Impact of Personality on Cognitive Aging: A Prospective Cohort Study.

OBJECTIVES: The aim of this study was to assess the association between personality factors and age-related longitudinal cognitive performance, and explore interactions of stress-proneness with apolipoprotein E (APOE) ɛ4, a prevalent risk factor for Alzheimer's disease (AD). METHODS: A total of 510 neuropsychiatrically healthy residents of Maricopa County recruited through media ads (mean age 57.6±10.6 years; 70% women; mean education 15.8±2.4 years; 213 APOE ɛ4 carriers) had neuropsychological testing every 2 years (mean duration follow-up 9.1±4.4 years), and the complete Neuroticism Extraversion Openness Personality Inventory-Revised. Several tests were administered within each of the following cognitive domains: memory, executive skills, language, visuospatial skills, and general cognition. Primary effects on cognitive trajectories and APOE ɛ4 interactions were ascertained with quadratic models. RESULTS: With personality factors treated as continuous variables, Neuroticism was associated with greater decline, and Conscientiousness associated with reduced decline consistently across tests in memory and executive domains. With personality factors trichotomized, the associations of Neuroticism and Conscientiousness were again highly consistent across tests within memory and to a lesser degree executive domains. While age-related memory decline was greater in APOE ɛ4 carriers as a group than ɛ4 noncarriers, verbal memory decline was mitigated in ɛ4 carriers with higher Conscientiousness, and visuospatial perception and memory decline was mitigated in ɛ4 carriers with higher Openness. CONCLUSIONS: Neuroticism and Conscientiousness were associated with changes in longitudinal performances on tests sensitive to memory and executive skills. APOE interactions were less consistent. Our findings are consistent with previous studies that have suggested that personality factors, particularly Neuroticism and Conscientiousness are associated with cognitive aging patterns. (JINS, 2016, 22, 765-776).

The neuropsychology of normal aging and preclinical Alzheimer's disease.

OBJECTIVE: A National Institute on Aging-sponsored work group on preclinical Alzheimer's disease (AD) articulated the need to characterize cognitive differences between normal aging and preclinical AD. METHODS: Seventy-one apolipoprotein E (APOE) ε4 homozygotes, 194 ε3/ε4 heterozygotes, and 356 ε4 noncarriers age 21 to 87 years who were cognitively healthy underwent neuropsychological testing every 2 years. Longitudinal trajectories of test scores were compared between APOE subgroups. RESULTS: There was a significant effect of age on all cognitive domains in both APOE ε4 carriers and noncarriers. A significant effect of APOE ε4 gene dose was confined to the memory domain and the Dementia Rating Scale. Cross-sectional comparisons did not discriminate the groups. CONCLUSIONS: Although cognitive aging patterns are similar in APOE ε4 carriers and noncarriers, preclinical AD is characterized by a significant ε4 gene dose effect that impacts memory and is detectable longitudinally. Preclinical neuropsychological testing strategies should emphasize memory-sensitive measures and longitudinal design.

Stroke team remote evaluation using a digital observation camera in Arizona: the initial mayo clinic experience trial.

BACKGROUND AND PURPOSE: Telemedicine techniques can be used to address the rural-metropolitan disparity in acute stroke care. The Stroke Team Remote Evaluation Using a Digital Observation Camera (STRokE DOC) trial reported more accurate decision making for telemedicine consultations compared with telephone-only and that the California-based research network facilitated a high rate of thrombolysis use, improved data collection, low risk of complications, low technical complications, and favorable assessment times. The main objective of the STRokE DOC Arizona TIME (The Initial Mayo Clinic Experience) trial was to determine the feasibility of establishing, de novo, a single-hub, multirural spoke hospital telestroke research network across a large geographical area in Arizona by replicating the STRokE DOC protocol. METHODS: Methods included prospective, single-hub, 2-spoke, randomized, blinded, controlled trial of a 2-way, site-independent, audiovisual telemedicine system designed for remote examination of adult patients with acute stroke versus telephone consultation to assess eligibility for treatment with intravenous thrombolysis. The primary outcome measure was whether the decision to give thrombolysis was correct. Secondary outcomes were rate of thrombolytic use, 90-day functional outcomes, incidence of intracerebral hemorrhages, and technical observations. RESULTS: From December 2007 to October 2008, 54 patients were assessed, 27 of whom were randomized to each arm. Mean National Institutes of Health Stroke Scale score at presentation was 7.3 (SD 6.2) points. No consultations were aborted; however, technical problems (74%) were prevalent in the telemedicine arm. Overall, the correct treatment decision was established in 87% of the consultations. Both modalities, telephone (89% correct) and telemedicine (85% correct), performed well. Intravenous thrombolytic treatment was used in 30% of the telemedicine and telephone consultations. Good functional outcomes at 90 days were not significantly different. There were no statistically significant differences in mortality (4% in telemedicine and 11% in telephone) or rates of intracerebral hemorrhage (4% in telemedicine and 0% in telephone). CONCLUSIONS: It is feasible to extend the original STRokE DOC trial protocol to a new state and establish an operational single-hub, multispoke rural hospital telestroke research network in Arizona. The trial was not designed to have sufficient power to detect a difference between the 2 consultative modes: telemedicine and telephone-only. Whether by telemedicine or telephone consultative modalities, there were appropriate treatment decisions, high rates of thrombolysis use, improved data collection, low rates of intracerebral hemorrhage, and equally favorable time requirements. The learning curve was steep for the hub and spoke personnel of the new telestroke network, as reflected by frequent technical problems. Overall, the results support the effectiveness of highly organized and structured stroke telemedicine networks for extending expert stroke care into rural remote communities lacking sufficient neurological expertise.

Assessment of patient and caregiver experiences of dementia-related symptoms: development of the Multidimensional Assessment of Neurodegenerative Symptoms questionnaire.

BACKGROUND: To provide preliminary validation data on a self- or informant-report multidimensional questionnaire of symptoms associated with neurodegenerative disorders. METHODS: Participants from 2 trials (n = 125), the Arizona APOE Cohort and the Arizona Alzheimer's Disease Center, completed the Multidimensional Assessment of Neurodegenerative Symptoms questionnaire (MANS) and other related measures. RESULTS: Measures of central tendency are provided for the sample as a whole and by cognitive status. Internal consistency of the MANS is excellent (alpha = 0.98). Factor analysis suggests 4 factors. Correlational analyses support the construct validity of the MANS with moderate to high (r = 0.54-0.87) correlations between the MANS and measures of mood, cognition and daily functioning. CONCLUSION: Results provide initial support for the MANS as a brief measure that is a reliable and valid indicator of cognitive, personality, functional and motor symptoms potentially related to neurodegenerative etiologies. Further research with the MANS is warranted.

Factors Associated With Use of Nonoral Nutrition and Hydration Support in Adult Patients With Postural Tachycardia Syndrome.

BACKGROUND: Patients with postural tachycardia syndrome (POTS) often have gastrointestinal (GI) symptoms. Occasionally, these symptoms can be so severe that nonoral nutrition/hydration support (NONHS), including intravenous fluids (IVFs), enteral nutrition (EN), and parenteral nutrition (PN), becomes necessary. METHODS: This is a retrospective cohort study of adult patients diagnosed with POTS at the Mayo Clinic Arizona from January 2010 to January 2017 with a minimum of 6 months of follow up. Demographic information, symptomatology, medications, GI testing, autonomic and autoantibody testing, and healthcare utilization data were abstracted from the electronic medical record. RESULTS: Three-hundred thirty-two patients with POTS were included, of which 32 required NONHS. Patients receiving NONHS were more likely to be female; have lower body mass index; have GI symptoms including nausea, vomiting, diarrhea, and constipation; have abdominal pain; use opiates; have delayed gastric emptying; see more specialists; and be seen in an emergency room or be hospitalized for symptoms. Of these patients, 21 (66%) required IVF, 19 (59%) required EN, and 9 (28%) required PN. Six (19%) patients required all 3 NONHS modalities at some point during their follow-up period. CONCLUSIONS: NONHS may be required in a subset of patients with POTS. Those receiving NONHS have more severe symptoms and abnormal GI motility and autonomic testing and exhibit greater healthcare utilization. Management of these patients is complex and challenging and requires a multidisciplinary approach. Further prospective studies are needed to identify optimal management strategies.

Neuromuscular disorders associated with paraproteinemia.

Neuromuscular disorders associated with monoclonal gammopathies are usually uncovered in approximately 10% of patients presenting with peripheral neuropathy complaints. This discovery should prompt further evaluation for underlying plasma cell dyscrasias. The most frequent monoclonal disorders associated with neuropathy are smoldering myeloma, multiple myeloma, Waldenström macroglobulinemia, solitary plasmacytoma, systemic immunoglobulin light chain (AL) amyloidosis, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes), and cryoglobulinemia. If these are excluded by careful evaluation the patient is classified as having monoclonal gammopathy of undetermined significance. Diagnostic criteria, risk stratification to determine prognosis, and current management for these disorders are reviewed in this article.

Personality Changes During the Transition from Cognitive Health to Mild Cognitive Impairment.

BACKGROUND/OBJECTIVES: Behavioral problems in individuals with Alzheimer's disease (AD) impose major management challenges. Current prevention strategies are anchored to cognitive outcomes, but behavioral outcomes may provide another, clinically relevant opportunity for preemptive therapy. We sought to determine whether personality changes that predispose to behavioral disorders arise during the transition from preclinical AD to mild cognitive impairment (MCI). DESIGN: Longitudinal observational cohort study. SETTING: Academic medical center. PARTICIPANTS: Members of an apolipoprotein E (APOE) ɛ4 genetically enriched cohort of Maricopa County residents who were neuropsychiatrically healthy at entry (N = 277). Over a mean interval of 7 years, 25 who developed MCI and had the Neuroticism, Extraversion, and Openness Personality Inventory-Revised (NEO-PI-R) before and during the MCI transition epoch were compared with 252 nontransitioners also with serial NEO-PI-R administrations. INTERVENTION: Longitudinal administration of the NEO-PI-R and neuropsychological test battery. MEASUREMENTS: Change in NEO-PI-R factor scores (neuroticism, extraversion, openness, agreeableness, conscientiousness) from entry to the epoch of MCI diagnosis or an equivalent follow-up duration in nontransitioners. RESULTS: NEO-PI-R neuroticism T-scores increased significantly more in MCI transitioners than in nontransitioners (mean 2.9, 95% confidence interval (CI) = 0.9-4.9 vs 0, 95% CI = -0.7-0.7, P = .02), and openness decreased more in MCI transitioners than in nontransitioners (-4.8, 95% CI = -7.3 to -2.4 vs -1.0, 95% CI = -1.6 to -0.4, P < .001). Concurrent subclinical but statistically significant changes in behavioral scores worsened more in MCI transitioners than nontransitioners for measures of depression, somatization, irritability, anxiety, and aggressive attitude. CONCLUSION: Personality and subclinical behavioral changes begin during the transition from preclinical AD to incident MCI and qualitatively resemble the clinically manifest behavioral disorders that subsequently arise in individuals with frank dementia.

Weight Loss in Parkinson's Disease: No Evidence for Role of Small Intestinal Bacterial Overgrowth.

BACKGROUND AND OBJECTIVE: Weight loss and small intestinal bacterial overgrowth (SIBO) are common in Parkinson's disease (PD). We aimed to study the relationship between weight loss and SIBO in PD. METHODS: This was a cross-sectional study with a prospective, interventional component. Consecutive patients seen in the PD clinic who agreed to participate underwent extensive history, movement exam, SIBO breath testing and answered questionnaires. A subset of those in the weight loss group were treated with rifaximin for 14 days and returned 3 months later for an assessment of their weight, GI symptoms, quality of life and SIBO status. All analyses were adjusted for age and disease duration. RESULTS: Fifty-one patients participated in the study; 37 without weight loss and 14 with weight loss. Total energy intake including the distribution of macronutrient intake was similar between groups while physical activity was less in those with weight loss. PD severity scores did not differ between groups; however, PD-specific quality of life scores were significantly worse for the summary index and the subscales of emotional well-being, social support and communication. The prevalence of constipation, dyspepsia and abdominal pain/discomfort was higher in those with weight loss. The prevalence of SIBO was 14% in the weight loss group and was not different between groups. Eight PD patients with weight loss were treated with rifaximin; no significant change in GI symptoms, quality of life or weight was seen 3 months later. CONCLUSION: Although a number of differences were identified in quality of life and gastrointestinal symptoms between groups with and without weight loss, SIBO was not associated with weight loss in patients with PD. Given the exploratory nature and small number of patients with weight loss, however, further study is suggested.

Cognitive domain decline in healthy apolipoprotein E epsilon4 homozygotes before the diagnosis of mild cognitive impairment.

BACKGROUND: Memory declines more rapidly with age in apolipoprotein E (APOE) epsilon4 carriers than in APOE epsilon4 noncarriers, and APOE epsilon4 homozygotes' cognitive performances correlate with stressors. These changes could represent presymptomatic disease in some, despite their youth. OBJECTIVE: To show that presymptomatic APOE epsilon4 homozygotes experience greater psychometric decline at a younger age than APOE epsilon4 heterozygotes and noncarriers before the diagnosis of mild cognitive impairment (MCI) and Alzheimer disease (AD). DESIGN: Prospective observational study SETTING: Academic medical center. PARTICIPANTS: A total of 43 APOE epsilon4 homozygotes, 59 APOE epsilon4 heterozygotes, and 112 APOE epsilon4 noncarriers aged 50 to 69 years were cognitively healthy and matched at entry according to age, educational level, and sex. INTERVENTION: Neuropsychological battery given every 2 years. MAIN OUTCOME MEASURES: Predefined test and cognitive domain decline criteria applied to consecutive epochs. RESULTS: Of 214 participants, 48 showed no decline on any test, 126 showed decline on only 1 test in 1 or more domains, and 40 showed decline on 2 or more tests in 1 or more domains. Cognitive domain decline occurred in 4 of 10 APOE epsilon4 homozygotes 60 years and older at entry (40.0%) compared with 5 of 66 APOE epsilon4 heterozygotes and noncarriers (7.6%) (P = .02) and was more predictive of subsequent decline than nondomain decline (17 of 24 [70.8%] vs 29 of 70 [41.4%]; P = .01). Decline on any memory test was predictive of further decline (P < .001), as was memory domain decline (P = .006) in all genetic subgroups. Seven participants developed MCI (in 6) or AD (in 1), of whom 5 were APOE epsilon4 homozygotes (P = .008). Retrospective comparison showed that those who experienced multidomain, memory, and language domain decline had lower spatial and memory scores at entry than those who experienced no decline. CONCLUSIONS: APOE epsilon4 homozygotes in their 60s have higher rates of cognitive domain decline than APOE epsilon4 heterozygotes or noncarriers before the diagnosis of MCI and AD, thus confirming and characterizing the existence of a pre-MCI state in this genetic subset.

Computer versus Compensatory Calendar Training in Individuals with Mild Cognitive Impairment: Functional Impact in a Pilot Study.

This pilot study examined the functional impact of computerized versus compensatory calendar training in cognitive rehabilitation participants with mild cognitive impairment (MCI). Fifty-seven participants with amnestic MCI completed randomly assigned calendar or computer training. A standard care control group was used for comparison. Measures of adherence, memory-based activities of daily living (mADLs), and self-efficacy were completed. The calendar training group demonstrated significant improvement in mADLs compared to controls, while the computer training group did not. Calendar training may be more effective in improving mADLs than computerized intervention. However, this study highlights how behavioral trials with fewer than 30-50 participants per arm are likely underpowered, resulting in seemingly null findings.

Behavioral Interventions to Prevent or Delay Dementia: Protocol for a Randomized Comparative Effectiveness Study.

BACKGROUND: Currently, people at risk for dementia and their caregivers are confronted with confusing choices about what behavioral interventions are most effective. OBJECTIVE: The objective of this study is to determine which empirically supported behavioral interventions most impact the outcomes highly valued by patients with mild cognitive impairment and their partners. METHODS: This protocol describes a comparative effectiveness trial targeting 300 participants with mild cognitive impairment and their study partners. The trial is being conducted at the Mayo Clinic campuses in Arizona, Florida, Minnesota, and the University of Washington in Seattle. The study examines the contribution of five behavioral interventions (yoga, memory compensation training, computerized cognitive training, support groups, and wellness education) on primary outcomes of participant and partner quality of life and self-efficacy. In this unique 10-day multicomponent intervention, groups of couples were randomized to have one of the five interventions withheld while receiving the other four. Although the longitudinal follow-up is still under way, enrollment results are available and reported. RESULTS: In total, 272 couples have been enrolled in the trial and follow-up visits continue. Outcomes will be assessed at the end-of-intervention and 6-, 12-, and 18-month follow-ups. We anticipate reporting on our primary and secondary outcomes across time points in the next 2 years. CONCLUSIONS: This paper describes the protocol for a randomized comparative effectiveness study of behavioral interventions to prevent or delay dementia. We describe of the rationale, design, power analysis, and analysis plan. Also because enrollment is complete and we are in follow-up phases of the study, we have included enrollment data from the trial. TRIAL REGISTRATION:  ClinicalTrials.gov NCT02265757; http://clinicaltrials.gov/ctsshow/ NCT02265757 (Archived by WebCite at http://www.webcitation.org/6ueRfwSYv).

Value of the oral glucose tolerance test in the evaluation of chronic idiopathic axonal polyneuropathy.

BACKGROUND: An underlying cause is found in only 7% to 30% of patients with chronic idiopathic axonal polyneuropathy (CIAP). Diabetes mellitus, inherited disorders, toxin exposure, and primary amyloidosis are the most common identified causes of sensory neuropathies affecting both large and small myelinated fibers. Undiagnosed impaired fasting glucose metabolism has been associated with CIAP at a higher frequency rate than in the general population. This increased prevalence rate was identified using the 2-hour oral glucose tolerance test (2h-OGTT) and a previous version of the American Diabetes Association (ADA) guidelines. OBJECTIVES: To determine the prevalence of abnormal fasting glucose metabolism in patients with CIAP and to compare the value of determining fasting plasma glucose levels using revised (2003) ADA criteria with the 2h-OGTT for predicting abnormal fasting glucose metabolism. PATIENTS: In this 24-month retrospective study, 100 consecutive patients were identified with no known cause for CIAP, including diabetes mellitus, between January 2003 and January 2005. All had both a fasting plasma glucose test and a 2h-OGTT in addition to a complete neurological examination. Neurophysiological studies, computer-assisted sensory examination, and quantitative sudomotor axonal reflex testing were used to classify CIAP into subtypes according to nerve fiber involvement. RESULTS: The prevalence of undiagnosed abnormal fasting glucose metabolism was found to be nearly 2-fold higher (62%) in patients with CIAP than in similar age-matched general population groups (33%). Using the 2003 revised ADA criteria, 39 patients (39%) had abnormal fasting plasma glucose metabolism (36 with impaired fasting glucose, 3 with diabetes mellitus), while the 2h-OGTT provided an even higher diagnostic rate of 62% (62 patients; P<.001) of impaired fasting glucose metabolism (38 with impaired glucose tolerance, 24 with diabetes mellitus). The abnormal glucose metabolism rates were found to be similar across the 3 subtypes (sensorimotor, pure sensory, and small-fiber neuropathy) of CIAP (P = .60, .72, and .61). CONCLUSIONS: This study adds to emerging evidence that abnormal glucose metabolism may be a risk factor for CIAP. Even with revised (2003) ADA criteria, the 2h-OGTT provides additional diagnostic information to the health care professional in the evaluation of CIAP. Subtypes of CIAP are equally likely to have abnormal glucose metabolism.

IVIG Versus PLEX in the Treatment of Worsening Myasthenia Gravis: What is the Evidence?: A Critically Appraised Topic.

BACKGROUND: Immune therapies such as intravenous immunoglobulin (IVIG) and plasma exchange (PLEX) are first line in the treatment of worsening myasthenia gravis. Although PLEX is favored in myasthenic crisis, IVIG is increasingly used in exacerbations due to cost and ease of administration. OBJECTIVES: To review and critically assess current evidence on the effects of IVIG and PLEX on functional outcomes in patients with worsening myasthenia gravis. METHODS: A structured critical appraisal was conducted on the objective topic. This included a creation of a structured question based on a clinical scenario, comprehensive literature search, selection of evidence for review, and critical appraisal of selected evidence. Evidence was summarized and commentary provided. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and content experts in the field of neuromuscular neurology. RESULTS: A single-blinded, randomized-controlled trial that compared IVIG and PLEX in 84 patients with worsening myasthenia gravis was selected for review. Primary outcome measure was functional status at 14 days after treatment, as assessed by the Quantitative Myasthenia Gravis Score. Change in Quantitative Myasthenia Gravis Score at day 14 for all subjects was 4.0, without statistically significant differences between IVIG and PLEX groups. CONCLUSIONS: IVIG and PLEX are equally effective in worsening myasthenia gravis. Treatment decisions may depend on several variables, including presence of respiratory distress, medical comorbidities, access to medication, and cost. PLEX will likely remain the treatment of choice in true myasthenic crisis.

Physical activity level and future risk of mild cognitive impairment or dementia: a critically appraised topic.

BACKGROUND: The relationships between physical activity, cognition, and development of neurodegenerative diseases represent an area of intense research interest. Meta-analyses and prospective cohort studies show that greater levels of physical activity are associated with lower dementia risk. Most studies, however, depend on self-report data that are subject to recall and other biases. Obtaining objective and quantitative physical activity data could strengthen observational study validity. OBJECTIVE: To examine the association between objectively measured daytime activity and mild cognitive impairment (MCI) or Alzheimer disease (AD). METHODS: The objective was addressed through the development of a structured, critically appraised topic. We incorporated a clinical scenario, background information, a structured question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom line conclusions. Participants included consultant and resident neurologists, clinical epidemiologists, a medical librarian, and behavioral neurology and neuropsychiatry content experts. RESULTS: We selected a prospective, single-center cohort study of 716 cognitively normal elderly participants followed for 3.5 years. Greater levels of physical activity, as measured using wrist actigraphy, were associated with a lower risk of incident MCI or AD (hazard ratio, 0.477; 95% confidence interval, 0.273-0.832). CONCLUSIONS: Objective measurement confirms that greater levels of physical activity are associated with decreased risk of a future diagnosis of MCI or AD. Further studies are needed to confirm the temporal association of exercise and future cognitive health and understand the relevant underlying biological mechanisms.

Amantadine for patients with severe traumatic brain injury: a critically appraised topic.

BACKGROUND: Research into traumatic brain injury (TBI) has increased significantly. Diagnostic testing and therapeutics for patients with severe TBI are 2 areas on which there is increasing focus. Amantadine hydrochloride is one treatment considered to have potential therapeutic value in this patient population. OBJECTIVE: The objective was addressed through the development of a structured critically appraised topic. This included a clinical scenario, structured question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and content experts in the disciplines of neurocritical care and physical medicine and rehabilitation. RESULTS: A multicenter, placebo-controlled, double-blind, randomized controlled trial was selected for review. The trial compared the rate of recovery, as determined by the overall Disability Rating Scale score, in a total of 184 patients with severe TBI. Patients were randomized to either receive amantadine (87) or visually identical placebo (97) over the 4-week study interval. The rate of recovery, as measured by the Disability Rating Scale, was found to be greater in the treatment arm as compared with the placebo arm (difference in slope -0.24 points/wk, P=0.007) over the 4-week treatment interval. CONCLUSIONS: The results from this study demonstrated that amantadine hydrochloride accelerates recovery in patients with severe TBI.

The effect of selective serotonin reuptake inhibitors on the frequency of psychogenic nonepileptic seizures: a critically appraised topic.

BACKGROUND: Psychogenic nonepileptic seizures (PNES) are commonly encountered problem in neurological practice and usually are accompanied by other psychiatric comorbidities. Despite its prevalence and profound impact on patients and families, there have been few trials addressing treatment. Cognitive behavioral therapy may be effective but the role of pharmacologic therapy remains unclear. OBJECTIVE: To critically evaluate evidence that PNES frequency may be reduced by treatment with selective serotonin reuptake inhibitors. METHODS: The objective was addressed through the development of a structured, critically appraised topic. We incorporated a clinical scenario, background information, a structured question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom line conclusions. Participants included consultant and resident neurologists, a medical librarian, epileptology, and psychiatry content experts. RESULTS: A pilot randomized control clinical trial was selected for critical appraisal. Thirty-eight PNES patients were randomized to flexible-dose sertraline (target dose, 200 mg/d) or placebo. Only 68% of patients contributed data to the primary analysis and baseline PNES frequency was notably dissimilar. Twelve-week seizure frequency rates, as compared with baseline, were 45% lower in the sertraline group (P=0.03) but unchanged in the placebo group (8% increase; P=0.78). After adjustment for baseline differences, between-treatment group comparison revealed a trend toward lower event frequency in the sertraline group (risk ratio 0.51; 95% confidence interval, 0.25-1.05; P=0.29). Psychosocial and quality of life measures did not differ between treatment groups. CONCLUSIONS: There is insufficient evidence to recommend routine treatment with sertraline to reduce PNES event frequency but these pilot data suggest a possible benefit worthy of further exploration.

Therapeutic hypothermia for severe traumatic brain injury: a critically appraised topic.

BACKGROUND: Traumatic brain injury (TBI) is common and confers a high rate of disability and mortality. Current treatments are primarily supportive. Therapeutic hypothermia has been proposed for severe TBI because of its ability to reduce intracranial pressure and putative neuroprotective effects. OBJECTIVE: To critically appraise the current evidence concerning the efficacy of therapeutic hypothermia in the treatment of severe TBI. METHODS: The objective was addressed through the development of a structured, critically appraised topic. This incorporated a clinical scenario, background information, a structured question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and critical care and neurocritical care content experts. RESULTS: A recent multicenter randomized controlled trial was selected for critical assessment; meta-analyses were also reviewed. Subjects with severe TBI were randomized to either rapid cooling to 33°C for 48 hours (treatment, n=52) or normothermia (control, n=45). Outcome assessments included mortality and disability at 6 months as measured by the Glasgow Outcome Scale. Initiation of hypothermia began within 2.5 hours of injury and patients were rewarmed over a mean of 17.2 hours. The study was terminated for futility; no difference in outcome or mortality was detected between treatment groups. Post hoc subgroup analysis showed that among subjects who required hematoma evacuation, hypothermia was associated with a lower rate of poor clinical outcome (number needed to treat=2.8; 95% confidence interval, 1.4-78.3, P=0.02) and a trend toward a decrease in mortality (P=0.16). CONCLUSIONS: Current cumulative evidence does not support general use of therapeutic hypothermia for acute severe TBI. However, further investigation of the role of therapeutic hypothermia may be warranted for specific TBI subgroups.

Is dabigatran cost effective compared with warfarin for stroke prevention in atrial fibrillation? A critically appraised topic.

BACKGROUND: Warfarin has provided protection against cardioembolic stroke in the setting of nonvalvular atrial fibrillation (NVAF) for the past 60 years. Dabigatran, the first oral direct thrombin inhibitor to be approved in the United States, promises to provide the same or better stroke protection with reduced risk of intracranial hemorrhage. However, it remains to be seen whether grand-scale adoption of dabigatran will be cost effective. OBJECTIVE: To critically assess current evidence regarding the cost effectiveness of dabigatran for preventing stroke in patients with NVAF compared with warfarin. METHODS: The objective was addressed through the development of a critically appraised topic that included a clinical scenario, structured question, literature search strategy, critical appraisal, assessment of results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and content experts in the field of vascular neurology. RESULTS: A cost-effectiveness analysis (CEA) that followed a hypothetical cohort of NVAF patients 65 years of age or older and CHADS2≥1 over their lifetime comparing dabigatran with adjusted-dose warfarin was reviewed. Assuming a willingness to pay a threshold of $50,000 per quality-adjusted life year (QALY), base case results favored high-dose (150 mg bid) dabigatran as a cost-effective alternative to warfarin. Sensitivity analysis asserted that the cost effectiveness of dabigatran improved if it could be obtained for ≤$13/d or if it was used in populations with high risk of stroke or intracranial hemorrhage. CONCLUSIONS: Dabigatran 150 mg bid ($12,286 per QALY) is a cost-effective alternative to International Normalized Ratio-adjusted warfarin for the prevention of ischemic stroke in patients 65 years of age or older with NVAF.

Is donepezil effective for multiple sclerosis-related cognitive dysfunction? A critically appraised topic.

BACKGROUND: Cognitive dysfunction affects approximately half of the patients with multiple sclerosis (MS). Cholinesterase inhibitor drugs are approved to treat cognitive dysfunction associated with degenerative dementia. OBJECTIVE: To critically assess current evidence regarding the efficacy of the cholinesterase inhibitor, donepezil in the treatment of MS-associated cognitive impairment. METHODS: The objective was addressed through the development of a structured critically appraised topic. This included a clinical scenario, structured question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and content experts in the fields of behavioral neurology and MS. RESULTS: A randomized control trial was selected for critical appraisal. This trial randomized MS patients to receive donepezil 10 mg daily or placebo for treatment of MS-related cognitive dysfunction. There was no significant treatment effect found between the 2 groups on either the primary outcome of memory or any of the secondary cognitive measures. Post hoc analyses suggested a trend favoring donepezil in subjects with greater baseline cognitive dysfunction. CONCLUSIONS: Donepezil 10 mg daily for 24 weeks is not superior to placebo in improving MS-related cognitive dysfunction.

Determination of hemispheric language dominance in the surgical epilepsy patient: diagnostic properties of functional magnetic resonance imaging.

BACKGROUND: Presurgical evaluation for refractory epilepsy typically includes assessment of cognitive and language functions. The reference standard for determination of hemispheric language dominance has been the intracarotid amobarbital test (IAT) but functional magnetic resonance imaging (fMRI) is increasingly used. OBJECTIVE: To critically assess current evidence regarding the diagnostic properties of fMRI in comparison with the IAT for determination of hemispheric language dominance. METHODS: The objective was addressed through the development of a structured critically appraised topic. This included a clinical scenario, structured question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and content experts in the fields of epilepsy and neurosurgery. RESULTS: A systematic review and meta-analysis that compared the sensitivity and specificity of fMRI to IAT-determined language lateralization was selected for critical appraisal. The review included data from 23 articles (n=442); study methodology varied widely. fMRI was 83.5% sensitive and 88.1% specific for detection of hemispheric language dominance. CONCLUSIONS: There are insufficient data to support routine use of fMRI for the purpose of determining hemispheric language dominance in patients with intractable epilepsy. Larger, well-designed studies of fMRI for language and other cognitive outcomes as part of the presurgical and postsurgical evaluation of epilepsy patients are necessary.