A randomized controlled trial with everolimus for IQ and autism in tuberous sclerosis complex

Abstract

ObjectiveTo investigate whether mammalian target of rapamycin inhibitor everolimus can improve intellectual disability, autism, and other neuropsychological deficits in children with tuberous sclerosis complex (TSC).MethodsIn this 12-month, randomized, double-blind, placebo-controlled trial, we attempted to enroll 60 children with TSC and IQ <80, learning disability, special schooling, or autism, aged 4–17 years, without intractable seizures to be assigned to receive everolimus or placebo. Everolimus was titrated to blood trough levels of 5–10 ng/mL. Primary outcome was full-scale IQ; secondary outcomes included autism, neuropsychological functioning, and behavioral problems.ResultsThirty-two children with TSC were randomized. Intention-to-treat analysis showed no benefit of everolimus on full-scale IQ (treatment effect −5.6 IQ points, 95% confidence interval −12.3 to 1.0). No effect was found on secondary outcomes, including autism and neuropsychological functioning, and questionnaires examining behavioral problems, social functioning, communication skills, executive functioning, sleep, quality of life, and sensory processing. All patients had adverse events. Two patients on everolimus and 2 patients on placebo discontinued treatment due to adverse events.ConclusionsEverolimus did not improve cognitive functioning, autism, or neuropsychological deficits in children with TSC. The use of everolimus in children with TSC with the aim of improving cognitive function and behavior should not be encouraged in this age group.Clinicaltrials.gov identifierNCT01730209.Classification of evidenceThis study provides Class I evidence that for children with TSC, everolimus does not improve intellectual disability, autism, behavioral problems, or other neuropsychological deficits.

Drug-responsive autism phenotypes in the 16p11.2 deletion mouse model: a central role for gene-environment interactions

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A Review of Investigations for Patients With Tuberous Sclerosis Complex Who Were Referred to the Tuberous Sclerosis Clinic at The Hospital for Sick Children: Identifying Gaps in Surveillance

“…28 Moreover, there has been growing interest in the treatment of TAND, through such modalities as mTOR inhibitors despite limited clinical evidence to directly support their use. 12,[30][31][32][33] Education of all health care providers is therefore imperative to ensure that TAND symptoms are better recognized and treated. Future studies should address ways to improve the recognition, knowledge, and treatment of TAND among health care providers as well as patients and their families.…”

Inhibition of mTOR during a postnatal critical sensitive window rescues deficits in GABAergic PV cell connectivity and social behavior caused by loss ofTSC1

“…Several recent studies have addressed whether everolimus treatment could have positive effects on cognition and autistic behaviour in TSC patients, but have so far produced controversial results (Hwang et al, 2016, Kilincaslan et al, 2017, Krueger et al, 2017, Mizuguchi et al, 2019, Ess and Franz, 2019, Overwater et al, 2019. One important point is that children younger than 4 years old were excluded from these studies.…”