Academic journal article Journal of Child and Adolescent Psychopharmacology

Beneficial Effects of Everolimus on Autism and Attention-Deficit/Hyperactivity Disorder Symptoms in a Group of Patients with Tuberous Sclerosis Complex

Academic journal article Journal of Child and Adolescent Psychopharmacology

Beneficial Effects of Everolimus on Autism and Attention-Deficit/Hyperactivity Disorder Symptoms in a Group of Patients with Tuberous Sclerosis Complex

Article excerpt

Address correspondence to: Ayse Kilincaslan, MD, Department of Child and Adolescent Psychiatry, Istanbul Faculty of Medicine, Istanbul University, Esnaf Hastanesi Ek Binasi, Beyazit, Fatih, Istanbul 34116, Turkey, E-mail: ayse.ka@windowslive.com

Introduction

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease, which is manifested by benign hamartomas in the brain, skin, heart, kidney, retina, and other organs (Roach et al. 1998). During their lifetime, around 90% of individuals with TSC display behavioral, psychiatric, intellectual, academic, and neuropsychological problems such as autism spectrum disorders (ASD), attention-deficit/hyperactivity disorder (ADHD), intellectual disability (ID), aggression, temper tantrums, academic failure, and epilepsy (Leclezio et al. 2015). These conditions are among the top concerns for families and have an enormous impact on caregiving burden and the quality of life (Kopp et al. 2008).

TSC is caused by the mutation of the TSC1 (encoding for TSC1, or hamartin) or TSC2 (encoding for TSC2, or tuberin) genes. Hamartin and tuberin bind together to form a biochemical complex that inhibits the mammalian target of rapamycin (mTOR) that controls translation, proliferation, and cell growth (Curatolo et al. 2010). This explains why patients with TSC have a predisposition to nonmalignant tumor formation in multiple organs. mTOR inhibitors (sirolimus and everolimus) act by specifically inhibiting the mTOR pathway by reducing the phosphorylation of downstream mTOR effectors. Everolimus is a recent and effective treatment for TSC patients with giant cell astrocytomas and renal angiomyolipoma and it has been shown to have a potential to reduce tumor volume (Bissler et al. 2013; Franz et al. 2013). Given that mTOR pathway is also involved in regulating such functions as protein synthesis and synaptic plasticity, researchers hypothesize that mTOR inhibitors may also be used to treat epilepsy and other neuropsychiatric manifestations of TSC (Wong 2013). Positive outcomes in the reversal of learning and social deficits have been observed in TSC mouse models with sirolimus (Ehninger et al. 2008; Sato et al. 2012; Tsai et al. 2012). Beneficial effects of everolimus have been reported in patients with TSC and refractory seizures (Krueger et al. 2013; Wiegand et al. 2013; Wheless 2015; French et al. 2016). It has been found out that everolimus also helped improve adaptive social behaviors, conduct problems, and insecurity/anxiety (Krueger et al. 2013). Davies et al. (2011) have observed increased immediate recall memory and executive function scores with sirolimus therapy in some patients with TSC.

In this article, we report the effects of everolimus therapy in a group of patients with TSC, refractory epilepsy, and emotional and behavioral disorders.

Methods

This study was carried out on six patients with TSC (four males and two females) in the Child Neurology and Child and Adolescent Psychiatry Departments, Istanbul Faculty of Medicine, Istanbul University between the years of 2014 and 2016. The patients, whose clinical and treatment characteristics were gathered from the medical records kept by the aforesaid departments, were treated on everolimus for different periods of time (at least 3 months).

All the patients underwent dermatological, cardiological, neurological, ophthalmological, and psychiatric examinations. The diagnoses were made by child neurology and psychiatry specialists. TSC was diagnosed according to revised clinical diagnostic criteria (Roach et al. 1998). The medical records of the patients were reviewed for seizure characteristics (e.g., type, age of onset, and response to the medication). Epilepsy was defined medically refractory when the patient reported at least eight seizures in 30 days despite adequate use of at least two approved antiepileptic drugs before everolimus (Krueger et al. 2013). Psychiatric diagnoses were made according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) (American Psychiatric Association 1994). …

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