Renal manifestations of tuberous sclerosis complex: patients’ and parents’ knowledge and routines for renal follow-up – a questionnaire study

Tuberous Sclerosis Complex (TSC) is a rare genetic disorder [1] characterised by benign tumours that can affect all organs (brain, kidneys, heart, lungs, and skin) at different stages in life [2, 3]. It is caused by mutations in the TSC 1 gene on chromosome 9 or the TSC 2 gene on chromosome 16 [1]. Epilepsy, neurocognitive impairments, autism, and dysfunctional renal and pulmonary organ systems [2, 3] are common symptoms.

Patients with TSC are at risk of suboptimal medical management for several reasons. First, it is a relatively rare disease affecting 1/6000 to 1/10000 live births [4‐6]. Therefore, some physicians may not be very well conversant with the disease, and this may result in late diagnosis and inappropriate treatment. Second, as TSC is a multisystem disease affecting many organs, coordinated follow-up is necessary from different medical specialties including neurology, paediatrics, genetics, nephrology, urology, dermatology, pneumology, and imaging [2, 3, 7, 8]. Third, TSC is a chronic, lifelong disease, and thus requires a transition in care from the paediatric department to the adult department. During such a transition, there is a risk that important information might be mislaid and follow-up and management might suffer. Fourth, the clinical manifestations of TSC are highly variable [8], some mild forms of TSC may be found in adults with no particular history, and therefore may not be properly diagnosed or managed by general practitioners. Fifth, intellectual disability (ID) occurs in about half of TSC patients [9], and may be a barrier to diagnosis and optimal care [10].

These challenges make it important that TSC patients and their families receive correct and appropriate information on symptoms, with surveillance and access to potential treatments throughout life [7]. This is particularly true for renal manifestations of TSC that tend to increase during adolescence [11‐13]. These manifestations vary considerably between patients [8] and are the leading cause of TSC-related deaths in adults [10, 14, 15]. TSC-associated renal manifestations include occurrence of renal angiomyolipomas (AMLs), cysts, and carcinomas, and occur in 48–85% of patients [10‐13]. Spontaneous bleeding of an AML is one of the most serious renal complications [16], and, at worst, may be life-threatening, potentially necessitating emergency nephrectomy [10, 17]. Although the causes of AML bleeding are not well understood, the risk increases with AML size [16], and several guidelines recommend renal imaging every one to 3 years to monitor AML growth and to trigger prophylactic treatment for those AML considered to be at risk of bleeding [7, 13, 18].

To the best of our knowledge, studies investigating patients’ and parents’ knowledge of renal AMLs or describing the routine renal follow-up of TSC patients (including which imaging modality is used, at what frequency, and in which specific age groups) are lacking.

The French Reference Centre for TSC and the Norwegian National Centre for Rare Epilepsy-Related disorders have surveyed renal manifestations among TSC patients. The first part [19] investigated the prevalence of renal AMLs and AML-related bleedings among TSC patients. In the present paper we report the results of the second part, where the aim has been to investigate patients’ and parents’ knowledge about renal AML in TSC and to identify current routines for renal follow-up.

Our study showed that patients’ and parents’ knowledge about TSC renal AMLs was far from optimal. Although most participants knew that TSC is associated with AMLs, a considerable proportion (42%) was unaware that AMLs could bleed. More worryingly, 14% of the participants did not know if they had AMLs.

Knowledge of the natural history of AMLs is limited [20], but it is well known that the risk of bleeding increases when the diameter is > 4 cm [11, 21]. Presence of micro-aneurysms may also predispose to bleeding [21, 22]. Unfortunately, the presence of micro-aneurysms can only be assessed by intra-arterial angiography and this criterion cannot be used on a routine basis [23].

Lack of knowledge about the risk of bleeding was found to occur more frequently in the group of patients without AML (54%) than in patients with AML (24%, Table 2). Information provided to patients should be sufficient to ensure that they have adequate knowledge, but without causing unnecessary anxiety. This balance can be difficult to achieve.

Whether patients without AML or those considered to have a low risk of bleeding should be informed about this risk is debatable. In our opinion, those patients that do not have AML, or only small AMLs, should be informed that their risk is minimal; this provides information but should not provoke unnecessary worry.

AMLs usually appear during childhood [11‐13]. The mean/median age of first detection of a renal abnormality (cyst or AML) in TSC ranges from 7.2 to 11.3 years [12, 24‐27]. AMLs mostly grow during the second decade of life [25, 26] and bleeding complications are rare before 18 years. Previous analysis from the same group of patients reported an absence of bleeding before 16 years of age, but a marked peak in bleeding complications between the ages of 20 and 30 years, both in France and Norway [19]. It therefore could be argued that it is not essential for patients and their parents to be provided with information on renal manifestations of TSC during childhood. Some parents with young children with severe epilepsy may be overwhelmed by the descriptions of complications occurring in adolescence or adulthood. This may explain why more than 50% of patients below 15 years and their families were unaware of the risk of bleeding. Whereas some patients or their parents may want to know about all the risks related to the disease immediately, others might not want to receive all the information at once. All should be provided with information about potential renal complications of TSC by the risk age for bleeding (15 years), or earlier if they are considered to be at risk. Information should also be provided about the symptoms of renal bleeding: flank pain, haematuria, and shock [13, 16, 20], and patients and their care givers should know what they should do if these symptoms occur. In the group of patients ≥15 years, a substantial proportion did not know about the bleeding risk of AMLs. Even when the patients who were diagnosed with TSC after the age of 15 years are excluded, a substantial proportion 55/149 (37%) received this information inappropriately late. The medical community needs to improve their dissemination of information to patients and their families, and to adapt this information to patients’ ages and individual risk factors for bleeding.

That knowledge about AMLs and related bleeding complications was lower in patients than in parents may be associated with patients’ learning difficulties or ID. It should be noted that there is a risk that the symptoms of these patients may be underestimated by their caregivers [28], with assessment of symptomatic AMLs described as being almost impossible in some patients due toID. In some cases, only severe behavioural changes have alerted their carers to their patients’ condition [29]. In addition, a substantial proportion of adults with ID lack someone to talk to about their health; they may ignore symptoms and not tell anyone when they are in pain [28].

The important role of patient s’ associations as sources of information is demonstrated by these being one of the main sources of information in France and Norway. Although the Internet is widely recognised as being a rapidly expanding source of healthcare information [30], surprisingly few reported it as a source of information. However, the importance of the Internet as an information source is probably under-reported in our study. First, although the questionnaire did not ask for specification, the patient associations’ websites probably played an important role in providing information. Second, the Internet was not formally mentioned in the French survey. In addition, as much of the information available on the Internet may be only in English, language difficulties may also limit its use among people who are not confident in reading English. The National Centre for Rare Epilepsy-Related Disorders in Norway has published an online TSC guide, written in Norwegian [31], with management and surveillance recommendations for physicians, healthcare professionals, caregivers, and patients. The intention is to increase knowledge of TSC, including renal AMLs and their associated risk of bleeding amongst these groups in Norway.

Imaging follow-up was inadequate in many of the patients in our study. A substantial proportion of patients (36% in France, 19% in Norway) did not receive renal imaging at least every 3 years, although regular renal imaging is recommended [7, 13]. In addition, although the risk of developing symptomatic AML increases with age [10, 19] and increased monitoring is recommended in adulthood [7, 26], the percentage of patients undergoing regular imaging was significantly higher in patients under 15 years. The reasons for increased monitoring in these younger patients are unclear, but may reflect increased awareness of TSC renal manifestations among neuro-paediatricians and paediatricians than among physicians for adults. Surveillance and treatment for TSC patients are not centralized in France and Norway, which probably could have facilitated regular imaging. ID and communication problems in adult patients with TSC may also be a contributory reason [10]. Patients with mild forms of TSC may also be at risk of inappropriate follow up because of late diagnosis and lack of contact with the health services. Ultrasound was the most frequent imaging modality used in our population. There is no clear consensus on the optimal imaging modality for follow-up [7, 13]. Ultrasound is relatively cheap and safe (based on non-ionizing radiation), but provides less reliable measurements of large AMLs, especially when they are coalescent. CT and MRI are more accurate, but more expensive and time consuming [32, 33]. Because of short acquisition times with CT, it may be possible to avoid general anaesthesia in patients with ID, but repeated CT exposes patients to high doses of radiation. MRI is a non-ionizing radiation technique, but its long acquisition times may mean that general anaesthesia is necessary for some patients [32]. A combined MRI (or CT) of abdomen and brain for patients in need of both, may reduce stress and facilitate regular imaging. The most recent recommendations favour CT or MRI, at least in adults [7, 13]. The more frequent use of ultrasound in our study may reflect older recommendations [18, 25, 26, 34].

Although similar trends were found in France and Norway, there were some differences between the two countries. Patient information was significantly better in France, but regular imaging follow-up was performed in significantly more patients in Norway. These disparities may reflect differences in healthcare organization. Although the follow-up guidelines were probably not implemented in 2013–2014, when the study was conducted in Norway, awareness regarding kidney changes and the need for regular investigations may have been greater at that time than in 2009–2011 when the study was conducted in France [7, 13].

Our study has some limitations. First, it is limited by selection bias. The response rate was only known in Norway and was 47% (100/214).The survey mostly targeted patients known from specialized hospital institutions or patient associations. These patients probably have the best information and follow-up, and therefore, in the wider patient group, information and follow-up may be poorer than our results indicate. Second, our results were mostly based on patients’ or caregivers’ responses; these may be inaccurate, particularly concerning imaging follow-up. Third, a substantial proportion of patients in both countries did not answer the questions regarding imaging follow-up. Reminders were sent to non-responders in Norway, resulting in a higher response rate in Norway (94%) than in France (68%).

Our study showed that patient information on renal AMLs in TSC and renal imaging follow-up were suboptimal in a substantial proportion of participants in Norway and France. Because renal bleeding complications usually occur after the age of 15 years, physicians and specialist nurses should ensure that patients, care givers and their families are properly informed on the risk of renal bleeding, at the latest when the patient is 15 years old. In addition, it is important that provision of advice is based upon the extent of renal manifestations in the individual patients. Monitoring of AML growth in both countries should be standardized in order to comply with current guidelines. The high-risk period between adolescence and adulthood should be of particular concern, and efforts should be directed towards improving collaboration between paediatricians and physicians for adults and to ensure appropriate follow-up in patients with ID and patients with mild forms of TSC.