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Systematic review of mTOR inhibitor treatment, biomarkers and prophylaxis for tuberous sclerosis complex-associated seizures

Jingwen Zhang
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DOI: https://doi.org/10.7861/clinmed.22-4-s48
Clin Med July 2022
Jingwen Zhang
AKing's College London GKT School of Medical Education, London, UK
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Introduction

Tuberous sclerosis complex (TSC) is a major genetic cause of epilepsy, characterised by benign multi-system tumours (eg brain, kidney and skin) and neurological disorders (eg epilepsy, autism and learning impairment). Mutations in TSC1 and TSC2 genes result in hyperactivation of mammalian target of rapamycin complex-1 (mTORC1) pathway, linked to epileptogenesis in TSC.

Materials and methods

To examine research findings on anti-epileptogenic effects of mTOR inhibitors and predictive biomarkers in TSC, PubMed searches with keywords ’(((mTOR) OR (mTOR inhibitor) OR (everolimus) OR (sirolimus)) AND ((seizure) OR (epilepsy))) AND ((tuberous sclerosis) OR (TSC))’ and keywords ’((tuberous sclerosis) AND (epilepsy)) AND (biomarker)’ were performed.

Results and discussion

For results of effectiveness of mTOR inhibitors in tuberous sclerosis complex-associated seizures see Table 1.

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Table 1.

Effectiveness of mTOR inhibitors in tuberous sclerosis complex-associated seizures

Everolimus

Long-term safety: 94% of 48 TSC patients with refractory epilepsy maintained improved seizure control over 4 years; safe and tolerable. Adverse effects decreased over time.1,2

White matter modification: Everolimus pharmacologically modifies the genetic defect of TSC (including normal-appearing white matter) in 28 patients for 12–18 months. Longer exposure and younger age (<10 years old) are associated with greater effects.3,4

Dosing and response: 5–7 ng/mL initially and 5–15 ng/mL if inadequate clinical response. It is more difficult for patients with higher baseline seizure frequency to respond.5,6

Patient stratification for treatment with mTOR inhibitors

Age: mTOR inhibitors are more effective in those <18 years old, with greatest effects observed in those <6 years old. Longer exposure and early initiation are associated with long-term efficacy, especially when given in critical time windows. More calcification in cortical tubers with age is associated with resistance to treatment.7–10

Baseline seizure frequency: Higher baseline seizure frequency is associated with more difficulty becoming a responder to adjunctive everolimus.

Calcification in cerebral parenchyma: Patients with cerebral parenchymal calcification in epileptic discharge sites are more likely to be resistant to appropriate antiepileptic drugs (AEDs) and adjunctive rapamycin.

Refractory seizures: Higher diffusivity increase is seen in refractory TSC-associated epilepsy, ie greater response to everolimus.

Predictive, diagnostic and prognostic biomarkers of epilepsy in TSC

Predictive biomarkers: Electroencephalography (EEG), genetics, miRNAs and inflammation.

Diagnostic biomarkers: Interictal scalp fast ripples (FR); alpha-[¹¹C]-methyl-L-tryptophan (AMT) as the only molecular probe in positron emission tomography capable of localising epileptic foci in the interictal state.

Prognostic biomarkers: Cyst-like tubers, predominance of poorly organised tubers, increased tuber count, white matter mean diffusivity and cerebellar lesions.

Conclusion

Clinical trials have proven the efficacy and safety of mTOR inhibitors, principally everolimus, for seizure control in TSC. Effects of everolimus were shown to be mediated by duration- and dose-dependent mechanisms and more pronounced in patients with young age, low baseline seizure frequency, low level of cerebral parenchymal calcification and refractory seizures. Predictive biomarkers (including EEGs, genetics, miRNAs and immuno-inflammation changes) could identify high-risk patients and prompt initiation of prophylaxis. Diagnostic and prognostic biomarkers could confirm diagnosis and monitor response to treatment and disease progression. Widespread effects of mTOR blockade are unknown and case reports of everolimus prophylaxis in TSC patients were inconclusive. Future clinical trials are needed to study everolimus prophylaxis in young, asymptomatic patients and in combination with other AEDs.

  • © Royal College of Physicians 2022. All rights reserved.

References

  1. ↵
    1. French JA
    , Lawson JA, Yapici Z, et al. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet 2016;388:2153–63.
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    , Lawson JA, Yapici Z, et al. Everolimus dosing recommendations for tuberous sclerosis complex–associated refractory seizures. Epilepsia 2018;59:1188–97.
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    1. Combes FP
    , Baneyx G, Coello N, et al. Population pharmacokinetics–pharmacodynamics of oral everolimus in patients with seizures associated with tuberous sclerosis complex. Journal of Pharmacokinetics and Pharmacodynamics 2018;45:707–19.
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    1. Bombardieri R
    , Pinci M, Moavero R, Cerminara C, Curatolo P. Early control of seizures improves long-term outcome in children with tuberous sclerosis complex. European Journal of Paediatric Neurology 2010;14:146–9.
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    1. Jóźwizak S
    , Kotulska K, Domańska-Pakieła D, et al. Antiepileptic treatment before the onset of seizures reduces epilepsy severity and risk of mental retardation in infants with tuberous sclerosis complex. European Journal of Paediatric Neurology 2011;15:424–31.
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    1. Jozwiak S
    , Słowińska M, Borkowska J, et al. Preventive Antiepileptic Treatment in Tuberous Sclerosis Complex: A Long-Term, Prospective Trial. Pediatric Neurology 2019;101:18–25.
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  10. ↵
    1. Cox RL
    , de Anda FC, Mangoubi T, Yoshii A. Multiple critical periods for rapamycin treatment to correct structural defects in Tsc-1-suppressed brain. Front Mol Neurosci 2018;11:409.
    OpenUrlCrossRef
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Systematic review of mTOR inhibitor treatment, biomarkers and prophylaxis for tuberous sclerosis complex-associated seizures
Jingwen Zhang
Clinical Medicine Jul 2022, 22 (Suppl 4) 48-49; DOI: 10.7861/clinmed.22-4-s48

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Systematic review of mTOR inhibitor treatment, biomarkers and prophylaxis for tuberous sclerosis complex-associated seizures
Jingwen Zhang
Clinical Medicine Jul 2022, 22 (Suppl 4) 48-49; DOI: 10.7861/clinmed.22-4-s48
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