Dysautonomia after severe traumatic brain injury

Background: Dysautonomia after traumatic brain injury (TBI) is characterized by episodes of increased heart rate, respiratory rate, temperature, blood pressure, muscle tone, decorticate or decerebrate posturing, and profuse sweating. This study addresses the incidence of dysautonomia after severe TBI, the clinical variables that are associated with dysautonomia, and the functional outcome of patients with dysautonomia. Methods: A historic cohort study in patients with severe TBI [Glasgow Coma Scale (GCS) ≤ 8 on admission]. Results: Seventy‐six of 119 patients survived and were eligible for follow‐up. The incidence of dysautonomia was 11.8%. Episodes of dysautonomia were prevalent during a mean period of 20.1 days (range 3–68) and were often initiated by discomfort. Patients with dysautonomia showed significant longer periods of coma (24.78 vs. 7.99 days) and mechanical ventilation (22.67 vs. 7.21 days). Dysautonomia was associated with diffuse axonal injury (DAI) [relative risk (RR) 20.83, CI 4.92–83.33] and the development of spasticity (RR 16.94, CI 3.96–71.42). Patients with dysautonomia experienced more secondary complications. They tended to have poorer outcome. Conclusions: Dysautonomia occurs in approximately 10% of patients surviving severe TBI and is associated with DAI and the development of spasticity at follow‐up. The initiation of dysautonomia by discomfort supports the Excitatory: Inhibitory Ratio model as pathophysiological mechanism.     

硫酸镁对大鼠脑弥漫性轴索损伤海马区Bcl-2和Bax蛋白表达影响的研究

目的研究脑弥漫性轴索损伤后神经细胞迟发性死亡的机制,探讨镁离子对大鼠脑弥漫性轴索损伤后神经元的保护作用。方法采用Marmarou方法制备大鼠重度脑弥漫性轴索损伤模型,分为创伤组(n=25)、生理盐水组(n=40)和硫酸镁组(n=40)。硫酸镁组伤后半小时给予25%硫酸镁(750μmol/kg),生理盐水组在相同时间给予等量的生理盐水腹腔注射,于伤后6小时、24小时、3天、5天及7天5个时相点处死。采用HE染色、免疫组织化学技术动态观察大鼠海马区的组织病理改变,Bcl-2和Bax蛋白的表达情况,以及使用硫酸镁干预后对上述表达的影响。结果①Bcl-2蛋白的表达:假手术组大鼠海马区仅见极少量Bcl-2阳性细胞,着色淡。在伤后6小时即有大量的Bcl-2阳性细胞,随时间渐增,24小时达到高峰,3～7天逐渐减少。②Bax蛋白的表达:在DAI后大鼠海马区有大量Bax阳性细胞,在伤后6小时就有所增加,24小时显著增加,3天达到高峰。Bcl-2/Bax值在损伤后随时间逐渐上升。③硫酸镁组中,海马区的Bax表达与对照组相比有所减少,而Bcl-2相应增加,Bcl-2/Bax比值也是上调的,均有统计学意义(P<0.05)。结论大鼠脑弥漫性轴索损伤后,海马区神经元存在有迟发性细胞死亡即凋亡现象。Bax与Bcl-2参与细胞凋亡过程。硫酸镁可通过抑制Bax蛋白,上调Bcl-2蛋白,减少神经细胞凋亡,对促进神经细胞修复和功能重塑有益。     

Sodium channelopathy induced by mild axonal trauma worsens outcome after a repeat injury

There is great concern that one mild traumatic brain injury (mTBI) predisposes individuals to an exacerbated response with a subsequent mTBI. Although no mechanism has been identified, mounting evidence suggests traumatic axonal injury (TAI) plays a role in this process. By using a cell culture system, a threshold of mild TAI was found where dynamic stretch of cortical axons at strains lower than 5% induced no overt pathological changes. However, the axons were found to display an increased expression of sodium channels (NaChs) by 24 hr. After a second, identical mild injury, pathologic increases in [Ca²⁺]_i were observed, leading to axon degeneration. The central role of NaChs in this response was demonstrated by blocking NaChs with tetrodotoxin prior to the second injury, which completely abolished postinjury increases in [Ca²⁺]_i. These data suggest that mild TAI induces a form of sodium channelopathy on axons that greatly exaggerates the pathophysiologic response to subsequent mild injuries. © 2009 Wiley‐Liss, Inc.     

镁离子结合机械通气早期治疗重型弥漫性轴索损伤的临床疗效

目的观察联合使用硫酸镁结合机械通气早期治疗重型弥漫性轴索损伤的临床疗效。 方法将武警广东省总队医院神经外科自2011年1月至2014年12月收治的96例重型弥漫性轴索损伤患者伤后24 h内随机分成常规组（42例,接受常规综合治疗）、治疗组（54例,除常规治疗方法外,加用25%硫酸镁治疗结合机械通气治疗）进行分别治疗。观察治疗7 d后各组监测血压、呼吸、心率、体温和血气分析变化情况,及治疗前后GCS评分和3个月后GOS评级情况并进行疗效分析。 结果治疗7 d后监测指标变化情况比较,治疗组患者各项指标改善高于常规组,且差异有统计学意义（P<0.05）;在入院治疗后1周、2周,治疗组GCS评分高于常规组,且差异有统计学意义（P<0.05）,3个月后GOS评级亦明显高于常规组,且差异有统计学意义（P<0.05）。 结论硫酸镁结合机械通气对早期治疗重型弥漫性轴索损伤能改善预后转归,降低病死率。     

颅脑损伤大鼠肠道防御素-5 mRNA表达

目的探讨弥漫性脑损伤后肠道防御素-5（RD-5）变化。方法大鼠32只，分为对照组8只；弥漫性脑损伤组24只，再分成3个亚组（24h，3d，7d）。观察回肠RD-5mRNA的表达，回肠肠粘膜的病理改变以及血液内毒素的变化。结果弥漫性脑损伤后24hRD-5 mRNA的表达显著升高（P〈0．01），伤后3d降低至正常水平以下；回肠肠粘膜损伤，血液内毒素伤后24h最高（P〈0．01），3至7d仍显著高于正常水平（P〈0．01）。结论弥漫性脑损伤早期RD-5 mRNA的表达增强可能是机体的一种保护性反应。     

The usefulness of diffusion tensor imaging in detection of diffuse axonal injury in a patient with head trauma

Diffuse axonal injury is the predominant mechanism of injuries in patients with traumatic brain injury. Neither conventional brain computed tomography nor magnetic resonance imaging has shown sufficient sensitivity in the diagnosis of diffuse axonal injury. In the current study, we attempted to demonstrate the usefulness of diffusion tensor imaging in the detection of lesion sites of diffuse axonal injury in a patient with head trauma who had been misdiagnosed as having a stroke. A 44-year-old man fell from a height of about 2 m. Brain magnetic resonance imaging (32 months after onset) showed leukomalactic lesions in the isthmus of the corpus callosum and the left temporal lobe. He presented with mild quadriparesis, intentional tremor of both hands, and trunkal ataxia. From diffusion tensor imaging results of 33 months after traumatic brain injury onset, we found diffuse axonal injury in the right corticospinal tract (centrum semiovale, pons), both fornices (columns and crus), and both inferior cerebellar peduncles (cerebellar portions). We think that diffusion tensor imaging could be a useful tool in the detection of lesion sites of diffuse axonal injury in patients with head trauma.     

弥漫性轴索损伤脑脊液神经元特异性烯醇化酶的动态变化及意义

目的 探讨弥漫性轴索损伤(DAI)病人脑脊液神经元特异性烯醇化酶(NSE)的动态变化及其临床意义.方法 分别用放射免疫测定法检测76例DAI病人(实验组)和15例无神经系统疾病者(对照组)的脑脊液NSE含量.实验组根据入院时GCS评分分为轻型组23例、中型组27例和重型组26例.分别于颅脑损伤后12h、1d、3d、7d、14d采集脑脊液标本,分析NSE水平与颅脑损伤严重程度及预后的关系.结果 与对照组比较,轻型组伤后12 h～3 d、中型组伤后12h～7d、重型组伤后12 h～14 d的NSE水平均明显增高(P＜0.05);重型组各时间点NSE水平明显高于轻型组和中型组(P＜0.01).随访3个月,轻型组、中型组和重型组预后不良率分别为0％、14.81％及73.08％.结论 脑脊液NSE水平可作为判断DAI损伤程度及预后的指标,并指导选择和调整治疗措施.     

Neurogenesis and glial proliferation are stimulated following diffuse traumatic brain injury in adult rats

Although increased neurogenesis has been described in rodent models of focal traumatic brain injury (TBI), the neurogenic response occurring after diffuse TBI uncomplicated by focal injury has not been examined to date, despite the pervasiveness of this distinct type of brain injury in the TBI patient population. Here we characterize multiple stages of neurogenesis following a traumatic axonal injury (TAI) model of diffuse TBI as well as the proliferative response of glial cells. TAI was induced in adult rats using an impact-acceleration model, and 5-bromo-2'-deoxyuridine (BrdU) was administered on days 1-4 posttrauma or sham operation to label mitotic cells. Using immunohistochemistry for BrdU combined with phenotype-specific markers, we found that proliferation was increased following TAI in the subventricular zone of the lateral ventricles and in the hippocampal subgranular zone, although the ultimate production of new dentate granule neurons at 8 weeks was not significantly enhanced. Also, abundant proliferating and reactive astrocytes, microglia, and polydendrocytes were detected throughout the brain following TAI, indicating that a robust glial response occurs in this model, although very few new cells in the nonneurogenic brain regions became mature neurons. We conclude that diffuse brain injury stimulates early stages of a neurogenic response similar to that described for models of focal TBI.     

弥漫性轴突损伤早期超微结构改变

目的通过观察弥漫性轴突损伤(DAI)患者伤后早期轴突的超微结构变化以探索DAI的发生机理.方法对12例DAI患者的14份活体脑组织标本进行透射电镜检查.结果 DAI患者在伤后早期可发生多方面的轴突改变,包括(1)轴突的细胞骨架破坏;(2)轴膜改变;(3)膜性细胞器的变化;(4)髓鞘的改变;(5)轴突出现肿胀和离断,轴突近侧断端呈现球状.结论在DAI的发生中,可能有多种机理参与.推测,在受到足够强的外力作用时,一些管径较细的轴突可能会立即断裂;其它受损轴突则会出现进行性的延迟性轴突断裂.在此演化过程中,细胞骨架破坏和轴膜受损继而通透性改变可能是造成轴突局灶性轴浆转运障碍最终离断的最重要的因素.     

Effects of progesterone on neurologic and morphologic outcome following diffuse traumatic brain injury in rats

Previous studies have identified that progesterone may be neuroprotective following traumatic brain injury (TBI). However, most of these have utilized models of TBI that produce a focal lesion or a significant ischemic component, neither of which is necessarily present in diffuse TBI. The current study uses a model of diffuse TBI in rats to examine the effects of progesterone on morphological changes and functional outcome following TBI. Male and ovariectomized female rats were subject to severe impact-acceleration injury under halothane anesthesia. After injury, animals were given a physiological, subcutaneous dose of progesterone (1.67 mg/kg) or equal volume of vehicle (sesame oil) daily throughout a 9-day neurologic assessment period where functional outcome was assessed using the rotarod and Barnes maze tests. There was a similar post-injury performance of male and ovariectomized female animals. Post-injury administration of progesterone improved the motor and cognitive performance of ovariectomized and male animals compared to vehicle-treated controls. Morphological differences between these animals, such as dark cell change, caspase-3 and APP immunoreactivity, were also investigated. Progesterone-treated males showed comparatively less dead or dying neurons, and marked attenuation of caspase-3 immunoreactivity. Both ovariectomized female and male animals treated with progesterone showed a profound reduction in axonal injury (seen via diminished APP immunoreactivity) when compared to controls. We conclude that physiological concentrations of progesterone administered after diffuse TBI confers beneficial effects on morphologic and functional outcome in both ovariectomized female and male animals.     

Neuropathological investigation of cerebral white matter lesions caused by closed head injury

In order to ascertain whether there is widespread axonal disruption of cerebral white matter in the so‐called ‘diffuse axonal injury’ (DAI), a type of closed head injury, proposed by Adams et al. the author investigated his own cases clinicopathologically. Twenty‐six male autopsied cases of head injury, aged between 19 and 84, 15 of which had sustained road traffic accidents, were examined; the others were due to falling from heights and so on. The study group all belonged to non‐missile head injuries and included 12 cases of diffuse brain injury, as well as 14 cases of focal brain injury, according to the classification of Gennarelli et al. The survival time ranged from 2 h to 21 years. Formalin‐fixed brains were cut coronally so as to make paraffin‐embedded hemispheric sections. Then these sections were stained conventionally (HE, Bodian, Kluver‐Barrera and Holzer) and immunohistochemically (GFAP) to assess axonal decrease, myelin pallor and gliosis by the use of light microscopy. In the 13 chronic cases that died more than 1 month after the accidents, the intensities of gliosis, myelin pallor and axonal decrease tended to correlate with each other. In the 13 acute cases who died less than 1 month after their accident, the degree of axonal decrease in white matter seemed to correlate with the severity of myelin pallor. Regardless of types of trauma, however, axonal retraction balls, the so‐called hallmark of DAI, were found only with myelin pallor suggesting the presence of brain swelling after the injury. Therefore these findings indicate that it may be difficult to accept the notion of DAI, that is, the presence of axonal retraction balls without brain swelling. In addition, diffuse vascular injury (2 cases) as well as rarefaction of subcortical white matter (6 cases) were presented and their pathogenesis individually discussed based on a literature review.     

169例脑弥漫性轴索损伤的诊断和预后分析

目的 评价目前对弥漫性轴索损伤（DAI）患者的诊断和病人预后的关系。方法 以多中心研究的方法，回顾性分析169例DAI患者的影像学表现及其分型、GCS评分与预后的关系。结果 DAI病人影像学表现越单纯，病灶越靠近大脑半球周边，GCS评分越高，预后越好。结论 现行的DAI病人诊断性影像学表现及分型、GCS评分及分型对判断DAI病人的预后具有指导意义。     

质子磁共振波谱在创伤性脑损伤中的应用

磁共振波谱(magnetic resonance spectroscopy,MRS)是目前唯一的、无创性的测定活体组织代谢与生化指标的技术[1],它能够反映细胞内物质和能量代谢状态,近年来发展迅速.     

Assessing connectivity related injury burden in diffuse traumatic brain injury

Many of the clinical and behavioral manifestations of traumatic brain injury (TBI) are thought to arise from disruption to the structural network of the brain due to diffuse axonal injury (DAI). However, a principled way of summarizing diffuse connectivity alterations to quantify injury burden is lacking. In this study, we developed a connectome injury score, Disruption Index of the Structural Connectome (DISC), which summarizes the cumulative effects of TBI‐induced connectivity abnormalities across the entire brain. Forty patients with moderate‐to‐severe TBI examined at 3 months postinjury and 35 uninjured healthy controls underwent magnetic resonance imaging with diffusion tensor imaging, and completed behavioral assessment including global clinical outcome measures and neuropsychological tests. TBI patients were selected to maximize the likelihood of DAI in the absence of large focal brain lesions. We found that hub‐like regions, with high betweenness centrality, were most likely to be impaired as a result of diffuse TBI. Clustering of participants revealed a subgroup of TBI patients with similar connectivity abnormality profiles who exhibited relatively poor cognitive performance. Among TBI patients, DISC was significantly correlated with post‐traumatic amnesia, verbal learning, executive function, and processing speed. Our experiments jointly demonstrated that assessing structural connectivity alterations may be useful in development of patient‐oriented diagnostic and prognostic tools. Hum Brain Mapp 38:2913–2922, 2017. © 2017 Wiley Periodicals, Inc.     

Localized in vivo H-MRS of traumatic brain injury

¹H-MRS examinations were carried out on 14 patients, recovering from traumatic brain injury (TBI), who were in a stabilized clinical status and showed a good clinical outcome. Magnetic resonance spectra were recorded in subcortical (SC) and mid-brain (MB) areas where no detectable lesions appeared under magnetic resonance imaging. These two brain areas were selected because they are crucial sites of damage due to the physiopathologic mechanisms of TBI. A significant increase in inositol and choline peaks was found in MB compared to a control group of healthy individuals, whereas lower N-acetyl-aspartate peaks in the same area were detected. Reduced levels in the latter metabolite were also evident in the SC area. A significant correlation emerged between the inositol concentration in MB and the Glasgow Coma Scale Score measured just after the trauma. No correlation was found between the Glasgow Outcome Scale (GOS) at the time of the ¹H-MRS examination and the peaks of all the metabolites. Our study demonstrated that ¹H-MRS is a sensitive tool to evidentiate brain metabolic damage after TBI even in areas with lesions that are not detectable with current imaging techniques. The present research also shows an association between the alteration in one of the brain metabolites and the clinical parameters of TBI severity, but does not provide a clinical index of the patient's recovery. Further longitudinal studies on more conspicuous groups of patients with TBI could help to clarify whether metabolite modifications revealed by ¹H-MRS could be predictive of clinical outcome.     

弥漫性轴索损伤的影像与临床分析

目的探讨弥漫性轴索损伤的影像学及临床特点,为诊断和治疗提供参考。方法对47例弥漫性轴索损伤患者的临床资料及影像学进行回顾性分析。结果随访3～12个月,根据格拉斯哥预后评分（GOS）：恢复良好12例,中残14例,重残8例,植物生存3例,死亡10例。不同影像学分级组的预后无显著差异。结论弥漫性轴索损伤是临床上常见的颅脑损伤类型,其诊断主要根据临床和影像学表现;目前CT和常规MRI尚不能作为诊断的必要条件,也不能作为准确评估患者预后的独立依据。     

Working memory brain activation following severe traumatic brain injury

Functional magnetic resonance imaging (fMRI) has shown that brain activation during performance of working memory (WM) tasks under high memory loads is altered in adults with severe traumatic brain injury (TBI) relative to uninjured subjects (Perlstein et al., 2004; Scheibel et al., 2003). Our study attempted to equate TBI patients and orthopedically injured (OI) subjects on performance of an N-Back task that used faces as stimuli. To minimize confusion in TBI patients that was revealed in pilot work, we presented the memory conditions in two separate tasks, 0- versus 1-back and 0- versus 2-back. In the 0- versus 1-back task, OI subjects activated bilateral frontal areas more extensively than TBI patients, and TBI patients activated posterior regions more extensively than OI subjects. In the 0- versus 2-back task, there were no significant differences between the groups. Analysis of changes in activation over time on 1-back disclosed that OI subjects had decreases in bilateral anterior and posterior regions, while TBI patients showed activation increases in those and other areas over time. In the 2-back condition, both groups showed decreases over time in fusiform and parahippocampal gyri, although the OI group also showed increases over time in frontal, parietal, and temporal areas not seen in the TBI patients. The greatest group differences were found in the 1-back condition, which places low demand on WM. Although the extent of activation in the 2-back condition did not differ between the two groups, deactivation in the 2-back condition was seen in the OI patients only, and both groups' patterns of activation over time varied, suggesting a dissociation between the TBI and OI patients in recruitment of neural areas mediating WM.     

Mg2+对大鼠弥漫性轴索损伤脑干NF-68KD的影响

目的探讨Mg2+对脑弥漫性轴索损伤(DAI)轴索细胞骨架神经丝(NF-68KD)是否有影响.方法选健康成年雄性SD大鼠(体重350～450 g)随机分为实验组、对照组、空白组,各组又分为6 h、24 h两个亚组.采用改良Marmarou模型制作DAI模型,伤后30 min分别给予MgSO4(250μmol/kg),生理盐水(0.2 ml),伤后6 h、24 h处死.用免疫组化技术行NF-68KD染色,分别累计脑干阳性轴索数,计算阳性轴索个数/mm2行统计分析.结果伤后6 h、24 h,实验组脑干NF-68KD阳性表达强度(阳性轴索个数/mm2)均明显低于对照组(P＜0.01).对照组伤后6 h、24 h均可见明显的轴索肿胀、断裂、回缩球,而实验组仅见轴索肿胀,未见轴索断裂及回缩球.结论Mg2+可在轴索细胞骨架蛋白水平阻止轴索的继发性损害,对DAI具有一定的保护作用.