Association between cerebrospinal fluid interleukin-6 concentrations and outcome after severe human traumatic brain injury.

Acute inflammation plays a significant role in the pathophysiology of traumatic brain injury (TBI). However, the specific relationships between inflammatory mediators and patient outcome following TBI have not been fully established. In this study, we measured plasma and cerebrospinal fluid interleukin-1 (IL-1) and interleukin-6 (IL-6) concentrations in 36 patients, following severe TBI. Patients were monitored with continuous measurements of somatosensory-evoked potentials (SSEP) to derive an established surrogate outcome measurement, the 96-h evoked potential (SSEP96). Clinical outcomes were assessed at 3 months using the Glasgow Outcome Scale (GOS). Peak cerebrospinal fluid (CSF) IL-1 and IL-6 concentrations were significantly higher than those observed in the plasma [median 6.5 pg/mL (range 1.4-25.0) vs. 3.0 (0.8-7.6) for IL-1, and 650 (130-7,214) vs. 253 (52-1,506) for IL-6, p < 0.001 for both]. Peak CSF IL-6 levels correlated with SSEP96 (r = 0.42; p = 0.0133), and peak CSF IL-6 levels were higher with improved GOS (p = 0.024). Multiple regression analysis identified that age (p = 0.0072), pupillary abnormality (p = 0.021), the presence of mass lesion (p = 0.023), and peak CSF IL-6 concentrations (p = 0.026) were all statistically significant predictors of clinical outcome following TBI. These results suggest that peak CSF IL-6 concentrations correlate with improved outcome following TBI. This finding helps to characterize the inflammatory reaction associated with TBI and may help to develop improved treatment strategies for patients with TBI.

Attenuation of the electrophysiological function of the corpus callosum after fluid percussion injury in the rat.

This study describes a new method used to evaluate axonal physiological dysfunction following fluid percussion induced traumatic brain injury (TBI) that may facilitate the study of the mechanisms and novel therapeutic strategies of posttraumatic diffuse axonal injury (DAI). Stimulated compound action potentials (CAP) were recorded extracellularly in the corpus callosum of superfused brain slices at 3 h, and 1, 3, and 7 days following central fluid percussion injury and demonstrated a temporal pattern of functional deterioration. The maximal CAP amplitude (CAPA) covaried with the intensity of impact 1 day following sham, mild (1.0-1.2 atm), and moderate (1.8-2.0 atm) injury (p < 0.05; 1.11 +/- 0.10, 0.82 +/- 0.11, and 0.49 +/- 0.08 mV, respectively). The CAPA in sham animals were approximately 1.1 mV and did not vary with survival interval (3 h, and 1, 3, and 7 days); however, they were significantly decreased at each time point following moderate injury (p < 0.05; 0.51 +/- 0.11, 0.49 +/- 0.08, 0.46 +/- 0.10, and 0.75 +/- 0.13 mV, respectively). The CAPA at 7 days in the injured group were higher than at 3 h, and 1 and 3 days. H&E and amyloid precursor protein (APP) light microscopic analysis confirmed previously reported trauma-induced axonal injury in the corpus callosum seen after fluid percussion injury. Increased APP expression was confirmed using Western blotting showing significant accumulation at 1 day (IOD 913.0 +/- 252.7; n = 3; p = 0.05), 3 days (IOD 753.1 +/- 159.1; n = 3; p = 0.03), and at 7 days (IOD 1093.8 = 105.0; n = 3; p = 0.001) compared to shams (IOD 217.6 +/- 20.4; n = 3). Thus, we report the characterization of white matter axonal dysfunction in the corpus callosum following TBI. This novel method was easily applied, and the results were consistent and reproducible. The electrophysiological changes were sensitive to the early effects of impact intensity, as well as to delayed changes occurring several days following injury. They also indicated a greater degree of attenuation than predicted by APP expression changes alone.

Prediction of recovery of continuous memory after traumatic brain injury.

OBJECTIVE: To evaluate the ability of measures of initial severity, tests of attention, and demographic characteristics to predict recovery of continuous memory for words over a 24-hour period in patients with acute traumatic brain injury. METHODS: Recovery of continuous memory was assessed prospectively in 94 patients with nonpenetrating traumatic brain injury. A classification and regression tree analysis identified a hierarchical subset of variables that may be used as a simple guideline for predicting recovery of continuous memory. Weibull regression models evaluated and compared the predictive ability of multiple variables. RESULTS: Four groups of patients were identified based on measures of severity of injury and demographic characteristics. These four groups had recovery profiles that were more precise than could be obtained by using the Glasgow Coma Scale alone: mild, about 1 week to recovery of continuous memory; moderate, 1 to 4 weeks; severe, 2 to 6 weeks; and extremely severe, 4 to 8 weeks. Regression analysis confirmed that measures of capacity (inherent resources such as indicated by age) and compromise (general functional brain state measured neuropsychologically) improved prediction over models based only on injury severity measures, such as the Glasgow Coma Scale. CONCLUSIONS: Approaches to predicting recovery of continuous memory in the acute period after traumatic brain injury that take into account multiple measures provide a more sensitive predictive index.

The acute period of recovery from traumatic brain injury: posttraumatic amnesia or posttraumatic confusional state?

OBJECT: The goal of this study was to characterize more fully the cognitive changes that occur during the period of acute recovery after traumatic brain injury (TBI). METHODS: The pattern of performance recovery on attention and memory tests was compared with the results of the Galveston Orientation and Amnesia Test (GOAT). Tests of memory and attention were administered serially to a hospitalized group of patients with TBI of varying severity. The tests differed in their level of complexity and/or requirement for more effortful or strategic processing. The authors found a regular pattern to recovery. As expected, ability to perform on simpler tests was recovered before performance on more effortful ones. The ability to recall three words freely after a 24-hour delay (the operational definition in this study of return to continuous memory) was recovered last, later than normal performance on the GOAT. Ability to perform simple attentional tasks was recovered before the less demanding memory task (recognition); ability to perform more complex attentional tasks was recovered before the free recall of three words after a 24-hour delay. This recovery of attention before memory was most notable and distinct in the group with mild TBI. CONCLUSIONS: The period of recovery after TBI, which is currently termed posttraumatic amnesia, appears to be primarily a confusional state and should be labeled as such. The authors propose a new definition for this acute recovery period and argue that the term posttraumatic confusional state should be used, because it more appropriately and completely characterizes the early period of recovery after TBI.

Cerebral oxidative metabolism and evoked potential deterioration after severe brain injury: new evidence of early posttraumatic ischemia.

BACKGROUND: We commonly observe progressive deterioration in somatosensory evoked potentials (SSEPs) after severe head injury. We had previously been unable to relate this deterioration to raised intracranial pressure but had noted a relationship with decreasing transcranial oxygen extraction (arteriovenous oxygen difference [AVDO2]). The purpose of this study was twofold: to prove the hypothesis that deterioration in SSEP values is associated with decreasing AVDO2 and to test the subsidiary hypotheses that deteriorating SSEPs were the result of either ischemia/reperfusion injury or failure of oxygen extraction/utilization. METHODS: Monitoring of 97 patients with severe traumatic brain injury (Glasgow Coma Scale scores of < or = 8 after resuscitation) included twice daily AVDO2 measurement and hourly SSEP recording for an average of 5 days. The last 51 patients also underwent 12-hourly measurement of cerebral blood flow (CBF), with calculation of the cerebral metabolic rate of oxygen. Cluster analysis was used to classify patients based on initial AVDO2 values and subsequent SSEP trends. The time courses of CBF, SSEPs, AVDO2, and cerebral metabolic rate of oxygen were examined in the groups defined by the cluster analysis. The clinical outcomes considered were survival or nonsurvival and the Glasgow Outcome Scale scores obtained at 3 months or more after injury. RESULTS: Cluster analysis confirmed the association between high initial AVDO2 values and subsequent SSEP deterioration. Patients in this category initially had significantly higher AVDO2, lower CBF, and higher cerebral metabolic rates of oxygen but recovered to adequate levels within 24 to 36 hours after injury. SSEP values were initially identical in the patients with normal AVDO2 values and those with elevated AVDO2 but differed significantly at 60 hours after injury and beyond. CONCLUSION: The findings of increased oxygen utilization and lowered CBF in the patients with deteriorating SSEPs strongly imply that early ischemia rather than failure of O2 extraction or utilization is responsible for the associated SSEP deterioration. This issue of defining thresholds for ischemia based on AVDO2 is confounded by the dependency of CBF and AVDO2 values on the time after injury.

Clinical significance of CSF glutamate concentrations following severe traumatic brain injury in humans.

Glutamate excitotoxicity is a putative mechanism of secondary damage after traumatic brain injury (TBI). No relationship between glutamate release and clinical status has been shown in humans, however. We hypothesize a dose-response relationship between CSF glutamate concentrations and severity of injury, electrophysiological deterioration as measured by somatosensory evoked potential amplitudes, and clinical outcome. From August 1991 to March 1996, intensive monitoring of 55 patients with severe TBI (GCS < or = 8 after resuscitation) included twice daily CSF glutamate levels and hourly somatosensory evoked potentials (SSEPs) for an average of 5 days. Clinical outcomes were survival/nonsurvival and Glasgow outcome score (GOS) at 3 months or more post-injury. Glutamate levels were not associated with severity of injury, electrophysiological deterioration, or clinical outcome. Neither peak nor mean glutamate levels significantly improved a simple logistic regression model which used only age and presence of bilaterally unreactive pupils to predict survival. Using this methodology CSF glutamate concentrations did not display a dose-response relationship to severity of injury, electrophysiological deterioration, or predict clinical outcomes following TBI in a group of 55 patients. An early effect of glutamate, an effect dependent on time of exposure to glutamate or other modulating effects cannot be ruled out.

Monitoring severe head injury: a comparison of EEG and somatosensory evoked potentials.

We report on our experience with long-term monitoring of the EEG power spectrum and somatosensory evoked potentials (SSEPs) in 103 patients with severe closed head injury (Glasgow Coma Scale-GCS < or = 8). Patients were monitored for an average of 5 days post injury and monitoring was terminated when they died, regained consciousness or their intracranial physiologic parameters (primarily intracranial pressure-ICP) were stable for 2-3 days. Patients were treated according to a standard protocol that included mechanical ventilation, sedation, and neuromuscular blockade. At 7 of 9 twelve hour time intervals post injury, SSEPs were significantly (p < .05) different between outcome groups using the Glasgow Outcome Score collapsed to 3 categories. The percent slow (delta) activity in the EEG was not significantly different between outcome groups at any time point, post injury. The total power in the EEG power spectrum differed only at the last time epoch post injury (108 hr.). Based on the superior prognostic capabilities of the SSEP, we routinely base critical management decisions on SSEP values. We have not been able to rely on EEG parameters for these same decisions due to the lack of clear distinction between good and poor prognosis groups based on common EEG parameters.

Head injuries due to falls caused by seizures: a group at high risk for traumatic intracranial hematomas.

This prospective review of adult patients with head injuries examines the incidence of head injuries due to falls caused by seizures, the incidence and severity of intracranial hematomas, and the morbidity and mortality rates in this patient population. A head injury was attributed to a fall caused by a seizure if the seizure was witnessed to have caused the fall, or the patient had a known seizure history, appeared postictal or was found convulsing after the fall, and no other cause for the fall was evident. A total of 1760 adult head-injured patients were consecutively admitted to the authors' service between 1986 and 1993. Five hundred eighty-two head injuries (33.1%) were due to falls and 22 (3.8%) of these were caused by seizures. Based on the prevalence rates for epilepsy in the general population of 0.5 to 2%, these results indicate that epileptics are several times more likely to suffer a head injury due to a fall. Mass lesions were found in 20 (90.9%) of these 22 patients and the remaining two patients suffered mild diffuse head injuries. There was a high incidence of extraaxial mass lesions: 17 (85%) of the 20 intracranial hematomas were either epidural (five cases) or acute subdural (12 cases) hematomas. Eighteen (81.8%) of the 22 patients required evacuation of a hematoma. Both the incidence of intracranial hematomas (90.9% vs. 39.8%, p < 0.001, chi-square analysis) and the rate of hematoma evacuation (81.8% vs. 32.3%; p < 0.001) was significantly greater in patients injured in falls due to seizures (22 cases) than in the group injured in falls from all other causes (560 cases). The higher incidence of hematomas and the need for evacuation were not explained by differences in age, seventy of head injury, or incidence of alcohol intoxication. Despite the greater incidence of mass lesions and the need for operative treatment in patients injured because of seizures, their mortality rate was similar to that of patients injured in falls from other causes. On the basis of their review of patients admitted to a neurosurgical center with complaints of head injury, the authors conclude that patients with head injuries due to a fall caused by a seizure should undergo computerized tomography scanning early in their management. Until a mass lesion has been excluded, any decrease in level of consciousness or focal neurological deficit should not be attributed to the seizure itself.

Isolated suprascapular nerve palsy: a review of nine cases.

BACKGROUND: In nine patients, suprascapular nerve palsy followed serious accidents associated with fractures of the cervical vertebrae, clavicle or scapula and after weight lifting, wrestling and a fall on the elbow or shoulder. METHOD: All patients were examined as to muscle wasting, weakness and shoulder fixation. EMG examination was done in all cases and six patients underwent surgical exploration. RESULTS: The palsy was incomplete on clinical and EMG examination in all patients. On exploration, scarring, entrapment, tethering or kinking at the suprascapular notch was four and two had post-traumatic neuromas. CONCLUSIONS: In contrast to published studies, none of our patients presented with shoulder pain, a spontaneous onset nor with involvement limited to the infraspinatus muscle. The differential diagnosis should include C5 root lesion, brachial plexus neuritis, frozen shoulder and tear of the rotator cuff.

Electrophysiologic assessment of intracerebral contusions in closed head injury.

To determine whether intracerebral contusions should be evacuated in severe closed head injuries, patients with Glasgow Coma Scale scores < or = 8 and with radiologic evidence of midline shift on computed tomography admitted from 1987 through 1993 to our intensive care unit were monitored with median nerve somatosensory evoked potentials (SSEPs). A total of 44 patients and 84 hemispheres were included in the study. Initial SSEPs, calculated by a quantitative peak-peak amplitude method, were not significantly different between hemispheres that contained localized contusions > or = 2.5 cm, those that had evidence of diffuse injury or punctate lesions < 2.5 cm not considered suitable for surgical evacuation, and those without evidence of parenchymal hemorrhage (mean 14.64 microV, p = 0.43). The SSEPs deteriorated 41.2% from initial baseline levels in diffusely injured and 22.6% in contused hemispheres, whereas in normal-appearing hemispheres, SSEPs improved 51.1% (p = 0.01). The difference in SSEPs, however, was not significant between the contused and diffusely injured hemispheres. The results suggest that in severe closed head injury, cerebral hemispheres without radiologic evidence of structural damage have a high likelihood of improving after initial impact injury. Furthermore, hemispheres with localized contusions showed no more deterioration than those with more diffuse injury, implying that hemispheric electrical deterioration is not related to size of localized contusions but rather to underlying axonal damage. This indicates that surgical evacuation of localized contusions unless accompanied by mass effect is probably not warranted.

Somatosensory evoked potentials and intracranial pressure in severe head injury.

The purpose of this study was to explore the relationship between neurologic function, using a quantitative measurement of continuous somatosensory evoked potentials (SSEPs), and intracranial pressure (ICP) following traumatic brain injury. During a 6 year period, severely head-injured patients with a Glascow Coma Scale < or = 8 who were not moribund were monitored with SSEPs and ICP measurements. SSEPs from each hemisphere and ICP were recorded hourly for each patient. Neurologic outcomes were scored using the Glasgow Outcome Scale at three months post injury. Although initial SSEP amplitude did not correlate well with outcome, final SSEP summed peak to peak amplitude from both hemispheres (p = .0001), the best hemisphere (p = .0004), and the worst hemisphere (p = .0001) correlated well with the Glasgow Outcome Scale groups. Of a total of 72 patients, 40 had deteriorating SSEPs and 32 had stable or improving SSEPs. Peak ICP values were not statistically different in these groups (p = .6). Among patients with deteriorating SSEPs, 52.5% lost the greatest proportion of hemispheric electrical activity prior to ICP elevation. In the remaining patients, the percent reduction of SSEP activity after peak ICP levels was not statistically different from the percent reduction in SSEP activity prior to the peak ICP levels (p = .9). This data suggests that in a select group of patients with severe head injury, ICP does not cause SSEP deterioration, but rather is the consequence of deterioration of brain function.

Somatosensory evoked potential monitoring following severe closed head injury.

This paper describes the results of somatosensory evoked potential (SSEP) monitoring in 65 patients with severe head injury. Intracranial pressure (ICP) monitoring data were available for 63 patients, and arterial-jugular oxygen content (AVDO2) data for 52 patients. Eighty-nine percent of patients with no SSEP activity beyond 50 msec post-stimulus in either hemisphere died or were vegetative survivors (3 month Glasgow Outcome Score). All 17 patients with a good or moderate outcome had long latency cortical activity (i.e. > or = 70 msec post-stimulus) in both hemispheres. Among patients with absent activity in 1 hemisphere, 53% died and 47% were severely disabled (chi 2 = 40, p = 0.0000). In the latter group, age was a significant factor among patients who died or were severely disabled (p < 0.02). Forty-four of 65 patients had either clear-cut deterioration or improvement in SSEPs over the course of monitoring. There were no significant differences in peak ICP between patients with improving or deteriorating SSEPs. In contrast, those with deteriorating SSEPs had a significant drop in AVDO2, compared with patients with improving SSEPs (p < 0.01). Long-term continuous monitoring of SSEPs shows that following severe injury, neurologic function may undergo significant change in approximately two-thirds of patients. Furthermore, ICP does not appear to play a prominent role in neurologic deterioration. AVDO2 measurements indicate that deterioration is more likely associated with perturbation of cerebral oxidative metabolism. SSEP monitoring following severe head injury has proven prognostic value, and is recommended for patients who must be pharmacologically paralyzed for ICP or ventilator management.

A new quantitative measure for monitoring somatosensory evoked potentials.

This paper describes the development and testing of a computer algorithm to automate the process of peak identification and somatosensory evoked potential (SSEP) grading. We tested the accuracy of computerized peak detection and evaluated grading schemes using a test set of 60 SSEPs ranked from worst to best by the programmer (RJM) and a blinded grader (PO). The computer algorithm recognized 95% of peaks identified by visual inspection. Twelve percent of peaks identified by the computer were noise. Summed peak to peak amplitude gave the most accurate ranking of SSEPs. Rank correlation between computer and blinded and unblinded expert grading was r = .82 for PO, r = .92 for RJM, p < .0001 for both. Computer and manually summed amplitudes were highly correlated (Pearson r = .98, p < .0001). Correlation between the 2 expert graders was .86, p < .0001. Computer graded SSEPs were significantly related to clinical outcome at 3 months, p < .0001. Automatic grading of SSEPs using summed peak to peak amplitude is highly correlated with expert grading. The measure is objective, continuous, and well suited to statistical analysis.

Neurologic trauma concerns.

Patients with underlying medical illnesses or conditions will comprise a progressively larger proportion of head-injury patients given the aging of the general population and improved survival in serious illnesses. Age and underlying illness can influence the presentation, management, and outcome of head injuries by increasing the frequency, severity, and complications from head injury. This article examines the conditions that are most often associated with head injury.

Excitatory amino acids in cerebrospinal fluid following traumatic brain injury in humans.

Evidence from models of traumatic brain injury implicates excitotoxicity as an integral process in the ultimate neuronal damage that follows. Concentrations of the excitatory amino acid glutamate were serially measured in the cerebrospinal fluid (CSF) of patients with traumatic brain injuries and in control patients for comparison. The purpose of the study was to determine whether glutamate concentrations were significantly elevated following traumatic brain injury and, if so, whether they were elevated in a time frame that would allow the use of antagonist therapy. Cerebrospinal fluid was sampled fresh from ventricular drains every 12 hours and analyzed using high-performance liquid chromatography for the excitatory amino acids. The peak concentrations of glutamate in the CSF of the 12 brain-injured patients ranged from 14 to 474 microM and were significantly higher than those in the three control patients, 4.9 to 17 microM (Mann-Whitney U-test, p < 0.02). Glutamate concentrations in five of the eight patients who were still being sampled on Day 3 were beyond the control group range. The implication of this study is that severely head-injured patients are exposed to high concentrations of a neurotoxic amino acid for days following injury and thus may benefit from antagonist intervention.

Risk factors predicting operable intracranial hematomas in head injury.

A study was performed to examine the incidence of operable traumatic intracranial hematomas accompanying head injuries of differing degrees of severity, and to see if factors predicting operable mass lesions could be identified. Logistic analysis was used to identify independent predictors of operable traumatic intracranial hematomas. Data were gathered prospectively on 1039 patients admitted with head injury between January, 1986, and December, 1990. Patient age, Glasgow Coma Scale (GCS) score, pupillary inequality, and injury by falling were all independent predictors of the presence of operable intracranial hematomas (p = 0.0000, 0.0000, 0.0182, and 0.0001, respectively). Injury to vehicle occupants was less likely to result in operable mass lesions (p = 0.0001) than injury by other means. The incidence of traumatic intracranial hematomas in patients over 50 years old was three to four times higher than in those under 30 years of age. Not surprisingly, the incidence of operable hematomas increased with decreasing GCS scores. However, even at a GCS score of 13 to 15, patients with other risk factors had a substantial incidence of operable mass lesions. There was a 29% incidence of operable intracranial hematomas for patients with a GCS score of 13 to 15, aged over 40 years and injured in a fall. It is suggested that patients who are middle-aged or older, or those injured in falls, are at particular risk for traumatic intracranial hematomas even if their GCS score is high. These patients should have early definitive investigation with computerized tomography in order to identify operable hematomas and to initiate surgical treatment prior to neurological deterioration from mass effect.

Traumatic intracranial mass lesions: how soon for evacuation?

The purpose of this paper is to identify, by simple clinical parameters, those patients who are at particular risk for traumatic intracranial hematomas following accidental injury and to review the effects of delays in treatment on death from head injury. The findings indicate that vehicle occupants 30 years of age or younger are significantly (p less than 0.001) more likely to suffer from a "diffuse" head injury and serious truncal injury than they are to suffer a traumatic intracranial mass lesion. Conversely, older patients (60 years of age or older) injured in falls are more likely to have operable intracranial mass lesions without significant injury to the torso (p less than 0.001). Recommendations concerning early diagnosis and treatment of accident victims are made from these data.

Relative incidence of intracranial mass lesions and severe torso injury after accidental injury: implications for triage and management.

In a previous study of head injury patients we found that old age, low Glasgow Coma Scale (GCS) score, pupillary inequality, and falls were significant predictors of intracranial mass lesions (IMLs). Injury to motor vehicle occupants was less likely to result in IML. The present study defines predictors of severe torso injury (STI) in 646 patients admitted to a trauma unit and compares these with predictors of IML obtained in the previous study. Tachycardia and low blood pressure were associated with an increased incidence of STI (p = 0.003, p = 0.0000). The incidence of STI in falls differed from that of IML (13.2% vs. 47.7%, p less than 0.001). There was a greater incidence of STI than IML in MVAs (33.6% vs. 14.8%, p less than 0.001). Patients 70 years of age or older had a higher incidence of IMLs than STIs (p less than 0.001). Patients less than 30 years old had a significantly greater incidence of STIs than IMLs (p less than 0.001). These data suggest that in MVA victims who are less than 30 years old, are hypotensive, and tachycardic, the diagnosis and emergent treatment of severe torso injury should take precedence over measures designed to detect and treat intracranial mass lesions. The converse is true for older patients injured in falls.