Seizures in Tuberous Sclerosis: Mechanism-Based Interventions EXIST.
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ABSTRACT:
SUBMITTER: Koubeissi M
PROVIDER: S-EPMC5967581 | biostudies-literature | 2018 Jan-Feb
REPOSITORIES: biostudies-literature
Publications
Seizures in Tuberous Sclerosis: Mechanism-Based Interventions <i>EXIST</i>.
Epilepsy currents 20180101 1
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Project description:BackgroundTuberous sclerosis complex (TSC) is a genetic multisystem disorder that affects the brain in almost every patient. It is caused by a mutation in the TSC1 or TSC2 genes, which regulate mammalian target of rapamycin (mTOR), a key player in control of cellular growth and protein synthesis. The most frequent neurological symptoms are seizures, which occur in up to 90% of patients and often are intractable, followed by autism spectrum disorders, intellectual disability, attention deficit-hyperactivity disorder, and sleep problems. Conventional treatment has frequently proven insufficient for neurological and behavioral symptoms, particularly seizure control. This review focuses on the role of TSC/mTOR in neuronal development and network formation and recent mechanism-based treatment approaches.MethodsWe performed a literature review to identify ongoing therapeutic challenges and novel strategies.ResultsTo achieve a better quality of life for many patients, current therapy approaches are directed at restoring dysregulated mTOR signaling. Studies in animals have provided insight into aberrant neuronal network formation caused by constitutive activation of the mTOR pathway, and initial studies in TSC patients using magnetic resonance diffusion tensor imaging and electroencephalogram support a model of impaired neuronal connectivity in TSC. Rapamycin, an mTOR inhibitor, has been used successfully in Tsc-deficient mice to prevent and treat seizures and behavioral abnormalities. There is recent evidence in humans of improved seizure control with mTOR inhibitors.ConclusionsCurrent research provides insight into aberrant neuronal connectivity in TSC and the role of mTOR inhibitors as a promising therapeutic approach.
| S-EPMC3959246 | biostudies-literature
Project description:ObjectiveThe present analysis examined the exposure-response relationship by means of the predose everolimus concentration (Cmin ) and the seizure response in patients with tuberous sclerosis complex-associated seizures in the EXIST-3 study. Recommendations have been made for the target Cmin range of everolimus for therapeutic drug monitoring (TDM) and the doses necessary to achieve this target Cmin .MethodsA model-based approach was used to predict patients' daily Cmin . Time-normalized Cmin (TN-Cmin ) was calculated as the average predicted Cmin in a time interval. TN-Cmin was used to link exposure to efficacy and safety end points via model-based approaches. A conditional logistic regression stratified by age subgroup was used to estimate the probability of response in relation to exposure. A multiplicative linear regression model was used to estimate the exposure-response relationship for seizure frequency (SF). An extended Cox regression model was used to link exposure to the time to first adverse event.ResultsThere was a strong, consistent, and highly significant relationship between everolimus exposure and efficacy, measured by TN-Cmin and SF, regardless of patient's age and concomitant use of cytochrome P450 3A4 (CYP3A4) inhibitors/inducers. Results of an extended Cox regression analyses indicated that twofold increases in TN-Cmin were not associated with statistically significant increases in the risk of stomatitis or infections.SignificanceThe recommended TDM is to target everolimus Cmin within a range of 5-7 ng/mL initially and 5-15 ng/mL in the event of an inadequate clinical response, and safety is consistent with previous reports. Starting doses depend on age and the concomitant use of CYP3A4/P-glycoprotein inducers/inhibitors.
| S-EPMC6033043 | biostudies-literature
Project description:ObjectiveEpilepsy is commonly seen in Tuberous Sclerosis Complex (TSC). The relationship between seizures and developmental outcomes has been reported, but few studies have examined this relationship in a prospective, longitudinal manner. The objective of the study was to evaluate the relationship between seizures and early development in TSC.MethodsAnalysis of 130 patients ages 0-36months with TSC participating in the TSC Autism Center of Excellence Network, a large multicenter, prospective observational study evaluating biomarkers predictive of autism spectrum disorder (ASD), was performed. Infants were evaluated longitudinally with standardized evaluations, including cognitive, adaptive, and autism-specific measures. Seizure history was collected continuously throughout, including seizure type and frequency.ResultsData were analyzed at 6, 12, 18, and 24months of age. Patients without a history of seizures performed better on all developmental assessments at all time points compared to patients with a history of seizures and exhibited normal development at 24months. Patients with a history of seizures not only performed worse, but developmental progress lagged behind the group without seizures. All patients with a history of infantile spasms performed worse on all developmental assessments at 12, 18, and 24months. Higher seizure frequency correlated with poorer outcomes on developmental testing at all time points, but particularly at 12months and beyond. Patients with higher seizure frequency during infancy continued to perform worse developmentally through 24months. A logistic model looking at the individual impact of infantile spasms, seizure frequency, and age of seizure onset as predictors of developmental delay revealed that age of seizure onset was the most important factor in determining developmental outcome.ConclusionsResults of this study further define the relationship between seizures and developmental outcomes in young children with TSC. Early seizure onset in infants with TSC negatively impacts very early neurodevelopment, which persists through 24months of age.
| S-EPMC5497719 | biostudies-literature
Project description:BackgroundA reduction in renal angiomyolipoma volume observed with everolimus (EVE) treatment in patients with tuberous sclerosis complex (TSC) has been postulated to translate to clinical benefit by reducing the risk of renal hemorrhage and chronic renal failure.MethodsThe long-term effects of EVE on renal function (∼4 years of treatment) were examined in patients treated with EVE in the Phase 3 EXIST-1 and EXIST-2 studies. Patients in EXIST-1 had TSC and subependymal giant cell astrocytoma (SEGA), and patients in EXIST-2 had renal angiomyolipoma and a definite diagnosis of TSC or sporadic lymphangioleiomyomatosis. EVE was administered at 4.5 mg/m2/day, with adjustment to achieve target trough levels of 5-15 ng/mL in EXIST-1 and at 10 mg/day in EXIST-2. Estimated glomerular filtration rate (eGFR) and creatinine levels were assessed at baseline, at Weeks 2, 4, 6, 8, 12 and 18, then every 3 months thereafter. Proteinuria was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.ResultsA total of 111 patients from EXIST-1 and 112 patients from EXIST-2 were included in this analysis. Respective mean ages at EVE initiation were 10.5 [standard deviation (SD) 6.45] and 33.2 (SD 10.29) years, and 3.6% and 37.5% of patients had undergone prior renal intervention. Mean baseline eGFR was 115 and 88 mL/min/1.73 m2 in EXIST-1 and EXIST-2, respectively. Overall, mean eGFR remained stable over time in both studies, with an decline in renal function mostly confined to some patients with severely compromised renal function before treatment. Patients with prior renal intervention exhibited low eGFR values throughout the study. The incidence of proteinuria increased after initiating treatment with EVE and was mostly Grade 1/2 in severity, with Grade 3 proteinuria reported in only two patients. Measurements of proteinuria were limited by the use of urine dipstick tests.ConclusionsThe use of EVE does not appear to be nephrotoxic in patients with SEGA or renal angiomyolipoma associated with TSC and may preserve renal function in most patients.ClinicalTrials.gov identifiers NCT00789828 and NCT00790400.
| S-EPMC6545468 | biostudies-literature
Project description:Seizures are clinically significant manifestations associated with 79%-90% of patients with tuberous sclerosis complex. Often occurring within the first year of life in the form of infantile spasms, seizures interfere with neuropsychiatric, social, and cognitive development and carry significant individual and societal consequences. Prompt identification and treatment of seizures is an important focus in the overall management of tuberous sclerosis complex patients. Medical management, either after seizure onset or prophylactically in infants with electroencephalographic abnormalities, is considered first-line therapy. Vigabatrin and adrenocorticotropic hormone have emerged over the past few decades as mainstay pharmacologic modalities. Furthermore, emerging research on mammalian target of rapamycin inhibitors demonstrated promise for the management of seizures and subependymal giant cell astrocytoma. For appropriate surgical candidates with an epileptogenic zone associated with one or more glioneuronal hamartomas, ideally in noneloquent cortex, resective surgery can be considered, which provides a cure in 56% of patients. For medically refractory patients who do not meet criteria for curative surgery, palliative surgical approaches focused on reducing seizure burden, in the form of corpus callosotomy and vagus nerve stimulation, are alternative management options. Lastly, the ketogenic diet, a reemerging therapy based on the anticonvulsant effects of ketone bodies, can be utilized independently or in conjunction with other treatment modalities for the management of difficult-to-treat seizures.
| S-EPMC4211915 | biostudies-literature
Project description:ObjectivesWe examined the long-term effects of everolimus in patients with renal angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis.MethodsFollowing favorable results from the double-blind core phase of EXIST-2 (NCT00790400), patients were allowed to receive open-label everolimus (extension phase). Patients initially randomly assigned to everolimus continued on the same dose; those who were receiving placebo crossed over to everolimus 10 mg/day. Dose modifications were based on tolerability. The primary end point was angiomyolipoma response rate, defined as a ≥50% reduction from baseline in the sum volume of target renal angiomyolipomas in the absence of new target angiomyolipomas, kidney volume increase of >20% from nadir, and angiomyolipoma-related bleeding grade ≥2. The key secondary end point was safety.ResultsOf the 112 patients who received ≥1 dose of everolimus, 58% (95% CI, 48.3% to 67.3%) achieved angiomyolipoma response. Almost all patients (97%) experienced reduction in renal lesion volumes at some point during the study period. Median duration of everolimus exposure was 46.9 months. Sixteen (14.3%) patients experienced angiomyolipoma progression at some point in the study. No angiomyolipoma-related bleeding or nephrectomies were reported. One patient on everolimus underwent embolization for worsening right flank pain. Subependymal giant cell astrocytoma lesion response was achieved in 48% of patients and skin lesion response in 68% of patients. The most common adverse events suspected to be treatment-related were stomatitis (42%), hypercholesterolemia (30.4%), acne (25.9%), aphthous stomatitis and nasopharyngitis (each 21.4%). Ten (8.9%) patients withdrew because of an adverse event. Renal function remained stable, and the frequency of emergent adverse events generally decreased over time.ConclusionsEverolimus treatment remained safe and effective over approximately 4 years. The overall risk/benefit assessment supports the use of everolimus as a viable treatment option for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis.Trial registrationClinicalTrials.gov NCT00790400.
| S-EPMC5549893 | biostudies-literature
Project description:BackgroundEverolimus, a mammalian target of rapamycin (mTOR) inhibitor, has demonstrated efficacy in treating subependymal giant cell astrocytomas (SEGAs) and other manifestations of tuberous sclerosis complex (TSC). However, long-term use of mTOR inhibitors might be necessary. This analysis explored long-term efficacy and safety of everolimus from the conclusion of the EXIST-1 study (NCT00789828).Methods and findingsEXIST-1 was an international, prospective, double-blind, placebo-controlled phase 3 trial examining everolimus in patients with new or growing TSC-related SEGA. After a double-blind core phase, all remaining patients could receive everolimus in a long-term, open-label extension. Everolimus was initiated at a dose (4.5 mg/m2/day) titrated to a target blood trough of 5-15 ng/mL. SEGA response rate (primary end point) was defined as the proportion of patients achieving confirmed ≥50% reduction in the sum volume of target SEGA lesions from baseline in the absence of worsening nontarget SEGA lesions, new target SEGA lesions, and new or worsening hydrocephalus. Of 111 patients (median age, 9.5 years) who received ≥1 dose of everolimus (median duration, 47.1 months), 57.7% (95% confidence interval [CI], 47.9-67.0) achieved SEGA response. Of 41 patients with target renal angiomyolipomas at baseline, 30 (73.2%) achieved renal angiomyolipoma response. In 105 patients with ≥1 skin lesion at baseline, skin lesion response rate was 58.1%. Incidence of adverse events (AEs) was comparable with that of previous reports, and occurrence of emergent AEs generally decreased over time. The most common AEs (≥30% incidence) suspected to be treatment-related were stomatitis (43.2%) and mouth ulceration (32.4%).ConclusionsEverolimus use led to sustained reduction in tumor volume, and new responses were observed for SEGA and renal angiomyolipoma from the blinded core phase of the study. These findings support the hypothesis that everolimus can safely reverse multisystem manifestations of TSC in a significant proportion of patients.Trial registrationClinicalTrials.gov NCT00789828.
| S-EPMC4924870 | biostudies-literature
Project description:Astrocyte dysfunction may contribute to epileptogenesis and other neurological deficits in Tuberous Sclerosis Complex (TSC). In particular, decreased expression and function of astrocyte glutamate transporters have been implicated in causing elevated extracellular glutamate levels, neuronal death, and epilepsy in a mouse model of TSC (Tsc1(GFAP)CKO mice), involving inactivation of the Tsc1 gene primarily in astrocytes. Here, we tested whether pharmacological induction of astrocyte glutamate transporter expression can prevent the neurological phenotype of Tsc1(GFAP)CKO mice. Early treatment with ceftriaxone prior to the onset of epilepsy increased expression of astrocyte glutamate transporters, decreased extracellular glutamate levels, neuronal death, and seizure frequency, and improved survival in Tsc1(GFAP)CKO mice. In contrast, late treatment with ceftriaxone after onset of epilepsy increased glutamate transporter expression, but had no effect on seizures. These results indicate that astrocyte glutamate transporters contribute to epileptogenesis in Tsc1(GFAP)CKO mice and suggest novel therapeutic strategies for epilepsy in TSC directed at astrocytes.
| S-EPMC2823985 | biostudies-literature
Project description:BackgroundTuberous Sclerosis Complex (TSC) is a rare genetic condition caused by mutation to TSC1 or TSC2 genes, with a population prevalence of 1/7000 births. TSC manifests behaviorally with features of autism, epilepsy, and intellectual disability. Resting state electroencephalography (EEG) offers a window into neural oscillatory activity and may serve as an intermediate biomarker between gene expression and behavioral manifestations. Such a biomarker could be useful in clinical trials as an endpoint or predictor of treatment response. However, seizures and antiepileptic medications also affect resting neural oscillatory activity and could undermine the utility of resting state EEG features as biomarkers in neurodevelopmental disorders such as TSC.MethodsThis paper compares resting state EEG features in a cross-sectional cohort of young children with TSC (n = 49, ages 12-37 months) to 49 age- and sex-matched typically developing controls. Within children with TSC, associations were examined between resting state EEG features, seizure severity composite score, and use of GABA agonists.ResultsCompared to matched typically developing children, children with TSC showed significantly greater beta power in permutation cluster analyses. Children with TSC also showed significantly greater aperiodic offset (reflecting nonoscillatory neuronal firing) after power spectra were parameterized using SpecParam into aperiodic and periodic components. Within children with TSC, both greater seizure severity and use of GABAergic antiepileptic medication were significantly and independently associated with increased periodic peak beta power.ConclusionsThe elevated peak beta power observed in children with TSC compared to matched typically developing controls may be driven by both seizures and GABA agonist use. It is recommended to collect seizure and medication data alongside EEG data for clinical trials. These results highlight the challenge of using resting state EEG features as biomarkers in trials with neurodevelopmental disabilities when epilepsy and anti-epileptic medication are common.
| S-EPMC11742757 | biostudies-literature
Project description:ObjectiveTuberous sclerosis complex (TSC) is one of the most common genetic causes of epilepsy. Seizures in TSC typically first present in infancy or early childhood, including focal seizures and infantile spasms. Infantile spasms in TSC are particularly characteristic in its strong responsiveness to vigabatrin. Although a number of mouse models of epilepsy in TSC have been described, there are very limited electroencephalographic (EEG) or seizure data during the preweanling neonatal and infantile-equivalent mouse periods. Tsc1GFAP CKO mice are a well-characterized mouse model of epilepsy in TSC, but whether these mice have seizures during early development has not been documented. The objective of this study was to determine whether preweanling Tsc1GFAP CKO mice have developmental EEG abnormalities or seizures, including spasms.MethodsLongitudinal video-EEG and electromyographic recordings were performed serially on Tsc1GFAP CKO and control mice from postnatal days 9-21 and analyzed for EEG background abnormalities, sleep-wake vigilance states, and spontaneous seizures. Spasms were also induced with varying doses of N-methyl-D-aspartate (NMDA).ResultsThe interictal EEG of Tsc1GFAP CKO mice had excessive discontinuity and slowing, suggesting a delayed developmental progression compared with control mice. Tsc1GFAP CKO mice also had increased vigilance state transitions and fragmentation. Tsc1GFAP CKO mice had spontaneous focal seizures in the early neonatal period and a reduced threshold for NMDA-induced spasms, but no spontaneous spasms were observed.SignificanceNeonatal Tsc1GFAP CKO mice recapitulate early developmental aspects of EEG abnormalities, focal seizures, and an increased propensity for spasms. This mouse model may be useful for early mechanistic and therapeutic studies of epileptogenesis in TSC.
| S-EPMC9417212 | biostudies-literature