Publications by authors named "Rima Nabbout"

204 Publications

Improving early diagnosis of rare diseases using Natural Language Processing in unstructured medical records: an illustration from Dravet syndrome.

Orphanet J Rare Dis 2021 Jul 13;16(1):309. Epub 2021 Jul 13.

Department of Pediatric Neurology, Necker-Enfants Malades Hospital, APHP, Centre de Référence Épilepsies Rares, Member of ERN EPICARE, Université de Paris, Paris, France.

Background: The growing use of Electronic Health Records (EHRs) is promoting the application of data mining in health-care. A promising use of big data in this field is to develop models to support early diagnosis and to establish natural history. Dravet Syndrome (DS) is a rare developmental and epileptic encephalopathy that commonly initiates in the first year of life with febrile seizures (FS). Age at diagnosis is often delayed after 2 years, as it is difficult to differentiate DS at onset from FS. We aimed to explore if some clinical terms (concepts) are significantly more used in the electronic narrative medical reports of individuals with DS before the age of 2 years compared to those of individuals with FS. These concepts would allow an earlier detection of patients with DS resulting in an earlier orientation toward expert centers that can provide early diagnosis and care.

Methods: Data were collected from the Necker Enfants Malades Hospital using a document-based data warehouse, Dr Warehouse, which employs Natural Language Processing, a computer technology consisting in processing written information. Using Unified Medical Language System Meta-thesaurus, phenotype concepts can be recognized in medical reports. We selected individuals with DS (DS Cohort) and individuals with FS (FS Cohort) with confirmed diagnosis after the age of 4 years. A phenome-wide analysis was performed evaluating the statistical associations between the phenotypes of DS and FS, based on concepts found in the reports produced before 2 years and using a series of logistic regressions.

Results: We found significative higher representation of concepts related to seizures' phenotypes distinguishing DS from FS in the first phases, namely the major recurrence of complex febrile convulsions (long-lasting and/or with focal signs) and other seizure-types. Some typical early onset non-seizure concepts also emerged, in relation to neurodevelopment and gait disorders.

Conclusions: Narrative medical reports of individuals younger than 2 years with FS contain specific concepts linked to DS diagnosis, which can be automatically detected by software exploiting NLP. This approach could represent an innovative and sustainable methodology to decrease time of diagnosis of DS and could be transposed to other rare diseases.
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http://dx.doi.org/10.1186/s13023-021-01936-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278630PMC
July 2021

A KCNC1 mutation in Epilepsy of Infancy with Focal Migrating Seizures produces functional channels that fail to be regulated by phosphorylation.

J Neurophysiol 2021 Jul 7. Epub 2021 Jul 7.

Department of Pharmacology, grid.47100.32Yale University School of Medicine, New Haven, CT, United States.

Channelopathies caused by mutations in genes encoding ion channels generally produce a clear change in channel function. Accordingly, mutations in KCNC1, which encodes the voltage-dependent Kv3.1 potassium channel, result in Progressive Myoclonus Epilepsy as well as other Developmental and Epileptic Encephalopathies, and these have been shown to reduce or fully abolish current amplitude. One exception to this is the mutation A513V Kv3.1b, located in the cytoplasmic C-terminal domain of the channel protein. This de novo variant was detected in a patient with Epilepsy of Infancy with Focal Migrating Seizures (EIFMS) but no difference could be detected between A513V Kv3.1 current and that of wild type Kv3.1. Using both biochemical and electrophysiological approaches, we have now confirmed that this variant produces functional channels but find that the A513V mutation renders the channel completely insensitive to regulation by phosphorylation at S503, a nearby regulatory site in the C-terminus. In this respect, the mutation resembles those in another channel, KCNT1, which are the major cause of EIFMS. Because the amplitude of Kv3.1 current is constantly adjusted by phosphorylation in vivo, our findings suggest that loss of such regulation contributes to EIFMS phenotype and emphasize the role of channel modulation for normal neuronal function.
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http://dx.doi.org/10.1152/jn.00257.2021DOI Listing
July 2021

Rare manifestations and malignancies in tuberous sclerosis complex: findings from the TuberOus SClerosis registry to increAse disease awareness (TOSCA).

Orphanet J Rare Dis 2021 Jul 6;16(1):301. Epub 2021 Jul 6.

Cardiology Clinical Academic Group, Molecular and Clinical Sciences Research Centre, St Georges University of London, London, UK.

Background: Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant disorder caused by pathogenic variants in either the TSC1 or TSC2 gene. Common manifestations of TSC have been grouped into major and minor clinical diagnostic criteria and assessed in clinical routine workup. However, case studies point towards the existence of rare disease manifestations and to the potential association of TSC with malignant tumors. In this study we sought to characterize rare manifestations and malignancies using a large cohort of patients.

Methods: TuberOus SClerosis registry to increAse disease awareness (TOSCA) is a multicenter, international disease registry collecting clinical manifestations and characteristics of patients with TSC, both retrospectively and prospectively. We report rates and characteristics of rare manifestations and malignancies in patients with TSC who had enrolled in the TOSCA registry. We also examined these manifestations by age, sex, and genotype (TSC1 or TSC2).

Results: Overall, 2211 patients with TSC were enrolled in the study. Rare manifestations were reported in 382 (17.3%) study participants and malignancies in 65 (2.9%). Of these rare manifestations, the most frequent were bone sclerotic foci (39.5%), scoliosis (23%), thyroid adenoma (5.5%), adrenal angiomyolipoma (4.5%), hemihypertrophy and pancreatic neuroendocrine tumors (pNET; both 3.1%). These rare manifestations were more commonly observed in adults than children (66.2% vs. 22.7%), in females versus males (58.4% vs. 41.6%; except for scoliosis: 48.9% vs. 51.1%), and in those with TSC2 versus TSC1 (67.0% vs. 21.1%; except for thyroid adenoma: 42.9% vs. 57.1%). In the 65 individuals with reported malignancies, the most common were renal cell carcinoma (47.7%), followed by breast (10.8%) and thyroid cancer (9.2%). Although malignancies were more common in adult patients, 26.1% were reported in children and 63.1% in individuals < 40 years. TSC1 mutations were over-represented in individuals with malignancies compared to the overall TOSCA cohort (32.1% vs. 18.5%).

Conclusion: Rare manifestations were observed in a significant proportion of individuals with TSC. We recommend further examination of rare manifestations in TSC. Collectively, malignancies were infrequent findings in our cohort. However, compared to the general population, malignant tumors occurred earlier in age and some tumor types were more common.
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http://dx.doi.org/10.1186/s13023-021-01917-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259106PMC
July 2021

Reply to Dravet, C. Different Outcomes of Acute Encephalopathy after Status Epilepticus in Patients with Dravet Syndrome. How to Avoid Them? Comment on "De Liso et al. Fatal Status Epilepticus in Dravet Syndrome. . 2020, , 889".

Brain Sci 2021 Jun 18;11(6). Epub 2021 Jun 18.

Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS, Full Member of European Reference Network EpiCARE, 00165 Rome, Italy.

It has been an honor for us to receive a comment on our article "Fatal Status Epilepticus in Dravet Syndrome" [...].
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http://dx.doi.org/10.3390/brainsci11060811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234181PMC
June 2021

Improved everyday executive functioning following profound reduction in seizure frequency with fenfluramine: Analysis from a phase 3 long-term extension study in children/young adults with Dravet syndrome.

Epilepsy Behav 2021 08 20;121(Pt A):108024. Epub 2021 May 20.

University of California San Francisco, Benioff Children's Hospital, 1975 4th Street, San Francisco, CA 94158, USA.

Objective: Individuals with Dravet syndrome (DS) experience frequent pharmacoresistant seizures beginning in infancy. Most exhibit poor neurodevelopmental outcomes including motor function difficulties, behavior problems, and cognitive impairment. Cognitive deficits in children with DS have been associated with seizure frequency and antiseizure medication (ASM) use. Recent research in children and young adults with DS has begun to examine the role of executive functions (EFs), as these include higher-order cognitive functions and may mediate the relationship between risk factors and cognitive impairment. Current conceptualizations, however, of EFs involve the broader self-regulation of cognitive, behavioral, and emotional domains. We explored relationships between reduction in convulsive seizure frequency and everyday EFs in a subset of children and young adults with DS treated with adjunctive fenfluramine for 1 year.

Methods: This is a post-hoc analysis of data from children and young adults with Dravet syndrome aged 5-18 years who participated in a phase 3 randomized, placebo-controlled clinical trial (core study) followed by completion of at least 1 year of fenfluramine treatment in an open-label extension (OLE) study. Eligible children and young adults started the OLE study at 0.2 mg/kg/day fenfluramine and were titrated to optimal seizure control and tolerability (maximum daily dose: 26 mg/day). Parents/caregivers documented convulsive seizure frequency per 28 days (i.e., monthly convulsive seizure frequency [MCSF]) by electronic diary. A parent/caregiver for each child also completed the Behavior Rating Inventory of Executive Function (BRIEF®) parent form, a questionnaire capturing parents'/caregivers' perceptions of everyday EF that was included as a safety measure to assess treatment-related adverse effects on EF during the trial. Ratings on BRIEF® were mapped to the current edition, the BRIEF®2 parent form, and were used to calculate T-scores for the Behavior Regulation Index (BRI), Emotion Regulation Index (ERI), Cognitive Regulation Index (CRI), and Global Executive Composite (GEC). Change in BRIEF®2 T-scores from baseline in the core study to Year 1 of the OLE study was calculated. Spearman's rho correlation coefficients assessed associations between change in BRIEF®2 indexes/composite T-scores and percentage change in MCSF. Children and young adults were divided into 2 groups based on percentage of MCSF reduction achieved from pre-randomization baseline in the core study to Year 1 of the OLE study: <50% and ≥50% MCSF reduction. Changes in the distribution of BRIEF®2 indexes/composite T-scores were compared between MCSF reduction groups using Mann-Whitney U tests. The proportions of children and young adults in these groups who showed clinically meaningful improvement in everyday EF, defined as Reliable Change Index (RCI) values ≥95% certainty relative to a reference population of neurotypically developing healthy volunteers, were then assessed by cross-tabulations and Somers' D tests (p ≤ 0.05). When there was a significant meaningful improvement in an index score, post-hoc analyses using the same statistical methods were conducted to evaluate the individual BRIEF®2 scales composing that index. Supplemental analyses examined the proportions of patients in MCSF reduction groups <25% and ≥75% who achieved clinically meaningful improvement or worsening in everyday EF using RCI values ≥95% certainty and ≥80% certainty, respectively, relative to the reference population.

Results: At the time of analysis, 58 children and young adults (mean age: 11 ± 4 years) had reached OLE Year 1 of fenfluramine treatment with a 75% median percentage reduction in seizure frequency from pre-randomization baseline. Overall, there was a significant correlation between change in MCSF and change in BRIEF®2 T-scores for ERI (p = 0.008), but not for BRI, CRI, or GEC (p > 0.05). At OLE Year 1, 78% (n = 45) of total children/young adults had ≥50% MCSF reduction (50% [n = 29] achieved ≥75% MCSF reduction) and 22% (n = 13) of total children/young adults had <50% MCSF reduction (12% [n = 7] showed <25% MCSF reduction). The ≥50% MCSF reduction group was significantly more likely to achieve clinically meaningful improvement (RCI ≥ 95% certainty) in ERI (p = 0.002) and in CRI (p = 0.001) than the <50% MCSF reduction group. There were no significant differences in the proportions of children and young adults in the 2 MCSF reduction groups showing clinically meaningful worsening (RCI ≥ 80% certainty) on the BRIEF®2 indexes/composite.

Significance: In children and young adults with DS, the magnitude of reduction in MCSF after long-term treatment with adjunctive fenfluramine was associated with clinically meaningful levels of improvement in everyday EF. Seventy-eight percent (78%) of children and young adults treated with adjunctive fenfluramine for 1 year in the OLE study achieved ≥50% reduction in MCSF, for a magnitude of efficacy associated with a significantly greater likelihood of experiencing clinically meaningful improvement in emotion regulation and cognitive regulation.
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http://dx.doi.org/10.1016/j.yebeh.2021.108024DOI Listing
August 2021

Predictive Performance of Population Pharmacokinetic Models of Levetiracetam in Children and Evaluation of Dosing Regimen.

J Clin Pharmacol 2021 May 16. Epub 2021 May 16.

Service de Pharmacologie Clinique, Hôpital Cochin, APHP, Paris, France.

Levetiracetam is a broad-spectrum antiepileptic drug that exhibits high interindividual variability in serum concentrations in children. A population pharmacokinetic approach can be used to explain this variability and optimize dosing schemes. The objectives are to identify the best predictive population pharmacokinetic model for children and to evaluate recommended doses using simulations and Bayesian forecasting. A validation cohort included children treated with levetiracetam who had a serum drug concentration assayed during therapeutic drug monitoring. We assessed the predictive performance of all the population pharmacokinetic models published in the literature using mean prediction errors, root mean squared errors, and visual predictive checks. A population model was finally constructed on the data, and dose simulations were performed to evaluate doses. We included 267 levetiracetam concentrations ranging from 2 to 69 mg/L from 194 children in the validation cohort. Six published models were externally evaluated. Most of the models underestimated the variability of our population. A 1-compartment model with first-order absorption and elimination with allometric scaling was finally fitted on our data. In our cohort, 57% of patients had a trough concentration <12 mg/L and 12% <5 mg/L. To reach a trough concentration >5 mg/L, doses ≥30 mg/kg/d for patients ≤50 kg and ≥2000 mg/d for patients >50 kg are required. In our population, a high percentage of children had low trough concentrations. Our population pharmacokinetic model could be used for therapeutic drug monitoring of levetiracetam in children.
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http://dx.doi.org/10.1002/jcph.1910DOI Listing
May 2021

Inflammation in pediatric epilepsies: Update on clinical features and treatment options.

Epilepsy Behav 2021 Apr 15:107959. Epub 2021 Apr 15.

Department of Pediatric Neurology, Necker Enfants Malades Hospital, Reference Centre for Rare Epilepsies and Member of the ERN EpiCARE, Imagine Institute UMR1163, Paris Descartes University, Paris, France.

The role of inflammation is increasingly recognized in triggering or sustaining epileptic activity. In the last decades, increasing research has provided definite evidence to support the link between immunity, inflammatory process, and epilepsy. Neuro- and systemic inflammation play a pivotal role in driving epileptogenesis through different pathogenetic mechanisms: the activation of innate immunity in glia, neurons, and microvasculature, the brain mediated by blood-brain barrier (BBB) impairment, and the imbalance of pro- and anti-inflammatory molecules produced by both arms of immunity. More recently, research has focused on the adverse effects of maternal or early-life immune activation and cytokine imbalance on fetal neurodevelopment and postnatal epilepsy. A complex crosstalk between the immune and nervous system, and a crucial interplay of genetic, epigenetic, and environmental factors may influence structures and functions of the developing brain. A better understanding of the inflammatory process in promoting epilepsy implies that targeting specific pathways may be effective in seizure control. Multiple targets have been identified so far, and several antiseizure interventions are obtained by inhibiting inflammatory signaling or protecting/restoring BBB. All this evidence has changed the field of epilepsy research and neuropharmacology. Further developments and new treatments will rapidly emerge to improve seizure management in inflammation-related epilepsies. This article is part of the Special Issue "Severe Infantile Epilepsies".
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http://dx.doi.org/10.1016/j.yebeh.2021.107959DOI Listing
April 2021

TuberOus SClerosis registry to increAse disease awareness (TOSCA) Post-Authorisation Safety Study of Everolimus in Patients With Tuberous Sclerosis Complex.

Front Neurol 2021 23;12:630378. Epub 2021 Mar 23.

Pediatric Neurology Unit, Department of Paediatrics, UZ Brussel VUB, Brussels, Belgium.

This non-interventional post-authorisation safety study (PASS) assessed the long-term safety of everolimus in patients with tuberous sclerosis complex (TSC) who participated in the TuberOus SClerosis registry to increase disease Awareness (TOSCA) clinical study and received everolimus for the licensed indications in the European Union. The rate of adverse events (AEs), AEs that led to dose adjustments or treatment discontinuation, AEs of potential clinical interest, treatment-related AEs (TRAEs), serious AEs (SAEs), and deaths were documented. One hundred seventy-nine patients were included in the first 5 years of observation; 118 of 179 patients had an AE of any grade, with the most common AEs being stomatitis (7.8%) and headache (7.3%). AEs caused dose adjustments in 56 patients (31.3%) and treatment discontinuation in nine patients (5%). AEs appeared to be more frequent and severe in children. On Tanner staging, all patients displayed signs of age-appropriate sexual maturation. Twenty-two of 106 female (20.8%) patients had menstrual cycle disorders. The most frequent TRAEs were stomatitis (6.7%) and aphthous mouth ulcer (5.6%). SAEs were reported in 54 patients (30.2%); the most frequent SAE was pneumonia (>3% patients; grade 2, 1.1%, and grade 3, 2.8%). Three deaths were reported, all in patients who had discontinued everolimus for more than 28 days, and none were thought to be related to everolimus according to the treating physicians. The PASS sub-study reflects the safety and tolerability of everolimus in the management of TSC in real-world routine clinical practice.
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http://dx.doi.org/10.3389/fneur.2021.630378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021912PMC
March 2021

Early epileptiform EEG activity in infants with tuberous sclerosis complex predicts epilepsy and neurodevelopmental outcomes.

Epilepsia 2021 May 29;62(5):1208-1219. Epub 2021 Mar 29.

Department of Development and Regeneration, Section Pediatric Neurology, Catholic University of Leuven (KU Leuven), Leuven, Belgium.

Objective: To study the association between timing and characteristics of the first electroencephalography (EEG) with epileptiform discharges (ED-EEG) and epilepsy and neurodevelopment at 24 months in infants with tuberous sclerosis complex (TSC).

Methods: Patients enrolled in the prospective Epileptogenesis in a genetic model of epilepsy - Tuberous sclerosis complex (EPISTOP) trial, had serial EEG monitoring until the age of 24 months. The timing and characteristics of the first ED-EEG were studied in relation to clinical outcome. Epilepsy-related outcomes were analyzed separately in a conventionally followed group (initiation of vigabatrin after seizure onset) and a preventive group (initiation of vigabatrin before seizures, but after appearance of interictal epileptiform discharges [IEDs]).

Results: Eighty-three infants with TSC were enrolled at a median age of 28 days (interquartile range [IQR] 14-54). Seventy-nine of 83 patients (95%) developed epileptiform discharges at a median age of 77 days (IQR 23-111). Patients with a pathogenic TSC2 variant were significantly younger (P-value .009) at first ED-EEG and more frequently had multifocal IED (P-value .042) than patients with a pathogenic TSC1 variant. A younger age at first ED-EEG was significantly associated with lower cognitive (P-value .010), language (P-value .001), and motor (P-value .013) developmental quotients at 24 months. In the conventional group, 48 of 60 developed seizures. In this group, the presence of focal slowing on the first ED-EEG was predictive of earlier seizure onset (P-value .030). Earlier recording of epileptiform discharges (P-value .019), especially when multifocal (P-value .026) was associated with higher risk of drug-resistant epilepsy. In the preventive group, timing, distribution of IED, or focal slowing, was not associated with the epilepsy outcomes. However, when multifocal IEDs were present on the first ED-EEG, preventive treatment delayed the onset of seizures significantly (P-value <.001).

Significance: Early EEG findings help to identify TSC infants at risk of severe epilepsy and neurodevelopmental delay and those who may benefit from preventive treatment with vigabatrin.
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http://dx.doi.org/10.1111/epi.16892DOI Listing
May 2021

West Syndrome Is an Exceptional Presentation of Pyridoxine- and Pyridoxal Phosphate-Dependent Epilepsy: Data From a French Cohort and Review of the Literature.

Front Pediatr 2021 5;9:621200. Epub 2021 Mar 5.

Service de neuropédiatrie, CHU d'Angers, Angers, France.

To characterize the electro-clinical presentation of patients with pyridoxine-dependent epilepsy (PDE) and pyridoxal phosphate (PLP)-dependent epilepsy in order to determine whether some of them could be diagnosed as West syndrome, i. e., West syndrome that starts after the age of 2 months without other types of seizures (focal seizures for instance) before the onset of epileptic spasms. We analyzed data from an unpublished cohort of 28 genetically confirmed cases of PDE with antiquitine (ATQ) deficiency and performed a review of the literature looking for description of West syndrome in patients with either PDE with ATQ deficiency or PLP-dependent epilepsy with Pyridox(am)ine phosphate oxidase (PNPO) deficiency. Of the 28 cases from the ATQ deficiency French cohort, 5 had spasms. In four cases, spasms were associated with other types of seizures (myoclonus, focal seizures). In the last case, seizures started on the day of birth. None of these cases corresponded to West syndrome. The review of the literature found only one case of PNPO deficiency presenting as West syndrome and no case of ATQ deficiency. The presentation of PDE- and PLP-dependent epilepsy as West syndrome is so exceptional that it probably does not justify a systematic trial of pyridoxine or PLP. We propose considering a therapeutic trial with these vitamins in West syndrome if spasms are associated with other seizure types or start before the age of 2 months.
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http://dx.doi.org/10.3389/fped.2021.621200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973036PMC
March 2021

Impact of the COVID-19 lockdown on patients and families with Dravet syndrome.

Epilepsia Open 2021 03 25;6(1):216-224. Epub 2021 Jan 25.

Centre de Référence Épilepsies Rares Necker Enfants MaladesUniversity Hospital Department of Pediatric Neurology Member of EPICARE European Reference Network Epicare Institut Imagine U1163 Université de Paris Paris France.

We explored the impact of coronavirus virus 2019 (COVID-19) pandemic on patients with Dravet syndrome (DS) and their family. With European patient advocacy groups (PAGs), we developed an online survey in 10 languages to question health status, behavior, personal protection, and health services before and after lockdown. Approximately 538 European PAG members received electronic invitations. Survey ran from April 14, to May 17, 2020, with 219 answers; median age 9 year 10 months. Protection against infection was highly used prior to COVID-19, but 88% added facemask-use according to pandemic recommendations. Only one patient was tested positive for COVID-19. Most had stable epilepsy during lockdown, and few families (4%) needed emergency care during lockdown. However, behavior disorder worsened in over one-third of patients, regardless of epilepsy changes. Half of appointments scheduled prior to lockdown were postponed; 12 patients (11%) had appointments fulfilled; and 39 (36%) had remote consultations. Responders welcomed remote consultations. Half of responders were unsatisfied with psychological remote support as only few (21 families) received this support. None of the five of patient in clinical trials stopped investigational treatment. Prior adoption of protective measures against general infection might have contributed to avoiding COVID-19 infections. Protocols for the favored remote contact ought to now be prepared.
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http://dx.doi.org/10.1002/epi4.12464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918338PMC
March 2021

A survey of the European Reference Network EpiCARE on clinical practice for selected rare epilepsies.

Epilepsia Open 2021 03 13;6(1):160-170. Epub 2021 Jan 13.

IRCCS Mondino Foundation Pavia Italy.

Objective: Clinical care of rare and complex epilepsies is challenging, because evidence-based treatment guidelines are scarce, the experience of many physicians is limited, and interdisciplinary treatment of comorbidities is required. The pathomechanisms of rare epilepsies are, however, increasingly understood, which potentially fosters novel targeted therapies. The objectives of our survey were to obtain an overview of the clinical practice in European tertiary epilepsy centers treating patients with 5 arbitrarily selected rare epilepsies and to get an estimate of potentially available patients for future studies.

Methods: Members of the ( were invited to participate in a web-based survey on clinical practice of patients with Dravet syndrome, tuberous sclerosis complex (TSC), autoimmune encephalitis, and progressive myoclonic epilepsies including Unverricht Lundborg and Unverricht-like diseases. A consensus-based questionnaire was generated for each disease.

Results: Twenty-six of 30 invited epilepsy centers participated. Cohorts were present in most responding centers for TSC (87%), Dravet syndrome (85%), and autoimmune encephalitis (71%). Patients with TSC and Dravet syndrome represented the largest cohorts in these centers. The antiseizure drug treatments were rather consistent across the centers especially with regard to Dravet syndrome, infantile spasms in TSC, and Unverricht Lundborg / Unverricht-like disease. Available, widely used targeted therapies included everolimus in TSC and immunosuppressive therapies in autoimmune encephalitis. Screening for comorbidities was routinely done, but specific treatment protocols were lacking in most centers.

Significance: The survey summarizes the current clinical practice for selected rare epilepsies in tertiary European epilepsy centers and demonstrates consistency as well as heterogeneity in the treatment, underscoring the need for controlled trials and recommendations. The survey also provides estimates for potential participants of clinical trials recruited via EpiCARE, emphasizing the great potential of Reference Networks for future studies to evaluate new targeted therapies and to identify novel biomarkers.
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http://dx.doi.org/10.1002/epi4.12459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918306PMC
March 2021

Proposal to optimize evaluation and treatment of Febrile infection-related epilepsy syndrome (FIRES): A Report from FIRES workshop.

Epilepsia Open 2021 03 13;6(1):62-72. Epub 2021 Jan 13.

Department of Pediatrics Phoenix Children's Hospital Phoenix AZ USA.

Febrile infection-related epilepsy syndrome (FIRES) is a rare catastrophic epileptic encephalopathy that presents suddenly in otherwise normal children and young adults causing significant neurological disability, chronic epilepsy, and high rates of mortality. To suggest a therapy protocol to improve outcome of FIRES, workshops were held in conjunction with American Epilepsy Society annual meeting between 2017 and 2019. An international group of pediatric epileptologists, pediatric neurointensivists, rheumatologists and basic scientists with interest and expertise in FIRES convened to propose an algorithm for a standardized approach to the diagnosis and treatment of FIRES. The broad differential for refractory status epilepticus (RSE) should include FIRES, to allow empiric therapies to be started early in the clinical course. FIRES should be considered in all previously healthy patients older than two years of age who present with explosive onset of seizures rapidly progressing to RSE, following a febrile illness in the preceding two weeks. Once FIRES is suspected, early administrations of ketogenic diet and anakinra (the IL-1 receptor antagonist that blocks biologic activity of IL-1β) are recommended.
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http://dx.doi.org/10.1002/epi4.12447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918329PMC
March 2021

Safety considerations selecting antiseizure medications for the treatment of individuals with Dravet syndrome.

Expert Opin Drug Saf 2021 May 28;20(5):561-576. Epub 2021 Feb 28.

Reference Centre for Rare Epilepsies, Department of Pediatric Neurology, Necker Enfants Malades University Hospital, Université De Paris, Paris, France.

: Management of individuals with Dravet Syndrome has evolved significantly over the past 10 years. Progress has been made in understanding the pathophysiology, the long-term outcome and possible consequences of inappropriate therapies, new drugs have been approved by the regulatory authorities and patients and families expressed their needs beyond seizures' control.: The authors aimed at providing an overview of the main antiseizure medications used in Dravet syndrome with a particular focus on safety considerations. As the highly active phase of seizures takes place before the age of 5 years, the characteristics of antiseizure medications in infancy and childhood have also been considered due to their impact on antiseizure medication safety.: Recent treatments, evaluated via randomized clinical trials, are promising in terms of efficacy and safety in individuals with DS. However, the balance between expected benefits and risks taken must be accurately assessed on an individual basis. There is a lack of data to understand the needs of patients and families, a major point particularly in this population, where the evaluation of efficacy and safety beyond seizures is difficult due to cognitive delay and behavioral disorders and where this evaluation is coming almost exclusively from caregivers.
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http://dx.doi.org/10.1080/14740338.2021.1890025DOI Listing
May 2021

Fetal Brain Magnetic Resonance Imaging Findings Predict Neurodevelopment in Children with Tuberous Sclerosis Complex.

J Pediatr 2021 Jun 26;233:156-162.e2. Epub 2021 Feb 26.

Department of Pediatric Neurology, Necker Enfants Maladies Hospital, Paris, France (Member of the European Reference Network EpiCARE).

Objective: To correlate fetal brain magnetic resonance imaging (MRI) findings with epilepsy characteristics and neurodevelopment at 2 years of age in children with tuberous sclerosis complex (TSC) to improve prenatal counseling.

Study Design: This retrospective cohort study was performed in a collaboration between centers of the EPISTOP consortium. We included children with definite TSC, fetal MRIs, and available follow-up data at 2 years of age. A pediatric neuroradiologist masked to the patient's clinical characteristics evaluated all fetal MRIs. MRIs were categorized for each of the 10 brain lobes as score 0: no (sub)cortical lesions or doubt; score 1: a single small lesion; score 2: more than one small lesion or at least one large lesion (>5 mm). Neurologic manifestations were correlated to lesion sum scores.

Results: Forty-one children were included. Median gestational age at MRI was 33.3 weeks; (sub)cortical lesions were detected in 97.6%. Mean lesion sum score was 4.5. At 2 years, 58.5% of patients had epilepsy and 22% had drug-resistant epilepsy. Cognitive, language, and motor development were delayed in 38%, 81%, and 50% of patients, respectively. Autism spectrum disorder (ASD) was diagnosed in 20.5%. Fetal MRI lesion sum scores were significantly associated with cognitive and motor development, and with ASD diagnosis, but not with epilepsy characteristics.

Conclusions: Fetal cerebral lesion scores correlate with neurodevelopment and ASD at 2 years in children with TSC.
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http://dx.doi.org/10.1016/j.jpeds.2021.02.060DOI Listing
June 2021

SYNGAP1-DEE: A visual sensitive epilepsy.

Clin Neurophysiol 2021 Apr 3;132(4):841-850. Epub 2021 Feb 3.

Reference Centre for Rare Epilepsies, Department of Pediatric Neurology, Necker Enfants Malades Hospital, Imagine Institute, Paris Descartes University, Paris, France; Department of Paediatric Neurology, Necker-Enfants Malades Hospital, University of Paris, AP-HP, Paris, France. Electronic address:

Objective: To further delineate the electroclinical features of individuals with SYNGAP1 pathogenic variants.

Methods: Participants with pathogenic SYNGAP1 variants and available video-electroencephalogram (EEG) recordings were recruited within five European epilepsy reference centers. We obtained molecular and clinical data, analyzed EEG recordings and archived video-EEGs of seizures and detailed characteristics of interictal and ictal EEG patterns for every patient.

Results: We recruited 15 previously unreported patients and analyzed 72 EEGs. Two distinct EEG patterns emerged, both triggered by eye closure. Pattern 1 (14/15 individuals) consisted of rhythmic posterior/diffuse delta waves appearing with eye-closure and persisting until eye opening (strongly suggestive of fixation-off sensitivity). Pattern 2 (9/15 individuals) consisted of diffuse polyspike-and-wave discharges triggered by eye closure (eye-closure sensitivity). Both patterns presented in 8/15. Including archived video-EEG clips of seizures from 9/15 patients, we analyzed 254 seizures. Of 224 seizures experienced while awake, 161 (72%) occurred at or following eye closure. In 119/161, pattern 1 preceded an atypical absence, myoclonic seizure or myoclonic absence; in 42/161, pattern 2 was associated with eyelid myoclonia, absences and myoclonic or atonic seizures.

Conclusions: Fixation-off and eye closure were the main triggers for seizures in this SYNGAP1 cohort.

Significance: Combining these clinical and electroencephalographic features could help guide genetic diagnosis.
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http://dx.doi.org/10.1016/j.clinph.2021.01.014DOI Listing
April 2021

Jerking during absences: video-EEG and polygraphy of epileptic myoclonus associated with two paediatric epilepsy syndromes.

Epileptic Disord 2021 Feb;23(1):191-200

Department of Clinical Neurophysiology, Necker-Enfants Malades Hospital, APHP, Paris, France.

Epileptic myoclonus (EM) is reported in many paediatric epilepsies from neonatal period to adolescence. Myoclonus can be the only seizure type or may occur among others, independently or in combination as a single ictal event. We report two children presenting with absences associated with myoclonus, predominating on one side, in a setting of two different types of absence seizures and two different electro-clinical syndromes. Patients were explored with long-duration video-EEG coupled to surface EMG polygraphy. EEG was visually analysed and complemented by jerk-locked back-averaging. Two types of seizure, encompassing myoclonus and absence, were identified: myoclonic absences in the context of epilepsy with myoclonic absences and atypical absences with atonic component (negative myoclonus) in the context of encephalopathy related to status epilepticus during slow sleep (ESES). In the latter case, rhythmic upper limb jerking, mimicking positive myoclonus, corresponded to recovery of muscular tone after each negative myoclonus. Due to the rhythmic recovery of muscle tone, subsequent rhythmic negative myoclonus may exhibit a similar clinical picture to that of rhythmic positive myoclonus. Video-EEG recording coupled to EMG polygraphy is essential in order to precisely characterize motor manifestations during seizures with myoclonus [Published with video sequences].
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http://dx.doi.org/10.1684/epd.2021.1240DOI Listing
February 2021

In silico model reveals the key role of GABA in KCNT1-epilepsy in infancy with migrating focal seizures.

Epilepsia 2021 Mar 22;62(3):683-697. Epub 2021 Feb 22.

LTSI-U1099, Université de Rennes 1, INSERM, Rennes, France.

Objective: This study was undertaken to investigate how gain of function (GOF) of slack channel due to a KCNT1 pathogenic variant induces abnormal neuronal cortical network activity and generates specific electroencephalographic (EEG) patterns of epilepsy in infancy with migrating focal seizures.

Methods: We used detailed microscopic computational models of neurons to explore the impact of GOF of slack channel (explicitly coded) on each subtype of neurons and on a cortical micronetwork. Then, we adapted a thalamocortical macroscopic model considering results obtained in detailed models and immature properties related to epileptic brain in infancy. Finally, we compared simulated EEGs resulting from the macroscopic model with interictal and ictal patterns of affected individuals using our previously reported EEG markers.

Results: The pathogenic variants of KCNT1 strongly decreased the firing rate properties of γ-aminobutyric acidergic (GABAergic) interneurons and, to a lesser extent, those of pyramidal cells. This change led to hyperexcitability with increased synchronization in a cortical micronetwork. At the macroscopic scale, introducing slack GOF effect resulted in epilepsy of infancy with migrating focal seizures (EIMFS) EEG interictal patterns. Increased excitation-to-inhibition ratio triggered seizure, but we had to add dynamic depolarizing GABA between somatostatin-positive interneurons and pyramidal cells to obtain migrating seizure. The simulated migrating seizures were close to EIMFS seizures, with similar values regarding the delay between the different ictal activities (one of the specific EEG markers of migrating focal seizures due to KCNT1 pathogenic variants).

Significance: This study illustrates the interest of biomathematical models to explore pathophysiological mechanisms bridging the gap between the functional effect of gene pathogenic variants and specific EEG phenotype. Such models can be complementary to in vitro cellular and animal models. This multiscale approach provides an in silico framework that can be further used to identify candidate innovative therapies.
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http://dx.doi.org/10.1111/epi.16834DOI Listing
March 2021

Deep phenotyping unstructured data mining in an extensive pediatric database to unravel a common KCNA2 variant in neurodevelopmental syndromes.

Genet Med 2021 05 26;23(5):968-971. Epub 2021 Jan 26.

Reference Centre for Rare Epilepsies, Department of Pediatric Neurology, Necker Enfants Malades hospital, Universite de Paris, Paris, France.

Purpose: Electronic health records are gaining popularity to detect and propose interdisciplinary treatments for patients with similar medical histories, diagnoses, and outcomes. These files are compiled by different nonexperts and expert clinicians. Data mining in these unstructured data is a transposable and sustainable methodology to search for patients presenting a high similitude of clinical features.

Methods: Exome and targeted next-generation sequencing bioinformatics analyses were performed at the Imagine Institute. Similarity Index (SI), an algorithm based on a vector space model (VSM) that exploits concepts extracted from clinical narrative reports was used to identify patients with highly similar clinical features.

Results: Here we describe a case of "automated diagnosis" indicated by Dr. Warehouse, a biomedical data warehouse oriented toward clinical narrative reports, developed at Necker Children's Hospital using around 500,000 patients' records. Through the use of this warehouse, we were able to match and identify two patients sharing very specific clinical neonatal and childhood features harboring the same de novo variant in KCNA2.

Conclusion: This innovative application of database clustering clinical features could advance identification of patients with rare and common genetic conditions and detect with high accuracy the natural history of patients harboring similar genetic pathogenic variants.
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http://dx.doi.org/10.1038/s41436-020-01039-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105164PMC
May 2021

Complete hemispherotomy leads to lateralized functional organization and lower level of consciousness in the isolated hemisphere.

Epilepsia Open 2020 Dec 24;5(4):537-549. Epub 2020 Sep 24.

Assistance Publique Hôpitaux de Paris Hôpital Necker-Enfants Malades Paris France.

Objective: To quantify whole-brain functional organization after complete hemispherotomy, characterizing unexplored plasticity pathways and the conscious level of the dissected hemispheres.

Methods: Evaluation with multimodal magnetic resonance imaging in two pediatric patients undergoing right hemispherotomy including complete callosotomy with a perithalamic section. Regional cerebral blood flow and fMRI network connectivity assessed the functional integrity of both hemispheres after surgery. The level of consciousness was tested by means of a support vector machine classifier which compared the intrinsic organization of the dissected hemispheres with those of patients suffering from disorders of consciousness.

Results: After hemispherotomy, both patients showed typical daily functionality. We found no interhemispheric transfer of functional connectivity in either patient as predicted by the operation. The healthy left hemispheres displayed focal blood hyperperfusion in motor and limbic areas, with preserved network-level organization. Unexpectedly, the disconnected right hemispheres showed sustained network organization despite low regional cerebral blood flow. Subcortically, functional connectivity was increased in the left thalamo-cortical loop and between the cerebelli. One patient further showed unusual ipsilateral right cerebello-cortical connectivity, which was explained by the mediation of the vascular system. The healthy left hemisphere had higher probability to be classified as in a minimally conscious state compared to the isolated right hemisphere.

Significance: Complete hemispherotomy leads to a lateralized whole-brain organization, with the remaining hemisphere claiming most of the brain's energetic reserves supported by subcortical structures. Our results further underline the contribution of nonneuronal vascular signals on contralateral connectivity, shedding light on the nature of network organization in the isolated tissue. The disconnected hemisphere is characterized by a level of consciousness which is necessary but insufficient for conscious processing, paving the way for more specific inquiries about its role in awareness in the absence of behavioral output.
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http://dx.doi.org/10.1002/epi4.12433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733653PMC
December 2020

Dosing Recommendations for Lamotrigine in Children: Evaluation Based on Previous and New Population Pharmacokinetic Models.

J Clin Pharmacol 2021 May 14;61(5):677-687. Epub 2020 Dec 14.

Service de Pharmacologie Clinique, Hôpital Cochin, APHP, Paris, France.

Lamotrigine is a broad-spectrum antiepileptic drug with high interindividual variability in serum concentrations in children. The aims of this study were to evaluate the predictive performance of pediatric population pharmacokinetic (PPK) models published on lamotrigine, to build a new model with our monitoring data and to evaluate the current recommended doses. A validation cohort included patients treated with lamotrigine who had a serum level assayed during therapeutic drug monitoring (TDM). PPK models published in the literature were first applied to the validation cohort. We assessed their predictive performance using mean prediction errors, root mean squared errors, and visual predictive checks. A new model was then built using the data. Dose simulations were performed to evaluate the doses recommended. We included 270 lamotrigine concentrations ranging from 0.5 to 17.9 mg/L from 175 patients. The median (range) age and weight were 11.8 years (0.8-18 years) and 32.7 kg (8-110 kg). We tested 6 PPK models; most had acceptable bias and precision but underestimated the variability of the cohort. We built a 1-compartment model with first-order absorption and elimination, allometric scaling, and effects of inhibitor and inducer comedications. In our cohort, 22.6% of trough concentrations were below 2.5 mg/L. In conclusion, we proposed a PPK model that can be used for TDM of lamotrigine in children. In our population, a high percentage of children had low trough concentrations of lamotrigine. As the intervals of recommended doses are large, we suggest aiming at the higher range of doses to reach the target concentration.
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http://dx.doi.org/10.1002/jcph.1791DOI Listing
May 2021

Fatal Status Epilepticus in Dravet Syndrome.

Brain Sci 2020 Nov 23;10(11). Epub 2020 Nov 23.

Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS, Full Member of European Reference Network EpiCARE, 00165 Rome, Italy.

Dravet Syndrome (DS) is burdened by high epilepsy-related premature mortality due to status epilepticus (SE). We surveyed centres within Europe through the Dravet Italia Onlus and EpiCARE network (European Reference Network for Rare and Complex Epilepsies). We collated responses on seven DS SCN1A+ patients who died following refractory SE (mean age 6.9 year, range 1.3-23.4 year); six were on valproate, clobazam, and stiripentol. All patients had previous SE. Fatal SE was always triggered by fever: either respiratory infection or one case of hexavalent vaccination. SE lasted between 80 min and 9 h and all patients received IV benzodiazepines. Four patients died during or within hours of SE; in three patients, SE was followed by coma with death occurring after 13-60 days. Our survey supports the hypothesis that unresponsive fever is a core characteristic feature of acute encephalopathy. We highlight the need for management protocols for prolonged seizures and SE in DS.
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http://dx.doi.org/10.3390/brainsci10110889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700506PMC
November 2020

Prevention of Epilepsy in Infants with Tuberous Sclerosis Complex in the EPISTOP Trial.

Ann Neurol 2021 02 27;89(2):304-314. Epub 2020 Nov 27.

Department of Neurology and Epileptology, The Children's Memorial Health Institute, Warsaw, Poland.

Objective: Epilepsy develops in 70 to 90% of children with tuberous sclerosis complex (TSC) and is often resistant to medication. Recently, the concept of preventive antiepileptic treatment to modify the natural history of epilepsy has been proposed. EPISTOP was a clinical trial designed to compare preventive versus conventional antiepileptic treatment in TSC infants.

Methods: In this multicenter study, 94 infants with TSC without seizure history were followed with monthly video electroencephalography (EEG), and received vigabatrin either as conventional antiepileptic treatment, started after the first electrographic or clinical seizure, or preventively when epileptiform EEG activity before seizures was detected. At 6 sites, subjects were randomly allocated to treatment in a 1:1 ratio in a randomized controlled trial (RCT). At 4 sites, treatment allocation was fixed; this was denoted an open-label trial (OLT). Subjects were followed until 2 years of age. The primary endpoint was the time to first clinical seizure.

Results: In 54 subjects, epileptiform EEG abnormalities were identified before seizures. Twenty-seven were included in the RCT and 27 in the OLT. The time to the first clinical seizure was significantly longer with preventive than conventional treatment [RCT: 364 days (95% confidence interval [CI] = 223-535) vs 124 days (95% CI = 33-149); OLT: 426 days (95% CI = 258-628) vs 106 days (95% CI = 11-149)]. At 24 months, our pooled analysis showed preventive treatment reduced the risk of clinical seizures (odds ratio [OR] = 0.21, p = 0.032), drug-resistant epilepsy (OR = 0.23, p = 0.022), and infantile spasms (OR = 0, p < 0.001). No adverse events related to preventive treatment were noted.

Interpretation: Preventive treatment with vigabatrin was safe and modified the natural history of seizures in TSC, reducing the risk and severity of epilepsy. ANN NEUROL 2021;89:304-314.
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http://dx.doi.org/10.1002/ana.25956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898885PMC
February 2021

Prediction of Neurodevelopment in Infants With Tuberous Sclerosis Complex Using Early EEG Characteristics.

Front Neurol 2020 16;11:582891. Epub 2020 Oct 16.

Pediatric Neurology, Department of Development and Regeneration, University of Leuven KU Leuven, Leuven, Belgium.

Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder with a high risk of early-onset epilepsy and a high prevalence of neurodevelopmental comorbidities, including intellectual disability and autism spectrum disorder (ASD). Therefore, TSC is an interesting disease model to investigate early biomarkers of neurodevelopmental comorbidities when interventions are favourable. We investigated whether early EEG characteristics can be used to predict neurodevelopment in infants with TSC. The first recorded EEG of 64 infants with TSC, enrolled in the international prospective EPISTOP trial (recorded at a median gestational age 42 4/7 weeks) was first visually assessed. EEG characteristics were correlated with ASD risk based on the ADOS-2 score, and cognitive, language, and motor developmental quotients (Bayley Scales of Infant and Toddler Development III) at the age of 24 months. Quantitative EEG analysis was used to validate the relationship between EEG background abnormalities and ASD risk. An abnormal first EEG (OR = 4.1, -value = 0.027) and more specifically a dysmature EEG background (OR = 4.6, -value = 0.017) was associated with a higher probability of ASD traits at the age of 24 months. This association between an early abnormal EEG and ASD risk remained significant in a multivariable model, adjusting for mutation and treatment (adjusted OR = 4.2, -value = 0.029). A dysmature EEG background was also associated with lower cognitive (-value = 0.029), language (-value = 0.001), and motor (-value = 0.017) developmental quotients at the age of 24 months. Our findings suggest that early EEG characteristics in newborns and infants with TSC can be used to predict neurodevelopmental comorbidities.
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http://dx.doi.org/10.3389/fneur.2020.582891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596378PMC
October 2020

Attachment insecurity in infants with infantile spasms: Maternal anxiety and sadness, and infant's temperament outweigh disease severity.

Epilepsy Behav 2020 12 5;113:107401. Epub 2020 Nov 5.

Child and Adolescent Psychiatry Unit, Necker Enfant Malades Hospital, Paris, France; Department of Pediatric Neurology, Reference centre for Rare Epilepsies, Pediatric Neurology, Necker Enfants-Malades Hospital, Paris, France. Electronic address:

Objective: The aim of this study was to investigate attachment behavior in a population of infants with infantile spasms (ISs) using the Strange Situation Procedure (SSP) and to explore factors associated with the infants' attachment behavior.

Methods: The SSP was assessed in a population of 29 children with ISs during the second year of life. In mothers, we assessed anxiety, depression, maternal emotions, and perception of the temperament of the child, and sociodemographic characteristics. In children, we assessed epilepsy characteristics, response to antiepileptic drugs (AEDs) at the time of the SSP, and the child's outcome at 3 years of age, in terms of intellectual disability (ID), and autism spectrum disorder (ASD).

Results: Insecure attachment was higher than in the general population (68% versus 32%). It was associated with maternal anxiety, sadness, and maternal representation of the child at 12 months but with none of the child characteristics including ID, ASD, response to AEDs, or ISs etiology.

Significance: Nonspecific dimensions were more important than disease characteristics for the infants' attachment behavior. In conclusion, we propose that interventions targeting mother-child interaction could prevent attachment insecurity and the developmental consequences of early epilepsy.
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http://dx.doi.org/10.1016/j.yebeh.2020.107401DOI Listing
December 2020

Fenfluramine HCl (Fintepla ) provides long-term clinically meaningful reduction in seizure frequency: Analysis of an ongoing open-label extension study.

Epilepsia 2020 11 19;61(11):2396-2404. Epub 2020 Oct 19.

Zogenix, Inc, Emeryville, CA, USA.

Objective: Fenfluramine has been shown to provide clinically meaningful and statistically significant reductions in convulsive seizure frequency in children and adolescents (aged 2-18 years) with Dravet syndrome in two randomized, placebo-controlled clinical trials. The objective of this analysis was to assess longer-term safety and efficacy of fenfluramine in patients who completed one of the double-blind studies and entered an open-label extension (OLE) study.

Methods: Patients enrolling in the OLE study initiated fenfluramine at 0.2 mg/kg/d regardless of their treatment assignment in the double-blind study. After 4 weeks, the fenfluramine dose could be titrated based on efficacy and tolerability to maximum of 0.7 mg/kg/d (absolute maximum 27 mg/d) or maximum of 0.4 mg/kg/d (absolute maximum 17 mg/d) in patients receiving concomitant stiripentol. The number and type of seizures were recorded daily in an electronic diary, and safety, including echocardiography, was assessed at Months 1, 2, and 3, and at 3-month intervals thereafter.

Results: A total of 232 patients were enrolled as of March 13, 2018. During this analysis period, patients were treated for a median 256 days (range = 46-634 days). Over the entire OLE analysis period, the median decrease in convulsive seizure frequency compared to baseline in the double-blind studies was -66.8% (range = -100% to 234.9%; P < .001). The median reduction in seizure frequency was similar in patients <6 (-75.7%) and ≥6 years old (-64.7%). The most commonly reported adverse events included pyrexia (21.6%), nasopharyngitis (19.4%), and decreased appetite (-15.9%). No valvular heart disease (VHD) or pulmonary arterial hypertension (PAH) was observed.

Significance: Study results demonstrate that fenfluramine provides clinically meaningful (≥50%) seizure frequency reduction over an extended period in patients with Dravet syndrome. No patient developed VHD or PAH, and fenfluramine was generally well tolerated.
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http://dx.doi.org/10.1111/epi.16722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756901PMC
November 2020

Impact of predictive, preventive and precision medicine strategies in epilepsy.

Nat Rev Neurol 2020 Dec 19;16(12):674-688. Epub 2020 Oct 19.

Reference Centre for Rare Epilepsies, Department of Pediatric Neurology, Necker Enfants Malades University hospital, Université de Paris, Paris, France.

Over the last decade, advances in genetics, neuroimaging and EEG have enabled the aetiology of epilepsy to be identified earlier in the disease course than ever before. At the same time, progress in the study of experimental models of epilepsy has provided a better understanding of the mechanisms underlying the condition and has enabled the identification of therapies that target specific aetiologies. We are now witnessing the impact of these advances in our daily clinical practice. Thus, now is the time for a paradigm shift in epilepsy treatment from a reactive attitude, treating patients after the onset of epilepsy and the initiation of seizures, to a proactive attitude that is more broadly integrated into a 'P4 medicine' approach. This P4 approach, which is personalized, predictive, preventive and participatory, puts patients at the centre of their own care and, ultimately, aims to prevent the onset of epilepsy. This aim will be achieved by adapting epilepsy treatments not only to a given syndrome but also to a given patient and moving from the usual anti-seizure treatments to personalized treatments designed to target specific aetiologies. In this Review, we present the current state of this ongoing revolution, emphasizing the impact on clinical practice.
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http://dx.doi.org/10.1038/s41582-020-0409-4DOI Listing
December 2020

Renal Manifestations of Tuberous Sclerosis Complex: Key Findings From the Final Analysis of the TOSCA Study Focussing Mainly on Renal Angiomyolipomas.

Front Neurol 2020 16;11:972. Epub 2020 Sep 16.

Klinikverbund Allgäu gGmbH, Kempten, Germany.

Renal angiomyolipomas are one of the most common renal manifestations in patients with tuberous sclerosis complex (TSC), with potentially life-threatening complications and a poor prognosis. Despite the considerable progress in understanding TSC-associated renal angiomyolipomas, there are no large scale real-world data. The aim of our present study was to describe in detail the prevalence and outcome of renal angiomyolipomas in patients with TSC, enrolled into the TuberOus SClerosis registry to increase disease Awareness (TOSCA) from 170 sites across 31 countries worldwide. We also sought to evaluate the relationship of TSC-associated renal angiomyolipomas with age, gender and genotype. The potential risk factors for renal angiomyolipoma-related bleeding and chronic kidney disease (CKD) were studied in patients who participated in the TOSCA renal angiomyolipoma substudy. Of the 2,211 eligible patients, 1,062 (48%) reported a history of renal angiomyolipomas. The median age of TSC diagnosis for the all subjects ( = 2,211) was 1 year. The median age of diagnosis of renal angiomyolipoma in the 1,062 patients was 13 years. Renal angiomyolipomas were significantly more prevalent in female patients ( < 0.0001). Rates of angiomyolipomas >3 cm ( = 0.0119), growing lesions ( = 0.0439), and interventions for angiomyolipomas ( = 0.0058) were also higher in females than males. Pre-emptive intervention for renal angiomyolipomas with embolisation, surgery, or mammalian target of rapamycin (mTOR) inhibitor may have abolished the gender difference in impaired renal function, hypertension, and other complications. The rate of interventions for angiomyolipomas was less common in children than in adults, but interventions were reported in all age groups. In the substudy of 76 patients the complication rate was too low to be useful in predicting risk for more severe CKD. In addition, in this substudy no patient had a renal hemorrhage after commencing on an mTOR inhibitor. Our findings confirmed that renal angiomyolipomas in subjects with mutations develop on average at the later age, are relatively smaller in size and less likely to be growing; however, by age 40 years, no difference was observed in the percentage of patients with and mutations needing intervention. The peak of appearance of new renal angiomyolipomas was observed in patients aged between 18 and 40 years, but, given that angiomyolipomas can occur later, lifelong surveillance is necessary. We found that pre-emptive intervention was dramatically successful in altering the outcome compared to historical controls; with high pre-emptive intervention rates but low rates of bleeding and other complications. This validates the policy of surveillance and pre-emptive intervention recommended by clinical guidelines.
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http://dx.doi.org/10.3389/fneur.2020.00972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526256PMC
September 2020

Burden of Illness and Quality of Life in Tuberous Sclerosis Complex: Findings From the TOSCA Study.

Front Neurol 2020 28;11:904. Epub 2020 Aug 28.

Cardiology Clinical Academic Group, Molecular and Clinical Sciences Research Centre, St Georges University of London, London, United Kingdom.

Research on tuberous sclerosis complex (TSC) to date has focused mainly on the physical manifestations of the disease. In contrast, the psychosocial impact of TSC has received far less attention. The aim of this study was therefore to examine the impact of TSC on health, quality of life (QoL), and psychosocial well-being of individuals with TSC and their families. Questionnaires with disease-specific questions on burden of illness (BOI) and validated QoL questionnaires were used. After completion of additional informed consent, we included 143 individuals who participated in the TOSCA (TuberOus SClerosis registry to increase disease Awareness) study. Our results highlighted the substantial burden of TSC on the personal lives of individuals with TSC and their families. Nearly half of the patients experienced negative progress in their education or career due to TSC (42.1%), as well as many of their caregivers (17.6% employed; 58.8% unemployed). Most caregivers (76.5%) indicated that TSC affected family life, and social and working relationships. Further, well-coordinated care was lacking: a smooth transition from pediatric to adult care was mentioned by only 36.8% of adult patients, and financial, social, and psychological support in 21.1, 0, and 7.9%, respectively. In addition, the moderate rates of pain/discomfort (35%) and anxiety/depression (43.4%) reported across all ages and levels of disease demonstrate the high BOI and low QoL in this vulnerable population.
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http://dx.doi.org/10.3389/fneur.2020.00904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485558PMC
August 2020

Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome.

Epilepsia 2020 11 21;61(11):2461-2473. Epub 2020 Sep 21.

Reference Center for Rare Developmental Abnormalities CLAD-Ouest, Rennes University Hospital Center, Rennes, France.

Objective: We aimed to delineate the phenotypic spectrum and long-term outcome of individuals with KCNB1 encephalopathy.

Methods: We collected genetic, clinical, electroencephalographic, and imaging data of individuals with KCNB1 pathogenic variants recruited through an international collaboration, with the support of the family association "KCNB1 France." Patients were classified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE). In addition, we reviewed published cases and provided the long-term outcome in patients older than 12 years from our series and from literature.

Results: Our series included 36 patients (21 males, median age = 10 years, range = 1.6 months-34 years). Twenty patients (56%) had DEE with infantile onset seizures (seizure onset = 10 months, range = 10 days-3.5 years), whereas 16 (33%) had DE with late onset epilepsy in 10 (seizure onset = 5 years, range = 18 months-25 years) and without epilepsy in six. Cognitive impairment was more severe in individuals with DEE compared to those with DE. Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series and 37 published individuals in nine reports) showed developmental delay in all with severe to profound intellectual disability in 67% (n = 41/61) and autistic features in 56% (n = 32/57). Long-term outcome in 22 individuals older than 12 years (14 in our series and eight published individuals) showed poor cognitive, psychiatric, and behavioral outcome. Epilepsy course was variable. Missense variants were associated with more frequent and more severe epilepsy compared to truncating variants.

Significance: Our study describes the phenotypic spectrum of KCNB1 encephalopathy, which varies from severe DEE to DE with or without epilepsy. Although cognitive impairment is worse in patients with DEE, long-term outcome is poor for most and missense variants are associated with more severe epilepsy outcome. Further understanding of disease mechanisms should facilitate the development of targeted therapies, much needed to improve the neurodevelopmental prognosis.
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http://dx.doi.org/10.1111/epi.16679DOI Listing
November 2020
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