Clinical Efficacy And Safety Of Rapamycin In The Treatment Of Tuberous Sclerosis Complicated With Refractory Epilepsy

BACKGROUND:Tuberous sclerosis complex TSC is a neurocutaneous syndrome caused by a gene mutation.The genetic mode is autosomal dominant,and the clinical manifestations are epilepsy,sebaceous adenoma and mental retardation.The pathological changes of TSC are benign tumor-like hyperplasia,which can spread to any organ of the body,among which skin,brain,heart,kidney and liver are the most common,and the most prominent clinical manifestations in the central nervous system.The prominent manifestations of TSC in the nervous system are epilepsy,cognitive impairment and autism spectrum disorders.In TSC mutations,mutations in TSC1/TSC2 lead to overactivation of the Mammalian target of rapamycin mTOR signaling pathway and abnormalities in cell cycle regulation,leading to abnormalities in cell cycle regulation,neuroexcitability,and seizures.Epilepsy is the most common and clinically challenging manifestation of TSC,affecting approximately 80-90%of TSC patientsChildren with TSC are at high risk for epilepsy.Seizures peak in most children within the first year of life,and eventually about one-third of children develop seizures that are difficult to treat with drugs and surgery.Frequent seizures are the main causes of disability,declining living standards and increasing family financial burden in TSC children.MTOR inhibitors treat TSC at a precise target and inhibit abnormal activity in the mTOR signaling pathway by reducing phosphorylation of downstream mTOR effectors.Currently,mTOR inhibitor has been successfully used to treat tsc-related symptoms such as Subependymal giant cell astrocytoma SEGA,renal angiomyolipoma,lymphangiomyolipomatosis of the lung,sebaceous adenoma of the face,etc.However,there are few data on the efficacy and safety of mTOR inhibitors in the treatment of TSC with refractory epilepsy.Therefore,the treatment of TSC with refractory epilepsy is still a difficult problem.This study provides certain clinical evidence for the treatment of TSC with refractory epilepsy by observing the clinical efficacy and safety of rapamycin in the treatment of TSC with refractory epilepsyOBJECTIVE:To investigate the clinical efficacy and safety of rapamycin in tuberous sclerosis complex with refractory epilepsy METHODS:Through the retrospective research method to collect in December 2017-December 2019 in henan province people’s hospital outpatient pediatric epilepsy treated TSC merger for children with intractable epilepsy meet into and exclusion criteria,a total of 55 cases of children with TSC,including 22 cases in taking antiepileptic drugs(Anti-epileptic drugs AEDs)at the same time adding rapamycin oral treatment,33 cases of oral AEDs antiepileptic treatment,according to the patient’s medication compliance,22 cases of oral AEDs and rapamycin,as the experimental group,33 cases of oral AEDs children as control group.All the children in the experimental group and the control group with TSC complicated with refractory epilepsy were followed up for 12 months(there was no change in the type of AEDs during the follow-up),and the two groups were compared in terms of general information,reduction rate of seizure frequency,efficacy of drugs,improvement of EEG,and safety.RESULTS:Among the 55 enrolled children,male:female=1.6:1,with the age ranging from 13 to 132 months,the age range of the first episode ranging from 1 to 120 months,and the course of disease ranging from 6 to 192 months.There were 18 patients with a family history of tuberous sclerosis,10 of whom underwent familial exon gene detection,3 of whom had mutations in the TSC1 gene,6 of whom had mutations in the TSC2 gene,and 1 of whom had no detected mutations.In this study,the mutation of TSC2 was significantly higher than that of TSC 1.At baseline(before treatment),the general data and clinical characteristics of the experimental group and the control group were analyzed,and the difference was not statistically significant.In 6 months and 12 months after treatment group the average frequency of epileptic seizure of the decrement of the baseline period were 52.1%and 51.2%respectively,including 9 cases of children with TSC for more than six consecutive months without seizures,rapamycin can decrease the frequency of epilepsy seizures,and increase no seizures days,while the control group the average frequency of seizures in children with no less increase instead.At the 12-month follow-up,the clinical efficacy of the experimental group and the control group(X2=11.00,P=0.01)and the eeg changes(X2=5.24,P=0.022)were statistically significant,and 4 cases(40%)of the experimental group showed improvement of viscera,while the control group showed no reduction or disappearance of viscera masses.There were 8 cases of adverse reactions in the experimental group during the treatment with rapamycin,all of which were mild/moderate and tolerable,and no serious adverse reactionsCONCLUSION:Rapamycin can significantly reduce the frequency of seizures of nodular sclerosis complicate d with refractory epilepsy and reduce the tumor volume of each organ,and it is safe for children.