Cerebral venous thrombosis and deep medullary vein thrombosis: Padua experience over the last two decades.

BACKGROUND: Cerebral venous thrombosis (CVT) is a cerebrovascular disorder that accounts for 20% of perinatal strokes. CVT incidence ranges from 0.67 to 1.12 per 100,000 newborns, while the incidence of "deep medullary vein thrombosis" (DMVT), a subtype of CVT, cannot be accurately estimated. This study aims to analyze the case history of CVT in the neonatal period, with a specific focus on DMVT. MATERIALS AND METHODS: Newborns diagnosed with CVT, with or without DMVT, between January 2002 and April 2023, were collected using the Italian Registry of Infantile Thrombosis (RITI). Cerebral MRIs were reviewed by an expert neuroradiologist following a standardized protocol. RESULTS: Forty-two newborns with CVT were identified, of which 27/42 (64%) had CVT, and the remaining 15/42 (36%) had DMVT (isolated DMVT in 9/15). Symptom onset occurred in the first week of life (median 8 days, IQR 4-14) with a male prevalence of 59%. The most common risk factors for CVT were complicated delivery (38%), prematurity (40%), congenital heart diseases (48%), and infections (40%). Seizures were the predominant presenting symptom in 52% of all cases. Hemorrhagic infarction was higher in cases with isolated DMVT (77%) compared to patients with CVT without DMVT (p = 0.013). Antithrombotic treatment was initiated in 36% of patients. Neurological impairment was observed in 48% of cases at discharge, while 18 out of 31 infants (58%) presented one or more neurological deficits at long term follow up.     Conclusion: DMVT occurs in over a third of neonates with CVT. Multicentric studies are essential to establish standardized protocols for therapy, neuroimaging, and follow-up in these patients.

Primary Stabbing Headache in Children and Adolescents.

BACKGROUND: Primary Stabbing Headache (PSH) is characterized by brief, focal, and paroxysmal pain ("stab"), occurring sporadically or in clusters. Data on pediatric cases are poor. METHODS: We performed a comprehensive literature review by searching PubMed, Cochrane, and Embase in order to collect pediatric case reports and case series of PSH. RESULTS: A total of 12 out of 162 articles assessed for eligibility were finally included. The prevalence of PSH and probable PSH varies from 2.5 to 10% among children with primary headaches and it is higher among children aged less than 6 years old. The mean age of onset is between 7 and 11 years of age. Attack duration greatly varies, ranging from a few seconds to several minutes. The intensity of pain is usually from moderate to severe. Associated symptoms are infrequent but may be observed (mainly photophobia, vertigo, nausea, and vomiting). Neuroradiological findings are usually unremarkable; EEG may show sporadic epileptiform abnormalities (up to 30% of cases). Preventive therapy is anecdotal, including treatment with indomethacin, trazodone, valproate, and amitriptyline. CONCLUSION: PSH is a common but still underdiagnosed entity among children with primary headaches; further and larger cohort studies are needed to better assess, in particular, prognosis and response to therapy.

Corrigendum: The new Italian registry of infantile thrombosis (RITI): a reflection on its journey, challenges and pitfalls.

[This corrects the article DOI: 10.3389/fped.2023.1094246.].

PICU Admission of Children for Status Epilepticus: Is There a Different Approach Between Referral and Second-Level Hospitals in an Italian Region?

Appropriate status epilepticus (SE) management is key to minimize admission to the pediatric intensive care unit (PICU). We retrospectively describe 115 children admitted to the PICU of the tertiary-care referral hospital of Padova for seizures, SE, and SE-related complications (59% from second-level hospitals, 41% from the referral hospital) and compare SE management among hospitals. Compared with the referral center, in second-level hospitals, anesthetics were more often administered as first/second drug (P < .001), and intubation was more frequent (P < .001). Intubation was significantly associated with SE onset at home (P = .045) and benzodiazepine-associated respiratory depression (P = .044). There was no association between intubation and SE duration, etiology, PICU length of stay, and morbidity at discharge. In conclusion, adherence to treatment protocols on SE management after the first-line drug differs between referral center and second-level hospitals. Lack of association with SE characteristics and patient's outcome suggests PICU admission could be due to inappropriate invasive management.

Role of Vagus Nerve Stimulation in Refractory and Super Refractory Status Epilepticus: A Pediatric Case Series.

BACKGROUND: Status epilepticus is a life-threatening condition that is defined as refractory (RSE) when the seizure activity continues despite treatment with benzodiazepine and a second appropriate treatment. Super refractory status epilepticus (SRSE) is an RSE that persists or recurs for ≥24 h. Few papers have reported the outcomes of pediatric patients affected by RSE and SRSE and treated with neuromodulation therapies. Vagus nerve stimulation (VNS) is an approved treatment for drug-resistant epilepsy. We present our findings of pediatric patients treated with VNS for RSE/SRSE. METHODS: We present a case series of seven consecutive pediatric patients treated with VNS for SRSE since 2012 by a single surgeon in Monza and Padua. A rapid titration was started soon after implantation. We considered electroclinical data before and after VNS implantation and at the last follow-up. RESULTS: We achieved the resolution of SRSE in five out of seven patients in a mean time of two weeks. At the last follow-up, these patients had a significant reduction of seizure burden without any relapse of SE. DISCUSSION AND CONCLUSIONS: Based on our limited findings, we discuss the potential role of VNS therapy in similar but distinct clinical contexts. For patients with drug-resistant epilepsy and RSE/SRSE, prompt VNS consideration is suggested, offering rapid responses and potentially reducing pharmacological load. Meanwhile, in NORSE/FIRES, we suggest early neuromodulation during the acute phase if standard treatments prove ineffective or not tolerated. This approach may leverage VNS's potential anti-inflammatory effects and neuromodulation, enhancing patient-specific treatments. Expanding case studies and prolonged follow-ups are recommended to strengthen these clinical insights.

Treatment of Frequent or Chronic Primary Headaches in Children and Adolescents: Focus on Acupuncture.

BACKGROUND: Acupuncture is a spreading and promising intervention, which has proven to be very useful in the treatment and prevention of chronic pain, in particular chronic headaches, in adults; the literature about the treatment of pediatric chronic headaches is scarce. In addition, few guidelines advise its use in children. The aim of this review is to collect all relevant studies with available data about the use, effect, and tolerability of acupuncture as a treatment for pediatric primary headaches. METHODS: This is a narrative review based on eight studies selected from 135 papers including pediatric cases treated with acupuncture for headache. RESULTS: Despite the differences in tools, procedures, and application sites, acupuncture demonstrated a positive effect on both the frequency and intensity of headaches and was well tolerated. There are no studies considering the long-term efficacy of acupuncture. CONCLUSION: Further additional studies are needed on acupuncture in children and adolescents, with larger series and standardized procedures, in order to better assess efficacy, tolerability, and long-term prognosis and to define guidelines for the use of this promising and safe treatment. It is particularly relevant to identify safe and well-tolerated treatment options in pediatric patients affected by recurrent and debilitating headaches.

Alemtuzumab following natalizumab is more effective in adult-onset than paediatric-onset multiple sclerosis.

Background: Paediatric-onset multiple sclerosis (POMS) therapeutic approach derives from of adult-onset multiple sclerosis (AOMS) tailored algorithms. Objectives: To evaluate in a common clinical scenario the efficacy and safety of alemtuzumab (ALZ) in POMS and AOMS. Methods: All patients switching from natalizumab (NTZ) to ALZ for safety concerns (high anti-John Cunningham Virus Antibody Index value, anti-JCV Index) were enrolled in this single-centre, retrospective, case-control open-label study. Results: Ten POMS and 27 AOMS were followed up for 51.3 months. After month 12, we found a lower risk of clinical or radiological relapses among AOMS patients and among patients with older age at ALZ (both p < 0.05). Survival analysis revealed an increased risk of relapse in POMS compared with AOMS (logrank p = 0.00498) and patients starting ALZ before age 22.75 years than the elder ones (logrank p = 0.0018). Survival analysis did not disclose any difference between AOMS and POMS (logrank p = 0.27) in terms of progression independent of any relapse activity (PIRA). In addition, no evidence of relapse-associated worsening was observed. Autoimmune events were reported by 5 AOMS and no POMS (29.4% versus 0.0%, p = 0.057), and survival analysis was not significant (logrank p = 0.0786). Conclusion: ALZ seems more effective in AOMS than in POMS following NTZ. These findings underrate ALZ effectiveness when shifting from NTZ in POMS.

Aesthetic transaxillary subpectoral placement of vagus nerve stimulator in children and young adults: A technical note.

INTRODUCTION: Vagus nerve stimulation (VNS) is a neuromodulation therapy for drug-resistant epilepsy (DRE), refractory status epilepticus, and treatment-resistant depression. The lead is tunneled into the subcutaneous space and connected to the generator, which is usually implanted in a subcutaneous pocket below the clavicle. Surgical complications in the chest region include skin breakdown or infection. An alternative approach is to perform a subclavear subpectoral implantation. In our surgical series, we report a new aesthetic implantation method for VNS generators in children and young patients: the transaxillary subpectoral placement. MATERIALS AND METHODS: From May 2021 to May 2023, 10 vagus nerve stimulation generators were placed subpectorally with a transaxillary approach by the authors. We considered operative time, surgical complications such as blood loss, infections, device migration, pain, and adverse events at follow-up. RESULTS: In this surgical series, we reviewed all cases of subpectoral implantation of VNS generators in children and young adults at our institution in the last 2 years. All patients were treated with subpectoral Sentiva 1000 (Livanova PLC) insertion with axillary access by a neurosurgeon and a pediatric surgeon. The operative time was slightly longer compared to the traditional subcutaneous implant. All generators reported impedances within the optimal range. Blood loss was not significant and no other perioperative complications were reported. Patients and families were highly satisfied with the outcomes in terms of comfort and aesthetic results after surgery and at the last follow-up. No cases of infection occurred, and no malfunctions or displacements of the generator were registered at clinical follow-up. CONCLUSION: The transaxillary subpectoral placement of theVNS generator is an aesthetic and anatomic approach, which provides several benefits to children and young adults.

Electroclinical Features in Two Novel STRADA Patients and a Functional Yeast Assay for the Validation of Missense STRADA Mutations.

Loss of function of the STRADA gene, an upstream mTOR inhibitor, causes a rare neurodevelopmental disorder characterized by polyhydramnios, megalencephaly, and symptomatic epilepsy (PMSE syndrome). Patients display a homogeneous phenotype including early-onset drug-resistant epilepsy, severe psychomotor delay, multisystemic comorbidities, and increased risk of premature death. The administration of sirolimus, an mTOR inhibitor, is helpful in controlling seizures in this syndrome. We report the electroclinical phenotype of two novel patients and the development of a yeast model to validate the pathogenicity of missense variants. Patient 1 harbored a missense STRADA variant and had a peculiar electroclinical phenotype with a relatively mild epilepsy course. Patient 2 harbored a truncating STRADA variant and showed a typical PMSE phenotype and a favorable response to early treatment with sirolimus. When we modeled the p.(Ser264Arg) STRADA change in its yeast homolog SPS1, it impaired SPS1 function. The results underlie the importance of a timely molecular diagnosis in these patients and show that yeast is a simple yet effective model to validate the pathogenicity of missense variants.

The maturation of aperiodic EEG activity across development reveals a progressive differentiation of wakefulness from sleep.

During development, the brain undergoes radical structural and functional changes following a posterior-to-anterior gradient, associated with profound changes of cortical electrical activity during both wakefulness and sleep. However, a systematic assessment of the developmental effects on aperiodic EEG activity maturation across vigilance states is lacking, particularly regarding its topographical aspects. Here, in a population of 160 healthy infants, children and teenagers (from 2 to 17 years, 10 subjects for each year), we investigated the development of aperiodic EEG activity in wakefulness and sleep. Specifically, we parameterized the shape of the aperiodic background of the EEG Power Spectral Density (PSD) by means of the spectral exponent and offset; the exponent reflects the rate of exponential decay of power over increasing frequencies and the offset reflects an estimate of the y-intercept of the PSD. We found that sleep and development caused the EEG-PSD to rotate over opposite directions: during wakefulness the PSD showed a flatter decay and reduced offset over development, while during sleep it showed a steeper decay and a higher offset as sleep becomes deeper. During deep sleep (N2, N3) only the spectral offset decreased over age, indexing a broad-band voltage reduction. As a result, the difference between values in deep sleep and those in both light sleep (N1) and wakefulness increased with age, suggesting a progressive differentiation of wakefulness from sleep EEG activity, most prominent over the frontal regions, the latest to complete maturation. Notably, the broad-band spectral exponent values during deep sleep stages were entirely separated from wakefulness values, consistently across developmental ages and in line with previous findings in adults. Concerning topographical development, the location showing the steepest PSD decay and largest offset shifted from posterior to anterior regions with age. This shift, particularly evident during deep sleep, paralleled the migration of sleep slow wave activity and was consistent with neuroanatomical and cognitive development. Overall, aperiodic EEG activity distinguishes wakefulness from sleep regardless of age; while, during development, it reveals a postero-anterior topographical maturation and a progressive differentiation of wakefulness from sleep. Our study could help to interpret changes due to pathological conditions and may elucidate the neurophysiological processes underlying the development of wakefulness and sleep.

Deep Medullary Vein Thrombosis in Newborns: A Systematic Literature Review.

BACKGROUND: Deep medullary vein (DMV) thrombosis is a rare cause of brain damage in both preterm and full-term neonates. In this study, we aimed to collect data on clinical and radiological presentation, treatment, and outcome of neonatal DMV thrombosis. METHODS: Systematic literature review on neonatal DMV thrombosis was carried out in PubMed, ClinicalTrial.gov, Scopus, and Web of Science up to December 2022. RESULTS: Seventy-five published cases of DMV thrombosis were identified and analysed (preterm newborns were 46%). Neonatal distress, respiratory resuscitation, or need for inotropes were present in 34/75 (45%) of patients. Signs and symptoms at presentation included seizures (38/75, 48%), apnoea (27/75, 36%), lethargy or irritability (26/75, 35%). At magnetic resonance imaging (MRI), fan-shaped linear T2 hypointense lesions were documented in all cases. All had ischaemic injuries, most often involving the frontal (62/74, 84%) and parietal lobes (56/74, 76%). Signs of haemorrhagic infarction were present in 53/54 (98%). Antithrombotic treatment was not mentioned in any of the studies included. Although mortality was low (2/75, 2.6%), a large proportion of patients developed neurological sequelae (intellectual disability in 19/51 [37%] and epilepsy in 9/51 [18%] cases). CONCLUSIONS: DMV thrombosis is rarely identified in the literature, even if it is possibly under-recognized or under-reported. Presentation in neonatal age is with seizures and non-specific systemic signs/symptoms that often cause diagnostic delay, despite the pathognomonic MRI picture. The high rate of morbidity, which determines significant social and health costs, requires further in-depth studies aimed at earlier diagnosis and evidence-based prevention and therapeutic strategies.

Sleep spindles across youth affected by schizophrenia or anti-N-methyl-D-aspartate-receptor encephalitis.

Background: Sleep disturbances are intertwined with the progression and pathophysiology of psychotic symptoms in schizophrenia. Reductions in sleep spindles, a major electrophysiological oscillation during non-rapid eye movement sleep, have been identified in patients with schizophrenia as a potential biomarker representing the impaired integrity of the thalamocortical network. Altered glutamatergic neurotransmission within this network via a hypofunction of the N-methyl-D-aspartate receptor (NMDAR) is one of the hypotheses at the heart of schizophrenia. This pathomechanism and the symptomatology are shared by anti-NMDAR encephalitis (NMDARE), where antibodies specific to the NMDAR induce a reduction of functional NMDAR. However, sleep spindle parameters have yet to be investigated in NMDARE and a comparison of these rare patients with young individuals with schizophrenia and healthy controls (HC) is lacking. This study aims to assess and compare sleep spindles across young patients affected by Childhood-Onset Schizophrenia (COS), Early-Onset Schizophrenia, (EOS), or NMDARE and HC. Further, the potential relationship between sleep spindle parameters in COS and EOS and the duration of the disease is examined. Methods: Sleep EEG data of patients with COS (N = 17), EOS (N = 11), NMDARE (N = 8) aged 7-21 years old, and age- and sex-matched HC (N = 36) were assessed in 17 (COS, EOS) or 5 (NMDARE) electrodes. Sleep spindle parameters (sleep spindle density, maximum amplitude, and sigma power) were analyzed. Results: Central sleep spindle density, maximum amplitude, and sigma power were reduced when comparing all patients with psychosis to all HC. Between patient group comparisons showed no differences in central spindle density but lower central maximum amplitude and sigma power in patients with COS compared to patients with EOS or NMDARE. Assessing the topography of spindle density, it was significantly reduced over 15/17 electrodes in COS, 3/17 in EOS, and 0/5 in NMDARE compared to HC. In the pooled sample of COS and EOS, a longer duration of illness was associated with lower central sigma power. Conclusions: Patients with COS demonstrated more pronounced impairments of sleep spindles compared to patients with EOS and NMDARE. In this sample, there is no strong evidence that changes in NMDAR activity are related to spindle deficits.

Efficacy and safety of ketamine for neonatal refractory status epilepticus: case report and systematic review.

Background: Evidence-based data on treatment of neonatal status epilepticus (SE) are scarce. We aimed to collect data on the efficacy and safety of ketamine for the treatment of neonatal SE and to assess its possible role in the treatment of neonatal SE. Methods: We described a novel case and conducted a systematic literature review on neonatal SE treated with ketamine. The search was carried out in Pubmed, Cochrane, Clinical Trial Gov, Scopus and Web of Science. Results: Seven published cases of neonatal SE treated with ketamine were identified and analyzed together with our novel case. Seizures typically presented during the first 24 h of life (6/8). Seizures were resistant to a mean of five antiseizure medications. Ketamine, a NMDA receptor antagonist, appeared to be safe and effective in all neonates treated. Neurologic sequelae including hypotonia and spasticity were reported for 4/5 of the surviving children (5/8). 3/5 of them were seizure free at 1-17 months of life. Discussion: Neonatal brain is more susceptible to seizures due to a shift towards increased excitation because of a paradoxical excitatory effect of GABA, a greater density of NMDA receptors and higher extracellular concentrations of glutamate. Status epilepticus and neonatal encephalopathy could further enhance these mechanisms, providing a rationale for the use of ketamine in this setting. Conclusions: Ketamine in the treatment of neonatal SE showed a promising efficacy and safety profile. However, further in-depth studies and clinical trials on larger populations are needed.

Hemiplegic Migraine in Children and Adolescents.

BACKGROUND: Only a few studies have focused on hemiplegic migraine (HM) in children despite its early age of onset. The aim of this review is to describe the peculiar characteristics of pediatric HM. METHODS: This is a narrative review based on 14 studies on pediatric HM selected from 262 papers. RESULTS: Different from HM in adults, pediatric HM affects both genders equally. Early transient neurological symptoms (prolonged aphasia during a febrile episode, isolated seizures, transient hemiparesis, and prolonged clumsiness after minor head trauma) can precede HM long before its onset. The prevalence of non-motor auras among children is lower than it is in adults. Pediatric sporadic HM patients have longer and more severe attacks compared to familial cases, especially during the initial years after disease onset, while familial HM cases tend to have the disease for longer. During follow-up, the frequency, intensity, and duration of HM attacks often decrease. The outcome is favorable in most patients; however, neurological conditions and comorbidities can be associated. CONCLUSION: Further studies are needed to better define the clinical phenotype and the natural history of pediatric HM and to refine genotype-phenotype correlations in order to improve the knowledge on HM physiopathology, diagnosis, and outcome.

The new Italian registry of infantile thrombosis (RITI): A reflection on its journey, challenges and pitfalls.

Introduction: Thrombotic events in neonates and children represent a rare although severe occurrence in view of the associated risk of mortality and sequelae. Quality evidence is limited in this field, and registry studies provide an essential base for research. The aim of this paper is to present the new Italian Registry of Infantile Thrombosis (RITI), set it into the scene of international thrombosis and stroke registries, and provide some insight on the challenges associated with registry management. Methods: We present the detailed structure and content of the new RITI registry, a brief overview of its main data, and a reflection on its features, pitfalls and the main challenges related to its management. Results: The RITI, initially started in 2007 and officially re-launched in 2017 after structural modifications, is a non-interventional retrospective and prospective registry study collecting data on neonatal and pediatric patients (0-18 years) who experienced a systemic or cerebral thrombotic event in Italy. The RITI is managed by a multidisciplinary team with expertise in pediatric thrombosis, and participation is open to all Italian physicians, on a voluntary basis. The overall aim of the registry is to acquire new evidence to better characterize the population of children with thrombotic events and improve their management and outcome. 48 Italian pediatric and intensive care units are actively involved in the RITI, including 85 medical doctors from 16 Italian regions. A total of 1,001 neonates and children affected by cerebral or systemic thrombosis have been enrolled. Discussion: The RITI is one of the largest available European registries of neonatal and pediatric thrombosis. National registries like the RITI represent a model for the study of rare conditions based on multidisciplinary and multicenter collaboration, aimed at overcoming the limitations due to small populations of patients, and creating a network of experts for patient referral and continuous education. Moreover, registry studies have a pivotal role in the research on pediatric thrombosis, due to the limited feasibility of high-quality studies. In our experience, the main critical stages, pitfalls and challenges in registry management include adequate registry designing, diffusion, data completeness and quality control.

Cold-Stimulus Headache in Children and Adolescents.

The literature on cold-stimulus headache (CSH) is relatively sparse compared to other primary headache disorders and the studies on the pediatric population are very limited. This systematic review aims to analyze the evidence on CSH in children and adolescents focusing on epidemiology, clinical features, pathogenic mechanisms, and treatments. Our review included 25 studies, among which 9 papers include pediatric cases (4 pediatric samples, 5 mixed samples of children and adults). The aim of this work is to highlight the features of CSH in children and adolescents. In children, the prevalence of CSH is higher than in adults and it is not gender-specific. There is a relevant family history for CSH and the comorbidity with migraine is significant. The triggers and clinical features of CSH due to ingesting a cold stimulus in children overlap with those in adults. CSH due to external application of a cold stimulus (or to environmentally low temperatures) is not studied in children and adolescents. We describe in detail a new pediatric case of CSH triggered by low ambient temperatures; to the best of our knowledge, this represents the first description in the literature. In conclusion, CSH in children is probably underestimated and has peculiar features compared to adults; further studies are needed to better understand its clinical features and pathophysiology.

Cannabidiol use in patients with Dravet syndrome and Lennox-Gastaut syndrome: experts' opinions using a nominal group technique (NGT) approach.

BACKGROUND: Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) currently present a therapeutic challenge. A pharmaceutical cannabidiol (CBD) specialty (Epidyolex®) has been approved by the FDA and EMA for the treatment of seizures in these syndromes. However, in Italy, the use of galenic formulations versus the pharmaceutical CBD has not been clearly regulated. AIM: To share and disseminate expert' opinions on how to use and administer pharmaceutical CBD in patients with DS and LGS as well as identifying a possible strategy for the switch from galenic to pharmaceutical specialty. METHODS: A nominal group technique (NGT) was used, involving eight Italian adult and pediatric neurologists. Two questionnaires were consecutively administered and the Clinician' responses were discussed in a final meeting in order to draw the own conclusions. RESULTS: The use of a pharmaceutical CBD is considered preferable to galenic formulations, in terms of reproducibility, safety, and control of the delivered dose. CONCLUSION: The use of a pharmaceutical CBD in DS and LGS patients is useful for both seizure treatment and quality of life (QoL) improvement. However, further studies are needed to confirm the improvement in QoL and the best strategy for switching from a galenic formulation to pharmaceutical CBD.

Myoclonic super-refractory status epilepticus with favourable evolution in a teenager with FIRES: Is the association of vagus nerve stimulation and cannabidiol effective?

BACKGROUND: Febrile infection-related epilepsy syndrome (FIRES) is a rare and catastrophic clinical syndrome occurring in previously healthy patients. Aetiology is still unknown and outcome usually poor. We describe a case of myoclonic prolonged super refractory status epilepticus (P-SRSE) in FIRES in a patient admitted to the paediatric intensive care unit of Padova, Italy. CASE REPORT: A previously healthy 14-year-old girl with onset of myoclonic status epilepticus after a mild febrile illness was admitted to our hospital with a diagnosis of FIRES. Extensive diagnostic work-up was inconclusive. Status epilepticus and electroclinical seizures recurred every time weaning from anaesthetic agents was attempted. Eventually, a vagal nerve stimulator (VNS) was implanted and cannabidiol (CBD) administered, 43 days and 70 days after P-SRSE onset, respectively. Two days after CBD introduction, status epilepticus weaned and the girl rapidly regained complete consciousness showing a brilliant and unexpected recovery. At last follow-up, 12 months later, she is 8-months seizure free on multiple antiseizure medications, has only mild neuropsychological impairment with no neurological and intellective deficit. CONCLUSIONS: To our knowledge, this represents a unique case with an extremely favourable evolution with a possible effect of the association of VNS and CBD to traditional antiseizure medications.

Extended Glasgow Outcome Scale to Evaluate the Functional Impairment of Patients With Subcortical Band Heterotopia: A Multicentric Cross-sectional Study.

BACKGROUND: Subcortical band heterotopia (SBH) is a rare malformation of the cortical development characterized by a heterotopic band of gray matter between cortex and ventricles. The clinical presentation typically includes intellectual disability and epilepsy. PURPOSE: To evaluate if the Extended Glasgow Outcome Scale-pediatric version (EGOS-ped) is a feasible tool for evaluating the functional disability of patients with (SBH). METHOD: Cross-sectional multicenter study of a cohort of 49 patients with SBH (female n = 30, 61%), recruited from 23 Italian centers. RESULTS: Thirty-nine of 49 (80%) cases showed high functional disability at EGOS-ped assessment. In the poor result subgroup (EGOS-ped >3) motor deficit, language impairment, and lower intelligence quotient were more frequent (P < 0.001, P = 0.02, and P = 0.01, respectively); the age at epilepsy onset was remarkably lower (P < 0.001); and the prevalence of epileptic encephalopathy (West syndrome or Lennox-Gastaut-like encephalopathy) was higher (P = 0.04). The thickness and the extension of the heterotopic band were associated with EGOS-ped score (P < 0.01 and P = 0.02). Pachygyria was found exclusively among patients with poor outcome (P < 0.01). CONCLUSIONS: The EGOS-ped proved to be a reliable tool for stratifying the functional disability of patients with SBH. According to this score, patients could be dichotomized: group 1 (80%) is characterized by a poor overall functionality with early epilepsy onset, thick heterotopic band, and pachygyria, whereas group 2 (20%) is characterized by a good overall functionality with later epilepsy onset and thinner heterotopic band.

Gain of function SCN1A disease-causing variants: Expanding the phenotypic spectrum and functional studies guiding the choice of effective antiseizure medication.

OBJECTIVE: This study was undertaken to refine the spectrum of SCN1A epileptic disorders other than Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+) and optimize antiseizure management by correlating phenotype-genotype relationship and functional consequences of SCN1A variants in a cohort of patients. METHODS: Sixteen probands carrying SCN1A pathogenic variants were ascertained via a national collaborative network. We also performed a literature review including individuals with SCN1A variants causing non-DS and non-GEFS+ phenotypes and compared the features of the two cohorts. Whole cell patch clamp experiments were performed for three representative SCN1A pathogenic variants. RESULTS: Nine of the 16 probands (56%) had de novo pathogenic variants causing developmental and epileptic encephalopathy (DEE) with seizure onset at a median age of 2 months and severe intellectual disability. Seven of the 16 probands (54%), five with inherited and two with de novo variants, manifested focal epilepsies with mild or no intellectual disability. Sodium channel blockers never worsened seizures, and 50% of patients experienced long periods of seizure freedom. We found 13 SCN1A missense variants; eight of them were novel and never reported. Functional studies of three representative variants showed a gain of channel function. The literature review led to the identification of 44 individuals with SCN1A variants and non-DS, non-GEFS+ phenotypes. The comparison with our cohort highlighted that DEE phenotypes are a common feature. SIGNIFICANCE: The boundaries of SCN1A disorders are wide and still expanding. In our cohort, >50% of patients manifested focal epilepsies, which are thus a frequent feature of SCN1A pathogenic variants beyond DS and GEFS+. SCN1A testing should therefore be included in the diagnostic workup of pediatric, familial and nonfamilial, focal epilepsies. Alternatively, non-DS/non-GEFS+ phenotypes might be associated with gain of channel function, and sodium channel blockers could control seizures by counteracting excessive channel function. Functional analysis evaluating the consequences of pathogenic SCN1A variants is thus relevant to tailor the appropriate antiseizure medication.