiatry, Faculty of Medicine and Surgery, University of Salerno, Italy. Electronic address:

Objective: To evaluate the efficacy and tolerability of add-on rufinamide in children with refractory epilepsy symptomatic of neuronal migration disorders.

Materials And Methods: We recruited 69 patients in a prospective, open-label, add-on treatment study from six Italian and one German centers for pediatric and adolescent epilepsy care according to the following criteria: age 3 or above; focal or generalized seizures refractory to at least three previous antiepileptic drugs (AEDs), alone or in combination, secondary to neuronal migration disorders; two or more seizures per month in the last 6 months; use of another AED, but no more than three, at baseline. Informed consent from parents and/or caregivers was obtained at the time of enrollment.

Results: We enrolled 69 patients with a mean age of 15 years (range 3-43). Forty-three patients (62%) had a 50-99% seizure reduction, and two (3%) became seizure-free. Seizure frequency was unchanged in 18 (26%) and worsened in 6 (8.7%). Twenty-nine patients (42%) reported adverse side effects, whilst taking rufinamide. Irritability was the most common side effect (11 patients), followed by decreased appetite (10), mood shift (6), vomiting (5), drowsiness (4), and decreased attention (2). Blood levels of concomitant anticonvulsive drugs were transiently abnormal in 5 patients.

Conclusion: In our population of severely refractory epilepsy due to neuronal migration disorders, rufinamide appeared to be effective and generally well tolerated.
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http://dx.doi.org/10.1016/j.eplepsyres.2014.01.013DOI Listing
March 2014

Telomere shortening and telomere position effect in mild ring 17 syndrome.

Epigenetics Chromatin 2014 Jan 7;7(1). Epub 2014 Jan 7.

Cytogenetics and Molecular Genetics Unit, 'Bambino Gesù' Children's Hospital, IRCCS, Piazza S. Onofrio 4, 00165 Rome, Italy.

Background: Ring chromosome 17 syndrome is a rare disease that arises from the breakage and reunion of the short and long arms of chromosome 17. Usually this abnormality results in deletion of genetic material, which explains the clinical features of the syndrome. Moreover, similar phenotypic features have been observed in cases with complete or partial loss of the telomeric repeats and conservation of the euchromatic regions. We studied two different cases of ring 17 syndrome, firstly, to clarify, by analyzing gene expression analysis using real-time qPCR, the role of the telomere absence in relationship with the clinical symptoms, and secondly, to look for a new model of the mechanism of ring chromosome transmission in a rare case of familial mosaicism, through cytomolecular and quantitative fluorescence in-situ hybridization (Q-FISH) investigations.

Results: The results for the first case showed that the expression levels of genes selected, which were located close to the p and q ends of chromosome 17, were significantly downregulated in comparison with controls. Moreover, for the second case, we demonstrated that the telomeres were conserved, but were significantly shorter than those of age-matched controls; data from segregation analysis showed that the ring chromosome was transmitted only to the affected subjects of the family.

Conclusions: Subtelomeric gene regulation is responsible for the phenotypic aspects of ring 17 syndrome; telomere shortening influences the phenotypic spectrum of this disease and strongly contributes to the familial transmission of the mosaic ring. Together, these results provide new insights into the genotype-phenotype relationships in mild ring 17 syndrome.
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http://dx.doi.org/10.1186/1756-8935-7-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3892072PMC
January 2014

Early onset absence epilepsy with onset in the first year of life: a multicenter cohort study.

Epilepsia 2013 Oct;54 Suppl 7:66-9

Child Neuropsychiatry, Regional Epilepsy Center, Brescia, Italy.

Purpose: Absence epilepsy with onset before age 4 years, or early onset absence epilepsy (EOAE), has been rarely reported, and children with onset in the first year of life are considered almost exceptional. We aimed to report the clinical and electrophysiologic features of a cohort of children with absence epilepsy starting within the first year of life.

Methods: This was a multicenter study including patients with absence epilepsy starting within the first year of life and identified over a 20-year period (1991-2011).

Key Findings: We identified 16 patients with absence epilepsy starting within the first year of life with a mean follow-up of 6.4 years. Mean age at seizure onset was 10.3 ± (standard deviation)1.4 months (range 8-12). Two patients experienced rare tonic-clonic seizures that started later than the absences. None of the subjects had episodes of absence status epilepticus. Eleven subjects were seizure-free with the first antiepileptic drug. In eight children, therapy was withdrawn after a mean 3.2 years of treatment. None evolved into a different form of idiopathic generalized epilepsy. SLC2A1 gene analysis in 12 children (75%) failed to reveal glucose transporter 1 deficiency.

Significance: EOAE, including patients with onset within the first year of life, should be no more considered a distinct idiopathic generalized epilepsy (IGE) syndrome, as it shows electroclinical features, response to therapy, and prognosis similar to childhood absence epilepsy. Moreover, early age of onset is not predictive of GLUT-1 deficiency and genetic analysis may be therefore avoided in patients meeting strict inclusion criteria.
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http://dx.doi.org/10.1111/epi.12311DOI Listing
October 2013

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

Clinical Reasoning: a girl presenting with stiffness episodes during sleep, cafe-au-lait spots, and flecked retina.

Neurology 2013 Jan;80(5):e42-6

Pediatric Neurology Unit, Neuroscience Department, Tor Vergata University Hospital, Rome.

A 4-year-old girl who had been born of normal pregnancy and delivery and had an unremarkable family or personal history was referred to a neuropsychiatric department because of the appearance of peculiar nocturnal episodes. Parents described that their child abruptly became stiff during sleep. These episodes usually ranged from 20 to 40 seconds, and after that the child continued to sleep. Initially she presented 1 episode per week, but there was a progressive increase in frequency up to 3 to 4 times per night. The child never presented similar episodes while awake. Her examination revealed some café-au-lait spots, congenital microcephaly (3rd centile) and low stature for the age (10th centile). She did not present any neurologic deficit, but she failed to develop an age-appropriate speech, with a delay in the main language milestones.
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http://dx.doi.org/10.1212/WNL.0b013e31827f1346DOI Listing
January 2013

Lacosamide in pediatric and adult patients: comparison of efficacy and safety.

Seizure 2013 Apr 5;22(3):210-6. Epub 2013 Jan 5.

Department of Paediatrics, University of Chieti, Chieti, Italy.

Purpose: This multicenter, prospective study investigates the efficacy and safety of lacosamide adjunctive therapy in pediatric and adult patients with uncontrolled epilepsy.

Method: This study was carried out between September 2010 and December 2011 at 16 Italian and 1 German neurologic centers. Lacosamide was added to the baseline therapy at a starting dose of 1 mg/kg/day in patients aged <16 years (group A) and 100 mg daily in subjects aged 16 and older (group B), and titrated to the target dose, ranging from 3 to 12 mg/kg/day or from 100 to 600 mg daily, respectively. After completing the titration period, patients entered a 12-month maintenance period and they were followed up at 3, 6 and 12 months. The primary assessment of efficacy was based on the change from baseline in seizure frequency per 28 days and was evaluated at 3, 6 and 12 months as follows: number and proportion of 100% responders, 50% responders, non-responders and worsening patients. Safety evaluation was also performed at 3, 6 and 12 months.

Results: A total of 118 patients (59 group A, 59 group B) with uncontrolled generalized and focal epilepsy were enrolled. Patient mean±SD age was 15.9±6.80 years and the age range was 4-38 years. At 3-month evaluation, of 118 treated patients 56 subjects (47.4% group A; 47.4% group B; p=0.8537) experienced at least a 50% reduction in seizure frequency. At 6 and 12-month follow-up, the 50% responders were 57 (52.5% group A; 44.1% group B; p=0.4612) and 51 (47.4% group A; 39% group B; p=0.4573), respectively. Thirty-five subjects (30.5% group A; 28.8% group B; p=1) experienced side effects during the treatment period. The most common adverse events were dyspepsia for group A and dizziness for group B.

Conclusion: Lacosamide may be a useful and safe pharmacological treatment option for both pediatric and adult patients with uncontrolled seizures.
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http://dx.doi.org/10.1016/j.seizure.2012.12.009DOI Listing
April 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

PRRT2 is mutated in familial and non-familial benign infantile seizures.

Eur J Paediatr Neurol 2013 Jan 17;17(1):77-81. Epub 2012 Aug 17.

Neurology Unit, Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS, P.zza S. Onofrio 4, 00165 Rome, Italy.

Background: Mutations of protein-rich transmembrane protein 2 (PRRT2) were recently associated to benign familial infantile seizures (BFIS) (MIM 605751) and paroxysmal kinesigenic dyskinesias (PKD) (MIM12800).

Aims: To report mutations of PRRT2 in BFIS, infantile convulsions and choreoathetosis (ICCA), and in sporadic cases affected by benign infantile epilepsy (BIE).

Methods: A mutational screening of PRRT2 was performed in 5 families, and in 7 sporadic cases affected by BIE. All clinical and neurophysiological details were reviewed.

Results: Thirty-three members among 5 families were collected. Fifteen individuals had infantile seizures and one had infantile seizures followed by paroxysmal kinesigenic dyskinesia (PKD). We found the c.649_650InsC PRRT2 mutation in all tested patients (13 out of 15). Age at onset ranged from 3.5 to 10 months. Focal seizures, with or without secondary generalization, occurred mainly in cluster. One patient at the age of 11 years presented with PKD successfully treated with carbamazepine. All patients had a normal cognitive development. Two out of 7 non-familial cases (28.5%) carried a de novo PRRT2 mutation: the c.649_650InsC mutation in one with clustered seizures at the age of 5 months and an unreported c.718C-T p.R240X mutation in the other who, after cluster focal seizures at the age of 5 months, experienced absences at the age of 5 years.

Conclusion: Our findings emphasize that PRRT2 mutations might be responsible of both BFIS and ICCA, but might be causative also for sporadic cases of benign infantile seizures. The phenotypic spectrum comprises BFIS, ICCA, and PKD.
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http://dx.doi.org/10.1016/j.ejpn.2012.07.006DOI Listing
January 2013

Reflex myoclonic epilepsy in infancy: a multicenter clinical study.

Epilepsy Res 2013 Feb 20;103(2-3):237-44. Epub 2012 Jul 20.

Department of Pediatrics, University of Chieti, Chieti, Italy.

Purpose: To describe the clinical and electroencephalographic (EEG) features of reflex myoclonic epilepsy in infancy (RMEI) and long-term cognitive outcome.

Methods: We enrolled 31 children from 16 neuropediatric centres in Italy, who underwent clinical and video-EEG evaluation. Cognitive assessment was performed in all patients using standardized psychometric tests.

Results: The age at onset ranged from 3 to 24 months of age. Seizures were characterised in all patients by symmetric myoclonic seizures (MS), triggered by sudden unexpected acoustic (38.7%) or tactile stimuli (29%) or both (29%). Spontaneous attacks were reported in 32.2% of the cases. Ictal EEG showed generalized high-amplitude 3 Hz polyspike and wave discharges, synchronous with brief rhythmic bursts of electromyographic activity. Patients were re-evaluated after a period of 7.2 ± 5.6 years. The prognosis for seizure control was excellent in all cases and reflex MS disappeared spontaneously or after valproate treatment. The cognitive outcome was excellent in 90.3% of children.

Conclusions: RMEI appears to be a variety of idiopathic generalized epilepsy with specific features that occurs in developmentally normal children.
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http://dx.doi.org/10.1016/j.eplepsyres.2012.07.004DOI Listing
February 2013