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Mild traumatic brain injury (mTBI) is a significant cause of disability, especially when symptoms become chronic. This chronicity is often linked to oculomotor dysfunction (OMD). To our knowledge, this is the first prospective study to localize aberrations in brain function between mTBI cohorts, by comparing patients with mTBI with OMD with an mTBI control group without OMD, using task and resting-state functional magnetic resonance imaging (fMRI). Ten subjects with mTBI who had OMD (OMD group) were compared with nine subjects with mTBI who had no findings of OMD (control group). These groups were determined by a developmental optometrist using objective testing for OMD. The (convergence) task fMRI data demonstrated significantly decreased brain activity, measured as decreases in the blood oxygen level dependent (BOLD) signal, in the OMD group compared with the control group in three brain regions: the left posterior lingual gyrus, the bilateral anterior lingual gyrus and cuneus, and the parahippocampal gyrus. When doing a seed-based resting state fMRI analysis in the lingual/parahippocampal region, a large cluster covering the left middle frontal gyrus and the dorsolateral pre-frontal cortex (Brodmann areas 9 and 10), with decreased functional correlation in the OMD group, was identified. Together these observations provide evidence for neural networks of interactions involving the control of eye movement for visual processing, reading comprehension, spatial localization and navigation, and spatial working memory that appear to be decreased in mTBI patients with OMD compared with mTBI patients without OMD. The clinical symptomatology associated with post-traumatic OMD correlates well with these MRI findings.

The Glasgow Outcome Scale-Extended (GOS-E), an ordinal scale measuring global outcome, is used commonly as the primary outcome measure in clinical trials of traumatic brain injury. Analysis is often based on a dichotomization and thus has inherent statistical limitations, including loss of information related to the collapse of adjacent categories. A fixed dichotomization defines favorable outcome consistently for all subjects, whereas a sliding dichotomy tailors the definition of favorable outcome according to baseline prognosis/severity. Literature indicates that the sliding dichotomy is more statistically efficient than the fixed dichotomy; however, the sliding dichotomy still collapses categories and therefore discards information. We propose an alternative, a sliding scoring system for the GOS-E, intended to address the limitations of the sliding dichotomy. The score is assigned based on the number of levels between the achieved score and the favorable cut-point. The proposed scoring system reflects the magnitude of change, where change is defined according to each subject's baseline prognosis. Because the score is approximately continuous, statistical methods can rely on the normal distribution, both for analysis and study design. Two examples show the corresponding potential for improved power. A sliding score approach allows for quantification of the magnitude of change while still accounting for prognosis. Scientific advantages include increased power and an intuitive interpretation.

There has been no major advancement in a quarter of a century for the treatment of acute severe traumatic brain injury (TBI). This review summarizes 40 years of clinical and pre-clinical research on the treatment of acute TBI with hyperbaric oxygen therapy (HBO(2)) in the context of an impending National Institute of Neurologic Disorders and Stroke–funded, multi-center, randomized, adaptive Phase II clinical trial —the Hyperbaric Oxygen Brain Injury Treatment (HOBIT) trial. Thirty studies (eight clinical and 22 pre-clinical) that administered HBO(2) within 30 days of a TBI were identified from PubMed searches. The pre-clinical studies consistently reported positive treatment effects across a variety of outcome measures with almost no safety concerns, thus providing strong proof-of-concept evidence for treating severe TBI in the acute setting. Of the eight clinical studies reviewed, four were based on the senior author's (GR) investigation of HBO(2) as a treatment for acute severe TBI. These studies provided evidence that HBO(2) significantly improves physiologic measures without causing cerebral or pulmonary toxicity and can potentially improve clinical outcome. These results were consistent across the other four reviewed clinical studies, thus providing preliminary clinical data supporting the HOBIT trial. This comprehensive review demonstrates that HBO(2) has the potential to be the first significant treatment in the acute phase of severe TBI.

The goals of phase II clinical trials are to gain important information about the performance of novel treatments and decide whether to conduct a larger phase III trial. This can be complicated in cases when the phase II trial objective is to identify a novel treatment having several factors. Such multifactor treatment scenarios can be explored using fixed sample size trials. However, the alternative design could be response adaptive randomization with interim analyses and additionally, longitudinal modeling whereby more data could be used in the estimation process. This combined approach allows a quicker and more responsive adaptation to early estimates of later endpoints. Such alternative clinical trial designs are potentially more powerful, faster, and smaller than fixed randomized designs. Such designs are particularly challenging, however, because phase II trials tend to be smaller than subsequent confirmatory phase III trials. The phase II trial may need to explore a large number of treatment variations to ensure that the efficacy of optimal clinical conditions is not overlooked. Adaptive trial designs need to be carefully evaluated to understand how they will perform and to take full advantage of their potential benefits. This manuscript discusses a Bayesian response adaptive randomization design with a longitudinal model that uses a multifactor approach for predicting phase III study success via the phase II data. The approach is based on an actual clinical trial design for the hyperbaric oxygen brain injury treatment trial. Specific details of the thought process and the models informing the trial design are provided. Copyright © 2016 John Wiley & Sons, Ltd.

Object Preclinical and clinical investigations indicate that the positive effect of hyperbaric oxygen (HBO2) for severe traumatic brain injury (TBI) occurs after rather than during treatment. The brain appears better able to use baseline O2 levels following HBO2 treatments. In this study, the authors evaluate the combination of HBO2 and normobaric hyperoxia (NBH) as a single treatment. Methods Forty-two patients who sustained severe TBI (mean Glasgow Coma Scale [GCS] score 5.7) were prospectively randomized within 24 hours of injury to either: 1) combined HBO2/NBH (60 minutes of HBO2 at 1.5 atmospheres absolute [ATA] followed by NBH, 3 hours of 100% fraction of inspired oxygen [FiO2] at 1.0 ATA) or 2) control, standard care. Treatments occurred once every 24 hours for 3 consecutive days. Intracranial pressure, surrogate markers for cerebral metabolism, and O2 toxicity were monitored. Clinical outcome was assessed at 6 months using the sliding dichotomized Glasgow Outcome Scale (GOS) score. Mixed-effects linear modeling was used to statistically test differences between the treatment and control groups. Functional outcome and mortality rates were compared using chi-square tests. Results There were no significant differences in demographic characteristics between the 2 groups. In comparison with values in the control group, brain tissue partial pressure of O2 (PO2) levels were significantly increased during and following combined HBO2/NBH treatments in both the noninjured and pericontusional brain (p < 0.0001). Microdialysate lactate/pyruvate ratios were significantly decreased in the noninjured brain in the combined HBO2/NBH group as compared with controls (p < 0.0078). The combined HBO2/NBH group's intracranial pressure values were significantly lower than those of the control group during treatment, and the improvement continued until the next treatment session (p < 0.0006). The combined HBO2/NBH group's levels of microdialysate glycerol were significantly lower than those of the control group in both noninjured and pericontusional brain (p < 0.001). The combined HBO2/NBH group's level of CSF F2-isoprostane was decreased at 6 hours after treatment as compared with that of controls, but the difference did not quite reach statistical significance (p = 0.0692). There was an absolute 26% reduction in mortality for the combined HBO2/NBH group (p = 0.048) and an absolute 36% improvement in favorable outcome using the sliding dichotomized GOS (p = 0.024) as compared with the control group. Conclusions In this Phase II clinical trial, in comparison with standard care (control treatment) combined HBO2/NBH treatments significantly improved markers of oxidative metabolism in relatively uninjured brain as well as pericontusional tissue, reduced intracranial hypertension, and demonstrated improvement in markers of cerebral toxicity. There was significant reduction in mortality and improved favorable outcome as measured by GOS. The combination of HBO2 and NBH therapy appears to have potential therapeutic efficacy as compared with the 2 treatments in isolation. Clinical trial registration no.: NCT00170352 (ClinicalTrials.gov).

The purpose of this study was to explore a novel treatment involving removal of free water from ventricular cerebrospinal fluid (CSF) for the reduction of cerebra]l edema. The hypothesis is that removal of free water from the CSF will increase the osmolarity of the CSF, which will favor movement of tissue-bound water into the ventricles, where the water can be removed. Reductive ventricular osmotherapy (RVOT) was tested in a flowing solution of artificial CSF (aCSF) with two end-points: (1) the effect of RVOT on osmolarity of the CSF, and (2) the effect of RVOT on water content of ex vivo cerebral tissue. RVOT catheters are made up of membranes permeable only to water vapor. When a sweep gas is drawn through the catheter, free water in the form of water vapor is removed from the solution. With RVOT treatment, aCSF osmolarity increased from a baseline osmolarity of 318.8 ± 0.8 mOsm/L to 339.0 ± 3.3 mOsm/L (mean ± standard deviation) within 2 h. After 10 h of treatment, aCSF osmolarity approached an asymptote at 344.0 ± 4.2 mOsm/L, which was significantly greater than control aCSF osmolarity (p <

Object Oxygen delivered in supraphysiological amounts is currently under investigation as a therapy for severe traumatic brain injury (TBI). Hyperoxia can be delivered to the brain under normobaric as well as hyperbaric conditions. In this study the authors directly compare hyperbaric oxygen (HBO2) and normobaric hyperoxia (NBH) treatment effects. Methods Sixty-nine patients who had sustained severe TBIs (mean Glasgow Coma Scale Score 5.8) were prospectively randomized to 1 of 3 groups within 24 hours of injury: 1) HBO2, 60 minutes of HBO2 at 1.5 ATA; 2) NBH, 3 hours of 100% fraction of inspired oxygen at 1 ATA; and 3) control, standard care. Treatments occurred once every 24 hours for 3 consecutive days. Brain tissue PO2, microdialysis, and intracranial pressure were continuously monitored. Cerebral blood flow (CBF), arteriovenous differences in oxygen, cerebral metabolic rate of oxygen (CMRO2), CSF lactate and F2-isoprostane concentrations, and bronchial alveolar lavage (BAL) fluid interleukin (IL)–8 and IL-6 assays were obtained pretreatment and 1 and 6 hours posttreatment. Mixed-effects linear modeling was used to statistically test differences among the treatment arms as well as changes from pretreatment to posttreatment. Results In comparison with values in the control group, the brain tissue PO2 levels were significantly increased during treatment in both the HBO2 (mean ± SEM, 223 ± 29 mm Hg) and NBH (86 ± 12 mm Hg) groups (p < 0.0001) and following HBO2 until the next treatment session (p = 0.003). Hyperbaric O2 significantly increased CBF and CMRO2 for 6 hours (p ≤ 0.01). Cerebrospinal fluid lactate concentrations decreased posttreatment in both the HBO2 and NBH groups (p < 0.05). The dialysate lactate levels in patients who had received HBO2 decreased for 5 hours posttreatment (p = 0.017). Microdialysis lactate/pyruvate (L/P) ratios were significantly decreased posttreatment in both HBO2 and NBH groups (p < 0.05). Cerebral blood flow, CMRO2, microdialysate lactate, and the L/P ratio had significantly greater improvement when a brain tissue PO2 ≥ 200 mm Hg was achieved during treatment (p < 0.01). Intracranial pressure was significantly lower after HBO2 until the next treatment session (p < 0.001) in comparison with levels in the control group. The treatment effect persisted over all 3 days. No increase was seen in the CSF F2-isoprostane levels, microdialysate glycerol, and BAL inflammatory markers, which were used to monitor potential O2 toxicity. Conclusions Hyperbaric O2 has a more robust posttreatment effect than NBH on oxidative cerebral metabolism related to its ability to produce a brain tissue PO2 ≥ 200 mm Hg. However, it appears that O2 treatment for severe TBI is not an all or nothing phenomenon but represents a graduated effect. No signs of pulmonary or cerebral O2 toxicity were present.

OBJECTIVE: Hypertonic saline is emerging as a potentially effective single osmotic agent for control of acute elevations in intracranial pressure (ICP) caused by severe traumatic brain injury. This study examines its effect on ICP, cerebral perfusion pressure (CPP), and brain tissue oxygen tension (Pbto 2 ). METHODS: Twenty-five consecutive patients with severe traumatic brain injury who were treated with 23.4% NaCl for elevated ICP were evaluated. Bolt catheter probes were placed in the noninjured hemisphere, and hourly ICP, mean arterial pressure, CPP, and Pbto 2 values were recorded. Thirty milliliters of 23.4% NaCl was infused over 15 minutes for intracranial hypertension, defined as ICP greater than 20 mm Hg. Twenty-one male patients and 4 female patients aged 16 to 64 years were included. The mean presenting Glasgow Coma Scale score was 5.7. RESULTS: Mean pretreatment values included an ICP level of 25.9 mm Hg and a Pbto 2 value of 32 mm Hg. The posttreatment ICP level was decreased by a mean of 8.3 mm Hg (P < 0.0001), and there was an improvement in Pbto 2 of 3.1 mm Hg (P < 0.01). ICP of more than 31 mm Hg decreased by 14.2 mm Hg. Pretreatment CPP values of less than 70 mm Hg increased by a mean of 6 mm Hg (P < 0.0001). No complications occurred from this treatment, with the exception of electrolyte and chemistry abnormalities. At 6 months postinjury, the mortality rate was 28%, with 48% of patients achieving a favorable outcome by the dichotomized Glasgow Outcome Scale. CONCLUSION: Hypertonic saline as a single osmotic agent decreased ICP while improving CPP and Pbto 2 in patients with severe traumatic brain injury. Patients with higher baseline ICP and lower CPP levels responded to hypertonic saline more significantly.

Objectives: This critical literature review examines historical and current investigations on the efficacy and mechanisms of hyperbaric oxygen (HBO) treatment in traumatic brain injury (TBI). Potential safety risks and oxygen toxicity, as well as HBO's future potential, are also discussed. Methods: Directed literature review. Results: Historically, cerebral vasoconstriction and increased oxygen availability were seen as the primary mechanisms of HBO in TBI. HBO now appears to be improving cerebral aerobic metabolism at a cellular level, namely, by enhancing damaged mitochondrial recovery. HBO given at the ideal treatment paradigm, 1.5 ATA for 60 minutes, does not appear to produce oxygen toxicity and is relatively safe. Discussion: The use of HBO in TBI remains controversial. Growing evidence, however, shows that HBO may be a potential treatment for patients with severe brain injury. Further investigations, including a multicenter prospective randomized clinical trial, will be required to definit...

The goals of phase II clinical trials are to gain important information about the performance of novel treatments and decide whether to conduct a larger phase III trial. This can be complicated in cases when the phase II trial objective is to identify a novel treatment having several factors. Such multifactor treatment scenarios can be explored using fixed sample size trials. However, the alternative design could be response adaptive randomization with interim analyses and additionally, longitudinal modeling whereby more data could be used in the estimation process. This combined approach allows a quicker and more responsive adaptation to early estimates of later endpoints. Such alternative clinical trial designs are potentially more powerful, faster, and smaller than fixed randomized designs. Such designs are particularly challenging, however, because phase II trials tend to be smaller than subsequent confirmatory phase III trials. The phase II trial may need to explore a large number of treatment variations to ensure that the efficacy of optimal clinical conditions is not overlooked. Adaptive trial designs need to be carefully evaluated to understand how they will perform and to take full advantage of their potential benefits. This manuscript discusses a Bayesian response adaptive randomization design with a longitudinal model that uses a multifactor approach for predicting phase III study success via the phase II data. The approach is based on an actual clinical trial design for the hyperbaric oxygen brain injury treatment trial. Specific details of the thought process and the models informing the trial design are provided. Copyright © 2016 John WileySons, Ltd.

Object. Hyperbaric oxygenation (HBO) therapy has been shown to reduce mortality by 50% in a prospective randomized trial of severely brain injured patients conducted at the authors' institution. The purpose of the present study was to determine the effects of HBO on cerebral blood flow (CBF), cerebral metabolism, and intracranial pressure (ICP), and to determine the optimal HBO treatment paradigm. Methods. Oxygen (100% O2, 1.5 atm absolute) was delivered to 37 patients in a hyperbaric chamber for 60 minutes every 24 hours (maximum of seven treatments/patient). Cerebral blood flow, arteriovenous oxygen difference (AVDO2), cerebral metabolic rate of oxygen (CMRO2), ventricular cerebrospinal fluid (CSF) lactate, and ICP values were obtained 1 hour before and 1 hour and 6 hours after a session in an HBO chamber. Patients were assigned to one of three categories according to whether they had reduced, normal, or raised CBF before HBO. In patients in whom CBF levels were reduced before HBO sessions, both CBF and CMRO2 levels were raised 1 hour and 6 hours after HBO (p < 0.05). In patients in whom CBF levels were normal before HBO sessions, both CBF and CMRO2 levels were increased at 1 hour (p < 0.05), but were decreased by 6 hours after HBO. Cerebral blood flow was reduced 1 hour and 6 hours after HBO (p < 0.05), but CMRO2 was unchanged in patients who had exhibited a raised CBF before an HBO session. In all patients AVDO2 remained constant both before and after HBO. Levels of CSF lactate were consistently decreased 1 hour and 6 hours after HBO, regardless of the patient's CBF category before undergoing HBO (p < 0.05). Intracranial pressure values higher than 15 mm Hg before HBO were decreased 1 hour and 6 hours after HBO (p < 0.05). The effects of each HBO treatment did not last until the next session in the hyperbaric chamber. Conclusions. The increased CMRO2 and decreased CSF lactate levels after treatment indicate that HBO may improve aerobic metabolism in severely brain injured patients. This is the first study to demonstrate a prolonged effect of HBO treatment on CBF and cerebral metabolism. On the basis of their data the authors assert that shorter, more frequent exposure to HBO may optimize treatment.

OBJECTIVE: Recent studies suggest that in some circumstances, alcohol intoxication at the time of severe head injury may be neuroprotective. The objective of this study was to determine the effect of acute and chronic alcohol ingestion on outcome in rodents sustaining multiple episodes of mild traumatic brain injury while intoxicated. METHOD: For two weeks before experimentation, adult male Sprague-Dawley rats received intoxicating levels of 95% ethanol (3 g/kg) or normal saline (NS) every other day by orogastric instillation. On the day of experimentation, the animals were randomized to receive alcohol or NS. Two hours later, the animals received either mild (1.2 +/- 0.4 ATA) fluid percussion injury (FPI) or no injury. The injured animals received a total of three episodes of FPI (once every four days). Mean reflex recovery time (RRT) was determined (seconds +/- SEM) immediately after each episode. Mean latency time (seconds +/- SEM) for Morris Water Maze (MWM) performance was assessed at post-trauma days 11-19. RESULTS: The chronic alcohol-exposed (CA) and the non-alcohol-exposed (NA) animals intoxicated when injured had prolonged escape, righting, and corneal RRTs after each FPI compared with the nonintoxicated injured animals and the non-injured shams. However, the CA animals had significantly shorter RRTs when compared with the NA rats. All the injured animals had MWM deficits on testing days 1-6 compared with the noninjured controls. On the last two MWM testing days, the injured NA animals had significantly better MWM performance than the injured CA rats. CONCLUSIONS: The injured intoxicated CA animals had a more rapid recovery of reflexes compared with the injured intoxicated NA animals. Despite initial MWM deficits, the injured NA rodents eventually began to learn the MWM. The injured CA rats never learned the maze. Under the conditions of this study, acute alcohol intoxication at the time of multiple episodes of minor head trauma did not provide neuroprotection for NA or CA rodents. Language: en

Background: Light deprivation significantly accelerates recovery from attention deficits (neglect) after cortical ablation in rats. We hypothesized that light deprivation would improve recovery after traumatic contusive brain injury (TBI) and do so by enhancing dopaminergic function in the ipsilateral basal ganglia. Methods: Adult rats received left frontal contusion injury and were placed into darkness or standard light/dark cycling for 48 hours. Neurologic evaluation included attentional and sensorimotor tasks. Amphetamine-induced production of the immediate early gene protein product Fos was quantified to determine neuronal dopaminergic response in caudate-putamen (striatum). Results: Unilateral frontal TBI produced severe contralateral deficits in all tasks. Postoperative light deprivation resulted in improved recovery from attentional but not sensorimotor deficits. Five days after injury, ipsilateral striatal Fos expression was reduced by 51% in TBI rats experiencing normal light cycling (p < 0.006). In contrast, postoperative light deprivation normalized striatal Fos expression. By 6 weeks, all TBI rats demonstrated nearly full recovery and striatal Fos expression was symmetrical between the two striata. Conclusion: Postoperative light deprivation may improve recovery from TBI-induced attention deficits by normalizing basal ganglia function.

Background: It has been suggested that early fixation of a fracture is deleterious to eventual neurologic outcome. We undertook this study to determine whether the timing of fracture fixation is correlated to neurologic outcome. Methods: We retrospectively reviewed patients with severe head and orthopedic injuries requiring fracture fixation. Patients were divided into two groups: early fracture fixation ( 24 hours after injury). Results: One hundred twenty-three patients met entry criteria. During fracture fixation, the early group had a significant 2-, 3-, and 2-fold increase in crystalloid, blood infusion, and blood loss, respectively. There was no difference in oxygen saturation and systolic blood pressure or episodes of cranial hypertension or hypoperfusion. There was no difference in outcomes as measured by in-hospital complications, stay in the intensive care unit or hospital, mortality rates, hospital discharge or follow-up Glasgow Coma Scores, or long-term orthopedic or neurologic results. Conclusions: Patients undergoing fracture fixation with severe head injury mandate monitoring of intracranial pressure and perfusion and tailored fluid resuscitation to meet specific organ end points. Integrating end organ perfusion and pressure with meticulous fluid status during the definitive repair phase may reduce the exposure to secondary brain injury in patients undergoing early fracture fixation. (Surgery 1998;124:739-45.)

IL-8 involvement in neutrophil activation and chemotaxis may be important in inflammatory responses within the central nervous system, secondary to meningitis, encephalitis, and traumatic injury. The source of IL-8 within the brain during these inflammatory processes, however, is unknown. To explore the role of microglia in the production of IL-8, human fetal microglia, which are the resident macrophages of the brain, were treated with LPS and pro- and anti-inflammatory cytokines to determine their effects on IL-8 production. We found that IL-8 protein levels increased in response to LPS or IL-1β, or to TNF-α, which also corresponded to elevated IL-8 mRNA levels by RT-PCR. Pretreatment with IL-4, IL-10, or TGF-β1 potently inhibited the stimulatory effects of these proinflammatory agents. These findings indicate that human microglia synthesize IL-8 in response to proinflammatory stimuli, and that anti-inflammatory cytokines down-regulate the production of this chemokine. These results may have important therapeutic implications for certain central nervous system insults involving inflammation.

Neurosurgery began as a distinct discipline at the University of Minnesota in 1937 with the appointment of William Peyton as head of the division. Under the leadership of Peyton, Lyle French, and Shelley Chou, the Department rose to national prominence. Substantial contributions included the introduction of dexamethasone to the practice of neurosurgery by Galicich and French, early procedures for the transthoracic correction of spinal deformity, important contributions to the understanding of brain death, the early laboratory work that led to the development of nimodopine, one of the first intraoperative magnetic resonance imaging facilities in the United States (1996), and the training of many academic neurosurgeons and department chairmen. The challenges of managed care and more recent changes in the health care system have been met, and the Department is a thriving clinical, educational, and research center for 21st-century neurosurgery.

This study was designed to evaluate the production of cerebral edema [as measured by tissue specific gravity (SpG)] following moderate fluid percussion (FP) and cortical impact (CI) injury in rodents. To determine the effects of a secondary systemic insult, hypoxia (13% oxygen for 30 min) was added to some experimental groups immediately after head injury. To determine the effects of hyperbaric oxygen (HBO) on injured cortical tissue, additional animal groups were exposed to HBO (1.5 atm, for 60 min), beginning 4 h after head trauma. Both injury models produced equal amounts of tissue edema at the site of injury (mean SpG +/- SEM = 1.035 +/- 0.001), when measured 6 h posttrauma. There was no significant edema at the tissue sites immediately adjacent to the trauma sites. The addition of hypoxia to either injury system did not increase edema formation beyond that produced by injury alone. HBO reduced the water content of the trauma site in animals that had received FP, but not in animals receiving CI. We conclude that with the injury parameters used in this protocol, both FP and CI appear to produce focal cerebral edema at the site of trauma. Hypoxia does not worsen edema. HBO appears to reduce edema produced by FP, but not by CI.

BACKGROUND The presence of osmotic gradients in the development of cerebral edema and the effectiveness of osmotherapy are well recognized. A modification of ventriculostomy catheters described in this article provides a method of osmotherapy that is not currently available. The reductive ventricular osmotherapy (RVOT) catheter removes free water from ventricular cerebrospinal fluid (CSF) by incorporating hollow fibers that remove water vapor, thereby providing osmotherapy without increasing osmotic load. OBJECTIVE To increase osmolarity in the ventricular CSF through use of RVOT in vivo. METHODS Twelve Yorkshire swine with contusional injury were randomized to external ventricular drainage (EVD) or RVOT for 12 hours. MR imaging was obtained. Serum, CSF, and brain ultrafiltrate were analyzed. Histology was compared using Fluor-Jade B and hematoxylin and eosin (H & E) stains. RESULTS With RVOT, CSF osmolality increased from 292 ± 2.7 to 345 ± 8.0 mOsmol/kg (mean ± SE, P = 0.0006), and the apparent diffusion coefficient (ADC) in the injury region increased from 0.735 ± 0.047 to 1.135 ± .063 (P = 0.004) over 24 hours. With EVD controls, CSF osmolarity and ADC were not significantly changed. Histologically, all RVOT pigs showed no evidence of neuronal degeneration (Grade 1/4) compared to moderate degeneration (Grade 2.6 ± .4/4) seen in EVD treated animals (P = 0.02). The difference in intracranial pressure (ICP) by area under the curve approached significance at P = .065 by Mann Whitney test. CONCLUSION RVOT can increase CSF osmolarity in vivo after experimental traumatic brain injury (TBI). In anticipated clinical use, only a slight increase in CSF osmolarity may be required to reduce cerebral edema.

Osmotherapy has been the cornerstone in the management of patients with elevated intracranial pressure (ICP) following traumatic brain injury (TBI). Several studies have demonstrated that hypertonic saline (HTS) is a safe and effective osmotherapy agent. This study evaluated the effectiveness of HTS in reducing intracranial hypertension in the presence of a wide range of serum and cerebrospinal fluid (CSF) osmolalities.Forty-two doses of 23.4% saline boluses for treatment of refractory intracranial hypertension were reviewed retrospectively. Thirty milliliters of 23.4% NaCl was infused over 15 min for intracranial hypertension, defined as ICP 20 mmHg. The CSF and serum osmolalities from frozen stored samples were measured with an osmometer. The values of serum sodium, hourly ICP, blood urea nitrogen (BUN), and creatinine were obtained directly from the medical records.The serum and CSF osmolalities correlated very closely to serum sodium (r 0.9, P 0.0001). The reduction in ICP from the baseline (measured from either the mean ICP or the lowest ICP measurement in the first 6 h after bolus HTS treatment) was statistically significant regardless of serum osmolality. The mean reduction from baseline to follow-up values was 8.8 mm Hg (P 0.0001). The decrease in ICP was as evident with serum osmolalities 320 as it was at ≤320.This study demonstrates that 23.4% HTS bolus is effective for the reduction of elevated ICP in patients with severe TBI even in the presence of high serum and CSF osmolalities.

Patients who "talk and deteriorate" are defined as those who utter recognizable words at some time after head injury and then deteriorate to a severe head-injured condition (Glasgow Coma Scale score of 8 or less) within 48 hours of injury. They represent a very small but important subgroup of patients with brain injury. In approximately 75% of these patients, the cause of this deterioration is intracranial hematoma. Despite the fact that talking indicates nonlethal impact brain injury, deterioration is a marker of poor prognosis. Outcome depends on early recognition of deterioration and rapid removal of mass lesions. The challenge for emergency physicians is to distinguish patients at risk for deterioration from the many patients evaluated after head injury.

We administered hyperbaric oxygen or air in a double-blind prospective protocol to 39 patients with ischemic cerebral infarction. We interrupted the study when we noticed what appeared to be a trend favoring the air-treated patients, whose neurological deficits were less severe (mean +/- SEM score on graded neurological examination: air, 25.6 +/- 4.9; oxygen, 34.5 +/- 7.5) and whose infarcts were smaller (air, 29.0 +/- 12.2 cm3; oxygen, 49.2 +/- 11.7 cm3) at 4 months. The trend, we decided, was probably an artifact of the randomization process. Nevertheless, we chose not to resume the trial because the treatment was difficult to administer by schedule (for various reasons the treatment protocol was broken in 15 of the 39 patients), was poorly tolerated (eight of the 39 patients refused to continue treatments), and did not produce dramatic improvement.

In the management of cervical spine injuries, it is not always clear when to use halo immobilization alone, surgical fusion alone, or a combination of the two. To investigate the relative effectiveness of each of these approaches, we reviewed the medical records of 140 patients with cervical spine injuries treated with either halo immobilization or surgical fusion, or both. Seventy (50%) of the patients were neurologically intact on admission (two of these were paraplegic from previous injuries). Halo immobilization was used as the primary treatment in 99 patients, and yielded a successful fusion rate of 78%. Within this group, the 26 patients with hyperflexion-anterior subluxation injuries had only a 54% successful fusion rate, while the rate for the 73 with non-flexion injuries was 87% (Chi-square = 11.36; p = 0.0008). Surgical fusion was used as the primary treatment in 41 patients and as a subsequent treatment in the 22 for whom halo immobilization did not bring about fusion. Of these 63 patients treated with surgical fusion, six remained unstable after the surgery; five of these six had sustained a hyperflexion-anterior subluxation. One patient experienced neurologic deterioration after surgical fusion. There were three deaths in the entire series. Excluding fusion failure, complications with halo immobilization were frequent (25%) but usually minor; with surgical fusion, less frequent (6%) but usually more severe. We draw the following conclusions. 1) Halo immobilization brings about satisfactory healing for most fracture types. 2) Both halo immobilization and surgical fusion have relatively high failure rates in the treatment of hyperflexion-anterior subluxation injury, with or without bilaterally locked facets.(ABSTRACT TRUNCATED AT 250 WORDS)

Object Hyperbaric oxygen (HBO2) has been shown to improve outcome after severe traumatic brain injury, but its underlying mechanisms are unknown. Following lateral fluid-percussion injury (FPI), the authors tested the effects of HBO2 treatment as well as enhanced normobaric oxygenation on mitochondrial function, as measured by both cognitive recovery and cellular adenosine triphosphate (ATP) levels. Methods Adult male Sprague–Dawley rats were subjected to moderate lateral FPI or sham injury and were allocated to one of four treatment groups: 1) FPI treated with 4 hours of normobaric 30% O2; 2) FPI treated with 4 hours of normobaric 100% O2; 3) FPI treated with 1 hour of HBO2 plus 3 hours of normobaric 100% O2; and 4) sham-injured treated with normobaric 30% O2. Cognitive outcome was assessed using the Morris water maze (MWM) on Days 11 to 15 after injury. Animals were then killed 21 days postinjury to assess hippocampal neuronal loss. Adenosine triphosphate was extracted from the neocortex and measured using high-performance liquid chromatography. The results showed that injured animals treated with HBO2 or normobaric 100% O2 alone had significantly higher levels of cerebral ATP as compared with animals treated using normobaric 30% O2 (p ≤ 0.05). The injured animals treated with HBO2 had significant improvements in cognitive recovery, as characterized by a shorter latency in MWM performance (p ≤ 0.05), and decreased neuronal loss in the CA2/3 and hilar regions as compared with those treated with 30% or 100% O2 (p ≤ 0.05). Conclusions Both hyperbaric and normobaric hyperoxia increased cerebral ATP levels after lateral FPI. In addition, HBO2 treatment improved cognitive recovery and reduced hippocampal neuronal cell loss after brain injury in the rat.

Object. In the current study, the authors examined the effects of hyperbaric O2 (HBO) following fluid-percussion brain injury and its implications on brain tissue oxygenation (PO2) and O2 consumption (VO2) and mitochondrial function (redox potential). Methods. Cerebral tissue PO2 was measured following induction of a lateral fluid-percussion brain injury in rats. Hyperbaric O2 treatment (100% O2 at 1.5 ata) significantly increased brain tissue PO2 in both injured and sham-injured animals. For VO2 and redox potential experiments, animals were treated using 30% O2 or HBO therapy for 1 or 4 hours (that is, 4 hours 30% O2 or 1 hour HBO and 3 hours 100% O2). Microrespirometer measurements of VO2 demonstrated significant increases following HBO treatment in both injured and sham-injured animals when compared with animals that underwent 30% O2 treatment. Mitochondrial redox potential, as measured by Alamar blue fluorescence, demonstrated injury-induced reductions at 1 hour postinjury. These reductions were partially reversed at 4 hours postinjury in animals treated with 30% O2 and completely reversed at 4 hours postinjury in animals on HBO therapy when compared with animals treated for only 1 hour. Conclusions. Analysis of data in the current study demonstrates that HBO significantly increases brain tissue PO2 after injury. Nonetheless, treatment with HBO was insufficient to overcome injury-induced reductions in mitochondrial redox potential at 1 hour postinjury but was able to restore redox potential by 4 hours postinjury. Furthermore, HBO induced an increase in VO2 in both injured and sham-injured animals. Taken together, these data demonstrate that mitochondrial function is depressed by injury and that the recovery of aerobic metabolic function may be enhanced by treatment with HBO.

Using human fetal microglial cell cultures, we found that the gram-negative bacterial cell wall component lipopolysaccharide (LPS) stimulated RANTES (regulated upon activation of normal T cell expressed and secreted) production through the protein kinase C signaling pathway and that activation of transcription nuclear factor (NF)-κB was required for this effect. Similarly, the proinflammatory cytokines interleukin (IL)-1β and tumor necrosis factor-α dose-dependently stimulated microglial cell RANTES production via NF-κB activation. Anti-inflammatory cytokines, IL-10, and transforming growth factor (TGF)-β sequentially inhibited LPS- and cytokine-induced microglial cell NF-κB activation, RANTES mRNA expression, and protein release. Proinflammatory cytokines but not LPS also stimulated RANTES production by human astrocytes. These findings demonstrate that human microglia synthesize RANTES in response to proinflammatory stimuli, and that the anti-inflammatory cytokines IL-10 and TGF-β down-regulate the production of this β-chemokine. These results may have important therapeutic implications for inflammatory diseases of the brain. J. Leukoc. Biol. 65: 815–821; 1999.

✓ The authors reviewed 29 cases of spinal tuberculosis treated from 1973 to 1993 with an average follow-up time of 7.4 years. Clinical findings included back pain, paraparesis, kyphosis, fever, sensory disturbance, and bowel and bladder dysfunction. Twenty-two patients (76%) presented with neurological deficit; 12 (41%) were initially misdiagnosed. Sixteen patients (55%) had predominant vertebral body involvement; nine had marked bone collapse with neurological compromise. Eleven individuals (39%) had intraspinal granulomatous tissue causing neurological dysfunction in the absence of bone destruction, and two (7%) had intramedullary tuberculomas. All patients received antituberculous medications: 13 were initially treated with bracing alone, eight underwent laminectomy and debridement of extra- or intradural granulomatous tissue, and eight underwent anterior, posterior, or combined fusion procedures. No patient with neurological deficit recovered or stabilized with nonoperative management. Thirteen patients were readmitted with progression of inadequately treated osteomyelitis; 12 (92%) of these required new or more radical fusion procedures. Anterior fusion failure was associated with marked preoperative kyphosis and multilevel disease requiring a graft that spanned more than two disc spaces. Courses of antibiotic medications shorter than 6 months were invariably associated with disease recurrence. It was concluded that 1) patients should receive at least 12 months of appropriate antituberculous therapy; 2) individuals with neurological deficit should undergo surgical decompression; 3) laminectomy and debridement are adequate for intraspinal granulomatous tissue in the absence of significant bone destruction; 4) when vertebral body involvement has produced wedging and kyphosis, aggressive debridement and fusion are indicated to prevent delayed instability and progression of disease.

✓ The authors enrolled 168 patients with closed-head trauma into a prospective trial to evaluate the effect of hyperbaric oxygen in the treatment of brain injury. Patients were included if they had a total Glasgow Coma Scale (GCS) score of 9 or less for at least 6 hours. After the GCS score was established and consent obtained, the patient was randomly assigned, stratified by GCS score and age, to either a treatment or a control group. Hyperbaric oxygen was administered to the treatment group in a monoplace chamber every 8 hours for 1 hour at 1.5 atm absolute; this treatment course continued for 2 weeks or until the patient was either brain dead or awake. An average of 21 treatments per patient was given. Outcome was assessed by blinded independent examiners. The entire group of 168 patients was followed for 12 months, with two patients lost to follow-up study. The mortality rate was 17% for the 84 hyperbaric oxygen-treated patients and 32% for the 82 control patients (chi-squared test, 1 df, p = 0.037). Among the 80 patients with an initial GCS score of 4, 5, or 6, the mortality rate was 17% for the hyperbaric oxygen-treated group and 42% for the controls (chi-squared test, 1 df, p = 0.04). Analysis of the 87 patients with peak intracranial pressures (ICP) greater than 20 mm Hg revealed a 21 % mortality rate for the hyperbaric oxygen-treated patients, as opposed to 48% for the control group (chi-squared test, 1 df, p = 0.02). Myringotomy to reduce pain during hyperbaric oxygen treatment helped to reduce ICP. Analysis of the outcome of survivors reveals that hyperbaric oxygen treatment did not increase the number of patients in the favorable outcome categories (good recovery and moderate disability). The possibility that a different hyperbaric oxygen treatment paradigm or the addition of other agents, such as a 21-aminosteroid, may improve quality of survival is being explored.

BACKGROUND In patients with intracranial pathology, especially when comatose, it is desirable to have knowledge of the intracranial pressure (ICP). To investigate the relationship between ICP and transcranial Doppler (TCD) derived pulsatility index (PI) in neurosurgical patients, a prospective study was performed on patients admitted to our neurointensive care unit. METHODS Daily TCD mean flow velocity (mFV) measurements were made. TCD measurements were routinely performed bilaterally on the middle cerebral artery (MCA). PI (peak systolic-end diastolic velocities/mean flow velocity) was calculated. RESULTS Eighty-one patients with various intracranial disorders who had an intraventricular catheter for registration of the ICP were investigated: 46 (57%) patients had subarachnoid hemorrhage, 21 (26%) patients had closed head injury, and 14 (18%) patients had other neurosurgical disorders. A total of 658 TCD measurements were made. ICP registrations were made parallel with all TCD measurements. A significant correlation (p 120 cm/s) and subnormal (

✓ A case of progressive posttraumatic superior sagittal sinus thrombosis is presented, with the complication of pulmonary embolism. A good clinical outcome followed treatment with barbiturate coma.

We have used the rapid progression of post-traumatic uncal herniation in spite of intensive medical therapy as the indication for twist drill trephination in the emergency department. During a 54-month period, 51 trephinations were performed on 41 patients. The trephine was placed through the temporal bone ipsilateral to the dilated pupil, and the dura mater was opened to allow partial evacuation of a hematoma. All patients subsequently underwent craniotomy, autopsy, and/or cerebral computed tomography (CT). The trephination was diagnostically accurate for the absence or presence of an extracerebral hematoma in 42 of 51 trephinations (82%). In 6 of these cases the dilated pupil responded to partial hematoma evacuation by decreasing in size. In 3 of the 6 there was a marked overall improvement in neurological status subsequent to trephination. These 3 patients later recovered to an independent functional state. Only 23 of these 41 patients (56%) with herniation profiles actually had significant extracerebral hematomas. This fact emphasizes the inadvisability of taking this type of patient directly to the operating room without a diagnostic study. A rapidly performed CT scan is the obvious first choice. However, if there is any delay in obtaining this study or when uncal herniation occurs rapidly, a twist drill trephination can be of value in diagnosing the absence or presence of a treatable extracerebral hematoma. There were no complications related to this procedure in this group.

✓ Subependymomas are extremely rare tumors in the pediatric population and, when they occur, they are usually of a mixed type with elements of subependymoma and ependymoma. This report is of a 2½-year-old male infant with a pure subependymoma of the fourth ventricle.

From July 1978 to September 1981, 27 patients from a group of 210 patients with severe head injuries developed uncontrolled intracranial hypertension despite intensive medical and surgical management. These 27 patients were considered appropriate candidates for barbiturate therapy. Abnormal posturing or flaccidity was present in 70%; of the patients, and 41%; had bilaterally fixed pupils. Twenty-five of 27 patients had mass lesions requiring operation. Of the 15 patients who responded to barbiturate therapy with normalization of intracranial pressure for 24 hours, 5 died (33%; mortality). Nine of the 12 patients who did not respond to the barbiturate therapy died (75%; mortality). The total mortality in this group of 27 patients was 52%;. Of the survivors, 69%; had a recovery classified as good recovery/moderate disability, and 31%; were in a severe disability/vegetative state. The morbidity and mortality in these patients is high, but comparisons with previous studies show that this is a selected group of severe head injuries with a high percentage of poor prognostic indicators. Our experience suggests that barbiturates can be effective in lowering intracranial pressure in patients with otherwise unresponsive intracranial hypertension and, by doing so, may decrease the mortality in a group of patients considered untreatable by the usual therapeutic modalities.

Stimulating electrodes were placed on the terminal branches of the pudendal nerve to the external urethral and external anal sphincters. The proximity of the electrodes to the sphincters assured organ specificity. Evoked responses produced by stimulation of these terminal nerve branches were recorded in the fascicles and rootlets of the lower thoracic, lumbar, and sacral nerve roots. By this method, the segmental spinal cord origin of the innervation of the external urethral and anal sphincters was determined for the Rhesus monkey and chimpanzee. The data indicated that the pudendal nerves to the urethral and anal sphincters in the Rhesus monkey arose from the sixth and seventh lumbar spinal segments and the first and second sacral spinal segments which are homologous to the S-1 and S-4 segments found to give innervation to these structures in the chimpanzee. The primate experiments thus indicate that the spinal origin of the pudendal nerve was more rostrally located by one segment or more than was the origin of the pelvic nerves to the urinary bladder.

The understanding, diagnosis and management of neurologic dysfunction of the bladder have undergone considerable changes during the last 2 decades. These changes were the result of animal experimentation into physiology and pharmacology and the accelerated use of biomedical engineering technology. The implementation of these advances will require physician re-education in the neurology of micturition.

Of 215 patients with severe head injuries, 33 (15%) closed head injury patients who talked before their conditions deteriorated to a Glasgow coma scale score of 8 or less were identified. Of this select group, 15 died (45%), but none of the remaining were left in a vegetative state and 14 patients had a "favorable" outcome (42%). Twenty-five patients (76%) underwent surgical decompression. In these 25 patients, 14 subdural hematomas, 4 epidural hematomas, and 7 intracerebral contusions and hematomas were the initial surgical lesions. Twenty of the 25 patients were operated on within 4 hours (16 within 2 hours) of their neurological deterioration. Eleven of the 25 surgically treated died, for a mortality rate of 44%. All 15 deaths were studied further. Autopsies with examination of the brain were performed in 13 patients. Five patients died with severe brain injuries not complicated by iatrogenic factors, and 4 patients died of severe associated injuries. Iatrogenic factors significantly complicated the deaths of 6 patients (40%). It is concluded that most patients who "talk and deteriorate" have sustained very serious life-threatening injuries. Intracranial hematomas are the most frequent cause of this situation, and rapid diagnosis and decompression is the most important factor in salvaging these patients.

Stimulating electrodes were placed on the terminal branches of the pelvic nerves to the urinary bladder and the pudendal nerve to the sphincters in seven Rhesus monkeys and two chimpanzees. The proximity of the electrodes to these structures assured organ specificity. Evoked responses produced by stimulation of these terminal nerve branches were recorded in the fascicles and rootlets of the lower thoracic, lumbar, and sacral nerve roots. During identifical stimulating and recording conditions, the amplitude as well as presence or absence of the evoked responses recorded was variable within the various roots. The amplitude of the evoked responses or their absence depended on the number of fibers within a particular fascicle which conducted impulses to the urinary bladder or the urethral and anal sphincters. By this method, it was determined that there was segregation or compartmentalization of the nervous innervation to the urinary bladder and sphincters within the spinal roots. In addition, the segmental spinal cord origin of the innervation of the urinary bladder was determined for the Rhesus monkey and chimpanzee. In the Rhesus monkey, the pelvic nerves to the urinary bladder arose from the first and second sacral segments and to a much lesser extent from the seventh lumbar segment. In the chimpanzee the sacral segments one to four gave rise to innervation of the urinary bladder.

✓ Nine cases of delayed posttraumatic intracerebral hematomas (DTICH) were found retrospectively among 656 patients with closed head injuries admitted to the Hennepin County Medical Center in a 12-month period. All cases had severe head injuries sustained with the head in motion. The interval from cranial injury to diagnosis of DTICH by computerized tomography (CT) varied from 8 hours to 13 days. Eight patients were comatose on admission, three had focal seizures, and three had focal findings. The diagnosis was made on repeat CT scans obtained because of the development of focal findings in four cases, lack of improvement in four cases, and general neurological deterioration in one case. Four patients had initially negative CT scans. Four demonstrated only extracerebral hematomas on initial CT scan. One patient showed intracerebral hematoma on the initial scan followed by new hematomas on repeat study. The cases presented are discussed in light of pertinent literature.

A case of subarachnoid hematoma after a difficult lumbar puncture and anticoagulation is presented. Subarachnoid adhesions preventing the free flow of spinal fluid at the T-6 level served to limit the cranial progression of the hemorrhage and produced a transverse myelopathy at that level. The underlying pathology, clinical course, and myelographic findings are reviewed. Pertinent literature is presented.