Department of Neurology, Key Laboratory of Neurorepair and Regeneration, Tianjin and Ministry of Education, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China.
Department of Radiology, Tianjin Medical University General Hospital, Tianjin, China.
JAMA Neurol. 2014 Sep;71(9):1092-101. doi: 10.1001/jamaneurol.2014.1065.
Pronounced inflammatory reactions occurring shortly after intracerebral hemorrhage (ICH) contribute to the formation and progression of perihematomal edema (PHE) and secondary brain injury. We hypothesized that modulation of brain inflammation reduces edema, thus improving clinical outcomes in patients with ICH.
To investigate whether oral administration of fingolimod, a Food and Drug Administration-approved sphingosine 1-phosphate receptor modulator for multiple sclerosis, is safe and effective in alleviating PHE and neurologic deficits in patients with ICH.
DESIGN, SETTING, AND PARTICIPANTS: In this 2-arm, evaluator-blinded study, we included 23 patients with primary supratentorial ICH with hematomal volume of 5 to 30 mL. Clinical and neuroimaging feature-matched patients were treated with standard care with or without oral fingolimod. The study was conducted in Tianjin Medical University General Hospital, Tianjin, China.
All patients received standard management alone (control participants) or combined with fingolimod (FTY720, Gilenya), 0.5 mg, orally for 3 consecutive days. Treatment was initiated within 1 hour after the baseline computed tomographic scan and no later than 72 hours after the onset of symptoms.
Neurologic status and hematomal and PHE volumes (Ev) and relative PHE, defined as Ev divided by hematomal volume, were monitored by clinical assessment and magnetic resonance imaging, respectively, for 3 months.
Patients treated with fingolimod exhibited a reduction of neurologic impairment compared with control individuals, regained a Glasgow Coma Scale score of 15 by day 7 (100% vs 50%, P = .01), and had a National Institutes of Health Stroke Scale score reduction of 7.5 vs 0.5 (P < .001). Neurologic functions improved in these patients in the first week coincident with a reduction of circulating lymphocyte counts. At 3 months, a greater proportion of patients receiving fingolimod achieved full recovery of neurologic functions (modified Barthel Index score range, 95-100; 63% vs 0%; P = .001; modified Rankin Scale score range, 0-1; 63% vs 0%; P = .001), and fewer reported ICH-related lung infections. Perihematomal edema volume and rPHE were significantly smaller in fingolimod-treated patients than in control individuals (Ev at day 7, 47 mL vs 108 mL, P = .04; Ev at day 14, 55 mL vs 124 mL, P = .07; rPHE at day 7, 2.5 vs 6.4, P < .001; rPHE at day 14, 2.6 vs 7.7, P = .003, respectively). We recorded no differences between groups in the occurrence of adverse events.
In patients with small- to moderate-sized deep primary supratentorial ICH, administration of oral fingolimod within 72 hours of disease onset was safe, reduced PHE, attenuated neurologic deficits, and promoted recovery. The efficacy of fingolimod in preventing secondary brain injury in patients with ICH warrants further investigation in late-phase trials.
clinicaltrials.gov Identifier:NCT02002390.
脑出血（ICH）后即刻出现的明显炎症反应会导致血肿周围水肿（PHE）和继发性脑损伤的形成和进展。我们假设调节脑内炎症反应可减轻水肿，从而改善 ICH 患者的临床转归。
研究鞘氨醇 1-磷酸受体调节剂（fingolimod）口服给药是否安全有效，能否减轻 ICH 患者的 PHE 和神经功能缺损。
设计、场所和参与者：这是一项 2 臂、评估者设盲研究，共纳入 23 例原发性幕上 ICH 患者，血肿体积为 5 至 30 ml。将临床和神经影像学特征相匹配的患者分为标准治疗组（对照组）或标准治疗加 fingolimod 组（FTY720，Gilenya）。研究在天津市总医院进行。
所有患者均接受标准治疗（对照组）或标准治疗联合 fingolimod（0.5 mg，口服，连续 3 天）。治疗在基线 CT 扫描后 1 小时内开始，最晚不超过症状出现后 72 小时。
通过临床评估和磁共振成像分别监测神经状态和血肿及 PHE 体积（Ev）和相对 PHE（Ev 除以血肿体积），随访 3 个月。
与对照组相比，fingolimod 治疗组患者的神经损伤减轻，7 天内恢复到格拉斯哥昏迷量表（Glasgow Coma Scale）评分 15 分（100%比 50%，P = 0.01），7.5 分比 0.5 分（P < 0.001）的 NIH 卒中量表（NIH Stroke Scale）评分降低。这些患者的神经功能在第 1 周改善，同时循环淋巴细胞计数减少。3 个月时，fingolimod 治疗组有更大比例的患者实现了神经功能的完全恢复（改良巴氏指数评分范围 95-100 分；63%比 0%；P = 0.001；改良 Rankin 量表评分范围 0-1 分；63%比 0%；P = 0.001），更少报告 ICH 相关的肺部感染。与对照组相比，fingolimod 治疗组患者的 PHE 体积更小（第 7 天的 Ev 为 47 ml 比 108 ml，P = 0.04；第 14 天的 Ev 为 55 ml 比 124 ml，P = 0.07；第 7 天的 rPHE 为 2.5 比 6.4，P < 0.001；第 14 天的 rPHE 为 2.6 比 7.7，P = 0.003）。两组患者在不良事件的发生方面无差异。
在小至中等量幕上原发性 ICH 患者中，发病后 72 小时内口服 fingolimod 是安全的，可减轻 PHE、减轻神经功能缺损、促进恢复。fingolimod 预防 ICH 患者继发性脑损伤的疗效值得进一步在晚期试验中进行研究。
clinicaltrials.gov 标识符：NCT02002390。
