Multicenter randomized clinical trial of donepezil for memory impairment in multiple sclerosis.

OBJECTIVES: The goal of this study was to determine if memory would be improved by donepezil as compared to placebo in a multicenter, double-blind, randomized clinical trial (RCT). METHODS: Donepezil 10 mg daily was compared to placebo to treat memory impairment. Eligibility criteria included the following: age 18-59 years, clinically definite multiple sclerosis (MS), and performance ≤ ½ SD below published norms on the Rey Auditory Verbal Learning Test (RAVLT). Neuropsychological assessments were performed at baseline and 24 weeks. Primary outcomes were change on the Selective Reminding Test (SRT) of verbal memory and the participant's impression of memory change. Secondary outcomes included changes on other neuropsychological tests and the evaluating clinician's impression of memory change. RESULTS: A total of 120 participants were enrolled and randomized to either donepezil or placebo. No significant treatment effects were found between groups on either primary outcome of memory or any secondary cognitive outcomes. A trend was noted for the clinician's impression of memory change in favor of donepezil (37.7%) vs placebo (23.7%) (p = 0.097). No serious or unanticipated adverse events attributed to study medication developed. CONCLUSIONS: Donepezil did not improve memory as compared to placebo on either of the primary outcomes in this study. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence which does not support the hypothesis that 10 mg of donepezil daily for 24 weeks is superior to placebo in improving cognition as measured by the SRT in people with MS whose baseline RAVLT score was 0.5 SD or more below average.

Judgment in older adults: development and psychometric evaluation of the Test of Practical Judgment (TOP-J).

This article reports on the development and validation of a novel, objective test of judgment for use with older adults. The Test of Practical Judgment (TOP-J) is an open-ended measure that evaluates judgment related to safety, medical, social/ethical, and financial issues. Psychometric features were examined in a sample of 134 euthymic individuals with mild Alzheimer's disease (AD), amnestic mild cognitive impairment (MCI), or cognitive complaints but intact neuropsychological performance (CC), and demographically-matched healthy controls (HC). Measures of reliability were adequate to high, and TOP-J scores correlated with select measures of executive functioning, language, and memory. AD participants obtained impaired TOP-J scores relative to HCs, while MCI and CC participants showed an intermediate level of performance. Confirmatory factor analyses were consistent with a unidimensional structure. Results encourage further development of the TOP-J as an indicator of practical judgment skills in clinical and research settings. Longitudinal assessments are being performed to examine predictive validity of the TOP-J for cognitive progression in our clinical groups.

Vitamin D deficiency in a multinational refugee population.

BACKGROUND: Populations with increased skin pigmentation who have migrated to countries of high latitude are at increased risk of low vitamin D. This study aimed to determine the prevalence of low vitamin D among the refugee population arriving in New Zealand. METHODS: An audit of all refugees arriving at the national refugee resettlement centre from May 2004 to May 2005 was carried out. Serum 25-hydroxyvitamin D3 levels were measured and defined as normal (50-150 nmol/L) or low, with low subdivided into insufficient (25 to <50 nmol/L) and deficient (<25 nmol/L). Whether vitamin D status varied with age and sex was determined. RESULTS: Vitamin D was measured in 869 (99%) of the refugees and was low in 470 (54%, 95% confidence interval (CI) 51-57%). It was insufficient in 323 (37%, 95%CI 34-41%) and deficient in 147 (17%, 95%CI 15-20%). Female sex was associated with at least a 10 times increased risk of vitamin D deficiency (relative ratio 13.93, 95%CI 10.15-17.96). Women aged between 17 and 45 years and men aged 46 years and more were at greatest risk. CONCLUSION: Poor vitamin D status is prevalent among refugees arriving in New Zealand. Women, particularly those of child-bearing age are at greatest risk. Screening and ongoing surveillance for vitamin D deficiency should be considered for all recent refugee immigrants to New Zealand.

Regional brain atrophy in cognitively intact adults with a single APOE epsilon4 allele.

OBJECTIVE: To determine whether cognitively intact adults with the APOE epsilon3/epsilon4 genotype show reduced gray matter density on voxel-based morphometry (VBM) vs those homozygous for the epsilon3 allele. METHODS: Participants were healthy, cognitively intact, right-handed adults, age 19 to 80, who completed genotyping, neuropsychological testing, and MRI. Forty-nine participants had the epsilon3/epsilon3 genotype and 27 had the epsilon3/epsilon4 genotype. Gray matter data were analyzed using the general linear model as implemented in the Statistical Parametric Mapping package, adjusting for age and sex. RESULTS: The epsilon3/epsilon4 participants showed lower gray matter density than the epsilon3/epsilon3 participants in right medial temporal and bilateral frontotemporal regions as well as other areas. There were no regions in which epsilon3/epsilon4 participants showed higher gray matter density than epsilon3/epsilon3 participants. CONCLUSIONS: Regionally reduced gray matter density is detectable in cognitively intact adults with a single copy of the APOE epsilon4 allele.

Older adults with cognitive complaints show brain atrophy similar to that of amnestic MCI.

OBJECTIVE: To examine the neural basis of cognitive complaints in healthy older adults in the absence of memory impairment and to determine whether there are medial temporal lobe (MTL) gray matter (GM) changes as reported in Alzheimer disease (AD) and amnestic mild cognitive impairment (MCI). METHODS: Participants were 40 euthymic individuals with cognitive complaints (CCs) who had normal neuropsychological test performance. The authors compared their structural brain MRI scans to those of 40 patients with amnestic MCI and 40 healthy controls (HCs) using voxel-based morphometry and hippocampal volume analysis. RESULTS: The CC and MCI groups showed similar patterns of decreased GM relative to the HC group on whole brain analysis, with differences evident in the MTL, frontotemporal, and other neocortical regions. The degree of GM loss was associated with extent of both memory complaints and performance deficits. Manually segmented hippocampal volumes, adjusted for age and intracranial volume, were significantly reduced only in the MCI group, with the CC group showing an intermediate level. CONCLUSIONS: Cognitive complaints in older adults may indicate underlying neurodegenerative changes even when unaccompanied by deficits on formal testing. The cognitive complaint group may represent a pre-mild cognitive impairment stage and may provide an earlier therapeutic opportunity than mild cognitive impairment. MRI analysis approaches incorporating signal intensity may have greater sensitivity in early preclinical stages than volumetric methods.

Brain activation patterns associated with working memory in relapsing-remitting MS.

BACKGROUND: Patients with multiple sclerosis (MS) show changes in brain activation patterns during visual and motor tasks that include decreases in the typical local network for a function and increases in other brain regions. OBJECTIVE: To determine whether brain activation patterns associated with working memory are affected by MS. METHODS: Activation of working memory circuitry was examined using an fMRI n-back task in adults with mild relapsing-remitting MS (RRMS; n = 10) and demographically matched healthy controls (n = 10). RESULTS: Group differences in brain activation emerged during both low- and high-demand conditions (p < 0.001). Overall, patients showed less activation than controls in core prefrontal and parietal regions of working memory circuitry, and greater activation in other regions within and beyond typical working memory circuitry, including bilateral medial frontal, cingulate, parietal, bilateral middle temporal, and occipital regions. CONCLUSIONS: Relative to controls, patients with mild RRMS showed shifts in brain activation patterns within and beyond typical components of working memory circuitry.

Chronic deep brain stimulation for the treatment of tremor in multiple sclerosis: review and case reports.

BACKGROUND: Deep brain stimulation (DBS) offers a non-ablative alternative to thalamotomy for the surgical treatment of medically refractory tremor in multiple sclerosis. However, relatively few outcomes have been reported. OBJECTIVE: To provide a systematic review of the published cases of DBS use in multiple sclerosis and to present four additional patients. METHODS: Quantitative and qualitative review of the published reports and description of a case series from one centre. RESULTS: In the majority of reported cases (n=75), the surgical target for DBS implantation was the ventrointeromedial nucleus of the thalamus. Tremor reduction and improvement in daily functioning were achieved in most patients, with 87.7% experiencing at least some sustained improvement in tremor control postsurgery. Effects on daily functioning were less consistently assessed across studies; in papers reporting relevant data, 76.0% of patients experienced improvement in daily functioning. Adverse effects were similar to those reported for DBS in other patient populations. CONCLUSIONS: Few of the studies reviewed used highly standardised quantitative outcome measures, and follow up periods were generally one year or less. Nonetheless, the data suggest that chronic DBS often produces improved tremor control in multiple sclerosis. Complete cessation of tremor is not necessarily achieved, there are cases in which tremor control decreases over time, and frequent reprogramming appears to be necessary.

Sex differences in semantic language processing: a functional MRI study.

Predictions based on two models of sex differences in cerebral organization of language were compared by examining fMRI patterns of 10 females and 9 males during a semantic processing task. Both groups displayed activation of left inferior frontal gyrus (IFG), left superior temporal gyrus (STG), and cingulate. Females, but not males, showed bilateral IFG and STG activation. Further analyses revealed females had less diffuse left activation and greater right posterior temporal and insula region activation than males. Results support both an interhemispheric and an intrahemispheric model of sex differences in language, suggesting that the models may not be mutually exclusive.

The neuropsychology of multiple sclerosis: contributions of neuroimaging research.

Multiple sclerosis (MS) is often associated with cognitive and emotional changes that affect daily activities and quality of life. Deficits in memory, executive function, processing speed, and other cognitive domains are frequently reported. In addition, mood disturbances and fatigue are common. In this article, the authors highlight research on individual differences in the neuropsychology of MS, and emphasize neuroimaging studies that help elucidate the basis of the deficits.

A 12-week, open trial of donepezil hydrochloride in patients with multiple sclerosis and associated cognitive impairments.

Cognitive dysfunction occurs in up to 65% of patients with multiple sclerosis (MS), but there is no effective treatment for the symptoms. The authors conducted a 12-week, open-pilot study to assess the efficacy and tolerability of donepezil HCl administered in patients with MS and cognitive impairment. Seventeen patients at a long-term care facility with Mini-Mental State Examination scores of < or = 25 received 5 mg of donepezil HCl for a 4-week period, followed by 8 weeks of 10 mg of donepezil HCl. Cognitive, neurologic, functional, and behavioral assessments were conducted at baseline and at 4 and 12 weeks. Statistically significant improvement was observed in several cognitive domains including attention, memory, and executive functioning, as well as different aspects of behavior. These data suggest that donepezil HCl merits further study as a potentially viable treatment option for patients with cognitive impairment associated with MS.

Neuropsychological aspects of multiple sclerosis: a quantitative review.

Neuropsychological studies of multiple sclerosis (MS) from a 20-year period were reviewed using meta-analytic and vote-count techniques. Mean effect sizes comparing MS and healthy control groups on variables categorized by neuropsychological domain were small to moderate in magnitude; all were statistically significant (M(r) = .22 (.13) to .46 (.15), rW = .23 to .43, all p < .05). Interhemispheric transfer, general cognitive ability, and learning/memory were more highly related to MS than were visuoperceptual, visuospatial, and visuoconstructional ability, language and conceptual ability (all p < .05); other domains were generally intermediate. Despite previous reports to the contrary, disease subtype was not shown to be consistently related to neuropsychological status independently of other potential explanatory variables. Findings were interpreted with regard to future research and clinical activities involving patients with MS, including selection of tests for brief neuropsychological screening examinations.

Interhemispheric transfer in multiple sclerosis.

Interhemispheric transfer (IHT) was investigated in patients with multiple sclerosis (n = 20) and healthy control subjects (n = 23). On verbal dichotic listening and tachistoscopic reading tests, MS patients showed a pattern of left-sided suppression and/or right-sided enhancement, consistent with impairment of IHT. Patients with chronic-progressive MS were most affected. Clinical and empirical implications are noted.

High spinal nerve block for large bowel anastomosis. A prospective study.

In a randomized, prospective study of patients undergoing large bowel anastomosis, 47 patients received subarachnoid block and light general anaesthesia, and 51 received conventional general anaesthesia with intermittent positive pressure ventilation. Anastomotic dehiscence occurred in 17.0% of the spinal group and in 17.6% of patients anaesthetized by the conventional technique. Blood loss was significantly (P less than 0.001) lower in the spinal group than in the general anaesthesia group. Blood transfusion was required in 10.6% of patients in the spinal group and 21.6% of patients receiving general anaesthesia.

Effects of anaesthetic technique on deep vein thrombosis. A comparison of subarachnoid and general anaesthesia.

Forty patients with fractured neck of femur were allocated randomly to undergo surgery under general anaesthesia (GA) or subarachnoid anaesthesia (SAB). After operation, the incidence of deep vein thrombosis (DVT), assessed by venography, was found to be 40% in the SAB group, which was significantly lower than the incidence (76.2%) in the GA group. These observations may account for the previously reported effect of SAB, in comparison with GA, in reducing early postoperative mortality in this category of patient.

Long-term outcome after repair of fractured neck of femur. Comparison of subarachnoid and general anaesthesia.

One hundred and forty-eight patients undergoing "pin-and-plate" repair of fractured neck of femur received either subarachnoid blockade or general anaesthesia. The patients were followed up for 1 year after surgery. At the end of the year, 34% had died and 50% had returned home. Twelve per cent were either in hospital or in institutional care; 4% were lost to follow up. The mean duration of acute plus convalescent hospital bed occupancy was 84.4 days. There was a significantly lower mortality in the subarachnoid anaesthetic group by 14 days after surgery. The majority of the deaths in the general anaesthetic group were clustered between 6 and 16 days. However, at the end of 2 months the mortality rates were similar in both groups. It is conceivable that the difference in the distribution of deaths between the groups was a result of thrombo-embolism.

Gastric contents at induction of anaesthesia. Is a 4-hour fast necessary?

The study was undertaken to ascertain whether a light standard breakfast would influence the volume and median pH of gastric contents. Comparisons were obtained between a group of patients (n = 22) fasted overnight and a group (n = 23) allowed a light breakfast. There were no significant differences between the groups in respect of the volume of gastric contents aspirated, the median pH of the gastric contents or the number of patients with a pH of less than 3.0 unit.

Comparison of the effects of spinal anaesthesia and general anaesthesia on postoperative oxygenation and perioperative mortality.

One hundred patients presenting for surgical treatment of fractured neck of femur were allocated to receive either spinal (SAB) or general (GA) anaesthesia. Before operation, the mean PaO2 was 9.04 kPa. There was a significant decrease in PaO2 of 0.68 kPa in GA group at 1 h after operation, while blood-gas values were unchanged in SAB group. Eight patients (15.7%) in GA group and five patients (10.2%) in SAB group died within 4 weeks of surgery. The difference was not statistically significant.