Original ArticleEarly Detection of Tuberous Sclerosis Complex: An Opportunity for Improved Neurodevelopmental Outcome
Introduction
Tuberous sclerosis complex (TSC) is an autosomal dominant condition caused by heterozygous mutations in either the TSC1 or the TSC2 gene with an estimated prevalence of 8.8 per 100,000.1 TSC is associated with variable cognitive outcome, autism, epilepsy, and benign tumors in various organs (heart, skin, brain, kidneys, and lungs).2 A clinical diagnosis of TSC is based on the most recent updated diagnostic criteria.3 Approximately 76% to 96% of patients will develop seizures and 50% to 60% have some degree of developmental disability.4, 5, 6 Cognitive outcome is associated with early age of seizure onset and seizure severity.7, 8, 9
In most individuals, the diagnosis of TSC is made after seizures have begun. In a British cohort of 125 children with TSC, 62% presented with seizures; 17% were diagnosed prenatally, usually following the discovery of cardiac rhabdomyomas on fetal ultrasound; and a further 18% were diagnosed postnatally before the onset of seizures, through investigation of a cardiac murmur, discovery of TSC-related skin lesions, or family history.2
Diagnosis before the onset of seizures may facilitate the early recognition and treatment of seizures with antiepileptic drugs such as vigabatrin, which has the potential to reduce the severity of epilepsy and may, in turn, improve the developmental outcomes.10, 11 Emerging literature also suggests that the mechanistic target of rapamycin (mTOR) inhibitors may improve seizure and developmental outcomes.5, 12, 13, 14 Currently, prospective randomized trials aimed at improving the outcome with preventative use of vigabatrin are underway, including utilizing electroencephalographic (EEG) abnormalities to guide treatment decisions before the onset of clinical seizures.15 The use of mTOR inhibitors and other agents in such trials may follow. In this context, it is becoming increasingly important to strive for early diagnosis of TSC, preferably before the onset of seizures, to maximize clinical benefit. However, there is little natural history literature about the neurological and developmental outcomes of this group of patients. Therefore we performed a retrospective review of our multidisciplinary TSC clinic to determine if a diagnosis of TSC before epilepsy onset is associated with a different neurodevelopmental outcome.
Section snippets
Materials and Methods
The study population consisted of all children with TSC born between 2001 and 2015 who were seen either at the Royal Hospital for Women (RHW) or at the Sydney Children's Hospital (SCH), Randwick, New South Wales (NSW), Australia. The study cohort was ascertained through the use of an NSW statewide genetics database called Trakgene. All patients seen at a genetics service in NSW have their information entered into Trakgene at the time of referral. All patients with a clinical diagnosis of
The patient cohort
A total of 74 patients were included, which represented 80% of the NSW TSC population born between 2001 and 2015 registered in Trakgene. We did not have outcome data for the 20% who were not seen in our clinic, and they were therefore excluded from the study. All patients met the clinical diagnostic criteria for TSC.3 The diagnosis of TSC was made before the onset of seizures in 34 (46%) children. The median age at the time of the study was 6.5 years in the preseizure cohort and nine years in
Discussion
This study suggests that children diagnosed with TSC before seizure onset have a lower risk of severe developmental disability and less severe epilepsy. This preseizure cohort of children with TSC has been highlighted as representing an opportunity to improve outcome using directed surveillance and earlier targeted intervention.9, 17, 18 Increasing numbers of children are being diagnosed with TSC before seizures. It is critical that accurate information about outcomes and management be
Conclusions
Our study demonstrated that patients with TSC diagnosed before the onset of seizures (either prenatally or postnatally) appear to have a milder clinical course than those who were diagnosed after the onset of seizures. Therefore it is vital to optimize the diagnosis of patients before seizures develop to potentially improve the neurodevelopmental outcome. It is critical that accurate up-to-date information about clinical outcomes be provided to parents and clinicians rather than relying on the
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Cited by (27)
Monozygotic twins with cardiac rhabdomyomas associated with maternal tuberous sclerosis
2021, Clinica e Investigacion en Ginecologia y ObstetriciaApproach to Preventive Epilepsy Treatment in Tuberous Sclerosis Complex and Current Clinical Practice in 23 Countries
2021, Pediatric NeurologyCitation Excerpt :Chung et al.13 noted that children who were diagnosed with TSC before the onset of seizures had less severe epilepsy and better developmental outcome than children who were diagnosed after the onset of epilepsy. According to these authors, the difference resulted from the increased vigilance and shorter time between seizure onset and treatment introduction.13 Recent studies of infants with TSC have shown that EEG findings may be a reliable prognostic biomarker of epileptogenesis.14-17
Epilepsy and Neurodevelopmental Comorbidities in Tuberous Sclerosis Complex: A Natural History Study
2020, Pediatric NeurologyCitation Excerpt :In addition, the risk of developing clinical seizures was much less in the “preventative” group when compared with the “standard” therapy group (50% vs 96% P = 0.001) along with less number of entiepileptic drugs utilized and higher likelihood of successful antiepileptic drug withdrawal in the “preventative” group. Another study of 74 patients31 similarly showed that patients diagnosed with TSC after onset of clinical seizures had more severe epilepsy and developmental disability compared with the group treated before the onset of clinical seizures. Two larger prospective ongoing projects, EPISTOP22 and PREVENT,32 should further clarify the effect of early presymptomatic identification of electroencephalographic abnormalities and treatment before the onset of clinical epilepsy.
Modifying genetic epilepsies – Results from studies on tuberous sclerosis complex
2020, NeuropharmacologyCitation Excerpt :In these conditions early therapeutic intervention may prevent, delay or ameliorate the development of epilepsy, drug-resistant epilepsy and intellectual disability and significantly improve the quality of life of young patients and their families. There is an increasing number of papers demonstrating the utility of pre-seizure EEG surveillance in early diagnosis of TSC as a first step to preventive treatment (Benova et al., 2018; Chung et al., 2017; Whitney et al., 2017). Studies in SWS are in the pipeline (Pinto et al., 2016).
Conflict of Interest: All authors have no conflicts of interest to disclose.