Institute for Neurological Research, a private medical group, inc., Los Angeles, California, USA.
CNS Drugs. 2011 Feb;25(2):145-55. doi: 10.2165/11588400-000000000-00000.
Thrombolytic therapy reduces stroke size and disability by reperfusion and salvage of ischaemic penumbra. Emerging evidence suggests that retrieved penumbra may be the site of ongoing inflammatory pathology that includes extensive microglial activation. Microglial activation may be associated with excessive levels of tumour necrosis factor (TNF) and resultant neurotoxicity. Etanercept, a potent biologic TNF antagonist, reduces microglial activation in experimental models and has been therapeutically effective in models of brain and neuronal injury. Perispinal administration of etanercept, previously reported to be beneficial for the treatment of Alzheimer's disease, may facilitate delivery of etanercept into the brain.
The objective of this report is to document the initial clinical response to perispinal etanercept in the first chronic stroke cohort so treated.
Three consecutive patients with stable and persistent chronic neurological deficits due to strokes that had failed to resolve despite previous treatment and rehabilitation were evaluated at an outpatient clinic. They were treated off-label with perispinal etanercept as part of the clinic's practice of medicine.
All three patients had chronic hemiparesis, in addition to other stroke deficits. Their stroke distributions were right middle cerebral artery (MCA), brainstem (medulla) and left MCA. The two patients with MCA strokes had both received acute thrombolytic therapy. Each of the three patients was treated with an initial dose of perispinal etanercept 13, 35 and 36 months following their acute stroke, respectively. Significant clinical improvement following perispinal etanercept administration was observed in all patients. Onset of clinical response was evident within 10 minutes of perispinal injection in all patients. Improvements in hemiparesis, gait, hand function, hemi-sensory deficits, spatial perception, speech, cognition and behaviour were noted among the patients treated. Each patient received a second perispinal etanercept dose at 22-26 days after the first dose that was followed by additional clinical improvement.
Open-label administration of perispinal etanercept resulted in rapid neurological improvement in three consecutive patients with chronic neurological dysfunction due to strokes occurring 13-36 months earlier. These results suggest that stroke may result in chronic TNF-mediated pathophysiology that may be amenable to therapeutic intervention long after the acute event. Randomized clinical trials of perispinal etanercept for selected patients with chronic neurological dysfunction following stroke are indicated.
溶栓治疗通过再灌注和挽救缺血半暗带减少了中风的面积和残疾。新出现的证据表明，回收的半暗带可能是持续炎症病理的部位，包括广泛的小胶质细胞激活。小胶质细胞激活可能与肿瘤坏死因子（TNF）水平过高有关，并导致神经毒性。依那西普是一种有效的生物 TNF 拮抗剂，可减少实验模型中的小胶质细胞激活，并在脑和神经元损伤模型中具有治疗效果。先前有报道称，椎管内给予依那西普有益于治疗阿尔茨海默病，这可能有助于依那西普进入大脑。
本报告的目的是记录第一批接受这种治疗的慢性中风患者的初步临床反应。
在门诊诊所，对 3 名因中风导致稳定和持续的慢性神经功能缺损且经先前治疗和康复后仍未缓解的连续患者进行评估。他们作为诊所医疗实践的一部分，接受了椎管内依那西普的治疗。
所有 3 名患者均有慢性偏瘫，此外还有其他中风缺陷。他们的中风分布分别为大脑中动脉（MCA）、脑干（延髓）和左 MCA。2 名 MCA 中风患者均接受了急性溶栓治疗。这 3 名患者分别在急性中风后 13、35 和 36 个月接受了初始剂量的椎管内依那西普治疗。所有患者在接受椎管内依那西普治疗后均出现显著的临床改善。所有患者在椎管内注射后 10 分钟内均出现临床反应。接受治疗的患者偏瘫、步态、手部功能、半身感觉缺失、空间感知、言语、认知和行为均有所改善。每位患者在首次剂量后 22-26 天接受了第二次椎管内依那西普治疗，随后进一步改善了临床症状。
对 3 名因中风导致慢性神经功能障碍的连续患者进行开放性椎管内依那西普治疗，可迅速改善神经系统功能。这些结果表明，中风可能导致慢性 TNF 介导的病理生理变化，在急性事件发生后很长时间内可能需要治疗干预。需要对选择的中风后慢性神经功能障碍患者进行椎管内依那西普的随机临床试验。
