Robert C. Brunner

Amantadine to Improve Neurorecovery in Traumatic Brain Injury-Associated Diffuse Axonal Injury: A Pilot Double-blind Randomized Trial

Background:Traumatic brain injury (TBI) caused by a high-speed transportation accident results in a mechanism of injury commonly described as diffuse axonal injury (DAI), which is associated with a reduction in dopamine turnover in the brain. Because of its affect on both dopamine and N-methyl-D-aspartate (NMDA) channels, amantadine has been the subject of considerable interest and clinical use in acute TBI. Participants:In this study, 35 subjects, who had a TBI in a transportation accident and were initially seen with a Glasgow Coma Scale score of 10 or less within the first 24 hours after admission, were randomly assigned to a double-blind, placebo-controlled, crossover design trial. Main Outcome Measures:Amantadine, 200 mg, or placebo was each administered for 6 weeks (12 weeks total) to patients who were recruited consecutively. Results:There was an improvement in the Mini-Mental Status (MMSE) scores of 14.3 points (P = .0185), Disability Rating Scale (DRS) score of 9.8 points (P = .0022), Glasgow Outcome Scale (GOS) score of 0.8 points (P = .0077), and in the FIM Cognitive score (FIM-cog)™ of 15.1 points (P = .0033) in the group that received amantadine during the first 6 weeks (group 1), but there was no improvement in the second 6 weeks on placebo (P > .05). In group 2 (active drug second 6 weeks), there was an improvement in the MMSE of 10.5 points, in the DRS of 9.4 points (P = .0006), in the GOS of 0.5 points (P = .0231), and in the FIM-cog of 11.3 points (P = .0030, Wilcoxon signed rank) spontaneously in the first 6 weeks on placebo (P = .0015). However, group 2 gained a statistically significant additional 6.3 points of recovery in the MMSE (P = .0409), 3.8 points in the DRS (P = .0099), 0.5 points in the GOS (P = .4008), and 5.2 points in the FIM-cog (P = .0173, Wilcoxon signed rank) between the sixth week and the twelfth week of treatment on the active drug. Conclusions:There was a consistent trend toward a more rapid functional improvement regardless of when a patient with DAI-associated TBI was started on amantadine in the first 3 months after injury.

Natural History of Headache after Traumatic Brain Injury

Headache is one of the most common persisting symptoms after traumatic brain injury (TBI). Yet there is a paucity of prospective longitudinal studies of the incidence and prevalence of headache in a sample with a range of injury severity. We sought to describe the natural history of headache in the first year after TBI, and to determine the roles of prior history of headache, sex, and severity of TBI as risk factors for post-traumatic headache. A cohort of 452 acute, consecutive patients admitted to inpatient rehabilitation services with TBI were enrolled during their inpatient rehabilitation from February 2008 to June 2009. Subjects were enrolled across 7 acute rehabilitation centers designated as TBI Model Systems centers. They were prospectively assessed by structured interviews prior to inpatient rehabilitation discharge, and at 3, 6, and 12 months after injury. Results of this natural history study suggest that 71% of participants reported headache during the first year after injury. The prevalence of headache remained high over the first year, with more than 41% of participants reporting headache at 3, 6, and 12 months post-injury. Persons with a pre-injury history of headache (p<0.001) and females (p<0.01) were significantly more likely to report headache. The incidence of headache had no relation to TBI severity (p=0.67). Overall, headache is common in the first year after TBI, independent of the severity of injury range examined in this study. Use of the International Classification of Headache Disorders criteria requiring onset of headache within 1 week of injury underestimates rates of post-traumatic headache. Better understanding of the natural history of headache including timing, type, and risk factors should aid in the design of treatment studies to prevent or reduce the chronicity of headache and its disruptive effects on quality of life.

Zolpidem and restoration of consciousness.

Objective Zolpidem has been reported to cause temporary recovery of consciousness in vegetative and minimally conscious patients, but how often and why this occurs are unknown. The authors aimed to determine the frequency of this phenomenon and whether it can be predicted from demographic and clinical variables. Design This is a placebo-controlled, double-blind, single-dose, crossover study performed by caregivers and replicated by trained professionals, for naive participants. Four previously identified responders were also studied to further characterize the clinical drug response. Results Eighty-four participants with traumatic and nontraumatic disorders of consciousness of at least 4 mos’ duration were studied. Four “definite responders” were identified, but no demographic or clinical features were predictive of the response. Indicators of a drug response included increased movement, social interaction, command following, attempts at communication, and functional object use; typically lasted 1–2 hrs; and sometimes ended with increased somnolence. Adverse events were more common on zolpidem than placebo, but most were rated as mild. Conclusions Approximately 5% (4.8%) of the participants responded to zolpidem, but the responders could not be distinguished in advance from the nonresponders. Future research is needed to understand the mechanism of zolpidem in enhancing consciousness and its potential role in treatment and research.

Orally delivered baclofen to control spastic hypertonia in acquired brain injury.

To determine if oral/systemic delivery of baclofen can effectively decrease spastic hypertonia due to acquired brain injury (traumatic brain injury, stroke, anoxia, or encephalopathy). Tertiary care outpatient rehabilitation center directly attached to a university hospital. Patients were a convenience sample recruited consecutively who had been referred for treatment of their spastic hypertonia to our spasticity clinic over a 5-year period. The spastic hypertonia was due to an acquired brain injury by either traumatic brain injury (TBI), stroke, or anoxic brain injury. All patients were more than 6 months postinjury or illness. Retrospective review of patients before and after initiation of treatment with oral baclofen, per standardized clinical data sheets. Thirty-five patients (22 TBI patients) were started on oral baclofen and were reevaluated between 1 to 3 months after initiation of treatment. Data for motor tone (Ashworth scores), spasm scores (Penn spasm frequency score), and deep tendon reflex scores were collected on the affected upper extremity (UE) and lower extremity (LE) side(s). Normal extremities were not assessed. Differences over time were assessed via descriptive statistics and Wilcoxon signed-rank. After 1 to 3 months of treatment when subjects had reached their maximal tolerated dosage, the average LE Ashworth score in the affected lower extremities (LEs) decreased from 3.5 to 3.2 (P = .0003), the reflex score decreased from 2.5 to 2.2 (P = .0274), and there was no statistical difference in the spasm score (P > .05). When the 22 TBI patients are analyzed separately, the average LE Ashworth score decreased from 3.5 to 3.2 (P = .0044) and the reflex score decreased from 2.7 to 2.0 (P = .0003). There was no statistically significant change in UE tone, spasm frequency, or reflexes after 1 to 3 months of treatment (P > .05). The average dosage at follow-up was 57 mg/day of baclofen (range 15–120 mg/day). There was a 17% incidence of somnolence that limited the maximum daily dosage of the medication. The oral delivery of baclofen is capable of reducing LE spastic hypertonia resulting from acquired brain injury. The lack of effect upon the upper extremities may be due to receptor specificity issues. GABA-B receptors may be less involved in the modulation of UE spastic hypertonia.

A Preliminary Assessment of the Benefits of the Addition of Botulinum Toxin A to a Conventional Therapy Program on the Function of People With Longstanding Stroke

OBJECTIVE To determine if botulinum toxin type A (BTX-A) combined with therapy can facilitate improved upper-extremity (UE) functional status versus therapy alone. DESIGN Double-blind randomized crossover trial. SETTING Tertiary care outpatient rehabilitation center. PARTICIPANTS Convenience sample of 21 men and women (ages 19-80 y) with stroke more than 6 months after insult who had tone greater than 3 on the Ashworth Scale for 2 joints in the involved UE. INTERVENTION Subjects were consecutively recruited and randomized to a double-blind crossover trial. Subjects received either BTX-A combined with a defined therapy program or placebo injection combined with a therapy program in two 12-week sessions. MAIN OUTCOME MEASURES The primary functional outcome measure was the Motor Activity Log (MAL). Subjects were also assessed on physiologic measures including tone (Ashworth Scale), range of motion, and motor strength. RESULTS Improvements were noted in the functional status of the subjects in both arms of the study as measured by the MAL. All subjects had a significant change in functional status on MAL with therapy (P<.05). The use of BTX-A combined with therapy as compared with therapy only improved the functional status of the subjects on the MAL Quality of Movement subscale (P=.0180, t test) and showed a trend toward significance in the Amount of Use subscale (P=.0605, analysis of variance). Six weeks after treatment, the BTX-A combined with therapy decreased the Ashworth score statistically (P=.0271), but the therapy alone group decreased a similar amount at 6 weeks (P=.0117), indicating that most of the physiologic tone change could be attributed to therapy. After each 12-week period, tone had largely returned to baseline (P>.05). CONCLUSION A focused therapy program showed the most improvement in function in this defined stroke population. BTX-A combined with a focused traditional therapy program slightly enhanced the functional status of stroke subjects beyond that obtained with therapy alone 12 weeks after injection.

Impact of Early Administration of Sertraline on Depressive Symptoms in the First Year after Traumatic Brain Injury

The potential for sertraline administered in the first 3 months after moderate to severe traumatic brain injury (TBI) to decrease the incidence of depression in the first year after injury was assessed in a double-blinded randomized control trial. Subjects were enrolled an average of 21 days after injury (none >8 weeks) followed by oral administration of placebo (50 subjects) or sertraline 50 mg (49 subjects) for 3 months. Subjects were not depressed at the time of study initiation. Outcome was assessed using the Hamilton Depression Rating Scale (HDRS) and the Depression Scale of the Neurobehavioral Functioning Inventory (NFI). Based on intent-to-treat and efficacy subset analyses, those receiving placebo exhibited significantly greater depressive symptoms than those receiving sertraline during the first 3 months after injury while receiving placebo/drug (10% of placebo group achieving a score of 6 or greater on the HDRS, 0% of the sertraline group; p < 0.023.). There was no significant difference in depressive symptoms during the remainder of the year between the two groups. Sertraline is effective in diminishing depressive symptoms even among those not clinically depressed while the medication is being taken. However, the results do not support the idea that administration early in recovery diminishes the expression of depressive symptoms after the drug is stopped. There is no basis from this study to assume that sertraline administered early in recovery after TBI, when neurotransmitter functioning is often altered, has ongoing effects on the serotonin system after sertraline is discontinued.

Impact of early administration of sertraline on cognitive and behavioral recovery in the first year after moderate to severe traumatic brain injury.

Objective:To assess the efficacy of sertraline administered in the first 3 months after moderate to severe traumatic brain injury (TBI) in improving cognitive and behavioral outcomes. Design:Double-blind, randomized controlled trial. Setting:Academic medical center. Participants:Ninety-nine individuals randomized to placebo (n = 50) or sertraline 50 mg (n = 49) conditions. There were no group differences in age, gender, education, or severity of injury. Interventions:Participants were enrolled an average of 21 days after injury (none > 8 weeks), followed by oral administration of placebo or sertraline 50 mg for 3 months. Main Outcome Measures:Wechsler Memory Scale—Third Edition Logical Memory, Trail Making Test, Wechsler Adult Intelligence Scale—Third Edition Working Memory Index, Symbol-Digit Modalities Test, Wisconsin Card Sorting Test (64-item), Neurobehavioral Functioning Inventory administered 3, 6, and 12 months after the onset of injury. Results:Early administration of sertraline did not result in improved cognitive functioning during the year after injury compared with placebo administration. Those receiving placebo performed marginally better than the treatment group on a measure of executive function, but this appeared to be inauthentic. The treatment group followed expected recovery patterns based on existing literature. The placebo group performed better than expected on some measures, primarily due to differential dropout. Conclusions:Sertraline does not appear to prevent development of cognitive and behavioral problems following TBI, although this does not negate evidence for the treatment (as opposed to prophylactic) role of sertraline to address emotional and neurobehavioral problems in individuals with TBI.

Prophylaxis for Venous Thromboembolism During Rehabilitation for Traumatic Brain Injury: A Multicenter Observational Study

BACKGROUND Deep venous thrombosis (DVT) is a major cause of mortality and morbidity after traumatic brain injury (TBI). There is no consensus regarding appropriate screening, prophylaxis, or treatment during acute rehabilitation. METHODS This prospective observational study evaluated prophylactic anticoagulation during rehabilitation in patients with TBI aged 16 years or older admitted to 12 TBI Model Systems rehabilitation centers (July 2004-December 2007). After propensity score stratification within center, the odds ratio associated with incidence of symptomatic DVT or pulmonary embolism (PE) for patients who did and did not receive prophylactic anticoagulation was estimated using conditional logistic regression in patients who were not screened for DVT on rehabilitation admission or who screened negative; the analysis was repeated in these two subgroups. RESULTS Patients with identified DVTs at rehabilitation admission (n = 266) were excluded, leaving 1,897 patients: 1,002 screened negative, 895 unscreened; 932 received prophylactic anticoagulation, and 965 did not. Symptomatic DVT/PE was detected in 32 patients (15 of 932 [1.6%] with prophylaxis, 17 of 965 [1.8%] without). After propensity score adjustment, the odds ratio (95% confidence interval) for symptomatic DVT/PE with prophylaxis versus no prophylaxis was 0.80 (0.33-1.94) in the full analytic population and 0.46 (0.12-1.84) in the screened-negative subgroup. The only probable venous thromboembolism-related death occurred in the prophylactic anticoagulation group. Fewer new/expanded intracranial hemorrhages occurred among patients who received prophylactic anticoagulation. CONCLUSIONS Prophylactic anticoagulation during rehabilitation seemed safe for TBI patients whose physicians deemed it appropriate, but did not conclusively reduce venous thromboembolism. Given the number of DVTs present before rehabilitation, screening and prophylaxis during acute care may be more important.

Do Rehospitalization Rates Differ Among Injury Severity Levels in the NIDRR Traumatic Brain Injury Model Systems Program

OBJECTIVE To compare the rate and nature of rehospitalization in a cohort of patients enrolled in the National Institute on Disability and Rehabilitation Research Traumatic Brain Injury Model Systems (TBIMS) who have disorders of consciousness (DOC) at the time of rehabilitation admission with those in persons with moderate or severe traumatic brain injury (TBI) but without DOC at rehabilitation admission. DESIGN Prospective observational study. SETTING Inpatient rehabilitation within TBIMS with annual follow-up. PARTICIPANTS Of 9028 persons enrolled from 1988 to 2009 (N=9028), 366 from 20 centers met criteria for DOC at rehabilitation admission and follow-up data, and another 5132 individuals met criteria for moderate (n=769) or severe TBI (n=4363). INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Participants and/or their family members completed follow-up data collection including questions about frequency and nature of rehospitalizations at 1 year postinjury. For the subset of participants with DOC, additional follow-up was conducted at 2 and 5 years postinjury. RESULTS The DOC group demonstrated an overall 2-fold increase in rehospitalization in the first year postinjury relative to those with moderate or severe TBI without DOC. Persons with DOC at rehabilitation admission have a higher rate of rehospitalization across several categories than persons with moderate or severe TBI. CONCLUSIONS Although the specific details of rehospitalization are unknown, greater injury severity resulting in DOC status on rehabilitation admission has long-term implications. Data highlight the need for a longitudinal approach to patient management.

Natural History of Headache Five Years after Traumatic Brain Injury

Headache is one of the most frequently reported symptoms following traumatic brain injury (TBI). Little is known about how these headaches change over time. We describe the natural history of headache in individuals with moderate to severe TBI over 5 years after injury. A total of 316 patients were prospectively enrolled and followed at 3, 6, 12, and 60 months after injury. Individuals were 72% male, 73% white, and 55% injured in motor vehicle crashes, with an average age of 42. Pre-injury headache was reported in 17% of individuals. New or worse headache prevalence remained consistent with at least 33% at all time points. Incidence was >17% at all time points with first report of new or worse headache in 20% of participants at 60 months. Disability related to headache was high, with average headache pain (on 0-10 scale) ranging from 5.5 at baseline to 5.7 at 60 months post-injury, and reports of substantial impact on daily life across all time points. More than half of classifiable headaches matched the profile of migraine or probable migraine. Headache is a substantial problem after TBI. Results suggest that ongoing assessment and treatment of headache after TBI is needed, as this symptom may be a problem up to 5 years post-injury.