Meyding-Lamadé U, Jacobi C, Martinez-Torres F, Lenhard T, Kress B, Kieser M, Klose C, Einhäupl K, Bösel J, Mackert M-B, Homberg V, Koennecke C, Weißheit G, Claus D, Kieseier B, Bardutzky J, Neumann-Haefelin T, Lorenz M W, Steinmetz H, Gerloff C, Schneider D, Grau A, Klein M, Dziewas R, Bogdahn U, Jakob W, Linker R, Fuchs K, Sander A, Luntz S, Hoppe-Tichy T, Hanley D F, von Kummer R, Craemer E
Department of Neurology, Krankenhaus Nordwest, Frankfurt, Germany.
Department of Neurology, University of Heidelberg, Heidelberg, Germany.
Neurol Res Pract. 2019 Sep 12;1:26. doi: 10.1186/s42466-019-0031-3. eCollection 2019.
Comprehensive treatment of Herpes-simplex-virus-encephalitis (HSVE) remains a major clinical challenge. The current therapy gold standard is aciclovir, a drug that inhibits viral replication. Despite antiviral treatment, mortality remains around 20% and a majority of survivors suffer from severe disability. Experimental research and recent retrospective clinical observations suggest a favourable therapy response to adjuvant dexamethasone. Currently there is no randomized clinical trial evidence, however, to support the routine use of adjuvant corticosteroid treatment in HSVE.
The German trial of Aciclovir and Corticosteroids in Herpes-simplex-virus-Encephalitis (GACHE) studied the effect of adjuvant dexamethasone versus placebo on top of standard aciclovir treatment in adult patients aged 18 up to 85 years with proven HSVE in German academic centers of Neurology in a randomized and double blind fashion. The trial was open from November 2007 to December 2012. The initially planned sample size was 372 patients with the option to increase to up to 450 patients after the second interim analysis. The primary endpoint was a binary functional outcome after 6 months assessed using the modified Rankin scale (mRS 0-2 vs. 3-6). Secondary endpoints included mortality after 6 and 12 months, functional outcome after 6 months measured with the Glasgow outcome scale (GOS), functional outcome after 12 months measured with mRS and GOS, quality of life as measured with the EuroQol 5D instrument after 6 and 12 months, neuropsychological testing after 6 months, cranial magnetic resonance imaging findings after 6 months, seizures up to day of discharge or at the latest at day 30, and after 6 and 12 months.
The trial was stopped prematurely for slow recruitment after 41 patients had been randomized, 21 of them treated with dexamethasone and 20 with placebo. No difference was observed in the primary endpoint. In the full analysis set ( = 19 in each group), 12 patients in each treatment arm achieved a mRS of 0-2. Similarly, we did not observe significant differences in the secondary endpoints (GOS, mRS, quality of life, neuropsychological testing).
GACHE being prematurely terminated demonstrated challenges encountered performing randomized, placebo-controlled trials in rare life threatening neurological diseases. Based upon our trial results the use of adjuvant steroids in addition to antiviral treatment remains experimental and is at the decision of the individual treating physician. Unfortunately, the small number of study participants does not allow firm conclusions.
EudraCT-Nr. 2005-003201-81.
单纯疱疹病毒性脑炎（HSVE）的综合治疗仍然是一项重大临床挑战。目前的治疗金标准是阿昔洛韦，一种抑制病毒复制的药物。尽管进行了抗病毒治疗，但死亡率仍约为20%，且大多数幸存者患有严重残疾。实验研究和近期回顾性临床观察表明，辅助使用地塞米松治疗反应良好。然而，目前尚无随机临床试验证据支持在HSVE中常规使用辅助性皮质类固醇治疗。
德国单纯疱疹病毒性脑炎阿昔洛韦与皮质类固醇试验（GACHE）以随机双盲方式，研究了在德国神经病学学术中心18至85岁确诊为HSVE的成年患者中，辅助使用地塞米松与安慰剂对比标准阿昔洛韦治疗的效果。该试验于2007年11月至2012年12月开放。最初计划的样本量为372例患者，在第二次中期分析后可选择增加至450例患者。主要终点是6个月后使用改良Rankin量表评估的二元功能结局（mRS 0-2与3-6）。次要终点包括6个月和12个月后的死亡率、6个月时使用格拉斯哥结局量表（GOS）测量的功能结局、12个月时使用mRS和GOS测量的功能结局、6个月和12个月后使用欧洲五维健康量表测量的生活质量、6个月后的神经心理学测试、6个月后的头颅磁共振成像结果、出院时或最迟30天时以及6个月和12个月后的癫痫发作情况。
在41例患者被随机分组后，由于入组缓慢，试验提前终止，其中21例接受地塞米松治疗，20例接受安慰剂治疗。在主要终点方面未观察到差异。在全分析集（每组n = 19）中，每个治疗组有12例患者的mRS为0-2。同样，我们在次要终点（GOS、mRS、生活质量、神经心理学测试）方面也未观察到显著差异。
GACHE试验提前终止表明在罕见的危及生命的神经系统疾病中进行随机、安慰剂对照试验面临挑战。基于我们的试验结果，除抗病毒治疗外使用辅助性类固醇仍处于试验阶段，由个体治疗医生决定。遗憾的是，研究参与者数量较少，无法得出确凿结论。
EudraCT-Nr. 2005-003201-81。
