Childhood tuberous sclerosis complex in southern Sweden: a paradigm shift in diagnosis and treatment

As the presenting feature suggestive of TSC, CRs were significantly more commonly detected in individuals born during 2010–2020 than during 1983–2009. A low neonatal diagnostic frequency of CRs in the late nineteen-nineties and early two-thousands has been published previously [14]. A CR was the most common first diagnostic feature (2/3) of children born during 2010–2020, in contrast to seizure onset, which was the presenting TSC feature in > 70% of the older individuals in our cohort. CR led to diagnosis of TSC, within their first month of life, in all children born during the last decade. This is important, as early diagnosis allows identification of emerging problems, such as epilepsy, and provides an opportunity for therapeutic interventions that can potentially alter the disease course [15]. CRs have been diagnosable by foetal ultrasound techniques since 1982 [16], but increasing awareness amongst paediatric cardiologists, improved high-resolution US technologies. Moreover, availability of foetal MRI may explain this significant change during the last 10 years [17].

CRs are usually asymptomatic, but may cause severe morbidity requiring surgical intervention [14], as experienced in two new-borns in this cohort. Pre-excitation was observed in 15% of the individuals, and is a well-known ECG-feature in TSC, where the CR itself is believed to serve as an accessory pathway [18]. Tachycardia was supraventricular in all but one individual, who developed ventricular tachycardia over time. Serial echocardiographic examinations are advised every 1–3 years in the absence of inflow/outflow obstruction and ventricular dysfunction, until the tumour regresses [17]. Thereafter, continued cardiac follow-up with ECG is recommended every 3–5 years [1, 17]. Our study subjects were followed with echocardiography in early life more frequently than these recommendations. However, when cardiac surveillance was stopped, ECG controls also seemed to halt. Echocardiography was the only modality used for cardiac imaging in this retrospective cohort, although MRI is also used [17]. Some case reports indicate successful treatment, with rapid tumour reduction, using both everolimus and sirolimus [19, 20], even for obstructive disease. No patient was treated with mTORi for cardiac indications during the study period; however, we have experience of this as later treatment (Björk Werner, Eklund, personal comm.).

The epilepsy frequency in our cohort (82.7%) agreed with the recently published TOSCA study [21], but was higher than national Swedish data on TSC and epilepsy published by Welin et al. [2]. This may be because epilepsy frequency is overestimated in data from non-population-based studies, as most TSC cohorts, including ours, contain severely affected individuals that require hospital-based care. Furthermore, 34.9% of the epilepsy individuals developed infantile spasms, in line with the TOSCA study [21]. The spasms were the presenting epileptic feature in 80%. Various drugs were used to treat seizures. GABA-potentiating drugs (e.g., valproate, benzodiazepines, barbiturates, and vigabatrin) were predominant (> 40% of prescriptions), similar to the TOSCA study [21]. The use of vigabatrin increased in the most recent decade, in line with recent guidelines [5]. Epilepsy in TSC is often difficult to treat and almost two-thirds had DRE lasting at least one age-span. As epilepsy surgery is the only curative option for DRE, it is noteworthy that half the individuals were never referred for specialist team discussion, thus missing this opportunity. Since 2011, eight individuals were treated with an mTORi for a neurological indication, with an effect both on SEGA growth and seizure frequency. In 4/8 individuals, the number of ASDs could be reduced. ID is often aggravated by DRE. Of our study subjects, 56% fulfilled ID criteria, similar to the findings of the Tuberous Sclerosis 2000 study group [22]. ADHD and autism were also common, but were probably under-appreciated [23], which calls for attention to the related symptoms in daily TSC care.

AMLs and renal cysts were equally observed in this population, as described previously [4, 24]. Renal cysts, however, were found in the first year of life in all individuals with CRs identified prenatally during the latest decade compared to 34,6% of individuals screened for renal lesions in previous decades. Abdominal imaging is mandatory at diagnosis, regardless of age [1]. In our study renal lesions were difficult to define by US during the first month of life. Small AMLs may be hard to distinguish from cysts on US, even in older children, in daily practice [25]. MRI is the preferred modality because of the better structural assessment of the lesions, but requires general anaesthesia in small children and children who are unable to cooperate with the procedure. Progress of renal lesions in our cohort could not be evaluated due to the use of different imaging modalities during the follow-up of the study individuals.

The laboratory analysis and blood pressure measurement showed absence of systematic examination. Both renal cysts and AMLs can cause hypertension and chronic kidney disease with increasing age. Annual assessment of renal function and blood pressure was already recommended in older guidelines [26], and proteinuria assessment has been included in the most recent guidelines [1]. Proteinuria may be a marker of early kidney damage and a potential side effect of mTORi treatment [27, 28]. Everolimus is approved for treatment of asymptomatic growing AMLs > 3 cm in diameter. Some data indicate that mTORi may reduce cyst number and size in individuals with TSC [29], but the effectiveness in TSC-associated renal cystic disease has not yet been fully evaluated. Interestingly, the decreased renal cyst size during everolimus treatment was observed in two individuals in this study.

The occurrence of astrocytic hamartomas and achromatic patches in this paediatric cohort was please merge the text here from the next row somewhat lower than the reported frequency in other cohorts including adults [4]. Of 10 individuals controlled with ERG during vigabatrin medication, retinal effects could be seen in three, with some improvement during the follow-up. Despite involving a small group of individuals, this highlights the importance of closely monitoring these patients for retinal changes. No individual was investigated for CVI problems despite a clear correlation in the literature between neurological ailment and CVI [30]. Ophthalmologists should be encouraged to focus on this diagnosis. Learning ability and quality of life for CVI patients may be substantially improved by a specially trained vision therapist.

Our study has limitations common in retrospective analyses, including incomplete data due to lack of documentation in medical records. No primary healthcare assessment was available and data collection was focused on regional hospitals and centres for habilitation thus some cases with mild disease might have been missed.