Combination of Neutrophil-to-Lymphocyte Ratio and Admission Glasgow Coma Scale Score Is Independent Predictor of Clinical Outcome in Diffuse Axonal Injury.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is an independent predictor of clinical outcome of different diseases, such as acute ischemic stroke, intracerebral hemorrhage, malignant tumor, and traumatic brain injury. However, the prognostic value of NLR plus admission Glasgow Coma Scale score (NLR-GCS) is still unclear in patients with diffuse axonal injury (DAI). Therefore this study assessed the relationship between the NLR-GCS and 6-month outcome of DAI patients. METHODS: The clinical characteristics of DAI patients admitted to our department between January 2014 and January 2020 were retrospectively analyzed. The candidate risk factors were screened by using univariate analysis, and the independence of resultant risk factors was evaluated by the binary logistic regression analysis and least absolute shrinkage and selection operator regression analysis. The predictive value of NLR-GCS in an unfavorable outcome was assessed by the receiver operating characteristics curve analysis. RESULTS: A total of 93 DAI patients were included. Binary logistic regression analysis and least absolute shrinkage and selection operator regression analysis showed the level of NLR on admission was an independent risk factor of unfavorable outcomes in DAI patients. The ROC curve analysis showed that the predictive capacity of the combination of NLR and admission GCS score and combination of NLR and coma duration outperformed NLR, admission GCS score, and coma duration alone. CONCLUSIONS: The higher NLR level on admission is independently associated with unfavorable outcomes of DAI patients at 6 months. Furthermore, the combination of NLR and admission GCS score provides the superior predictive capacity to either NLR or GCS alone.

Traumatic axonal injury influences the cognitive effect of non-invasive brain stimulation.

Non-invasive brain stimulation has been widely investigated as a potential treatment for a range of neurological and psychiatric conditions, including brain injury. However, the behavioural effects of brain stimulation are variable, for reasons that are poorly understood. This is a particular challenge for traumatic brain injury, where patterns of damage and their clinical effects are heterogeneous. Here we test the hypothesis that the response to transcranial direct current stimulation following traumatic brain injury is dependent on white matter damage within the stimulated network. We used a novel simultaneous stimulation-MRI protocol applying anodal, cathodal and sham stimulation to 24 healthy control subjects and 35 patients with moderate/severe traumatic brain injury. Stimulation was applied to the right inferior frontal gyrus/anterior insula node of the salience network, which was targeted because our previous work had shown its importance to executive function. Stimulation was applied during performance of the Stop Signal Task, which assesses response inhibition, a key component of executive function. Structural MRI was used to assess the extent of brain injury, including diffusion MRI assessment of post-traumatic axonal injury. Functional MRI, which was simultaneously acquired to delivery of stimulation, assessed the effects of stimulation on cognitive network function. Anodal stimulation improved response inhibition in control participants, an effect that was not observed in the patient group. The extent of traumatic axonal injury within the salience network strongly influenced the behavioural response to stimulation. Increasing damage to the tract connecting the stimulated right inferior frontal gyrus/anterior insula to the rest of the salience network was associated with reduced beneficial effects of stimulation. In addition, anodal stimulation normalized default mode network activation in patients with poor response inhibition, suggesting that stimulation modulates communication between the networks involved in supporting cognitive control. These results demonstrate an important principle: that white matter structure of the connections within a stimulated brain network influences the behavioural response to stimulation. This suggests that a personalized approach to non-invasive brain stimulation is likely to be necessary, with structural integrity of the targeted brain networks an important criterion for patient selection and an individualized approach to the selection of stimulation parameters.

Progressive increase in brain glucose metabolism after intrathecal administration of autologous mesenchymal stromal cells in patients with diffuse axonal injury.

BACKGROUND AIMS: Cell therapy in neurological disability after traumatic brain injury (TBI) is in its initial clinical stage. We describe our preliminary clinical experience with three patients with diffuse axonal injury (DAI) who were treated with intrathecal administration of autologous mesenchymal stromal cells (MSCs). METHODS: Three patients with established neurological sequelae due to DAI received intrathecally autologous MSCs. The total number of MSCs administered was 60 × 106 (one patient), 100 × 106 (one patient) and 300 × 106 (one patient). RESULTS: All three patients showed improvement after cell therapy, and subsequent studies with 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) showed a diffuse and progressive increase in brain glucose metabolism. CONCLUSION: Our present results suggest benefit of intrathecal administration of MSCs in patients with DAI, as well as a relationship between this type of treatment and increase in brain glucose metabolism. These preliminary findings raise the question of convenience of assessing the potential benefit of intrathecal administration of MSCs for brain diseases in which a decrease in glucose metabolism represents a crucial pathophysiological finding, such as Alzheimer's disease (AD) and other dementias.

Asociación entre el déficit de vitamina D y los potenciales evocados visuales en la esclerosis múltiple / Relationship between vitamin D deficiency and visually evoked potentials in multiple sclerosis

OBJETIVO: Evaluar la posible relación entre los niveles séricos de 25-OH-vitamina D y los potenciales evocados visuales (PEV) de los pacientes con esclerosis múltiple (EM) residentes en la zona sur de Gran Canaria. MATERIAL Y MÉTODOS: Se incluyó a 49 pacientes con EM. Se les realizó determinación de 25-OH-vitamina D, PEV, exploración neurológica para determinar la discapacidad y se recogieron variables clínicas tales como el antecedente de neuritis óptica. RESULTADOS: El valor medio de 25-OH-vitamina D de los pacientes fue de 28,1 ± 9,5 ng/ml, la latencia de los PEV fue de 119,1 ± 23,2 ms y la amplitud de 8,5 ± 4,4 μV. Los pacientes con niveles normales de 25-OH-vitamina D tuvieron mayor número de brotes en el año previo al estudio (p = 0,049) y aquellos con déficit de vitamina D y neuritis óptica previa no presentaron reducción de la amplitud de los PEV (p = 0,006). CONCLUSIÓN: Los pacientes con déficit de vitamina D tienen menor actividad clínica de la EM y no presentan afectación axonal en PEV tras haber sufrido neuritis óptica. Estas asociaciones, aunque estadísticamente significativas, no parecen clínicamente plausibles, por lo que sería preciso realizar nuevos estudios que intentasen confirmar esta posible asociación

OBJECTIVE: To evaluate the possible relationship between serum 25-OH vitamin D levels and visually evoked potentials (VEP) in patients with multiple sclerosis (MS), residents in the south zone of Gran Canaria. MATERIAL AND METHODS: The study included 49 patients with MS, on whom 25-OH-vitamin D was determined, along with VEP, and a neurological examination to determine incapacity. Clinical variables, such as a history of optic neuritis were recorded. RESULTS: The mean value of 25-OH-vitamin D of the patients was 28.1 ± 9.5 ng/ml. The VEP latency was 119.1 ± 23.2 ms and the amplitude, 8.5 ± 4.4 μV. Patients with a higher 25-OH-vitamin D had a greater number of outbreaks in the year prior to the study (P=.049), and those with vitamin D deficiency and previous optic neuritis showed no reduction in the amplitude of the VEP (P=.006). CONCLUSION: Patients with vitamin D deficiency have lower clinical activity of the MS and show no axonal involvement in VEP after having suffered optic neuritis. These relationships, although statistically significant, do not seem clinically plausible, thus new studies are needed to try and confirm this possible relationship

Transcranial magnetic stimulation in brain injury.

OBJECTIVES: Transcranial magnetic stimulations (TMS) have been used for many years as a diagnostic tool to explore changes in cortical excitability, and more recently as a tool for therapeutic neuromodulation. We are interested in their applications following brain injury: stroke, traumatic and anoxic brain injury. DATA SYNTHESIS: Following brain injury, there is decreased cortical excitability and changes in interhemispheric interactions depending on the type, the severity, and the time-lapse between the injury and the treatment implemented. rTMS (repetitive TMS) is a therapeutic neuromodulation tool which restores the interhemispheric interactions following stroke by inhibiting the healthy cortex with frequencies ≤1Hz, or by exciting the lesioned cortex with frequencies between 3 and 50Hz. Results in motor recovery are promising and those in improving aphasia or visuospatial neglect are also encouraging. Finally, the use of TMS is mainly limited by the risk of seizure, and is therefore contraindicated for many patients. CONCLUSION: TMS is a useful non-invasive brain stimulation tool to diagnose the effects of brain injury, to study the mechanisms of recovery and a non-invasive neuromodulation promising tool to influence the post-lesional recovery.

Evaluation of TGF ß1, IL-8 and nitric oxide in the serum of diffuse axonal injury patients and its association with clinical status and outcome.

AIM: The aim was to evaluate the level of interleukin 8 (IL-8), transforming growth factor ß1 (TGF ß1) and Nitric oxide (NO) in diffuse axonal injury (DAI) and its association to the outcome and clinical status. MATERIAL AND METHODS: This cross-sectional study was conducted on 20 patients with DAI and 20 patients with multiple traumas without head injury and 20 healthy subjects as controls. Blood levels of IL-8, TGF ß1 and nitric oxide in the 1st, 2nd, 3rd and 7th days of injury were measured. Glasgow coma scale (GCS) of patients was recorded. The patients' outcome was evaluated by Glasgow Outcome Scale (GOS). RESULTS: The level of TGF ß1 was increasing during the admission and had the maximum level at the 7th day. In the DAI group, there was significant correlation between GOS score and serum IL-8 at 7th day of admission (r=-0.68, p= 0.002). In this group the GCS was found to be significantly correlated with the IL-8 concentration at 7th day of admission (p= 0.026, r=-0.55). CONCLUSION: IL-8 has negative correlation with GCS and GOS. TGF ß1 could protect the brain from cytotoxics, hypoxia and acidosis so its level comes down in brain injuries as a result of its overuse.

Increased CSF concentrations of myelin basic protein after TBI in infants and children: absence of significant effect of therapeutic hypothermia.

BACKGROUND: The objectives of this study were to determine effects of severe traumatic brain injury (TBI) on cerebrospinal fluid (CSF) concentrations of myelin basic protein (MBP) and to assess relationships between clinical variables and CSF MBP concentrations. METHODS: We measured serial CSF MBP concentrations in children enrolled in a randomized controlled trial evaluating therapeutic hypothermia (TH) after severe pediatric TBI. Control CSF was obtained from children evaluated, but found not to be having CNS infection. Generalized estimating equation models and Wilcoxon Rank-Sum test were used for comparisons of MBP concentrations. RESULTS: There were 27 TBI cases and 57 controls. Overall mean (± SEM) TBI case MBP concentrations for 5 days after injury were markedly greater than controls (50.49 ± 6.97 vs. 0.11 ± 0.01 ng/ml, p < 0.01). Mean MBP concentrations were lower in TBI patients <1 year versus >1 year (9.18 ± 1.67 vs. 60.22 ± 8.26 ng/ml, p = 0.03), as well as in cases with abusive head trauma (AHT) versus non-abusive TBI (14.46 ± 3.15 vs. 61.17 ± 8.65 ng/ml, p = 0.03). TH did not affect MBP concentrations. CONCLUSIONS: Mean CSF MBP increases markedly after severe pediatric TBI, but is not affected by TH. Infancy and AHT are associated with low MBP concentrations, suggesting that age-dependent myelination influences MBP concentrations after injury. Given the magnitude of MBP increases, axonal injury likely represents an important therapeutic target in pediatric TBI.

Significance of differences between brain temperature and core temperature (δ T) during mild hypothermia in patients with diffuse axonal injury.

The differences between brain and bladder temperature (delta T), and the relationship of delta T to cerebral perfusion pressure (CPP) and jugular venous oxygen saturation (SjO(2)) were studied during hypothermia in 11 patients with severe traumatic brain injury, of whom 5 underwent conservative treatment for diffuse axonal injury (DAI) (DAI group) and 6 who underwent decompressive craniectomy for hematoma (SDH group). All patients underwent hypothermia treatment. Brain temperature was monitored via an intraparenchymal catheter. Bladder temperature was used as the core temperature. SjO(2) was measured continuously. The outcome of all patients was evaluated at discharge using the Glasgow Outcome Scale. Delta T in the SDH group was significantly lower than that in the DAI group. No relationship was found between delta T and CPP during the investigation period. A significant correlation between delta T and SjO(2) was seen in the DAI group, but not in the SDH group. Decompressive craniectomy affects the brain temperature through external environmental factors. Measurement of brain temperature may be a reliable indicator of cerebral blood flow and brain metabolism in patients with DAI and closed cranium during hypothermia. Further experience is required to test this proposal.

Negative effect of hypopituitarism following brain trauma in patients with diffuse axonal injury.

OBJECT: The aim of this prospective observational study was to assess the incidence and pattern of hypopituitarism after diffuse axonal injury (DAI) and to identify its effect on these patients in terms of functional outcome. METHODS: Of 1307 patients with traumatic brain injury treated at the authors' institution between March 2005 and June 2008, 65 patients with DAI were enrolled in the present study. The authors determined basal hormone levels, initial Glasgow Coma Scale scores, the Marshall CT grades, the presence of abnormal signal intensity indicating lesions on MR images, and duration of unconsciousness. At the 6-month follow-up visits, functional outcomes were estimated using the Modified Barthel Index. Univariate and multivariate analyses were performed to identify factors that influenced functional outcomes. RESULTS: Twenty-one patients with hypopituitarism (Group A) had more lesions in the body of the corpus callosum, basal ganglia, thalamus, and the gray-white matter junction than those without hypopituitarism (Group B). In Group A, growth hormone deficiency (17 patients, 80.9%) was the most common, and multiple pituitary hormone deficiencies were found in 12 patients (57.1%). The mean Modified Barthel Index score at the 6-month follow-up was 64.7 in Group A and 88.5 in Group B (p = 0.027). Duration of unconsciousness (p = 0.035), the Marshall CT grade (p = 0.021), hypopituitarism (p = 0.044), and abnormal signal intensities on MR imaging in midline or deep structures of the brain (p = 0.001) were found to be associated with functional outcome. CONCLUSIONS: The findings in this prospective observational study suggest that hypopituitarism in patients with DAI has a relationship not only with injuries in the midline or deep structures of the brain, but also with a poor outcome.

Heat stress preconditioning improves cognitive outcome after diffuse axonal injury in rats.

This study investigates the influence of heat stress preconditioning on cognitive outcome for rats with diffuse axonal injury (DAI), and attempts to examine the underlying mechanisms. Wistar rats were divided into four groups: rats subjected to heat stress preconditioning 24 h before induction of DAI (n = 10; HSDAI group), a DAI alone group (n = 10), a heat stress alone group (n = 10), and a sham-injury group (n = 10). From day 14 post-injury, the rats' learning abilities and memory were tested using the Morris water maze (MWM) task, followed by long-term potentiation (LTP) recording of the hippocampus. In addition, hematoxylin and eosin staining (H&E) and immunohistochemical staining (IHC) were conducted to determine the presence of brain lesions and expression of heat shock protein 70 (HSP70) at 24 h, and on days 14 and 20 post-injury. The rats in the DAI group displayed impaired MWM performance and attenuated LTP compared to the sham group (p < 0.05); the rats in the HSDAI and HS groups showed significant improvement in both MWM and LTP compared with the DAI group (p < 0.05), and no significant differences with the sham group (p > 0.05). Following injury, retraction balls, shrunken neurons, and HSP70 expression were visible in the brains of rats from the DAI and HSDAI groups; recovery was expedited in the rats belonging to the HSDAI group, as these pathological changes were alleviated, coincident with higher expression of HSP70. The rats' abilities for learning and memory were impaired following DAI; this may be due to the disconnection of brain regions, damage to neurons in the hippocampus, and a decrease in synaptic plasticity. Heat stress preconditioning is able to significantly attenuate this cognitive impairment, possibly mediated by the neuroprotective effect of HSP70.

Diffuse axonal injury: novel insights into detection and treatment.

Diffuse axonal injury (DAI) is one of the most common and important pathologic features of traumatic brain injury. The definitive diagnosis of DAI, especially in its early stage, is difficult. In addition, most therapeutic agents for patients with DAI are non-specific. The CT scan is widely used to identify signs of DAI. Although its sensitivity is limited to moderate to severe DAI, it remains a useful first-line imaging tool that may also identify co-morbid injuries such as intracerebral hemorrhage. Recently, investigations have sought to apply advanced imaging techniques and laboratory techniques to detect DAI. Meanwhile, some potential specific treatments that may protect injured axons or stimulate axonal regeneration have been developed. We review some new diagnostic technologies and specific therapeutic strategies for DAI.

Severe traumatic brain injury: outcome in patients with diffuse axonal injury managed conservatively in Hospital Sultanah Aminah, Johor Bahru--an observational study.

Patients with isolated severe head injury with diffuse axonal injury and without any surgical lesion may be treated safely without cerebral resuscitation and intracranial pressure (ICP) monitoring. Seventy two patients were divided into three groups of patients receiving treatment based on ICP-CPP-targeted, or conservative methods either with or without ventilation support. The characteristics of these three groups were compared based on age, gender, Glasgow Coma Scale (GCS), pupillary reaction to light, computerized tomography scanning according to the Marshall classification, duration of intensive care unit (ICU) stays, Glasgow Outcome Score (GOS) and possible complications. There were higher risk of mortality (p < 0.001), worse GCS improvement upon discharge (p < 0.001) and longer ICU stays (p = 0.016) in ICP group compared to Intubation group. There were no significant statistical differences of GOS at 3rd and 6th months between all three groups.

Immediate short-duration hypothermia provides long-term protection in an in vivo model of traumatic axonal injury.

A prospective, multicenter, randomized trial did not demonstrate improved outcomes in severe traumatic brain injured patients treated with mild hypothermia [Clifton, G.L., Miller, E.R., Choi, S.C., Levin, H.S., McCauley, S., Smith, K.R., Jr., Muizelaar, J.P., Wagner, F.C., Jr., Marion, D.W., Luerssen, T.G., Chesnut, R.M., Schwartz, M., 2001. Lack of effect of induction of hypothermia after acute brain injury. N. Engl. J. Med. 344, 556-563.]. However, the mean time to target temperature was over 8 h and patient inclusion was based on Glasgow Coma Scale score so brain pathology was likely diverse. There remains significant interest in the benefits of hypothermia after traumatic brain injury (TBI) and, in particular, traumatic axonal injury (TAI), which is believed to significantly contribute to morbidity and mortality of TBI patients. The long-term beneficial effect of mild hypothermia on TAI has not been established. To address this issue, we developed an in vivo rat optic nerve stretch model of TAI. Adult male Sprague-Dawley rats underwent unilateral optic nerve stretch at 6, 7 or 8 mm piston displacement. The increased number of axonal swellings and bulbs immunopositive for non-phosphorylated neurofilament (SMI-32) seen four days after injury was statistically significant after 8 mm displacement. Ultrastructural analysis 2 weeks after 8 mm displacement revealed a 45.0% decrease (p<0.0001) in myelinated axonal density in the optic nerve core. There was loss of axons regardless of axon size. Immediate post-injury hypothermia (32 degrees C) for 3 h reduced axonal degeneration in the core (p=0.027). There was no differential protection based on axon size. These results support further clinical investigation of temporally optimized therapeutic hypothermia after traumatic brain injury.

Cerebral atrophy after traumatic white matter injury: correlation with acute neuroimaging and outcome.

Traumatic brain injury (TBI) is a pathologically heterogeneous disease, including injury to both neuronal cell bodies and axonal processes. Global atrophy of both gray and white matter is common after TBI. This study was designed to determine the relationship between neuroimaging markers of acute diffuse axonal injury (DAI) and cerebral atrophy months later. We performed high-resolution magnetic resonance imaging (MRI) at 3 Tesla (T) in 20 patients who suffered non-penetrating TBI, during the acute (within 1 month after the injury) and chronic stage (at least 6 months after the injury). Volume of abnormal fluid-attenuated inversion-recovery (FLAIR) signal seen in white matter in both acute and follow-up scans was quantified. White and gray matter volumes were also quantified. Functional outcome was measured using the Functional Status Examination (FSE) at the time of the chronic scan. Change in brain volumes, including whole brain volume (WBV), white matter volume (WMV), and gray matter volume (GMV), correlates significantly with acute DAI volume (r = -0.69, -0.59, -0.58, respectively; p <0.01 for all). Volume of acute FLAIR hyperintensities correlates with volume of decreased FLAIR signal in the follow-up scans (r = -0.86, p < 0.001). FSE performance correlates with acute hyperintensity volume and chronic cerebral atrophy (r = 0.53, p = 0.02; r = -0.45, p = 0.03, respectively). Acute axonal lesions measured by FLAIR imaging are strongly predictive of post-traumatic cerebral atrophy. Our findings suggest that axonal pathology measured as white matter lesions following TBI can be identified using MRI, and may be a useful measure for DAI-directed therapies.

Estimulación eléctrica y natación en la fase aguda de la axonotmesis: influencia sobre la regeneración nerviosa y la recuperación funcional / Electrical stimulation and swimming in the acute phase of axonotmesis: Their influence on nerve regeneration and functional recovery

Introducción. Poco se ha discutido sobre la influencia de la estimulación eléctrica fásica de baja frecuencia (EEFBF) y del ejercicio físico sobre la calidad de la regeneración nerviosa periférica y la recuperación funcional. Objetivo. Evaluar la influencia de la EEFBF, de la natación y de la asociación entre ambas con respecto a la morfología del nervio isquiático regeneradotras la axonotmesis. Materiales y métodos. Treinta ratones Wistar (222,05 ± 42,2 g) se distribuyeron en grupos: control (C), denervado (D), denervado + natación (DN), denervado + electroestimulación (DE) y denervado + natación + electroestimulación (DNE). Después de 24 horas de la axonotmesis, se electroestimuló el músculo sóleo de los grupos DE y DNE. Los grupos DN y DNE nadaron durante 22 días. Se evaluó el número de axones, los datos morfométricos del nervio y el índice funcional del nervio ciático (IFC). Resultados. El número de axones en los grupos denervados fue mayor que en el grupo control, y en el grupo DE fue mayor que en el D. El diámetro axonal fue menor en los grupos denervados; sin embargo, en el grupo DN fue mayor que en el D. Los demás parámetros morfométricos no fueron muy diferentes a los del grupo C. El IFC entre los días 7 y 14 del postoperatorio difirió del índice preoperatorio y el día 21 postoperatorio; sin embargo, el grupo DNE difirió del preoperatorio. Conclusiones. La natación y la EEFBF aplicadas individualmente no interfieren en la maduración delas fibras regeneradas o en la recuperación funcional. La EEFBF favoreció la regeneración axonal, y la asociación de los tratamientos retrasó la recuperación funcional, sin influir en la regeneración nerviosa

Introduction. Little attention has been given to the influence of low-frequency phasic electrical stimulation (LFPES) and physical exercise on the quality of peripheral nerve regeneration and functional recovery. Aim. To evaluate the influence of LFPES, swimming and the association between the two in terms of the morphology of the regenerated sciatic nervefollowing axonotmesis. Materials and methods. Thirty Wistar mice (222.05 ± 42.2 g) were distributed into groups: control (C),denervated (D), denervated + swimming (DS), denervated + electrostimulation (DE) and denervated + swimming + electrostimulation (DSE). After 24 hours of axonotmesis, the soleus muscle of the DE and DSE groups was stimulated electrically. The DS and DSE groups swam over a period of 22 days. The number of axons, morphometric data on the nerve and the functional index of the sciatic nerve (FIS) were evaluated. Results. The number of axons in the denervated groups was higher than in the control group, and in the DE group the figure was higher than in the D group. The axonal diameter was smaller in the denervated groups, yet in the DS group it was higher than in the D group. The other morphometric parameters were quitesimilar to those of the C group. The FIS between days 7 and 14 of the post-operative period was different to the pre-operative index and that measured on day 21 of the post-operative period; the DSE group, however, differed from the pre-operative values. Conclusions. Swimming and LFPES, applied on an individual basis, do not affect the maturation of the regenerated fibres or functional recovery. LFPES favoured axonal regeneration and combining the treatments delayed functional recoverywithout having any influence on nerve regeneration