A randomized, double-blind, placebo-controlled trial of lamotrigine for prescription corticosteroid effects on the human hippocampus.

In animals, stress and corticosteroid excess are associated with decreases in memory performance and hippocampal volume that may be prevented with agents that decrease glutamate release. Humans also demonstrate changes in memory and hippocampus with corticosteroids. In this report the effects of glutamate-release inhibitor lamotrigine on hippocampal structure and memory were examined in people receiving medically needed prescription corticosteroid therapy. A total of 54 outpatient adults (n = 28 women) receiving chronic (≥ 6 months) oral corticosteroid therapy were randomized to lamotrigine or placebo for 48 weeks. Declarative memory was assessed using the Rey Auditory Verbal Learning Test (RAVLT); structural magnetic resonance imaging (MRI) as well as single-voxel proton MR spectroscopy (1HMRS) focused on hippocampus were obtained at baseline and week 48. Utilizing a mixed-model approach, structural and biochemical data were examined by separate ANOVAs, and memory was assessed with a multi-level longitudinal model. RAVLT total scores demonstrated significantly better declarative memory performance with lamotrigine than placebo (p = 0.047). Hippocampal subfield volumes were not significantly different between the treatment groups. In summary, lamotrigine was associated with less decline in declarative memory performance than placebo in corticosteroid-treated patients. Findings suggest that, in humans as well as in animal models, glutamate release inhibitors may attenuate some of the effects on the human memory associated with corticosteroids.

A comparison of clinician-rated neuropsychological and self-rated cognitive assessments in patients with asthma and rheumatologic disorders.

Although data are mixed, asthma and rheumatologic conditions may be associated with cognitive impairment. Medications may play a role because corticosteroids are associated with memory impairment. Therefore, an easily administered assessment of cognition would be useful in these patients. We assessed relationships between self-rated and clinician-rated cognitive performance and mood in patients with asthma and rheumatologic diseases. Participants included 31adults treated for asthma or rheumatologic disorders (17 receiving chronic prednisone therapy, and 14 not receiving prednisone). An objective assessment of a variety of cognitive domains was administered through clinician and patient-rated assessments of cognition. Composite scores for the objective (Global Clinical Rating [GCR]) and subjective (Neuropsychological Impairment Scale: Global Measure of Impairment [GMI]) measures of cognition were derived. Depression was assessed with the 17-item Hamilton Rating Scale for Depression (HRSD-17). A linear regression was conducted with GMI scores as dependent variable and GCR, HRSD-17 scores, and prednisone-use status, as independent variables. Significant differences between prednisone-treated patients and other patients were observed on the GCR, GMI, and HRSD-17. In the regression analysis, HRSD-17 scores, but not GCR scores, significantly predicted GMI scores. Prednisone-treated patients had higher levels of depressive symptoms and subjective and objective cognitive deficits than those not taking prednisone. In the combined patient groups, subjective cognitive assessment was more strongly related to depressive symptoms than objective cognition. Findings suggest physicians should be aware of the potential for cognitive deficits in patients taking corticosteroids and, when appropriate, should consider the use of objective neurocognitive tests or neuropsychology consultation to better characterize its presence and severity.

Impact of age on long-term recovery from traumatic brain injury.

OBJECTIVE: To determine whether older persons are at increased risk for progressive functional decline after traumatic brain injury (TBI). DESIGN: Longitudinal cohort study. SETTING: Traumatic Brain Injury Model Systems (TBIMS) rehabilitation centers. PARTICIPANTS: Subjects enrolled in the TBIMS national dataset. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Disability Rating Scale (DRS), FIM instrument cognitive items, and the Glasgow Outcome Scale-Extended. RESULTS: Participants were separated into 3 age tertiles: youngest (16-26y), intermediate (27-39y), and oldest (> or =40y). DRS scores were comparable across age groups at admission to a rehabilitation center. The oldest group was slightly more disabled at discharge from rehabilitation despite having less severe acute injury severity than the younger groups. Although DRS scores for the 2 younger groups improved significantly from year 1 to year 5, the greatest magnitude of improvement in disability was seen among the youngest group. In addition, after dividing patients into groups according to whether their DRS scores improved (13%), declined (10%), or remained stable (77%) over time, the likelihood of decline was found to be greater for the 2 older groups than for the youngest group. A multiple regression model showed that age has a significant negative influence on DRS score 5 years post-TBI after accounting for the effects of covariates. CONCLUSIONS: This study supported our primary hypothesis that older patients show greater decline over the first 5 years after TBI than younger patients. In addition, the greatest amount of improvement in disability was observed among the youngest group of survivors. These results suggest that TBI survivors, especially older patients, may be candidates for neuroprotective therapies after TBI.

Feasibility of a brief neuropsychologic test battery during acute inpatient rehabilitation after traumatic brain injury.

OBJECTIVES: To determine (1) if more than 50% of patients with moderate to severe traumatic brain injury (TBI) who met study criteria can complete a battery of neuropsychologic tests in less than 75 minutes 2 to 6 weeks after injury regardless of posttraumatic amnesia (PTA) status; (2) which tests are most likely to be completed; and (3) range of scores obtained. DESIGN: Prospective multicenter observational study. SETTING: Acute inpatient neurorehabilitation hospitals. PARTICIPANTS: Screened 543 Traumatic Brain Injury Model System patients with moderate to severe TBI; 354 were tested at 2 to 6 weeks postinjury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Percentage of patients able to complete the neuropsychologic tests in less than 75 minutes. RESULTS: Two hundred eighteen (62%) patients completed the battery in 66 minutes on average. Mean interval from injury to testing was 28.3+/-7.1 days. Tests completed with the highest frequency were California Verbal Learning Test-II, FAS, and animal naming. Performance was less impaired (P<.001) on all measures for patients who had emerged from PTA. CONCLUSIONS: Approximately two thirds of screened patients were able to complete a brief neuropsychologic test battery at 2 to 6 weeks postinjury, regardless of PTA status. Although patients out of PTA were less impaired on all test measures, confusion did not preclude participation in the test battery or prohibit assignment of test scores. Early neuropsychologic assessment after TBI is feasible even for many patients who are still in PTA.

The predictive validity of a brief inpatient neuropsychologic battery for persons with traumatic brain injury.

OBJECTIVE: To examine the predictive validity of a brief neuropsychologic test battery consisting of the Galveston Orientation and Amnesia Test, the California Verbal Learning Test-II, Trail-Making Test (TMT), Symbol Digit Modalities Test, grooved pegboard, phonemic and categorical word generation tasks, the Wechsler Test of Adult Reading (WTAR), and the Wisconsin Card Sorting Test-64 relative to functional outcome at 1 year in persons with traumatic brain injury. DESIGN: Inception cohort study. Follow-up period of 12 months. SETTING: Seven Traumatic Brain Injury Model System centers. Neuropsychologic testing was conducted during the acute inpatient rehabilitation stay and functional outcome measures were obtained at 1-year outpatient follow-up. PARTICIPANTS: Adults (N=174) who met criteria for admission to inpatient brain injury rehabilitation. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: FIM instrument, Disability Rating Scale, Supervision Rating Scale, Satisfaction With Life Scale (SWLS), and Glasgow Outcome Scale-Extended. RESULTS: Multiple regression analyses revealed that performance on the neuropsychologic test battery was predictive of outcome at 1 year postinjury for all outcome measures, except FIM motor scores and the SWLS. Cognitive performance using this battery was found to predict 1-year outcomes above and beyond functional variables and injury severity variables collected during inpatient rehabilitation, thereby indicating incremental validity for this test battery. Individual tests that were found to be significant predictors of 1-year outcomes included the WTAR and TMT part B. CONCLUSIONS: These findings support the clinical utility and ecological validity of this battery with respect to level of disability, functional independence, and supervision required.

Amygdala volume in patients receiving chronic corticosteroid therapy.

BACKGROUND: Hippocampal volume reduction and declarative memory deficits are reported in humans and animals exposed to exogenous corticosteroids. The amygdala is another brain structure involved in the stress response that has important interactions with the hypothalamic-pituitary-adrenal axis. To our knowledge, no studies in animals or humans have examined the impact of exogenous corticosteroid administration on the amygdala. We assessed amygdala volume in patients receiving chronic prescription corticosteroid therapy and control subjects with similar medical histories not receiving corticosteroids. METHODS: Fifteen patients on long-term prednisone therapy and 13 control subjects of similar age, gender, ethnicity, education, height, and medical history were assessed with magnetic resonance imaging. Amygdala volume was manually traced and compared between groups using a two-way analysis of variance (ANOVA). Correlations between amygdala volume, age, and corticosteroid dose/duration were assessed using Pearson's correlation coefficient. RESULTS: Compared with control subjects, corticosteroid-treated patients had significantly smaller amygdala volumes. Right amygdala volume correlated significantly with age in control subjects and with duration of corticosteroid therapy in patients. CONCLUSIONS: Patients receiving chronic corticosteroid therapy had smaller amygdala volumes than control subjects that correlated with duration of corticosteroid therapy. These findings suggest that corticosteroid exposure may be associated with changes in the amygdala as well as hippocampus.

Impact of levetiracetam on mood and cognition during prednisone therapy.

PURPOSE: Corticosteroid excess is associated with impairment in declarative memory and hippocampal changes. In animals, phenytoin blocks the effects of stress on memory and hippocampal histology. Levetiracetam also shows neuroprotective properties in some animal models. This report examines whether levetiracetam prevents mood or cognitive changes secondary to prescription corticosteroids. MATERIALS AND METHODS: Thirty outpatients given systemic corticosteroid therapy for asthma were randomized to either levetiracetam (1500 mg/day) or placebo given concurrently with the corticosteroids. Mood was assessed with the Hamilton rating scale for depression (HRSD), Young mania rating scale (YMRS) and activation (ACT) subscale of the internal state scale, declarative memory with the Rey auditory verbal learning test (RAVLT), and attention and executive functioning with the Stroop color and word test at baseline and after approximately 7 days of corticosteroid plus levetiracetam or placebo therapy. RESULTS: Levetiracetam and placebo groups showed significant improvement from baseline to exit on RAVLT total words recalled with a non-significant change on other outcomes. No significant between-group differences were found. Initial prednisone dose showed a significant correlation with change in some cognitive domains. CONCLUSIONS: Levetiracetam was well tolerated when combined with prednisone. Significant between-group differences in mood and cognition were not found.

Effects of chronic prednisone therapy on mood and memory.

BACKGROUND: In animals, stress and corticosteroids can be associated with both reversible and irreversible changes in the hippocampus. Changes in memory and hippocampal structure, perhaps in part due to cortisol elevations, are reported in some patients with mood disorders. Minimal data are available on the effects of long-term exposure to corticosteroids on the human hippocampus. We previously reported greater depressive symptom severity, poorer memory and smaller hippocampal volumes in patients with asthma or rheumatic diseases receiving long-term prednisone therapy than in controls. METHODS: In this report, patients and controls were assessed a mean of 4 years after the first assessment to determine if depressive and manic symptoms and cognition remained stable, improved or worsened. Seven prednisone-treated patients and six controls were identified and agreed to reassessment with psychiatric symptom and neurocognitive measures. Follow-up MRIs for hippocampal volume analysis were available for two prednisone-treated participants. RESULTS: With the exception of an increase in depressive symptoms in those receiving prednisone, participants and controls did not show significant change in mood or cognition from the initial assessment. One participant discontinued prednisone and showed improvement in psychiatric symptoms and cognition. Hippocampal volumes were available in two prednisone-treated participants and showed inconsistent findings. LIMITATIONS: A limitation is the small sample size. CONCLUSIONS: Our findings, although preliminary in nature, suggest that long-term prednisone therapy is associated with initial changes in mood, memory and hippocampal volume that appear to stabilize over time.

Deep venous thrombosis management following traumatic brain injury: a practice survey of the traumatic brain injury model systems.

OBJECTIVE: To determine national patterns of screening, prophylaxis, and treatment of deep venous thrombosis (DVT) following traumatic brain injury (TBI) within the Traumatic Brain Injury Model Systems (TBIMS). DESIGN: e-mail survey instrument. SETTING: Multicenter Regional TBIMS. RESULTS: Fifteen of the 16 rehabilitation centers within the TBIMS responded to the survey (94% response rate). Approximately half of these centers routinely screen to detect subclinical DVTs (56% venous duplex ultrasonography, 12% plasma D-dimer) on admission to inpatient rehabilitation. Fifty-six percent of respondents use anticoagulation prophylactically, while 69% use mechanical means for DVT prophylaxis. Eighty fatal pulmonary emboli were reported for TBI patients in 189 practice-years, corresponding to 0.42 fatalities per year of practice. CONCLUSIONS: No consensus exists regarding the optimal methods for screening, prevention, or treatment of DVT in TBI patients in the acute rehabilitation setting of the TBIMS. The number of fatal pulmonary emboli reported among these centers emphasizes the need to develop evidence-based clinical practice guidelines for the prevention and treatment of venous thromboembolism in this patient population.

Effect of two prednisone exposures on mood and declarative memory.

Corticosteroids are essential for life and an integral part of the stress response. However, in excess, corticosteroids can be associated with a variety of effects on the brain including hippocampal atrophy and even neuronal death, mood changes, and declarative memory impairment. The magnitude of mood change in patients receiving prednisone is reportedly associated with previous lifetime corticosteroid exposure, consistent with a sensitization or kindling process whereby greater effects are observed with repeated exposure. To our knowledge, the effect of multiple corticosteroid exposures on mood and memory has not been previously examined prospectively in animals or humans. In this study, 30 human volunteers, with no history of systemic prescription corticosteroid therapy, were given (in random order using a crossover design) two 3-day exposures of prednisone (60 mg/day) and one of identical placebo, with 11-day washouts between each medication exposure. Before and after each 3-day prednisone/placebo exposure, declarative memory was assessed using different versions of the Rey Auditory Verbal Learning Test (RAVLT) to minimize practice or learning effects, while mood was assessed with the 21-item Hamilton Rating Scale for Depression, Young Mania Rating Scale and Internal State Scale. No significant mood changes were found. However, a significant decrease in aspects of RAVLT performance was observed after the first prednisone exposure consistent with a decline in declarative memory performance. The decline in RAVLT performance was significantly smaller after the second prednisone exposure as compared to the initial prednisone exposure. Thus, a second prednisone exposure was associated with an attenuated prednisone-effect on declarative memory. These data suggest tolerance or habituation, rather than sensitization, to prednisone effects on declarative memory during a second exposure. Implications and possible explanations for the findings are discussed.

Functional outcome scales in traumatic brain injury: a comparison of the Glasgow Outcome Scale (Extended) and the Functional Status Examination.

Clinical trials aimed at developing therapies for traumatic brain injury (TBI) require outcome measures that are reliable, validated, and easily administered. The most widely used of these measures, the Glasgow Outcome Scale (GOS) and the GOS-Extended (GOS-E), have been criticized as suffering from ceiling effects. In an attempt to develop a more useful and dynamic outcome measure, the Functional Status Examination (FSE) was developed, which grades outcome across 10 functional domains. The FSE has been demonstrated to be reliable and sensitive in monitoring recovery after TBI. This manuscript compares FSE with GOS-E in a cohort of patients with a wide range of injury severities. 177 individuals who survived at least 6 months after TBI were studied. The FSE and GOS-E were administered 6-12 months after injury. FSE and GOS-E scores correlated well with each other. FSE scores were distributed throughout the range, indicating that ceiling and floor effects were not present. Physiologic measures of injury severity (Glasgow Coma Score [GCS]) did not correlate with anatomic measures (Abbreviated Injury Scale [AIS] and Injury Severity Score [ISS]). GCS correlated weakly with both outcome measures, but AIS/ISS did not. We conclude that FSE and GOS-E are reliable outcome measures for TBI survivors, and FSE may offer some advantages over GOS-E due its ability to provide a more detailed description of deficits. The majority of the variance in outcome is not accounted for by currently available measures of injury severity.

Interrater reliability of clinical ratings and neurocognitive diagnoses in HIV.

We examined the interrater (IRR) of clinical ratings of neuropsychological (NP) impairment and neurocognitive diagnoses in HIV. Thirty participants with advanced HIV-infection who were enrolled in a multicenter HIV brain banking research project underwent comprehensive NP and neuromedical evaluations. Using a standardized system of guidelines, neuropsychologists from six participating sites independently assigned clinical ratings of NP impairment, as well as multilevel diagnoses reflecting the inferred etiology of the impairments and their effects on everyday functioning. Findings indicated excellent IRR in rating the presence and severity of NP impairment, but overall modest IRR for neurocognitive diagnoses. Not surprisingly, most diagnostic disagreements concerned the etiology of impairments in persons with medical and neuropsychiatric risk factors in addition to HIV.

Elevated plasma homocysteine levels in patients treated with levodopa: association with vascular disease.

BACKGROUND: Hyperhomocysteinemia is a risk factor for vascular disease and potentially for dementia and depression. The most common cause of elevated homocysteine levels is deficiency of folate or vitamin B(12). However, patients with Parkinson disease (PD) may have elevated homocysteine levels resulting from methylation of levodopa and dopamine by catechol O-methyltransferase, an enzyme that uses S-adenosylmethionine as a methyl donor and yields S-adenosylhomocysteine. Since S-adenosylhomocysteine is rapidly converted to homocysteine, levodopa therapy may put patients at increased risk for vascular disease by raising homocysteine levels. OBJECTIVES: To determine whether elevations in plasma homocysteine levels caused by levodopa use are associated with increased prevalence of coronary artery disease (CAD), and to determine what role folate and vitamin B(12) have in levodopa-induced hyperhomocysteinemia. DESIGN/METHODS: Subjects included 235 patients with PD followed up in a movement disorders clinic. Of these, 201 had been treated with levodopa, and 34 had not. Blood samples were collected for the measurement of homocysteine, folate, cobalamin, and methylmalonic acid levels. A history of CAD (prior myocardial infarctions, coronary artery bypass grafting, or coronary angioplasty procedures) was prospectively elicited. We analyzed parametric data by means of 1-way analysis of variance or the t test, and categorical data by means of the Fisher exact test or chi(2) test. RESULTS: Mean +/- SD plasma homocysteine levels were significantly higher in patients treated with levodopa (16.1 +/- 6.2 micro mol/L), compared with levodopa-naïve patients (12.2 +/- 4.2 micro mol/L; P<.001). We found no difference in the plasma concentration of folate, cobalamin, or methylmalonic acid between the 2 groups. Patients whose homocysteine levels were in the higher quartile (>or=17.7 micro mol/L) had increased prevalence of CAD (relative risk, 1.75; 95% confidence interval, 1.08-2.70;P=.04). CONCLUSIONS: Levodopa therapy, rather than PD, is a cause of hyperhomocysteinemia in patients with PD. Deficiency of folate or vitamin B(12) levels does not explain the elevated homocysteine levels in these patients. To our knowledge, this is the first report that levodopa-related hyperhomocysteinemia is associated with increased risk for CAD. These findings have implications for the treatment of PD in patients at risk for vascular disease, and potentially for those at risk for dementia and depression.

Bilateral Memory Dysfunction in Epilepsy Surgery Candidates Detected by the Intracarotid Amobarbital Procedure (Wada Memory Test).

The intracarotid amobarbital procedure (IAP) is widely used in the evaluation of candidates for resective epilepsy surgery, in part to identify patients at risk for postoperative amnesia. Yet there is no widely accepted standardized protocol, and there is a paucity of quantitative data to assess the factors associated with poor IAP performance. This report summarizes our findings on 110 patients with intractable focal epilepsy who underwent IAP testing at our center. Ipsilateral IAP scores for patients with left-sided seizure foci were significantly lower than those for patients with right-sided seizure foci. Falsely and poorly lateralizing scores were also significantly more common in subjects with left-sided seizure onsets. Twenty-four percent of subjects failed the IAP bilaterally, and patients who failed the IAP bilaterally had significantly lower scores on neuropsychologic measures. There was no difference between patients who passed and failed in the location, etiology, duration, or age of onset of epilepsy. We conclude that bilateral memory dysfunction is common in patients with intractable partial epilepsy. Whether memory dysfunction detected by IAP testing as performed at our center is predictive of functionally limiting postoperative amnesia remains to be determined.