Presentation and Diagnosis of Tuberous Sclerosis Complex in Infants

Davis, Peter E.; Filip-Dhima, Rajna; Sideridis, Georgios D.; Peters, Jurriaan M.; Au, Kit Sing; Northrup, Hope; Bebin, E. Martina; Wu, Joyce; Krueger, Darcy A.; Şahin, Mustafa

doi:10.1542/peds.2016-4040

Cited by 101 publications

(93 citation statements)

References 44 publications

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“…Age of onset ranged from day of birth to 22 months, with a median age of onset at 4 months (interquartile range = 4.56 months). Of those with seizures, 62.5% (20/32) had infantile spasms, a rate that is similar to previously published estimates [Davis et al, ]. Information regarding the presence of cortical tubers was present for 80% of the TSC sample ( n = 28).…”

Section: Methodssupporting

confidence: 86%

Early patterns of functional brain development associated with autism spectrum disorder in tuberous sclerosis complex

Dickinson¹,

Varcin

Şahin

et al. 2019

Autism Research

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Tuberous sclerosis complex (TSC) is a rare genetic disorder that confers a high risk for autism spectrum disorders (ASD), with behavioral predictors of ASD emerging early in life. Deviations in structural and functional neural connectivity are highly implicated in both TSC and ASD. For the first time, we explore whether electroencephalographic (EEG) measures of neural network function precede or predict the emergence of ASD in TSC. We determine whether altered brain function (a) is present in infancy in TSC, (b) differentiates infants with TSC based on ASD diagnostic status, and (c) is associated with later cognitive function. We studied 35 infants with TSC (N = 35), and a group of typically developing infants (N = 20) at 12 and 24 months of age. Infants with TSC were later subdivided into ASD and non-ASD groups based on clinical evaluation. We measured features of spontaneous alpha oscillations (6–12 Hz) that are closely associated with neural network development: alpha power, alpha phase coherence (APC), and peak alpha frequency (PAF). Infants with TSC demonstrated reduced interhemispheric APC compared to controls at 12 months of age, and these differences were found to be most pronounced at 24 months in the infants who later developed ASD. Across all infants, PAF at 24 months was associated with verbal and nonverbal cognition at 36 months. Associations between early network function and later neurodevelopmental and cognitive outcomes highlight the potential utility of early scalable EEG markers to identify infants with TSC requiring additional targeted intervention initiated very early in life.

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Section: Methodssupporting

confidence: 86%

Early patterns of functional brain development associated with autism spectrum disorder in tuberous sclerosis complex

Dickinson¹,

Varcin

Şahin

et al. 2019

Autism Research

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“…4,[11][12][13] We recognize that this study did not incorporate the neuroimaging findings for this cohort, which also may be a contributing factor to the cognitive decline in some of the participants. Our data suggest that there is a specific association between severity of epilepsy and comorbid conditions, including developmental delay, reported previously in retrospective and prospective series.…”

Section: Discussionmentioning

confidence: 99%

Scalp EEG spikes predict impending epilepsy in TSC infants: A longitudinal observational study

Goyal

Peters

et al. 2019

Epilepsia

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Objective:To determine if routine electroencephalography (EEG) in seizure-naive infants with tuberous sclerosis complex (TSC) can predict epilepsy and subsequent neurocognitive outcomes. Methods: Forty infants 7 months of age or younger and meeting the genetic or clinical diagnostic criteria for tuberous sclerosis were enrolled. Exclusion criteria included prior history of seizures or treatment with antiseizure medications. At each visit, seizure history and 1-hour awake and asleep video-EEG, standardized across all sites, were obtained until 2 years of age. Developmental assessments (Mullen and Vineland-II) were completed at 6, 12, and 24 months of age. Results: Of 40 infants enrolled (mean age of 82.4 days), 32 completed the study.Two were lost to follow-up and six were treated with antiepileptic drugs (AEDs) due to electrographic seizures and/or interictal epileptiform discharges (IEDs) on their EEG studies prior to the onset of clinical seizures. Seventeen of the 32 remaining children developed epilepsy at a mean age of 7.5 months (standard deviation[SD] = 4.4). Generalized/focal slowing, hypsarrhythmia, and generalized/focal attenuation were not predictive for the development of clinical seizures. Presence of IEDs had a 77.3% positive predictive value and absence a 70% negative predictive value for developing seizures by 2 years of age. IEDs preceded clinical seizure onset by 3.6 months (mean). Developmental testing showed significant decline, only in infants with ongoing seizures, but not infants who never developed seizures or whose seizures came under control. Significance: IEDs identify impending epilepsy in the majority (77%) of seizure-naive infants with TSC. The use of a 1-hour awake and asleep EEG can be used as a biomarker for ongoing epileptogenesis in most, but not all, infants with TSC. Persistent seizures, but not history of interictal epileptiform activity or history of well-controlled seizures, correlated with low scores on the Vineland and Mullen tests at 2 years of age.

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“…The studies collected clinical and genetic data, neuropsychological testing, serial magnetic resonance imaging (MRI) studies, and serial EEG studies, through age 3 years. Complete study protocol and design were reported previously . The study protocols were approved by the institutional review board at each site with direction from the leading regulatory core at Cincinnati Children's Hospital Medical Center.…”

Section: Methodsmentioning

confidence: 99%

Increased electroencephalography connectivity precedes epileptic spasm onset in infants with tuberous sclerosis complex

et al. 2019

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Objective To identify whether abnormal electroencephalography (EEG) connectivity is present before the onset of epileptic spasms (ES) in infants with tuberous sclerosis complex (TSC). Methods Scalp EEG recordings were collected prospectively in infants diagnosed with TSC in the first year of life. This study compared the earliest recorded EEG from infants prior to ES onset (n = 16) and from infants who did not develop ES (n = 28). Five minutes of stage II or quiet sleep was clipped and filtered into canonical EEG frequency bands. Mutual information values between each pair of EEG channels were compared directly and used as a weighted graph to calculate graph measures of global efficiency, characteristic path length, average clustering coefficient, and modularity. Results At the group level, infants who later developed ES had increased EEG connectivity in sleep. They had higher mutual information values between most EEG channels in all frequency bands adjusted for age. Infants who later developed ES had higher global efficiency and average clustering coefficients, shorter characteristic path lengths, and lower modularity across most frequency bands adjusted for age. This suggests that infants who went on to develop ES had increased local and long‐range EEG connectivity with less segregation of graph regions into distinct modules. Significance This study suggests that increased neural connectivity precedes clinical ES onset in a cohort of infants with TSC. Overconnectivity may reflect progressive pathologic network synchronization culminating in generalized ES. Further research is needed before scalp EEG connectivity measures can be used as a potential biomarker of ES risk and treatment response in pre‐symptomatic infants with TSC.

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Presentation and Diagnosis of Tuberous Sclerosis Complex in Infants

Abstract: Infants with TSC can often be identified early, before the onset of neurologic sequelae, enabling earlier diagnosis, surveillance, and possibly disease-modifying treatment.

Cited by 101 publications

References 44 publications

Early patterns of functional brain development associated with autism spectrum disorder in tuberous sclerosis complex

Early patterns of functional brain development associated with autism spectrum disorder in tuberous sclerosis complex

Scalp EEG spikes predict impending epilepsy in TSC infants: A longitudinal observational study

Increased electroencephalography connectivity precedes epileptic spasm onset in infants with tuberous sclerosis complex

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