Auvin et al. Orphanet Journal of Rare Diseases (2019) 14:91 https://doi.org/10.1186/s13023-019-1072-y RESEARCH Open Access A step-wise approach for establishing a multidisciplinary team for the management of tuberous sclerosis complex: a Delphi consensus report Stéphane Auvin1,2*, John J. Bissler3, Vincent Cottin4, Ayataka Fujimoto5, Günther F. L. Hofbauer6, Anna C. Jansen7, Sergiusz Jóźwiak8,9, Larissa Kerecuk10, J. Christopher Kingswood11, Romina Moavero12,13, Roser Torra14 and Vicente Villanueva15 Abstract Background: Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder associated with mutations in TSC1 and TSC2 genes, upregulation of mammalian target of rapamycin signaling, and subsequent tumor formation in various organs. Due to the many manifestations of TSC and their potential complications, management requires the expertise of multiple medical disciplines. A multidisciplinary care approach is recommended by consensus guidelines. Use of multidisciplinary teams (MDTs) has been shown to be beneficial in treating other complex diseases, such as cancer. In a lifelong disease such as TSC, an MDT may facilitate the transition from pediatric to adult care. However, little guidance exists in the literature regarding how to organize an MDT in TSC. Methods: To discuss the best approach to assembling an MDT, this project was initiated in October 2017 with a meeting of 12 physicians from various specialties and various countries. Following this first meeting, the experts generated statements on the most important aspects to implement in establishing an MDT for TSC by 3 rounds of selection using a Delphi process via electronic correspondence. Finally, TSC patient advocates reviewed the findings and provided additional insights from a patient perspective. Results: A 3-step roadmap was recommended, starting with identifying a single individual to begin organizing care (Step 1), then establishing a small core team (Step 2), and finally, establishing a larger multi-disciplinary team (Step 3). Because of the multisystemic nature of TSC, the MDT should include specialists such as a neurologist, a neurosurgeon, a nephrologist, a urologist, a pulmonologist, an ophthalmologist, a cardiologist, a dermatologist, a geneticist, and a psychiatrist/psychologist. The MDT should recommend a care plan for each patient based on the individual’s needs and in consultation with him/her or his/her family. Some of the most important aspects of an MDT that were agreed upon included identifying a case manager to help coordinate care, providing access to health care professionals of varying specialties, and including a lead physician who takes medical responsibility for patients’ overall care. Conclusions: The results of our consensus provide guidance to support the initiation of an MDT in TSC. Keywords: Tuberous sclerosis complex, Multidisciplinary care, Multidisciplinary team * Correspondence: stephane.auvin.rdb@gmail.com; stephane.auvin@aphp.fr 1 Service de Neurologie Pédiatrique et des Maladies Métaboliques, APHP, Robert-Debré Children’s Hospital, 48 Boulevard Serurier, 75019, 19 Paris Cedex, France 2 INSERM U1141, Paris, France Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Auvin et al. Orphanet Journal of Rare Diseases (2019) 14:91 Page 2 of 10 Background as everolimus [13, 14]. Patients with TSC are also more Tuberous sclerosis complex (TSC) is a rare autosomal likely to develop some malignancies, particularly renal cell dominant genetic disorder occurring in 1 in 6000 live carcinomas and pancreatic neuroendocrine tumors, and births [1, 2]. It is caused by mutations in either the usually at a younger age than the general population [15– TSC1 or TSC2 gene, which result in upregulation of the 17]. Another concern, primarily for female adolescents mammalian target of rapamycin (mTOR) pathway and and adults, is the potential development of lymphangio- subsequent tumor growth in various organs such as the leiomyomatosis in the lungs, which, if present, requires brain, heart, skin, eyes, kidney, lung, and liver [2, 3]. consultation with a pulmonologist [2, 5]. Clinical phenotypes of TSC can vary greatly from pa- The 2012 International Tuberous Sclerosis Complex tient to patient, ranging from milder (such as a single Consensus Conference established recommendations manifestation of TSC) to more severe disease (such as for the diagnosis and treatment of TSC [18, 19]. Be- affecting multiple organs, developing early epilepsy and cause of the complex multisystem nature of the neurodevelopmental issues) [4]. In addition, many mani- disease, a multidisciplinary approach in the manage- festations of TSC have age-dependent expression [2]. ment of TSC was recommended [6, 19–21]. The use These factors together can complicate evaluation and of multidisciplinary teams (MDTs) has been shown to management of TSC. be beneficial in improving management and outcomes Because many manifestations can lead to complica- in patients with other complex diseases [22–26]. For tions and evolve over a patient’s lifetime, the expertise example, multidisciplinary discussion is recommended of multiple disciplines is needed to effectively manage in the diagnosis of idiopathic pulmonary fibrosis [26]. patients with TSC. For example, cardiac rhabdomyo- In a retrospective observational study, MDT discus- mas can develop prenatally and are thus one of the sions were responsible for the definite diagnosis in earliest detectable signs of TSC [2, 5]. Although they 80.5% of 938 patients with interstitial lung disease are usually asymptomatic and regress with age, these [25]. Of these 938 patients, 455 had received a diag- lesions occasionally cause arrhythmias and lead to nosis from a referring physician before multidisciplin- ventricular dysfunction and thus may require consult- ary discussion, and 41.9% of those patients had their ation with a cardiologist [2, 5]. Hypomelanotic mac- diagnosis changed after multidisciplinary discussion ules on the skin can be present at birth, while other [25]. In addition, diagnosis through multidisciplinary cutaneous lesions such as facial angiofibromas and discussion was able to better discriminate between ungual fibromas develop later in life and may require idiopathic pulmonary fibrosis and other interstitial treatment by dermatologists [2, 6]. Because skin le- lung diseases compared with diagnoses made before sions are prominent manifestations that can be visible multidisciplinary discussion [25]. In cancer, MDTs at a young age, dermatologists are also in a position resulted in more evidence-based medicine and more to identify TSC early in the disease course [7]. timely treatment, and in some cases, led to improved In addition, brain lesions such as cortical tubers, survival [27]. Patient-reported experience of care had subependymal nodules, and subependymal giant cell the greatest improvement for the particular cancers astrocytomas, and seizures (which are frequently diffi- for which MDTs were more established [27]. In TSC, cult to treat) can also develop early in a patient’s life a multidisciplinary approach is also important in and may require input from neurologists, neurosur- facilitating transition of care from childhood to adult- geons, and epileptologists [2, 5, 8]. TSC is associated hood as individuals age [20, 21, 28, 29]. Young adult with a wide range of behavioral, psychiatric, intellec- patients have expressed the need for multidisciplinary tual, learning, neuropsychological, and psychosocial care that is well informed and easily accessible, fo- difficulties, which manifest in childhood and persist cuses on the patient as a whole (including mental throughout life. These TSC-associated neuropsychi- and physical health among other factors), and atric disorders (TAND) therefore require regular includes his/her family as they transition to adult care monitoring and coordination with early intervention [28]. Multidisciplinary care can be useful to reduce and educational specialists, psychologists, psychia- the significant burden placed on caregivers of patients trists, and social workers (childhood to adult special- with TSC, especially concerning the amount of health ists) [6, 9–12]. care utilization (e.g., doctor visits, procedures, or As a patient ages, cysts and angiomyolipomas can de- tests) required to treat the patient [30], as well as on velop in the kidneys, which may lead to chronic kidney the patients themselves, although further studies are disease, and thus require the consultation of a nephrolo- needed to evaluate the benefits of MDT on patient gist [2, 5]. Nephrologists may also have an important role and caregivers. managing medications related to the treatment of TSC Some reports have encouraged the use of specialized that require additional monitoring of renal function, such TSC clinics, which may not be available for all patients Auvin et al. Orphanet Journal of Rare Diseases (2019) 14:91 Page 3 of 10 because of cost and geography [20]. There are others to 10 based on importance (1 being least important who have reported their personal experience in run- and 10 being most important), after which the top 16 ning an MDT clinic for TSC, including a list of prac- statements were identified based on those that met a titioners involved and how care in their clinic is cutoff score of ≥7.5. For Step 3, the top 16 statements organized [29]. Other groups have focused on the pa- were again scored from 1 to 10 by members of the tient concerns MDTs should consider when imple- committee, based on priority of implementation (10 menting a transition of care from youth to adulthood being the most urgent and 1 could be implemented [28]. Still others have performed studies showing how later). These 16 statements are discussed in detail fur- their use of MDT has increased rates of patient ther below. The group also discussed the stages of follow-up and opportunities for exams or treatments developing a TSC clinic during the formulation of the [31]. However, there is still a lack of published litera- manuscript. ture on how best to approach establishing an MDT. Input and insight from TSC patients/patient advo- The aim of this report is to announce the results of a cates regarding the committee’s findings were sought, task force identifying key steps in developing an which included feedback on existing concepts and MDT in TSC as well as the key components of the additional areas of importance from the patient development and function of the MDT. perspective. Methods Results A group of 12 physicians from various specialties in- Organizing a multidisciplinary care team for the cluding neurology (pediatric and adult), psychiatry, management of TSC TAND, neurosurgery, dermatology, nephrology, and Three steps were identified by the task force/group pulmonology convened face to face in October 2017 (Table 1). The authors recommend that throughout this to discuss the steps needed for organizing an MDT. process, input from patients and their families, available A 3-step roadmap was agreed upon to help develop research, and sharing of data between specialties should an MDT, starting with identifying a single individual be considered in evaluating how to organize the team to begin organizing care, then establishing a small (Fig. 1). core team, and finally establishing a larger multidis- ciplinary team. Step 1—single person In addition to proposing steps for establishing the To establish the MDT, the first step is to start with a MDT, the committee of physicians also discussed, single dedicated physician. Ideally, this physician should based on their expertise, the aspects of the MDT that be able to liaise with the family of the patient and other were most important to implement. These recommen- physicians, nurses, and patient managers, with a shared dations were produced via a 3-step Delphi process vision for multidisciplinary care. The physician should [32] led by one of the authors (SA) via online corres- connect with all specialists required for patient manage- pondence. Step 1 required each member to generate a ment in TSC. Patient organizations can assist with iden- list of 10 statements summarizing key aspects that tifying physicians interested in developing the MDT were important in developing an MDT. For Step 2, team and connecting them with other physicians. An all statements were collated, and members were asked important specialist to include at this stage is a clinical to rank statements in the overall list on a scale of 1 geneticist, who can explain the results of the genetic Table 1 Three-step process in establishing a larger multidisciplinary team Steps Participants Main Action Step A single physician who has a passion for TSC • Treat patients with TSC 1 • Liaise with patient families, organizations, and other physicians • Identify a care coordinator • Initial drive of the MDT process Step Core team (comprising a care coordinator and members of the core medical • Liaise with patients/families 2 specialties) • Coordinate physicians for management decisions • Organize patient follow-up and referrals • Liaise with other centers • Collaborate with TSC patient organization if available and able Step Full MDT and reference network with the assistance of the care coordinator • Operational MDT 3 MDT multidisciplinary team, TSC tuberous sclerosis complex Auvin et al. Orphanet Journal of Rare Diseases (2019) 14:91 Page 4 of 10 Fig. 1 Consensus-established roadmap for development of an MDT analysis and provide counselling about risk of inherit- may further tap into reference networks for other practi- ance. Because clinical geneticists see both children and tioners, focusing on those who specialize in rare adults, in some cases they might be in the position to diseases. fulfill the role of the Step 1 physician as well as care co- ordinator of the MDT. Step 3—multidisciplinary team This initial person does not need to be a senior mem- To assemble the larger MDT, the core team should re- ber of the medical team; however, he or she should have cruit members from the reference network they have some experience in managing patients with TSC. In established. Ideally, an MDT to manage TSC should in- addition, as the starting point for the team, this individ- clude physicians with specialties that are required to ap- ual should have the energy and stamina to commit to propriately address the needs of the patients. These this endeavor and have a sense of personal ownership of specialties can include pediatrics, genetics, diagnostic the project. radiology, interventional radiology, cardiology, pediatric/ Finally, as information on TSC is ever evolving, the adult neurology, respiratory medicine, pediatric/adult physician should maintain up-to-date knowledge and be nephrology, dermatology, neurosurgery, oncology, fetal able to attend relevant international conferences to bet- medicine, urology, ophthalmology, psychiatry, psych- ter understand the patient perspective and participate in ology, intellectual disability psychiatry, and surgery [12, clinical research. 33]. At this stage, the team should reassess its way of functioning and evaluate whether it adequately meets Step 2—small Core team the needs of the patient community on a regular basis. It The next step to establishing the MDT is the is particularly important to establish who is responsible organization of a small core team, with the goal of for soliciting this feedback (e.g., the treating physician or obtaining support from the core specialties. Although nurse). there is not one set method to establishing the core Ideally, one should begin securing a dedicated care co- team, typically the core team should comprise one care ordinator when putting together the core team; however, coordinator/nurse and one or more physicians (special- a dedicated care coordinator (part-time or full-time, de- ists). This core team ensures more continuous connec- pending on the expected size of the team) is required tion between the patients/families and the greater TSC when the MDT is established. Team members would team. This allows for easier discussion between physi- also benefit from developing leadership and manage- cians regarding the most effective decisions in manage- ment skills in order to accommodate a plan for shared ment and fosters organization of future patient (or to transfer) leadership as the team grows. follow-ups. The core team should help organize appropriate refer- Most important factors in establishing the rals and coordinate scheduling of procedures/office visits multidisciplinary team and be responsible for identifying contacts at other treat- The 16 statements produced by the committee re- ment centers or referral sites, if needed. The core team garding the most important factors in establishing the Auvin et al. Orphanet Journal of Rare Diseases (2019) 14:91 Page 5 of 10 Table 2 Top 16 most important aspects to implement in a multidisciplinary TSC team Mean SD Score 1 Identification of a patient care coordinator (nurse or other professional) for duties including case management, answering 9.2 1.1 questions, direct contact with patient, triage for specialists, etc. 2 Creation of a list of health care professionals associated with the clinic involved in management of patients with TSC, including 8.7 1.6 their current email, phone number, and availability to see patients 3 Identification of a lead physician (with at least 1 or 2 deputies) who takes medical responsibility for the patients’ overall care and 8.4 1.1 managerial responsibility for organizing the clinic 4 Organization/identification of care pathway in the clinic and establishing investigation schedule according to patient age (to 7.9 1.1 avoid multiple visits to the hospital) 5 Following accepted TSC guidelines/protocol 7.7 2.4 6 Identification of a network of local or regional health care professionals outside of the clinic 7.5 1.2 7 Creation of a plan for diagnosis and management of TSC psychiatric comorbidities (e.g., TAND, autism) 7.4 2.0 8 Establishment of a patient database for case management and research 7.2 1.5 9 Creation of TSC center of excellence for complex cases 6.8 2.6 10 Creation of a plan for transition from pediatric to adult care, including specified age of transition, steps taken, and identification 6.7 2.4 of health care professionals for adult care 11 Establishment of MDT meetings that include case discussion, discussion of guidelines, logistics 6.6 1.6 12 Creation of a prenatal diagnosis program (i.e., identifying cardiac tumors) 6.5 2.7 13 Ability to perform investigation imaging such as MRI and CT under sedation (or possibly general anesthesia) 6.4 2.7 14 Establishment of a link between clinic and local patient/family TSC organizations—ideally have a representative of TSC 6.3 1.7 organization present at clinics 15 Establishment as a source for dissemination of information on TSC for patients and health care professionals, including any 6.2 1.1 appointments, reports, etc. 16 Establishment of communication with patient’s primary care physician and other family physicians to clarify responsibilities 5.9 1.6 CT computed tomography, MDT multi-disciplinary team, MRI magnetic resonance imaging, SD standard deviation, TAND TSC-associated neuropsychiatric disorder, TSC tuberous sclerosis complex MDT can be found in Table 2, which also includes managing patients with TSC, use of a hub-and-spoke the mean (standard deviation) score that was calcu- model would assist in keeping primary care physicians lated for each item at Step 3 of the process described involved and informed. Two-way communication be- above. tween the clinic and the patient’s primary physician is of The panelists agreed that identifying a patient care co- paramount importance. In some countries the primary ordinator was the most important aspect of establishing physician will be a general practitioner or office general- the MDT. An MDT cannot function without ist doctor, whereas in others it will be a specialist (e.g., organization and cooperation; thus, having a care coord- pediatrician or neurologist). In addition, establishing a inator allows for the MDT to perform the rest of its schedule of patient investigation and monitoring is functions in providing care efficiently and effectively. important to avoid compounding the frequency of visits. Other highly important aspects of establishing an A good MDT must also create a plan to handle diag- MDT include creating a list of other health care profes- nosis and management of TAND-related conditions. As sionals who would participate in the care of patients the majority of patients with TSC will develop some type with TSC within the clinic. The MDT should have a pool of neuropsychiatric manifestations across their lifespan, of able health care professionals readily available for pa- managing these manifestations is critical, especially as tient referral depending on the patient’s needs. A lead TAND is a very significant burden on daily life [9, 34]. physician who is ultimately responsible for patient care Establishing a patient database was also considered to and the organization of the clinic should be identified, as be beneficial to better organize patient care. The patient well as core physicians in the clinic who may be needed database can be used for case management and discus- to provide care for the patient. The MDT should identify sion as well as serve as a source for clinical research. and communicate with a network of local or regional Once established, the MDT can evolve into a TSC health care professionals outside of the clinic, including Center of Excellence, which is a TSC clinic that provides primary care providers and those who treat somatic and care coordination, provides many services and can ac- behavioral aspects of TSC. Due to the complexity of cess any others needed, and commits to undertake Auvin et al. Orphanet Journal of Rare Diseases (2019) 14:91 Page 6 of 10 research by building up experience and keeping abreast Young patients with TSC will require routine imaging of—and ideally participating in—TSC research. Such a via magnetic resonance imaging (MRI), so it is important center can also exchange experience with other Centers that the MDT has the capability to perform these im- of Excellence. These centers would preferably incorpor- aging studies with sedation (possibly general anesthesia ate spaces where all specialists can be found in one in some cases) and, where possible, they should combine clinic, where the patient can reach each of them easily, imaging studies of multiple areas, such as the brain and or provide a virtual clinic service to simplify patient abdomen using an adapted imaging protocol [19]. interaction with specialists. Becoming a Center of Excel- Patient and disease organizations can help in support- lence in TSC is ideal, although this may not be feasible ing patients and research. It is useful for the MDT to in all facilities; nevertheless, the MDT should strive establish a relationship with such organizations, prefera- towards this goal. bly with a representative of a TSC organization partici- The team should create a plan for transitioning pating in their clinics. Close collaboration with the pediatric patients to adult care. Medical issues and con- patient organizations throughout can be of benefit at all cerns change with age and may pose challenges for stages of MDT development, including initial set-up, patients who transition to more adult-oriented care [6]. growth, full expert team, and later can be helpful for Ideally, the process of establishing and building an MDT regular assessment of further needs. Patient organiza- TSC clinic for adults should be underway at the same tions can also give complementary support such as offer- time that clinics for children are being established, or ing social-emotional feedback, giving information on the the same clinic should be used for both children and disease in lay-language, connecting patients with others adults. Transition to adult care may be especially chal- in similar situations, and providing a feeling of lenging for individuals with TSC because of community. TSC-associated intellectual disability and other Lastly, it is important for the MDT to serve as a TAND-related issues. Therefore, the MDT for adults source of information for patients and other health care must have familiarity with managing intellectual disabil- professionals and to communicate effectively with pa- ity and TAND. tients’ primary care physicians. The MDT will also benefit from holding regular meet- ings. These meetings can increase collaboration and TSC clinic development promote discussion of patient cases and current guide- The development of a TSC clinic can occur in several lines, [18, 19] and can be used to keep team members stages (Table 3). The primary characteristic of a TSC up to date on the progress of basic or clinical research, clinic is that it is a service willing to take responsibility and may be conducted either in the clinic or elsewhere. for coordinating and ensuring access to systematic and In addition, meetings provide an opportunity to discuss holistic care for patients with TSC and their families. and align on protocols used in the clinic. This includes delivering care based on established Creation of a prenatal diagnosis program is another clinical guidelines. If it is a pediatric-only clinic, an important function of the MDT. Cardiac rhabdomyo- established plan should be in place for the transition of mas are a major feature of TSC and are commonly older pediatric patients to adult services. The clinic observed in prenatal ultrasound of patients with TSC should comply with good medical practice, ensuring (up to 80%) [18, 35]. In addition, brain lesions such communication of individual patient management plans as cortical tubers and subependymal nodules are often to all appropriate parties and also disseminating know- reported prenatally, and subependymal giant cell as- ledge of TSC and its management in general. Access to trocytomas that develop in early childhood are other MRI and computed tomography scans under sedation is early indicators of TSC [2, 8]. Prenatal diagnosis pro- also vital, ideally combining imaging of the brain and grams should also include genetic testing, not only to abdomen in a single program. In addition, all TSC confirm diagnoses but to assess the patient’s potential clinics and TSC centers of excellence should be aware of phenotype [36]. Early identification of patients with laboratories in their country where genetic analyses are TSC offers the opportunity to provide optimal paren- performed and should be able to request these tests tal education on epilepsy and TAND and to initiate when needed. early treatment and interventions with the aim of im- proving clinical outcomes [37]. For example, early Patient perspective identification and management of seizures in infants The MDT provides patients with a team-based approach with TSC can potentially improve cognitive outcomes to care decisions. Without the MDT, patients may end [38]. Research into useful approaches to make an up receiving a variety of differing medical opinions, a early diagnosis before seizure onset has been recently very challenging sequence of regular examinations, and conducted [35]. medications prescribed by different specialists. Patients Auvin et al. Orphanet Journal of Rare Diseases (2019) 14:91 Page 7 of 10 Table 3 Stages of TSC clinic development Stage of Clinic Services Provided Development Maturity Level 1 • Care coordinator o Schedule appointments and investigations o First point of contact for advice • Lead Clinician o With TSC interest and expertise o Created referral pathways • Close collaboration with patient/family organizations Maturity • Care provided jointly by a core group of TSC-knowledgeable physicians from relevant specialtiesa Level 2 • MDTs to review cases and agree on management plans • Facilitate advice and care from a broader network of specialties and from a wider geographic area than the clinic can provide • Establish links with other TSC clinics (via MDTs or other joint meetings for peer-to-peer continuing education) • Formalize surveillance for TAND problems, e.g., using the TAND checklist • Use database to facilitate monitoring of patients Maturity • Work with larger network of local TSC-knowledgeable specialists; within the same care provider or closely Level 3 allied care providers • Establish and promote local and regional network of specialists and care providers; acting as expert center providing advice and at least annual holistic review • Provide expertise for review of mental health and coordination of referrals for mental health problems Maturity • All the above, plus engage with research into TSC Level 4 (Center of Excellence) MDT multi-disciplinary team, TAND TSC-associated neuropsychiatric disorder, TSC tuberous sclerosis complex a Specialties useful in providing TSC services: pediatrics, genetics, diagnostic radiology, interventional radiology, cardiology, pediatric/adult neurology, respiratory medicine, pediatric/adult nephrology, dermatology, neurosurgery, oncology, fetal medicine, urology, ophthalmology, psychiatry, psychology, intellectual disability specialists, surgery appreciate that the MDT provides them with a single activities, and so on. Patient organizations can also help treatment plan so that medical advice is not contradict- in finding the best clinicians with a passion for taking ory. To this end, patients emphasize the importance of care of patients with TSC. having a single care coordinator or an individual who is responsible within the group of health care professionals. Discussion The level of communication with the patient’s other Based on the discussions of our multidisciplinary con- health care providers is also important. In addition, pa- sensus group, we agreed upon a 3-step approach as an tients appreciate the increased organization of care that efficient and straightforward method for creating an comes with the MDT, such as combined imaging stud- MDT. Ultimately, we recommended that the formation ies, and in general, prefer the holistic approach to treat- of an MDT start with a single physician who has a ment that the MDT offers (education, social support, passion for treating patients with TSC and is eager to li- etc.). In general, future studies should focus on assessing aise with patient families, organizations, and other physi- the benefits of MDT on patient care, including what as- cians, and who can help drive the process. Second, a pects of the MDT are most important and what works core team composed of individuals essential to the func- best. tioning of the clinic, such as a care coordinator and TAND is an especially important concern of TSC members of the core medical specialties, should be to patients/caregivers. Although not generally life- formed. Lastly, a full MDT can be developed by threatening, TAND represents the most significant incorporating additional specialists identified through an burden on daily life experienced by patients with TSC, established reference network with the assistance of the and as such, it has not been assessed and addressed suffi- care coordinator. Based on our subsequent online cor- ciently. A committed MDT should undertake a systematic respondence and Delphi process, securing this care evaluation of TAND, facilitate prevention of TANDs, and coordinator was considered the most important aspect have a plan in place for crisis intervention. of the MDT to implement. Other important factors for Patient organizations should have an integral role in the MDT to incorporate included identifying a lead the formation of the MDT. There are numerous possi- physician, the core group of physicians, and the team as- bilities for collaboration between these organizations sociated with the clinic. Informing treating physicians/ and the MDT, such as helping patients find the right family doctors/first-line health care workers is essential kind of social support, education, family support, leisure for a good patient follow-up, especially if the patient Auvin et al. Orphanet Journal of Rare Diseases (2019) 14:91 Page 8 of 10 lives relatively far from the MDT. This team should also and facilitates the transition from pediatric to adult care. agree to follow established guidelines and agreed-upon Furthermore, the MDT is able to organize participation protocols and work towards establishing transition of in clinical research and provide educational opportun- care as patients age [28, 29]. Others have published on ities for health care professionals within the team. establishing an MDT and noted similar features such as For patients and their caregivers, the MDT can ease the specialists involved, a care coordinator, contact with the burden of utilizing and coordinating care by provid- primary care physicians, and including a patient data- ing a central point of contact for physician visits, im- base [29]; however, this prior report was descriptive of aging/testing, and patient/family education. For example, their personal experience as opposed to providing the MDT can coordinate physician and imaging visits committee-based recommendations and including the such that for any imaging that requires sedation could patient’s perspective as in our research. also be used for concurrent eye and dental examinations, Currently, more literature regarding the benefits blood tests, or additional imaging studies (e.g., of the and goals of establishing a multidisciplinary care team brain, kidney) that may be required. In addition, the in TSC is needed. This report discusses the steps to team should be able to organize services to aid patients establish an MDT and our accompanying rationale. regarding particular aspects of TSC management, such Future studies demonstrating the benefit of MDTs as genetic counseling, transition of care services, mental would be of value, particularly considering the bene- health, and social support, and even provide fits demonstrated from previous studies evaluating on-the-scene observation, assessment, and intervention MDTs for the treatment of cancer [27]. One of the for TAND-related issues. Finally, the team should build a few available studies in TSC by Fujimoto et al. de- protocol that is adapted to the needs of patients with TSC, scribes how the implementation of a TSC board to the facilities of the center, and available resources. organize interdisciplinary management led to higher Our report has several limitations. While in our initial rates of regular follow-up, opportunities for patients meeting we had planned to include patients/patient to undergo examinations, opportunities for patients to advocates in the development of our report, they were receive neurologic treatment, and mTOR inhibitor not included in the initial manuscript stages. However, usage compared with before the TSC board was the patients/patient advocates who were consulted con- implemented [31]. Studies of MDTs for TSC could tributed substantial feedback which greatly influenced also evaluate differences in treatment outcomes and our final report. In addition, the attendees of the initial patient satisfaction. Consensus recommendations do meeting, which called for one expert for each specialty advocate for the efficient use of resources through the involved in TSC management, were specialists and thus establishment of transition clinics where both children the expertise presented comes primarily from the and adults can receive treatment. The aim of these specialist perspective for practical reasons. No MDT for- clinics is to reduce duplicative tests and services mation specialists were consulted. We acknowledge that while ensuring that appropriate surveillance and man- the composition of those who participated to this Delphi agement are in place to prevent more costly medical process and theoretical exercise do not necessarily repre- complications and reduce mortality associated with sent the composition of the MDT itself and some partic- TSC [19, 39]. Additional questions to be answered by ipants in the management of TSC were not directly future studies include what value certain specialties consulted. For example, while continuous and general can add to an MDT, how they can best work with care is performed by general pediatricians in children, other parts of the health system (and education and general internal medicine in adults, general practitioners social support system), and how they can contribute for all ages, these general practitioners were not included to improving long-term health and quality of life for as part of the expert committee on TSC, though the co- patients with TSC and their families. Future studies authors do have experience as pediatricians and internal should also focus on how to best provide a holistic medicine physicians in addition to their specialties. approach to managing TSC, including such areas as Other potential participants in the management of TSC education and psychosocial support. who were not consulted or discussed at length in this From the perspective of health care providers, an report include nurses, paramedics, psychologists/behav- MDT allows for an organized approach to tackling a ioral therapists, intellectual disabilities specialists, phys- multi-faceted disease. It enables improved management iotherapists, communication specialists, behavioral of care through establishing agreed-upon protocols, care therapists, and social workers. All of these care providers coordinators and other points of contact, and modes of may not necessarily be a formal part of the MDT but communication. The MDT also promotes communica- play important roles in patient care. The authors also tion between specialists to help ensure that all are aware point out that our suggestions do not account for of the patients’ co-existing conditions and medications national or regional differences in care or discuss factors Auvin et al. Orphanet Journal of Rare Diseases (2019) 14:91 Page 9 of 10 which may facilitate or limit formation of MDTs and S Jóźwiak was partly financed by the European Community’s Seventh recommend these areas for future study. Framework Programme (FP7/2007–2013; EPISTOP, grant agreement no. 602391), the Polish Ministerial funds for science (years 2013–2019) for the implementation of international co-financed project and the grant EPIMAR- Conclusions KER of the Polish National Center for Research and Development No STRA- The authors recommend a 3-step approach to building TEGMED3/306306/4/2016. L Kerecuk has served as a speaker for and received travel honoraria from an MDT, starting with a single dedicated individual to Novartis, and as a consultant for Roche Pharmaceuticals. begin organizing care, expanding to the development of JC Kingswood has received research grants (to his institution) from Novartis a core team, and finally, establishing a full MDT. The and has served as a consultant for Novartis. R Moavero has participated in advisory boards for Novartis and has research authors recommend implementation of certain key as- that was partly funded by EPISTOP. pects to create an effective MDT—most importantly, R Torra has nothing to disclose. identifying a case manager to help coordinate care, pro- V Villanueva has participated in advisory boards and symposia for Eisai, UCB Pharma, BIAL, Esteve, Novartis, and GW Pharma. viding access to health care professionals from a number of specialties, and including a lead physician who takes medical responsibility for the patients’ overall care. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in Abbreviations published maps and institutional affiliations. MDT: Multidisciplinary team; MRI: Magnetic resonance imaging; mTOR: Mammalian target of rapamycin; TAND: TSC-associated Author details neuropsychiatric disorder; TSC: Tuberous sclerosis complex 1 Service de Neurologie Pédiatrique et des Maladies Métaboliques, APHP, Robert-Debré Children’s Hospital, 48 Boulevard Serurier, 75019, 19 Paris Acknowledgements Cedex, France. 2INSERM U1141, Paris, France. 3St. Jude Children’s Research The authors would like to especially thank Clare Stuart (Tuberous Sclerosis Hospital and Le Bonheur Children’s Hospital, 848 Adams Ave, Memphis, TN Australia, New South Wales, Australia) and Eva Schoeters (be-TSC vzw, 38103, USA. 4Claude Bernard University of Lyon 1, Reference Center for Rare Antwerp, Belgium) for their feedback on our work from the patient Pulmonary Diseases, Louis Pradel Hospital, UMR754, 69677 Lyon, Cedex, perspective. Editorial assistance was provided by Traci Stuve, MA, and Robert France. 5Seirei Hamamatsu General Hospital, 2 Chome-12-12 Sumiyoshi, Naka J. Schoen, PharmD, of ApotheCom (Yardley, PA, USA) and was funded by Ward, Hamamatsu, Japan. 6University Hospital Zurich, Rämistrasse 100, 8091 Novartis Pharmaceuticals Corporation. Zurich, Switzerland. 7UZ Brussel, Vrije Universiteit Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium. 8Department of Child Neurology, Warsaw Medical Funding University, Banacha 1, 02-097 Warsaw, Poland. 9Department of Neurology Novartis Pharmaceuticals Corporation hosted the meeting of physicians that and Epileptology, The Children’s Memorial Health Institute, Warsaw, Poland. served as the basis for this manuscript and provided funding support for 10 Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham medical/editorial writing assistance. B15 2TG, UK. 11St Georges Hospital, Blackshaw Rd, London SW17 0QT, UK. 12 Tor Vergata University Hospital, Via Columbia, 2, 00133 Rome, Italy. 13 Availability of data and materials Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy. 14Fundació Puigvert, Not applicable Universitat Autónoma Barcelona, REDINREN, Carrer de Cartagena, 340-350, 08025 Barcelona, Spain. 15Hospital Universitario y Politécnico La Fe, Avinguda Authors’ contributions de Fernando Abril Martorell, 106, 46026 Valencia, Spain. SA led the Delphi process in cooperation with the other authors. All authors contributed to the conception, writing, and critical review of the manuscript Received: 4 February 2019 Accepted: 17 April 2019 and approved the final version. Ethics approval and consent to participate Not applicable References 1. Osborne JP, Fryer A, Webb D. Epidemiology of tuberous sclerosis. Ann N Y Consent for publication Acad Sci. 1991;615:125–7. Not applicable 2. Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet. 2008; 372(9639):657–68. Competing interests 3. Franz DN, Bissler JJ, McCormack FX. Tuberous sclerosis complex: S Auvin has served as a speaker and consultant for Advicenne Pharma, Eisai, neurological, renal and pulmonary manifestations. Neuropediatrics. 2010; GW Pharmaceuticals, Novartis Pharmaceuticals, Nutricia, UCB Pharma, 41(5):199–208. Ultragenyx, Vitaflo, and Zogenix. 4. Caban C, Khan N, Hasbani DM, Crino PB. Genetics of tuberous sclerosis JJ Bissler has received research grants (to his institution) from Novartis, has complex: implications for clinical practice. Appl Clin Genet. 2017;10:1–8. served as a consultant for and participated in advisory boards for Novartis, 5. Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl and has received travel honoraria from Novartis. J Med. 2006;355(13):1345–56. V Cottin has served as a consultant and speaker for and received travel 6. Thiele EA, Granata T, Matricardi S, Chugani HT. Transition into adulthood: honoraria from Actelion Pharmaceuticals, Boehringer Ingelheim, and Roche tuberous sclerosis complex, Sturge-weber syndrome, and Rasmussen Pharmaceuticals, has received research grants (to his institution) from Roche encephalitis. Epilepsia. 2014;55(Suppl 3):29–33. and Sanofi, served as a consultant for Bayer / MSD, Novartis, and Galapagos, 7. Cardis MA, DeKlotz CMC. Cutaneous manifestations of tuberous sclerosis and served as a committee member for Gilead Sciences, Promedior, and complex and the paediatrician's role. Arch Dis Child. 2017;102(9):858–63. Celgene. 8. Kingswood JC, d'Augeres GB, Belousova E, Ferreira JC, Carter T, Castellana R, A Fujimoto has nothing to disclose. et al. TuberOus SClerosis registry to increase disease awareness (TOSCA) - GFL Hofbauer has received speaker’s fees and consulting honoraria from baseline data on 2093 patients. Orphanet J Rare Dis. 2017;12(1):2. Novartis. 9. de Vries PJ, Whittemore VH, Leclezio L, Byars AW, Dunn D, Ess KC, et al. AC Jansen has received honoraria from Novartis and has no other relevant Tuberous sclerosis associated neuropsychiatric disorders (TAND) and the affiliations or financial involvement with any organization or entity with a TAND checklist. Pediatr Neurol. 2015;52(1):25–35. financial interest in, or financial conflict with, the subject matter of material 10. Leclezio L, de Vries PJ. Advances in the treatment of tuberous sclerosis discussed in the manuscript. complex. Curr Opin Psychiatry. 2015;28(2):113–20. Auvin et al. Orphanet Journal of Rare Diseases (2019) 14:91 Page 10 of 10 11. Leclezio L, Jansen A, Whittemore VH, de Vries PJ. Pilot validation of the time. How to make the diagnosis before seizures? Orphanet J Rare Dis. tuberous sclerosis-associated neuropsychiatric disorders (TAND) checklist. 2018;13(1):25. Pediatr Neurol. 2015;52(1):16–24. 36. Peron A, Au KS, Northrup H. Genetics, genomics, and genotype-phenotype 12. de Vries PJ, Wilde L, de Vries MC, Moavero R, Pearson DA, Curatolo P. correlations of TSC: insights for clinical practice. Am J Med Genet C Semin A clinical update on tuberous sclerosis complex-associated Med Genet. 2018;178(3):281–90. neuropsychiatric disorders (TAND). Am J Med Genet C Semin Med 37. Curatolo P, Nabbout R, Lagae L, Aronica E, Ferreira JC, Feucht M, et al. Genet. 2018;178(3):309–20. Management of epilepsy associated with tuberous sclerosis complex: 13. Afinitor/Afinitor Disperz [prescribing information]. East Hanover, NJ: Novartis updated clinical recommendations. Eur J Paediatr Neurol. 2018;22(5):738–48. Pharmaceuticals Corporation; April 2018. 38. Jozwiak S, Kotulska K, Domanska-Pakiela D, Lojszczyk B, Syczewska M, 14. Votubia [summary of product characteristics]. Nuremberg, Germany: Chmielewski D, et al. Antiepileptic treatment before the onset of seizures Novartis Pharma GmbH; 2018. reduces epilepsy severity and risk of mental retardation in infants with 15. Peron A, Vignoli A, La Briola F, Volpi A, Montanari E, Morenghi E, et al. Do tuberous sclerosis complex. Eur J Paediatr Neurol. 2011;15(5):424–31. patients with tuberous sclerosis complex have an increased risk for 39. Amin S, Lux A, Calder N, Laugharne M, Osborne J, O'Callaghan F. Causes of malignancies? Am J Med Genet A. 2016;170(6):1538–44. mortality in individuals with tuberous sclerosis complex. Dev Med Child 16. Mortaji P, Morris KT, Samedi V, Eberhardt S, Ryan S. Pancreatic Neurol. 2017;59(6):612–7. neuroendocrine tumor in a patient with a TSC1 variant: case report and review of the literature. Familial Cancer. 2018;17(2):275–80. 17. Ito T, Igarashi H, Jensen RT. Pancreatic neuroendocrine tumors: clinical features, diagnosis and medical treatment: advances. Best Pract Res Clin Gastroenterol. 2012;26(6):737–53. 18. Northrup H, Krueger DA. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 international tuberous sclerosis complex consensus conference. Pediatr Neurol. 2013;49:243–54. 19. Krueger DA, Northrup H. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 international tuberous sclerosis complex consensus conference. Pediatr Neurol. 2013;49:255–65. 20. Nabbout R, Andrade DM, Bahi-Buisson N, Cross H, Desquerre I, Dulac O, et al. Outcome of childhood-onset epilepsy from adolescence to adulthood: transition issues. Epilepsy Behav. 2017;69:161–9. 21. Curatolo P, Moavero R, de Vries PJ. Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurol. 2015;14(7):733–45. 22. Basta YL, Baur OL, van Dieren S, Klinkenbijl JH, Fockens P, Tytgat KM. Is there a benefit of multidisciplinary cancer team meetings for patients with gastrointestinal malignancies? Ann Surg Oncol. 2016;23(8):2430–7. 23. Taylor C, Shewbridge A, Harris J, Green JS. Benefits of multidisciplinary teamwork in the management of breast cancer. Breast Cancer. 2013;5: 79–85. 24. Licitra L, Keilholz U, Tahara M, Lin JC, Chomette P, Ceruse P, et al. Evaluation of the benefit and use of multidisciplinary teams in the treatment of head and neck cancer. Oral Oncol. 2016;59:73–9. 25. De Sadeleer LJ, Meert C, Yserbyt J, Slabbynck H, Verschakelen JA, Verbeken EK, et al. Diagnostic ability of a dynamic multidisciplinary discussion in interstitial lung diseases: a retrospective observational study of 938 cases. Chest. 2018;153(6):1416–23. 26. Lynch DA, Sverzellati N, Travis WD, Brown KK, Colby TV, Galvin JR, et al. Diagnostic criteria for idiopathic pulmonary fibrosis: a Fleischner society white paper. Lancet Respir Med. 2018;6(2):138–53. 27. Taylor C, Munro AJ, Glynne-Jones R, Griffith C, Trevatt P, Richards M, et al. Multidisciplinary team working in cancer: what is the evidence? BMJ. 2010; 340:c951. 28. Both P, Ten Holt L, Mous S, Patist J, Rietman A, Dieleman G, et al. Tuberous sclerosis complex: concerns and needs of patients and parents from the transitional period to adulthood. Epilepsy Behav. 2018;83:13–21. 29. Peron A, Canevini MP, Ghelma F, Di Marco F, Vignoli A. Healthcare transition from childhood to adulthood in tuberous sclerosis complex. Am J Med Genet C Semin Med Genet. 2018;178(3):355–64. 30. Rentz AM, Skalicky AM, Pashos CL, Liu Z, Magestro M, Pelletier CL, et al. Caring for children with tuberous sclerosis complex: what is the physical and mental health impact on caregivers? J Child Neurol. 2015;30(12):1574–81. 31. Fujimoto A, Okanishi T, Imai S, Ogai M, Fukunaga A, Nakamura H, et al. Establishment of a regional interdisciplinary medical system for managing patients with tuberous sclerosis complex (TSC). Sci Rep. 2018;8(1):16747. 32. Hsu C-C, Sandford BA. The Delphi technique: making sense of consensus. Pract Assess Res Eval. 2007;12(10):8. 33. De Waele L, Lagae L, Mekahli D. Tuberous sclerosis complex: the past and the future. Pediatr Nephrol. 2015;30(10):1771–80. 34. Hallett L, Foster T, Liu Z, Blieden M, Valentim J. Burden of disease and unmet needs in tuberous sclerosis complex with neurological manifestations: systematic review. Curr Med Res Opin. 2011;27(8):1571–83. 35. Slowinska M, Jozwiak S, Peron A, Borkowska J, Chmielewski D, Sadowski K, et al. Early diagnosis of tuberous sclerosis complex: a race against