Everolimus treatment of refractory epilepsy in tuberous sclerosis complex

Krueger, Darcy A.; Wilfong, Angus A.; Holland‐Bouley, Katherine; Anderson, Anne E.; Agricola, Karen; Tudor, Cindy; Mays, Maxwell; Lopez, Christina; Kim, Miok; Franz, David Neal

doi:10.1002/ana.23960

Cited by 352 publications

(271 citation statements)

References 47 publications

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“…14 Subsequent studies have yielded similar results. 15,16 Epilepsy is a disabling, longer-term manifestation of TSC, yet long-term outcomes have yet to be assessed.…”

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confidence: 76%

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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“…14 Subsequent studies have yielded similar results. 15,16 Epilepsy is a disabling, longer-term manifestation of TSC, yet long-term outcomes have yet to be assessed.…”

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confidence: 76%

Long-term treatment of epilepsy with everolimus in tuberous sclerosis

et al. 2016

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“…Several preclinical studies and early human case reports have demonstrated that mTORC1 inhibitors such as sirolimus or everolimus are useful for treating seizures 39,[51][52][53][54] , whereas more recent prospective trials have shown that benefits could not be demonstrated when seizure frequency was analysed as a secondary outcome measure 55,56 . Moreover, 10-20% of TSC patients showed exacerbation of seizures after everolimus treatment, even in the clinical trial that demonstrated the efficacy of everolimus 57 . Thus, in addition to mTORC1 inhibitors, new approaches for the treatment of neurological symptoms in TSC patients are needed to improve not only seizure control but also cognitive function and patient quality of life.…”

Section: Discussionmentioning

confidence: 99%

Rheb activation disrupts spine synapse formation through accumulation of syntenin in tuberous sclerosis complex

et al. 2015

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Rheb is a small GTP-binding protein and its GTPase activity is activated by the complex of Tsc1 and Tsc2 whose mutations cause tuberous sclerosis complex (TSC). We previously reported that cultured TSC neurons showed impaired spine synapse morphogenesis in an mTORC1-independent manner. Here we show that the PDZ protein syntenin preferentially binds to the GDP-bound form of Rheb. The levels of syntenin are significantly higher in TSC neurons than in wild-type neurons because the Rheb-GDP-syntenin complex is prone to proteasomal degradation. Accumulated syntenin in TSC neurons disrupts spine synapse formation through inhibition of the association between syndecan-2 and calcium/calmodulindependent serine protein kinase. Instead, syntenin enhances excitatory shaft synapse formation on dendrites by interacting with ephrinB3. Downregulation of syntenin in TSC neurons restores both spine and shaft synapse densities. These findings suggest that Rheb-syntenin signalling may be a novel therapeutic target for abnormalities in spine and shaft synapses in TSC neurons.

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“…In this cohort of 26 patients, 16 suffered from seizures, and everolimus treatment modestly benefitted nine patients with seizure reduction. A more recent study showed that seizure frequency was reduced in TSC patients treated with everolimus (Krueger et al 2013). In their cohort of 20 patients treated with everolimus, seizure frequency was reduced by 50% in 12 of 20 subjects.…”

Section: Focal Cortical Dysplasia and Tuberous Sclerosis: Paradigm Mtmentioning

confidence: 95%

“…In their cohort of 20 patients treated with everolimus, seizure frequency was reduced by 50% in 12 of 20 subjects. Significant reductions in seizure duration and improvement in parent-reported behavior and quality of life were also observed (Krueger et al 2013). Clearly, mTOR inhibition may provide a novel cell-signaling cascade target in refractory epilepsy.…”

Section: Focal Cortical Dysplasia and Tuberous Sclerosis: Paradigm Mtmentioning

confidence: 95%