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.     

Connectomic assessment of injury burden and longitudinal structural network alterations in moderate‐to‐severe traumatic brain injury

Traumatic brain injury (TBI) is a major public health problem. Caused by external mechanical forces, a major characteristic of TBI is the shearing of axons across the white matter, which causes structural connectivity disruptions between brain regions. This diffuse injury leads to cognitive deficits, frequently requiring rehabilitation. Heterogeneity is another characteristic of TBI as severity and cognitive sequelae of the disease have a wide variation across patients, posing a big challenge for treatment. Thus, measures assessing network‐wide structural connectivity disruptions in TBI are necessary to quantify injury burden of individuals, which would help in achieving personalized treatment, patient monitoring, and rehabilitation planning. Despite TBI being a disconnectivity syndrome, connectomic assessment of structural disconnectivity has been relatively limited. In this study, we propose a novel connectomic measure that we call network normality score (NNS) to capture the integrity of structural connectivity in TBI patients by leveraging two major characteristics of the disease: diffuseness of axonal injury and heterogeneity of the disease. Over a longitudinal cohort of moderate‐to‐severe TBI patients, we demonstrate that structural network topology of patients is more heterogeneous and significantly different than that of healthy controls at 3 months postinjury, where dissimilarity further increases up to 12 months. We also show that NNS captures injury burden as quantified by posttraumatic amnesia and that alterations in the structural brain network is not related to cognitive recovery. Finally, we compare NNS to major graph theory measures used in TBI literature and demonstrate the superiority of NNS in characterizing the disease.     

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.     

The structural connectome of children with traumatic brain injury

This study aimed to investigate the impact of mild to severe pediatric TBI on the structural connectome. Children aged 8–14 years with trauma control (TC) injury (n = 27) were compared to children with mild TBI and risk factors for complicated TBI (mild^RF+, n = 20) or moderate/severe TBI (n = 16) at 2.8 years post‐injury. Probabilistic tractography on diffusion tensor imaging data was used in combination with graph theory to study structural connectivity. Functional outcome was measured using neurocognitive tests and parent and teacher questionnaires for behavioral functioning. The results revealed no evidence for an impact of mild^RF+ TBI on the structural connectome. In contrast, the moderate/severe TBI group showed longer characteristic path length (P = 0.022, d = 0.82) than the TC group. Furthermore, longer characteristic path length was related to poorer intelligence and poorer working memory in children with TBI. In conclusion, children have abnormal organization of the structural connectome after moderate/severe TBI, which may be implicated in neurocognitive dysfunction associated with pediatric TBI. These findings should be interpreted in the context of our exploratory analyses, which indicate that the definition and weighting of connectivity (e.g., streamline density, fractional anisotropy) influence the properties of the reconstructed connectome and its sensitivity to the impact and outcome of pediatric TBI. Hum Brain Mapp 38:3603–3614, 2017. © 2017 Wiley Periodicals, Inc.     

Clinicoradiological and therapeutic considerations in severe diffuse traumatic brain injury in children

Forty-one children with severe head injuries and diffuse brain lesions were selected from a consecutive series of 62 children in traumatic coma (21 focal mass lesions) and studied. According to the CT pattern, two main types of intracranial lesions were considered: diffuse axonal injury (DAI) and diffuse brain swelling (DBS). High mortality, due to secondary increases of intracranial pressure (ICP), correlated well with the patterns of severe DBS, absence of perimesencephalic cisterns, and obliteration of the ventricles. However, children with normal CTs, and/or obvious shearing injuries indicative of DAI, had favorable outcomes; there was no mortality if increased ICP was not present. We conclude that although there does not seem to be any routine indications for ICP monitoring in children with pure DAI, early ICP monitoring and aggressive management of increasing ICP should be considered in comatose children with DBS, especially when associated with subarachnoid hemorrage and respiratory or circulatory failure.Presented at the 11th Meeting of the European Society for Paediatric Neurosurgery, Naples 1988     

MRI及磁共振波谱对弥漫性轴索损伤的临床诊断优势

目的探讨MRI及磁共振波谱(MRS)对早期重型颅脑损伤中弥漫性轴索损伤的临床诊断优势。方法选取2010年1月~2014年5月在解放军第171医院接受CT检查及综合治疗的27例急性重型颅脑损伤患者,入院7 d内进行头颅MRI及MRS检查,采用磁共振扫描仪及超导磁共振进行T1、T2、Flair序列扫描,选择合适的靶点进行MRS检查,明确颅脑损伤的部位及性质。对头颅CT、MRI及MRS的弥漫性轴索损伤影像学图片及资料进行比照,并且对比头颅CT与MRI+MRS对弥漫性轴索损伤其中包括原发性脑干损伤的检出率,并分析MRS检出损伤部位与预后的关系。结果 CT对弥漫性轴索损伤的总检出率为33.3%,其中原发性脑干损伤的检出率为25.9%;MRI及MRS对弥漫性轴索损伤的总检出率为85.2%,其中原发性脑干损伤的检出率为51.9%,差异均具有统计学意义(均P0.05)。MRI及MRS检出损伤的患者组的Barthal指数及DRS均分与未检出异常的组间差异均具有统计学意义(均P0.05)。Barthal指数41~60分和≤40分患者的NAA/Cr、NAA/Cho与60分患者比较,差异具有统计学意义(均P0.05)。DRS均分为4~30分患者的NAA/Cr、NAA/Cho与DRS均分为0~3分比较,差异具有统计学意义(均P0.05)。结论 MRI与MRS在早期重型颅脑损伤中弥漫性轴索损伤的临床诊断上具有明显优势,值得临床推广。     

Protein accumulation in traumatic brain injury

Traumatic brain injury (TBI) is one of the most devastating diseases in our society, accounting for a high percentage of mortality and disability. A major consequence of TBI is the rapid and long-term accumulation of proteins. This process largely reflects the interruption of axonal transport as a result of extensive axonal injury. Although many proteins are found accumulating after TBI, three have received particular attention; β-amyloid precursor protein and its proteolytic products, amyloid-β (Aβ) peptides, neurofilament proteins, and synuclein proteins. Massive coaccumulations of all of these proteins are found in damaged axons throughout the white matter after TBI. Additionally, these proteins form aggregates in other neuronal compartments and in brain parenchyma after brain trauma. Interestingly, TBI is also an epigenetic risk factor for developing neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease. Here, the similarities and differences of these accumulations with pathologies of neurodegenerative diseases will be explored. In addition, the potential deleterious roles of protein accumulations on functional outcome and progressive neurodegeneration following TBI will be examined.     

The prognostic factors related to traumatic brain stem injury

Objective

This study was conducted to assess the clinical significance of traumatic brain stem injury (TBSI) reflected on Glasgow Coma Score (GCS) and Glasgow Outcome Score (GOS) by various clinical variables.

Methods

A total of 136 TBSI patients were selected out of 2695 head-injured patients. All initial computerized tomography and/or magnetic resonance imaging studies were retrospectively analyzed according to demographic- and injury variables which result in GCS and GOS.

Results

In univariate analysis, mode of injury showed a significant effect on combined injury (p<0.001), as were the cases with skull fracture on radiologic finding (p<0.000). The GCS showed a various correlation with radiologic finding (p<0.000), mode of injury (p<0.002), but less favorably with impact site (p<0.052), age (p<0.054) and skull fracture (p<0.057), in order of statistical significances. However, only GOS showed a definite correlation to radiologic finding (p<0.000). In multivariate analysis, the individual variables to enhance an unfavorable effect on GCS were radiologic finding [odds ratio (OR) 7.327, 95% confidence interval (CI)], mode of injury (OR; 4.499, 95% CI) and age (OR; 3.141, 95% CI). Those which influence an unfavorable effect on GOS were radiologic finding (OR; 25.420, 95% CI) and age (OR; 2.674, 95% CI).

Conclusion

In evaluation of TBSI on outcome, the variables such as radiological finding, mode of injury, and age were revealed as three important ones to have an unfavorable effect on early stage outcome expressed as GCS. However, mode of injury was shown not to have an unfavorable effect on late stage outcome as GOS. Among all unfavorable variables, radiological finding was confirmed as the only powerful prognostic variable both on GCS and GOS.     

脑弥漫性轴索损伤的发生机制

弥漫性轴索损伤（diffuse axonal injury，DAI）是颅脑损伤中一种常见的原发性损伤，在平时和战时均常见，是颅脑损伤患者重残及植物生存的最常见原因之一，伤情重，治疗困难．预后差。文献报道其死亡率高达42％-62％。[第一段]     

Structural connectome differences in pediatric mild traumatic brain and orthopedic injury

Sophisticated network‐based approaches such as structural connectomics may help to detect a biomarker of mild traumatic brain injury (mTBI) in children. This study compared the structural connectome of children with mTBI or mild orthopedic injury (OI) to that of typically developing (TD) children. Children aged 8–16.99 years with mTBI (n = 83) or OI (n = 37) were recruited from the emergency department and completed 3T diffusion MRI 2–20 days postinjury. TD children (n = 39) were recruited from the community and completed diffusion MRI. Graph theory metrics were calculated for the binarized average fractional anisotropy among 90 regions. Multivariable linear regression and linear mixed effects models were used to compare groups, with covariates age, hemisphere, and sex, correcting for multiple comparisons. The two injury groups did not differ on graph theory metrics, but both differed from TD children in global metrics (local network efficiency: TD > OI, mTBI, d = 0.49; clustering coefficient: TD < OI, mTBI, d = 0.49) and regional metrics for the fusiform gyrus (lower degree centrality and nodal efficiency: TD > OI, mTBI, d = 0.80 to 0.96; characteristic path length: TD < OI, mTBI, d = −0.75 to −0.90) and in the superior and middle orbital frontal gyrus, paracentral lobule, insula, and thalamus (clustering coefficient: TD > OI, mTBI, d = 0.66 to 0.68). Both mTBI and OI demonstrated reduced global and regional network efficiency and segregation as compared to TD children. Findings suggest a general effect of childhood injury that could reflect pre‐ and postinjury factors that can alter brain structure. An OI group provides a more conservative comparison group than TD children for structural neuroimaging research in pediatric mTBI.     

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。     

轻度低温治疗27例弥漫性轴索损伤病人的临床疗效

目的 探讨早期使用轻度低温治疗中、重型弥漫性轴索损伤(DAI)病人的疗效。方法 对我科收治的27例中、重型弥漫性轴索损伤病人，早期使用冰毯机降温至轻度低温(35℃～35．5℃)脑保护，加用冬眠Ⅰ号等药物配合治疗，但不使用呼吸机和肌松剂。结果 17例存活，10例死亡。存活病人中恢复良好11例，重残6例。结论 该方法适合于基层医院或条件相对不足的医疗单位，仍能取得良好疗效。     

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.     

Functional connectivity in mild traumatic brain injury

Objectives: Research suggests that the majority of mild traumatic brain injury (mTBI) patients exhibit both cognitive and emotional dysfunction within the first weeks of injury, followed by symptom resolution 3–6 months postinjury. The neuronal correlates of said dysfunction are difficult to detect with standard clinical neuroimaging, complicating differential diagnosis and early identification of patients who may not recover. This study examined whether resting state functional magnetic resonance imaging (fMRI) provides objective markers of injury and predicts cognitive, emotional, and somatic complaints in mTBI patients semiacutely (<3 weeks postinjury) and in late recovery (3–5 month) phases. Methods: Twenty‐seven semiacute mTBI patients and 26 gender, age, and education‐matched controls were studied. Fifteen of 27 patients returned for a follow‐up visit 3–5 months postinjury. The main dependent variables were spontaneous fluctuations (temporal correlation) in the default‐mode (DMN) and fronto‐parietal task‐related networks as measured by fMRI. Results: Significant differences in self‐reported cognitive, emotional, and somatic complaints were observed (all P < 0.05), despite normal clinical (T1 and T2) imaging and neuropsychological testing results. Mild TBI patients demonstrated decreased functional connectivity within the DMN and hyper‐connectivity between the DMN and lateral prefrontal cortex. Measures of functional connectivity exhibited high levels of sensitivity and specificity for patient classification and predicted cognitive complaints in the semi‐acute injury stage. However, no changes in functional connectivity were observed across a 4‐month recovery period. Conclusions: Abnormal connectivity between the DMN and frontal cortex may provide objective biomarkers of mTBI and underlie cognitive impairment. Hum Brain Mapp, 2011. © 2011 Wiley‐Liss, Inc.     

Structural connectivity abnormality in children with acute mild traumatic brain injury using graph theoretical analysis

The traumatic biomechanical forces associated with mild traumatic brain injury (mTBI) typically impart diffuse, as opposed to focal, brain injury potentially disrupting the structural connectivity between neural networks. Graph theoretical analysis using diffusion tensor imaging was used to assess injury‐related differences in structural connectivity between 23 children (age 11–16 years) with mTBI and 20 age‐matched children with isolated orthopedic injuries (OI) scanned within 96 h postinjury. The distribution of hub regions and the associations between alterations in regional network measures and symptom burden, as assessed by the postconcussion symptom scale score (PCSS), were also examined. In comparison to the OI group, the mTBI group was found to have significantly higher small‐worldness (P < 0.0001), higher normalized clustering coefficients (P < 0.0001), higher normalized characteristic path length (P = 0.007), higher modularity (P = 0.0005), and lower global efficiency (P < 0.0001). A series of hub regions in the mTBI group were found to have significant alterations in regional network measures including nodal degree, nodal clustering coefficient, and nodal between‐ness centrality. Correlation analysis showed that PCSS total score acquired at the time of imaging was significantly associated with the nodal degree of two hubs, the superior frontal gyrus at orbital section and the middle frontal gyrus. These findings provide new evidence of acute white matter alteration at both global and regional network level following mTBI in children furthering our understanding of underlying mechanisms of acute neurological insult associated with mTBI. Hum Brain Mapp 36:779–792, 2015. © 2014 Wiley Periodicals, Inc.     

Imaging biomarkers of vascular and axonal injury are spatially distinct in chronic traumatic brain injury

Traumatic Brain Injury (TBI) is associated with both diffuse axonal injury (DAI) and diffuse vascular injury (DVI), which result from inertial shearing forces. These terms are often used interchangeably, but the spatial relationships between DAI and DVI have not been carefully studied. Multimodal magnetic resonance imaging (MRI) can help distinguish these injury mechanisms: diffusion tensor imaging (DTI) provides information about axonal integrity, while arterial spin labeling (ASL) can be used to measure cerebral blood flow (CBF), and the reactivity of the Blood Oxygen Level Dependent (BOLD) signal to a hypercapnia challenge reflects cerebrovascular reactivity (CVR). Subjects with chronic TBI (n = 27) and healthy controls (n = 14) were studied with multimodal MRI. Mean values of mean diffusivity (MD), fractional anisotropy (FA), CBF, and CVR were extracted for pre-determined regions of interest (ROIs). Normalized z-score maps were generated from the pool of healthy controls. Abnormal ROIs in one modality were not predictive of abnormalities in another. Approximately 9-10% of abnormal voxels for CVR and CBF also showed an abnormal voxel value for MD, while only 1% of abnormal CVR and CBF voxels show a concomitant abnormal FA value. These data indicate that DAI and DVI represent two distinct TBI endophenotypes that are spatially independent.     

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。     

Chronic cognitive sequelae after traumatic brain injury are not related to growth hormone deficiency in adults

Objective: The objective of the study was to asses the possible influence of hypothalamo–pituitary deficiencies, and growth hormone (GH) deficiency in particular, on cognition in adult patients with traumatic brain injury (TBI). TBI is a recently identified risk factor for cognitive deficits and hypopituitarism. Even the patients with favorable outcome after TBI may present with persistent bodily, psychosocial, and cognitive impairments, resembling patients with untreated partial or complete pituitary insufficiency. Design: We performed retrospective and cross‐sectional study of endocrine and cognitive function in TBI in 61 patients (aged 37.7 ± 1.7 years) of both sexes (44 m,17 f), at least 1 year after TBI (3.9 ± 0.6 years). Serum insulin‐like growth factor 1 (IGF‐I), thyroxin, thyroid‐stimulating hormone (TSH), follicle‐stimulating hormone (FSH), luteinizing hormone (LH), testosterone (in men), prolactin, and cortisol were measured, and GH secretion was assessed by growth hormone releasing hormone (GHRH) + growth hormone releasing peptide‐6 (GHRP‐6) test. Cognitive function was assessed by using a standard neuropsychological battery. Results: GH deficiency (GHD) and GH insufficiency (GHI) were found in 20 patients (32.8%). After adjustment for confounders [age, body mass index (BMI), education level, time elapsed from TBI], there were no significant differences in results of neuropsychological tests between patients with TBI with GHD, GHI, and normal GH secretion. There were no correlations of neuropsychological variables with stimulated peak GH secretion or IGF‐I level. Conclusions: GHD persists long after the TBI, independently of trauma severity and age at traumatic event. GH secretion is more sensitive to TBI than other pituitary hormones. No evidence is found for an association of cognitive function impairment and somatotropic axis impairment in adult patients tested more than 1 year after the TBI.     

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.