Publications by authors named "Maria Roberta Cilio"

53 Publications

Neonatal presentation of genetic epilepsies: Early differentiation from acute provoked seizures.

Epilepsia 2021 Aug 21;62(8):1907-1920. Epub 2021 Jun 21.

Department of Pediatrics, Saint-Luc University Hospital, Catholic University of Louvain, Brussels, Belgium.

Objective: Although most seizures in neonates are due to acute brain injury, some represent the first sign of neonatal onset genetic epilepsies. Delay in recognition and lack of expert assessment of neonates with epilepsy may result in worse developmental outcomes. As in older children and adults, seizure semiology in neonates is an essential determinant in diagnosis. We aimed to establish whether seizure type at presentation in neonates can suggest a genetic etiology.

Methods: We retrospectively analyzed the clinical and electroencephalographic (EEG) characteristics of seizures in neonates admitted in two Level IV neonatal intensive care units, diagnosed with genetic epilepsy, for whom a video-EEG recording at presentation was available for review, and compared them on a 1:2 ratio with neonates with seizures due to stroke or hypoxic-ischemic encephalopathy.

Results: Twenty neonates with genetic epilepsy were identified and compared to 40 neonates with acute provoked seizures. Genetic epilepsies were associated with pathogenic variants in KCNQ2 (n = 12), KCNQ3 (n = 2), SCN2A (n = 2), KCNT1 (n = 1), PRRT2 (n = 1), and BRAT1 (n = 2). All neonates with genetic epilepsy had seizures with clinical correlates that were either tonic (18/20) or myoclonic (2/20). In contrast, 17 of 40 (42%) neonates with acute provoked seizures had electrographic only seizures, and the majority of the remainder had clonic seizures. Time to first seizure was longer in neonates with genetic epilepsies (median = 60 h of life) compared to neonates with acute provoked seizures (median = 15 h of life, p < .001). Sodium channel-blocking antiseizure medications were effective in 13 of 14 (92%) neonates with tonic seizures who were trialed at onset or during the course of the epilepsy.

Significance: Seizure semiology is an easily accessible sign of genetic epilepsies in neonates. Early identification of the seizure type can prompt appropriate workup and treatment. Tonic seizures are associated with channelopathies and are often controlled by sodium channel-blocking antiseizure medications.
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http://dx.doi.org/10.1111/epi.16957DOI Listing
August 2021

Seizure Control in Neonates Undergoing Screening vs Confirmatory EEG Monitoring.

Neurology 2021 08 2;97(6):e587-e596. Epub 2021 Jun 2.

From the Divisions of Child Neurology and Pediatrics (Neonatology) (C.J.W.) and Division of Neonatal & Developmental Medicine, Department of Pediatrics (S.L.B.), Stanford University; Quantitative Sciences Unit (V.S.), Department of Medicine, Stanford University School of Medicine, Palo Alto, CA; Departments of Neurology (N.S.A., S.L.M.), Pediatrics (N.S.A., S.L.M.), and Anesthesia & Critical Care Medicine (N.S.A.), University of Pennsylvania Perelman School of Medicine; Department of Pediatrics (Division of Neurology) (N.S.A., S.L.M.), Children's Hospital of Philadelphia, PA; Departments of Pediatrics and Population Health Sciences (M.E.L.), Duke University School of Medicine, Durham, NC; Department of Pediatrics (C.T.), College of Medicine, Division of Neurology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH; Departments of Epidemiology and Biostatistics (C.E.M., H.C.G.) and Pediatrics (E.E.R.) and Department of Neurology and Weill Institute for Neuroscience and Department of Pediatrics, UCSF Benioff Children's Hospital (H.C.G.), University of California San Francisco; Neurology (T.C.), George Washington University School of Medicine, Children's National Hospital, Washington, DC; Department of Neurology (J.S.S.), Boston Children's Hospital, Harvard Medical School, MA; Department of Neurology (C.J.C.), Massachusetts General Hospital, Harvard Medical School, Boston; Division of Pediatric Neurology (M.R.C.), Department of Pediatrics, Saint-Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium; and Division of Pediatric Neurology (R.A.S.), Department of Pediatrics, Michigan Medicine, University of Michigan, Ann Arbor.

Objective: To determine whether screening continuous EEG monitoring (cEEG) is associated with greater odds of treatment success for neonatal seizures.

Methods: We included term neonates with acute symptomatic seizures enrolled in the Neonatal Seizure Registry (NSR), a prospective, multicenter cohort of neonates with seizures. We compared 2 cEEG approaches: (1) screening cEEG, initiated for indications of encephalopathy or paralysis without suspected clinical seizures; and (2) confirmatory cEEG, initiated for the indication of clinical events suspicious for seizures, either alone or in addition to other indications. The primary outcome was successful response to initial seizure treatment, defined as seizures resolved without recurrence within 30 minutes after initial loading dose of antiseizure medicine. Multivariable logistic regression analyses assessed the association between cEEG approach and successful seizure treatment.

Results: Among 514 neonates included, 161 (31%) had screening cEEG and 353 (69%) had confirmatory cEEG. Neonates with screening cEEG had a higher proportion of successful initial seizure treatment than neonates with confirmatory cEEG (39% vs 18%; < 0.0001). After adjusting for covariates, there remained a greater odds ratio (OR) for successful initial seizure treatment in the screening vs confirmatory cEEG groups (adjusted OR 2.44, 95% confidence interval 1.45-4.11, = 0.0008).

Conclusions: These findings provide evidence from a large, contemporary cohort of neonates that a screening cEEG approach may improve odds of successful treatment of acute seizures.

Classification Of Evidence: This study provides Class III evidence that for neonates a screening cEEG approach, compared to a confirmatory EEG approach, increases the probability of successful treatment of acute seizures.
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http://dx.doi.org/10.1212/WNL.0000000000012293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424499PMC
August 2021

The ILAE classification of seizures and the epilepsies: Modification for seizures in the neonate. Position paper by the ILAE Task Force on Neonatal Seizures.

Epilepsia 2021 03 1;62(3):615-628. Epub 2021 Feb 1.

Paediatric Neurosciences Research Group, Royal Hospital for Children & Institute of Health & Wellbeing, University of Glasgow, Glasgow, UK.

Seizures are the most common neurological emergency in the neonatal period and in contrast to those in infancy and childhood, are often provoked seizures with an acute cause and may be electrographic-only. Hence, neonatal seizures may not fit easily into classification schemes for seizures and epilepsies primarily developed for older children and adults. A Neonatal Seizures Task Force was established by the International League Against Epilepsy (ILAE) to develop a modification of the 2017 ILAE Classification of Seizures and Epilepsies, relevant to neonates. The neonatal classification framework emphasizes the role of electroencephalography (EEG) in the diagnosis of seizures in the neonate and includes a classification of seizure types relevant to this age group. The seizure type is determined by the predominant clinical feature. Many neonatal seizures are electrographic-only with no evident clinical features; therefore, these are included in the proposed classification. Clinical events without an EEG correlate are not included. Because seizures in the neonatal period have been shown to have a focal onset, a division into focal and generalized is unnecessary. Seizures can have a motor (automatisms, clonic, epileptic spasms, myoclonic, tonic), non-motor (autonomic, behavior arrest), or sequential presentation. The classification allows the user to choose the level of detail when classifying seizures in this age group.
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http://dx.doi.org/10.1111/epi.16815DOI Listing
March 2021

Vomiting and retching as presenting signs of focal epilepsy in children.

Epileptic Disord 2020 Dec;22(6):823-827

Pediatric Neurology Unit, Cliniques Universitaires Saint-Luc, Brussels, Belgium, Institute of Clinical and Experimental Research, Université Catholique de Louvain, Brussels, Belgium.

Ictal vomiting is a rare condition easily misdiagnosed as a common disease. We report two children presenting with retching and vomiting as the main ictal manifestation. Patient 1 was a four-year-old girl with a history of daily nocturnal vomiting for two months, first interpreted as a functional disorder, then as a viral infection. She presented with vomiting accompanied by focal right-sided hemifacial clonic jerking, occurring multiple times per day. Video-EEG demonstrated ictal discharges associated with the retching and vomiting, over a normal background, and occasional interictal focal spikes. MRI was normal. PET demonstrated left-sided opercular hypometabolism. Patient 2 was a girl with a history of focal epilepsy, secondary to a right central dysembryoplastic tumour, first resected with subsequent seizure freedom at the age of three years. At five years of age, she presented with recurrent episodes of retching and vomiting initially diagnosed as migraine. Video-EEG showed ictal discharges, clinically correlating with retching, vomiting and clonic facial jerking, with normal interictal activity. Brain MRI showed a progression of the tumour. A second resection resulted in seizure freedom. Ictal vomiting often goes undiagnosed, especially in children, causing treatment delays. An ictal origin should be considered, particularly when the episodes are recurrent and stereotyped. [Published with video sequences].
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http://dx.doi.org/10.1684/epd.2020.1227DOI Listing
December 2020

A Novel Kv7.3 Variant in the Voltage-Sensing S Segment in a Family With Benign Neonatal Epilepsy: Functional Characterization and Rescue by β-Hydroxybutyrate.

Front Physiol 2020 4;11:1040. Epub 2020 Sep 4.

Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, United States.

Pathogenic variants in and , paralogous genes encoding Kv7.2 and Kv7.3 voltage-gated K channel subunits, are responsible for early-onset developmental/epileptic disorders characterized by heterogeneous clinical phenotypes ranging from benign familial neonatal epilepsy (BFNE) to early-onset developmental and epileptic encephalopathy (DEE). variants account for the majority of pedigrees with BFNE and variants are responsible for a much smaller subgroup, but the reasons for this imbalance remain unclear. Analysis of additional pedigrees is needed to further clarify the nature of this genetic heterogeneity and to improve prediction of pathogenicity for novel variants. We identified a BFNE family with two siblings and a parent affected. Exome sequencing on samples from both parents and siblings revealed a novel variant (c.719T>G; p.M240R), segregating in the three affected individuals. The M240 residue is conserved among human Kv7.2-5 and lies between the two arginines (R5 and R6) closest to the intracellular side of the voltage-sensing S transmembrane segment. Whole cell patch-clamp recordings in Chinese hamster ovary (CHO) cells revealed that homomeric Kv7.3 M240R channels were not functional, whereas heteromeric channels incorporating Kv7.3 M240R mutant subunits with Kv7.2 and Kv7.3 displayed a depolarizing shift of about 10 mV in activation gating. Molecular modeling results suggested that the M240R substitution preferentially stabilized the resting state and possibly destabilized the activated state of the Kv7.3 subunits, a result consistent with functional data. Exposure to β-hydroxybutyrate (BHB), a ketone body generated during the ketogenic diet (KD), reversed channel dysfunction induced by the M240R variant. In conclusion, we describe the first missense loss-of-function (LoF) pathogenic variant within the S segment of Kv7.3 identified in patients with BFNE. Studied under conditions mimicking heterozygosity, the M240R variant mainly affects the voltage sensitivity, in contrast to previously analyzed BFNE Kv7.3 variants that reduce current density. Our pharmacological results provide a rationale for the use of KD in patients carrying LoF variants in Kv7.2 or Kv7.3 subunits.
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http://dx.doi.org/10.3389/fphys.2020.01040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498716PMC
September 2020

Response to cannabidiol in epilepsy of infancy with migrating focal seizures associated with KCNT1 mutations: An open-label, prospective, interventional study.

Eur J Paediatr Neurol 2020 Mar 31;25:77-81. Epub 2019 Dec 31.

Department of Neurology, Benioff Children's Hospital, University of California San Francisco, 1975 4th St, San Francisco, CA, USA, 94118; Department of Pediatrics and Institute of Clinical and Experimental Research, University Hospital Saint-Luc, University of Louvain, Avenue Hippocrate 10, 1200, Bruxelles, Belgium.

Epilepsy of Infancy with Migrating Focal Seizures (EIMFS) is a rare, developmental and epileptic encephalopathy most commonly associated with mutations in KCNT1, a potassium channel. Polymorphous migrating focal seizures begin within 6 months of life and are pharmacoresistant to standard anticonvulsants. Additional therapies are needed to decrease seizure frequency and subsequent developmental deterioration associated with EIMFS. Cannabidiol (CBD) has recently arisen in public interest due to its potential in treatment-resistant epilepsies as demonstrated in randomized controlled trials for Dravet Syndrome and Lennox-Gastaut Syndrome. Here we evaluate the response of three patients, all diagnosed with EIMFS secondary to KCNT1 mutations, to pharmaceutical grade CBD. Two patients showed no benefit and have since voluntarily stopped CBD. One patient showed no overall reduction in seizure frequency, however showed a notable reduction in seizure intensity with possible developmental progression. Further studies are needed to assess the potential benefit of CBD in treatment-resistant epilepsies such as EIMFS, with a focus on early identification and intervention.
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http://dx.doi.org/10.1016/j.ejpn.2019.12.024DOI Listing
March 2020

Neonatal Developmental and Epileptic Encephalopathies.

Semin Pediatr Neurol 2019 12 11;32:100770. Epub 2019 Sep 11.

Division of Pediatric Neurology, Saint-Luc University Hospital, and Institute of Experimental and Clinical Research (IREC), University of Louvain, Brussels, Belgium. Electronic address:

The new concept of developmental and epileptic encephalopathy is based on the understanding that many genetic epilepsies are associated with developmental impairment as a direct consequence of the genetic mutation, in addition to the effect of the frequent epileptic activity on brain development. As an example, in infants with KCNQ2 or STXBP1 encephalopathy, seizures may be controlled early after onset or cease spontaneously after a few years, but the developmental consequences tend to remain profound. The term "developmental and epileptic encephalopathy" expresses the concept that the genetic defect may be responsible for both the epilepsy and adverse development which is crucial to understanding the disease process for both families and clinicians. The increased use of EEG monitoring, neuroimaging, and metabolic and genetic testing in the Neonatal Intensive Care Unit has greatly improved our understanding of neonatal-onset epilepsies as seen with the syndromes Ohtahara and Early Myoclonic Encephalopathy outlined in the 1970s into distinct etiology-specific electroclinical phenotypes.
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http://dx.doi.org/10.1016/j.spen.2019.08.006DOI Listing
December 2019

Genetics of neonatal-onset epilepsies.

Handb Clin Neurol 2019 ;162:415-433

Department of Pediatrics, University of California San Francisco, San Francisco, CA, United States; Department of Neurology, University of California San Francisco, San Francisco, CA, United States. Electronic address:

Although the majority of seizures in neonates are related to acute brain injury, a substantial minority are the first symptom of a neonatal-onset epilepsy often linked to a pathogenic genetic variant. Historically, studies on neonatal seizures including treatment response and long-term consequences have lumped all etiologies together. However, etiology has been consistently shown to be the most important determinant of outcome. In the past few years, an increasing number of monogenic disorders have been described and might explain up to a third of neonatal-onset epilepsy syndromes previously included under the umbrella of Ohtahara syndrome and early myoclonic encephalopathy. In this chapter, we define the concept of genetic epilepsy and review the classification. Then, we review the most relevant monogenic neonatal-onset epilepsies, detail their underlying pathophysiologic mechanisms, and present their electroclinical phenotypes. We highlight that, in some cases, such as neonates with KCNQ2 or KCNT1 gene mutations, the early recognition of the electroclinical phenotype can lead to targeted diagnostic testing and precision medicine treatment, enabling the possibility of improved outcome.
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http://dx.doi.org/10.1016/B978-0-444-64029-1.00020-5DOI Listing
January 2020

Pharmacokinetics and Tolerability of Multiple Doses of Pharmaceutical-Grade Synthetic Cannabidiol in Pediatric Patients with Treatment-Resistant Epilepsy.

CNS Drugs 2019 06;33(6):593-604

UCSF Benioff Children's Hospital, University of California San Francisco, San Francisco, CA, USA.

Background: Prior studies have evaluated the use of various constituents of cannabis for their anti-seizure effects. Specifically, cannabidiol, a non-psychoactive component of cannabis, has been investigated for treatment-resistant epilepsy, but more information is needed particularly on its use in a pediatric population.

Objective: The objective of this study was to evaluate the pharmacokinetics and safety of a synthetic pharmaceutical-grade cannabidiol oral solution in pediatric patients with treatment-resistant epilepsy.

Methods: In this open-label study, pediatric patients (aged 1 to ≤ 17 years) with treatment-resistant epilepsy received cannabidiol oral solution administered as add-on to their current antiepileptic drug regimen. Patients received a single dose (5, 10, or 20 mg/kg) on day 1 and twice-daily dosing on days 4 through 10 (10-mg/kg [cohort 1], 20-mg/kg [cohort 2], or 40-mg/kg [cohort 3] total daily dose). Serial blood samples were collected on day 1 before dosing and up to 72 h post-dose, and on day 10 before dosing and up to 24 h post-dose. Blood samples to assess trough concentrations of cannabidiol were collected on day 6 (for patients aged 12 to ≤ 17 years), day 8 (for patients aged 2 to ≤ 17 years), and day 9 (for patients aged 6 to ≤ 17 years).

Results: Overall, 61 patients across three cohorts received one of three doses of cannabidiol oral solution (mean age, 7.6 years). The age composition was similar in the three cohorts. There was a trend for increased cannabidiol exposure with increased cannabidiol oral solution dosing, but overall exposure varied. Approximately 2-6 days of twice-daily dosing provided steady-state concentrations of cannabidiol. A bi-directional drug interaction occurred with cannabidiol and clobazam. Concomitant administration of clobazam with 40 mg/kg/day of cannabidiol oral solution resulted in a 2.5-fold increase in mean cannabidiol exposure. Mean plasma clobazam concentrations were 1.7- and 2.2-fold greater in patients receiving clobazam concomitantly with 40 mg/kg/day of cannabidiol oral solution compared with 10 mg/kg/day and 20 mg/kg/day. Mean plasma norclobazam values were 1.3- and 1.9-fold higher for patients taking clobazam plus 40 mg/kg/day of cannabidiol oral solution compared with the 10-mg/kg/day and 20-mg/kg/day groups. All doses were generally well tolerated, and common adverse events that occurred at > 10% were somnolence (21.3%), anemia (18.0%), and diarrhea (16.4%).

Conclusions: Inter-individual variability in systemic cannabidiol exposure after pediatric patient treatment with cannabidiol oral solution was observed but decreased with multiple doses. Short-term administration was generally safe and well tolerated.

Trial Registration: ClinicalTrials.gov (NCT02324673).
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http://dx.doi.org/10.1007/s40263-019-00624-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534520PMC
June 2019

Neonatal seizures: Is there a relationship between ictal electroclinical features and etiology? A critical appraisal based on a systematic literature review.

Epilepsia Open 2019 Mar 25;4(1):10-29. Epub 2019 Jan 25.

Clinical Neuroscience UCL-Institute of Child Health London UK.

The aim of this study was to evaluate whether specific etiologies of neonatal seizures have distinct ictal electroclinical features. A systematic review of English articles using the PubMed database since 2004 (last update 9/26/16). Search terms included text words and Medical Subject Headings (MeSH) terms related to neonatal seizures. Eligible articles included reports of neonates with seizures with a full description of seizure semiology and electroclinical findings. Independent extraction of data was performed by 2 authors using predefined data fields, including study quality indicators. Data were collected for every individual patient described in the articles. The dataset was analyzed with the Fisher exact test. The initial search led to 8507 titles; using filters, 2910 titles and abstracts were identified, with 177 full texts selected to be read. Fifty-seven studies were included in the analysis with 151 neonates (37.7 male and 62.9% term). Genetic etiologies (51%) and sequential seizures (41.1%) predominated in this sample and hypoxic-ischemic encephalopathy (HIE) accounted for only 4%. The low prevalence of HIE observed was probably due to a publication bias. A significant association was found between etiology and seizure type: hemorrhage with autonomic seizures ( = 0.003), central nervous system (CNS) infection and stroke with clonic seizures ( = 0.042,  < 0.001, respectively), metabolic/vitamin-related disorders, and inborn errors of metabolism with myoclonic seizures ( < 0.001). There were also specific electroencephalography (EEG) patterns seen with certain etiologies: vascular disorders and electrolyte imbalance with focal ictal discharges ( < 0.001,  = 0.049 respectively), vitamin-related disorders with multifocal ( = 0.003), and all categories of genetic disorders with burst-suppression ( < 0.001). Clonic and autonomic seizures were more frequently present with focal EEG abnormalities ( = 0.001 and  < 0.001), whereas tonic and myoclonic seizures present with burst-suppression ( = 0.001,  = 0.005). In conclusion, our data suggest that specific associations of etiologies of neonatal seizures with distinct clinical features and EEG patterns might help in the decision to establish appropriate treatment.
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http://dx.doi.org/10.1002/epi4.12298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398099PMC
March 2019

Response to antiseizure medications in neonates with acute symptomatic seizures.

Epilepsia 2019 03 20;60(3):e20-e24. Epub 2019 Feb 20.

Department of Pediatrics, University of Michigan, Ann Arbor, Michigan.

In a prospective cohort of 534 neonates with acute symptomatic seizures, 66% had incomplete response to the initial loading dose of antiseizure medication (ASM). Treatment response did not differ by gestational age, sex, medication, or dose. The risk of incomplete response was highest for seizures due to intracranial hemorrhage and lowest for hypoxic-ischemic encephalopathy, although the difference was not significant after adjusting for high seizure burden and therapeutic hypothermia treatment. Future trial design may test ASMs in neonates with all acute symptomatic seizure etiologies and could target neonates with seizures refractory to an initial ASM.
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http://dx.doi.org/10.1111/epi.14671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443409PMC
March 2019

Augmented Reticular Thalamic Bursting and Seizures in Scn1a-Dravet Syndrome.

Cell Rep 2019 01;26(1):54-64.e6

Gladstone Institute of Neurological Disease, San Francisco, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA; Neurosciences Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address:

Loss of function in the Scn1a gene leads to a severe epileptic encephalopathy called Dravet syndrome (DS). Reduced excitability in cortical inhibitory neurons is thought to be the major cause of DS seizures. Here, in contrast, we show enhanced excitability in thalamic inhibitory neurons that promotes the non-convulsive seizures that are a prominent yet poorly understood feature of DS. In a mouse model of DS with a loss of function in Scn1a, reticular thalamic cells exhibited abnormally long bursts of firing caused by the downregulation of calcium-activated potassium SK channels. Our study supports a mechanism in which loss of SK activity causes the reticular thalamic neurons to become hyperexcitable and promote non-convulsive seizures in DS. We propose that reduced excitability of inhibitory neurons is not global in DS and that non-GABAergic mechanisms such as SK channels may be important targets for treatment.
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http://dx.doi.org/10.1016/j.celrep.2018.12.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555418PMC
January 2019

Long-Term Safety, Tolerability, and Efficacy of Cannabidiol in Children with Refractory Epilepsy: Results from an Expanded Access Program in the US.

CNS Drugs 2019 01;33(1):47-60

Department of Neurology, University of California San Francisco, San Francisco, CA, USA.

Background: Purified cannabidiol is a new antiepileptic drug that has recently been approved for use in patients with Lennox-Gastaut and Dravet syndromes, but most published studies have not extended beyond 12-16 weeks.

Objective: The objective of this study was to evaluate the long-term safety, tolerability, and efficacy of cannabidiol in children with epilepsy.

Methods: Patients aged 1-17 years with refractory epilepsy were enrolled in an open-label prospective study through individual patient and expanded access programs between April 2013 and December 2014. Seizure types were video-electroencephalogram confirmed prior to enrollment. After a 28-day evaluation period, during which baseline seizure frequency was assessed, cannabidiol was given as add-on therapy at 5 mg/kg/day and titrated weekly by 5-mg/kg increments to a dose of 25 mg/kg/day. Blood tests were performed at baseline, after 1, 2, and 3 months, and every 3 months thereafter. Trough concentrations of concomitant antiepileptic drugs were measured at baseline, after 1, 2, and 3 months of therapy, and as clinically indicated afterwards. Concomitant antiepileptic drugs, ketogenic diet ratio, and vagal nerve stimulator settings remained unchanged during the baseline period and the first 3 months of treatment, unless there was a significant increase in plasma concentrations. Seizure frequency was reported daily in seizure diaries by parents or caregivers. Clinical assessments occurred after 15 days of treatment, at 1 month, at 3 months, and every 3 months thereafter. Diaries of seizure frequency and adverse events were reviewed at each visit. The primary efficacy outcome was a reduction in seizure frequency and responders were defined as those patients achieving a > 50% reduction in motor seizures.

Results: Twenty-six children were enrolled. Most had genetic epilepsies with daily or weekly seizures and multiple seizure types. All were refractory to prior antiepileptic drugs (range 4-11, mean 7), and were taking two antiepileptic drugs on average. Duration of therapy ranged from 4 to 53 months (mean 21 months). Adverse events were reported in 21 patients (80.8%), including reduced appetite in ten (38.4%), diarrhea in nine (34.6%), and weight loss in eight (30.7%). Four (15.4%) had changes in antiepileptic drug concentrations and three had elevated aspartate aminotransferase and alanine aminotransferase levels when cannabidiol was administered together with valproate. Serious adverse events, reported in six patients (23.1%), included status epilepticus in three, catatonia in two, and hypoalbuminemia in one. Fifteen patients (57.7%) discontinued cannabidiol for lack of efficacy, one because of status epilepticus, and one for severe weight loss. The retention rate declined rapidly in the first 6 months and more gradually thereafter. At 24 months, the number of patients continuing cannabidiol as adjunctive therapy was nine of the original 26 (34.6%). Of these patients, seven (26.9%) had a sustained > 50% reduction in motor seizures, including three (11.5%) who remain seizure free.

Conclusion: Over a 4-year period, cannabidiol was effective in 26.9% of children with otherwise refractory epilepsy. It was well tolerated in about 20% of patients, but 80.8% had adverse events, including 23.1% with serious adverse events. Decreased appetite and diarrhea were frequent along with weight loss that became evident only later in the treatment.
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http://dx.doi.org/10.1007/s40263-018-0589-2DOI Listing
January 2019

The ClinGen Epilepsy Gene Curation Expert Panel-Bridging the divide between clinical domain knowledge and formal gene curation criteria.

Hum Mutat 2018 11;39(11):1476-1484

Division of Genetic Medicine, University of Washington, Seattle, Washington, USA.

The field of epilepsy genetics is advancing rapidly and epilepsy is emerging as a frequent indication for diagnostic genetic testing. Within the larger ClinGen framework, the ClinGen Epilepsy Gene Curation Expert Panel is tasked with connecting two increasingly separate fields: the domain of traditional clinical epileptology, with its own established language and classification criteria, and the rapidly evolving area of diagnostic genetic testing that adheres to formal criteria for gene and variant curation. We identify critical components unique to the epilepsy gene curation effort, including: (a) precise phenotype definitions within existing disease and phenotype ontologies; (b) consideration of when epilepsy should be curated as a distinct disease entity; (c) strategies for gene selection; and (d) emerging rules for evaluating functional models for seizure disorders. Given that de novo variants play a prominent role in many of the epilepsies, sufficient genetic evidence is often awarded early in the curation process. Therefore, the emphasis of gene curation is frequently shifted toward an iterative precuration process to better capture phenotypic associations. We demonstrate that within the spectrum of neurodevelopmental disorders, gene curation for epilepsy-associated genes is feasible and suggest epilepsy-specific conventions, laying the groundwork for a curation process of all major epilepsy-associated genes.
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http://dx.doi.org/10.1002/humu.23632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418072PMC
November 2018

Lack of response to quinidine in KCNT1-related neonatal epilepsy.

Epilepsia 2018 10 4;59(10):1889-1898. Epub 2018 Sep 4.

Department of Neurology, University of California San Francisco, San Francisco, California.

Objective: To evaluate the clinical efficacy and safety of quinidine in patients with KCNT1-related epilepsy of infancy with migrating focal seizures (EIMFS) in the infantile period and to compare with the effect of quinidine on mutant channels in vitro.

Methods: We identified 4 patients with EIMFS with onset in the neonatal period, pathogenic variants in the KCNT1 gene, and lack of response to AEDs. Patients were prospectively enrolled, treated with quinidine, and monitored according to a predefined protocol. Electroclinical, neuroimaging, and genetic data were reviewed. Two patients had novel variants in the KCNT1 gene that were modeled in Xenopus oocytes with channel properties characterized using electrophysiology recordings.

Results: Three of four patients were treated with quinidine early in their disease course, prior to 6 months of age. No significant side effects were noted with quinidine therapy. In addition, there were no significant changes in electroencephalography (EEG)-confirmed seizure burden during therapy, and patients had near hourly seizures before, during, and after treatment. Two patients had previously reported gain-of-function mutations, which demonstrated sensitivity to high levels of quinidine in the oocyte assay. Two patients with novel variants, showed characteristic gain-of-function and were thus predicted to be pathogenic. Of interest, these variants were essentially insensitive to high levels of quinidine.

Significance: Patients had no reported benefit to quinidine therapy despite age at treatment initiation. Pharmacogenetic results in oocytes were consistent with clinical treatment failure in 2 patients, suggesting that single-dose pharmacologic assessment may be helpful in predicting which patients are exceedingly unlikely to achieve benefit with quinidine. In the 2 patients who had a lack of therapeutic benefit despite sensitivity to high concentrations of quinidine with in vitro oocyte assay, it is likely that the achievable exposure levels in the brain were too low to cause significant in vivo channel blockade.
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http://dx.doi.org/10.1111/epi.14551DOI Listing
October 2018

Predictive value of early EEG for seizures in neonates with hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia.

Pediatr Res 2018 09 3;84(3):399-402. Epub 2018 May 3.

Departments of Neurology and Pediatrics, University of California San Francisco, California, USA.

Objectives: To assess the prognostic significance of an early normal/mildly abnormal conventional EEG (cEEG) on seizure risk in neonates undergoing therapeutic hypothermia.

Methods: We reviewed the video-EEG recordings from a large cohort of neonates treated with therapeutic hypothermia for hypoxic-ischemic encephalopathy from 2008 to 2017 in a single tertiary center. Continuous video-EEG was started as soon as possible (median 8.2 h) and continued throughout hypothermia and rewarming. We studied those neonates with a normal/mildly abnormal EEG during the first 24 h of monitoring.

Results: A total of 331 neonates were treated with hypothermia and 323 had cEEG recordings available for review; 99 were excluded because of a moderately/severely abnormal cEEG background and/or seizure during the first 24 h of recording, and an additional eight because of early rewarming. The remaining 216 had a normal/mildly abnormal cEEG in the first 24 h. None of these patients subsequently developed seizures.

Conclusion: A normal/mildly abnormal cEEG during the first 24 h indicates a very low risk of subsequent seizures. This suggests that cEEG monitoring can be safely discontinued after 24 h if it has remained normal or excessively discontinuous and no seizures are detected, limiting the need for this resource-intensive and expensive tool.
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http://dx.doi.org/10.1038/s41390-018-0040-xDOI Listing
September 2018

Dynamic action potential clamp predicts functional separation in mild familial and severe de novo forms of epilepsy.

Proc Natl Acad Sci U S A 2018 06 29;115(24):E5516-E5525. Epub 2018 May 29.

Ion Channels and Disease Group, The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia;

De novo variants in developmental and epileptic encephalopathy (DEE) show distinctive genotype-phenotype correlations. The two most recurrent variants in DEE, R1882Q and R853Q, are associated with different ages and seizure types at onset. R1882Q presents on day 1 of life with focal seizures, while infantile spasms is the dominant seizure type seen in R853Q cases, presenting at a median age of 8 months. Voltage clamp, which characterizes the functional properties of ion channels, predicted gain-of-function for R1882Q and loss-of-function for R853Q. Dynamic action potential clamp, that we implement here as a method for modeling neurophysiological consequences of a given epilepsy variant, predicted that the R1882Q variant would cause a dramatic increase in firing, whereas the R853Q variant would cause a marked reduction in action potential firing. Dynamic clamp was also able to functionally separate the L1563V variant, seen in benign familial neonatal-infantile seizures from R1882Q, seen in DEE, suggesting a diagnostic potential for this type of analysis. Overall, the study shows a strong correlation between clinical phenotype, genotype, and functional modeling. Dynamic clamp is well positioned to impact our understanding of pathomechanisms and for development of disease mechanism-targeted therapies in genetic epilepsy.
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http://dx.doi.org/10.1073/pnas.1800077115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004444PMC
June 2018

Neonatal epilepsies: Clinical management.

Semin Fetal Neonatal Med 2018 06 31;23(3):204-212. Epub 2018 Jan 31.

Department of Pediatrics, University of California, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, CA, USA. Electronic address:

Whereas the majority of seizures in neonates are related to acute brain injury, a substantial minority are the first symptom of a neonatal-onset epilepsy, often linked to a pathogenic genetic variant. This defect may disrupt cortical development (e.g., lissencephaly, focal cortical dysplasia), lead to metabolic changes (e.g., pyridoxine-dependent epilepsy, sulfite oxidase deficiency) or lead to cortical dysfunction without metabolic or macroscopic structural changes (e.g., channelopathies, STXBP1). Historically, studies on treatment response and long-term consequences of neonatal seizures have lumped all etiologies together. However, etiology has been consistently shown to be the most important determinant of outcome. Here, we address the elements differentiating neonatal-onset epilepsies from acute symptomatic seizures. We review some common neonatal-onset epilepsies and emphasize how pathognomonic electro-clinical phenotypes such as the ones associated with KCNQ2 or KCNT1 gene mutation, when recognized early, can lead to targeted diagnostic testing and precision medicine treatment, enabling the possibility of improved outcome.
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http://dx.doi.org/10.1016/j.siny.2018.01.004DOI Listing
June 2018

A Distinctive Ictal Amplitude-Integrated Electroencephalography Pattern in Newborns with Neonatal Epilepsy Associated with KCNQ2 Mutations.

Neonatology 2017 20;112(4):387-393. Epub 2017 Sep 20.

Department of Neonatology, Centro Hospitalar São João, Faculty of Medicine, University of Porto, Porto, Portugal.

Background: Recurrent and prolonged seizures are harmful for the developing brain, emphasizing the importance of early seizure recognition and effective therapy. Amplitude-integrated electroencephalography (aEEG) has become a valuable tool to diagnose epileptic seizures, and, in parallel, genetic etiologies are increasingly being recognized, changing the paradigm of the workup and management of neonatal seizures.

Objective: To report the ictal aEEG pattern in neonates with KCNQ2-related epilepsy.

Subjects And Methods: In this multicenter descriptive study, clinical data and aEEG findings of 9 newborns with KCNQ2 mutations are reported.

Results: Refractory seizures occurred in the early neonatal period with similar seizure type, including tonic features, apnea, and desaturation. A distinct aEEG seizure pattern, consisting of a sudden rise of the lower and upper margin of the aEEG, followed by a marked depression of the aEEG amplitude, was found in 8 of the 9 patients. Prompt recognition of this pattern led to early treatment with carbamazepine in the 2 most recent cases.

Conclusion: Early recognition of the electroclinical phenotype by using aEEG may direct genetic testing and a precision medicine approach with sodium channel blockers in neonates with KCNQ2 mutations.
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http://dx.doi.org/10.1159/000478651DOI Listing
July 2018

Profile of neonatal epilepsies: Characteristics of a prospective US cohort.

Neurology 2017 Aug 21;89(9):893-899. Epub 2017 Jul 21.

From the Department of Pediatrics & Communicable Diseases (R.A.S.), University of Michigan, Ann Arbor; Departments of Neurology & Pediatrics (C.J.W.), Stanford University, Palo Alto, CA; Department of Neurology (T.N.T., N.W.), Children's National Health System, George Washington University School of Medicine, Washington, DC; Departments of Neurology and Pediatrics (H.C.G., M.R.C.), UCSF Benioff Children's Hospital, and Department of Epidemiology & Biostatistics (H.C.G.), University of California San Francisco; Department of Neurology (C.J.C.), Massachusetts General Hospital, Boston; Departments of Neurology and Pediatrics (S.L.M., N.S.A.), The Children's Hospital of Philadelphia and The Perelman School of Medicine at the University of Pennsylvania; and Department of Neurology (J.S.S.), Boston Children's Hospital, MA.

Objective: Although individual neonatal epilepsy syndromes are rare, as a group they represent a sizable subgroup of neonatal seizure etiologies. We evaluated the profile of neonatal epilepsies in a prospective cohort of newborns with seizures.

Methods: Consecutive newborns with seizures were enrolled in the Neonatal Seizure Registry (an association of 7 US children's hospitals). Treatment and diagnostic testing were at the clinicians' discretion. Neonates with seizures related to epileptic encephalopathies (without structural brain abnormalities), brain malformations, or benign familial epilepsies were included in this analysis.

Results: Among 611 consecutive newborns with seizures, 79 (13%) had epilepsy (35 epileptic encephalopathy, 32 congenital brain malformations, 11 benign familial neonatal epilepsy [BFNE], 1 benign neonatal seizures). Twenty-nine (83%) with epileptic encephalopathy had genetic testing and 24/29 (83%) had a genetic etiology. Pathogenic or likely pathogenic variants (n = 10) were the most commonly identified etiology of epileptic encephalopathy. Among 23 neonates with brain malformations who had genetic testing, 7 had putative genetic etiologies. Six infants with BFNE had genetic testing; 3 had pathogenic variants and 1 had a pathogenic variant. Comorbid illnesses that predisposed to acute symptomatic seizures occurred in 3/35 neonates with epileptic encephalopathy vs 10/32 with brain malformations ( = 0.03). Death or discharge to hospice were more common among newborns with brain malformations (11/32) than those with epileptic encephalopathy (3/35, = 0.01).

Conclusions: Neonatal epilepsy is often due to identifiable genetic causes. Genetic testing is now warranted for newborns with epilepsy in order to guide management and inform discussions of prognosis.
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http://dx.doi.org/10.1212/WNL.0000000000004284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577964PMC
August 2017

Neonatal nonepileptic myoclonus is a prominent clinical feature of KCNQ2 gain-of-function variants R201C and R201H.

Epilepsia 2017 03 31;58(3):436-445. Epub 2017 Jan 31.

Departments of Neurology and Pediatrics, University of California San Francisco, San Francisco, California, U.S.A.

Objective: To analyze whether KCNQ2 R201C and R201H variants, which show atypical gain-of-function electrophysiologic properties in vitro, have a distinct clinical presentation and outcome.

Methods: Ten children with heterozygous, de novo KCNQ2 R201C or R201H variants were identified worldwide, using an institutional review board (IRB)-approved KCNQ2 patient registry and database. We reviewed medical records and, where possible, interviewed parents and treating physicians using a structured, detailed phenotype inventory focusing on the neonatal presentation and subsequent course.

Results: Nine patients had encephalopathy from birth and presented with prominent startle-like myoclonus, which could be triggered by sound or touch. In seven patients, electroencephalography (EEG) was performed in the neonatal period and showed a burst-suppression pattern. However, myoclonus did not have an EEG correlate. In many patients the paroxysmal movements were misdiagnosed as seizures. Seven patients developed epileptic spasms in infancy. In all patients, EEG showed a slow background and multifocal epileptiform discharges later in life. Other prominent features included respiratory dysfunction (perinatal respiratory failure and/or chronic hypoventilation), hypomyelination, reduced brain volume, and profound developmental delay. One patient had a later onset, and sequencing indicated that a low abundance (~20%) R201C variant had arisen by postzygotic mosaicism.

Significance: Heterozygous KCNQ2 R201C and R201H gain-of-function variants present with profound neonatal encephalopathy in the absence of neonatal seizures. Neonates present with nonepileptic myoclonus that is often misdiagnosed and treated as seizures. Prognosis is poor. This clinical presentation is distinct from the phenotype associated with loss-of-function variants, supporting the value of in vitro functional screening. These findings suggest that gain-of-function and loss-of-function variants need different targeted therapeutic approaches.
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http://dx.doi.org/10.1111/epi.13676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339037PMC
March 2017

Rapid and safe response to low-dose carbamazepine in neonatal epilepsy.

Epilepsia 2016 12 26;57(12):2019-2030. Epub 2016 Nov 26.

Department of Neurology, University of California San Francisco, San Francisco, California, U.S.A.

Objective: To evaluate treatment responses in benign familial neonatal epilepsy (BFNE).

Methods: We recruited patients with BFNE through a multicenter international collaboration and reviewed electroclinical and genetic details, and treatment response. All patients were tested at minimum for mutations/deletions in the KCNQ2, KCNQ3, and SCN2A genes.

Results: Nineteen patients were included in this study. A family history of neonatal seizures was positive in 16 patients, and one additional patient had a family history of infantile seizures. Mutations or deletions of KCNQ2 were found in 14, and of KCNQ3 in 2, of the 19 patients. In all patients, seizures began at 2-5 days of life and occurred multiple times per day. Four patients developed status epilepticus. Seizures were focal, alternating between hemispheres, and characterized by asymmetric tonic posturing associated with apnea and desaturation, followed by unilateral or bilateral asynchronous clonic jerking. Twelve of 19 patients were treated with multiple medications prior to seizure cessation. Seventeen of (88%) 19 patients were seizure-free within hours of receiving oral carbamazepine (CBZ) or oxcarbazepine (OXC). Earlier initiation of CBZ was associated with shorter hospitalization (p < 0.01). No side effects of CBZ were reported. All patients had normal development and remain seizure-free at a mean follow-up period of 7.8 years (6 months-16 years).

Significance: This study provides evidence that CBZ is safe and rapidly effective in neonates with BFNE, even in status epilepticus. We propose that CBZ should be the drug of choice in benign familial neonatal seizures.
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http://dx.doi.org/10.1111/epi.13596DOI Listing
December 2016

Current understanding and neurobiology of epileptic encephalopathies.

Neurobiol Dis 2016 08 16;92(Pt A):72-89. Epub 2016 Mar 16.

Department of Neuroscience, IRCCS-"Mario Negri" Institute for Pharmacological Research, Milano, Italy.

Epileptic encephalopathies are a group of diseases in which epileptic activity itself contributes to severe cognitive and behavioral impairments above and beyond what might be expected from the underlying pathology alone. These impairments can worsen over time. This concept has been continually redefined since its introduction. A few syndromes are considered epileptic encephalopathies: early myoclonic encephalopathy and Ohtahara syndrome in the neonatal period, epilepsy of infancy with migrating focal seizures, West syndrome or infantile spasms, Dravet syndrome during infancy, Lennox-Gastaut syndrome, epileptic encephalopathy with continuous spikes-and-waves during sleep, and Landau-Kleffner syndrome during childhood. The inappropriate use of this term to refer to all severe epilepsy syndromes with intractable seizures and severe cognitive dysfunction has led to confusion regarding the concept of epileptic encephalopathy. Here, we review our current understanding of those epilepsy syndromes considered to be epileptic encephalopathies. Genetic studies have provided a better knowledge of neonatal and infantile epilepsy syndromes, while neuroimaging studies have shed light on the underlying causes of childhood-onset epileptic encephalopathies such as Lennox-Gastaut syndrome. Apart from infantile spasm models, we lack animal models to explain the neurobiological mechanisms at work in these conditions. Experimental studies suggest that neuroinflammation may be a common neurobiological pathway that contributes to seizure refractoriness and cognitive involvement in the developing brain.
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http://dx.doi.org/10.1016/j.nbd.2016.03.007DOI Listing
August 2016

Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes.

PLoS One 2016 18;11(3):e0150426. Epub 2016 Mar 18.

Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.

Objective: The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they have already been identified previously in a patient with epilepsy. Here, we critically re-evaluate the pathogenicity of this class of variants in a cohort of patients with common epilepsy syndromes and subsequently ask whether a significant fraction of benign variants have been misclassified as pathogenic.

Methods: We screened a discovery cohort of 448 patients with a broad range of common genetic epilepsies and 734 controls for previously reported SCN1A mutations that were assumed to be disease causing. We re-evaluated the evidence for pathogenicity of the identified variants using in silico predictions, segregation, original reports, available functional data and assessment of allele frequencies in healthy individuals as well as in a follow up cohort of 777 patients.

Results And Interpretation: We identified 8 known missense mutations, previously reported as pathogenic, in a total of 17 unrelated epilepsy patients (17/448; 3.80%). Our re-evaluation indicates that 7 out of these 8 variants (p.R27T; p.R28C; p.R542Q; p.R604H; p.T1250M; p.E1308D; p.R1928G; NP_001159435.1) are not pathogenic. Only the p.T1174S mutation may be considered as a genetic risk factor for epilepsy of small effect size based on the enrichment in patients (P = 6.60 x 10-4; OR = 0.32, fishers exact test), previous functional studies but incomplete penetrance. Thus, incorporation of previous studies in genetic counseling of SCN1A sequencing results is challenging and may produce incorrect conclusions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0150426PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4798642PMC
August 2016

Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial.

Lancet Neurol 2016 Mar 24;15(3):270-8. Epub 2015 Dec 24.

Departments of Neurology and Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA, USA.

Background: Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe morbidity and increased mortality. Cannabis-based treatments for epilepsy have generated much interest, but scientific data are scarce. We aimed to establish whether addition of cannabidiol to existing anti-epileptic regimens would be safe, tolerated, and efficacious in children and young adults with treatment-resistant epilepsy.

Methods: In this open-label trial, patients (aged 1-30 years) with severe, intractable, childhood-onset, treatment-resistant epilepsy, who were receiving stable doses of antiepileptic drugs before study entry, were enrolled in an expanded-access programme at 11 epilepsy centres across the USA. Patients were given oral cannabidiol at 2-5 mg/kg per day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day (dependent on study site). The primary objective was to establish the safety and tolerability of cannabidiol and the primary efficacy endpoint was median percentage change in the mean monthly frequency of motor seizures at 12 weeks. The efficacy analysis was by modified intention to treat. Comparisons of the percentage change in frequency of motor seizures were done with a Mann-Whitney U test.

Results: Between Jan 15, 2014, and Jan 15, 2015, 214 patients were enrolled; 162 (76%) patients who had at least 12 weeks of follow-up after the first dose of cannabidiol were included in the safety and tolerability analysis, and 137 (64%) patients were included in the efficacy analysis. In the safety group, 33 (20%) patients had Dravet syndrome and 31 (19%) patients had Lennox-Gastaut syndrome. The remaining patients had intractable epilepsies of different causes and type. Adverse events were reported in 128 (79%) of the 162 patients within the safety group. Adverse events reported in more than 10% of patients were somnolence (n=41 [25%]), decreased appetite (n=31 [19%]), diarrhoea (n=31 [19%]), fatigue (n=21 [13%]), and convulsion (n=18 [11%]). Five (3%) patients discontinued treatment because of an adverse event. Serious adverse events were reported in 48 (30%) patients, including one death-a sudden unexpected death in epilepsy regarded as unrelated to study drug. 20 (12%) patients had severe adverse events possibly related to cannabidiol use, the most common of which was status epilepticus (n=9 [6%]). The median monthly frequency of motor seizures was 30.0 (IQR 11.0-96.0) at baseline and 15.8 (5.6-57.6) over the 12 week treatment period. The median reduction in monthly motor seizures was 36.5% (IQR 0-64.7).

Interpretation: Our findings suggest that cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. Randomised controlled trials are warranted to characterise the safety profile and true efficacy of this compound.

Funding: GW Pharmaceuticals, Epilepsy Therapy Project of the Epilepsy Foundation, Finding A Cure for Epilepsy and Seizures.
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http://dx.doi.org/10.1016/S1474-4422(15)00379-8DOI Listing
March 2016

Mild hypothermia and hemorrhagic lesions in neonates with hypoxic-ischemic encephalopathy: experience in an outborn center.

J Matern Fetal Neonatal Med 2016 17;29(12):1963-6. Epub 2015 Aug 17.

a Neonatal Intensive Care Unit, Department of Medical and Surgical Neonatology .

Objective: Therapeutic hypothermia (TH) started within six hours from birth has been shown to improve neurodevelopmental outcomes in newborns with moderate-to-severe hypoxic-ischemic encephalopathy.

Methods: Twenty-nine consecutive newborns treated with whole body cooling at the Bambino Gesú Children's Hospital between March 2011 and December 2012 were included in this study. All infants were out-born neonates. Passive cooling was always started at the birth center and continued during transportation. Pre- and post-transport risk index of physiological stability (TRIPS) scores were calculated for each patient to evaluate the impact of the transportation. Magnetic resonance imaging (MRI) was performed within 10 days of life to investigate the presence of brain injury.

Results: Among the 26 survivors, 14 had no detectable lesions and 12 presented with brain injury on MRI. Four babies presented with cerebral bleeding. Babies with cerebral hemorrhage had a worse pre-transport TRIPS score, but among these neonates no worsening between pre and post-transport score was registered.

Conclusion: The presence of cerebral hemorrhagic lesions seemed to be related to the initial clinical conditions of the baby rather than to the transport itself. Our data confirm that TH performed in an out-born center is efficient and safe.
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http://dx.doi.org/10.3109/14767058.2015.1070138DOI Listing
January 2017

Transcriptional regulator PRDM12 is essential for human pain perception.

Nat Genet 2015 Jul 25;47(7):803-8. Epub 2015 May 25.

1] Department of Medical Genetics, University of Cambridge, Cambridge, UK. [2] Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.

Pain perception has evolved as a warning mechanism to alert organisms to tissue damage and dangerous environments. In humans, however, undesirable, excessive or chronic pain is a common and major societal burden for which available medical treatments are currently suboptimal. New therapeutic options have recently been derived from studies of individuals with congenital insensitivity to pain (CIP). Here we identified 10 different homozygous mutations in PRDM12 (encoding PRDI-BF1 and RIZ homology domain-containing protein 12) in subjects with CIP from 11 families. Prdm proteins are a family of epigenetic regulators that control neural specification and neurogenesis. We determined that Prdm12 is expressed in nociceptors and their progenitors and participates in the development of sensory neurons in Xenopus embryos. Moreover, CIP-associated mutants abrogate the histone-modifying potential associated with wild-type Prdm12. Prdm12 emerges as a key factor in the orchestration of sensory neurogenesis and may hold promise as a target for new pain therapeutics.
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http://dx.doi.org/10.1038/ng.3308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212047PMC
July 2015
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