Tuberous sclerosis complex (TSC): expert recommendations for provision of coordinated care.
- 1Research Institute of Molecular and Clinical Sciences, St George's University of London, United Kingdom
- 2St George’s University Hospitals NHS Foundation Trust, United Kingdom
- 3Alder Hey Children's NHS Foundation Trust, United Kingdom
- 4University Hospitals Birmingham NHS Foundation Trust, United Kingdom
- 5King's College London, United Kingdom
- 6York Teaching Hospital NHS Foundation Trust, United Kingdom
- 7Wirral University Teaching Hospital NHS Foundation Trust, United Kingdom
- 8Tuberous Sclerosis Association, United Kingdom
- 9Leeds Teaching Hospitals NHS Trust, United Kingdom
- 10University College London, United Kingdom
- 11Royal Free London NHS Foundation Trust, United Kingdom
- 12Newcastle upon Tyne Hospitals NHS Foundation Trust, United Kingdom
- 13Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust (MFT), United Kingdom
- 14Centre for Genomic Medicine, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom
- 15University of Nottingham, United Kingdom
- 16National Centre for Lymphangioleiomyomatosis, Nottingham University Hospitals NHS Trust, United Kingdom
- 17NHS Greater Glasgow and Clyde, United Kingdom
- 18Birmingham Children's Hospital NHS Foundation Trust, United Kingdom
- 19Belfast Health and Social Care Trust, United Kingdom
- 20Great Ormond Street Hospital for Children NHS Foundation Trust, United Kingdom
- 21Evelina London Children's Hospital, United Kingdom
- 22Medical School, University of Sheffield, United Kingdom
- 23Sheffield Kidney Institute, United Kingdom
- 24Institute of Medical Genetics, School of Medicine, Cardiff University, United Kingdom
- 25Noble’s Hospital, Isle of Man
- 26Brighton and Sussex University Hospitals NHS Trust, United Kingdom
Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem genetic disorder characterised by benign hamartomatous growths in multiple organs, including the skin, brain, kidneys and lungs(1–3). The estimated prevalence is 1:600-1:10,000 live births in the general population(4–6). Patients present at different ages with different manifestations, and varying degrees of organ involvement (Figure 1). CNS manifestations of TSC mainly present in childhood, affect around 85% of patients(7), frequently resulting in epilepsy refractory to treatment, intellectual impairment, autistic spectrum disorder, attention deficit hyperactivity disorder and behavioural problems(1–3). Renal angiomyolipomas (AMLs) occur in approximately 80% of patients(8); kidney disease is the leading cause of death in adults with TSC(9). TSC is complex and highly varied (Figure 1) necessitating careful coordination of care, which is lacking for most patients in the UK. Some TSC manifestations are rarer; e.g. subependymal giant cell astrocytoma (SEGA) occurs in around 20% of patients(10) (Figure 2).
The major unsolved problem in TSC is refractory epilepsy and TSC-associated neuropsychiatric disorders (TAND); of which preliminary evidence suggests refractory epilepsy is a major cause(11,12).
Classically, a clinical diagnosis of TSC is made by identifying major and minor features (Table 1)(1,13). With wider availability of genetic testing, identification of pathogenic mutations in TSC1 or TSC2 is now sufficient to establish a diagnosis, regardless of the presence of clinical features(1,13), and is particularly useful in confirming a suspected diagnosis, as many clinical TSC manifestations are infrequent in young patients(1,13).
The approval of the mTORC1 inhibitor - everolimus - for the treatment of AMLs, SEGA and refractory epilepsy represents a significant advance in the potential management of the disease(14,15). Whilst not licensed in Europe, the Federal Drugs Agency (FDA) have also approved sirolimus for use in pulmonary lymphangioleiomyomatosis (LAM)(15). Furthermore, appropriate early treatment has been shown to reduce the long-term impact of TSC on patients(11,12).
A retrospective UK cohort study linking Clinical Practice Research Datalink (CPRD) to Hospital Episode Statistics (HES) data identified 334 patients with TSC revealed a much lower frequency of complications than would be expected from previous research; the disparity possibly reflecting under-recognition, and hence suggestive of inadequate medical care(16).
It is clear from these findings, and the observation that many new patients referred to TSC clinics have never had holistic systematic monitoring, that many patients receive inadequate care. In the UK, about 1000 TSC families are known to the Tuberous Sclerosis Association ((TSA) – the UK patient organisation), and a similar number (usually the same families) attend UK specialist TSC clinics. Therefore in most cases, the quality of care delivered is unknown.
Given the range of organ systems affected by TSC, its treatment requires coordination across a number of medical specialties over a patient’s lifetime (Table 2). Currently in the UK, 16 centres host specialist TSC clinics – but most UK TSC patients are not currently managed within them. These specialist clinics have often been founded by enthusiastic clinicians but are frequently inadequately funded.
The transition from paediatric to adult services can be particularly challenging in the absence of a systematic service. In Wales, a specialist TSC clinic that has been established through a partnership, between a pharmaceutical company and the NHS, awaits the development of a fully sustainable commissioning model. In Northern Ireland, a TSC clinic has been running since 1995, and directly reviews the majority of TSC patients in the region.
In the UK, specialised service specifications are in place for adults and children with genetic disorders such as cystic fibrosis and inherited metabolic disorders. These are funded by NHS England, the Department of Health, Social Services and Public Safety in Northern Ireland, and Welsh Health Specialised Services Committee in Wales. However, no similar service or service specification is yet available for TSC patients.
We propose a comprehensive, holistic model of care - to manage patients that present with a range of manifestations, requiring specialist management from a wide range of specialties (Figures 1 & 2).
Review of International Guidelines on TSC surveillance and management
The 2012 consensus statement on TSC surveillance and management, together with UK guidelines published this year make a number of recommendations for patient screening(1,13,17), with additional recommendations specific to AML, SEGA, LAM and TSC-related epilepsy reported in disease-specific guidelines(18–20).
Additional baseline investigations to assess the extent of disease and organ involvement (Table 3), play an important role in guiding later treatment decisions.
The treatment and long-term surveillance needs (Table 4)(13) should be determined, based on the extent of disease at baseline, and tailored to the patient.
Recommendations for the Delivery of Services for TSC Patients
A ‘hub and spoke’ model of care is proposed, with a central network of TSC-centres, co-ordinated by specialists, and supported by a regional network of clinicians, that offer access to a comprehensive set of TSC-related specialist services. Since holistic care of TSC patients requires input from many different specialties, treatment of TSC patients should be discussed within the regional network by a multidisciplinary team (MDT), with the aim of ensuring that each TSC patient and their family have a tailored care plan to manage current disease manifestations, and surveillance for future TSC manifestations.
To achieve this, Specialist TSC services should ensure:
• Diagnosis: patients with TSC are identified by clinical evaluation and/or genetic testing.
• Surveillance: provision of multi-disciplinary evaluation – through alignment with regional genetic services (for genetic counselling to patients and their families), and with other clinical specialties to ensure access to appropriate care for all patients.
• Treatment: the appropriate access and use of TSC therapies.
• Information & Support: collaboration with patients/family and other organisations to provide access to TSC-specific information.
• Research: facilitate patients and their families to become involved in relevant research projects.
Regional TSC clinics should be responsible for the diagnosis of patients with TSC, and the provision of routine care and support for patients and their families. Regional clinics should be supported by a dedicated TSC specialist coordinator, who has responsibility for coordinating the service, ensuring timely surveillance, and coordinating care between different specialist services, developing individualised plans for patient follow-up, and ensuring continuity of care for TSC patients transitioning to adulthood. Alongside this, linking regional clinics with TSC patient support groups, (e.g. in the UK, the TSA is vital to ensure that patients and their families receive comprehensive support). Regional clinics are in an ideal position to gather clinical and prevalence data to monitor needs locally and facilitate future research.
To allow regional TSC clinics to fulfil this pluripotent role, they need to offer or have access to a range of core services, including:
1. Genetic Testing & Genetic Counselling
2. Neurology & Neuroimaging
3. Nephrology, Urology, General and Interventional Radiology services
4. Clinical Psychology, Psychiatry & Developmental Paediatrics
5. Collaboration with patient/family organisations
The roles of each of these core services is summarised in Table 5. Where regional centres are unable to provide a core service, there should be a clear pathway through which that service can be accessed. Furthermore, regional centres should also have access to the necessary facilities to cater for the specific needs of TSC patients. For example, TSC-related intellectual impairment and autistic spectrum disorder may necessitate that surveillance brain and renal imaging be performed under general anaesthetic. This requires co-ordination of such procedures in an appropriate day-unit, or via a formal inpatient admission, with the support of specialised paediatric and adult anaesthetists.
In addition to the ‘core’ services, in order to provide comprehensive treatment to TSC patients, regional TSC centres would also need to have access to additional specialist support services, including Dermatology, Respiratory, Cardiology, Neuropsychiatry, and Obstetrics/Gynaecology. The role of each of these additional services in relation to TSC patients is summarised in Table 6.
TSC Clinics need access to highly specialised services, of which there are four in the UK, including for Pulmonary LAM, Paediatric epilepsy surgery, Neurosurgery & Neuro-oncology and Neuropsychiatric services, (summarised in Table 7).
In addition to ensuring access to appropriate services, there are key responsibilities for the regional centres in ensuring holistic care for TSC patients and their families.
Regional services need to ensure provision of the supportive care needed by patients and their families, including referral for individualised education plans for patients, genetic counselling for family members and ongoing support for both the patient and their family from a patient association.
There is a need to monitor patient movement through the service to ensure that all patients are offered appropriate, regular surveillance and timely follow-up. Patients should be offered the most up-to-date, evidence-based surveillance, and those patients with multiple complications of TSC should attend joint clinics or have the monitoring of different manifestations performed in a single session (e.g. combined surveillance / monitoring of SEGA and renal AML through a coordinated MRI scan of both brain & renal tract – particularly where a general anaesthetic is required to achieve the imaging), in order to minimise individual patients’ time in hospital. Such efforts would not only help to reduce the costs of patient monitoring, but help to improve patients’ and carers’ experience of care, and their quality of life.
TSC regional centres should ensure that the service is aligned with National guidelines such as those published by NICE or the Renal Association on how to manage transitional care for patients moving from paediatric to adult services, with bespoke plans drawn up for individual patients where necessary.
TSC centres and networks should collaborate with the current available networks of local / community services (e.g. Community paediatricians and mental health services) to optimise care and minimise cost.
Finally, there is a need to audit the services offered to and used by patients with TSC, so as to ensure that patients are treated appropriately. A very helpful way to ensure that clinic services develop into exactly what is needed by patients and families is to audit services using PREMS (Patient reported experience measures)(21) and PROMS (Patient reported outcome measures)(22).
Regular review of services will help to identify any potential opportunities for improved efficiency, as well as ensure that patients are consistently screened and treated according to best practice. With this aim, a national database should be established to facilitate the coordination of care between centres, auditing of services, planning of resource allocation and TSC-related research.
The rarity and heterogeneity of TSC presentations offers a number of challenges to the implementation of best practice care; treatment and follow-up is consequently frequently fragmented, disjointed and suboptimal.
There is a need to improve TSC management to ensure patients have early access to appropriate treatment and preventive measures – both to minimise long-term effects of TSC where possible, and to support a frequently vulnerable patient group and their families. In particular, there are three elements that are both essential for the success of a TSC clinic, yet frequently missing. These include dedicated neuropsychiatric input, access to CT/MRI imaging under general anaesthetic, and perhaps most importantly, a dedicated specialist TSC co-ordinator. A mechanism to deliver optimal care is essential if patients are to gain the best outcomes; including monitoring and intervention for SEGA, renal AMLs, LAM and TAND, and early improvement in refractory epilepsy.
We advocate that specialist expertise be provided by centralised TSC ‘hubs’, with routine patient management coordinated centrally and undertaken in regional TSC networks to facilitate optimal resource use and improve the comprehensive care of TSC patients. The TSC hub-and-spoke model will form a coordinated care network, that will also provide a structure to facilitate the education of health care professionals and affected families, and to facilitate TSC research. This model for TSC care may also serve as a blueprint for improving the quality of care for patients with other rare diseases in evolving, ever more efficient, healthcare services.
Keywords: Tuberous sclerosis complex (TSC), United Kingdom (UK), service specification, Commissioning, surveillance, guidelines, Clinics, Rare disease (RD)
Received: 15 Jun 2019;
Accepted: 07 Oct 2019.
Copyright: © 2019 Annear, Appleton, Bassi, Bhatt, Bolton, Crawford, Crowe, Tossi, Elmslie, Finlay, Gale, Henderson, Jones, Johnson, Joss, Kerecuk, Lipkin, Morrison, O'Callaghan, Cadwgan, Ong, Sampson, Shepherd and Kingswood. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Dr. Nicholas M. Annear, Research Institute of Molecular and Clinical Sciences, St George's University of London, London, United Kingdom, email@example.com