Predictors and impact of non-adherence in adults with attention-deficit/hyperactivity disorder receiving OROS methylphenidate: results from a randomized, placebo-controlled trial.

BACKGROUND: Medication non-adherence has an important impact on treatment efficacy and healthcare burden across a range of conditions and therapeutic areas. The aim of this analysis was to determine predictors of non-adherence and impact of non-adherence on treatment response in adults with attention-deficit/hyperactivity disorder (ADHD). METHODS: Post-hoc analysis of a 13-week randomized, double-blind placebo-controlled study of OROS methylphenidate (MPH) 54 and 72 mg/day. Primary efficacy variable was the Conners' Adult ADHD Rating Scale - Screening Version (CAARS:O-SV). Daily adherence was calculated as average daily adherence (100 × capsules taken/2), with overall adherence calculated as the average daily adherence. Predictors of adherence were assessed using mixed-effects logistic regression. Descriptive statistics were generated for change in CAARS:O-SV score for adherent (> 95% adherence) and non-adherent subjects. Predictors of change were analyzed using a mixed model. RESULTS: Subjects were allocated to OROS MPH (54 mg, n = 87; 72 mg, n = 92) or placebo (n = 97). Mean adherence was 92.6% and 93.3% (OROS MPH 54 and 72 mg/day, respectively), versus 97.5% (placebo). Adherence was higher and less variable in completers. Factors significantly associated with non-adherence included female sex, shorter time since ADHD diagnosis, higher education level (completion of university) and score on the Drug Use Screening Inventory psychiatric disorders subscale. Improvements from baseline in CAARS:O-SV score were numerically greater in subjects defined as adherent than in those who were non-adherent. Significant predictors of CAARS:O-SV change in patients who completed the study included percentage adherence up to the point of assessment (p < 0.0001), baseline score (p < 0.0001) and family history of ADHD (p = 0.0003). CONCLUSION: The results of this analysis suggest that newly diagnosed patients, those with a high score on the DUSI-R psychiatric disorder scale, women, and subjects with high educational degrees may be at increased risk of non-adherence. Clinicians and policymakers should therefore pay special attention to these individuals, as non-adherence is a significant predictor of reduced response to treatment. TRIAL REGISTRATION: EudraCT #: 2007-002111-82.

Long-term efficacy and safety outcomes with OROS-MPH in adults with ADHD.

Methylphenidate (MPH) is widely prescribed for adults with attention deficit hyperactivity disorder (ADHD), but data on long-term treatment and maintenance of effect are lacking. Osmotic release oral system-methylphenidate (OROS-MPH) was evaluated in a 52-wk open-label study in subjects who had previously completed a short-term placebo-controlled trial and short-term open-label extension. Efficacy was assessed using the investigator- and subject-rated Conners' Adult ADHD Rating Scales (CAARS:O-SV and CAARS:S-S), and the Clinical Global Impression - Severity (CGI-S), Sheehan Disability Scale (SDS) and Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). Subjects completing ≥52 wk of treatment were eligible for a 4-wk randomized, placebo-controlled withdrawal phase in which loss of treatment effect was assessed using CAARS:O-SV and CGI-S. In the open-label phase (n=156), mean CAARS:O-SV score decreased from baseline by 1.9±7.8 (p<0.01), and small, statistically significant improvements from baseline were observed for CAARS:S-S, CGI-S and SDS. In the double-blind phase (OROS-MPH, n=23; placebo, n=22), CAARS:O-SV increased from double-blind baseline in the OROS-MPH and placebo arms (4.0±7.6 vs. 6.5±7.8, not statistically significant). Long-term OROS-MPH treatment was well tolerated, and there was no evidence of withdrawal or rebound after discontinuation. In conclusion, the short-term benefits of OROS-MPH continue during long-term open-label treatment. Maintenance of efficacy in a placebo-controlled withdrawal design remains to be confirmed in larger patient populations.

The negative impact of attention-deficit/hyperactivity disorder on occupational health in adults and adolescents.

PURPOSE: To review the negative effects of attention-deficit/hyperactivity disorder (ADHD) in adolescence and adulthood on work productivity and occupational health. METHODS: A review of the MEDLINE database was carried out to identify direct and indirect effects of ADHD on work, employment and occupational health. RESULTS: ADHD is associated with higher levels of unemployment versus controls. Adults with ADHD who are employed experience workplace impairment and reduced productivity, as well as behavioural issues such as irritability and low frustration tolerance. Adults with ADHD are also at increased risk of accidents, trauma and workplace injuries, particularly traffic accidents. Indirect effects of ADHD on occupational health include reduced educational achievement and increased rates of substance abuse and criminality. Overall, ADHD in adults has a substantial economic impact as a result of absenteeism and lost productivity. Psychoeducation, combined with stimulant medications if necessary, is recommended as first-line treatment for adults with ADHD. Limited data available suggest that stimulant treatment can improve work productivity and efficacy, and reduce the risks associated with driving, although further studies are necessary. CONCLUSIONS: ADHD can affect the ability to gain and maintain employment and to work safely and productively. As ADHD is a treatable condition, patients, employers and physicians have a role to play in ensuring optimal occupational health.

Perimenstrual migraines and their response to preventive therapy with topiramate.

INTRODUCTION: Preventive treatment with topiramate is effective for overall reduction of migraine frequency, but there are few data regarding its efficacy on perimenstrual migraines. To determine whether topiramate can prevent perimenstrual migraines, we analyzed data from premenopausal women as a subgroup of the Prolonged Migraine Prevention with Topiramate (PROMPT) study. METHODS: In total, 198 women from the PROMPT study with menstrually related migraine (MRM) were evaluated. After a one-to-two-month prospective baseline period, patients received open-label topiramate (50-200 mg/day) for six months. RESULTS: During topiramate treatment, mean monthly migraine frequency was reduced from 7.03 at baseline to 4.36 (mean change: -2.66; p < .001, endpoint analysis). Mean percentage reductions were similar for migraines during and outside the perimenstrual period (-45.9% and -46.1%, respectively). In patients with aura, reductions in migraine days with (-48.3%) or without (-43.4%) aura were similar to those in patients without aura (-45.4%). Reductions were also similar whether women were taking combined oral contraceptives (-47.0%) or were not (-46.6%). CONCLUSIONS: Topiramate reduces the frequency, but not severity or duration, of perimenstrual migraines in women with MRM, including migraines with and without aura, and regardless of combined oral contraceptive use.

Assessing the unmet treatment need in partial-onset epilepsy: looking beyond seizure control.

Patients with resistant epilepsy are often coprescribed multiple medications and are more likely to experience drug-drug interactions and adverse events (AEs). A new generation of antiepileptic drugs (AEDs) has been developed with improved safety/tolerability profiles. To evaluate the unmet treatment needs in epilepsy, a comprehensive search of the English-language literature was conducted on Medline and other databases using the terms "partial epilepsy" and "focal seizure," focusing on newer AEDs. Sixty-nine articles were identified. Most patients experienced AEs, which were generally mild-moderate in severity. Drug-drug interactions existed for 6 of 11 AEDs for which data were available. There is evidence for depressive symptoms being associated with zonisamide, and mood-stabilizing effects were shown for lamotrigine and pregabalin. Levetiracetam and eslicarbazepine improved cognitive function. Vigabatrin may increase the risk of developing psychosis. Health-related quality of life (HRQoL) was inversely correlated with seizure frequency. Discontinuation rates were often high, although treatment retention improved with slower dose titration. Adjunctive therapy with newer AEDs has the potential to enhance HRQoL and treatment continuation in patients with partial epilepsy. There remains room for improvement in the management of epilepsy, and better treatments and longer-term trials are needed to meet the special requirements of refractory patients.

Factors predicting the probability of relapse after discontinuation of migraine preventive treatment with topiramate.

INTRODUCTION: Demographic and clinical variables were examined in a post hoc analysis of the PROlonged Migraine Prevention with Topiramate (PROMPT) study to determine potential contribution to relapse. METHODS: After a six-month open-label (OL) topiramate phase, patients were randomised to continue topiramate or switch to placebo in a six-month double-blind (DB) phase. 'Relapse' was investigated in terms of change in monthly migraine days after randomisation compared with the month before randomisation, and was analysed during the first ('initial relapse') and last month ('sustained relapse') of the DB phase. More than 40 potential predicting factors were entered into analyses of variance and covariance. RESULTS: For initial relapse, variable-by-treatment interactions were significant for the Headache Impact Test (HIT-6) at DB baseline, and decline in acute medication intake or reporting of 'anxiety' in the OL phase. For sustained relapse, no statistically significant interactions were observed. CONCLUSION: Relapse after topiramate discontinuation in migraine prophylaxis appears to be unaffected by patient characteristics or baseline migraine frequency.

Seizure and cognitive outcomes in children and adolescents with epilepsy treated with topiramate.

This 12-week open label study explored cognitive and seizure outcomes of 53 children treated with topiramate (TPM). The digit symbol test and verbal learning memory test were administered at baseline and study endpoint. Topiramate was started either in monotherapy or add-on therapy. Overall, 57% of children experienced a ≥50% seizure reduction, 36% became seizure free and cognitive testing revealed no significant changes during TPM therapy. Due to the heterogeneity of the study population, post hoc analyses were added to compare patients in initial or conversion to TPM monotherapy as well as patients who continued add-on therapy. Verbal learning memory test parameters showed neither significant differences within any subgroup comparing baseline with endpoint nor significant differences between described subgroups except for one finding. The digit symbol test revealed no differences between each subgroup between baseline and endpoint. Comparing pre-post differences, TPM monotherapy was associated with better cognitive outcomes than treatment in add-on therapy. These results have to be interpreted with caution given the short study duration and the heterogeneity of the study population. Despite these limitations, our overall results suggest that treatment with topiramate is associated with improved seizure control without significant changes in cognitive functions at the low doses tested.

European survey of the level of satisfaction of patients and physicians in the management of epilepsy in general practice.

Many people with epilepsy report treatment-emergent adverse effects (AEs) while on drug therapy despite optimized treatment. We explored the level of treatment satisfaction with current management among people with epilepsy and treating physicians from seven different European countries. There was discordance between patients and physicians: patients would like greater involvement in discussions regarding treatment options and, although generally satisfied with their current medication, saw the need for a more effective balance between seizure control and AEs. Conversely, physicians were less satisfied with current treatments, but were less concerned with AEs. People with epilepsy also wanted to be better educated about epilepsy and its management. Key challenges for the future include improvement in the self-management of epilepsy by patients and more proactive patient-physician interactions. An additional aim is to improve the public's perception of epilepsy so as to remove any associated stigma.

Prevention of episodic migraines with topiramate: results from a non-interventional study in a general practice setting.

The majority of patients with migraine headaches are treated in non-specialized institutions though data on treatment outcomes are largely derived from tertiary care centers. The current non-interventional study explores efficacy and tolerability outcomes of patients with episodic migraines receiving topiramate as preventive agent in a general practice setting. A total of 366 patients (87% female, mean age 41.8 +/- 11.6 years) were eligible for migraine prevention and treated with flexible dose topiramate for 6 months (core phase), and optionally for a total of 12 months (follow-up phase). Overall, 261 patients (77.7% of safety analysis set, SAF) completed the core phase. Reasons for discontinuation included adverse events (2.1%), lost to follow-up (1.8%), other reasons (1.5%), and end of therapy (0.3%) though in the majority of patients who discontinued no reasons were listed. The median daily dose at endpoint was 50 mg/day (range, 25-187.5 mg/day). The median days with migraine headaches decreased from 6.0 to 1.2 days (p < 0.001), median pain intensity score decreased from 17.0 to 3.2 points (p < 0.001). In women with reported menstruation-associated migraine, the median number of migraine attacks decreased from 4.0 to 0.9 (p < 0.001). Absenteeism as well as triptan use decreased significantly, and significant improvements in activities of daily living and quality of life were reported. The most frequently reported AEs were paraesthesia (4.2%) and nausea (3%). Results suggest that migraine prevention with topiramate in a general practice is generally well tolerated and associated with a significant improvement in migraine headaches and related functional impairment.

Topiramate for migraine prevention in a naturalistic setting: results from an open label, flexible dose study.

BACKGROUND: Headaches are one of the most common neurological symptoms and migraines are the most common primary headache disorder. The global prevalence of migraines is around 10% and the condition is associated with a high burden of disease. Despite an abundance of good quality evidence, only 1 in 5 of patients who fulfill the criteria for preventive migraine therapy are appropriately treated. Data on patient outcomes with preventive medication derive mostly from specialized academic centers, which contrasts with normal clinical practice where the majority of patients are treated outside tertiary care centers. OBJECTIVE: To explore tolerability, safety and efficacy outcomes of patients receiving topiramate for migraine prevention in a naturalistic setting. METHODS: After a 4-week prospective baseline, patients with a diagnosis of migraine according to International Headache Society criteria and eligible for migraine prevention were treated with flexible dosing of topiramate for 24 weeks (core phase), and optionally for a total of 48 weeks. The primary safety analysis included adverse events (AEs) during the core phase. For the main efficacy measures, the absolute changes from baseline to end of core phase as well as last follow-up visit were calculated for migraine days per 4 weeks, migraine attacks per 4 weeks, mean maximum visual analogue scale of migraine headache per 4 weeks and mean maximum pain intensity of migraine headache (4-point scale) per 4 weeks. In addition, changes in individual quality of life aspects were captured. RESULTS: The intention-to-treat population (ITT) consisted of 161 patients (90.7% female, mean age 45.7 +/- 11.1 years). Topiramate median dose was 45.7 mg/day at endpoint. Some 74.1% of patients reported treatment emergent AEs, most frequently paresthesias (18.4%) and nausea (12.4%). Some 20.0% of patients withdrew from the study due to AEs. The mean number of migraine days per 4 week decreased from 6.2 +/- 3.9 days at baseline to 3.9 +/- 3.5 days at last core visit (P < .001). Mean maximum pain intensity per 4 week changed from 7.0 +/- 2.3 at baseline to 4.7 +/- 3.2 at last visit core phase (P < .001). Consumption of triptans and analgesics reduced during the course of the core phase (P < .005). Fifty-one percent of all patients experienced at least a 50% reduction in migraine days during the core phase. CONCLUSION: Topiramate used for migraine prevention in non-academic institutions is generally safe, well tolerated and results in good control of migraine headaches and improvement in several aspects of quality of life.

Topiramate in patients with epilepsy and intellectual disability.

This noninterventional single-arm study explored effectiveness and behavioral outcomes in intellectually disabled patients treated with topiramate for epilepsy. Data from 21 patients diagnosed with cerebral palsy were available for evaluation. Behavioral changes were assessed using the validated Aberrant Behavior Checklist and Matson Evaluation of Social Skills for Individuals with Severe Retardation (MESSIER) scales. Some improvement in nearly all behavioral aspects was observed under concomitant topiramate therapy; for example, the Aberrant Behavior Checklist total score changed from 33.7+/-25.8 to 25.3+/-19.1 (P=0.047). In addition, seizure frequency decreased from 16.1+/-22.2/4 weeks to 12.2+/-17.0/4 weeks (N=21, P=0.164). Fifty-two percent of the patients experienced at least 50% seizure reduction during the 24-week treatment period. The safety profile is in accordance with the current Summary of Product Characteristics of Topiramate. Two unexpected deaths were attributed to sudden unexpected death in epilepsy.

The Association of Multimorbidity With Preclinical AD Stages and SNAP in Cognitively Unimpaired Persons.

BACKGROUND: Multimorbidity (defined as ≥2 chronic conditions) has been associated with increased risk of mild cognitive impairment and cross-sectionally with imaging biomarkers of neurodegeneration in cognitively unimpaired persons aged ≥70 years. Its association with preclinical Alzheimer's disease stages has not been studied in detail yet. The objective of the study was to assess the cross-sectional association of multimorbidity with preclinical Alzheimer's disease stages and suspected non-amyloid pathophysiology in cognitively unimpaired participants of the Mayo Clinic Study of Aging (≥50 years of age). METHODS: The study included 1,535 cognitively unimpaired participants with multimorbidity, 11C-PiB positron emission topography and magnetic resonance imaging data available. Abnormal (elevated) 11C-PiB-positron emission topography retention ratio (A+; standardized uptake value ratio >1.42) and abnormal (reduced) Alzheimer's disease signature cortical thickness (N+; <2.67 mm) were used to define biomarker combinations (A-N-, A+N-, A-N+, A+N+). Chronic medical conditions were ascertained by using the Rochester Epidemiology Project medical records linkage system and International Classification of Diseases criteria. Cross-sectional associations were examined using multinomial logistic regression models adjusting for age, sex, education, and apolipoprotein E ɛ4 allele status. RESULTS: Frequency of A+, N+, A+N+, and A-N+ biomarker groups increased significantly with increasing number of chronic conditions. Multimorbidity was significantly associated with A+N+ (vs A-N-; odds ratio, 1.76, 95% confidence interval 1.02, 2.90) and A-N+ (vs A-N-; odds ratio, 2.16, 95% confidence interval 1.47, 3.18). There was a dose-response relationship between increasing number of chronic conditions (eg, 0-1, 2-3, and 4+) and the odds of A+N+ and A-N+ (vs A-N-). CONCLUSIONS: Multimorbidity was associated with biomarker combinations that included neurodegeneration with or without elevated amyloid deposition (ie, A-N+, A+N+). The associations should be validated in longitudinal studies.

Topiramate monotherapy in the treatment of newly or recently diagnosed epilepsy.

BACKGROUND: The efficacy of topiramate (TPM) as an adjunctive treatment for epilepsy has been established in placebo-controlled clinical trials. Clinical trials of antiepileptic monotherapy usually evaluate low and high doses of study drug or compare study drug with another active agent. OBJECTIVE: This article reviews available evidence for the use of TPM as monotherapy in patients with newly or recently diagnosed epilepsy. METHODS: A search of MEDLINE, EMBASE, BIOSIS, SCISEARCH, and the Cochrane Database of Systematic Reviews (all years) for reports of controlled trials of TPM monotherapy in patients with recently diagnosed (within the previous 3 years) epilepsy was conducted in January 2008 using the terms topiramate, epilepsy, newly diagnosed, recently diagnosed, and monotherapy. Identified trials were included in the review if they were published in peer-reviewed journals and enrolled > or = 20 patients. RESULTS: Three randomized, double-blind, controlled trials met the criteria for inclusion in the review. In a comparison of TPM 50 and 500 mg/d, the higher dose was associated with significantly greater freedom from seizures at 6 months compared with the lower dose (54% vs 39%, respectively; P = 0.02). The time to first seizure was significantly associated with mean plasma TPM concentrations (P = 0.015). In a comparison of TPM 50 and 400 mg/d, the time to first seizure was significantly longer with the higher dose compared with the lower dose (P<0.001, Kaplan-Meier analysis), and the probability of 12-month seizure freedom was significantly higher (76% vs 59%, respectively; P = 0.001). Again, the time to first seizure was significantly associated with mean plasma TPM concentrations (P = 0.029). In a comparative study of TPM 100 and 200 mg/d, carbamazepine 600 mg/d, and valproate 1250 mg/d, there was no significant difference in rates of 6-month seizure freedom with TPM 100 and 200 mg/d (49% and 44%, respectively), carbamazepine (44%), and valproate (44%). Adverse events in the 3 studies were similar between TPM dose groups, although the incidence generally increased with increasing doses, occurred early in treatment, and decreased with prolonged therapy. In a pooled analysis of the 3 trials, the most commonly occurring adverse events during dose titration were paresthesia (25%), fatigue (16%), dizziness (13%), somnolence (13%), and nausea (10%); the most frequent adverse events during maintenance therapy were headache (20%), decreased appetite (11%), and weight loss (11%). CONCLUSION: In the 3 studies reviewed, TPM monotherapy was effective and generally well tolerated in patients with newly diagnosed epilepsy.

Association Between Functional Performance and Alzheimer's Disease Biomarkers in Individuals Without Dementia.

OBJECTIVES: To examine the cross-sectional association between functional performance and Alzheimer's disease (AD) neuroimaging biomarkers in individuals without dementia (cognitively unimpaired (CU), and those with mild cognitive impairment (MCI)). DESIGN: Cross-sectional. SETTING: Olmsted County, Minnesota. PARTICIPANTS: Population-based Mayo Clinic Study of Aging (MCSA) participants (aged ≥ 50, mean age 71.3 ± 10.2; 53.4% male; 28.3% apolipoprotein (APO)E ε4 allele carriers, 1,578 CU, 204 MCI) who underwent 11 C-Pittsburgh compound B (11 C-PiB) positron emission tomography (PET) (N=1,782). MEASUREMENTS: We defined an abnormal (high) 11 C-PiB-PET retention ratio as a standardized uptake value ratio greater than 1.42 (high amyloid; A+), abnormal (reduced) AD signature cortical thickness (neurodegeneration; N+) as less than 2.67 mm (MRI measurement), and biomarker groups according to the combination of abnormality (or not) for amyloid accumulation (A+/A-) and neurodegeneration (N+/N-). Functional performance was assessed using the Clinical Dementia Rating (CDR) Sum of Boxes (SOB) for functional domains and the Functional Activities Questionnaire (FAQ). RESULTS: Participants with a CDR-SOB (functional) score greater than 0 were almost 4 times as likely to have N + (odds ratio (OR)=3.92, 95% confidence interval (CI)=1.77-8.67, adjusting for age, sex, education, global cognitive z-score, and APOE ε4 allele status; p<.001) and those with a FAQ score greater than 0 were 1.5 times as likely to have A + (OR=1.48, 95% CI=1.04-2.11, p=.03). Higher FAQ scores were associated with greater odds of A+N + and A-N + in CU participants. CONCLUSION: The findings of this cross-sectional study supplement limited available information that supports an association between functional performance and AD neuroimaging biomarkers very early in the dementia pathophysiology. The associations should be validated in longitudinal studies. J Am Geriatr Soc 66:2274-2281, 2018.

Prevalence and Outcomes of Amyloid Positivity Among Persons Without Dementia in a Longitudinal, Population-Based Setting.

Importance: Brain amyloid deposition is a marker of Alzheimer disease (AD) pathology. The population-based prevalence and outcomes of amyloid positivity in a population without dementia are important for understanding the trajectory of amyloid positivity to clinically significant outcomes and for designing AD prevention trials. Objective: To determine prevalence and outcomes of amyloid positivity in a population without dementia. Design, Setting, and Participants: In the prospective, population-based Mayo Clinic Study of Aging in Olmsted County, Minnesota, participants without dementia were randomly selected from the county population and were clinically and cognitively evaluated at baseline and every 15 months from August 1, 2008, to September 18, 2018. They were also invited to undergo carbon11-Pittburgh compound B positron emission tomography (PET) imaging. Exposures: Amyloid positivity (defined as a standardized uptake value ratio >1.42 on PET). Main Outcomes and Measures: Prevalence of amyloid positivity in the Olmsted County population without dementia and risk of progression from no cognitive impairment (ie, normal cognition for age) to incident amnestic MCI (aMCI) and from MCI or aMCI to incident AD dementia. Results: Of 3894 participants, 1671 underwent PET imaging and were included in the study; 2198 did not undergo imaging, and 25 were excluded for other reasons. The mean (SD) age of participants was 71.3 (9.8) years; 892 (53.4%) were men, and 179 (10.7%) had prevalent MCI. The prevalence of amyloid positivity without cognitive impairment in the population without dementia increased from 2.7% (95% CI, 0.5% to 4.9%) in persons aged 50 to 59 years to 41.3% (95% CI, 33.4% to 49.2%) in those aged 80 to 89 years at baseline. Prevalence of amyloid-positive MCI in the population without dementia increased from 0% in persons aged 50 to 59 years to 16.4% (95% CI, 10.3% to 22.5%) in those aged 80 to 89 years. The incident aMCI risk increased more than 2-fold in participants without cognitive impairment who were amyloid positive vs those who were amyloid negative (hazard ratio [HR], 2.26; 95% CI, 1.52 to 3.35; P < .001). The risk of AD dementia was 1.86 (95% CI, 0.89 to 3.88; P = .10) for amyloid-positive participants with MCI vs amyloid-negative participants with MCI, 1.63 (95% CI, 0.78 to 3.41; P = .20) for participants with aMCI who were amyloid positive vs amyloid negative, and 2.56 (95% CI, 1.35 to 4.88; P = .004) for amyloid-positive participants who were either without cognitive impairment or had aMCI vs those who were amyloid negative. Global cognitive and memory domain z scores declined significantly in amyloid-positive individuals during follow-up. The mean (SD) follow-up time from baseline was 3.7 (1.9) years to incident aMCI and 3.8 (2.0) years to incident AD dementia. Conclusions and Relevance: Population-based prevalence of amyloid-positive status and progression rates of amyloid positivity provide valid information for designing AD prevention trials and assessing the public health outcomes of AD prevention and interventions.

The impact of ß-amyloid positron emission tomography on the diagnostic and treatment decisions of dementia experts.

AIM: Amyloid positron emission tomography (aPET) measurement of Alzheimer's disease (AD) pathology could improve the accurate diagnosis of cognitive disorders. Appropriate use criteria recommend that only dementia experts order aPET. MATERIALS & METHODS: We surveyed 145 dementia experts about their current approaches to evaluation and treatment and the likely influence of aPET. RESULTS: Experts expected aPET to alter diagnostic procedures and patient management and also increase diagnostic certainty. They anticipated confirming AD or altering pharmacological treatment following positive results more than excluding AD following negative results. Experts familiar with aPET reported changes that were more consistent with appropriate use criteria and published evidence. CONCLUSIONS: Knowledge about aPET strongly influenced effects on diagnostic certainty and changed clinical practice. Dementia experts may need additional training to achieve optimal benefit from aPET.

Histopathology and Florbetaben PET in Patients Incorrectly Diagnosed with Alzheimer's Disease.

Of 57 individuals diagnosed with Alzheimer's disease (AD) in a phase III study, 13 (23%) had amyloid-ß (Aß) levels on postmortem histopathology that did not explain the dementia. Based on postmortem histopathology, a wide range of different non-AD conditions was identified, including frontotemporal dementia, hippocampal sclerosis, and dementia with Lewy bodies. Of the histopathologically Aß negative scored cases ante-mortem Florbetaben PET scans were classified as negative for Aß in 11 patients based on visual analysis and in all 12 quantifiable cases based on composite standardized uptake value ratios. Thus, florbetaben PET can assist physicians in the differential diagnosis of neurodegenerative disorders by reliably excluding Aß pathology.

Detection of regional blood perfusion changes in epileptic seizures with dynamic brain perfusion CT--a pilot study.

BACKGROUND AND PURPOSE: Perfusion CT (P-CT) is used for acute stroke management, not, however, for evaluating epilepsy. To test the hypothesis that P-CT may identify patients with increased regional cerebral blood flow during subtle status epilepticus (SSE), we compared P-CT in SSE to different postictal conditions. METHODS: Fifteen patients (mean age 47 years, range 21-74) underwent P-CT immediately after evaluation in our emergency room. Asymmetry indices between affected and unaffected hemispheres were calculated for regional cerebral blood volume (rCBV), regional cerebral blood flow (rCBF), and mean transit time (MTT). Regional perfusion changes were compared to EEG findings. RESULTS: Three patients in subtle status epilepticus (group 1) had increased regional perfusion with electro-clinical correlate. Six patients showed postictal slowing on EEG corresponding to an area of regional hypoperfusion (group 2). CT and EEG were normal in six patients with a first epileptic seizure (group 3). Cluster analysis of asymmetry indices separated SSE from the other two groups in all three parameters, while rCBF helped to distinguish between chronic focal epilepsies and single events. CONCLUSION: Preliminary results indicate that P-CT may help to identify patients with SSE during emergency workup. This technique provides important information to neurologists or emergency physicians in the difficult clinical differential diagnosis of altered mental status due to subtle status epilepticus.

EEG findings in steroid-responsive encephalopathy associated with autoimmune thyroiditis.

OBJECTIVE: To analyze the electroencephalogram (EEG) findings of patients with steroid-responsive encephalopathy associated with autoimmune (Hashimoto) thyroiditis. METHODS: We reviewed 51 EEGs and the clinical records of 17 patients (5 men and 12 women, 27-84 years old). RESULTS: All patients had mild to severe generalized slowing on the EEG which corresponded to the clinical severity of the underlying encephalopathy. Other findings included triphasic waves, epileptiform abnormalities, photomyogenic response, and photoparoxysmal response. Follow-up EEGs of 13 patients showed slowing in 7 and a return to normal in 6. Myoclonic jerks were recorded during the EEG study of 8 patients but did not have an EEG correlate. The EEG and clinical condition improved after treatment with corticosteroids. When encephalopathy recurred, the EEG showed corresponding abnormalities. CONCLUSIONS: EEG findings in steroid-responsive encephalopathy associated with autoimmune thyroiditis consist mainly of slow wave abnormalities that reflect the degree of severity of the underlying encephalopathy. The EEG findings often paralleled the course of the disease, showing improvement with improvement in the clinical condition and worsening with recurrence of symptoms. SIGNIFICANCE: The EEG is helpful in evaluating and following patients with steroid-responsive encephalopathy associated with autoimmune thyroiditis in reflecting the degree of central nervous system (CNS) involvement, in determining whether their condition is better or worse, and in ruling out other causes of encephalopathy.

Correlation of symptomatic improvements with functional improvements and patient-reported outcomes in adults with attention-deficit/hyperactivity disorder treated with OROS methylphenidate.

OBJECTIVES: To evaluate correlations between symptom severity and daily functioning in adults with ADHD. METHODS: In the 5-week, double-blind LAMDA study, 401 adults with ADHD were randomly assigned to Osmotic-Release Oral System (OROS) methylphenidate (MPH) 18, 36 or 72 mg/day, or placebo. The primary variable - investigator-rated Conners' Adult ADHD Rating Scale (CAARS:O-SV) - has been presented previously. Secondary endpoints included the self-reported version of CAARS (CAARS-S:S) and Clinical Global Impression - Severity (CGI-S). Daily functioning and quality of life were assessed using the Sheehan Disability Scale (SDS) and Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). Relationships between symptom and functional outcomes were evaluated in post-hoc Pearson partial correlation, multivariate regression and mediator analyses. RESULTS: Improvements in CAARS-S:S, CGI-S and SDS scores were significantly greater in each OROS MPH arm versus placebo (P < 0.01 for all comparisons). Correlations between symptom and functioning scores were significant for all comparisons (P < 0.0001). In regression analyses, CAARS Hyperactivity/Impulsivity subscale and CGI-S were correlated with SDS (P < 0.05). CAARS Inattention was correlated with the SDS Family Life domain (P < 0.05). In a mediator analysis, the impact of treatment on SDS scores was fully mediated by improvement in CAARS:O-SV score. CONCLUSIONS: OROS MPH 18-72 mg/day was associated with significant improvements in ADHD symptoms, which correlated with improved daily functioning and health-related quality of life.