Early Neurodevelopmental Screening in Tuberous Sclerosis Complex: A Potential Window of Opportunity

Abstract

BACKGROUND Infants born with tuberous sclerosis complex (TSC), a genetic condition resulting from a mutation in TSC1 or TSC2, are at increased risk for intellectual disability and/or autism. Features of epilepsy, neuropathology, genetics as well as timing and type of mechanism-based medications have been proposed as risk factors. Neurodevelopmental outcomes have been reported among these studies; however, few include data about the individuals’ early neurodevelopmental profile, a factor that may contribute significantly to these outcomes. Further, there is no clinical standard for the neurodevelopmental assessment of these infants. The paucity of data regarding the natural history of neurodevelopment in infants with TSC and the lack of a gold standard for neurodevelopmental evaluation presents a significant challenge for clinicians and researchers. METHOD During the first year of life, we tracked the onset of infantile spasms, the type and timing of antiepileptic treatments and the associated response of 2 age-matched infants with TSC. We also employed Capute Scales as a part of a structured neurodevelopmental evaluation to characterize and compare their neurodevelopmental profiles. RESULTS Infant 1 developed infantile spasms as confirmed by hypsarrhythmia at 4 months. Treatment with vigabatrin was initiated within 24 hours with near immediate cessation of seizures and no further seizures to date. Expressive language delay was detected at 12 months and treated with speech/language therapy. Infant 2 developed complex partial seizures at 1 month. Treatment included levetiracetam, oxcarbazepine and the ketogenic diet. Vigabatrin was initiated upon detection of hypsarrhythmia after 4 months. Intractable epilepsy persists to date. Global developmental delay was evident by 8 months and treated with physical, occupational and speech/language therapy. CONCLUSION Many risk factors have been associated with intellectual disability and/or autism in individuals with TSC; however, few data are available regarding practical clinical tools for early identification. In our case series, inclusion of the Capute Scales as a part of routine medical care led to the identification of developmental delays in the first 12 months of life and selection of targeted neurodevelopmental interventions. Development of a risk-based assessment using this approach will be the focus of future studies as it may provide a potential window of opportunity for both research and clinical purposes. In research, it may serve as an objective outcome measure. Clinically, this type of assessment has potential for informing clinical treatment decisions and serving as a prognostic indicator of long term cognitive and psychiatric outcomes.

Roles of mTOR Signaling in Brain Development

“…Besides of these neurological disorders, brain tumors (gliomas, ependymomas and medulloblastomas) also have a close relationship with the abnormalities of brain regional NSC/progenitor cell populations during development in children [ 13 39 40 ]. In general, both developmental disorders and pediatric brain tumors are diagnosed in early developmental stages and childhood [ 41 42 43 44 ] raising a possibility that the NSC/progenitor cell populations rather than differentiated brain cells could have an implication in disease phenotypes. Although the causing factors of the diseases are not fully uncovered, there are several known genetic factors which are commonly found in the patients with learning disability, autism, epilepsy and pediatric brain tumors.…”

Rapamycin therapy for neonatal tuberous sclerosis complex with cardiac rhabdomyomas: A case report and review

“…The current study describes a case of multiple cardiac rhabdomyomas confirmed by routine echocardiogram screening in week 31 of pregnancy. The infant experienced seizures in the neonatal period (2 weeks of age), which is earlier than previously reported cases in which the onset was 1 month of age ( 14 ). Genetic mutation analysis revealed a novel mutation in TSC2.…”

Perfil neuropsiquiátrico de crianças, adolescentes e jovens adultos com complexo de esclerose tuberosa

“…Ressalta-se a importância de investigar pacientes com sinais potenciais de CET com o objetivo de realizar diagnóstico precoce. Tem-se, inclusive, discutido a importância da intervenção precoce como forma de melhorar o prognóstico 29,30 .…”