Prolonged hypocortisolemia in hydrocortisone replacement regimens in adrenocorticotrophic hormone deficiency.

OBJECTIVES: Studies of adults have shown that thrice-daily hydrocortisone dosing results in more physiologic cortisol profiles than twice-daily dosing. There are no data on thrice-daily dosing and only limited data on twice-daily dosing in children despite the possible adverse effects of glucocorticoid underreplacement or overreplacement. METHODS: Using 24-hour cortisol and glucose profiles, along with computerized cognitive testing, our aim was to assess prescribed hydrocortisone regimens in children and adolescents with hypopituitarism. RESULTS: Twenty patients with adrenocorticotrophic hormone deficiency participated. The hydrocortisone dosing regimen was thrice daily in 9 patients and twice daily in 11 patients (mean total daily dose: 8.3 +/- 2.6 and 7.6 +/- 2.1 mg/m2 per day, respectively). Those on twice-daily dosing had more waking hours (between 8:00 am and 8:00 pm) below the reference range than those on thrice-daily dosing (5.5 vs 2.1) and more daytime prolonged hypocortisolemia, defined as plasma cortisol level of < 50 nmol/L for > or = 4 hours (64% vs 0%). Morning doses > 4 mg/m2 caused larger postdose peaks than < 4 mg/m2 (151 vs 47 nmol/L, above the 97.5th percentile). However, there was no difference in the length of time taken to reach nadir below the 2.5th percentile (5.2 vs 4.8 hours). This was true for evening doses of > 2.5 mg/m2 and < 2.5 mg/m2. No hypoglycemia or hyperglycemia was detected in association with low or high cortisol levels. On predose and postdose cognitive testing (34 paired tests), no significant change in reaction speed was detected (453.3 vs 438.8 milliseconds) or in subgroup analysis of those who had symptoms of lethargy, predose cortisol levels of < 50 nmol/L, or prolonged hypocortisolemia. CONCLUSIONS: Thrice-daily dosing resulted in less frequent and prolonged hypocortisolemia than twice-daily regimens, but we were unable to relate either regimen to acute clinical end points of glycemia, lethargy, or cognitive function.

Effects of GH on cognitive function in elderly patients with adult-onset GH deficiency: a placebo-controlled 12-month study.

OBJECTIVE: Young adults with childhood-onset GH deficiency (GHD) have reduced memory and attention, which can be improved by treatment with GH. Little information is available on cognitive function in elderly GHD patients. DESIGN: Single center, double-blind, randomized, placebo-controlled study of 52-week duration. METHODS: Elderly GH therapy naïve GHD patients (n=34; age range 60-77 years) were enrolled and randomized to receive placebo or GH therapy which was titrated to achieve a target IGF-I level of +1 to +2 s.d. of the normal mean for age. Cognitive function was assessed at baseline and after 24 and 52 weeks, using a computerized psychometric test package (Neurobehavioral Examination System-2). RESULTS: The mean GH dose was 0.16+/-0.06 mg/day; mean IGF-I increased from 135+/-59 ng/ml at baseline to 213+/-77 ng/ml during active treatment. The GH-treated group had better mean serial digit learning scores compared with placebo group (P<0.05). Assessment of effect sizes showed that improvements in memory occurred with GH after 24 weeks. The overall adverse event rates were similar in the GH and the placebo group. CONCLUSION: This study indicates that GH replacement may be accompanied by improvement in certain measures of cognitive function in elderly patients with GHD.

Practice effects associated with the repeated assessment of cognitive function using the CogState battery at 10-minute, one week and one month test-retest intervals.

There are many situations in which cognitive tests need to be administered on more than two occasions and at very brief test-retest intervals to detect change in group performance. However, previous literature has not specifically addressed these important issues. The main aim of the current study was to examine these two factors by using a computerized cognitive battery designed specifically for the repeated assessment of cognition (i.e., CogState) in healthy young adult individuals. A further aim of the study was to examine how many times the battery needed to be completed before performance, as measured by the battery, stabilized. Forty-five adults (age range: 18-40 years) completed the battery four times at 10-minute test-retest intervals, and a fifth time at an interval of one week. The results illustrated that when brief test-retest intervals were used (i.e., 10 minutes), performance stabilized after the second assessment, as significant practice effects were generally observed between the first and the second assessments. Practice effects were also observed on some of the tasks at a one-week test-retest interval. Due to these findings, 55 adults (age range: 18-40 years) completed the battery twice at 10-minute test-retest intervals (i.e., to eliminate the initial practice effect), and a third time at an interval of one month. No practice effects were observed. The implications of the results are discussed in terms of methods that can be adopted in order to minimize practice effects when this particular cognitive battery is used.

The effects of growth hormone (GH) deficiency and GH replacement on cognitive performance in adults: a meta-analysis of the current literature.

OBJECTIVE: There is growing evidence in the neuropsychological literature that growth hormone (GH) deficiency is associated with cognitive impairment. There is also evidence that this impairment may be ameliorated with GH replacement therapy. The current study assessed the nature and severity of cognitive impairment associated with growth hormone deficiency, as well as effect of GH replacement on cognitive function by conducting a meta-analysis of the published literature to date. METHOD: Thirteen studies met the inclusion criteria and these included: five cross-sectional studies investigating GH deficiency; and, eight (eight prospective, two of which also included cross-sectional comparisons) investigating GH replacement. Effect sizes (Cohen's d) falling into six cognitive domains were computed (separately for GH deficiency and GH replacement). RESULTS: For GH deficiency, each of the cognitive domains assessed (besides language) showed moderate to large impairments when compared to matched controls (Effect sizes -0.46 to -1.46). For GH replacement, even though treated patients still performed moderately to largely below that of controls, when compared to their own baselines (as in prospective analyses), moderate improvements were found in cognitive performance, particularly attention and memory. CONCLUSION: This meta-analysis clearly demonstrates the link between GH and cognitive performance, where poor performance can be ameliorated with GH treatment.

The nature and severity of cognitive impairment associated with adjuvant chemotherapy in women with breast cancer: a meta-analysis of the current literature.

OBJECTIVE: Several studies have identified that adjuvant chemotherapy for breast cancer is associated with cognitive impairment; however, the magnitude of this impairment is unclear. This study assessed the severity and nature of cognitive impairment associated with adjuvant chemotherapy by conducting a meta-analysis of the published literature to date. METHOD: Six studies (five cross-sectional and one prospective) meeting the inclusion criteria provided a total of 208 breast cancer patients who had undergone adjuvant chemotherapy, 122 control participants and 122 effect sizes (Cohen's d) falling into six cognitive domains. First, the mean of all the effect sizes within each cognitive domain was calculated (separately for cross-sectional and prospective studies); second, a mean effect size was calculated for all of the effect sizes in each cross-sectional study; and third, regression analyses were conducted to determine any relationships between effect size for each study and four different variables. RESULTS: For the cross-sectional studies, each of the cognitive domains assessed (besides attention) showed small to moderate effect sizes (-0.18 to -0.51). The effect sizes for each study were small to moderate (-0.07 to -0.50) and regression analysis detected a significant negative logarithmic relationship (R2 = .63) between study effect size and the time since last receiving chemotherapy. For the prospective study, effect sizes ranged from small to large (0.11-1.09) and indicated improvements in cognitive function from the beginning of chemotherapy treatment to 3 weeks and even 1 year following treatment. CONCLUSION: This meta-analysis suggests that cognitive impairment occurs reliably in women who have undergone adjuvant chemotherapy for breast cancer but that the magnitude of this impairment depends on the type of design that was used (i.e., cross-sectional or prospective). Thus, more prospective studies are required before definite conclusions about the effects of adjuvant chemotherapy on cognition can be made.

Fatigue-related impairment in the speed, accuracy and variability of psychomotor performance: comparison with blood alcohol levels.

Cognitive performance is impaired by fatigue arising from sustained wakefulness and alcohol. Three recent papers directly compared the effects of increasing fatigue and blood alcohol concentration (%BAC) to provide a framework for understanding fatigue-related cognitive impairment. While the expression of fatigue-related cognitive impairments in terms of %BAC equivalents is sound, the methodology in each study was flawed in that the statistics used to compare the effects of %BAC and fatigue on cognition did not account for variation between or within each condition. The point estimates of the difference between a baseline and any level of fatigue or %BAC provided no indication of the size of difference that could reasonably be expected by chance. Importantly, all studies showed that variation increased as cognitive performance declined because of both increasing fatigue and %BAC. The current study compared the effect of increasing levels of %BAC and fatigue on the simple reaction task from the CogState test battery on 40 healthy adults using statistical methods that account for intra-individual and within-group variability in performance. After 24 h of sustained wakefulness and with 0.08%BAC, individuals showed maximal cognitive impairment; however, the magnitude of impairment found for fatigue was equivalent only to that observed for 0.05%BAC. Re-analysis of the data using percentage change scores indicated that the magnitude of fatigue-related cognitive impairment was much greater than that detected for 0.08%BAC. This suggests that previous studies that have not accounted for variability in the performance data have overestimated the effect of fatigue on cognitive performance.

Qualitative similarities in cognitive impairment associated with 24 h of sustained wakefulness and a blood alcohol concentration of 0.05%.

Previous studies that have quantified fatigue-related cognitive impairment as blood alcohol concentration (BAC) equivalents have been limited by two issues: the effect of practice on tests of cognition and, more importantly, the statistic used to quantify change in cognitive performance. The current study addressed these issues by adopting an ABACA design, which allowed for the adequate control of practice effects, and by using effect size metrics, which enabled direct comparisons to be made in performance impairments as a result of fatigue (i.e. sustained wakefulness of 24 h) and alcohol (i.e. BAC of 0.05%). Cognitive performance under the fatigue and alcohol conditions required the use of the CogState battery. It was demonstrated that fatigue caused greater impairment than alcohol on the speed of continuous attention and memory and learning, and on the accuracy of complex matching. Alcohol was more detrimental than fatigue only on the accuracy of memory and learning. Performances on the remaining tasks were the same for both the fatigue and alcohol conditions. These differences and similarities in performance impairment are discussed emphasizing the deleterious cognitive effects of relatively short periods of sustained wakefulness.

Determining the extent of cognitive change after coronary surgery: a review of statistical procedures.

Currently, cognitive decline after coronary surgery is said to be significant if the individual's postoperative test score is at least 1 standard deviation (SD) worse than their preoperative score. This "1-SD" technique fails to account for factors that may confound interpretation of serially acquired cognitive test scores, including regression to the mean, measurement error caused by poor test-retest reliability, and practice effects. We review the many alternative and potentially superior statistical techniques that have been described in the neuropsychologic and psychiatric literature for differentiating "true" changes in cognitive test score from changes caused by these factors.