TYPE Original Research PUBLISHED 01 September 2022 DOI 10.3389/fneur.2022.975034 The Charlotte Project: OPEN ACCESS Recommendations for patient-reported outcomes and EDITED BY Marina Trivisano, Bambino Gesù Children’s Hospital (IRCCS), Italy REVIEWED BY clinical parameters in Dravet syndrome through a qualitative Ganna Balagura, Giannina Gaslini Institute (IRCCS), Italy Maurizio Elia, IRCCS Oasi Maria SS, Italy Giorgia Giussani, Mario Negri Pharmacological Research and Delphi consensus study Institute (IRCCS), Italy *CORRESPONDENCE Ángel Aledo-Serrano1*, Ana Mingorance2 , Ángel Aledo-Serrano aaledo@neurologiaclinica.es Vicente Villanueva3 , Juan José García-Peñas4 , SPECIALTY SECTION Antonio Gil-Nagel1 , Susana Boronat5 , JoséÁngel Aibar6 , This article was submitted to Epilepsy, Silvia Cámara4 , María José Yániz7 , Luis Miguel Aras8 , a section of the journal Bárbara Blanco9 and Rocío Sánchez-Carpintero7 on behalf of Frontiers in Neurology the Charlotte Project Group RECEIVED 21 June 2022 ACCEPTED 15 August 2022 1 Epilepsy Program, Neurology Department, Ruber Internacional Hospital, Madrid, Spain, 2 Dracaena PUBLISHED 01 September 2022 Consulting SL, Loulou Foundation, London, United Kingdom, 3 Hospital Universitario y Politécnico CITATION La Fe, Valencia, Spain, 4 Hospital Infantil Universitario Niño Jesús, Madrid, Spain, 5 Hospital de la Santa Aledo-Serrano Á, Mingorance A, Creu i Sant Pau, Barcelona, Spain, 6 Fundación Síndrome de Dravet, Madrid, Spain, 7 Clínica Villanueva V, García-Peñas JJ, Universidad Navarra, Pamplona, Spain, 8 Apoyo Dravet, San Sebastian, Spain, 9 Hospital Universitario Gil-Nagel A, Boronat S, Aibar J, Virgen del Rocío, Seville, Spain Cámara S, Yániz MJ, Aras LM, Blanco B and Sánchez-Carpintero R (2022) The Charlotte Project: Recommendations Objective: The appropriate management of patients with Dravet Syndrome for patient-reported outcomes and clinical parameters in Dravet syndrome (DS) is challenging, given the severity of symptoms and the burden of the through a qualitative and Delphi disease for patients and caregivers. This study aimed to identify, through consensus study. Front. Neurol. 13:975034. a qualitative methodology and a Delphi consensus-driven process, a set doi: 10.3389/fneur.2022.975034 of recommendations for the management of DS to guide clinicians in the COPYRIGHT assessment of the clinical condition and quality of life (QoL) of DS patients, © 2022 Aledo-Serrano, Mingorance, with a special focus on patient- and caregiver-reported outcomes (PROs). Villanueva, García-Peñas, Gil-Nagel, Boronat, Aibar, Cámara, Yániz, Aras, Methods: This study was conducted in five phases, led by a multidisciplinary Blanco and Sánchez-Carpintero. This scientific committee (SC) including pediatric neurologists, epileptologists, a is an open-access article distributed under the terms of the Creative neuropsychologist, an epilepsy nurse, and members of DS patient advocates. Commons Attribution License (CC BY). In phases 1 and 2, a questionnaire related to patients’ QoL was prepared The use, distribution or reproduction and answered by caregivers and the SC. In phase 3, the SC generated, in other forums is permitted, provided the original author(s) and the copyright based on these answers and on a focus group discussion, a 70-item Delphi owner(s) are credited and that the questionnaire, covering six topic categories on a nine-point Likert scale. original publication in this journal is cited, in accordance with accepted In phase 4, 32 panelists, from different Spanish institutions and with a academic practice. No use, distribution multidisciplinary background, answered the questionnaire. Consensus was or reproduction is permitted which obtained and defined as strong or moderate if ≥80% and 67–79% of panelists, does not comply with these terms. respectively, rated the statement with ≥7. Phase 5 consisted of the preparation of the manuscript. Results: The panelists agreed on a total of 69 items (98.6%), 54 (77.14%), and 15 (21.43%) with strong and moderate consensus, respectively. Frontiers in Neurology 01 frontiersin.org Aledo-Serrano et al. 10.3389/fneur.2022.975034 The experts’ recommendations included the need for frequent assessment of patient and caregivers QoL parameters. The experts agreed that QoL should be assessed through specific questionnaires covering different domains. Likewise, the results showed consensus regarding the regular evaluation of several clinical parameters related to neurodevelopment, attention, behavior, other comorbidities, and sudden unexpected death in epilepsy (SUDEP). A consensus was also reached on the instruments, specific parameters, and caregivers’ education in the routine clinical management of patients with DS. Conclusions: This consensus resulted in a set of recommendations for the assessment of clinical and QoL parameters, including PROs, related to the general evaluation of QoL, neurodevelopment, attention, behavior, other comorbidities affecting QoL, SUDEP, and QoL of caregivers/relatives and patients with DS. KEYWORDS neurodevelopment, developmental and epileptic encephalopathies, epilepsy, genetic epilepsy, caregivers, patient-reported outcomes, SCN1A Introduction Due to the severity and the burden of the disease, the quantity and quality of the support required from caregivers Dravet syndrome (DS) is a life-threatening epilepsy and relatives can be emotionally and financially challenging, syndrome that begins in infancy or early childhood and resulting in a significant financial impact for families (17, 18). includes a wide spectrum of symptoms ranging from mild Furthermore, mortality rates in DS are high and, in 59% to severe (1). Additionally, DS is included in the group of of the cases, they are due to Sudden Unexpected Death in developmental and epileptic encephalopathies (DEE). Patients Epilepsy (SUDEP) (19). Accordingly, experts acknowledge the with DS initially present with prolonged focal or generalized need to assess different aspects of DS beyond seizures in the onset motor seizures, which are usually fever-induced, starting clinical management of DS, including the impact of DS on before 15 months of age (often during the first year) (2). As caregivers’ and relatives’ QoL (14). In this regard, patient- the disease progresses, DS patients develop other symptoms, reported outcome measures (PROMs) are an increasingly used including neurodevelopmental impairments (3). Up to 88% of tool that has proven useful in various pathologies (20), but DS patients have mutations in the SCN1A gene (4), which there is still little evidence in the context of patients with encodes a sodium channel involved in nervous system function. DS (21). Pathogenic variants of the SCN1A gene result in a wide range of Several guidelines and recommendations on DS are disease severities, from severe DS, on one end of the spectrum, available, including a recently published European treatment to milder pathologies on the other end, such as genetic epilepsy guideline (22). However, owing to the complexity of DS with febrile seizures plus (GEFS+) and the genetic syndrome involvement and the significant uncertainty associated with its with febrile seizures (FS or FS+) (5–8). clinical assessment (23–27), there is still a need for instruments Dravet syndrome, first described in 1978 (1), has an assessing the relevant aspects of DS for patients follow-up in estimated incidence of 1/12,000 to 1/40,000 live births (9, 10), the routine clinical practice, such as PROMs. Similarly, there although there is still a diagnostic gap, especially in adult is limited literature summarizing recommendations regarding patients. Children with DS experience significant developmental the comorbidities of DS from different perspectives, such as delays associated with behavioral problems, which become professionals from multiple disciplines and caregivers. This particularly apparent in the second to fourth years of life study aimed to identify, through a qualitative focus group (11, 12). Even though these symptoms become more stable including patients and caregivers and a Delphi consensus- after adolescence, they persist throughout adulthood, impairing driven process, a core set of recommendations for the patients’ quality of life (QoL) (12). Furthermore, the severity management of DS to guide clinicians in the evaluation of these cognitive and behavioral problems cause psychosocial of both the clinical condition and QoL of DS patients, sequelae in the short and long term, requiring extensive with a special focus on patient/caregiver reported outcomes. care from caregivers and relatives (1, 13–15). DS patients Recommendations regarding the assessment of the QoL experience fine and gross motor skill impairments and other of caregivers and relatives of patients with DS were a physical disorders, including ataxia and gait disturbances (1, 16). secondary objective. Frontiers in Neurology 02 frontiersin.org Aledo-Serrano et al. 10.3389/fneur.2022.975034 Materials and methods English language) in the literature databases PUBMED and EMBASE in March–April 2021 (last 10 years period) included Study design “Dravet Syndrome,” “Patient-reported outcome,” “Quality of life,” “Comorbidity,” and “Caregiver”. Also, during this phase, The Delphi technique is a structured method broadly used an ad hoc questionnaire was designed for this project to assess to collect relevant information on a specific issue and consists the views of the patients and the scientific committee regarding of a series of questionnaires or “rounds” targeted to experts aspects related to QoL, the impact of comorbidities on QoL, (28). The key features of this method are participant anonymity and caregivers’ QoL. The coordinator of the project (Dr. Aledo) and controlled feedback. The Charlotte Project was carried out was in charge of designing the questionnaire. In the beginning, in five phases. In phases 1 and 2, a questionnaire assessing the QoL-related publications found by the literature search different QoL aspects was prepared. In Phase 2, caregivers were examined. Relying on literature and clinical experience, answered the questionnaire and the results were discussed using the questions were developed (Supplementary Table 2). In the a qualitative methodology to collect caregivers’ perspectives. second phase, the qualitative phase completed between May and Patient characteristics and relationship with participating June 2021, representatives of the Dravet Syndrome Foundation caregivers are shown in Supplementary Table 1. The scientific (DSF) Spain contacted caregivers (i.e., patients’ relatives) and committee also answered the questionnaire. During phase 3, the invited them to participate in a meeting. During the meeting, Delphi statements were developed based on the results of the the eight invited caregivers answered the questionnaire and previous phases. In phases 4 and 5, the Delphi questionnaire was discussed relevant issues in a focus group. Additionally, answered by a panel of experts, results were analyzed, and the caregivers of DS patients shared their opinions and experiences manuscript was prepared. related to the care and management of the disease from physical, social, and emotional perspectives. The 10 members of the scientific committee also answered the questionnaire Study phases individually. During the third phase, the scientific committee compared, analyzed, and discussed the answers provided both A diagram of the study phases is presented in Figure 1. In by patients and the members of the scientific committee. The the initial phase, conducted between March and April 2021, conclusions obtained during the meeting were used to prepare the literature regarding the assessment of QoL, comorbidities, the statements to be included in the Delphi questionnaire. The and patient-reported outcomes measures (PROMs) in DS and final version of the questionnaire included 70 items written as other related DEEs was reviewed. Keywords searched (in statements to be answered on a nine-point Likert scale, where FIGURE 1 Study phase diagram. Frontiers in Neurology 03 frontiersin.org Aledo-Serrano et al. 10.3389/fneur.2022.975034 1 was totally disagree and 9 totally agree. Additionally, the rated the statement with 7 or higher (29). Statements that scientific committee selected the expert panel to participate did not reach this level of agreement were interpreted as in the Delphi phase. The fourth phase was the Delphi phase, “undetermined”. conducted between September and October 2021, in which the panelists answered the questionnaire in one round. A free text space was also included to allow participants to provide Data analysis additional comments for each item. A second round was not considered necessary, due to the high degree of consensus SPSS Statistics version 20 by IBM (Armonk, NY, USA) was reached. In the fifth and final phase (November 2021), the used to create and analyze the database. The median and the manuscript was prepared. percentage of responses in the 7–9 range were calculated, and their values were used to define consensus. Scientific committee The project was led by a scientific committee that was Ethical aspects comprised of a multidisciplinary team with seven experts This study was performed following the Helsinki in the field of DS, including three pediatric neurologists, Declaration. Data from the Delphi questionnaire were three epileptologists (both pediatric and adult), one anonymized for the analysis. All the personal data were neuropsychologist, one epilepsy nurse, one neuroscientist dissociated from the results in compliance with the EU General specialized in DEEs and working with patient organizations, Data Protection Regulation (GDPR). and two members of DS patient advocates. Expert panel Results The 70 statements developed by the scientific committee The scientific committee selected a group of 32 epilepsy covered a total of six categories: (1) general aspects of the experts with a multidisciplinary background as participants QoL evaluation of patients with DS (15 items), (2) evaluation (Supplementary Figure 1). The criteria for their selection of neurodevelopment (24 items), (3) assessment of attention included professional knowledge and experience in the field and behavior (9 items), (4) evaluation of other comorbidities of DS. All participants were members of the Spanish Epilepsy affecting QoL (14 items), (5) Sudden unexpected death in Society, as well as the Epilepsy section of the Spanish Society of epilepsy (SUDEP) (4 items), and (6) assessment of the QoL of Pediatric Neurology or the Spanish Society of Neurology. caregivers/relatives (3 items). Of the 32 DS experts invited to participate in the Delphi process, a total of 28 (87.5%) answered the questionnaire (Supplementary Table 3). The panel experts Consensus definition reached a consensus on “agreement” in the first round on a total of 69 of the 70 items (98.57%). A strong consensus was An item or statement was considered consensual when there obtained on 54 items (77.14%) and a moderate consensus was was “agreement” of opinion in the panel. This happens when reached on 15 items (21.43%). Key results for each category are the panelists’ votes outside one of the three-point regions [(1– detailed below. 3), (4–6), (7–9)] containing the median were less than one- third of the answers (<33.3%). The median value determines the group consensus: majority “disagreement” if the median was within 1–3 and majority “agreement” if the median was General aspects of the evaluation of the within 7–9. Cases where the median was within the 4–6 QoL of patients with DS region were considered “doubtful”. Conversely, “discordance” was considered when the scores of one-third or more of A 100% consensus was obtained across category 1 with the panelists were in the (1–3) region and another third an agreement on all the 15 statements, although 4 (26.7%) or more in the (7–9) region. The remaining statements for were categorized into the moderate consensus range (Table 1). which no concordance or discordance was obtained were The panelists agreed that the evaluation of the QoL of considered to have an “undetermined” level of consensus. A the patient at each visit with the specialist was important. strong consensus was defined if 80% or more of panelists Self-administered structured questionnaires for relatives or providing an opinion rated the statement with 7 or higher. caregivers in an electronic format was the recommended A moderate consensus was considered if 67–79% of panelists method for evaluating QoL. Frontiers in Neurology 04 frontiersin.org Aledo-Serrano et al. 10.3389/fneur.2022.975034 TABLE 1 General aspects on the assessment of the quality of life of patients with Dravet syndrome (block 1). Statement Median % Consensus Result Consensus level 1.1 It is recommended to evaluate the quality of life of the patient to 9 100 Agreement Strong determine the impact of the disease on their physical, mental and social wellbeing, facilitating follow-up and decision-making by physicians 1.2 At each visit with the specialist, it is recommended to assess the quality 8 75.0 Agreement Moderate of life of the patient taking into account the patient’s biological or chronological age, according to the characteristics to be evaluated 1.3 It is recommended to assess the quality of life of the patient through 8 78.6 Agreement Moderate specific questionnaires aimed at the parents or caregivers, taking into account the patient’s biological or chronological age, according to the characteristics to be evaluated 1.4 In assessing quality of life, caregivers and family members should have 8 85.7 Agreement Strong tools such as self-administered questionnaires to be able to report the patient’s situation to the specialist in a structured and concrete way 1.5 The quality of life questionnaires used to monitor the patient should 8 100 Agreement Strong include specific questions on: Aspects related to physical health status 1.6 The quality of life questionnaires used to monitor the patient should 9 96.4 Agreement Strong include specific questions on: Aspects related to the psychological status 1.7 The quality of life questionnaires used to monitor the patient should 9 96.4 Agreement Strong include specific questions on: Aspects related to the social environment and functioning, such as the family or school environment 1.8 The quality of life questionnaires used to monitor the patient should 7 75.1 Agreement Moderate include specific questions on: Aspects related to the financial, housing conditions and supporting material 1.9 The quality of life questionnaires used for patient follow-up should 9 96.4 Agreement Strong include specific questions on: Aspects related to adverse effects of drug treatment 1.10 The quality of life questionnaires used to monitor the patient should 7 82.1 Agreement Strong include specific questions on: Aspects related to the relationship of the patient and caregivers with healthcare professionals 1.11 The quality of life questionnaires used to monitor the patient should 7 82.1 Agreement Strong include specific questions on: Aspects related to the relationship of the patient and caregivers with the healthcare system 1.12 The electronic format is considered the optimal method for collecting 8 82.2 Agreement Strong information on quality of life (with different alternatives for non-technology users, such as paper format) 1.13 The pediatrician, family doctor, pediatric neurologist, or neurologist 7 67.9 Agreement Moderate should be the one to assess the results of the questionnaires on quality of life provided and to ask for them regularly and specifically in their visits and consultations 1.14 Patient quality of life questionnaires should always be provided and 8 85.7 Agreement Strong managed by healthcare professionals, with specialized nursing personnel, at the hospital or in a primary care center being the most recommended setting 1.15 It is recommended to monitor and maintain fluent and constant 9 100 Agreement Strong communication between the different professionals involved in the quality of life of the patient, their family members, and caregivers Grey emphasis is used to highlights statements where there was no agreement or agreement was only moderate. Frontiers in Neurology 05 frontiersin.org Aledo-Serrano et al. 10.3389/fneur.2022.975034 Regarding the content of the QoL questionnaires used Assessment of attention and behavior in to monitor patients, the experts reached a consensus that patients with DS these tools should be specific to the syndrome and should consider the biological or chronological age of the patients. All the initial nine statements proposed in category 3 The questionnaires should include aspects related to the reached consensus agreement status (Table 3), although one patient’s physical health, the psychological status, the social (11.11%) fell into the moderate consensus category. The environment and functioning, the economic situation, panelists recommended evaluating the behavior of the patient housing conditions and supporting material, adverse effects at each consultation with the specialist or at least every 3– of pharmacological treatment, and the relationships of the 6 months through educational/stimulation centers. According patient and caregivers with healthcare professionals and the to the experts’ opinion, this evaluation should consider certain healthcare system. comorbidities and/or situations that might be associated with To conclude this category, the panelists reached a the behavior. The recommended parameters for behavior consensus agreement regarding the administration and evaluation included aggressiveness, impulsivity, hyperactivity, assessment of the QoL questionnaire. The experts stated and difficulty paying attention, low cognitive flexibility, that an electronic format is an optimal method and that frustration intolerance, temper tantrums, family stress, and the the questionnaire should be administered and evaluated school situation. Finally, the experts recommended assessing the by healthcare professionals, always in communication and use of scales on a regular basis to systematize and formalize coordination with each other and with the patient’s family the behavior assessment, as well as to support a possible and caregivers. therapeutic decision. Evaluation of neurodevelopment in Assessment of other comorbidities that patients with DS affect the QoL in patients with DS The panelists overall agreed on category 4 items, obtaining The panelists reached a consensus agreement on consensus agreement on 13 of the 14 statements (92.86%), as all 24 statements (100%) of category 2, of which 6 shown in Table 4. Two of these items (14.28%) were considered (25.0%) had a moderate consensus (Table 2). In their as a moderate consensus according to the panelists’ opinions. opinion, a neurodevelopmental evaluation of DS patients The experts recommended enquiring about the patient’s sleep is recommended at each visit with the specialist, at (quantity and quality) at each visit with the specialist, at least different frequencies depending on the age of the patient. every 3–6 months, considering the need for sleep medication The panelists agreed that the evaluation of various and its effectiveness as well as the frequency of nighttime neurological parameters related to patient care and seizures, in particular generalized tonic-clonic seizures. communication skills should be carried out at least every Overall, the panelists agreed on various recommendations 3–6 months. related to the assessment of sleep-related problems (including The panelists agreed on the importance of assessing several the use of the Bruni and the Pittsburgh scales), with the comorbidities or complications related to cognitive impairment. exception of the actigraphy study, for which consensus Likewise, experts agreed on recommendations related to the was undetermined. Additionally, the experts recommended evaluation and study of gait and ataxia, including the frequency spending time specifically explaining to the family and/or of evaluation. caregivers the potential comorbidities associated with seizures Experts agreed on the likely suitability of a series of scales to during sleep. measure neurological and motor development in patients with Experts also recommended assessing other comorbidities DS, including Bayley-III Cognitive Scale, Wechsler Intelligence at least every 3–6 months, including digestive and respiratory Scale for Children-V, Peabody 2 Developmental Motor Scale- disorders, and available specific guidelines for vaccination 2, Behavior Rating Scale of Executive Function-2 (BRIEF-2), periods and infectious processes for both family members and Gross Motor Function Classification System (GMFCS), Gillette the physicians of the Healthcare Center. Functional Assessment Questionnaire, and Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT). These scales should be used considering the specific objectives proposed by the adult/pediatric neurologist in collaboration Sudden unexpected death in epilepsy with the neuropsychologist. Finally, the experts agreed on other parameters to be considered when assessing motor development, Consensus was reached on all 4 items in category 5 as well as on the frequency of these measurements. (100%), with a strong consensus for all of them (Table 5). Frontiers in Neurology 06 frontiersin.org Aledo-Serrano et al. 10.3389/fneur.2022.975034 TABLE 2 Evaluation of neurodevelopment in patients with Dravet syndrome (block 2). Statement Median % Consensus Result Consensus level 2.1 It is recommended to assess the neurodevelopment of patients with Dravet 9 82.2 Agreement Strong syndrome at each visit with the specialist (every 3 months from 0 to 3 years, every 6 months from 3 to 6 years, and every 12 months from 7 years onwards) 2.2 It is recommended for all patients with Dravet syndrome to be assessed and 9 96.4 Agreement Strong monitored by a multidisciplinary team of neuropsychologists, speech therapists, occupational therapists and physiotherapists, grouping specialists in the same appointment to facilitate family trips to the healthcare center 2.3 It is recommended to monitor neurodevelopment up to 6 years of age through 9 100 Agreement Strong early care centers with EOEPs (Educational and Psychopedagogical Guidance Teams), or other comprehensive neurodevelopmental assessment centers with awareness for different domains affected by Dravet syndrome, such as language, attention, executive functions, or gross and fine motor development 2.4 In the evaluation of cognitive development, it is advisable to evaluate the 8 82.1 Agreement Strong communication and language of patients with Dravet syndrome at each visit with the specialist 2.5 Clinical evaluation of expressive, comprehensive, and non-verbal language and 9 92.9 Agreement Strong its impact on learning, socialization, and safety is recommended, at least every 3–6 months 2.6 Clinical evaluation of social interaction and communicative interest is 9 89.3 Agreement Strong recommended, at least every 3–6 months 2.7 Speech evaluation is recommended, at least every 3–6 months 8 92.9 Agreement Strong 2.8 Clinical evaluation of attention and executive functions is recommended at least 8 92.9 Agreement Strong every 3–6 months 2.9 During the neurodevelopmental assessment, the application of measurement 9 92.8 Agreement Strong tools or scales quantifying the different neurodevelopmental domains should be assessed every 3–6–12 months, according to the patient’s needs 2.10 The neurologist and/or the pediatric neurologist, in collaboration with the 8 78.5 Agreement Moderate neuropsychologist, should decide which scale may be more advisable to use for the evaluation of motor and cognitive development in each case, considering specific objectives and depending on the characteristics of each test 2.11 It is recommended to use the Cognitive Bayley III scale to assess different 7 75 Agreement Moderate neurodevelopmental domains 2.12 It is recommended to use the Wechsler Intelligence scale for children to assess 7 67.9 Agreement Moderate cognitive development 2.13 It is recommended to use the Peabody 2 Motor Development scale to assess 7 71.4 Agreement Moderate motor development 2.14 It is recommended to use the BRIEF-2 Executive Function Behavioral 7 78.6 Agreement Moderate Assessment scale to assess executive capabilities 2.15 It is important to assess the comorbidities or complications related to cognitive 9 96.4 Agreement Strong problems in Dravet syndrome, such as: Autism Spectrum Disorder (ASD), Attention Deficit and Hyperactivity Disorder (ADHD), language problems, depression, academic frustration, social isolation, and bullying 2.16 Gait development should be evaluated specifically at each consultation with the 9 85.7 Agreement Strong specialist, at least every 3–6 months 2.17 It is recommended to analyze and study ataxia and gait coordination at each 9 89.3 Agreement Strong consultation with the specialist, at least every 3–6 months 2.18 When evaluating gait development, the use of a cart/walker or other support 8 89.3 Agreement Strong devices and orthoses is recommended at each visit, at least every 3–6 months (Continued) Frontiers in Neurology 07 frontiersin.org Aledo-Serrano et al. 10.3389/fneur.2022.975034 TABLE 2 (Continued) Statement Median % Consensus Result Consensus level 2.19 It is recommended to reinforce the evaluation of motor skills and movement 8 89.3 Agreement Strong disorders such as parkinsonism, through assessment tools and scales, in order to obtain information systematically and periodically, at least every 6 months−1 year 2.20 It is important to record videos for the evaluation of the patient’s gait (by 8 85.7 Agreement Strong relatives or by the specialist) at each visit 2.21 For the evaluation of motor development, it is recommended to quantify using 8 71.5 Agreement Moderate specific scales with a periodicity of <1 year. Some examples are: Gross Motor Function Classification System (GMFCS) scale, Gillette scale, Pedi-CAT scale (mobility domain) 2.22 During the evaluation of motor development, it is important to consider falls, 8 89.3 Agreement Strong accidents and injuries at each visit, at least every 3–6 months 2.23 During the evaluation of motor development, it is important to take into account 9 85.8 Agreement Strong muscle retraction, muscle tone and pain at each visit, at least every 3–6 months 2.24 It is important to take into account orthopedic deformities in the lower limbs, as 9 96.4 Agreement Strong well as pathological curvatures of the spine (scoliosis, kyphoscoliosis, etc.) with an annual evaluation by Rehabilitation and Traumatology or more frequent if the clinician requires it Grey emphasis is used to highlights statements where there was no agreement or agreement was only moderate. The panelists recommended providing information on the Discussion risk of SUDEP in DS through a specific conversation with the patient and family/caregivers. According to the experts, To our knowledge, this is the first study to establish the pediatric/adult neurologist should lead the conversation recommendations regarding QoL and PROs assessment and and include prevention strategies and instructions for the the main comorbidities in DS, using a Delphi technique management of “near-SUDEP” situations. The panelists agreed and qualitative methodology, including caregivers and a on the possibility of training caregivers on cardiopulmonary multidisciplinary group of experts. Caregivers with a variety resuscitation techniques. Finally, the experts recommended of familiar relationships and providing care to patients with carrying out an annual or biannual cardiological evaluation, a wide range of ages were included, and experts represented based on patient risk. highly qualified professionals involved in the treatment and care of DS patients in Spain. The experts reached a consensus on recommendations for the management and follow-up of DS, Assessment of the QoL of focusing on the assessment of patients’ and caregivers’ QoL and other outcomes. The high degree of consensus reached by the caregivers/relatives panelists is noteworthy, with consensus agreement reached for 69 of the total 70 items proposed (Table 7), covering the six The results of the category regarding the assessment categories related to (1) general aspects of QoL evaluation of of the QoL of caregivers/relatives are shown in Table 6. patients with DS, (2) neurodevelopmental evaluation in patients Although the three items reached an agreement, only one with DS, (3) assessment of attention and behavior in patients was classified as a strong consensus (33.33%), and the other with DS, (4) evaluation of other comorbidities affecting QoL two (66.66%) fell into the moderate consensus category. The in patients with DS, (5) Sudden unexpected death in epilepsy experts reached a consensus agreement on the 3 statements (SUDEP), and (6) assessment of the QoL of caregivers/relatives. included in the questionnaire. The panelists recommended Full consensus agreement was obtained on the items included collecting information on the impact of the disease on the QoL in all the categories, with the exception of category 4, where one of caregivers and studying the dynamics between the patient, item was considered undetermined. Fifteen out of the 70 items caregivers, and siblings at least every 3–6 months. The experts (21.43%) obtained a moderate consensus, indicating a certain recommended using quantitative assessment scales for caregiver level of controversy. burden and QoL, such as the Zarit Burden Interview (ZBI). Frontiers in Neurology 08 frontiersin.org Aledo-Serrano et al. 10.3389/fneur.2022.975034 TABLE 3 Assessment of attention and behavior in patients with Dravet syndrome. Statement Median % Consensus Result Consensus level 3.1 It is recommended to evaluate the behavior of patients with Dravet syndrome at 9 92.9 Agreement Strong each consultation with the specialist, at least every 3–6 months 3.2 The care and behavior of the patient should be evaluated in the educational 9 92.9 Agreement Strong center/stimulation center at each consultation with the specialist, at least every 3–6 months 3.3 When evaluating behavior, aggressiveness (heterogrevisity and 9 96.4 Agreement Strong self-aggressiveness) must be taken into account 3.4 In assessing behavior, impulsivity, hyperactivity and difficulty paying attention 9 100 Agreement Strong must be taken into account 3.5 In the evaluation of behavior, low cognitive flexibility, such as a poor tolerance to 9 96.4 Agreement Strong frustration, as well as tantrums must be taken into account 3.6 When evaluating behavior, family stress and the patient’s school situation should 9 92.9 Agreement Strong be considered 3.7 For the behavioral assessment, psychiatric evaluation is recommended at least 8 67.9 Agreement Moderate once a year; and then every 3–6 months, especially if the patient required medication 3.8 It is important to take into account certain comorbidities and/or situations 9 92.9 Agreement Strong associated with behavior, such as Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD), school failure, isolation, school exclusion and decreasing social exposure, at least every 3–6 months 3.9 In order to systematize and formalize the behavior assessment, as well as to 8 82.1 Agreement Strong support a possible therapeutic decision, the use of scales on a regular basis (at least every 6 months or 1 year) should be assessed, such as: (A) La Child Behavior Checklist (CBCL) scale and the scale for the Assessment of Attention Deficit Hyperactivity Disorder (EDAH and ADHD-RS). (B) The scale of the Child and Adolescent Assessment System (SENA) with a psychopathological approach (anxiety, depression and hyperactivity), which can be categorized by age. (C) The Vinel and scale (to be performed by the patient’s relatives) on autonomy. (D) The BRIEF 2 scale (2 versions: preschool/school). It serves both to assess executive function and behavior in relation to it Grey emphasis is used to highlights statements where there was no agreement or agreement was only moderate. Appropriate assessment of clinical and QoL parameters The recommendations regarding general aspects of QoL of patients with DS is crucial due to the importance of the evaluation of patients with DS indicate that experts overall symptoms and burden of the disease (14, 30, 31). In this regard, consider the evaluation of the patient’s QoL at each visit with the it is important to note that some treatments can negatively affect clinician to be of great importance. This opinion is supported by DS patients, as is the case of sodium channel blockers (SCBs) several publications indicating an association between clinical on cognition (32). Although a European clinical guideline parameters and the QoL status of patients with DS (23, 30, was recently published (22), the publication focused on the 34). The experts also recommended including a wide range treatment of DS, leaving gaps with respect to the QoL and of parameters in the assessment of patients’ QoL, considering comorbidity assessment in DS. Seizure severity, cognition, and its multidimensional nature. Although there was a consensus motor and behavioral problems appear to be the primary drivers agreement on most of the contents of the instruments for of QoL (32, 33). However, despite the available publications, assessing QoL, including pharmacological treatment, social, clear guidelines for its routine assessment in both DS patients physical, and psychological aspects (35–37), a higher proportion and caregivers are still missing (23–27). This Delphi consensus of panelists disagreed on the assessment of the financial was developed to meet such needs and aimed to provide a set of and home situation, support material, relationships with recommendations for clinicians involved in the management of healthcare professionals and the healthcare system. Likewise, patients with DS. despite reaching a consensus agreement, several panelists Frontiers in Neurology 09 frontiersin.org Aledo-Serrano et al. 10.3389/fneur.2022.975034 TABLE 4 Evaluation of other comorbidities that affect quality of life in patients with Dravet syndrome. Statement Median % Consensus Result Consensus level 4.1 It is recommended to assess patients’ sleep and quality of sleep at each visit with 9 96.4 Agreement Strong the specialist, at least every 3–6 months 4.2 It is recommended to consider the need for medication and its effectiveness 9 92.1 Agreement Strong during the sleep assessment 4.3 It is recommended to consider the frequency of seizures during sleep at the sleep 9 100 Agreement Strong assessment 4.4 Regarding generalized tonic-clonic seizures during sleep, it is important to ask 9 100 Agreement Strong about them at each visit, at least every 3–6 months, and collect them independently in the seizure diaries 4.5 Due to its relevance, it is recommended to assess the use of specific systems for 8 85.8 Agreement Strong the evaluation of seizures through different tools, for example: the crisis diary or applications for the collection of seizures, monitoring through video-EEG of periodically, the use of videos at home (camera in the room), the measurement of vital signs after the crisis (for example, pulse oximeter), the use of wearables and specific apps for monitoring during sleep 4.6 It is recommended to take time to specifically explain to the family and/or 9 89.3 Agreement Strong caregivers the potential comorbidities associated with seizures during sleep. [For example: the risk of Sudden unexpected death in epilepsy -SUDEP-, daytime sleepiness (patients and relatives), the effect on marital life and the impact on social activities of the parents.] 4.7 Daytime sleepiness should be specifically explored at each visit, at least every 3–6 9 92.9 Agreement Strong months, in order to obtain a more complete view of the quality of the patient’s nighttime sleep. For this, details must be obtained about the following aspects: the need for a specific medication, the need to measure drug plasma levels, school performance and lack of attention, secondary irritability, and sleep attacks during the day (no. naps). 4.8 The use of specific scales to measure the quality of sleep of the patient and 8 71.4 Agreement Moderate caregivers at least every 6 months should be considered, such as: the Bruni scale (sleepiness and quality of sleep in children) and the Pittsburgh scale (for adult patients, family members, and caregivers) 4.9 In cases of difficult clinical evaluation of the sleep disorder, it is recommended to 7 60.7 Undetermined – complement the evaluation with the practice of an actigraphy study (wristwatch actigraph) 4.10 When there are symptoms of the sleep sphere, it is recommended to perform a 8 92.8 Agreement Strong video-EEG that includes nocturnal sleep-associated, depending on the case, with polysomnography 4.11 When there are symptoms in the sleeping area, it is advisable to carry out a 8 78.6 Agreement Moderate clinical survey directed to screen for SAHS and consider doing a PSG study 4.12 It is advisable to assess digestive comorbidity, gastroesophageal reflux, 8 89.3 Agreement Strong constipation at each visit, at least every 3–6 months 4.13 It is advisable to assess respiratory problems and frequent infections at each visit, 8 92.9 Agreement Strong at least every 3–6 months 4.14 It is advisable to have specific guidelines for vaccination periods and infectious 9 96.4 Agreement Strong processes for both family members and the doctors of the Health Center EEG, electroencephalograph; SUDEP, Sudden unexpected death in epilepsy; SAHS, sleep apnea/hypopnea syndrome; PSG, polysomnography. Grey emphasis is used to highlights statements where there was no agreement or agreement was only moderate. Frontiers in Neurology 10 frontiersin.org Aledo-Serrano et al. 10.3389/fneur.2022.975034 TABLE 5 Sudden unexpected death in epilepsy (SUDEP). Statement Median % Consensus Result Consensus level 5.1 It is advisable to inform through a specific conversation with the patient and 8 89.3 Agreement Strong family/caregivers about the risk of SUDEP in Dravet syndrome during the visit with the specialist 5.2 It is the pediatric neurologist or neurologist who must decide the moment and 8 92.9 Agreement Strong the context to talk about prevention strategies and management of the patient in the case of potential “near-SUDEP” situations 5.3 It is recommended to establish actions such as the possibility of carrying out a 8 85.7 Agreement Strong basic CPR course (Cardiopulmonary Resuscitation) in order to be prepared for an emergency situation 5.4 It is recommended to carry out an annual or biannual cardiological evaluation, 8 82.1 Agreement Strong based on risks, including an ECG assessment of a potential long QTc and eventually a Holter ECG ECG, electrocardiogram; SUDEP, sudden unexpected death in epilepsy. TABLE 6 Assessment of the quality of life of caregivers/relatives. Statement Median % Consensus Result Consensus level 6.1 It is recommended to collect information on the impact of the disease on the 8 82.1 Agreement Strong quality of life of caregivers at each visit, at least every 3–6 months 6.2 It is important to study the dynamics between the patient, caregivers, and 8 78.6 Agreement Moderate siblings in order to globally analyze the situation of families and the impact it has on their quality of life and on their daily, family, social, and work activities, at least every 3–6 months 6.3 It is recommended to use quantified assessment scales for caregiver burden and 8 67.9 Agreement Moderate quality of life, such as the Zarit scale Grey emphasis is used to highlights statements where there was no agreement or agreement was only moderate. disagreed on the need for questionnaires to be administered Wechsler, Peabody 2, and BRIEF-2, there was less agreement on by physicians. In conclusion, the recommendations of this the consensus. category are in favor of establishing the use of PROs Regarding the assessment of attention and behavior in in the clinical practice of DS. Given the infrequent use patients with DS, the panelists recommended evaluating the of PROs in this pathology (21), the publication of these behavior of patients with DS in the educational/stimulation recommendations may be a stimulus for their development center at each consultation with the specialist, with a frequency and implementation. of at least 3–6 months. For this statement, the percentage of For neurodevelopmental evaluation in patients with DS, the consensus reached 67.9%, close to the limit of agreement, which panelists recommended that assessments be conducted at each may be due to the indicated follow-up time. Several panelists visit with the specialist, with varying frequencies depending commented that a follow-up of 6 months is sufficient and more on the patient’s age. Given the neurodevelopmental delay in in line with the reality of clinical practice, with limited time DS children (38–40), the experts considered that a frequent for each patient visit. The motivation for this recommendation measurement of neurodevelopment was appropriate. Because of is that behavioral problems in DS are very common and have the multiple areas that may be affected by a neurodevelopment a tremendous impact on these patients’ lives (47). Patients delay (38–40), the panelists recommended its assessment using with DS present multiple behavioral problems and, therefore, several scales that have been previously validated in the experts recommend evaluating several parameters within this pediatric setting (41–46), although in the case of Bayley III, domain (47). Frontiers in Neurology 11 frontiersin.org Aledo-Serrano et al. 10.3389/fneur.2022.975034 TABLE 7 Summary of recommendations. It is recommended to evaluate the quality of life of the patient to determine the impact of the disease on their physical, mental and social wellbeing, facilitating follow-up, and decision-making by physicians At each visit with the specialist, it is recommended to assess the quality of life of the patient taking into account the patient’s biological or chronological age, according to the characteristics to be evaluated It is recommended to assess the quality of life of the patient through specific questionnaires aimed at the parents or caregivers, taking into account the patient’s biological or chronological age, according to the characteristics to be evaluated In assessing quality of life, caregivers and family members should have tools such as self-administered questionnaires to be able to report the patient’s situation to the specialist in a structured and concrete way The quality of life questionnaires used to monitor the patient should include specific questions on: Aspects related to physical health status The quality of life questionnaires used to monitor the patient should include specific questions on: Aspects related to the psychological status The quality of life questionnaires used to monitor the patient should include specific questions on: Aspects related to the social environment and functioning, such as the family or school environment The quality of life questionnaires used to monitor the patient should include specific questions on: Aspects related to the financial, housing conditions and supporting material The quality of life questionnaires used for patient follow-up should include specific questions on: Aspects related to adverse effects of drug treatment The quality of life questionnaires used to monitor the patient should include specific questions on: Aspects related to the relationship of the patient and caregivers with healthcare professionals The quality of life questionnaires used to monitor the patient should include specific questions on: Aspects related to the relationship of the patient and caregivers with the healthcare system The electronic format is considered the optimal method for collecting information on quality of life (with different alternatives for non-technology users, such as paper format) The pediatrician, family doctor, pediatric neurologist, or neurologist should be the one to assess the results of the questionnaires on quality of life provided and to ask for them regularly and specifically in their visits and consultations Patient quality of life questionnaires should always be provided and managed by healthcare professionals, with specialized nursing personnel, at the hospital or in a primary care center being the most recommended setting It is recommended to monitor and maintain fluent and constant communication between the different professionals involved in the quality of life of the patient, their family members, and caregivers It is recommended to assess the neurodevelopment of patients with Dravet syndrome at each visit with the specialist (every 3 months from 0 to 3 years, every 6 months from 3 to 6 years, and every 12 months from 7 years onwards) It is recommended for all patients with Dravet syndrome to be assessed and monitored by a multidisciplinary team of neuropsychologists, speech therapists, occupational therapists and physiotherapists, grouping specialists in the same appointment to facilitate family trips to the healthcare center It is recommended to monitor neurodevelopment up to 6 years of age through early care centers with EOEPs (Educational and Psychopedagogical Guidance Teams), or other comprehensive neurodevelopmental assessment centers with awareness for different domains affected by Dravet syndrome, such as language, attention, executive functions, or gross and fine motor development In the evaluation of cognitive development, it is advisable to evaluate the communication and language of patients with Dravet syndrome at each visit with the specialist Clinical evaluation of expressive, comprehensive, and non-verbal language and its impact on learning, socialization, and safety is recommended, at least every 3–6 months Clinical evaluation of social interaction and communicative interest is recommended, at least every 3–6 months Speech evaluation is recommended, at least every 3–6 months Clinical evaluation of attention and executive functions is recommended at least every 3–6 months During the neurodevelopmental assessment, the application of measurement tools or scales quantifying the different neurodevelopmental domains should be assessed every 3–6–12 months, according to the patient’s needs The neurologist and/or the pediatric neurologist, in collaboration with the neuropsychologist, should decide which scale may be more advisable to use for the evaluation of motor and cognitive development in each case, considering specific objectives and depending on the characteristics of each test It is recommended to use the Cognitive Bayley III scale to assess different neurodevelopmental domains It is recommended to use the Wechsler Intelligence scale for children to assess cognitive development It is recommended to use the Peabody 2 Motor Development scale to assess motor development It is recommended to use the BRIEF-2 Executive Function Behavioral Assessment scale to assess executive capabilities (Continued) Frontiers in Neurology 12 frontiersin.org Aledo-Serrano et al. 10.3389/fneur.2022.975034 TABLE 7 (Continued) It is recommended to evaluate the quality of life of the patient to determine the impact of the disease on their physical, mental and social wellbeing, facilitating follow-up, and decision-making by physicians It is important to assess the comorbidities or complications related to cognitive problems in Dravet syndrome, such as: Autism Spectrum Disorder (ASD), Attention Deficit and Hyperactivity Disorder (ADHD), language problems, depression, academic frustration, social isolation, and bullying Gait development should be evaluated specifically at each consultation with the specialist, at least every 3–6 months It is recommended to analyze and study ataxia and gait coordination at each consultation with the specialist, at least every 3–6 months When evaluating gait development, the use of a cart/walker or other support devices and orthoses is recommended at each visit, at least every 3–6 months It is recommended to reinforce the evaluation of motor skills and movement disorders such as parkinsonism, through assessment tools and scales, in order to obtain information systematically and periodically, at least every 6 months-1 year It is important to record videos for the evaluation of the patient’s gait (by relatives or by the specialist) at each visit For the evaluation of motor development, it is recommended to quantify using specific scales with a periodicity of <1 year. Some examples are: Gross Motor Function Classification System (GMFCS) scale, Gillette scale, Pedi-CAT scale (mobility domain) During the evaluation of motor development, it is important to consider falls, accidents and injuries at each visit, at least every 3–6 months During the evaluation of motor development, it is important to take into account muscle retraction, muscle tone and pain at each visit, at least every 3–6 months It is important to take into account orthopedic deformities in the lower limbs, as well as pathological curvatures of the spine (scoliosis, kyphoscoliosis, etc.) with an annual evaluation by Rehabilitation and Traumatology or more frequent if the clinician requires it It is recommended to evaluate the behavior of patients with Dravet syndrome at each consultation with the specialist, at least every 3–6 months The care and behavior of the patient should be evaluated in the educational center/stimulation center at each consultation with the specialist, at least every 3–6 months When evaluating behavior, aggressiveness (heterogrevisity and self-aggressiveness) must be taken into account In assessing behavior, impulsivity, hyperactivity and difficulty paying attention must be taken into account In the evaluation of behavior, low cognitive flexibility, such as a poor tolerance to frustration, as well as tantrums must be taken into account When evaluating behavior, family stress and the patient’s school situation should be considered For the behavioral assessment, psychiatric evaluation is recommended at least once a year; and then every 3–6 months, especially if the patient required medication It is important to take into account certain comorbidities and/or situations associated with behavior, such as Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD), school failure, isolation, school exclusion and decreasing social exposure, at least every 3–6 months In order to systematize and formalize the behavior assessment, as well as to support a possible therapeutic decision, the use of scales on a regular basis (at least every 6 months or 1 year) should be assessed, such as: (A) La Child Behavior Checklist (CBCL) scale and the scale for the Assessment of Attention Deficit Hyperactivity Disorder (EDAH and ADHD-RS). (B) The scale of the Child and Adolescent Assessment System (SENA) with a psychopathological approach (anxiety, depression and hyperactivity), which can be categorized by age. (C) The Vinel and scale (to be performed by the patient’s relatives) on autonomy. (D) The BRIEF 2 scale (2 versions: preschool/school). It serves both to assess executive function and behavior in relation to it It is recommended to assess patients’ sleep and quality of sleep at each visit with the specialist, at least every 3–6 months It is recommended to consider the need for medication and its effectiveness during the sleep assessment It is recommended to consider the frequency of seizures during sleep at the sleep assessment Regarding generalized tonic-clonic seizures during sleep, it is important to ask about them at each visit, at least every 3–6 months, and collect them independently in the seizure diaries Due to its relevance, it is recommended to assess the use of specific systems for the evaluation of seizures through different tools, for example: the crisis diary or applications for the collection of seizures, monitoring through video-EEG of periodically, the use of videos at home (camera in the room), the measurement of vital signs after the crisis (for example, pulse oximeter), the use of wearables and specific apps for monitoring during sleep It is recommended to take time to specifically explain to the family and/or caregivers the potential comorbidities associated with seizures during sleep. (For example: the risk of Sudden unexpected death in epilepsy -SUDEP-, daytime sleepiness (patients and relatives), the effect on marital life and the impact on social activities of the parents) Daytime sleepiness should be specifically explored at each visit, at least every 3–6 months, in order to obtain a more complete view of the quality of the patient’s nighttime sleep. For this, details must be obtained about the following aspects: the need for a specific medication, the need to measure drug plasma levels, school performance and lack of attention, secondary irritability, and sleep attacks during the day (no. naps). The use of specific scales to measure the quality of sleep of the patient and caregivers at least every 6 months should be considered, such as: the Bruni scale (sleepiness and quality of sleep in children) and the Pittsburgh scale (for adult patients, family members, and caregivers) When there are symptoms of the sleep sphere, it is recommended to perform a video-EEG that includes nocturnal sleep-associated, depending on the case, with polysomnography When there are symptoms in the sleeping area, it is advisable to carry out a clinical survey directed to screen for SAHS and consider doing a PSG study It is advisable to assess digestive comorbidity, gastroesophageal reflux, constipation at each visit, at least every 3–6 months It is advisable to assess respiratory problems and frequent infections at each visit, at least every 3–6 months (Continued) Frontiers in Neurology 13 frontiersin.org Aledo-Serrano et al. 10.3389/fneur.2022.975034 TABLE 7 (Continued) It is recommended to evaluate the quality of life of the patient to determine the impact of the disease on their physical, mental and social wellbeing, facilitating follow-up, and decision-making by physicians It is advisable to have specific guidelines for vaccination periods and infectious processes for both family members and the doctors of the Health Center It is advisable to inform through a specific conversation with the patient and family/caregivers about the risk of SUDEP in Dravet syndrome during the visit with the specialist It is the pediatric neurologist or neurologist who must decide the moment and the context to talk about prevention strategies and management of the patient in the case of potential “near-SUDEP” situations It is recommended to establish actions such as the possibility of carrying out a basic CPR course (Cardiopulmonary Resuscitation) in order to be prepared for an emergency situation It is recommended to carry out an annual or biannual cardiological evaluation, based on risks, including an ECG assessment of a potential long QTc and eventually a Holter ECG It is recommended to collect information on the impact of the disease on the quality of life of caregivers at each visit, at least every 3–6 months It is important to study the dynamics between the patient, caregivers, and siblings in order to globally analyze the situation of families and the impact it has on their quality of life and on their daily, family, social, and work activities, at least every 3–6 months It is recommended to use quantified assessment scales for caregiver burden and quality of life, such as the Zarit scale EEG, electroencephalograph; SUDEP, Sudden unexpected death in epilepsy; SAHS, sleep apnea/hypopnea syndrome; PSG, polysomnography. Grey denotes recommendations with moderate agreement. During the assessment of other comorbidities affecting QoL proposed as an assessment measure, presumably because it has in patients with DS, a total of 13 statements of the 14 proposed been used in the field of epilepsy (53). obtained a consensus agreement. The only item not validated The Delphi technique is widely used in health studies as in the entire Delphi questionnaire was the one related to a method to obtain useful information from experts when the use of actigraphy study for evaluating a sleep disorder. the published body of evidence is incomplete (23, 24, 28, The reason for this may be the scarcity of studies on this 55). However, the conclusions obtained with this methodology subject conducted in the SD population (48). The remaining may have several limitations associated with the setting and items on the importance of assessing sleep, as well as other design of this Delphi questionnaire. In the present study, the comorbidities, reached consensus agreement by the experts, panelists were exclusively from Spain and, thus, their experience likely motivated by the high prevalence of other diseases in was focused on the Spanish healthcare system. Therefore, the patients with DS (49–51). In this regard, the advice to assess recommendations of this study, such as those related to the respiratory problems may be due to the fact that seizures frequency of assessments, may not be appropriate for other can increase the risk of pulmonary complications, such as countries or regions. Likewise, this study has not assessed aspiration pneumonia, which occurs when patients inhale food, the impact that the implementation of these recommendations stomach acid, or saliva into the lungs, potentially resulting in could have on the current Spanish healthcare system from sepsis (50). the point of view of the potential need for more human SUDEP is the leading reported cause of death reported and non-human resources. Clinicians with experience in other in DS, accounting for nearly half of all premature deaths healthcare systems should assess whether each recommendation (52). The experts recommended assessing several aspects in this paper can be translated into their clinical practice, and related to SUDEP in category 5. The panelists agreed that adapt or discard those that they do not consider appropriate. it is advisable to inform through a specific discussion Nevertheless, this study used a Delphi questionnaire developed with the patient and family/caregivers about the risk of by experts with the input from patient caregivers, which SUDEP and to educate them on prevention and self- allowed for capturing controversial issues from the experts’ assessment strategies. Given the association between SUDEP and caregivers’ perspectives. Another possible limitation of and heart failure, periodic cardiological evaluations were the study relates to the limited number of caregivers who recommended (52). participated in the focus group. Although the intention was to DS is a disease with a significant impact on patients’ make it as representative and diverse as possible, it is possible caregivers and relatives (53, 54). For this reason, in category that some bias could become apparent at some points, given 6, the experts reached a consensus to recommend collecting that not all the perspectives of caregivers of DS patients may information regarding the impact of the disease on the QoL have been represented. In addition, further studies involving of caregivers and to study the dynamics between patients, professionals from a wider range of disciplines involved in caregivers, and siblings at least every 3–6 months. The ZBI was the care and management of patients with DS, such as social Frontiers in Neurology 14 frontiersin.org Aledo-Serrano et al. 10.3389/fneur.2022.975034 workers or therapists, may provide a more accurate view on the Author contributions management of PROs in the daily life of DS patients and their families. Another limitation of the study associated to the Delphi ÁA-S has contributed to the design and conception of technique is related to the consensus definition, which is not the study. All authors have contributed to the acquisition, standard, and therefore, different criteria can be found in the analysis, interpretation of the data, have participated in the literature (23, 29). For this reason, we deemed appropriate to drafting and reviewing of the manuscript, and approving the define two categories of consensus, moderate and strong (29). submitted version. We considered that although agreement was reached on most of the items consulted, those that fell into the moderate consensus Funding category may have raised more controversy among the experts. The high burden on QoL for DS patients and their This study was funded and promoted by Zogenix Spain, now caregivers, as well as the lack of concise guidelines on the a part of UCB. evaluation of various clinical parameters, makes it necessary to issue expert recommendations to fill these gaps. The present study intended to meet these needs through an expert consensus, Acknowledgments which may be a useful guide for clinicians involved in the routine follow-up and management of patients with DS. In particular, The authors wish to thank the panel experts for their this study focused on PROs, which constitute a patient-centered participation in the Delphi questionnaire (Annex I). We would alternative to incorporate into future clinical practice of patients also like to thank patients’ caregivers for contributing with with DS, as classical measures fail to cover all aspects of the their perspective to this project by reviewing and commenting disease (56). Furthermore, this study may serve as an example on the Delphi questionnaire statements (Annex II), the Dravet for the development of recommendations to assess PROs and Syndrome Foundation (DSF) Spain for recruiting them for this other outcomes in other DEEs. study and participating in the focus group and Apoyo Dravet for participating in the focus group. The authors would like to thank Luzán 5 for their collaboration with meetings logistics and the Data availability statement technical assistance and i2e3 Biomedical Research Institute for providing medical writing support. The original contributions presented in the study are included in the article/Supplementary material, further inquiries Conflict of interest can be directed to the corresponding author. Author ÁA-S has received funding for educational and research activities from Angelini, Zogenix, UCB, PTC pharma, Ethics statement Blueprint genetics, GW, Eisai. Author AG-N has received advisory or research funds by Arvelle/Angelini, Bial, Biocodex, Ethical review and approval was not required for the EISAI, Esteve, GW Pharma, Jazz Pharmaceuticals, PTC study on human participants in accordance with the local Therapeutics, Stoke, UCB Pharma and Zogenix. Author JA is legislation and institutional requirements. Written informed president of the Dravet Syndrome Foundation Spain (DSF). He consent from the patients/participants or patients/participants’ and/or the DSF have received grants and/or financial support legal guardian/next of kin was not required to participate in from GW Pharma, Zogenix, Ovid Therapeutics, Encoded this study in accordance with the national legislation and the Therapeutics, Biocodex, Praxis, Health in Code, Takeda, UCB, institutional requirements. Epygenix, Jazz Pharmaceuticals and StrideBio to help carry out some of the DSF’s foundational activities or provide consulting services. Author JA honoraria have always been The Charlotte Project group donated directly or indirectly to the DSF. Author RS-C has been a trial investigator for GW Pharmaceuticals, Takeda Adrián García-Ron, Alberto Vieco, Alfonso Amado Pharmaceutical Company Ltd. Author and Zogenix and has Puentes, Helena Alarcón Martínez, Irene García Morales, served on advisory boards for Novartis, GW Pharmaceuticals, Javier Aparicio Calvo, Jesús Eirís Puñal, Juan Jesús Rodriguez Biocodex and Zogenix. Author JG-P has received advisory or Uranga, Juan José Poza Aldea, Julián Lara Herguedas, Julio lecture funds by BIAL, EISAI, GW, NUTRICIA, SANOFI, UCB Ramos-Lizana, Mercè Falip Centelles, Mercedes Garcés and ZOGENIX. VV has participated in advisory boards and Sánchez, Miquel Raspall Chaure, Patricia Smeyers Dura, Rafael symposia organized by Angellini, Bial, Eisai Inc., GW pharma, Toledano Delgado, Rocío Calvo Medina, Salvador Ibáñez Novartis, Takeda, UCB, Zogenix. Author AM was employed Micó, Sergio Aguilera Albesa, Víctor Soto Insuga, and Xiana by Dracaena Consulting SL. Author LA was employed by Rodríguez Osorio. Apoyo Dravet. Frontiers in Neurology 15 frontiersin.org Aledo-Serrano et al. 10.3389/fneur.2022.975034 The remaining authors declare that the research was the editors and the reviewers. Any product that may be conducted in the absence of any commercial or financial evaluated in this article, or claim that may be made by relationships that could be construed as a potential conflict its manufacturer, is not guaranteed or endorsed by the of interest. publisher. Publisher’s note Supplementary material All claims expressed in this article are solely those The Supplementary Material for this article can be of the authors and do not necessarily represent those found online at: https://www.frontiersin.org/articles/10.3389/ of their affiliated organizations, or those of the publisher, fneur.2022.975034/full#supplementary-material References 1. Dravet C. The core Dravet syndrome phenotype. Epilepsia. (2011) 52(Suppl. 17. Nolan K, Camfield CS, Camfield PR. Coping with a child with 2):3–9. doi: 10.1111/j.1528-1167.2011.02994.x Dravet syndrome: insights from families. J Child Neurol. (2008) 23:690– 4. doi: 10.1177/0883073808314162 2. Villeneuve N, Laguitton V, Viellard M, Lépine A, Chabrol B, Dravet C, et al. Cognitive and adaptive evaluation of 21 consecutive patients with Dravet 18. Whittington MD, Knupp KG, Vanderveen G, Kim C, Gammaitoni A, syndrome. Epilepsy Behav. (2014) 31:143–8. doi: 10.1016/j.yebeh.2013.11.021 Campbell JD. 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