Clinical Electroencephalographic Biomarker for Impending Epilepsy in Asymptomatic Tuberous Sclerosis Complex Infants

Wu, Joyce; Peters, Jurriaan M.; Goyal, Monisha; Krueger, Darcy A.; Şahin, Mustafa; Northrup, Hope; Au, Kit Sing; Cutter, Gary; Bebin, E. Martina

doi:10.1016/j.pediatrneurol.2015.09.013

Cited by 100 publications

(99 citation statements)

References 19 publications

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“…Serial EEG follow-up of young infants with TSC is currently recommended by European (Curatolo et al, 2012), American (Wu et al, 2016), and Australian experts (Chung et al, 2017). Serial EEG follow-up of young infants with TSC is currently recommended by European (Curatolo et al, 2012), American (Wu et al, 2016), and Australian experts (Chung et al, 2017).…”

Section: Preseizure (Preventive) Treatment Of Epilepsymentioning

confidence: 99%

Current concepts on epilepsy management in tuberous sclerosis complex

Canevini

Curatolo

Briola

et al. 2018

American J of Med Genetics Pt C

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Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disease affecting approximately 1 in 6,000 people, 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 12 months of life is associated with high risk of cognitive decline and neuropsychiatric problems including autism. Prenatal or early infantile diagnosis of TSC, before the onset of epilepsy, provides a unique opportunity to monitor EEG before the onset of clinical seizures, thus enabling early intervention in the process of epileptogenesis. In this review, we discuss the current status of knowledge on epileptogenesis in TSC, and present recommendations of American and European experts in the field of epilepsy.

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Section: Preseizure (Preventive) Treatment Of Epilepsymentioning

confidence: 99%

Current concepts on epilepsy management in tuberous sclerosis complex

Canevini

Curatolo

Briola

et al. 2018

American J of Med Genetics Pt C

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“…1 Infantile spasms, frequently coexisting with partial seizures, are also common during infancy. 1,23 Due to the unclear safety profile of everolimus treatment in infants with TSC, individuals under the age of 2 years were excluded from our study. Hence, whether or not everolimus treatment at younger ages would have similar benefit, when infantile spasms are most prevalent in TSC, still needs to be determined.…”

Section: Classification Of Evidence This Interventional Study Providesmentioning

confidence: 99%

Long-term treatment of epilepsy with everolimus in tuberous sclerosis

et al. 2016

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Objective: To evaluate the long-term benefit and safety of everolimus for the treatment of medically refractory epilepsy in patients with tuberous sclerosis complex (TSC).Methods: Everolimus was titrated over 4 weeks and continued an additional 8 weeks in a prospective, open-label, phase I/II clinical trial design. Participants demonstrating initial benefit continued treatment until study completion (48 months). The primary endpoint was percentage of patients with a $50% reduction in seizure frequency compared to baseline. Secondary endpoints assessed absolute seizure frequency, adverse events (AEs), behavior, and quality of life.Results: Of the 20 participants who completed the initial study phase, 18 continued extended treatment. Fourteen of 18 (78%) participants completed the study, all but 1 of whom reported $50% reduction in seizure frequency at 48 months. All participants reported at least 1 AE, the vast majority (94%) of which were graded mild or moderate severity. Improvements in behavior and quality of life were also observed, but failed to achieve statistical significance at 48 months.Conclusions: Improved seizure control was maintained for 4 years in the majority of patients with TSC with medically refractory epilepsy treated with everolimus. Long-term treatment with everolimus is safe and well-tolerated in this population. Everolimus may be a therapeutic option for refractory epilepsy in TSC. More than 80% of individuals with tuberous sclerosis complex (TSC) develop epilepsy, usually within the first year of life.1 Epilepsy in an estimated third of these individuals is refractory to conventional anticonvulsant medications, 2 heightening the urgency for development of effective treatments. TSC1 and TSC2, the causative genes for TSC, regulate the protein kinase mammalian target of rapamycin complex 1 (mTORC1). Pharmacologic inhibitors of mTORC1 are now approved to treat multiple clinical aspects of TSC, including subependymal giant cell astrocytomas (SEGA), 3,4 renal angiomyolipomas, 5 and pulmonary lymphangioleiomyomatosis. 6 mTORC1 inhibitors also have been reported to be effective for treatment of topical angiofibromas and cardiac rhabdomyomas in TSC. 7,8 Preclinical studies in TSC mouse models demonstrate that mTORC1 inhibitors effectively prevent seizures.9,10 TSC patients in early (open-label) clinical trials to treat SEGA with everolimus reported reduced frequency of daily seizures and increased rates of seizure freedom, 4,[11][12][13] but seizure benefit could not be demonstrated in more recent (placebo-controlled, randomized) From the Departments of Pediatrics and Neurology

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“…Good evidence supports the use of EEG screening to identify infants with TSC with incipient epilepsy(Wu et al, 2016). Of note, when mTOR inhibitors are used with the ketogenic diet, ketone production is often enhanced.…”

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confidence: 99%

mTOR inhibitor therapy as a disease modifying therapy for tuberous sclerosis complex

Franz

Krueger

2018

American J of Med Genetics Pt C

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Between 1993 and 2003, through experiments involving Drosophila sp., cancer biologists identified the protein kinase known as the mammalian target of rapamycin, its pathway, and its relationship to the genes responsible for tuberous sclerosis. Thereafter, clinical research has resulted in regulatory approval of mTOR inhibitors for four distinct manifestations of the disease: giant cell astrocytoma, angiomyolipoma, lymphangioleiomyomatosis, and epilepsy. These developments are summarized and the practical use of mTOR inhibitors to improve the lives of patients with tuberous sclerosis reviewed.

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Clinical Electroencephalographic Biomarker for Impending Epilepsy in Asymptomatic Tuberous Sclerosis Complex Infants

Cited by 100 publications

References 19 publications

Current concepts on epilepsy management in tuberous sclerosis complex

Current concepts on epilepsy management in tuberous sclerosis complex

Long-term treatment of epilepsy with everolimus in tuberous sclerosis

mTOR inhibitor therapy as a disease modifying therapy for tuberous sclerosis complex

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