Institute of Neurological Recovery, 100 UCLA Medical Plaza, Suites 205-210, Los Angeles, CA 90095, USA.
CNS Drugs. 2012 Dec;26(12):1051-70. doi: 10.1007/s40263-012-0013-2.
Brain injury from stroke and traumatic brain injury (TBI) may result in a persistent neuroinflammatory response in the injury penumbra. This response may include microglial activation and excess levels of tumour necrosis factor (TNF). Previous experimental data suggest that etanercept, a selective TNF inhibitor, has the ability to ameliorate microglial activation and modulate the adverse synaptic effects of excess TNF. Perispinal administration may enhance etanercept delivery across the blood-CSF barrier.
The objective of this study was to systematically examine the clinical response following perispinal administration of etanercept in a cohort of patients with chronic neurological dysfunction after stroke and TBI.
After approval by an independent external institutional review board (IRB), a chart review of all patients with chronic neurological dysfunction following stroke or TBI who were treated open-label with perispinal etanercept (PSE) from November 1, 2010 to July 14, 2012 at a group medical practice was performed.
The treated cohort included 629 consecutive patients. Charts of 617 patients following stroke and 12 patients following TBI were reviewed. The mean age of the stroke patients was 65.8 years ± 13.15 (range 13-97). The mean interval between treatment with PSE and stroke was 42.0 ± 57.84 months (range 0.5-419); for TBI the mean interval was 115.2 ± 160.22 months (range 4-537). Statistically significant improvements in motor impairment, spasticity, sensory impairment, cognition, psychological/behavioural function, aphasia and pain were noted in the stroke group, with a wide variety of additional clinical improvements noted in individuals, such as reductions in pseudobulbar affect and urinary incontinence. Improvements in multiple domains were typical. Significant improvement was noted irrespective of the length of time before treatment was initiated; there was evidence of a strong treatment effect even in the subgroup of patients treated more than 10 years after stroke and TBI. In the TBI cohort, motor impairment and spasticity were statistically significantly reduced.
Irrespective of the methodological limitations, the present results provide clinical evidence that stroke and TBI may lead to a persistent and ongoing neuroinflammatory response in the brain that is amenable to therapeutic intervention by selective inhibition of TNF, even years after the acute injury.
Excess TNF contributes to chronic neurological, neuropsychiatric and clinical impairment after stroke and TBI. Perispinal administration of etanercept produces clinical improvement in patients with chronic neurological dysfunction following stroke and TBI. The therapeutic window extends beyond a decade after stroke and TBI. Randomized clinical trials will be necessary to further quantify and characterize the clinical response.
中风和创伤性脑损伤（TBI）引起的脑损伤可能导致损伤半影区内持续的神经炎症反应。这种反应可能包括小胶质细胞激活和肿瘤坏死因子（TNF）过量。先前的实验数据表明，etanercept（一种选择性 TNF 抑制剂）具有改善小胶质细胞激活和调节过量 TNF 的不良突触效应的能力。脊柱旁给药可能增强 etanercept 通过血脑屏障的输送。
本研究旨在系统检查慢性中风和 TBI 后神经功能障碍患者脊柱旁给予 etanercept 的临床反应。
在一组医学实践中，于 2010 年 11 月 1 日至 2012 年 7 月 14 日，对所有慢性中风或 TBI 后出现慢性神经功能障碍且接受脊柱旁 etanercept（PSE）开放标签治疗的患者进行独立外部机构审查委员会（IRB）批准后，对所有患者进行图表审查。
治疗队列包括 629 例连续患者。对 617 例中风患者和 12 例 TBI 患者的图表进行了回顾。中风患者的平均年龄为 65.8 岁±13.15（范围 13-97）。PSE 治疗与中风之间的平均间隔为 42.0±57.84 个月（范围 0.5-419）；TBI 的平均间隔为 115.2±160.22 个月（范围 4-537）。在中风组中，运动障碍、痉挛、感觉障碍、认知、心理/行为功能、失语症和疼痛均有显著改善，个体还出现了多种其他临床改善，如假性延髓情感障碍和尿失禁减少。多个领域都有改善。无论治疗开始前的时间长短，都有显著改善；即使在中风和 TBI 后 10 年以上接受治疗的患者亚组中，也有证据表明治疗效果很强。在 TBI 队列中，运动障碍和痉挛显著减少。
尽管存在方法学限制，但本研究结果提供了临床证据，表明中风和 TBI 可能导致大脑内持续存在和持续的神经炎症反应，通过选择性抑制 TNF 进行治疗可能有效，即使在急性损伤后多年也是如此。
过量的 TNF 导致中风和 TBI 后的慢性神经、神经精神和临床障碍。脊柱旁给予 etanercept 可改善中风和 TBI 后慢性神经功能障碍患者的临床症状。治疗窗超过中风和 TBI 后 10 年。需要进行随机临床试验以进一步量化和描述临床反应。
