Edited by: Alessandro Simonati, University of Verona, Italy
Reviewed by: Wang-Tso Lee, National Taiwan University Hospital, Taiwan; Jill Edith Cadwgan, Evelina London Children's Hospital, United Kingdom
This article was submitted to Pediatric Neurology, a section of the journal Frontiers in Neurology
†Novartis employee at the time of manuscript concept approval
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Research on tuberous sclerosis complex (TSC) to date has focused mainly on the physical manifestations of the disease. In contrast, the psychosocial impact of TSC has received far less attention. The aim of this study was therefore to examine the impact of TSC on health, quality of life (QoL), and psychosocial well-being of individuals with TSC and their families. Questionnaires with disease-specific questions on burden of illness (BOI) and validated QoL questionnaires were used. After completion of additional informed consent, we included 143 individuals who participated in the TOSCA (TuberOus SClerosis registry to increase disease Awareness) study. Our results highlighted the substantial burden of TSC on the personal lives of individuals with TSC and their families. Nearly half of the patients experienced negative progress in their education or career due to TSC (42.1%), as well as many of their caregivers (17.6% employed; 58.8% unemployed). Most caregivers (76.5%) indicated that TSC affected family life, and social and working relationships. Further, well-coordinated care was lacking: a smooth transition from pediatric to adult care was mentioned by only 36.8% of adult patients, and financial, social, and psychological support in 21.1, 0, and 7.9%, respectively. In addition, the moderate rates of pain/discomfort (35%) and anxiety/depression (43.4%) reported across all ages and levels of disease demonstrate the high BOI and low QoL in this vulnerable population.
Tuberous sclerosis complex (TSC) is a multi-system genetic disorder with a global incidence of 1 per 6,000–10,000 live births. Over a million people are estimated to be affected worldwide (
To date, the majority of TSC research has concentrated on the pathophysiology, epidemiology, diagnosis, and treatment of the condition (
TOSCA, a natural history registry in TSC, was conducted in 170 sites across 31 countries worldwide. A detailed description of the methods of the TOSCA study has been provided previously (
Selection of countries participating in this research project was based on the availability of the validated QoL questionnaires in the primary language used in that country. Based on this criterion, TSC individuals of any age from seven European countries were eligible for this specific research project, after signing an additional consent form.
All enrolled individuals were asked to complete a set of ancillary questions addressing social care needs (circumstances of living arrangements, financial, social, and psychological support, and information sources), healthcare needs (health insurance, medical care and level of satisfaction, genetic testing, and genetic counselling), impact on education and employment, impact on family, and transition from paediatric to adult care (
For evaluating QoL, validated questionnaires in local languages were administered to individuals with TSC/caregivers who participated in this research project. These included the following: (1) EuroQol-5D (EQ-5D), a self-complete questionnaire for adults (age, ≥18 years); the EQ-5D proxy version 1 was completed by the caregiver for children or adolescents for adults who were unable to complete the report by themselves; (2) QoL in Epilepsy Inventory-31-Problems (QOLIE-31)-P for adults (age, ≥18 years) with epilepsy, completed by the individuals themselves; (3) QoL in Childhood Epilepsy (QOLCE) for children <10 years old with epilepsy (completed by caregivers); (4) QoL in Epilepsy Inventory for Adolescents-48 (QOLIE-AD-48) for children aged 11–17 years with epilepsy, completed by the subjects themselves.
Data on QoL and BOI were recorded once (i.e., no follow up requested) before the data cut-off date (10 August, 2017). A copy of the collected paper questionnaires was sent from each clinical site to the clinical research organization (CRO) for data entry in the TOSCA study. Data were then extracted and analysed by the CRO. Responses to the BOI questions and QOL scales were summarised by descriptive statistics (number of responders, mean, standard deviation, median, range, frequency), considering age-based subgroup as children (<11 years), adolescents (age 11 to <18 years) and adults (age ≥18 years).
Individuals with TSC or their caregivers, rated their level of impairment across five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each dimension has three levels: no problems, some problem and confined to bed. The mean thermometer score for EQ-5D and mean health state score for QOLIE-31-P questionnaire were recorded on a scale from 0 to 100, with 0 being the worst health state imaginable and 100 the best. Furthermore, each patient rated the importance of the seven QOLIE 31-P sub scales (energy, mood, daily activities, cognition, medication effects, seizure worry, and overall quality of life) from one to seven, with one being the most important topic and seven the least important one. The sub-scale scores of QOLIE-31-P questionnaire were the means of the converted item scores multiplied by the distress score. The total QOLIE-31-P score was calculated by dividing the sum of the sub scales by the sum of the distress scores multiplied by 100. If more than half the items in a sub-scale had not answered, the sub-scale was not included in the total score. For each sub scale of QOLCE, the answer for each item was converted to a 0 to 100 point score, where high scores reflect the highest level of functioning.
Hundred fouty three individuals (88 children and adolescents, and 55 adults) from seven European countries were enrolled in this research project as part of the TOSCA study (
Demographic characteristics.
Male | 54 (37.8) |
Female | 88 (61.5) |
n | 142 |
Mean (SD) | 19.8 (15.24) |
Median (range) | 14 (3–72) |
n | 141 |
Mean (SD) | 13.5 (9.44) |
Median (range) | 11.2 (1.6–43.5) |
Belgium | 24 (16.8) |
France | 30 (21.0) |
Germany | 11 (7.7) |
Italy | 58 (40.6) |
Spain | 11 (7.7) |
Sweden | 6 (4.2) |
UK | 3 (2.1) |
n(%) | 67 (46.9) |
Duration of epilepsy (years) at start of research project | |
|
66 |
Mean (SD) | 16.6 (12.53) |
Median (range) | 12.8 (2.7–55.4) |
17 adolescents (19.3%; aged between 11 and <18 years) and 38 adults (69.1%) completed the questionnaire independently. Of these, one (5.9%) adolescent and five adults (13.2%) needed extra assistance at home. In most cases, assistance was provided by unpaid caregivers (a family member or friend). 29.4% adolescents and 42.1% of adults felt that assistance and support at home was not sufficient (
Social care needs: self- and caregiver-reported outcomes.
Lives alone | NA | 5 (13.2) | NA | 1 (5.9) |
Lives with spouse/partner | NA | 21 (55.3) | NA | 2 (11.8) |
Lives with other family | NA | 10 (26.3) | NA | 13 (76.5) |
Information missing | NA | 2 (5.3) | NA | 1 (5.9) |
Yes | NA | 3 (7.9) | NA | 8 (47.1) |
No | NA | 35 (92.1) | NA | 9 (52.9) |
Nurse | 0 | 0 | 1 (1.4) | 1 (5.9) |
Daily assistance by professional carer (paid) | 1 (5.9) | 0 | 5 (7.0) | 1 (5.9) |
Caregiver assistance from friend/family/relative (not paid) | 0 | 5 (13.2) | 16 (22.5) | 7 (41.2) |
Individuals felt that assistance and support at home was not sufficient | 5 (29.4) | 16 (42.1) | 31 (43.7) | 6 (35.3) |
Disability allowance | 6 (35.3) | 8 (21.1) | 39 (54.9) | 13 (76.5) |
Caregiver allowance | 1 (5.9) | 0 | 9 (12.7) | 0 |
Social worker assistance | 1 (5.9) | 0 | 6 (8.5) | 1 (5.9) |
Social services support | 1 (5.9) | 0 | 3 (4.2) | 2 (11.8) |
Psychological counselling | 2 (11.8) | 3 (7.9) | 10 (14.1) | 0 |
Physician | 7 (41.2) | 25 (65.8) | 46 (64.8) | 9 (52.9) |
Internet/Websites | 9 (52.9) | 14 (36.8) | 49 (69.0) | 7 (41.2) |
Patient group | 2 (11.8) | 5 (13.2) | 20 (28.2) | 6 (35.3) |
Social worker | 1 (5.9) | 1 (2.6) | 21 (29.6) | 3 (17.6) |
Local government | 1 (5.9) | 4 (10.5) | 6 (8.5) | 2 (11.8) |
Nurse | 0 | 2 (5.3) | 3 (4.2) | 3 (17.6) |
Physician | 9 (52.9) | 25 (65.8) | 34 (47.9) | 8 (47.1) |
Internet/Websites | 4 (23.5) | 4 (10.5) | 19 (26.8) | 3 (17.6) |
Patient group | 2 (11.8) | 2 (5.3) | 12 (16.9) | 4 (23.5) |
Social worker | 1 (5.9) | 0 | 13 (18.3) | 3 (17.6) |
Local government | 1 (5.9) | 2 (5.3) | 3 (4.2) | 0 |
Nurse | 0 | 0 | 1 (1.4) | 0 |
Nine adolescents (52.9%) and 16 adults (42.1%) had access to public and/or private insurance (
Health care needs: self- and caregiver-reported outcomes.
Private insurance | 2 (11.8) | 7 (18.4) | 31 (43.7) | 6 (35.3) |
Public insurance | 6 (35.3) | 14 (36.8) | 37 (52.1) | 4 (23.5) |
No insurance | 7 (41.2) | 15 (39.5) | 11 (15.5) | 8 (47.1) |
Individuals thought to have paid extra for private insurance due to TSC condition | 0 | 0 | 1 (1.4) | 0 |
Public insurance was denied due to TSC | 0 | 2 (5.3) | 9 (12.7) | 1 (5.9) |
Patient had genetic testing for TSC | 13 (76.5) | 31 (81.6) | 57 (80.3) | 16 (94.1) |
Patient was offered genetic testing but did not do it | 1 (5.9) | 1 (2.6) | 3 (4.2) | 0 |
Patient had not been offered genetic testing for TSC | 0 | 3 (7.9) | 7 (9.9) | 1 (5.9) |
Patient had genetic counselling | 9 (52.9) | 26 (68.4) | 43 (60.6) | 10 (58.8) |
Patient was offered genetic counselling but decided not to have it | 0 | 0 | 3 (4.2) | 0 |
Patient had not been offered genetic counselling for TSC | 4 (23.5) | 6 (15.8) | 19 (26.8) | 4 (23.5) |
1 | 8 (47.1) | 12 (31.6) | 17 (23.9) | 6 (35.3) |
2 | 3 (17.6) | 5 (13.2) | 11 (15.5) | 1 (5.9) |
3 | 0 | 3 (7.9) | 11 (15.5) | 2 (11.8) |
>3 | 6 (35.3) | 15 (39.5) | 31 (43.7) | 7 (41.2) |
Data not provided | 0 | 3 (7.9) | 1 (1.4) | 1 (5.9) |
General practitioner/family doctor | 1 (5.9) | 9 (23.7) | 17 (23.9) | 6 (35.3) |
TSC specialist | 12 (70.6) | 28 (73.7) | 39 (54.9) | 16 (94.1) |
Other specialist | 7 (41.2) | 19 (50.0) | 49 (69.0) | 7 (41.2) |
Individuals had access to clinic when required | 13 (76.5) | 29 (76.3) | 43 (60.6) | 16 (94.1) |
Distance to TSC clinic from home | ||||
<50 km | 10 (58.8) | 14 (36.8) | 18 (25.4) | 4 (23.5) |
>50 km | 3 (17.6) | 15 (39.5) | 30 (42.3) | 12 (70.6) |
Yes | 9 (52.9) | 14 (36.8) | 36 (50.7) | 9 (52.9) |
No | 7 (41.2) | 22 (57.9) | 33 (46.5) | 7 (41.2) |
Data not available | 1 (5.9) | 2 (5.3) | 2 (2.8) | 1 (5.9) |
Satisfaction with treatment aspects in
TSC was reported to have impacted the career/education progress in three adolescents (17.6%;
Impact of TSC on education, employment and relationships.
Impact of TSC on career/education of self or caregivers (in case of children) |
3 (17.6) | 16 (42.1) | 47 (66.2) | 12 (70.6) |
Career progression/promotions | 0 | 4 (25.0) | 17 (36.2) | 1 (8.3) |
Choice of career | 0 | 4 (25.0) | 16 (34.0) | 1 (8.3) |
Loss of employment | 2 (66.7) | 5 (31.3) | 10 (21.2) | 1 (8.3) |
Part-time work rather than full time | 0 | 5 (31.3) | 25 (53.2) | 1 (8.3) |
Education level attained | 1 (33.3) | 6 (37.5) | 3 (6.4) | 10 (83.3) |
Employed (either full or part-time) | 11 (64.7) | 20 (52.6) | 47 (66.2) | 3 (17.6) |
Unable to work due to condition | 0 | 4 (10.5) | 8 (11.3) | 10 (58.8) |
Unable to work but not due to condition | 0 | 3 (7.9) | 8 (11.3) | 1 (5.9) |
Student | 2 (11.8) | 2 (5.3) | 0 | 1 (5.9) |
Homemaker | 4 (23.5) | 7 (18.4) | 10 (14.1) | 1 (5.9) |
Family relationships | 3 (17.6) | 8 (21.1) | 29 (40.8) | 4 (23.5) |
Social relationships | 2 (11.8) | 14 (36.8) | 36 (50.7) | 11 (64.7) |
Working colleague relationships | 0 | 4 (10.5) | 17 (23.9) | 1 (5.9) |
Child is in mainstream education | 14 (82.4) | NA | 43 (60.6) | NA |
Child receives additional support in class | 6 (35.3) | NA | 31 (43.7) | NA |
Additional support causes child additional problems | 2 (11.8) | NA | 13 (18.3) | NA |
Parents/Caregivers completed the questionnaires for 71 children and adolescents (80.7%; 38 girls and 32 boys) and 17 adults (30.9%; 11 female and 6 male) who were unable to complete the questionnaires by themselves.
Of the 71 caregiver-reported children and adolescents, 20 (28.2%) needed help at home, provided mainly by unpaid caregivers in 80% of cases (
TSC was managed by TSC specialists in 39 (54.9%) caregiver-reported children and adolescents, and 16 (94.1%) caregiver-reported adults (
Caregivers have reported that TSC had affected the career or education of their children and adolescents in different ways. These include part-time work rather than full time (53.2%), impact on career progression/promotions (36.2%), choice of career (34.0%), loss of employment (21.2%), impact on educational attainment (6.4%). Of the 17 caregiver-reported adults, only three (17.6%) were employed while 10 (58.8%) were unable to work due to TSC. Ten (83.3%) carer-reported adults reported impact of educational attainment. Relationships of caregivers had been impacted due to child's TSC in 53.5% of cases with impact on the family, social, and working colleague relationships were reported in 29 (40.8%), 36 (50.7%), and 17 (23.9%) cases, respectively. Impact on the family, social and working relationships by TSC condition have been noted in 76.5% of caregiver-reported adults.
Overall, EQ-5D (or Q-5D proxy version 1) questionnaires were completed for all 143 participants. Difficulty in mobility was reported by 34 individuals (23.8%) and 32 (22.4%) experienced difficulty in self-care. Twenty-six individuals (18.2%) were unable to perform usual activities, fifty individuals (35%) had moderate pain or discomfort and four individuals (2.8%) had extreme pain or discomfort. Sixty-two individuals (43.4%) reported moderate anxiety/depression, while six individuals (4.2%) reported extreme anxiety/depression. Anxiety/depression and pain/discomfort were reported in both self-reported as well as caregiver-reported groups and present in both children and adolescents, and adults (
Summary of EQ-5D Questionnaire in
The QOLIE-31-P questionnaire was completed by 24 individuals. The total score of the QOLIE-31-P questionnaire was 71.6 (standard deviation [SD]: ±16.7,
Summary of QOLIE-31-P, QOLCE and QOLIE-AD-48 questionnaire scores.
Energy | 24 | 47.0 | 27.6 | 45.0 | 2.5–90 |
Mood | 24 | 53.4 | 29.8 | 63.5 | 3.6–92 |
Daily activities | 24 | 67.0 | 33.3 | 73.1 | 3.8–100 |
Cognition | 24 | 63.6 | 37.5 | 71.1 | 0.3–100 |
Medication effects | 24 | 56.9 | 31.5 | 57.5 | 1.3–100 |
Seizure worry | 24 | 49.8 | 31.4 | 45.8 | 0.4–100 |
Overall QoL | 24 | 53.8 | 29.1 | 58.1 | 3.3–95 |
Final Score | 24 | 71.6 | 16.7 | 75.8 | 27.3–93.4 |
QoL | 67 | 51.5 | 27.5 | 50.0 | 0–100 |
Physical restrictions | 69 | 44.6 | 24.4 | 45.8 | 0–100 |
Energy/fatigue | 67 | 54.5 | 22.7 | 62.5 | 0–100 |
Depression | 68 | 70.7 | 17.6 | 75.0 | 8.3–100 |
Anxiety | 68 | 58.8 | 20.5 | 50.0 | 25–100 |
Control/helplessness | 64 | 56.1 | 20.1 | 50.0 | 18.8–100 |
Self-esteem | 65 | 63.9 | 19.6 | 70.0 | 15–95 |
Attention/concentration | 66 | 37.5 | 28.7 | 32.3 | 0–100 |
Memory | 58 | 54.2 | 23.8 | 56.3 | 0–100 |
Language | 60 | 42.1 | 28.7 | 44.4 | 0–100 |
Other cognitive functions | 64 | 31.7 | 29.0 | 25.0 | 0–100 |
Social interactions | 56 | 53.6 | 21.7 | 60.0 | 0–100 |
Social activities | 67 | 63.8 | 35.5 | 66.7 | 0–100 |
Stigma | 56 | 66.1 | 36.4 | 75.0 | 0–100 |
Behaviour | 69 | 50.5 | 20.6 | 48.4 | 0–93.8 |
General health | 68 | 48.5 | 27.3 | 50 | 0–100 |
Final score | 70 | 52.3 | 18.9 | 51.5 | 12.2–91.7 |
Epilepsy impact | 8 | 82.7 | 20.2 | 91.7 | 39.6–95.8 |
Memory/concentration | 8 | 74.1 | 22.3 | 82.5 | 45–100 |
Physical functioning | 8 | 83.1 | 18.1 | 87.5 | 55–100 |
Stigma | 8 | 81.9 | 22.2 | 83.3 | 33.3–100 |
Social support | 8 | 69.5 | 22.5 | 59.4 | 43.8–100 |
School behaviour | 8 | 97.7 | 3.2 | 100.0 | 93.8–100 |
Attitudes toward epilepsy | 7 | 30.4 | 7.6 | 31.3 | 18.8–37.5 |
Health perceptions | 8 | 61.5 | 9.9 | 58.3 | 50.0–75 |
Final score | 7 | 74.2 | 13.9 | 81.2 | 46.1–85.7 |
The QOLCE questionnaire was completed by 70 caregivers. The mean QOLCE score was 52.3 (SD: ±18.9,
Eight adolescents aged 11–17 years with epilepsy completed the questionnaire. The mean total QOLIE-AD-48 questionnaire score was 74.2 (SD: ±13.9,
This study aimed to evaluate BOI and QoL in children and adolescents, and adults with TSC and their families. BOI focused on social care needs, health (care) needs, and impact of TSC on education, employment, and family life. Individuals' QoL was assessed by means of standardized measures of QoL. To our knowledge, this study represented the most comprehensive and multinational evaluation of BOI and QoL in TSC to date.
Four main findings were highlighted by this study. BOI in families with TSC patients was high, as shown by their experiences of insufficient assistance at home and from social services. Individuals with TSC reported significant use of healthcare services but considered the support from TSC associations and patient organizations as inadequate. Also, the impact of TSC on individuals' education, employment, and social and family life was profound. Regarding quality of life, both children and adolescents, and adults reported moderate-to-severe levels of pain or discomfort and anxiety or depression, which was also indicated by their caregivers.
Individuals with TSC and their families have unmet needs with respect to support from social workers who provide various services, corresponding to previous findings (
Individuals with TSC showed various clinical manifestations for which they visited health specialists. Throughout their lives, they made significant use of healthcare services as a result of the regular multidisciplinary medical care indicated for the management of TSC (
The observed lack of appropriate care services was also reflected in differences between individuals in terms of health insurance, and genetic testing, and counselling. These findings indicate a need for revision and standardization of insurance policies for people with TSC or chronic conditions in general, as well as clinical care characterized by a personalized and transparent approach. Despite this imbalance between care need and care provision, individuals in this study reported satisfaction with how their disease was treated and monitored. Furthermore, the transition from paediatric to adult TSC care was an important area of concern (
TSC had a strong influence on the education and professional career of affected individuals. Especially in adults, their level of education, choice of career, career progression and promotion, and employment rate were impacted by the disease. Apart from the presence of TSC, other influences, directly or indirectly, related to the illness should be taken into account. Having few professional expectations for the future, being confronted with negative attitudes of colleagues and lacking arrangements to improve working conditions, might all further reduce the patient's opportunities at work (
TSC has significant effects on the social well-being and family life of both young and adult individuals with TSC. The patients' high dependence on their environment can lead to feelings of disorientation, loneliness, and clinically significant stress levels in patients, but also in family members (
With regard to QoL, moderate to severe levels of pain or discomfort and anxiety or depression were reported by individuals with TSC of all ages as well as by their caregivers. In order to achieve a comprehensive view of health-related QoL in individuals with TSC, research suggested to investigate other indicators such as fatigue, emotional stress, and participation (
When interpreting the results of this study, certain limitations need to be taken into account. Not all patients completed all questionnaires in the study, and only a small subsample of patients from the TOSCA registry enrolled in the present study. Although the information was collected from both individuals who were able to self-report as well as from caregivers of individuals who were unable to self-report, the overall disease severity of the cohort is likely to be milder compared to that of the global TOSCA registry cohort. Only 46.85% of patients in the current study was reported to have epilepsy in contrast to 83.5% in the overall TOSCA cohort (
Although no data on intellectual ability were collected, 65% of children were following mainstream education. Although school systems differ across countries and attending mainstream education does not imply that children have normal intellectual ability, it seems likely that this reflects again a potential bias towards the milder end of the spectrum. The lack of a personal perspective is another limitation of the study. The questionnaire used to measure BOI contained questions that were developed together with families, which ensures a large patient-oriented input. Although no qualitative research was conducted, a short analysis of the questionnaire's open data fields did confirm the quantified BOI (data not shown).
Our study confirms the impact of TSC on education, career and social life of patients, and their families. This disease-specific impact is also reflected in patients' quality of life, including moderate-to-high levels of pain or discomfort and anxiety or depression. Unfortunately, despite families' frequent use of healthcare services, provision of well-organized TSC care is not evident as shown by their experiences of insufficient social support and discontinuous pediatric to adult care trajectories. These difficulties further increase the impact on the different life domains of families living with TSC, who would benefit from better coordinated educational, psychosocial, and medical support.
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: Novartis supports the publication of scientifically rigorous analysis that is relevant to patient care, regardless of a positive or negative outcome. Qualified external researchers can request access to anonymized patient-level data, respecting patient informed consent, contacting study sponsor authors. The protocol can be accessed through EnCePP portal
The studies involving human participants were reviewed and approved by independent ethics committee/institutional review board for each centre involved in the study (see
AJ, EB, MB, PC, MD, JF, MF, CH, SJ, JK, JL, AM, RN, VS, MS, RT, and BZ designing the study, patient accrual, clinical care, data interpretation, drafting, revising, final review, and approval of the manuscript. SV data interpretation, drafting, revising, final review, and approval of the manuscript. PV designing the study, data interpretation, drafting, revising, final review, and approval of the manuscript. CF designing the study, data interpretation, drafting, revising, final review, and approval of the manuscript. CF, GB, TC, VC, FO'C, JQ, YT, and SY designing the study, data interpretation, drafting, revising, final review, and approval of the manuscript. LD'A designing the study, trial management, data collection, data analysis, data interpretation, drafting, revising, final review, and approval of the manuscript. RM designing the study, data analysis, data interpretation, drafting, revising, final review, and approval of the manuscript. SS designing the study, trial statistician, data analysis, data interpretation, drafting, revising, final review, and approval of the manuscript. All authors contributed to the article and approved the submitted version.
AJ, PV, EB, TC, VC, PC, GB, JK, JF, MF, CF, CH, SJ, RN, FO'C, JQ, MS, RT, MD, JL, AM, SY, MB, and BZ received honoraria and support for the travels from Novartis. VC received personal fees for consulting, lecture fees, and travel from Actelion, Bayer, Biogen Idec, Boehringer Ingelheim, Gilead, GSK, MSD, Novartis, Pfizer, Roche, Sanofi; grants from Actelion, Boehringer Ingelheim, GSK, Pfizer, Roche; personal fees for developing educational material from Boehringer Ingelheim and Roche. PV has been on the study steering group of the EXIST-1, 2, and 3 studies sponsored by Novartis, and co-PI on two investigator-initiated studies part-funded by Novartis. RN received grant support, paid to her institution, from Eisai and lectures fees from Nutricia, Eisai, Advicenne, and GW Pharma. YT received personal fee from Novartis for lecture and for copyright of referential figures from the journals, and received grant from Japanese government for intractable epilepsy research. SJ was partly financed by the EC Seventh Framework Programme (FP7/2007-2013; EPISTOP, grant agreement no. 602391), the Polish Ministerial funds for science (years 2013-2018) for the implementation of international cofinanced project and the grant EPIMARKER of the Polish National Center for Research and Development No STRATEGMED3/306306/4/2016. JK, PC, CH, JL, and JQ received research grant from Novartis. RM, LD'A, and SS are employees of Novartis. This study was funded by Novartis Pharma AG. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We thank patients and their families, investigators, and staff from all participating sites. The authors thank Manojkumar Patel (Novartis Healthcare PVT Ltd) for providing medical writing support, which was funded by Novartis Pharmaceutical Corporation in accordance with Good Publication Practice (GPP3) guidelines (
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