What is the role of everolimus (mTOR inhibitor) in the treatment of seizures, particularly in patients with tuberous sclerosis complex (TSC)?

Everolimus in Seizure Treatment for Tuberous Sclerosis Complex

Everolimus is strongly recommended as an effective adjunctive therapy for treatment-resistant seizures in patients with tuberous sclerosis complex (TSC), with demonstrated efficacy in reducing seizure frequency by 39.6% at high exposure levels and achieving seizure freedom in up to 18.9% of patients during long-term treatment. 1, 2

Mechanism of Action and Rationale

Everolimus specifically targets the underlying pathophysiology of TSC by:

• Inhibiting mammalian target of rapamycin (mTOR), a serine-threonine kinase that is dysregulated in TSC 3
• Binding to intracellular protein FKBP-12, forming an inhibitory complex with mTOR complex 1 (mTORC1) 3
• Correcting the neuronal dysplasia, aberrant axonogenesis, and increased excitatory synaptic currents caused by mTOR overactivation 3

This mechanism makes everolimus unique among anti-seizure medications for TSC as it addresses the root cause rather than merely suppressing symptoms.

Dosing Guidelines

Adults with TSC:

• Starting dose: 5 mg/day (can be adjusted based on efficacy and side effects) 4
• Target trough levels: 5-15 ng/ml 4
• Maximum recommended trough level: Do not exceed 15 ng/ml 4

Children with TSC:

• Starting dose: 2.5 mg/m² 4
• Higher initial doses used in clinical trials: 4.5 mg/m²/day (EXIST-1) 4
• For infants 6 months to 2 years: 6 mg/m² has been shown effective through modeling studies 5

Efficacy in Seizure Control

The EXIST-3 trial demonstrated significant benefits:

• Response rates (≥50% reduction in seizure frequency):
  • 40.0% with high-exposure everolimus vs 15.1% with placebo 1
  • 28.2% with low-exposure everolimus vs 15.1% with placebo 1

Long-term outcomes from the post-extension phase showed:

• 18.9% of patients achieved seizure freedom at 12 weeks 2
• 64.8% had stable/improved seizure status at 12 weeks 2
• 50.7% of patients maintained persistent responses, with 63.9% of these lasting at least 48 weeks 2

Monitoring and Follow-up

• Obtain everolimus trough levels when:
  • Safety concerns arise
  • Adherence problems are suspected
  • Lack of efficacy is observed 4
• Assess clinical and radiological response after minimum 6 months of treatment 4
• For patients discontinuing therapy, monitor for angiomyolipoma regrowth through imaging 4

Adverse Events Management

Common adverse events include:

• Aphthous stomatitis
• Irregular menstruation
• Hypercholesterolaemia
• Urinary tract infection
• Stomatitis 4

Management approach:

• Adjust dose for grade 1-2 adverse events before considering discontinuation 4
• Temporarily discontinue during infection or severe adverse events 4
• Monitor electrolytes, glucose, and liver function regularly 6

Important Clinical Considerations

1. Duration of therapy:

   • Continue treatment as long as the patient tolerates it when there is a response 4
   • Minimum 12 months before assessing response to therapy 4

2. Risk of rebound:

   • Discontinuing everolimus may cause regrowth of angiomyolipomata 4
   • Seizures may recur after discontinuation 6

3. Multi-system benefits:

   • Everolimus also treats other TSC manifestations including subependymal giant cell astrocytomas (SEGAs) and renal angiomyolipomas 7
   • Reduces intratumoural aneurysms, decreasing bleeding risk 4

Pitfalls and Caveats

• Delayed response: A minimum follow-up of 6 months is required before assessing clinical response 4
• Infection risk: Higher infection rates in younger children (96% in <6 years vs 67% in ≥6 years) 3
• Discontinuation effects: Treatment benefits not maintained after stopping the medication 6
• Drug interactions: Dose adjustments needed with cytochrome 3A4/P-glycoprotein inducers 1

Everolimus represents a significant advancement in TSC-associated seizure management by addressing the underlying pathophysiology while simultaneously treating multiple manifestations of the disease.