The effect of telephone counselling on reducing post-traumatic symptoms after mild traumatic brain injury: a randomised trial.

BACKGROUND: Mild traumatic brain injury (MTBI) is a significant public health problem affecting approximately 1 million people annually in the USA. A total of 10-15% of individuals are estimated to have persistent post-traumatic symptoms. This study aimed to determine whether focused, scheduled telephone counselling during the first 3 months after MTBI decreases symptoms and improves functioning at 6 months. METHODS: This was a two-group, parallel, randomised clinical trial with the outcome assessed by blinded examiner at 6 months after injury. 366 of 389 eligible subjects aged 16 years or older with MTBI were enrolled in the emergency department, with an 85% follow-up completion rate. Five telephone calls were completed, individualised for patient concerns and scripted to address education, reassurance and reactivation. Two composites were analysed, one relating to post-traumatic symptoms that developed or worsened after injury and their impact on functioning, the other related to general health status. RESULTS: The telephone counselling group had a significantly better outcome for symptoms (6.6 difference in adjusted mean symptom score, 95% confidence interval (CI) 1.2 to 12.0), but no difference in general health outcome (1.5 difference in adjusted mean functional score, 95% CI 2.2 to 5.2). A smaller proportion of the treatment group had each individual symptom (except anxiety) at assessment. Similarly, fewer of the treatment group had daily functioning negatively impacted by symptoms with the largest differences in work, leisure activities, memory and concentration and financial independence. CONCLUSIONS: Telephone counselling, focusing on symptom management, was successful in reducing chronic symptoms after MTBI. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, #NCT00483444.

Workers' risk of unemployment after traumatic brain injury: a normed comparison.

We examined, among those persons working preinjury, the risk of unemployment 1 year after traumatic brain injury (TBI) relative to expected risk of unemployment for the sample under a validated risk-adjusted econometric model of employment in the U.S. population. Results indicate that 42% of TBI cases were unemployed versus 9% expected, relative risk (RR) = 4.5, 95% confidence interval (CI) (4.12, 4.95). The relative risk for unemployment was higher among males, those with higher education, persons with more severe injuries, and more impaired early neuropsychological or functional status. Difference in unemployment rates gave similar results for gender, severity of injury, and early neuropsychological and functional status. However, for education, the excess was smaller among those more highly educated, but the unemployment rate in the more highly educated in the general population was sufficiently small to yield a larger relative risk. In conclusion, after accounting for underlying risk of unemployment in the general population, unemployment is substantially higher after TBI for people who were employed when they were injured. The differential employment status varies depending on demographics, severity of brain injury, early functional outcome, and neurobehavioral indicators. For characteristics such as education, associated with rates of unemployment in the general population, different methods used to compare the rates may yield different results.

Self-report of extent of recovery and barriers to recovery after traumatic brain injury: a longitudinal study.

OBJECTIVE: To examine the perspective of survivors of traumatic brain injury (TBI) regarding the extent and nature of their recovery over time. DESIGN: Inception cohort, longitudinal study. SETTING: Level I trauma center. PARTICIPANTS: One hundred fifty-seven consecutively hospitalized individuals with TBI (mean age, 36.1 yr; 80% men) with a broad range of injury severity. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Participants reported the extent of their recovery and barriers to full recovery at 1, 6, and 12 months. RESULTS: Participants reported a median return to normal at the 3 follow-up times of 65%, 80%, and 85%. After 1 month, self-reported extent of recovery correlated well with performance on the Glasgow Outcome Scale (p <.001 at 6 and 12 mo) and Wechsler Adult Intelligence Scale Performance IQ (p =.001 at 12 mo). The major reported barrier to recovery was physical difficulties, which constituted over half of the concerns at all time periods. Report of physical-related concerns decreased significantly (p =.002) over time whereas cognition-related concerns increased significantly (p =.02). CONCLUSION: Brain injury survivors consider themselves to have greater recovery than previously reported by clinicians or family members, consider physical problems a significant factor in their recovery, and appear to become more aware of cognitive impairments over time.

Antiepileptogenesis and seizure prevention trials with antiepileptic drugs: meta-analysis of controlled trials.

PURPOSE: To synthesize evidence concerning the effect of antiepileptic drugs (AEDs) for seizure prevention and to contrast their effectiveness for provoked versus unprovoked seizures. METHODS: Medline, Embase, and The Cochrane Clinical Trials Register were the primary sources of trials, but all trials found were included. Minimal requirements: seizure-prevention outcome given as fraction of cases; AED or control assigned by random or quasi-random mechanism. Single abstracter. Aggregate relative risk and heterogeneity evaluated using Mantel-Haenszel analyses; random effects model used if heterogeneity was significant. RESULTS: Forty-seven trials evaluated seven drugs or combinations for preventing seizures associated with fever, alcohol, malaria, perinatal asphyxia, contrast media, tumors, craniotomy, and traumatic brain injury. Effective: Phenobarbital for recurrence of febrile seizures [relative risk (RR), 0.51; 95% confidence interval (CI), 0.32-0.82) and cerebral malaria (RR, 0.36; CI, 0.23-0.56). Diazepam for contrast media-associated seizures (RR, 0.10; CI, 0.01-0.79). Phenytoin for provoked seizures after craniotomy or traumatic brain injury (craniotomy: RR, 0.42; CI, 0.25-0.71; TBI: RR, 0.33; CI, 0.19-0.59). Carbamazepine for provoked seizures after traumatic brain injury (RR, 0.39; CI, 0.17-0.92). Lorazepam for alcohol-related seizures (RR, 0.12; CI, 0.04-0.40). More than 25% reduction ruled out valproate for unprovoked seizures after traumatic brain injury (RR, 1.28; CI, 0.76-2.16), and carbamazepine for unprovoked seizures after craniotomy (RR, 1.30; CI, 0.75-2.25). CONCLUSIONS: Effective or promising results predominate for provoked (acute, symptomatic) seizures. For unprovoked (epileptic) seizures, no drug has been shown to be effective, and some have had a clinically important effect ruled out.

Antiepileptogenic agents: how close are we?

Epilepsy is a common neurological condition, affecting about 4% of individuals over their lifetime. Epilepsy can be idiopathic, secondary to an underlying genetic abnormality or unknown causes, or acquired. Known potential causes account for about one third of epilepsy. Control of epilepsy has primarily focused on suppressing seizure activity after epilepsy has developed. An intriguing possibility is to control acquired epilepsy by preventing epileptogenesis, the process by which the brain becomes epileptic. Many laboratory models simulate human epilepsy as well as provide a system for studying epileptogenesis. The kindling model involves repeated application of subconvulsive electrical stimulation to the brain, leading to spontaneous seizures. Other models include the cortical or systemic injection of various chemicals. These models suggest that many antiepileptic drugs, from phenobarbital and valproate (valproic acid) to levetiracetam and tiagabine, have antiepileptogenic potential. Some promising other possibilities include N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) antagonists as well as the neurotrophins and their receptors. Phenobarbital, phenytoin, valproate, carbamazepine and, to a very limited extent, diazepam have been evaluated in clinical trials to test whether they actually prevent epileptogenesis in humans. Results have been very disappointing. Meta-analyses of 12 different drug-condition combinations show none with significantly lower unprovoked seizure rates among those receiving the active drug. In 4 of the 12, the observed rate was actually slightly higher among treated individuals. None of the newer drugs have been evaluated in antiepileptogenesis trials. Until some drugs demonstrate a clear antiepileptogenic effect in clinical trials, the best course to reduce the incidence of epilepsy is primary prevention of the risk-increasing events--for example, wearing helmets, using seat belts, or decreasing the risk of stroke by reducing smoking.

Utility of a composite measure to detect problematic alcohol use in persons with traumatic brain injury.

OBJECTIVES: To examine factors complicating the study of alcohol-related effects in traumatic brain injury (TBI) patients and to evaluate a composite measure to categorize such patients according to degree of alcohol-related problems. DESIGN: Inception cohort. SETTING: Level I trauma center. PATIENTS: Consecutively hospitalized adult TBI patients (n = 156; 73% men; 87% Caucasian; mean age, 30yr; mean education, 12yr). Selection criteria required objective evidence of brain trauma; minimum survival of 1 month postinjury; age 15 years or older; and English speaking. MAIN OUTCOME MEASURES: An index of problematic drinking based on a measure created by combining blood-alcohol level, quantity-frequency of consumption, and the Short Michigan Alcoholism Screening Test. Preinjury characteristics were obtained through structured interview. RESULTS: Participants with highly problematic drinking showed poorer premorbid psychosocial functioning, including lower educational attainment, greater likelihood of problems with the law, lower perceived social support, and greater prevalence of other substance abuse. CONCLUSION: The composite index is useful in identifying problematic drinkers among TBI patients. Results have implications for interpreting and planning research on the role of alcohol in TBI outcomes.

Incidence of intravenous site reactions in neurotrauma patients receiving valproate or phenytoin.

OBJECTIVE: To determine the incidence of intravenous site reactions to phenytoin and valproate in a large population of patients with neurotrauma. DESIGN: Retrospective chart review of two double-blind, randomized clinical trials evaluating the use of antiepileptic drugs to prevent posttraumatic seizures in patients with neurotrauma: phenytoin versus placebo (n = 390), and valproate versus phenytoin with placebo (n = 385). Information collected from the charts included the number, type, and location of intravenous lines and intravenous site events. SETTING: Tertiary care trauma and university teaching hospital. MAIN RESULTS: Intravenous site reactions occurred in 18% and 25% of patients receiving valproate or phenytoin, respectively, with the majority of events (70%) occurring in the first intravenous site. Patients received the neurosurgery study drug (NSSD) by either central or peripheral lines; all intravenous site reactions occurred in peripheral administration sites. When patients who received the drug by central line during the course of therapy were excluded, the estimated incidence of site reactions was 21% and 30% for valproate and phenytoin, respectively (p = 0.056). The time to the first event was shorter with phenytoin compared with valproate (2.0 +/- 1.3 vs. 3.0 +/- 1.9 d; p = 0.009). Fewer adverse events were noted with phenytoin in the phenytoin-without-valproate study than in the phenytoin-with-valproate study, with 4.3% and 8.2% of intravenous site events recorded in patients receiving placebo or phenytoin, respectively. There was no significant difference in the number of intravenous lines per patient used during NSSD drug infusion for phenytoin versus placebo or phenytoin versus valproate. CONCLUSIONS: Both intravenous phenytoin and valproate resulted in intravenous site reactions, with the loading doses responsible for the majority of the events.

Neuropsychological effects of valproate in traumatic brain injury: a randomized trial.

OBJECTIVES: To examine the neuropsychological side effects of valproate (VPA) given to prevent posttraumatic seizures. METHODS: In a randomized, double-masked, parallel group clinical trial, we compared the seizure prevention and neuropsychological effects of 1 or 6 months of VPA to 1 week of phenytoin. We studied 279 adult subjects who were randomized within 24 hours of injury and examined with a battery of neuropsychological measures at 1, 6, and 12 months after injury. We examined drug effects cross-sectionally at 1, 6, and 12 months and longitudinally by examining differential change from 1 to 6 months and from 6 to 12 months as a function of protocol-dictated changes in treatment. RESULTS: No significant adverse or beneficial neuropsychological effects of VPA were detected. CONCLUSIONS: Valproate (VPA) appears to have a benign neuropsychological side effects profile, making it a cognitively safe antiepileptic drug to use for controlling established seizures or stabilizing mood. However, based on this study, VPA should not be used for prophylaxis of posttraumatic seizures because it does not prevent posttraumatic seizures, there was a trend toward more deaths in the VPA groups, and it did not have positive effects on cognition.

Side effects and mortality associated with use of phenytoin for early posttraumatic seizure prophylaxis.

OBJECT: The goals of this study were to determine if the use of phenytoin to prevent early posttraumatic seizures following head injury was associated with significant adverse side effects and also to determine if the reduction in early posttraumatic seizures after phenytoin administration was associated with a change in mortality rates in head-injured patients. METHODS: The authors performed a secondary analysis of the data obtained in a prospective double-blind placebo-controlled study of 404 patients who were randomly assigned to receive phenytoin or placebo for the prevention of early and late posttraumatic seizures. The incidence of adverse drug effects during the first 2 weeks of treatment, however, was low and not significantly different between the treated and placebo groups. Hypersensitivity reactions occurred in 0.6% of the patients in the phenytoin-treated group compared with 0% in the placebo group (p = 1.0) during week 1, and in 2.5% of phenytoin-treated compared with 0% of placebo-treated patients (p = 0.12) for the first 2 weeks of treatment. Mortality rates were also similar in both groups. Although the mortality rate was higher in patients who developed seizures, this increase was related to the greater severity of the injuries sustained by these patients at the time of the original trauma. CONCLUSIONS: The results of this study indicate that the incidence of early posttraumatic seizure can be effectively reduced by prophylactic administration of phenytoin for 1 or 2 weeks without a significant increase in drug-related side effects. Reduction in posttraumatic seizure during the 1st week, however, was not associated with a reduction in the mortality rate.

Valproate therapy for prevention of posttraumatic seizures: a randomized trial.

OBJECT: Seizures frequently accompany moderate to severe traumatic brain injury. Phenytoin and carbamazepine are effective in preventing early, but not late, posttraumatic seizures. In this study the authors compare the safety and effectiveness of valproate with those of short-term phenytoin for prevention of seizures following traumatic brain injury. METHODS: The study was a randomized, double-blind, single-center, parallel-group clinical trial. Treatment began within 24 hours of injury. One hundred thirty-two patients at high risk for seizures were assigned to receive a 1-week course of phenytoin, 120 were assigned to receive a 1-month course of valproate, and 127 were assigned to receive a 6-month course of valproate. The cases were followed for up to 2 years. The rates of early seizures were low and similar when using either valproate or phenytoin (1.5% in the phenytoin treatment group and 4.5% in the valproate arms of the study; p = 0.14, relative risk [RR] = 2.9, 95% confidence interval [CI] 0.7-13.3). The rates of late seizures did not differ among treatment groups (15% in patients receiving the 1-week course of phenytoin, 16% in patients receiving the 1-month course of valproate, and 24% in those receiving the 6-month course of valproate; p = 0.19, RR = 1.4, 95% CI 0.8-2.4). The rates of mortality were not significantly different between treatment groups, but there was a trend toward a higher mortality rate in patients treated with valproate (7.2% in patients receiving phenytoin and 13.4% in those receiving valproate; p = 0.07, RR = 2.0, 95% CI 0.9-4.1). The incidence of serious adverse events, including coagulation problems and liver abnormalities, was similar in phenytoin- and valproate-treated patients. CONCLUSIONS: Valproate therapy shows no benefit over short-term phenytoin therapy for prevention of early seizures and neither treatment prevents late seizures. There was a trend toward a higher mortality rate among valproate-treated patients. The lack of additional benefit and the potentially higher mortality rate suggest that valproate should not be routinely used for the prevention of posttraumatic seizures.

Test-retest reliability and practice effects of expanded Halstead-Reitan Neuropsychological Test Battery.

Test-retest reliabilities and practice effects of a broad range of neuropsychological measures were examined in 384 normal or neurologically stable adults. Median test-retest interval was 11 months (range 3-16 months). The reliability estimates for most of the measures are reasonably good, ranging from .70 to low .90s. An exception is the relatively poor reliabilities of most memory measures. For all test measures, the value on initial testing is a strong determinant of the value on the second examination. Practice effects are seen on most measures. The magnitude of the practice effects, however, varies as a function of type of measure, test-retest interval, age, and overall competency level of the participant. This study provides several types of retest information that may be useful for future research and clinical work: comparative reliabilities of the various measures, estimate of error variability associated with each administration, standard deviation of the change, and comparative magnitude of practice effects on various tests.

Detecting significant change in neuropsychological test performance: a comparison of four models.

A major use of neuropsychological assessment is to measure changes in functioning over time; that is, to determine whether a difference in test performance indicates a real change in the individual or just chance variation. Using 7 illustrative test measures and retest data from 384 neurologically stable adults, this paper compares different methods of predicting retest scores, and of determining whether observed changes in performance are unusual. The methods include the Reliable Change Index, with and without correction for practice effect, and models based upon simple and multiple regression. For all test variables, the most powerful predictor of follow-up performance was initial performance. Adding demographic variables and overall neuropsychological competence at baseline significantly but slightly improved prediction of all follow-up scores. The simple Reliable Change Index without correction for practice performed least well, with high error rates and large prediction intervals (confidence intervals). Overall prediction accuracy was similar for the other three methods; however, different models produce large differences in predicted scores for some individuals, especially those with extremes of initial test performance, overall competency, or demographics. All 5 measures from the Halstead-Reitan Battery had residual (observed--predicted score) variability that increased with poorer initial performance. Two variables showed significant nonnormality in the distribution of residuals. For accurate prediction with smallest prediction--confidence intervals, we recommend multiple regression models with attention to differential variability and nonnormality of residuals.

Aging effect on psychosocial outcome in traumatic brain injury.

OBJECTIVE: To examine the effects of age on outcome in persons with traumatic brain injury. DESIGN: Longitudinal cohort design. SETTING: Level I trauma center. PATIENTS: A total of 411 hospitalized subjects with mild to severe traumatic brain injury prospectively studied to 1 year; their age range was 18 to 89 years. MAIN OUTCOME MEASURES: Glasgow Outcome Scale, living situation, and employment. RESULTS: Increasing age is associated with increasing levels of psychosocial limitations, especially in persons 60 years of age and older. Part of the reason is the greater severity of injury sustained by older persons as reflected in longer coma (despite equivalent initial coma depth) and greater numbers of complications and surgeries for subdural hematomas. However, the consequences of traumatic brain injuries appear to worsen with increasing age at each level of brain injury severity examined, including the milder injuries. CONCLUSIONS: Older adults clearly show less complete recovery 1 year after brain injury than younger adults, either because they have reduced reserves with which to tolerate brain injury or because their physiologic status creates a more destructive injury. Glasgow Coma Scale alone may underestimate the severity of brain injury in the aged as well as its associated consequences. Caution is advised in generalizing findings based principally on younger individuals to older adults with traumatic brain injuries.

Increases in metabolism of valproate and excretion of 6beta-hydroxycortisol in patients with traumatic brain injury.

AIMS: The objectives of this study were to determine the effect of brain trauma on the multiple pathways of metabolism of valproate and to evaluate the use of the urinary 6beta-hydroxycortisol to cortisol ratio in predicting changes in hepatic metabolism induced by brain injury. METHODS: Fourteen patients with severe head injuries received a 15 mg kg(-1) loading dose and a maintenance dose of valproate to maintain therapeutic plasma concentrations. A minimum of one steady state trough blood sample and one dosage interval urine were collected during days 3-6 and during days 7-14 post-injury. Total and unbound valproate plasma concentrations were determined by gas chromatography-flame ionization detection (GC-FID) with and without ultrafiltration. Urinary valproate metabolites were measured by gas chromatography/mass spectrometry (GC-MS) (n = 10). Urinary 6beta-hydroxycortisol and cortisol concentrations were determined by high performance liquid chromatography (h.p.l.c.) (n = 14). Total intrinsic clearance (CL[int]) for valproate and individual formation clearances (CL[f]) to its major metabolites were calculated. Data obtained during baseline (days 3-6) were averaged for each patient and were compared with averaged data obtained from days 7 to 14 using a paired t-test. RESULTS: Statistically significant increases in the CL(int), CL(f) of VPA glucuronide, 2-ene-VPA, and 4-OH-VPA pathways and the 6beta-hydroxycortisol to cortisol ratio were found. The percent change in the 6beta-hydroxycortisol to cortisol ratio correlated significantly with the changes in the CL(int) of valproate. CONCLUSIONS: Brain trauma results in induction of multiple pathways of valproate metabolism and increases in the 6beta-hydroxycortisol to cortisol ratio, suggesting a non-specific enzyme induction in response to head injury.

Risk of seizure recurrence after the first late posttraumatic seizure.

OBJECTIVE: To determine the incidence and risk factors for seizure recurrence after the onset of late posttraumatic seizures (ie, seizures occurring more than 7 days after injury). DESIGN: Longitudinal cohort design. SETTING: Level 1 trauma center. PATIENTS: Sixty-three moderately to severely head-injured adults who developed late posttraumatic seizures during the course of their participation in a randomized, placebo-controlled study of the effectiveness of prophylactic phenytoin (Dilantin) for prevention of posttraumatic seizures. MAIN OUTCOME MEASURES: Time from the first unprovoked late seizure to time of seizure recurrence. RESULTS: The cumulative incidence of recurrent late seizures was 86% by approximately 2 years. However, the frequency of recurrent seizures varied considerably across subjects: 52% experienced at least five late seizures, and 37% had 10 or more late seizures within 2 years of the first late seizure. The relative risk of recurrence was highest in patients with a history of acute subdural hematoma and prolonged coma (ie, longer than 7 days). CONCLUSIONS: When late seizures develop after severe head injury, the probability of recurrence is high, which suggests that patients be treated aggressively with anticonvulsant medication after a first unprovoked late seizure.

Revised Winter-Tozer equation for normalized phenytoin concentrations in trauma and elderly patients with hypoalbuminemia.

OBJECTIVE: To develop a revised equation reflecting the current practice of measuring unbound phenytoin at room temperature, and to evaluate the revised Winter-Tozer method of predicting normalized total phenytoin concentrations in two groups of patients with hypoalbuminemia-elderly nursing home patients and critically ill head trauma patients. DESIGN: Albumin, unbound phenytoin, and total phenytoin concentrations were obtained from two sources: prospectively from a group of elderly nursing home patients and by a retrospective chart review of trauma patients enrolled in a previous double-blind, placebo-controlled study. SETTING: Community nursing homes; a university-affiliated urban teaching hospital. PARTICIPANTS: Elderly nursing home patients (n = 46) taking chronic phenytoin therapy and patients enrolled in a double-blind, placebo-controlled study (n = 58) evaluating the use of phenytoin to prevent posttraumatic seizures. MAIN OUTCOME MEASURES: Prediction error analysis was performed by using the methods proposed by Sheiner and Beal. Bias and precision were evaluated by calculating the mean prediction error (MPE) and root mean squared error (RMSE), respectively. RESULTS: The Winter-Tozer equation consistently overpredicted the normalized phenytoin concentration in the elderly nursing home population (MPE = 3.2, RMSE = 5.9) and the trauma patients (MPE = 3.3, RMSE = 4.8). The equation was revised to reflect the increased protein binding of phenytoin with decreased temperature and resulted in significantly decreased bias in both groups of patients. CONCLUSIONS: The revised equation is useful in predicting normalized phenytoin concentrations in both elderly nursing home patients and critically ill trauma patients.

The impact of posttraumatic seizures on 1-year neuropsychological and psychosocial outcome of head injury.

This study examined the relationship of posttraumatic seizures and head injury severity to neuropsychological performance and psychosocial functioning in 210 adults who were prospectively followed and assessed 1 year after moderate to severe traumatic head injury. Eighteen percent (n = 38) of the patients experienced 1 or more late seizures (i.e., seizures occurring 8 or more days posttrauma) by the time of the 1-year followup. As expected, the head injured patients who experienced late posttraumatic seizures were those with the most severe head injuries, and they were significantly more impaired on the neuropsychological and psychosocial measures compared to those who remained seizure free. However, after the effects of head injury severity were controlled, there were no significant differences in neuropsychological and psychosocial outcome at 1 year as a function of having seizures. These findings suggest that worse outcomes in patients who develop posttraumatic seizures up to 1 year posttrauma largely reflect the effects of the brain injuries that cause seizures, rather than the effect of seizures.