Early Detection of Tuberous Sclerosis Complex: An Opportunity for Improved Neurodevelopmental Outcome

doi:10.1016/j.pediatrneurol.2017.05.014

Pediatric Neurology

Volume 76, November 2017, Pages 20-26

https://doi.org/10.1016/j.pediatrneurol.2017.05.014 Get rights and content

Abstract

Background

Tuberous sclerosis complex (TSC) is an autosomal dominant condition associated with epilepsy, benign tumors, and variable neurodevelopmental outcomes. The diagnosis is most commonly made after epilepsy onset, although a proportion are diagnosed prenatally. Presymptomatic or early treatment with agents such as vigabatrin offers the hope of improved neurodevelopmental outcome. Therefore early diagnosis, before the onset of seizures, is important. In a cohort of children with TSC, we evaluated the age and mode of initial presentation, assessed the neurocognitive and epilepsy outcome, and analyzed whether those diagnosed before the onset of seizures have a different outcome compared with those diagnosed postseizures.

Methods

We reviewed patients at the TSC clinic at Sydney Children's Hospital who were born between 2001 and 2015.

Results

A total of 74 patients were identified: 34 (46%) diagnosed preseizure (21 prenatally) and 40 (54%) postseizure. In the preseizure cohort, 77% presented with cardiac rhabdomyoma(s) and 72% developed seizures. The postseizure cohort had more severe epilepsy, requiring more antiepileptic drugs for seizure control (median five, compared with three in the preseizure cohort [P = 0.01]). Developmental disability occurred in 65% of the preseizure cohort compared with 72% of the postseizure cohort. Severe developmental disability most often occurred in children who had their first seizure before age 12 months.

Conclusion

Children who are diagnosed with TSC before the onset of seizures have less severe epilepsy and better developmental 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)

Fetal Brain Magnetic Resonance Imaging Findings Predict Neurodevelopment in Children with Tuberous Sclerosis Complex
2021, Journal of Pediatrics
To correlate fetal brain magnetic resonance imaging (MRI) findings with epilepsy characteristics and neurodevelopment at 2 years of age in children with tuberous sclerosis complex (TSC) to improve prenatal counseling.
This retrospective cohort study was performed in a collaboration between centers of the EPISTOP consortium. We included children with definite TSC, fetal MRIs, and available follow-up data at 2 years of age. A pediatric neuroradiologist masked to the patient's clinical characteristics evaluated all fetal MRIs. MRIs were categorized for each of the 10 brain lobes as score 0: no (sub)cortical lesions or doubt; score 1: a single small lesion; score 2: more than one small lesion or at least one large lesion (>5 mm). Neurologic manifestations were correlated to lesion sum scores.
Forty-one children were included. Median gestational age at MRI was 33.3 weeks; (sub)cortical lesions were detected in 97.6%. Mean lesion sum score was 4.5. At 2 years, 58.5% of patients had epilepsy and 22% had drug-resistant epilepsy. Cognitive, language, and motor development were delayed in 38%, 81%, and 50% of patients, respectively. Autism spectrum disorder (ASD) was diagnosed in 20.5%. Fetal MRI lesion sum scores were significantly associated with cognitive and motor development, and with ASD diagnosis, but not with epilepsy characteristics.
Fetal cerebral lesion scores correlate with neurodevelopment and ASD at 2 years in children with TSC.
Monozygotic twins with cardiac rhabdomyomas associated with maternal tuberous sclerosis
2021, Clinica e Investigacion en Ginecologia y Obstetricia
La esclerosis tuberosa es una enfermedad autosómica dominante que afecta cualquier órgano. Se presenta el caso de una paciente femenina de 23 años con diagnóstico de un año de evolución de esclerosis tuberosa por presencia de lesiones dermatológicas en cara, con embarazo gemelar monocorial biamniótico en donde ambos fetos cursan con rabdomiomas cardiacos. Actualmente en seguimiento con ecocardiografía fetal, por lo que se discute el control prenatal, así como los riesgos posnatales de ambos fetos. La importancia de esta revisión radica en el asesoramiento genético de la paciente y el abordaje multidisciplinario.
Tuberous sclerosis is an autosomal dominant disease affecting any organ. The case is presented on a 23 year-old patient with a diagnosis of tuberous sclerosis of 1 year onset with Monochorionic diamniotic twin pregnancy in which both foetuses had cardiac rhabdomyomas. The patient is currently on follow-up with foetal cardiac ultrasound. A discussion is presented on the prenatal monitoring, as well as postnatal risks of both foetuses. The importance of this review lies in the genetic counselling of the patient and the multidisciplinary approach.
Approach to Preventive Epilepsy Treatment in Tuberous Sclerosis Complex and Current Clinical Practice in 23 Countries
2021, Pediatric Neurology
Citation 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
Tuberous sclerosis complex (TSC) is associated with a high risk of early-onset epilepsy and developmental delay. Recently, EEG monitoring in infants with TSC and preventive antiepileptogenic treatment have been proposed to improve epilepsy and neurodevelopmental outcome. We explored how recent studies and recommendations regarding EEG monitoring and preventive epilepsy treatment have influenced the clinical practice of epilepsy management among children with TSC.
A survey on the epilepsy management approach in infants with TSC was sent by e-mail to 165 clinicians who actively participated in TSC international research conferences in years 2016 - 2019. Additionally, the e-mail addresses of TSC referral centers were collected from national TSC organizations. The survey was also distributed in the American Epilepsy Society newsletter. Only responses from centers providing neurological care for children with TSC were included in the study.
Sixty-one responses from 23 countries were analyzed. Sixty respondents answered questions concerning infants, and 57 of 60 respondents (95%) perform at least one EEG study before epilepsy onset and 42 (70.0%) conduct regular EEG monitoring. Most of the clinicians perform video EEG (42/61, 68.8%). Overall, 51.7% of respondents, mostly from Europe, Australia, and South America, endorse preventive antiepileptic treatment in infants with TSC. Vigabatrin is a preferred drug in patients younger than two years old for both focal (61.7%) and generalized (56.7%) seizures.
Despite the lack of published results of randomized trials, the concepts of preseizure EEG monitoring and epilepsy prevention are already being implemented in the majority of surveyed centers.
Epilepsy and Neurodevelopmental Comorbidities in Tuberous Sclerosis Complex: A Natural History Study
2020, Pediatric Neurology
Citation 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.
We studied the natural history, genotype influence, and inter-relationship of epilepsy and neuropsychiatric disorders in tuberous sclerosis complex.
Patients were identified using the TSC Natural History Database, the largest repository of longitudinally studied patients enrolled by the TSC Clinics Consortium.
A cohort of 1657 TSC Natural History Database patients was analyzed. Eighty-eight percent patients (91% TSC2 vs 82% TSC1; P = 0.002) had epilepsy; TSC2 was more frequent with epilepsy onset at age less than two years (TSC2 82% vs TSC1 54%; P < 0.001) and infantile spasms (TSC2 56% vs TSC1 27%; P < 0.001). Frequency of intellectual disability (intelligence quotient less than 70) was higher when epilepsy coexisted (P < 0.001), but was not impacted by genotype (P = 0.08). Severe intellectual disability (intelligence quotient less than 50) was associated with epilepsy onset at age less than two years (P = 0.007), but not with the epilepsy duration (P = 0.45). Autism was diagnosed in 23% and was associated with epilepsy (P < 0.001), particularly with epilepsy onset at age less than two years (P = 0.02) but not with genotype (P = 0.06). Attention-deficit/hyperactivity disorder (age greater than four years) was diagnosed in 18% and was associated with epilepsy (P < 0.001), but genotype made no difference. Nine percent had anxiety (age greater than seven years) and 6% had depression (age greater than nine years), but neither showed association with epilepsy or genotype.
Epilepsy is associated with intellectual disability, and when epilepsy begins before age two years the frequency and severity of intellectual disability is much higher. Epilepsy is also associated with autism and attention-deficit/hyperactivity disorder but not with anxiety and depression. Additional trials, blinded, prospective, and adequately powered, will help clarify if early and effective treatment of epilepsy may also mitigate intellectual disability, autism, and attention-deficit/hyperactivity disorder.
Modifying genetic epilepsies – Results from studies on tuberous sclerosis complex
2020, Neuropharmacology
Citation 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).
Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder affecting approximately 1 in 6,000 in general population and represents one of the most common genetic causes of epilepsy. Epilepsy affects 90% of the patients and appears in the first 2 years of life in the majority of them. Early onset of epilepsy in the first year of life is associated with high risk of cognitive decline and neuropsychiatric problems including autism.
Recently TSC has been recognized as a model of genetic epilepsies. TSC is a genetic condition with known dysregulated mTOR pathway and is increasingly viewed as a model for human epileptogenesis. Moreover, TSC is characterized by a hyperactivation of mTOR (mammalian target of rapamycin) pathway, and mTOR activation was showed to be implicated in epileptogenesis in many animal models and human epilepsies. Recently published studies documented positive effect of preventive or disease modifying treatment of epilepsy in infants with high risk of epilepsy with significantly lower incidence of epilepsy and better cognitive outcome. Further studies on preventive treatment of epilepsy in other genetic epilepsies of early childhood are considered.
This article is part of the special issue entitled ‘New Epilepsy Therapies for the 21st Century – From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy’.
A Review of Investigations for Patients With Tuberous Sclerosis Complex Who Were Referred to the Tuberous Sclerosis Clinic at The Hospital for Sick Children: Identifying Gaps in Surveillance
2020, Pediatric Neurology
As a newly established tuberous sclerosis clinic (TSC) clinic at The Hospital for Sick Children, we reviewed our referrals to determine if children with TSC received appropriate surveillance as advised by the 2012 International Tuberous Sclerosis Complex Consensus Recommendations.
We completed a retrospective review of all patients seen in the TSC clinic from January 2016 to December 2017 to determine if children referred to the clinic had appropriate surveillance as suggested by the Tuberous Sclerosis Complex Consensus Recommendations.
Ninety patients were seen in the TSC clinic. The median age at first visit was 9.9 years, and 47 were males. Seventy-six percent had undergone genetic testing before the initial clinic visit; however, genetic counseling was completed in only 66%. Brain magnetic resonance imaging was completed in 94%, abdominal imaging was completed in 91%, and an echocardiography and electrocardiography in 88% and 83%, respectively. In addition, dermatology and ophthalmology evaluations were completed in 78% and 91%, respectively. Assessment of TSC-associated neuropsychiatric disorders (TAND) was only completed in 4% of the patients.
Systems surveillance was completed in the majority before the first TSC clinic visit. However, TSC-associated neuropsychiatric disorder screening was completed in few cases. This suggests that referring physicians may not be familiar with the neuropsychiatric manifestations of TSC and that there may be underdiagnosed or undertreated illness. Future emphasis should be placed on educating all practitioners to assess and treat tuberous sclerosis complex-associated neuropsychiatric disorder in tuberous sclerosis complex.

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: Conflict of Interest: All authors have no conflicts of interest to disclose.

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Original ArticleEarly Detection of Tuberous Sclerosis Complex: An Opportunity for Improved Neurodevelopmental Outcome

Abstract

Background

Methods

Results

Conclusion

Introduction

Section snippets

Materials and Methods

The patient cohort

Discussion

Conclusions

Lancet

Pediatr Neurol

Eur J Paediatr Neurol

Pediatr Neurol

Lancet Neurol

Epilepsy Behav

Eur J Paediatr Neurol

Eur J Paediatr Neurol

J Pediatr

Eur J Paediatr Neurol

Pediatr Neurol

Eur J Paediatr Neurol

J Pediatr

Pediatr Neurol

Original Article
Early Detection of Tuberous Sclerosis Complex: An Opportunity for Improved Neurodevelopmental Outcome