Samueli Sharon, Abraham Klaus, Dressler Anastasia, Gröppel Gudrun, Mühlebner-Fahrngruber Angelika, Scholl Theresa, Kasprian Gregor, Laccone Franco, Feucht Martha
Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
Department of Biomedical Imaging and Image Guided Therapy, Medical University of Vienna, Vienna, Austria.
Orphanet J Rare Dis. 2016 Nov 3;11(1):145. doi: 10.1186/s13023-016-0530-z.
Epilepsy occurs in up to 90 % of all individuals with tuberous sclerosis complex (TSC). In 67 % disease onset is during childhood. In ≥ 50 % seizures are refractory to currently available treatment options. The mTOR-Inhibitor Everolimus (Votubia®) was approved for the treatment of subependymal giant cell astrocytoma (SEGA) and renal angiomyolipoma (AML) in Europe in 2011. It's anticonvulsive/antiepileptic properties are promising, but evidence is still limited. Study aim was to evaluate the efficacy and safety of Everolimus in children and adolescents with TSC-associated epilepsies.
Inclusion-criteria of this investigator-initiated, single-center, open, prospective study were: 1) the ascertained diagnosis of TSC; 2) age ≤ 18 years; 3) treatment indication for Votubia® according to the European Commission guidelines; 4) drug-resistant TSC-associated epilepsy, 5) prospective continuous follow-up for at least 6 months after treatment initiation and 6) informed consent to participate. Votubia® was orally administered once/day, starting with 4.5 mg/m and titrated to achieve blood trough concentrations between 5 and 15 ng/ml. Primary endpoint was the reduction in seizure frequency of ≥ 50 % compared to baseline.
Fifteen patients (nine male) with a median age of six (range; 1-18) years fulfilled the inclusion criteria. 26 % (4/15) had TSC1, 66 % (10/15) had TSC2 mutations. In one patient no mutation was found. Time of observation after treatment initiation was median 22 (range; 6-50) months. At last observation, 80 % (12/15) of the patients were responders, 58 % of them (7/12) were seizure free. The overall reduction in seizure frequency was 60 % in focal seizures, 80 % in generalized tonic clonic seizures and 87 % in drop attacks. The effect of Everolimus was seen already at low doses, early after treatment initiation. Loss of efficacy over time was not observed. Transient side effects were seen in 93 % (14/15) of the patients. In no case the drug had to be withdrawn.
Everolimus seems to be an effective treatment option not only for SEGA and AML, but also for TSC-related epilepsies. Although there are potential serious side effects, treatment was tolerated well by the majority of patients, provided that patients are under close surveillance of epileptologists who are familiar with immunosuppressive agents.
结节性硬化症（TSC）患者中高达90%会发生癫痫。67%的患者在儿童期发病。≥50%的患者癫痫发作对目前可用的治疗方案无效。mTOR抑制剂依维莫司（飞尼妥®）于2011年在欧洲被批准用于治疗室管膜下巨细胞星形细胞瘤（SEGA）和肾血管平滑肌脂肪瘤（AML）。其抗惊厥/抗癫痫特性很有前景，但证据仍然有限。本研究的目的是评估依维莫司在患有TSC相关癫痫的儿童和青少年中的疗效和安全性。
这项由研究者发起的单中心、开放、前瞻性研究的纳入标准为：1）确诊为TSC；2）年龄≤18岁；3）根据欧盟委员会指南有飞尼妥®的治疗指征；4）耐药性TSC相关癫痫；5）治疗开始后进行至少6个月的前瞻性持续随访；6）知情同意参与。飞尼妥®每日口服一次，起始剂量为4.5mg/m²，并进行滴定以达到5至15ng/ml的血药谷浓度。主要终点是与基线相比癫痫发作频率降低≥50%。
15名患者（9名男性）符合纳入标准，中位年龄为6岁（范围1 - 18岁）。26%（4/15）有TSC1突变，66%（10/1十五）有TSC2突变。1名患者未发现突变。治疗开始后的观察时间中位为22个月（范围6 - 50个月）。在最后一次观察时，80%（12/15）的患者有反应，其中58%（7/12）无癫痫发作。局灶性发作的癫痫发作频率总体降低60%，全身强直阵挛性发作降低80%，跌倒发作降低87%。依维莫司在低剂量时、治疗开始后早期就可见到效果。未观察到随着时间推移疗效丧失。93%（14/15）的患者出现短暂副作用。无一例患者需要停药。
依维莫司似乎不仅是治疗SEGA和AML的有效选择，也是治疗TSC相关癫痫的有效选择。尽管存在潜在的严重副作用，但只要患者在熟悉免疫抑制剂的癫痫专家密切监测下，大多数患者对治疗耐受性良好。
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