A European pilot study in Dravet Syndrome to delineate what really matters for the patients and families.

We aimed to identify caregivers' opinions on the outcome measures that matter in clinical trials in individuals with Dravet syndrome (DS). We conducted a prospective European multicenter study based on an 11 closed questions survey developed by the French reference center for rare epilepsies and DS patients' advocacy groups. Items included questions on seizures and daily life outcomes that a clinical trial on a therapy for individuals with DS should target. Statistical analyses were performed to evaluate the impact of the country of residence and of the patients' age. The survey was answered by 153 caregivers (68%: France, 28%: Germany, and 24%: Italy) off individuals with DS. Individuals with DS included 86 males (mean age of 11.4 [interquartile: 7-20.4] years). Families ranked as important almost all the items proposed. However, items related to daily life had the highest rank in all three countries compared to items about seizures (P = 0.02). Increase in individuals' age was associated with a higher age at diagnosis (ρ = 0.26, P = 0.02), and a lower impact of seizure duration (ρ = -0.25, P = 0.005) and on the need of hospital referral (ρ = -0.26, P = 0.005). These data can help tailor patient-centered outcome measures in future clinical and real-life trials for DS.

Non-invasive Ventilation in Children With Neuromuscular Disease.

The respiratory muscles are rarely spared in children with neuromuscular diseases (NMD) which puts them at risk of alveolar hypoventilation. The role of non-invasive ventilation (NIV) is then to assist or "replace" the weakened respiratory muscles in order to correct alveolar hypoventilation by maintaining a sufficient tidal volume and minute ventilation. As breathing is physiologically less efficient during sleep, NIV will be initially used at night but, with the progression of respiratory muscle weakness, NIV can be extended during daytime, preferentially by means of a mouthpiece in order to allow speech and eating. Although children with NMD represent the largest group of children requiring long term NIV, there is a lack of validated criteria to start NIV. There is an agreement to start long term NIV in case of isolated nocturnal hypoventilation, before the appearance of daytime hypercapnia, and/or in case of acute respiratory failure requiring any type of ventilatory support. NIV is associated with a correction in night- and daytime gas exchange, an increase in sleep efficiency and an increase in survival. NIV and/or intermittent positive pressure breathing (IPPB) have been shown to prevent thoracic deformities and consequent thoracic and lung hypoplasia in young children with NMD. NIV should be performed with a life support ventilator appropriate for the child's weight, with adequate alarms, and an integrated (±additional) battery. Humidification is recommended to improve respiratory comfort and prevent drying of bronchial secretions. A nasal interface (or nasal canula) is the preferred interface, a nasobuccal interface can be used with caution in case of mouth breathing. The efficacy of NIV should be assessed on the correction of alveolar ventilation. Patient ventilator synchrony and the absence of leaks can be assessed on a sleep study with NIV or on the analysis of the ventilator's in-built software. The ventilator settings and the interface should be adapted to the child's growth and progression of respiratory muscle weakness. NIV should be associated with an efficient clearance of bronchial secretions by a specific program on the ventilator, IPPB, or mechanical insufflation-exsufflation. Finally, these children should be managed by an expert pediatric multi-disciplinary team.

Non-invasive Ventilation and CPAP Failure in Children and Indications for Invasive Ventilation.

Non-invasive ventilation (NIV) and continuous positive airway pressure (CPAP) are effective treatments for children with severe sleep disordered breathing (SBD). However, some patients may present too severe SDB that do not respond to NIV/CPAP or insufficient compliance to treatment. A careful revaluation of the interface and of ventilator settings should be performed before considering alternative treatments. In patients with obstructive sleep apnea (OSA), alternatives to CPAP/NIV rely on the underlying disease. Ear-nose-throat (ENT) surgery such as adeno-tonsillectomy (AT), turbinectomy or supraglottoplasty represent an effective treatment in selected patients before starting CPAP/NIV and should be reconsidered in case of CPAP failure. Rapid maxillary expansion (RME) is restricted to children with OSA and a narrow palate who have little adenotonsillar tissue, or for those with residual OSA after AT. Weight loss is the first line therapy for obese children with OSA before starting CPAP and should remain a priority in the long-term. Selected patients may benefit from maxillo-facial surgery such as mandibular distraction osteogenesis (MDO) or from neurosurgery procedures like fronto-facial monobloc advancement. Nasopharyngeal airway (NPA) or high flow nasal cannula (HFNC) may constitute efficient alternatives to CPAP in selected patients. Hypoglossal nerve stimulation has been proposed in children with Down syndrome not tolerant to CPAP. Ultimately, tracheostomy represents the unique alternative in case of failure of all the above-mentioned treatments. All these treatments require a multidisciplinary approach with a personalized treatment tailored on the different diseases and sites of obstruction. In patients with neuromuscular, neurological or lung disorders, non-invasive management in case of NIV failure is more challenging. Diaphragmatic pacing has been proposed for some patients with central congenital hypoventilation syndrome (CCHS) or neurological disorders, however its experience in children is limited. Finally, invasive ventilation via tracheotomy represents again the ultimate alternative for children with severe disease and little or no ventilatory autonomy. However, ethical considerations weighting the efficacy against the burden of this treatment should be discussed before choosing this last option.

Add-on cannabidiol significantly decreases seizures in 3 patients with SYNGAP1 developmental and epileptic encephalopathy.

Mutations in SYNGAP1 are associated with developmental delay, epilepsy, and autism spectrum disorder (ASD). Epilepsy is often drug-resistant in this syndrome with frequent drop attacks. In a prospective study of add-on cannabidiol (CBD), we identified three patients with SYNGAP1 mutations: two boys and one girl. Seizure onset was at 3.5, 8, and 18 months (M), respectively, with numerous atypical absences per day associated with eyelid myoclonia (2/3 patients), upper limb myoclonic jerks (2/3 patients), and drop attacks (all patients). Seizures were resistant to at least 5 antiepileptic drugs (AEDs). After CBD introduction, two patients were responders since M2 and achieve a seizure reduction of 90% and 80%, respectively, at M9 with disappearance of drop attacks. EEGs showed an improvement regarding background activity and interictal anomalies. The last patient showed a late response at M7 of treatment with an 80% decrease in seizure frequency. Caregiver in all three evaluated as much improved the status of their children. Treatment was well-tolerated in all, and no major adverse events (AEs) were reported. CBD showed efficacy in patients with drug-resistant epilepsy due to SYNGAP1 mutations. Other patients with rare genetic developmental and epileptic encephalopathies with drug-resistant epilepsies might benefit from CBD.

Slow Titration of Cannabidiol Add-On in Drug-Resistant Epilepsies Can Improve Safety With Maintained Efficacy in an Open-Label Study.

Objective: To assess adverse events (AEs) and efficacy of add-on cannabidiol (CBD) with a slower titration protocol in pediatric clinical practice. Methods: We conducted a prospective, open-label, multicenter study in seven French reference centers for rare epilepsies. Patients had slow titration to reach a target dose of 10 mg/kg/day within at least 1 month and then gradually increased to a maximum dose of 20 mg/kg/day. We analyzed AEs and efficacy at M1 (month 1), M2, and M6, comparing two sets of subgroups: Dravet syndrome (DS) vs. Lennox-Gastaut (LGS) and patients with clobazam (CLB+) vs. patients without (CLB-). Results: One hundred and twenty-five patients were enrolled (62 LGS, 48 DS, 5 Tuberous sclerosis, and 10 other etiologies). Median concomitant antiepileptic drugs (AEDs) was three (25th percentile: 3, 75th percentile: 4). Patients received a dose of 10 (10-12), 14 (10-20), and 15.5 mg/kg/day (10-20) at M1, M2, and M6, respectively. Twenty-six patients discontinued CBD, 19 due to lack of efficacy, 2 due to AEs, 4 for both, and 1 had a sudden unexpected death in epilepsy. AEs were reported in 61 patients (48.8%), mainly somnolence (n = 26), asthenia (n = 20), and behavior disorders (n = 16). Abnormal transaminases (≥3 times) were reported in 11 patients receiving both valproate and clobazam. AEs were significantly higher at M2 (p = 0.03) and increased with the number of AEDs (p = 0.03). At M6, total seizure frequency change from baseline was -41% ± 37.5% (mean ± standard deviation), and 28 patients (37.8%) had a reduction ≥50%. AE and efficacy did not differ between DS vs. LGS and CLB+ vs. CLB- patients. Significance: A slower titration of CBD dose delivered better tolerance with comparable efficacy to previous trials. Concomitant CLB did not increase efficacy rates but in a few cases increased AEs. This slow titration scheme should help guide clinicians prescribing CBD and allow patients to benefit from its potential efficacy.

Follow-Up and Monitoring of Children Needing Long Term Home Ventilation.

Once continuous positive airway pressure (CPAP) or noninvasive ventilation (NIV) is started in a child, and the child is discharged home, follow-up needs to be organized with regular visits in order to check the tolerance and efficacy of the treatment. But there is a lack of validated clinical guidelines, mainly because of the heterogeneity of the ventilator servicing, the costs and health care systems among countries. Therefore, visits timing and strategies to monitor CPAP/NIV are not clearly defined. Moreover, depending on various factors such as the underlying disorder, the medical stability, the age of the child, and socio-economic factors, follow-up usually ranges between 1 month and 3-6 months, or even 1 year following treatment initiation, with an overnight hospital stay, an out-patient visit, a home visit, via telemonitoring or telemedicine, alone or in combination. Apart from clinical evaluation, nocturnal oximetry and capnography monitoring and/or poly(somno)graphy (P(S)G) are usually carried out during the follow-up visits to monitor the delivered pressure, leaks, residual respiratory events and synchrony between the patient and the ventilator. Built-in software data of CPAP/NIV devices can be used to assess the adherence of treatment, to monitor pressure efficiency, leaks, asynchronies, and to estimate the presence of residual respiratory events under CPAP/NIV if P(S)G is not available or in alternance with P(S)G. The possibility of CPAP/NIV weaning should be assessed on a regular basis, but no criteria for the timing and procedures have been validated. Weaning timing depends on the clinical condition that justified CPAP/NIV initiation, spontaneous improvement with growth, and the possibility and efficacy of various upper airway, maxillofacial and/or neurosurgical procedures. Weaning may be allowed in case of the disappearance of nocturnal and daytime symptoms of sleep-disordered breathing (SDB) after several nights without CPAP/NIV and the objective correction of SDB on a P(S)G. But no parameters are defined. In any case, a long term follow-up is necessary to ascertain the weaning success. Large prospective studies, together with international and national guidelines, are required in order to build evidence for standardizing practice for the follow-up and weaning of CPAP/NIV in children.

Head circumferences of patients with Dravet syndrome show growth slowdown.

The measurement of head circumference (HC) represents a useful and reliable tool to monitor brain growth. Many genetic conditions are associated with an abnormal pattern of head growth, but no specific pattern has been described in Dravet Syndrome (DS). To investigate the head growth trajectories in a pediatric population with DS, a retrospective analysis of medical records of patients with DS was performed in 2 epilepsy centers. Quantitative data were compared with z-score growth curve of standard population, and an independent samples t-test was performed using 6-month ranges. A total of 137 subjects aged less than 18 years were included, with a total of 529 HC values and a mean of 3.9 measures per patient. From birth until 24 months of life, HC values were almost equally distributed around the mean trajectory of the reference population from each side of the curve. This trend line deflects from the mean curve after 24 months showing a head growth slowdown reaching a statistical significance (p < .05) from 48 months for males and 60 for females. Future prospective studies are needed to assess factors that can impact head growth and explore possible phenotype-genotype correlation with HC.

Home Overnight Gas Exchange for Long-Term Noninvasive Ventilation in Children.

BACKGROUND: The aim of CPAP and noninvasive ventilation (NIV) is to correct sleep-disordered breathing and nocturnal gas exchange. The aim of the study was to analyze the results of a systematic home pulse oximetry ([Formula: see text]) and transcutaneous carbon dioxide ([Formula: see text]) monitoring in stable pediatric subjects on long-term CPAP/NIV or screened for CPAP/NIV weaning, and the consequent interventions in the subjects with abnormal gas exchange. METHODS: The home overnight [Formula: see text] and [Formula: see text] recordings of stable pediatric subjects treated with or weaned from CPAP, NIV, or high-flow nasal cannula between January 2017 and March 2018 were analyzed. RESULTS: A total of 110 recordings, performed in 79 subjects, median age 6 (interquartile range [IQR] 1.5-14) y, were analyzed. Fifty-two recordings (47%) were performed during NIV, 43 (39%) during CPAP, 2 (2%) during high-flow nasal cannula, and 13 (12%) during a spontaneous ventilation weaning trial from ventilatory support. The quality of recording was excellent in 81% of recordings, 5 recordings (5%) had <4 h of recording time, 5 (5%) had artifacts on the [Formula: see text] signal, and 16 (15%) had artifacts on the [Formula: see text] signal. Gas exchange abnormalities were observed in 11 subjects with [Formula: see text] > 50 mm Hg during ≥ 2% of recording time (n = 8), mean [Formula: see text] ≥ 50 mm Hg (n = 6), mean [Formula: see text] < 35 mm Hg (n = 3), and [Formula: see text] < 90% during ≥ 2% of recording time (n = 2). Consequent interventions were (multiple interventions possible): change of device settings (n = 6), change of interface (n = 2), switched to high-flow nasal cannula (n = 1), and a control recording (n = 2). CONCLUSIONS: A significant number (∼12%) of systematic home [Formula: see text] and [Formula: see text] recordings in stable pediatric subjects treated with CPAP/NIV were abnormal and may be corrected by adequate therapeutic interventions.

Impact of childhood Dravet syndrome on care givers of patients with DS, a major impact on mothers.

BACKGROUND: The aim of this study was to understand the impact of Dravet syndrome (DS) on patients with Dravet syndrome and their families, with a focus on the social and economic impact on both mothers and fathers. METHODS: A French language on-line survey was distributed (October 2014-January 2015) for completion by caregivers of patients aged <18 years with DS. The survey was hosted on the French Dravet Syndrome Alliance website, and the survey link was provided to patients and caregivers during clinics at the Necker Hospital (Paris, France). RESULTS: Survey responses were available for 91 patients (median age 7.6 years; 81.6% SCN1A mutation positive). Total seizure frequency was >2 per week for 16.1% of patients, 1-8 per month for 55.2% and < 1 per month for 28.7%; tonic-clonic and myoclonic were the most frequent seizure types. Patients showed various degrees of intellectual disability and DS had a high impact on concentration and school learning in 70.1% and 80.5%. In addition, patients showed appetite disorders in 73.6%, sleep disorders in 72.4% and behavior disorders in 62.1%. Most parents were married (80.5%) with higher rates than the French general population (53.5%). Educational achievement and socio-professional categories for the parents were higher than observed in the French general population, while monthly net income was similar. Preparation of medication was generally done by the mother and father (46.0% of patients) or the mother only (37.9%). Most caregivers reported very low or no difficulty with treatment preparation and low or no risk of error. Parents typically spent <30 min per day on treatment preparation and administration and around 4 h per week for attending therapy appointments. Although most patients and parents were perceived to have good general health, mothers had a worse perception of their own general health than fathers. Compared with fathers, mothers reported a greater impact of caring for a child with DS on their social life, relationships with family and friends, time and energy, and professional life. CONCLUSION: Families caring for a child with DS experience considerable social and economic impact, with an apparent greater burden of care on the mother than the father.

Transition of patients with childhood onset epilepsy: Perspectives from pediatric and adult neurologists.

Transition from pediatric to adult care systems is a major challenge in the management of adolescents with epilepsy. The comparison of pediatric and adult physicians' points of view on this issue is scarcely described. The aim of this study was to understand pediatric and adult neurologists' experience and opinions on transition in epilepsy in France. We investigate the age at which they usually transfer patients, their opinion on the factors that positively or negatively impact transition, on the help provided during this transition period, and their propositions to improve this process. We prepared a targeted questionnaire with two versions, one adapted for neurologists and the other for child neurologists. The questionnaires were diffused through the Reference Centre for Rare Epilepsies, the French Chapter of the League Against Epilepsy, the French Association for Office-based Neurologists, and the French Pediatric Neurology Society. A total of sixty-eight physicians involved mostly in epilepsy care answered this questionnaire: 39 child neurologists and 29 neurologists. Questionnaires were filled at 96.8%. Twenty-six child neurologists followed patients aged over 18 years (70%), and 18 neurologists followed patients under the age of 12 years (66.6%). Cognitive impairment in childhood led significantly to a later transfer to adult care. The major factors believed to delay the transfer were attachment between child neurologists and families as reported in 96.3% by neurologists and in 81.1% by child neurologists, p = 0.07 and lack of adaptation of adult neurology facilities to adolescents especially with intellectual disability (59.3% neurologists, 75.7% child neurologists, p = 0.16). Factors that helped a transfer around 18-19 years were mainly pharmacoresistant epilepsy (71% for neurologists vs. 19% for child neurologists, p < 105) and pregnancy (72% for child neurologists versus 50% for neurologists, p = 0.08). Factors that negatively impacted transition were the lack of information about daily life in adulthood (driving license, contraception, sexuality, carrier guidance, etc.), the weak transition preparation in pediatric system, the lack of knowledge of pediatric epilepsy syndromes, and the lack of global support for patients with intellectual disability and multidisciplinary care needs in adult system. Both groups proposed joint clinics (>65% of providers) and development of care networks between pediatric and adult care for patients with epilepsy (>55%) to improve transition as well as introducing courses on transition. Few physicians were aware of transition and transfer recommendations. Although child and adult neurologists still have some preconceived beliefs, they were able to identify the strengths and weaknesses of both care systems paving the way for proposals to improve transition and transfer of patients with epilepsy from pediatric to adult care.

High-flow nasal cannula for children not compliant with continuous positive airway pressure.

OBJECTIVES: Continuous positive airway pressure (CPAP) is an effective treatment of severe obstructive sleep apnea (OSA) but poor compliance is a major limitation. High-flow nasal cannula (HFNC) has been used as an alternative but data about efficacy and objective long-term compliance are scarce; this study aims to address this lack of data. PATIENTS/METHODS: All consecutive patients, aged 0-18 years, treated with CPAP for a severe OSA defined as an apnea-hypopnea index (AHI) > 10 events/h, and not compliant with home CPAP therapy, defined by a CPAP use of <2 h/night, after at least four weeks from CPAP initiation were considered eligible for the study. HFNC was started during an outpatient visit. Study outcomes were the objective compliance (number of hours use/night) after one month and the improvement of OSA on a respiratory polygraphy (RP) with HFNC. RESULTS: Eight patients (two boys, mean age 8.9 ± 6.2 years, mean AHI 33 ± 22 events/h) were included in the study: Down syndrome (N = 6), Pierre Robin syndrome (N = 1), Pfeiffer syndrome (N = 1). After one month, five (62%) patients slept with HFNC more than 4 h/night (mean compliance 7 h 10 min ± 0 h 36 min/night). HFNC corrected OSA in the five compliant patients (mean AHI 2 ± 2 events/h with HFNC). HFNC was not accepted by the three oldest patients with Down syndrome. CONCLUSION: A good compliance as well as a correction of OSA may be obtained with HFNC in selected children with OSA not compliant to CPAP. HFNC may be used as a rescue therapy for children not compliant with CPAP.