创伤性脑损伤的基础研究及相关脑脊液漏的临床治疗
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摘要
创伤性脑损伤（TBI）是全世界死亡和伤残的首要原因。颅脑创伤所导致的脑代谢紊乱是严重威胁生命的重要原因，对其进行广泛而深入的研究有着重要的现实意义。事实上目前许多常用的模型与人类所发生的外伤在受力与外部条件上是有差别的。实验模型常常应用头部固定打击，开颅手术后打击，延长麻醉时间等方法，这些都会对颅脑损伤的发展产生影响，减少继发性损伤，限制了颅内压（ICP）的监测。我们目前制作了一种新的加速打击脑外伤小鼠模型，称为打击运动模型。此模型不需长时间麻醉，不用限制头部运动，无需开颅手术，可以进行颅内压监测。损伤的严重程度可以通过气动冲击力来严格控制，设置不同的压力可以产生高度一致的轻微、中度或重度颅脑损伤。通过观察不同损伤程度的特征性病理组织学改变和行为缺陷，我们发现轻度脑外伤后动物表现出广泛的皮质和皮质下胶质细胞增生。虽然没有证据显示明确的皮质中断，血脑屏障开放，颅内压的变化或任何可察觉的认知障碍，但是相比中重度脑外伤模型，轻度脑外伤动物表现出的短暂的脑白质萎缩，弥漫性轴索损伤和神经元减少。并且轻度脑损伤出现一定程度的慢性感觉障碍伴随弥漫性神经损伤，这一结果强调了打击运动模型与目前现有的脑损伤模型相比有很大的进步，它使得我们可以对不同损伤程度的脑外伤（TBI）模型通过病理生理的研究进行有效评估。同时颅脑外伤后脑脊液漏临床十分常见，我们对颅脑外伤后造成的脑脊液漏进行引流途径的研究并通过对额窦骨折造成的脑脊液鼻漏应用新的方法进行有效的临床治疗。
第一部分创伤性脑损伤后小鼠脑白质变性、神经元缺失及行为学变化的研究
目的：建立小鼠轻度，中度或重度颅脑创伤实验模型，对损伤后脑组织进行组织学及行为学改变进行分析研究。评估脑损伤后脑组织及血脑屏障破坏程度，神经元缺失及轴突变性，并对损伤后小鼠行为学改变进行分析研究。
方法：所有实验中均采用雄性C57BL/6小鼠，乙醚诱导麻醉后应用改良控制性皮质损伤设备（CCI）造成大脑创伤，采用不同的打击速度制作不同程度的脑创伤模型，轻度4.8米/秒，中度5.2米/秒和重度5.6米/秒。应用2,3,5-三苯基氯化四氮唑（TTC）染色评价TBI后脑损伤的体积；伊文氏蓝外渗技术评估血脑屏障破坏程度；免疫组化染色观察创伤后脑部不同部位星形胶质细胞，微小胶质细胞，髓鞘碱性蛋白，磷酸化神经纤维，神经元的变化；干重-湿重法评估脑水肿的演变过程；并对颅内压及脑电活动进行监测，进行一系列行为学测试。
结果：
1打击运动颅脑损伤模型的成功建立
打击运动颅脑损伤模型首先的特点在于可以造成三种不同严重程度的损伤。仅需乙醚诱导麻醉后，迅速完成打击过程（平均19.9±1.9秒，17-24秒，N=26）。轻度脑外伤动物的觉醒时间与对照组动物没有显著差异，而中度和重度脑外伤动物表现出明显的苏醒延迟（P<0.01）。轻度到重度运动打击模型从麻醉到苏醒的整体时间范围为4.5-6.5分钟。未发现有造模过程导致急性死亡。366只小鼠造模共有16只死亡，其中轻度1只，中度1只，重度14只。
2损伤后不同程度组织破坏及血脑屏障的改变
2.1重度损伤组发现10.8％（16/148）有明显凹陷性颅骨骨折，但在轻度或中等损伤组没有观察到颅骨骨折。中度和重度组发现同侧硬膜下和/或蛛网膜下腔出血、明显挫伤，往往累积深部皮层及相关脑白质。
2.2脑外伤24小时后伊文氏蓝染色，轻度损伤组并没有表现出明显的损伤，而中度损伤只表现在小的损伤灶。相比轻度和中度损伤，重度脑外伤导致显著的大范围组织损伤与缺失，占对侧半球的体积近75％。
3损伤后反应性胶质细胞的演变
轻度脑外伤动物，弥漫GFAP和CD68免疫标记仅在局部受损伤一侧表达，穿透深度的皮质，皮质下白质，涉及纹状体，活化的小胶质细胞与反应性星形胶质细胞区域重叠，但一般仅限于皮层表面。3天后轻度胶质细胞增生并在第7天达到高峰。14天仍有表达，但在TBI后28天大部分消失。轻度脑外伤动物在任何时间点未发现明显胶质瘢痕或对侧脑损伤。重度脑外伤与中度的伤害相类似，但范围更加广泛，涵盖了同侧皮质，皮质下白质，纹状体和海马前部。对冲性损伤也明显位于皮质纹状体且范围更大。
4损伤后神经元缺失和轴突变性
4.1NeuN缺失轻度损伤后在任何时间点没有发现皮质或皮质下体积改变。中度损伤后，皮层组织中神经元第7天开始减少。轻度损伤组在内的所有不同程度脑损伤在3天和7天均有明显的神经元缺失，但不同损伤等级之间并没有统计学差异。重型颅脑损伤的动物除了组织的破坏和萎缩外，类似的损失是显而易见的，并且不同损伤组均有着剂量依赖性。
4.2免疫标记磷酸化神经丝（SMI-34），伤后14天通过对免疫磷酸化神经纤维（SMI-34）的观察分析发现同侧皮质和皮层下白质存在轴突变性。中度头部外伤后轴突变性更广泛，轻度脑外伤动物也可以观察到。
4.3髓鞘碱性蛋白（MBP）在中度脑外伤后14天GFAP阳性免疫反应周边区域，MBP在皮质的表达较对侧镜像区相对中断和不连续，重度损伤后14天皮质脱髓鞘更加严重。
5脑水肿轻度损伤模型在任何时间点均未发现脑水肿。相比之下，重度损伤模型脑组织同侧和对侧半球含水量在1和3天显著升高，而中度损伤后只在同侧半球有显著升高。对侧并没有表现出显著的脑水肿。在脑外伤7天后，重型颅脑损伤的对侧和中型颅脑损伤的同侧脑水肿均消退，但重型颅脑损伤动物的同侧仍升高。
6颅内压（ICP）中度损伤后ICP迅速增加并在伤后3天达到顶峰。除了ICP峰值和谷值均相对增高外，受伤后1天ICP脉搏波振幅也显著升高。基本在伤后4-6天回复正常水平。
7外伤后癫痫发作的评价脑电活动在更高的频段上没有明显改变,没有检测到创伤后癫痫样活动,且在发生在尖峰内的癫痫样活性增强没有统计学意义。
8行为学评估
8.1神经学评分
模型组在伤后3小时后表现出显著的神经功能损伤，中度和轻度损伤相对重度损伤分数要高，轻度脑外伤动物恢复快，24小时后基本恢复正常水平，中度在3天之间恢复，重型颅脑损伤的动物伤后3至7天逐渐恢复。
8.2旋转试验（Rotarod test）对照组动物协调性有明显提高，反映除了运动学习性能外完整的运动协调性。相比之下，中/重度TBI动物未能改善，一周后表现出持续的运动功能缺陷。
8.3旷场试验对照组与各模型组无统计学意义。从而说明了在创伤性脑外伤中旋转实验反应了受损的运动学习功能而不是简单的运动缺陷。
8.4新奇物识别实验在全程五周实验中对照组动物表现出稳定的对新物体的识别，轻度损伤表现正常，然而中度/重度TBI动物表现出对新事物辨识显著和持续的下降。
8.5巴恩斯迷宫(Barnes maze)实验脑外伤28天后。在连续3天的实验，对照组小鼠完成实验的时间明显缩短。轻度损伤小鼠与对照组相比无明显差别，然而中度/重度脑外伤小鼠表现出明显的认知障碍（P <0.05）。此外，与新奇物识别实验测试结果一致，轻度脑外伤动物没有表现出任何的认知缺陷，中度和重度TBI表现出长期运动和认知功能障碍。
结论：新TBI模型具有以下特点：（1）小鼠在受到打击后头部和身体可以自由运动，受力机制类似于现实生活中的意外伤害。（2）无需进行任何造模前的手术准备；（3）小鼠只需2-3min的诱导麻醉；（4）颅骨仍然闭合，避免颅骨骨折;（5）损伤程度可控性，包括轻度脑损伤特点：广泛的胶质细胞增生和脑白质变性。总体而言，这种简单的模型以造成稳定的脑白质病变伴随神经元的缺失，对不同程度损伤后的脑代谢改变的深入研究有重要意义，将对神经保护性试验研究产生十分有利的作用。
第二部分创伤性脑损伤（TBI）后水通道蛋白（AQP4）功能失调的动态改变及星形胶质细胞反应区域AQP4表达的复杂变化
目的：研究轻度及中度颅脑损伤后AQP4的动态改变和星形胶质细胞反应区域AQP4表达的复杂变化。
方法：10-12周龄的雄性C57BL/6小鼠，应用改良控制性皮层打击设备造模，通过免疫组化染色分析胶质纤维酸性蛋白（GFAP），小胶质细胞（CD68），神经元标记物(NeuN)，神经丝蛋白磷酸化标记物（SMI-34），水通道4（AQP4）和髓鞘碱性蛋白（MBP）损伤后的变化。
结果：
1轻、中度颅脑创伤模型的建立'轻度'和'中度'的脑损伤皮质撞击速度为4.8米/秒和5.2米/秒，深度和接触时间均保持不变（见第一部分）。
2创伤后胶质细胞反应性改变
轻度脑外伤动物3天伤后，打击部位星形胶质细胞（GFAP）和小胶质细胞（CD68）弥漫反应性增生（Fig.1B）。轻度脑外伤动物在任何时间点没有明显的胶质瘢痕出现，皮质改变在中度损伤后3天明显7天达到高峰，在7天形成明确的胶质瘢痕。
3TBI后脱髓鞘和轴突变性
轻度损伤在任何时间点没有发现明显的皮质或皮质下体积改变（Fig.2A-B），中度损伤后，皮层组织在伤后第7天出现改变（Fig.2A*P<0.05比对照）。轻度和中度头部外伤，包括胼胝体，外囊，皮质下白质有短暂的萎缩，在伤后第7天达到高峰（Fig.2C*P<0.05vs.对照）在14天趋于稳定。在胶质原纤维酸性蛋白免疫反应性的中度病变周围的区域，MBP较对侧表达明显减弱。（Fig.2D-F;*P<0.05vs.对照组）。磷酸化神经纤维（SMI-34）在伤后14天出现同侧皮质和皮质下白质轴突变性。轻度损伤也出现广泛轴突变性，但中度损伤更为明显（Fig.2I）。
4颅脑损伤后AQP4在局部的皮层和纹状体的表达发生复杂的变化。轻度损伤中AQP4在全脑的表达与血管周围AQP4表达均有明显减少。损伤后7天胶质瘢痕的形成使得AQP4上调表达增加，且AQP4的表达失调与星形胶质细胞反应性改变有关。
结论：创伤后反应性星形胶质细胞AQP4表达表现出明显的去极化，AQP4失调可能并不导致创伤后脑水肿和ICP的变化发展，而可能是一种代偿性反应。从轻度颅脑损伤后反应性星形胶质形成伴随AQP4功能失调来看，可以针对胶质细胞增生的治疗途径使AQP4表达正常化，减少中度或重度脑外伤创伤后癫痫发作的易感性，有利于脑内代谢废物的清除。
第三部分颅脑损伤后（TBI）脑脊液漏的基础研究及临床治疗
目的：对颅脑外伤后造成脑脊液漏进行引流途径研究并对额窦骨折造成的脑脊液鼻漏通过经皮注射纤维蛋白胶治疗的方法进行临床评估。
方法：影像学分析额窦鼻腔开口及其解剖学相关引流途径，对目前颅脑创伤所导致的难治性脑脊液鼻漏进行影像学定位诊断，并分析经皮注射纤维蛋白胶治疗额窦骨折脑脊液鼻漏的方法进行围手术期观察及预后的评估。
结果：对颅脑创伤导致额窦脑脊液鼻漏的基础研究有助于发现新的治疗途径。经皮穿刺注射纤维蛋白胶是有效治疗额窦脑脊液鼻漏的新方法。手术时间为27.6±7.98分钟，平均住院为11.25±4.99天，随访平均为11.5个月未见复发。
结论：对颅脑创伤导致额窦脑脊液鼻漏的基础研究有助于发现新的治疗途径。应用经皮穿刺纤维蛋白胶注射法治疗脑脊液鼻漏，只需要HRCT下检查额窦前后壁骨折情况定位漏口。此技术高效，损伤小，有利于临床推广，同时也表明基础研究对临床指导的重要性。
Traumatic brain injury (TBI) is a leading cause of death and disabilityworldwide. While experimental models have provided valuable insight intothe pathophysiology of traumatic brain injury, most commonly used modelsrepresent significant departures from the conditions and forces encountered byhuman patients. Head fixation, opening of the skull and prolonged anesthesiathat are typically employed in experimental TBI models likely alter the courseof TBI development, reducing secondary injury and preventing the monitoringof intracranial pressure (ICP). We have developed a murine model of TBI,termed ‘Hit&Run’, which produces consistent brain contusion in thetemporal lobe without prolonged anesthesia, head fixation or skull openingthat allows chronic monitoring of ICP. The severity of injury is tightlycontrolled by a pneumatic impactor, and differing pressure settings cangenerate highly consistent mild, moderate or severe TBI. In characterizing thehistopathology and behavioral deficits at these injury grades we observed thatmild TBI-treated animals exhibited widespread cortical and subcorticalreactive gliosis. While they did not show evidence of frank cortical disruption,blood brain barrier opening, changes in ICP or any detectable cognitive deficit,mild TBI animals exhibited transient white matter atrophy, diffuse axonalinjury and neuronal loss comparable to moderate and severe TBI animals. Thisdiffuse neuronal injury was accompanied by chronic sensorimotor deficits inmild TBI animals. These results highlight the ‘Hit&Run’ TBI model as animportant advance compared to current models of TBI in which thepathophysiology of mild to severe TBI can be evaluated. We further detailcomplex changes in post-traumatic AQP4expression and localization inreactive astrocytes that may make important contributions to edema formationand resolution after traumatic injury.
Most TBI cause cerebrospinal fluid (CSF) leak, at the same time, we studythe frontal sinus drainage pathway (FSDP) and evelop a novel method treatwith CSF rhinorrhea which make basic research transfer to clinicalachievement. We use percutaneous injection of fibrin glue manage frontalsinus CSF rhinorrhea which caused by trauma brain injury (TBI) set aexample for translational medicine, could be used more aggressively in a widearray of clinical scenarios.
Part1White matter degeneration, neuronal loss and behavior deficit inthe modified CCI model of traumatic brain injury (TBI)
Objectives: To develop a new experimental murine model that we call‘Hit&Run’ traumatic brain injury which is highly reproducible and can bemodulated to generate mild, moderate or severe grades of injury.
Methods: Male C57Bl/6mice, aged10-12weeks were used in ourexperiments. The device modified from the commercially available ControlledCortical Impact Device (CCI). Measurement of infarct volume and bloodbrain barrier disruption, Histology and image analysis, Evaluation of cerebraledema and intracranial pressure; Neurobehavioral tests include neuroscore,open field test, rotarod, novel object recognition test, Barnes maze test.
Results:
1Optimization of the Hit&Run traumatic brain injury model
Hit&Run injury was initially characterized at three different severities.Arousal time for mild TBI animals did not differ significantly from shamcontrol animals, whereas moderate and severe TBI animals exhibitedsignificantly longer arousal latencies. Out of366total TBI treated mice,delayed death was observed in1mild TBI mouse,1moderate TBI mouse and14severe TBI mice.
2Blood brain barrier disruption and infarction
2.1Depressed skull fractures were evident in10.8%(16out of148) insevere injury group, but not observed in either the moderate or the mild injurygroup. Ipsilateral subdural and/or subarachnoid hemorrhage and contusionwere evident in moderate and severe animals. Hemorrhages were confined to the site of impact in the moderate group, while in severe TBI animals, theinjury was more extensive, spreading into the deep cortex and underlyingwhite matter.
2.2Mice in the mild group did not exhibit any appreciable infarction,while those with moderate injury exhibited only small infarcts. Compared toboth mild and moderate injury, severe TBI resulted in dramatically largerinfarcts, encompassing nearly75%of the volume of the contralateralhemisphere.
3Evolution of reactive gliosis after injury
The disrupted cortex at three days was continuous with a wide surroundingfield of reactive astrogliosis and microgliosis. Between7and28days afterinjury, the glial scar did not change appreciably in dimensions with extensivesurrounding astrogliosis evident at7and14days post injury that began toresolve by28days. Severe TBI resembled moderate injury, but was moreextensive, encompassing much of the ipsilateral cortex, subcortical whitematter, striatum and portions of the anterior hippocampus. More pronouncedcontrecoup injury was observed in severe TBI animals.
4Neuronal loss and axonal degeneration after injury
4.1After moderate TBI, a delayed loss of cortical tissue was observedbeginning7days after injury. In severe TBI animals, a similar loss of corticalvolume was evident immediately at3days. Neuronal loss was plainly evidentin the gliotic regions at both3and7days in all injury grades, including mildTBI, and did not appear to systematically differ between grades. In the cortexof the moderate and severe groups, neuronal loss did not appear to progressfrom3to7days, while a significant decline was observed in the mild groupbetween these two time points.
4.2Immunolabeling for phosphorylated neurofilament (SMI-34)14daysafter injury revealed evidence of axonal degeneration in the ipsilateral cortexand subcortical white matter. While axon degeneration was more widespreadafter moderate TBI.
4.3MBP labeling in regions of GFAP-immunoreactivity surroundingmoderate lesions was both less intense and less continuous compared tomirror-image regions of the contralateral cortex. In the cortex surroundingsevers TBI lesions; demyelization was much more extensive at14dayspost-injury.
5Brain water content was significantly elevated at1and3days post-TBIin both the ipsilateral and contralateral hemispheres of severe TBI animals, inaddition to the ipsilateral hemisphere of moderate TBI animals. Thecontralateral moderate TBI brain did not exhibit significant cerebral edema. At7days post-TBI, cerebral edema resolved in the contralateral hemisphere ofthe severe TBI and the ipsilateral hemisphere of the moderate TBI animals.
6Intracranial pressures (ICP) quickly increased and peaked3dayspost-injury. ICP pulse wave amplitude significantly elevated at1daypost-injury. After TBI, ICP values normalized between4-6days post-injury.
7There was no statistically significant increase in seizure-like activity.The absence of detectable post-traumatic seizure-like activity in the moderateTBI grade is consistent with the lack of frank hippocampal disruption and thegrossly preserved neuronal numbers within the CA1and CA3regions.
8Behavioral evaluations
8.1Control animals exhibited no deficits in global neuroscore (score of0)at any time points. At3hours post-injury, all TBI groups exhibited significantdeficits in neuroscore values. These deficits were most pronounced in thesevere group, with moderate and mild groups exhibiting similar levels ofdeficit. Mild TBI animals recovered quickly, returning to control valuesbetween24hrs and3days post-injury. Moderate and severe TBI animalsrecovered gradually between3and7days post-injury.
8.2Rotarod test: Control animals improved in performance of the rotarodtest. In contrast, moderate/severe TBI animals failed to improve in the rotorodtask, exhibiting significant motor deficit beginning1week post-injury, andpersisting for the full duration of the experiment. Mild TBI animals exhibiteda deficit in the Rotarod task that was indistinguishable from that observed in moderate/severe animals.
8.3Open field test: Severe TBI showed a trending deficit and motorfunction and anxiety.
8.4The novel object recognition test: Control animals exhibited a stablenovel object preference in all five weeks of study. Moderate/severe TBIanimals exhibited a significant and persistent decline in novel objectrecognition test performance. Mild TBI animals did not exhibit a deficit innovel object recognition test performance at any time point.
8.5Barnes maze test: Control animals exhibited a declining latency tocomplete the maze task. As observed with novel object recognition,moderate/severe TBI mice exhibited a significant cognitive deficit, showingno change in latency to complete the task on subsequent trial days. Also inaccordance with novel object recognition test findings, mild TBI animals didnot show any cognitive deficit compared to the control cohort. Mild TBIanimals had not deficit in cognitive function but suffered a motor function ormotor learning deficit that was as great as observed in moderate and severeTBI.
Conclusions:
We have developed and characterized a new TBI model, termed ‘Hit&Run’ TBI, in which the mouse head and body are freely mobile during impact,while the brain is exposed to angular and linear acceleration forces similar tothose in real-life accidents. Additionally, the Hit&Run model has otheradvantages, including (1) no pre-injury surgery is required;(2) the mice areanesthetized for only2-3min prior to impact;(3) the skull remains closed andskull fractures are avoided;(4) the model results in widespread reactive gliosisand delayed axonal degeneration, as well as a consistent contrecoup injury;(5)the severity of injury can be modulated, including the production of mildinsult characterized by diffuse injury and white matter degeneration. In all,this model will be highly conducive to large experimental trials ofneuroprotection.
Part2Complex patterns of AQP4disorder after closed-skull traumaticbrain injury (TBI)
Objective: To investigate the dynamics of AQP4disorder after both mildand moderate closed-skull injury and complex changes in post-traumaticAQP4expression and localization in reactive astrocytes that may makeimportant contributions to edema formation and resolution after traumaticinjury.
Methods: Male C57Bl/6mice, aged10-12weeks were used in ourexperiments. The device used for “Hit&Run” TBI was modified from thecommercially-available Controlled Cortical Impact Device (CCI), Histologyand image analysis after labeling of glial fibrillary acidic protein (GFAP),CD68, NeuN, phosphorylated neurofilament (SMI-34), aquaproin-4(AQP4)and myelin basic protein (MBP).
Results:
1Hit&Run device and injury model
Hit&Run injury was characterized at two different severities.‘Mild’ and‘moderate’ injuries utilized cortical impactor velocities of4.8m/s and5.2m/s,respectively, while the impact depth and contact times were held constant.
2Development of post-traumatic reactive gliosis
In mild TBI animals3days post-injury, diffuse GFAP (reactive astrocytes)and CD68(reactive microglia) labeling were evident local to the impact site(Fig.1B). No defined glial scar was apparent in mild TBI animals at any timepoint. Cortical disruption was apparent in moderate TBI animals3dayspost-injury (Fig.1F) that evolved over the first week to form a well-definedglial scar surrounding the lesion cavity and reached a peak within3-7dayspost-injury.
3Demyelination and axonal degeneration after TBI
No measurable changes in cortical or subcortical volume were evident atany time point (Fig.2A-B). After moderate TBI, a delayed loss of corticaltissue was observed beginning7days after injury (Fig.2A;*P<0.05vs. control,2-way ANOVA). Loss of striatal tissue was muted compared to the cortex (Fig.1B;*P<0.05vs. control,2-way ANOVA). Both mild and moderate TBI, atransient atrophy of the subcortical white matter including the corpus callosumand the external capsule was evident that peaked at7days post-injury (Fig.2C;*P<0.05vs. control,2-way ANOVA) and normalized within14days of injury.In regions of GFAP-immunoreactivity surrounding moderate lesions, MBPlabeling was both less extensive and less continuous compared tomirror-image regions of the contralateral cortex (Fig.2D-F;*P<0.05vs.control,1-way ANOVA). Immunolabeling for phosphorylated neurofilament(SMI-34)14days after injury revealed evidence of axonal degeneration in theipsilateral cortex and subcortical white matter (Fig.2G, I, arrows). While axondegeneration was more widespread after moderate TBI (Fig.2G), it was alsoobserved in mild TBI animals (Fig.2I).
4AQP4expression and localization are undergoing complex changeswithin the cortex and striatum after TBI. A mild increase in global AQP4expression coincided with a marked decrease in perivascular AQP4expression.Reactive gliosis in the chronic phase may provide a therapeutic avenue tonormalize AQP4expression and reduce post-traumatic seizure susceptibilityand improve clearance of interstitial wastes after moderate or severe TBI.
Conclusion:
We find that post-traumatic reactive astrocytes exhibit markeddepolarization of AQP4expression, with localization shifting from theperivascular endfoot processes to the wider somal compartments. Our findingssuggest that AQP4disorder likely does not contribute to the development ofpost-traumatic cerebral edema and changes in ICP, but may represent acompensatory response to these events. The observation that AQP4disorderresolved with reactive astrogliosis after mild TBI suggests that targetingreactive gliosis in the chronic phase may provide a therapeutic avenue tonormalize AQP4expression and reduce post-traumatic seizure susceptibilityand improve clearance of interstitial wastes after moderate or severe TBI.
Part3Anatomical study and clinical treatment of frontal sinuscerebrospinal fluid rhinorrhea after trauma brain injury (TBI)
Objectives: In this study, we describe the frontal sinus drainage pathwayof cerebrospinal fluid (CSF) and examined the effectiveness of percutaneousinjected fibrin glue as a treatment for frontal sinus CSF rhinorrhea in a seriesof4cases.
Methods: All four cases were identified by experienced neurosurgeonsas frontal sinus CSF rhinorrhea from425patients, percutaneous injected fibringlue to frontal sinus after standard topical anesthesia. Postoperative care andefficacy evaluation were carry out by follow-up visits including CTexamination and routine physical examination, at2weeks and3,6, and12months after the surgery.
Results: Display of the FSDP is useful when evaluating the cause andpotential surgical therapy for obstruction of the frontal sinus. The frontalostium forms the upper border of the superior compartment of FSDP. Theinferior-compartment of the FSDP is formed by the ethmoid infundibulum.
In our case series, percutaneous injection of fibrin glue was successful inthe treatment of frontal sinus CSF rhinorrhea in all four patients. The surgerytime is27.6±7.98min; average hospitalization is11.25±4.99days. Norecurrence was found in an average of11.5months following injection offibrin glue. Frontal defects were found in3of the4cases (patients1,2and4);the glue was dispelled two days after the repair in the first case, butsubsequent re-repair was successful. Case2recovered well and received rightfrontal cranioplasty6months after repair. One patient (case3) eventually diedof tumor relapse in12month despite of successful repair of CSF rhinorrheawithout recurrence through10-month follow-up.
Conclusion: In summary, display of the FSDP is useful when evaluatingthe cause and potential surgical therapy for obstruction of the frontal sinus. Wehave developed a novel method for stopping CSF rhinorrhea from theposterior wall of the frontal sinus that only requires examination of theanterior-posterior wall and the frontal ostium under CT image. This techniquecauses minimal injury, and thus could be used more aggressively in a widearray of clinical scenarios. An additional advantage is the fact that patients do not have to wait until the outcome of conventional conservative treatmentbecomes clear. The success of this novel yet simple method for stopping CSFrhinorrhea in our case series has encouraged further use.
第一部分创伤性脑损伤后小鼠脑白质变性、神经元缺失及行为学变化的研究
目的：建立小鼠轻度，中度或重度颅脑创伤实验模型，对损伤后脑组织进行组织学及行为学改变进行分析研究。评估脑损伤后脑组织及血脑屏障破坏程度，神经元缺失及轴突变性，并对损伤后小鼠行为学改变进行分析研究。
方法：所有实验中均采用雄性C57BL/6小鼠，乙醚诱导麻醉后应用改良控制性皮质损伤设备（CCI）造成大脑创伤，采用不同的打击速度制作不同程度的脑创伤模型，轻度4.8米/秒，中度5.2米/秒和重度5.6米/秒。应用2,3,5-三苯基氯化四氮唑（TTC）染色评价TBI后脑损伤的体积；伊文氏蓝外渗技术评估血脑屏障破坏程度；免疫组化染色观察创伤后脑部不同部位星形胶质细胞，微小胶质细胞，髓鞘碱性蛋白，磷酸化神经纤维，神经元的变化；干重-湿重法评估脑水肿的演变过程；并对颅内压及脑电活动进行监测，进行一系列行为学测试。
结果：
1打击运动颅脑损伤模型的成功建立
打击运动颅脑损伤模型首先的特点在于可以造成三种不同严重程度的损伤。仅需乙醚诱导麻醉后，迅速完成打击过程（平均19.9±1.9秒，17-24秒，N=26）。轻度脑外伤动物的觉醒时间与对照组动物没有显著差异，而中度和重度脑外伤动物表现出明显的苏醒延迟（P<0.01）。轻度到重度运动打击模型从麻醉到苏醒的整体时间范围为4.5-6.5分钟。未发现有造模过程导致急性死亡。366只小鼠造模共有16只死亡，其中轻度1只，中度1只，重度14只。
2损伤后不同程度组织破坏及血脑屏障的改变
2.1重度损伤组发现10.8％（16/148）有明显凹陷性颅骨骨折，但在轻度或中等损伤组没有观察到颅骨骨折。中度和重度组发现同侧硬膜下和/或蛛网膜下腔出血、明显挫伤，往往累积深部皮层及相关脑白质。
2.2脑外伤24小时后伊文氏蓝染色，轻度损伤组并没有表现出明显的损伤，而中度损伤只表现在小的损伤灶。相比轻度和中度损伤，重度脑外伤导致显著的大范围组织损伤与缺失，占对侧半球的体积近75％。
3损伤后反应性胶质细胞的演变
轻度脑外伤动物，弥漫GFAP和CD68免疫标记仅在局部受损伤一侧表达，穿透深度的皮质，皮质下白质，涉及纹状体，活化的小胶质细胞与反应性星形胶质细胞区域重叠，但一般仅限于皮层表面。3天后轻度胶质细胞增生并在第7天达到高峰。14天仍有表达，但在TBI后28天大部分消失。轻度脑外伤动物在任何时间点未发现明显胶质瘢痕或对侧脑损伤。重度脑外伤与中度的伤害相类似，但范围更加广泛，涵盖了同侧皮质，皮质下白质，纹状体和海马前部。对冲性损伤也明显位于皮质纹状体且范围更大。
4损伤后神经元缺失和轴突变性
4.1NeuN缺失轻度损伤后在任何时间点没有发现皮质或皮质下体积改变。中度损伤后，皮层组织中神经元第7天开始减少。轻度损伤组在内的所有不同程度脑损伤在3天和7天均有明显的神经元缺失，但不同损伤等级之间并没有统计学差异。重型颅脑损伤的动物除了组织的破坏和萎缩外，类似的损失是显而易见的，并且不同损伤组均有着剂量依赖性。
4.2免疫标记磷酸化神经丝（SMI-34），伤后14天通过对免疫磷酸化神经纤维（SMI-34）的观察分析发现同侧皮质和皮层下白质存在轴突变性。中度头部外伤后轴突变性更广泛，轻度脑外伤动物也可以观察到。
4.3髓鞘碱性蛋白（MBP）在中度脑外伤后14天GFAP阳性免疫反应周边区域，MBP在皮质的表达较对侧镜像区相对中断和不连续，重度损伤后14天皮质脱髓鞘更加严重。
5脑水肿轻度损伤模型在任何时间点均未发现脑水肿。相比之下，重度损伤模型脑组织同侧和对侧半球含水量在1和3天显著升高，而中度损伤后只在同侧半球有显著升高。对侧并没有表现出显著的脑水肿。在脑外伤7天后，重型颅脑损伤的对侧和中型颅脑损伤的同侧脑水肿均消退，但重型颅脑损伤动物的同侧仍升高。
6颅内压（ICP）中度损伤后ICP迅速增加并在伤后3天达到顶峰。除了ICP峰值和谷值均相对增高外，受伤后1天ICP脉搏波振幅也显著升高。基本在伤后4-6天回复正常水平。
7外伤后癫痫发作的评价脑电活动在更高的频段上没有明显改变,没有检测到创伤后癫痫样活动,且在发生在尖峰内的癫痫样活性增强没有统计学意义。
8行为学评估
8.1神经学评分
模型组在伤后3小时后表现出显著的神经功能损伤，中度和轻度损伤相对重度损伤分数要高，轻度脑外伤动物恢复快，24小时后基本恢复正常水平，中度在3天之间恢复，重型颅脑损伤的动物伤后3至7天逐渐恢复。
8.2旋转试验（Rotarod test）对照组动物协调性有明显提高，反映除了运动学习性能外完整的运动协调性。相比之下，中/重度TBI动物未能改善，一周后表现出持续的运动功能缺陷。
8.3旷场试验对照组与各模型组无统计学意义。从而说明了在创伤性脑外伤中旋转实验反应了受损的运动学习功能而不是简单的运动缺陷。
8.4新奇物识别实验在全程五周实验中对照组动物表现出稳定的对新物体的识别，轻度损伤表现正常，然而中度/重度TBI动物表现出对新事物辨识显著和持续的下降。
8.5巴恩斯迷宫(Barnes maze)实验脑外伤28天后。在连续3天的实验，对照组小鼠完成实验的时间明显缩短。轻度损伤小鼠与对照组相比无明显差别，然而中度/重度脑外伤小鼠表现出明显的认知障碍（P <0.05）。此外，与新奇物识别实验测试结果一致，轻度脑外伤动物没有表现出任何的认知缺陷，中度和重度TBI表现出长期运动和认知功能障碍。
结论：新TBI模型具有以下特点：（1）小鼠在受到打击后头部和身体可以自由运动，受力机制类似于现实生活中的意外伤害。（2）无需进行任何造模前的手术准备；（3）小鼠只需2-3min的诱导麻醉；（4）颅骨仍然闭合，避免颅骨骨折;（5）损伤程度可控性，包括轻度脑损伤特点：广泛的胶质细胞增生和脑白质变性。总体而言，这种简单的模型以造成稳定的脑白质病变伴随神经元的缺失，对不同程度损伤后的脑代谢改变的深入研究有重要意义，将对神经保护性试验研究产生十分有利的作用。
第二部分创伤性脑损伤（TBI）后水通道蛋白（AQP4）功能失调的动态改变及星形胶质细胞反应区域AQP4表达的复杂变化
目的：研究轻度及中度颅脑损伤后AQP4的动态改变和星形胶质细胞反应区域AQP4表达的复杂变化。
方法：10-12周龄的雄性C57BL/6小鼠，应用改良控制性皮层打击设备造模，通过免疫组化染色分析胶质纤维酸性蛋白（GFAP），小胶质细胞（CD68），神经元标记物(NeuN)，神经丝蛋白磷酸化标记物（SMI-34），水通道4（AQP4）和髓鞘碱性蛋白（MBP）损伤后的变化。
结果：
1轻、中度颅脑创伤模型的建立'轻度'和'中度'的脑损伤皮质撞击速度为4.8米/秒和5.2米/秒，深度和接触时间均保持不变（见第一部分）。
2创伤后胶质细胞反应性改变
轻度脑外伤动物3天伤后，打击部位星形胶质细胞（GFAP）和小胶质细胞（CD68）弥漫反应性增生（Fig.1B）。轻度脑外伤动物在任何时间点没有明显的胶质瘢痕出现，皮质改变在中度损伤后3天明显7天达到高峰，在7天形成明确的胶质瘢痕。
3TBI后脱髓鞘和轴突变性
轻度损伤在任何时间点没有发现明显的皮质或皮质下体积改变（Fig.2A-B），中度损伤后，皮层组织在伤后第7天出现改变（Fig.2A*P<0.05比对照）。轻度和中度头部外伤，包括胼胝体，外囊，皮质下白质有短暂的萎缩，在伤后第7天达到高峰（Fig.2C*P<0.05vs.对照）在14天趋于稳定。在胶质原纤维酸性蛋白免疫反应性的中度病变周围的区域，MBP较对侧表达明显减弱。（Fig.2D-F;*P<0.05vs.对照组）。磷酸化神经纤维（SMI-34）在伤后14天出现同侧皮质和皮质下白质轴突变性。轻度损伤也出现广泛轴突变性，但中度损伤更为明显（Fig.2I）。
4颅脑损伤后AQP4在局部的皮层和纹状体的表达发生复杂的变化。轻度损伤中AQP4在全脑的表达与血管周围AQP4表达均有明显减少。损伤后7天胶质瘢痕的形成使得AQP4上调表达增加，且AQP4的表达失调与星形胶质细胞反应性改变有关。
结论：创伤后反应性星形胶质细胞AQP4表达表现出明显的去极化，AQP4失调可能并不导致创伤后脑水肿和ICP的变化发展，而可能是一种代偿性反应。从轻度颅脑损伤后反应性星形胶质形成伴随AQP4功能失调来看，可以针对胶质细胞增生的治疗途径使AQP4表达正常化，减少中度或重度脑外伤创伤后癫痫发作的易感性，有利于脑内代谢废物的清除。
第三部分颅脑损伤后（TBI）脑脊液漏的基础研究及临床治疗
目的：对颅脑外伤后造成脑脊液漏进行引流途径研究并对额窦骨折造成的脑脊液鼻漏通过经皮注射纤维蛋白胶治疗的方法进行临床评估。
方法：影像学分析额窦鼻腔开口及其解剖学相关引流途径，对目前颅脑创伤所导致的难治性脑脊液鼻漏进行影像学定位诊断，并分析经皮注射纤维蛋白胶治疗额窦骨折脑脊液鼻漏的方法进行围手术期观察及预后的评估。
结果：对颅脑创伤导致额窦脑脊液鼻漏的基础研究有助于发现新的治疗途径。经皮穿刺注射纤维蛋白胶是有效治疗额窦脑脊液鼻漏的新方法。手术时间为27.6±7.98分钟，平均住院为11.25±4.99天，随访平均为11.5个月未见复发。
结论：对颅脑创伤导致额窦脑脊液鼻漏的基础研究有助于发现新的治疗途径。应用经皮穿刺纤维蛋白胶注射法治疗脑脊液鼻漏，只需要HRCT下检查额窦前后壁骨折情况定位漏口。此技术高效，损伤小，有利于临床推广，同时也表明基础研究对临床指导的重要性。
Traumatic brain injury (TBI) is a leading cause of death and disabilityworldwide. While experimental models have provided valuable insight intothe pathophysiology of traumatic brain injury, most commonly used modelsrepresent significant departures from the conditions and forces encountered byhuman patients. Head fixation, opening of the skull and prolonged anesthesiathat are typically employed in experimental TBI models likely alter the courseof TBI development, reducing secondary injury and preventing the monitoringof intracranial pressure (ICP). We have developed a murine model of TBI,termed ‘Hit&Run’, which produces consistent brain contusion in thetemporal lobe without prolonged anesthesia, head fixation or skull openingthat allows chronic monitoring of ICP. The severity of injury is tightlycontrolled by a pneumatic impactor, and differing pressure settings cangenerate highly consistent mild, moderate or severe TBI. In characterizing thehistopathology and behavioral deficits at these injury grades we observed thatmild TBI-treated animals exhibited widespread cortical and subcorticalreactive gliosis. While they did not show evidence of frank cortical disruption,blood brain barrier opening, changes in ICP or any detectable cognitive deficit,mild TBI animals exhibited transient white matter atrophy, diffuse axonalinjury and neuronal loss comparable to moderate and severe TBI animals. Thisdiffuse neuronal injury was accompanied by chronic sensorimotor deficits inmild TBI animals. These results highlight the ‘Hit&Run’ TBI model as animportant advance compared to current models of TBI in which thepathophysiology of mild to severe TBI can be evaluated. We further detailcomplex changes in post-traumatic AQP4expression and localization inreactive astrocytes that may make important contributions to edema formationand resolution after traumatic injury.
Most TBI cause cerebrospinal fluid (CSF) leak, at the same time, we studythe frontal sinus drainage pathway (FSDP) and evelop a novel method treatwith CSF rhinorrhea which make basic research transfer to clinicalachievement. We use percutaneous injection of fibrin glue manage frontalsinus CSF rhinorrhea which caused by trauma brain injury (TBI) set aexample for translational medicine, could be used more aggressively in a widearray of clinical scenarios.
Part1White matter degeneration, neuronal loss and behavior deficit inthe modified CCI model of traumatic brain injury (TBI)
Objectives: To develop a new experimental murine model that we call‘Hit&Run’ traumatic brain injury which is highly reproducible and can bemodulated to generate mild, moderate or severe grades of injury.
Methods: Male C57Bl/6mice, aged10-12weeks were used in ourexperiments. The device modified from the commercially available ControlledCortical Impact Device (CCI). Measurement of infarct volume and bloodbrain barrier disruption, Histology and image analysis, Evaluation of cerebraledema and intracranial pressure; Neurobehavioral tests include neuroscore,open field test, rotarod, novel object recognition test, Barnes maze test.
Results:
1Optimization of the Hit&Run traumatic brain injury model
Hit&Run injury was initially characterized at three different severities.Arousal time for mild TBI animals did not differ significantly from shamcontrol animals, whereas moderate and severe TBI animals exhibitedsignificantly longer arousal latencies. Out of366total TBI treated mice,delayed death was observed in1mild TBI mouse,1moderate TBI mouse and14severe TBI mice.
2Blood brain barrier disruption and infarction
2.1Depressed skull fractures were evident in10.8%(16out of148) insevere injury group, but not observed in either the moderate or the mild injurygroup. Ipsilateral subdural and/or subarachnoid hemorrhage and contusionwere evident in moderate and severe animals. Hemorrhages were confined to the site of impact in the moderate group, while in severe TBI animals, theinjury was more extensive, spreading into the deep cortex and underlyingwhite matter.
2.2Mice in the mild group did not exhibit any appreciable infarction,while those with moderate injury exhibited only small infarcts. Compared toboth mild and moderate injury, severe TBI resulted in dramatically largerinfarcts, encompassing nearly75%of the volume of the contralateralhemisphere.
3Evolution of reactive gliosis after injury
The disrupted cortex at three days was continuous with a wide surroundingfield of reactive astrogliosis and microgliosis. Between7and28days afterinjury, the glial scar did not change appreciably in dimensions with extensivesurrounding astrogliosis evident at7and14days post injury that began toresolve by28days. Severe TBI resembled moderate injury, but was moreextensive, encompassing much of the ipsilateral cortex, subcortical whitematter, striatum and portions of the anterior hippocampus. More pronouncedcontrecoup injury was observed in severe TBI animals.
4Neuronal loss and axonal degeneration after injury
4.1After moderate TBI, a delayed loss of cortical tissue was observedbeginning7days after injury. In severe TBI animals, a similar loss of corticalvolume was evident immediately at3days. Neuronal loss was plainly evidentin the gliotic regions at both3and7days in all injury grades, including mildTBI, and did not appear to systematically differ between grades. In the cortexof the moderate and severe groups, neuronal loss did not appear to progressfrom3to7days, while a significant decline was observed in the mild groupbetween these two time points.
4.2Immunolabeling for phosphorylated neurofilament (SMI-34)14daysafter injury revealed evidence of axonal degeneration in the ipsilateral cortexand subcortical white matter. While axon degeneration was more widespreadafter moderate TBI.
4.3MBP labeling in regions of GFAP-immunoreactivity surroundingmoderate lesions was both less intense and less continuous compared tomirror-image regions of the contralateral cortex. In the cortex surroundingsevers TBI lesions; demyelization was much more extensive at14dayspost-injury.
5Brain water content was significantly elevated at1and3days post-TBIin both the ipsilateral and contralateral hemispheres of severe TBI animals, inaddition to the ipsilateral hemisphere of moderate TBI animals. Thecontralateral moderate TBI brain did not exhibit significant cerebral edema. At7days post-TBI, cerebral edema resolved in the contralateral hemisphere ofthe severe TBI and the ipsilateral hemisphere of the moderate TBI animals.
6Intracranial pressures (ICP) quickly increased and peaked3dayspost-injury. ICP pulse wave amplitude significantly elevated at1daypost-injury. After TBI, ICP values normalized between4-6days post-injury.
7There was no statistically significant increase in seizure-like activity.The absence of detectable post-traumatic seizure-like activity in the moderateTBI grade is consistent with the lack of frank hippocampal disruption and thegrossly preserved neuronal numbers within the CA1and CA3regions.
8Behavioral evaluations
8.1Control animals exhibited no deficits in global neuroscore (score of0)at any time points. At3hours post-injury, all TBI groups exhibited significantdeficits in neuroscore values. These deficits were most pronounced in thesevere group, with moderate and mild groups exhibiting similar levels ofdeficit. Mild TBI animals recovered quickly, returning to control valuesbetween24hrs and3days post-injury. Moderate and severe TBI animalsrecovered gradually between3and7days post-injury.
8.2Rotarod test: Control animals improved in performance of the rotarodtest. In contrast, moderate/severe TBI animals failed to improve in the rotorodtask, exhibiting significant motor deficit beginning1week post-injury, andpersisting for the full duration of the experiment. Mild TBI animals exhibiteda deficit in the Rotarod task that was indistinguishable from that observed in moderate/severe animals.
8.3Open field test: Severe TBI showed a trending deficit and motorfunction and anxiety.
8.4The novel object recognition test: Control animals exhibited a stablenovel object preference in all five weeks of study. Moderate/severe TBIanimals exhibited a significant and persistent decline in novel objectrecognition test performance. Mild TBI animals did not exhibit a deficit innovel object recognition test performance at any time point.
8.5Barnes maze test: Control animals exhibited a declining latency tocomplete the maze task. As observed with novel object recognition,moderate/severe TBI mice exhibited a significant cognitive deficit, showingno change in latency to complete the task on subsequent trial days. Also inaccordance with novel object recognition test findings, mild TBI animals didnot show any cognitive deficit compared to the control cohort. Mild TBIanimals had not deficit in cognitive function but suffered a motor function ormotor learning deficit that was as great as observed in moderate and severeTBI.
Conclusions:
We have developed and characterized a new TBI model, termed ‘Hit&Run’ TBI, in which the mouse head and body are freely mobile during impact,while the brain is exposed to angular and linear acceleration forces similar tothose in real-life accidents. Additionally, the Hit&Run model has otheradvantages, including (1) no pre-injury surgery is required;(2) the mice areanesthetized for only2-3min prior to impact;(3) the skull remains closed andskull fractures are avoided;(4) the model results in widespread reactive gliosisand delayed axonal degeneration, as well as a consistent contrecoup injury;(5)the severity of injury can be modulated, including the production of mildinsult characterized by diffuse injury and white matter degeneration. In all,this model will be highly conducive to large experimental trials ofneuroprotection.
Part2Complex patterns of AQP4disorder after closed-skull traumaticbrain injury (TBI)
Objective: To investigate the dynamics of AQP4disorder after both mildand moderate closed-skull injury and complex changes in post-traumaticAQP4expression and localization in reactive astrocytes that may makeimportant contributions to edema formation and resolution after traumaticinjury.
Methods: Male C57Bl/6mice, aged10-12weeks were used in ourexperiments. The device used for “Hit&Run” TBI was modified from thecommercially-available Controlled Cortical Impact Device (CCI), Histologyand image analysis after labeling of glial fibrillary acidic protein (GFAP),CD68, NeuN, phosphorylated neurofilament (SMI-34), aquaproin-4(AQP4)and myelin basic protein (MBP).
Results:
1Hit&Run device and injury model
Hit&Run injury was characterized at two different severities.‘Mild’ and‘moderate’ injuries utilized cortical impactor velocities of4.8m/s and5.2m/s,respectively, while the impact depth and contact times were held constant.
2Development of post-traumatic reactive gliosis
In mild TBI animals3days post-injury, diffuse GFAP (reactive astrocytes)and CD68(reactive microglia) labeling were evident local to the impact site(Fig.1B). No defined glial scar was apparent in mild TBI animals at any timepoint. Cortical disruption was apparent in moderate TBI animals3dayspost-injury (Fig.1F) that evolved over the first week to form a well-definedglial scar surrounding the lesion cavity and reached a peak within3-7dayspost-injury.
3Demyelination and axonal degeneration after TBI
No measurable changes in cortical or subcortical volume were evident atany time point (Fig.2A-B). After moderate TBI, a delayed loss of corticaltissue was observed beginning7days after injury (Fig.2A;*P<0.05vs. control,2-way ANOVA). Loss of striatal tissue was muted compared to the cortex (Fig.1B;*P<0.05vs. control,2-way ANOVA). Both mild and moderate TBI, atransient atrophy of the subcortical white matter including the corpus callosumand the external capsule was evident that peaked at7days post-injury (Fig.2C;*P<0.05vs. control,2-way ANOVA) and normalized within14days of injury.In regions of GFAP-immunoreactivity surrounding moderate lesions, MBPlabeling was both less extensive and less continuous compared tomirror-image regions of the contralateral cortex (Fig.2D-F;*P<0.05vs.control,1-way ANOVA). Immunolabeling for phosphorylated neurofilament(SMI-34)14days after injury revealed evidence of axonal degeneration in theipsilateral cortex and subcortical white matter (Fig.2G, I, arrows). While axondegeneration was more widespread after moderate TBI (Fig.2G), it was alsoobserved in mild TBI animals (Fig.2I).
4AQP4expression and localization are undergoing complex changeswithin the cortex and striatum after TBI. A mild increase in global AQP4expression coincided with a marked decrease in perivascular AQP4expression.Reactive gliosis in the chronic phase may provide a therapeutic avenue tonormalize AQP4expression and reduce post-traumatic seizure susceptibilityand improve clearance of interstitial wastes after moderate or severe TBI.
Conclusion:
We find that post-traumatic reactive astrocytes exhibit markeddepolarization of AQP4expression, with localization shifting from theperivascular endfoot processes to the wider somal compartments. Our findingssuggest that AQP4disorder likely does not contribute to the development ofpost-traumatic cerebral edema and changes in ICP, but may represent acompensatory response to these events. The observation that AQP4disorderresolved with reactive astrogliosis after mild TBI suggests that targetingreactive gliosis in the chronic phase may provide a therapeutic avenue tonormalize AQP4expression and reduce post-traumatic seizure susceptibilityand improve clearance of interstitial wastes after moderate or severe TBI.
Part3Anatomical study and clinical treatment of frontal sinuscerebrospinal fluid rhinorrhea after trauma brain injury (TBI)
Objectives: In this study, we describe the frontal sinus drainage pathwayof cerebrospinal fluid (CSF) and examined the effectiveness of percutaneousinjected fibrin glue as a treatment for frontal sinus CSF rhinorrhea in a seriesof4cases.
Methods: All four cases were identified by experienced neurosurgeonsas frontal sinus CSF rhinorrhea from425patients, percutaneous injected fibringlue to frontal sinus after standard topical anesthesia. Postoperative care andefficacy evaluation were carry out by follow-up visits including CTexamination and routine physical examination, at2weeks and3,6, and12months after the surgery.
Results: Display of the FSDP is useful when evaluating the cause andpotential surgical therapy for obstruction of the frontal sinus. The frontalostium forms the upper border of the superior compartment of FSDP. Theinferior-compartment of the FSDP is formed by the ethmoid infundibulum.
In our case series, percutaneous injection of fibrin glue was successful inthe treatment of frontal sinus CSF rhinorrhea in all four patients. The surgerytime is27.6±7.98min; average hospitalization is11.25±4.99days. Norecurrence was found in an average of11.5months following injection offibrin glue. Frontal defects were found in3of the4cases (patients1,2and4);the glue was dispelled two days after the repair in the first case, butsubsequent re-repair was successful. Case2recovered well and received rightfrontal cranioplasty6months after repair. One patient (case3) eventually diedof tumor relapse in12month despite of successful repair of CSF rhinorrheawithout recurrence through10-month follow-up.
Conclusion: In summary, display of the FSDP is useful when evaluatingthe cause and potential surgical therapy for obstruction of the frontal sinus. Wehave developed a novel method for stopping CSF rhinorrhea from theposterior wall of the frontal sinus that only requires examination of theanterior-posterior wall and the frontal ostium under CT image. This techniquecauses minimal injury, and thus could be used more aggressively in a widearray of clinical scenarios. An additional advantage is the fact that patients do not have to wait until the outcome of conventional conservative treatmentbecomes clear. The success of this novel yet simple method for stopping CSFrhinorrhea in our case series has encouraged further use.
引文
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1Albert-Weissenberger C, Siren AL. Experimental traumatic brain injury.Exp Transl Stroke Med,2010,2(1):16
2Morganti-Kossmann MC, Yan E, Bye N, et al. Animal models of traumaticbrain injury: is there an optimal model to reproduce human brain injury inthe laboratory? Injury,2010,41Suppl1: S10-3
3Finnie J. Animal models of traumatic brain injury: a review. Aust Vet J,2001,79(9):628-33
4Ghajar J. Essay: the future of traumatic brain injury. Mt Sinai J Med,2009,76(2):190-3
5Marklund N, Hillered L. Animal modelling of traumatic brain injury inpreclinical drug development: where do we go from here? Br J Pharmacol,2011,164(4):1207-29
6Tymianski M. Can molecular and cellular neuroprotection be translatedinto therapies for patients? yes, but not the way we tried it before. Stroke,2010,41(10Suppl): S87-90
7Masson F, Thicoipe M, Aye P, et al. Epidemiology of severe brain injuries:a prospective population-based study. J Trauma,2001,51(3):481-9
8Myburgh JA, Cooper DJ, Finfer SR, et al. Epidemiology and12-monthoutcomes from traumatic brain injury in australia and new zealand. JTrauma,2008,64(4):854-62
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15Tomura S, Nawashiro H, Otani N, et al. Effect of decompressivecraniectomy on aquaporin-4expression after lateral fluid percussion injuryin rats. J Neurotrauma,2011;28(2):237-43
16Oliva AA, Jr., Kang Y, et al. Fluid-percussion brain injury induces changesin aquaporin channel expression. Neuroscience,2011,180:272-9
17Ke C, Poon WS, Ng HK, et al. Impact of experimental acute hyponatremiaon severe traumatic brain injury in rats: influences on injuries,permeability of blood-brain barrier, ultrastructural features, andaquaporin-4expression. Exp Neurol,2002,178(2):194-206
18Higashida T, Kreipke CW, Rafols JA, et al. The role of hypoxiainduciblefactor-1alpha, aquaporin-4, and matrix metalloproteinase-9in blood-brainbarrier disruption and brain edema after traumatic brain injury. JNeurosurg,2011,114(1):92-101
19Guo Q, Sayeed I, Baronne LM, et al. Progesterone administrationmodulates AQP4expression and edema after traumatic brain injury inmale rats. Exp Neurol,2006,198(2):469-78
20Kiening KL, van Landeghem FK, Schreiber S, et al. Decreasedhemispheric Aquaporin-4is linked to evolving brain edema followingcontrolled cortical impact injury in rats. Neurosci Lett,2002,324(2):105-8
21Fukuda AM, Pop V, Spagnoli D, et al. Delayed increase of astrocyticaquaporin4after juvenile traumatic brain injury: possible role in edemaresolution? Neuroscience,2012,222:366-78
22Lopez NE, Krzyzaniak MJ, Blow C, et al. Ghrelin prevents disruption ofthe blood-brain barrier after traumatic brain injury. J Neurotrauma,2012,29(2):385-93
23Zhao J, Moore AN, Clifton GL, et al. Sulforaphane enhances aquaporin-4expression anddecreases cerebral edema following traumatic brain injury. JNeurosci Res,2005,82(4):499-506
24Glover LE, Tajiri N, Lau T, et al. Immediate, but not delayed,microsurgical skull reconstruction exacerbates brain damage inexperimental traumatic brain injury model. PloS one,2012,7(3): e33646
25Lopez NE, Krzyzaniak MJ, Costantini TW, et al. Vagal nerve stimulationdecreases blood-brain barrier disruption after traumatic brain injury. Thejournal of trauma and acute care surgery,2012,72(6):1562-6
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40Maruta J, Lee SW, Jacobs EF, et al. A unified science of concussion.Annals of the New YorkAcademy of Sciences,2010,1208:58-66
41Goldstein LE, Fisher AM, Tagge CA, et al. Chronic traumaticencephalopathy in blast-exposed military veterans and a blast neurotraumamouse model. Science translational medicine,2012,4(134):134ra60
42Sharp DJ, Ham TE. Investigating white matter injury after mild traumaticbrain injury. Currentopinion in neurology,2011,24(6):558-63
43Haj-Yasein NN, Jensen V, Ostby I, et al. Aquaporin-4regulatesextracellular space volume dynamics during high-frequency synapticstimulation: a gene deletion study in mouse hippocampus. Glia,2012,60(6):867-74
44Amiry-Moghaddam M, Williamson A, Palomba M, et al. Delayed K+clearance associated with aquaporin-4mislocalization: phenotypic defectsin brains of alpha-syntrophin-null mice. Proc Natl Acad Sci,2003,100(23):13615-20
45Iliff JJ, Wang M, Liao Y, et al. A Paravascular Pathway Facilitates CSFFlow Through the Brain Parenchyma and the Clearance of InterstitialSolutes, Including Amyloid beta. Science translational medicine,2012,4(147):147-111
46Amiry-Moghaddam M, Otsuka T, Hurn PD, et al. An alpha-syntrophin-dependent pool of AQP4in astroglial end-feet confers bidirectional waterflow between blood and brain. Proc Natl Acad Sci,2003,100(4):2106-11
47Wang M, Iliff JJ, Liao Y, et al. Cognitive deficits and delayed neuronalloss in a mouse model of multiple microinfarcts. J Neurosci,2012,32(50):17948-60
48Bloch O, Papadopoulos MC, Manley GT, et al. Aquaporin-4gene deletionin mice increases focal edema associated with staphylococcal brainabscess. J Neurochem,2005,95(1):254-62
49Stahel PF, Shohami E, Younis FM, et al. Experimental closed head injury:analysis of neurological outcome, blood-brain barrier dysfunction,intracranial neutrophil infiltration, and neuronal cell death in micedeficient in genes for pro-inflammatory cytokines. J Cereb Blood FlowMetab,2000,20(2):369-80
50Silverman MN, Macdougall MG, Hu F, et al. Endogenous glucocorticoidsprotect against TNF-alpha-induced increases in anxiety-like behavior invirally infected mice. Mol Psychiatry,2007,12(4):408-17
51Antunes M, Biala G. The novel object recognition memory: neurobiology,test procedure, andits modifications. Cogn Process,2012,13(2):93-110
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