A registry for Dravet syndrome: The Italian experience.

OBJECTIVES: We describe the Residras registry, dedicated to Dravet syndrome (DS) and to other phenotypes related to SCN1A mutations, as a paradigm of registry for rare and complex epilepsies. Our primary objectives are to present the tools and framework of the integrative platform, the main characteristics emerging from the patient cohort included in the registry, with emphasis on demographic, clinical outcome, and mortality. METHODS: Standardized data of enrolled pediatric and adult patients were collected in 24 Italian expert centers and regularly updated at least on a yearly basis. Patients were prospectively enrolled, at registry starting, but historical retrospective data were also included. RESULTS: At present, 281 individuals with DS and a confirmed SCN1A mutation are included. Most patients have data available on epilepsy (n = 263) and their overall neurological condition (n = 255), based on at least one follow-up update. Median age at first clinical assessment was 2 years (IQR 0-9) while at last follow-up was 11 years (IQR 5-18.5). During the 7-year activity of the registry, five patients died resulting in a mortality rate of 1.84 per 1000-person-years. When analyzing clinical changes over the first 5-year follow-up, we observed a significant difference in cognitive function (P < 0.001), an increased prevalence of behavioral disorders including attention deficit (P < 0.001), a significant worsening of language (P = 0.001), and intellectual disability (P < 0.001). SIGNIFICANCE: The Residras registry represents a large collection of standardized national data for the DS population. The registry platform relies on a shareable and interoperable framework, which promotes multicenter high-quality data collection. In the future, such integrated platform may represent an invaluable asset for easing access to cohorts of patients that may benefit from clinical trials with emerging novel therapies, for drug safety monitoring, and for delineating natural history. Its framework makes it improvable based on growing experience with its use and easily adaptable to other rare and complex epilepsy syndromes.

PRRT2 benign familial infantile seizures (BFIS) with atypical evolution to encephalopathy related to status epilepticus during sleep (ESES).

PURPOSE: Heterozygous variants in PRRT2 are mostly associated with benign phenotypes, being the major genetic cause of benign familial infantile seizures (BFIS), as well as in paroxysmal disorders. We report two children from unrelated families with BFIS that evolved to encephalopathy related to status epilepticus during sleep (ESES). METHODS AND RESULTS: Two probands presented with focal motor seizures at 3 months of age, with a limited course. Both children presented, at around 5 years of age, with centro-temporal interictal epileptiform discharges with a source in the frontal operculum, markedly activated by sleep, and associated with stagnation on neuropsychological development. Whole-exome sequencing and co-segregation analysis revealed a frameshift mutation c.649dupC in the proline-rich transmembrane protein 2 (PRRT2) in both probands and all affected family members. CONCLUSION: The mechanism leading to epilepsy and the phenotypic variability of PRRT2 variants remain poorly understood. However, its wide cortical and subcortical expression, in particular in the thalamus, could partially explain both the focal EEG pattern and the evolution to ESES. No variants in the PRRT2 gene have been previously reported in patients with ESES. Due to the rarity of this phenotype, other possible causative cofactors are likely contributing to the more severe course of BFIS in our probands.

Adaptive behaviour in adolescents and adults with Dravet syndrome.

AIM: To explore the feasibility of using an adaptive behaviour profile (ABP) assessment generated from a well-known measure-the Vineland Adaptive Behavior Scales, Second Edition (VABS-II)-as an instrument for outcome measures in adolescents and adults with Dravet syndrome. METHOD: We administered the VABS-II to 35 adolescents and adults with Dravet syndrome (15 males; mean age 24 years, SD 8 years, range: 12-46 years) and collected epilepsy history and neurological features at the time of assessment. We conducted a cross-sectional analysis of VABS-II raw scores and performed cluster analysis to identify different subgroups. We then explored possible relationships between clinical and epilepsy features, ABPs, and age. RESULTS: Most participants obtained the minimum standard scores in the various VABS-II subdomains, while the raw score analysis outlined interindividual and intraindividual differences among skills. We found two subpopulations: one with a 'lower' ABP and one with a 'higher' ABP, corresponding respectively to individuals in whom myoclonic seizures or generalized spike-and-wave activity were present ('complete phenotype') or absent ('incomplete phenotype') on electroencephalography. INTERPRETATION: This study further delineates the natural history of Dravet syndrome. The assessment of an ABP through the VABS-II raw score analysis provides a means by which to illustrate profiles of adaptive behaviour in adolescents and adults with Dravet syndrome but shows limitations related to poor sensitivity in measuring fine clinical details. There is a need for new and more specific tools to monitor patients with developmental and epileptic encephalopathies. WHAT THIS PAPER ADDS: Most adults with Dravet syndrome obtained the minimum standard scores in the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) subdomains. The VABS-II raw score analysis showed interindividual and intraindividual variability. Individuals with myoclonic seizures and/or generalized spike-and-wave activity on electroencephalography showed a worse adaptive behaviour profile.

Natural History Study of STXBP1-Developmental and Epileptic Encephalopathy Into Adulthood.

BACKGROUND AND OBJECTIVES: Pathogenic STXBP1 variants cause a severe early-onset developmental and epileptic encephalopathy (STXBP1-DEE). We aimed to investigate the natural history of STXBP1-DEE in adults focusing on seizure evolution, the presence of movement disorders, and the level of functional (in)dependence. METHODS: In this observational study, patients with a minimum age of 18 years carrying a (likely) pathogenic STXBP1 variant were recruited through medical genetics departments and epilepsy centers. Treating clinicians completed clinical questionnaires and performed semistructured video examinations while performing tasks from the (modified) Unified Parkinson Disease Rating Scale when possible. RESULTS: Thirty adult patients were included for summary statistics, with video recordings available for 19 patients. The median age at last follow-up was 24 years (range 18-58 years). All patients had epilepsy, with a median onset age of 3.5 months. At last follow-up, 80% of adults had treatment-resistant seizures despite long periods of seizure freedom in 37%. Tonic-clonic, focal, and tonic seizures were most frequent in adults. Epileptic spasms, an unusual feature beyond infancy, were present in 3 adults. All individuals had developmental impairment. Periods of regression were present in 59% and did not always correlate with flare-ups in seizure activity. Eighty-seven percent had severe or profound intellectual disability, 42% had autistic features, and 65% had significant behavioral problems. Video examinations showed gait disorders in all 12 patients able to walk, including postural abnormalities with external rotation of the feet, broad-based gait, and asymmetric posture/dystonia. Tremor, present in 56%, was predominantly of the intention/action type. Stereotypies were seen in 63%. Functional outcome concerning mobility was variable ranging from independent walking (50%) to wheelchair dependence (39%). Seventy-one percent of adults were nonverbal, and all were dependent on caregivers for most activities of daily living. DISCUSSION: STXBP1-DEE warrants continuous monitoring for seizures in adult life. Periods of regression are more frequent than previously established and can occur into adulthood. Movement disorders are often present and involve multiple systems. Although functional mobility is variable in adulthood, STXBP1-DEE frequently leads to severe cognitive impairments and a high level of functional dependence. Understanding the natural history of STXBP1-DEE is important for prognostication and will inform future therapeutic trials.

Ictal Electroencephalographic Characteristics of Nodding Syndrome: A Comparative Case-Series from South Sudan, Tanzania, and Uganda.

Nodding syndrome (NS) is a poorly understood form of childhood-onset epilepsy that is characterized by the pathognomonic ictal phenomenon of repetitive vertical head drops. To evaluate the underlying ictal neurophysiology, ictal EEG features were evaluated in nine participants with confirmed NS from South Sudan, Tanzania, and Uganda and ictal presence of high frequency gamma oscillations on scalp EEG were assessed. Ictal EEG during the head nodding episode predominantly showed generalized slow waves or sharp-and-slow wave complexes followed by electrodecrement. Augmentation of gamma activity (30-70 Hz) was seen during the head nodding episode in all the participants. We confirm that head nodding episodes in persons with NS from the three geographically distinct regions in sub-Saharan Africa share the common features of slow waves with electrodecrement and superimposed gamma activity. ANN NEUROL 2022;92:75-80.

Epilepsy features in ARID1B-related Coffin-Siris syndrome.

Coffin-Siris syndrome (CSS) is a rare congenital malformation syndrome, caused by mutations in the ARID1B gene in over half of the cases. While the clinical characteristics of the syndrome have been increasingly described, a detailed evaluation of the epileptic phenotype in patients with ARID1B alterations and CSS has not been approached yet. We report seven patients with ARID1B-related CSS, focusing on epilepsy and its electroclinical features. The evolution of epilepsy and EEG findings of children with CSS are described and compared with patients previously reported in the literature. The patients described here reveal common features, consistent with those of patients previously described in the literature. The epilepsy phenotype of CSS due to ARID1B pathogenic variants may be described as focal epilepsy with seizures, variable in frequency, arising from motor areas, with onset in the first years of life and susceptibility to fever, and interictal perisylvian (centrotemporal) epileptiform abnormalities that are enhanced during sleep with possible evolution to an EEG pattern of continuous spike and wave during sleep (without documented developmental regression). Additional information emerging from other patients is needed to confirm this definition.

Migrating Focal Seizures and Myoclonic Status in ARV1-Related Encephalopathy.

OBJECTIVE: To report longitudinal clinical, EEG, and MRI findings in 2 sisters carrying compound heterozygous ARV1 mutations and exhibiting a peculiar form of developmental and epileptic encephalopathy (DEE). Neuropathologic features are also described in one of the sisters. METHODS: Clinical course description, video-EEG polygraphic recordings, brain MRI, skin and muscle biopsies, whole-exome sequencing (WES), and brain neuropathology. RESULTS: Since their first months of life, both girls exhibited severe axial hypotonia, visual inattention, dyskinetic movements, severe developmental delay, and slow background EEG activity. Intractable nonmotor seizures started in both at the eighth month of life, exhibiting the electroclinical characteristics of epilepsy of infancy with migrating focal seizures (EIMFS). In the second year of life, continuous epileptiform EEG activity of extremely high amplitude appeared in association with myoclonic status, leading to severely impaired alertness and responsiveness. Repeated brain MRI revealed progressive atrophic changes and severe hypomyelination. WES identified a compound heterozygous in the ARV1 gene [(p.Ser122Glnfs*7) and (p.Trp163*)] in one patient and was subsequently confirmed in the other. Both sisters died prematurely during respiratory infections. Postmortem neuropathologic examination of the brain, performed in one, revealed atrophic brain changes, mainly involving the cerebellum. CONCLUSIONS: This report confirms that biallelic ARV1 mutations cause a severe form of DEE and adds epilepsy with migrating focal seizures and myoclonic status to the spectrum of epilepsy phenotypes. Considering the potential role of human ARV1 in glycosylphosphatidylinositol (GPI) anchor biosynthesis, this severe syndrome can be assigned to the group of inherited GPI deficiency disorders, with which it shares remarkably similar clinical and neuroimaging features. ARV1 should be considered in the genetic screening of individuals with EIMFS.

Remote Teamwork Management of NORSE During the COVID-19 Lockdown.

New-onset refractory status epilepticus (NORSE) is rare condition, and sharing knowledge is vital in its management, based on strict collaboration between multiple specialists, continuous EEG (c-EEG) monitoring, and prompt therapy modification. The coronavirus disease 2019 (COVID-19) pandemic challenged many of these established practices because of "social distancing" measures, making it necessary to work around physical restrictions. We report a case of a 10-year-old with NORSE admitted in a pediatric intensive-care unit and monitored with c-EEG and amplitude-integrated EEG. The monitoring interface was livestreamed using videoconference web-based platforms allowing remote viewing. Multiple daily web meetings took place between team members, where real-time therapy response was evaluated and confronted with medium-term trends in the epileptic activity, dictating further treatment and diagnostic steps. In addition to the known use of telemedicine in chronic conditions, we report how its use can be exploited to treat urgent conditions such as NORSE. By taking advantage of new tools and virtual environments, we were able to share treatment and diagnostic decisions and guarantee real-time therapy adjustments and a coherent course in treatment despite restrictions necessary for the COVID-19 pandemic. The constant specialist monitoring and the coherent and on-time communication of the patient's condition relieved the family stress, usually complained in these situations.

Consensus protocol for EEG and amplitude-integrated EEG assessment and monitoring in neonates.

The aim of this work is to establish inclusive guidelines on electroencephalography (EEG) applicable to all neonatal intensive care units (NICUs). Guidelines on ideal EEG monitoring for neonates are available, but there are significant barriers to their implementation in many centres around the world. These include barriers due to limited resources regarding the availability of equipment and technical and interpretive round-the-clock personnel. On the other hand, despite its limitations, amplitude-integrated EEG (aEEG) (previously called Cerebral Function Monitor [CFM]) is a common alternative used in NICUs. The Italian Neonatal Seizure Collaborative Network (INNESCO), working with all national scientific societies interested in the field of neonatal clinical neurophysiology, performed a systematic literature review and promoted interdisciplinary discussions among experts (neonatologists, paediatric neurologists, neurophysiologists, technicians) between 2017 and 2020 with the aim of elaborating shared recommendations. A consensus statement on videoEEG (vEEG) and aEEG for the principal neonatal indications was established. The authors propose a flexible frame of recommendations based on the complementary use of vEEG and aEEG applicable to the various neonatal units with different levels of complexity according to local resources and specific patient features. Suggestions for promoting cooperation between neonatologists, paediatric neurologists, and neurophysiologists, organisational restructuring, and teleneurophysiology implementation are provided.

SYNGAP1-DEE: A visual sensitive epilepsy.

OBJECTIVE: To further delineate the electroclinical features of individuals with SYNGAP1 pathogenic variants. METHODS: Participants with pathogenic SYNGAP1 variants and available video-electroencephalogram (EEG) recordings were recruited within five European epilepsy reference centers. We obtained molecular and clinical data, analyzed EEG recordings and archived video-EEGs of seizures and detailed characteristics of interictal and ictal EEG patterns for every patient. RESULTS: We recruited 15 previously unreported patients and analyzed 72 EEGs. Two distinct EEG patterns emerged, both triggered by eye closure. Pattern 1 (14/15 individuals) consisted of rhythmic posterior/diffuse delta waves appearing with eye-closure and persisting until eye opening (strongly suggestive of fixation-off sensitivity). Pattern 2 (9/15 individuals) consisted of diffuse polyspike-and-wave discharges triggered by eye closure (eye-closure sensitivity). Both patterns presented in 8/15. Including archived video-EEG clips of seizures from 9/15 patients, we analyzed 254 seizures. Of 224 seizures experienced while awake, 161 (72%) occurred at or following eye closure. In 119/161, pattern 1 preceded an atypical absence, myoclonic seizure or myoclonic absence; in 42/161, pattern 2 was associated with eyelid myoclonia, absences and myoclonic or atonic seizures. CONCLUSIONS: Fixation-off and eye closure were the main triggers for seizures in this SYNGAP1 cohort. SIGNIFICANCE: Combining these clinical and electroencephalographic features could help guide genetic diagnosis.

Epilepsy and movement disorders in CDG: Report on the oldest-known MOGS-CDG patient.

Congenital glycosylation disorders (CDG) are inherited metabolic diseases due to defective glycoprotein and glycolipid glycan assembly and attachment. MOGS-CDG is a rare disorder with seven patients from five families reported worldwide. We report on a 19-year-old girl with MOGS-CDG. At birth she presented facial dysmorphism, marked hypotonia, and drug-resistant tonic seizures. In the following months, her motility was strongly limited by dystonia, with forced posture of the head and of both hands. She showed a peculiar hyperkinetic movement disorder with a rhythmic and repetitive pattern repeatedly documented on EEG-polygraphy recordings. Brain MRI showed progressive cortical and subcortical atrophy. Epileptic spasms appeared in first months and ceased by the age of 7 years, while tonic seizures were still present at last assessment (19 years). We report the oldest-known MOGS-CDG patient and broaden the neurological phenotype of this CDG.

Efficacy and safety of Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: A real-world study.

OBJECTIVE: Dravet syndrome (DS) is a drug-resistant, infantile onset epilepsy syndrome with multiple seizure types and developmental delay. In recently published randomized controlled trials, fenfluramine (FFA) proved to be safe and effective in DS. METHODS: DS patients were treated with FFA in the Zogenix Early Access Program at four Italian pediatric epilepsy centers. FFA was administered as add-on, twice daily at an initial dose of 0.2 mg/kg/d up to 0.7 mg/kg/d. Seizures were recorded in a diary. Adverse events and cardiac safety (with Doppler echocardiography) were investigated every 3 to 6 months. RESULTS: Fifty-two patients were enrolled, with a median age of 8.6 years (interquartile range [IQR] = 4.1-13.9). Forty-five (86.5%) patients completed the efficacy analysis. The median follow-up was 9.0 months (IQR = 3.2-9.5). At last follow-up visit, there was a 77.4% median reduction in convulsive seizures. Thirty-two patients (71.1%) had a ≥50% reduction of convulsive seizures, 24 (53.3%) had a ≥75% reduction, and five (11.1%) were seizure-free. The most common adverse event was decreased appetite (n = 7, 13.4%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed. There was no correlation between type of genetic variants and response to FFA. SIGNIFICANCE: In this real-world study, FFA provided a clinically meaningful reduction in convulsive seizure frequency in the majority of patients with DS and was well tolerated.

Gait abnormalities in people with Dravet syndrome: A cross-sectional multi-center study.

OBJECTIVE: To quantify gait abnormalities in people with Dravet syndrome (DS). METHODS: Individuals with a confirmed diagnosis of DS were enrolled, and stratified according to knee flexion at initial contact (IC) and range of motion (ROM) during stance (atypical crouch: knee flexion >20° at IC and knee ROM >15° during stance; straight: knee flexion <20° at IC). A 1D ANOVA (α = 0.05) was used to test statistical differences among the joint kinematics and spatio-temporal parameters of the cohort and an age-matched control group. Clinical (neurological and orthopaedic evaluation) and anamnestic data (seizure type, drugs, genetic mutation) were collected; distribution between the two gait phenotypes was assessed with the Fisher exact test and, for mutation, with the chi-squared test (p < 0.05). Linear regression between maximum knee flexion and normalised walking speed was calculated. RESULTS: Seventy-one subjects were enrolled and evaluated with instrumented gait analysis. Fifty-two were included in final analysis (mean age 13.8 ± 7.3; M 26). Two gait patterns were detected: an atypical crouch gait (34.6%) with increased ankle, knee and hip flexion during stance, and reduced walking speed and stride length not associated with muscle-tendon retractions; and a pattern resembling those of healthy age-matched controls, but still showing reduced walking speed and stride length. No differences in clinical or anamnestic data emerged between the two groups. SIGNIFICANCE: Objectively quantified gait in DS shows two gait patterns with no clear-cut relation to clinical data. Kinematics abnormalities may be related to stabilization issues. These findings may guide rehabilitative and preventive measures.

Dravet syndrome: Early electroclinical findings and long-term outcome in adolescents and adults.

To describe the outcome of Dravet syndrome (DS) in adolescents and adults we conducted a longitudinal retrospective study of two independent cohorts of 34 adolescents (group 1) and 50 adults (group 2). In both cohorts, we collected information about genetic mutation, and semiology of seizures at onset and during disease course. At the last evaluation, we considered the following features: epilepsy (distinguishing myoclonic/complete and nonmyoclonic/incomplete phenotype), neurologic signs, intellectual disability (ID), and behavioral disorders. Moreover, in both cohorts, we performed a correlation analysis between early characteristics of the disease and the outcome of DS with regard to seizure persistence, ID, behavioral disorder, and neurologic impairment at last evaluation. Group 1 includes 22 adolescents with complete form of DS and 12 with incomplete form; group 2 includes 35 adults with complete form and 15 with incomplete form. The seizures persisted in 73.6% of adolescents and in 80% of adults, but epilepsy severity progressively decreased through age. Seizure persistence correlated with the complete phenotype and with the occurrence of reflex seizures. At last evaluation, ID was moderate or severe in 70.5% of adolescents and in 80% of adults. The most severe cognitive and motor impairment was observed in patients with persisting seizures. The severity of cognition, language, and neurologic impairment at last evaluation correlated statistically with the complete phenotype. The study confirms that the global outcome of DS is poor in most cases, albeit epilepsy severity decreases throughout adulthood. The improvement of epilepsy throughout ages is not associated with improvement in intellectual abilities and motor skills; this confirms that the unfavorable outcome is not a pure consequence of epilepsy.

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

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.

Diaper changing-induced reflex seizures in CDKL5-related epilepsy.

Mutations in the CDKL5 (cyclin-dependent kinase-like-5) gene are known to determine early-onset drug resistant epilepsies and severe cognitive impairment with absent language, hand stereotypies, and deceleration of head growth. Reflex seizures are epileptic events triggered by specific stimuli and diaper changing is a very rare triggering event, previously described in individual cases of both focal and unclassified epilepsy, as well as in Dravet syndrome. Our aim was to describe diaper changing-induced reflex seizures as one of the presenting features in a case of CDKL5-related epilepsy, providing video-EEG documentation and focusing discussion on hyperexcitability determined by the disease. [Published with video sequence on www.epilepticdisorders.com].

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

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.

Epilepsy in ring chromosome 20 syndrome.

OBJECTIVE: Ring chromosome 20 syndrome is characterized by severe, drug resistant childhood onset epilepsy, often accompanied by cognitive impairment. We characterized the electro-clinical phenotype and the long-term course of epilepsy in a large series. METHODS: We reviewed the electro-clinical phenotype of 25 patients (aged 8-59 years), and assessed the relationship between epilepsy severity and clinical and/or genetic variables. We also searched for reports of patients diagnosed with r(20) syndrome in the literature, included those whose clinical information was sufficiently accurate, and compared their clinical features with the ones of our patients. RESULTS: Epilepsy exhibited an age dependent course. When seizure onset occurred in childhood (21 patients), terrifying hallucinations associated with focal motor seizures, often sleep-related (8 patients), or dyscognitive seizures (13 patients), were prominent features, often evolving into epileptic encephalopathy associated with non-convulsive status epilepticus (11 patients). In the long-term, progressive stabilization of drug resistant epilepsy associated with non-convulsive status epilepticus, focal seizures with motor and autonomic features, and eyelid myoclonia were noticed. Epilepsy onset in adolescence (3 patients) was accompanied by a milder developmental course, dyscognitive seizures and non-convulsive status epilepticus, and no cognitive decline. Only three older patients became seizure free (>5 years) We found statistically significant correlations between age at epilepsy onset and cognitive level. Although in the study cohort the relationship between r(20) ratio, age at epilepsy onset and cognitive level was non-statistically significant, it reached significance evaluating the larger cohort of patients previously published. SIGNIFICANCE: In ring(20) syndrome, epilepsy has an age dependent course and a worse outcome when age at seizure onset is earlier. The r(20) ratio and severity of cognitive impairment appear to be directly related to each other and inversely correlated with the age at epilepsy onset.