Prediction of Neurodevelopment in Infants With Tuberous Sclerosis Complex Using Early EEG Characteristics

Ridder, Jessie De; Lavanga, Mario; Verhelle, Birgit; Vervisch, Jan; Lemmens, Katrien; Kotulska, Katarzyna; Moavero, Romina; Curatolo, Paolo; Weschke, Bernhard; Riney, Kate; Feucht, Martha; Kršek, Pavel; Nabbout, Rima; Jansen, Anna; Wojdan, Konrad; Domańska-Pakieła, Dorota; Kaczorowska-Frontczak, Magdalena; Hertzberg, Christoph; Ferrier, Cyrille H.; Samueli, Sharon; Beňová, Barbora; Aronica, Eleonora; Kwiatkowski, David J.; Jansen, Floor E.; Jóźwiak, Sergiusz; Huffel, Sabine Van; Lagae, Lieven

doi:10.3389/fneur.2020.582891

Cited by 25 publications

(28 citation statements)

References 47 publications

(72 reference statements)

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“…Thus, we speculate that the presence of inhibition-dominated networks in TSC may relate to neurodevelopmental delay and cortical dysfunction (e.g., due to cortical tubers and aberrant surrounding tissue). Indeed, signs of cortical dysfunction, dysmaturity, and epilepsy [e.g., as reflected by slowing of activity ( Krsek et al, 2010 ; Terney et al, 2010 ; Tao et al, 2011 ; Stoner et al, 2014 ; Britton et al, 2016 )] have been described in EEG recordings in TSC ( De Ridder et al, 2020 ). Importantly, we have previously associated EEG abnormalities to low f E/I in ASD ( Bruining et al, 2020 ) and in children with STXBP1 syndrome, which is another genetic disorder with a high prevalence of epilepsy ( Houtman et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Bumetanide Effects on Resting-State EEG in Tuberous Sclerosis Complex in Relation to Clinical Outcome: An Open-Label Study

et al. 2022

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Neuronal excitation-inhibition (E/I) imbalances are considered an important pathophysiological mechanism in neurodevelopmental disorders. Preclinical studies on tuberous sclerosis complex (TSC), suggest that altered chloride homeostasis may impair GABAergic inhibition and thereby E/I-balance regulation. Correction of chloride homeostasis may thus constitute a treatment target to alleviate behavioral symptoms. Recently, we showed that bumetanide—a chloride-regulating agent—improved behavioral symptoms in the open-label study Bumetanide to Ameliorate Tuberous Sclerosis Complex Hyperexcitable Behaviors trial (BATSCH trial; Eudra-CT: 2016-002408-13). Here, we present resting-state EEG as secondary analysis of BATSCH to investigate associations between EEG measures sensitive to network-level changes in E/I balance and clinical response to bumetanide. EEGs of 10 participants with TSC (aged 8–21 years) were available. Spectral power, long-range temporal correlations (LRTC), and functional E/I ratio (fE/I) in the alpha-frequency band were compared before and after 91 days of treatment. Pre-treatment measures were compared against 29 typically developing children (TDC). EEG measures were correlated with the Aberrant Behavioral Checklist-Irritability subscale (ABC-I), the Social Responsiveness Scale-2 (SRS-2), and the Repetitive Behavior Scale-Revised (RBS-R). At baseline, TSC showed lower alpha-band absolute power and fE/I than TDC. Absolute power increased through bumetanide treatment, which showed a moderate, albeit non-significant, correlation with improvement in RBS-R. Interestingly, correlations between baseline EEG measures and clinical outcomes suggest that most responsiveness might be expected in children with network characteristics around the E/I balance point. In sum, E/I imbalances pointing toward an inhibition-dominated network are present in TSC. We established neurophysiological effects of bumetanide although with an inconclusive relationship with clinical improvement. Nonetheless, our results further indicate that baseline network characteristics might influence treatment response. These findings highlight the possible utility of E/I-sensitive EEG measures to accompany new treatment interventions for TSC.Clinical Trial RegistrationEU Clinical Trial Register, EudraCT 2016-002408-13 (www.clinicaltrialsregister.eu/ctr-search/trial/2016-002408-13/NL). Registered 25 July 2016.

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Section: Discussionmentioning

confidence: 99%

Bumetanide Effects on Resting-State EEG in Tuberous Sclerosis Complex in Relation to Clinical Outcome: An Open-Label Study

et al. 2022

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“…in the latent period), has been determined to be a reliable prognostic biomarker for later epilepsy and indeed neurodevelopmental comorbidities ( Figure 1 ). 37 – 39 Crucially, this discovery has been instrumental in the design of clinical trials focussed on epilepsy prevention, including the EPISTOP and PREVeNT trials that are described below. In addition, in line with current European guidelines for infants and children to receive regular EEG monitoring, 17 a recent study showed that conducting at least one EEG study in TSC patients before epilepsy onset and continuing with regular EEG monitoring is now the standard of care in many centres, while it is becoming more common for clinicians to prescribe ASDs prophylactically when epileptiform discharges occur on EEG before the emergence of clinical seizures.…”

Section: Tsc-associated Epilepsy and Neuropsychiatric Disordersmentioning

confidence: 99%

Review of the treatment options for epilepsy in tuberous sclerosis complex: towards precision medicine

Schubert‐Bast

Strzelczyk

2021

Ther Adv Neurol Disord

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Tuberous sclerosis complex (TSC) is a rare genetic disorder caused by mutations in the TSC1 or TSC2 genes, which encode proteins that antagonise the mammalian isoform of the target of rapamycin complex 1 (mTORC1) – a key mediator of cell growth and metabolism. TSC is characterised by the development of benign tumours in multiple organs, together with neurological manifestations including epilepsy and TSC-associated neuropsychiatric disorders (TAND). Epilepsy occurs frequently and is associated with significant morbidity and mortality; however, the management is challenging due to the intractable nature of the seizures. Preventative epilepsy treatment is a key aim, especially as patients with epilepsy may be at a higher risk of developing severe cognitive and behavioural impairment. Vigabatrin given preventatively reduces the risk and severity of epilepsy although the benefits for TAND are inconclusive. These promising results could pave the way for evaluating other treatments in a preventative capacity, especially those that may address the underlying pathophysiology of TSC, including everolimus, cannabidiol and the ketogenic diet (KD). Everolimus is an mTOR inhibitor approved for the adjunctive treatment of refractory TSC-associated seizures that has demonstrated significant reductions in seizure frequency compared with placebo, improvements that were sustained after 2 years of treatment. Highly purified cannabidiol, recently approved in the US as Epidiolex® for TSC-associated seizures in patients ⩾1 years of age, and the KD, may also participate in the regulation of the mTOR pathway. This review focusses on the pivotal clinical evidence surrounding these potential targeted therapies that may form the foundation of precision medicine for TSC-associated epilepsy, as well as other current treatments including anti-seizure drugs, vagus nerve stimulation and surgery. New future therapies are also discussed, together with the potential for preventative treatment with targeted therapies. Due to advances in understanding the molecular genetics and pathophysiology, TSC represents a prototypic clinical syndrome for studying epileptogenesis and the impact of precision medicine.

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“…Five studies did not report significant findings after covariate adjustment. [19][20][21][22][23] Significant results are summarized in Figure S2a (online supporting information).…”

Section: Cognitive Outcomementioning

confidence: 99%

Neonatal quantitative electroencephalography and long‐term outcomes: a systematic review

Westende

Geraedts

Ramesdonk

et al. 2021

Develop Med Child Neuro

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To evaluate quantitative electroencephalogram (EEG) measures as predictors of longterm neurodevelopmental outcome in infants with a postconceptional age below 46 weeks, including typically developing infants born at term, infants with heterogeneous underlying pathologies, and infants born preterm.METHOD A comprehensive search was performed using PubMed, Embase, and Web of Science from study inception up to 8th January 2021. Studies that examined associations between neonatal quantitative EEG measures, based on conventional and amplitudeintegrated EEG, and standardized neurodevelopmental outcomes at 2 years of age or older were reviewed. Significant associations between neonatal quantitative EEG and long-term outcome measures were grouped into one or more of the following categories: cognitive outcome; motor outcome; composite scores; and other standardized outcome assessments. RESULTSTwenty-four out of 1740 studies were included. Multiple studies showed that conventional EEG-based absolute power in the delta, theta, alpha, and beta frequency bands and conventional and amplitude-integrated EEG-related amplitudes were positively associated with favourable long-term outcome across several domains, including cognition and motor performance. Furthermore, a lower presence of discontinuous background pattern was also associated with favourable outcomes. However, interpretation of the results is limited by heterogeneity in study design and populations.

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Prediction of Neurodevelopment in Infants With Tuberous Sclerosis Complex Using Early EEG Characteristics

Cited by 25 publications

References 47 publications

Bumetanide Effects on Resting-State EEG in Tuberous Sclerosis Complex in Relation to Clinical Outcome: An Open-Label Study

Bumetanide Effects on Resting-State EEG in Tuberous Sclerosis Complex in Relation to Clinical Outcome: An Open-Label Study

Review of the treatment options for epilepsy in tuberous sclerosis complex: towards precision medicine

Neonatal quantitative electroencephalography and long‐term outcomes: a systematic review

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