An Exploratory, Randomized, Double-Blind Clinical Trial of Dipraglurant for Blepharospasm.

BACKGROUND: Blepharospasm is treated with botulinum toxin, but obtaining satisfactory results is sometimes challenging. OBJECTIVE: The aim is to conduct an exploratory trial of oral dipraglurant for blepharospasm. METHODS: This study was an exploratory, phase 2a, randomized, double-blind, placebo-controlled trial of 15 participants who were assigned to receive a placebo or dipraglurant (50 or 100 mg) and assessed over 2 days, 1 and 2 hours following dosing. Outcome measures included multiple scales rated by clinicians or participants, digital video, and a wearable sensor. RESULTS: Dipraglurant was well tolerated, with no obvious impact on any of the measurement outcomes. Power analyses suggested fewer subjects would be required for studies using a within-subject versus independent group design, especially for certain measures. Some outcome measures appeared more suitable than others. CONCLUSION: Although dipraglurant appeared well tolerated, it did not produce a trend for clinical benefit. The results provide valuable information for planning further trials in blepharospasm. © 2024 International Parkinson and Movement Disorder Society.

Rasch analysis of the modified Fatigue Severity Scale in neuromuscular disorders and comparison between sex, age and diagnoses.

INTRODUCTION/AIMS: Fatigue is a common and debilitating symptom encountered in the neuromuscular clinic. The 7-item Fatigue Severity Scale (FSS-7) is a Rasch-modified assessment validated in inflammatory neuropathies but not across a typical neuromuscular patient population. The aim of this study was to validate this measure in neuromuscular disorders and to compare between patient sex, age and diagnoses. METHODS: The modified FSS-7 was mailed to patients recruited from a specialist neuromuscular clinic at the Walton Centre. Responses were subjected to Rasch analysis and descriptive statistics were performed on the Rasch converted data. RESULTS: The mFSS-7 met the Rasch model expectations with an overall Chi-square probability of 0.4918, a strict unidimensional scale free from differential item functioning (DIF) that satisfied the model with substantial test-retest reliability using Lin's concordance correlation coefficient 0.71 (95% CI 0.63-0.77). A 15.7% ceiling effect was observed in this patient cohort. Post hoc analysis did not show any significant difference in fatigue between sex, age or neuromuscular diagnoses. DISCUSSION: The self-completed Rasch mFSS-7 showed acceptable test-retest reliability across patients with varied disorders under follow-up in a specialist neuromuscular clinic. The ceiling effect constrains its use for those with the most severe fatigue. Future considerations could include assessment of the benefits of clinical interventions, particularly multidisciplinary team input or dedicated fatigue clinics.

Rasch analysis of the Unidimensional Self-Efficacy Scale in Neuromuscular Disorders and comparison between sex, age, and diagnoses.

INTRODUCTION/AIMS: Self-efficacy reflects a person's perceptions of their capabilities for specific tasks and influences motivation and performance. The Unidimensional Self-Efficacy in Neuromuscular Disorders (USE-NM) was modified from the Multiple Sclerosis (MS) USE-MS scale and administered to patients attending a specialist neuromuscular clinic. The aim was to investigate this measure in neuromuscular disorders and to compare between patient sex, age, and diagnosis. METHODS: The USE-NM was posted to patients recruited from a specialist neuromuscular clinic at the Walton Centre. Responses were subjected to Rasch analysis using RUMM2030 software and descriptive statistics were performed using SPSS version 28. RESULTS: One hundred and ninety-eight patients (56.1% male) grouped by age (<50; 50-59; 60-69; and >69 years) and with varied NM disorders returned the USE-NM. It did not meet the Rasch model expectations due to disordered thresholds of items 6 and 8 ("Sometimes I feel inadequate as a person because of my neuromuscular disorder" and "I feel that my social life would be better if I did not have a neuromuscular disorder"). Following item re-scoring, the modified USE-NM satisfied the Rasch model with a unidimensional scale free from differential item functioning and an overall chi-square probability of 0.146 with good reliability and validity. Post hoc nonparametric testing showed no significant difference in fatigue between sex, age, and neuromuscular diagnoses. DISCUSSION: The Rasch-modified USE-NM offers a measure of self-efficacy for neuromuscular disorders encountered in a typical specialist clinic. Future considerations could be given to assessing any benefits of multidisciplinary team input, across a specialist neuromuscular service.

Correlates and trajectories of relapses in relapsing-remitting multiple sclerosis.

BACKGROUND AND AIMS: In people with relapsing-remitting multiple sclerosis (pwRRMS), data from studies on non-pharmacological factors which may influence relapse risk, other than age, are inconsistent. There is a reduced risk of relapses with increasing age, but little is known about other trajectories in real-world MS care. METHODS: We studied longitudinal questionnaire data from 3885 pwRRMS, covering smoking, comorbidities, disease-modifying therapy (DMT), and patient-reported outcome measures, as well as relapses during the past year. We undertook Rasch analysis, group-based trajectory modelling, and multilevel negative binomial regression. RESULTS: The regression cohort of 6285 data sets from pwRRMS over time showed that being a current smoker was associated with 43.9% greater relapse risk; having 3 or more comorbidities increased risk and increasing age reduced risk. Those diagnosed within the last 2 years showed two distinct trajectories, both reducing in relapse frequency but 25.8% started with a higher rate and took 4 years to reduce to the rate of the second group. In the cohort with at least three data points completed, there were three groups: 73.7% followed a low stable relapse rate, 21.6% started from a higher rate and decreased, and 4.7% had an increasing then decreasing pattern. These different trajectory groups showed significant differences in fatigue, neuropathic pain, disability, health status, quality of life, self-efficacy, and DMT use. CONCLUSIONS: These results provide additional evidence for supporting pwRRMS to stop smoking and underline the importance of timely DMT decisions and treatment initiation soon after diagnosis with RRMS.

Measuring disability in multiple sclerosis: the WHODAS 2.0.

INTRODUCTION: Reliable measurement of disability in multiple sclerosis (MS) using a comprehensive, patient self-reported scale, such as the World Health Organization Disability Assessment Schedule (WHODAS) 2.0, would be of clinical and research benefit. METHODS: In the Trajectories of Outcome in Neurological Conditions-MS study, WHODAS 2.0 (WHODAS-36 items for working, WHODAS-32 items if not working, WHODAS-12 items short-form) was examined using Rasch analysis in 5809 people with MS. RESULTS: The 36- and 32-item parallel forms, and the cognitive and physical domains, showed reliability consistent with individual or group use. The 12-item short-form is valid for group use only. Interval level measurement for parametric statistics can be derived from all three scales which showed medium to strong effect sizes for discrimination across characteristics such as age, subtype, and disease duration. Smallest detectable difference for each scale was < 6 on the standardised metric of 0-100 so < 6% of the total range. There was no substantial differential item functioning (DIF) by age, gender, education, working full/part-time, or disease duration; the finding of no DIF for time or sample supports the use of WHODAS 2.0 for longitudinal studies, with the 36- and 32-item versions and the physical and cognitive domains valid for individual patient follow-up. CONCLUSIONS: Disability in MS can be comprehensively measured at interval level by the WHODAS 2.0, and validly monitored over time. Routine use of this self-reported measure in clinical and research practice would give valuable information on the trajectories of disability of individuals and groups.

[Psychometric Evaluation of the 'German Neurological Fatigue Index for Multiple Sclerosis (NFI-MS-G)' in a Sample of Rehabilitation Patients with Multiple Sclerosis]. / Psychometrische Prüfung des deutschsprachigen "Neurologischen Fragebogens zur Müdigkeit bei Multipler Sklerose (NFI-MS-G)" bei Rehabilitanden mit Multipler Sklerose.

PURPOSE: The purpose of this study was to provide a patient-reported outcome measure for people with multiple sclerosis (MS) comprehensively reflecting the construct of fatigue and developed upon the assumptions of the Rasch model. The Neurological Fatigue Index - Multiple Sclerosis (NFI-MS) is based on both a medical and patient-described symptom framework of fatigue and has been validated. Therefore, in this study the German version of the NFI-MS (NFI-MS-G) consisting of a physical and cognitive subscale and a summary scale was validated. METHOD: In this bi-centre-study, 309 people with MS undergoing outpatient rehabilitation or being≥2 months before or after their inpatient rehabilitation completed the German NFI-MS-G twice within 14-21 days together with other questionnaires. Correlation with established questionnaires and Rasch analysis were used for its validation. Additionally, psychometric properties of known-groups validity, internal consistency, test-retest reliability, measurement precision and readability were tested. Finally, the English NFI-MS and German NFI-MS-G were compared with each other to equate the language versions. RESULTS: The NFI-MS-G showed good internal construct validity, convergent and known-groups validity and internal consistency (Cronbach's alpha 0.84-0.93). The physical subscale showed minor local dependencies between items 1 and 7, 2 and 3 and 4 to 6, that could be treated by combining the respective items to testlets. Unidimensionality was found for the physical and cognitive subscales but not for the summary scale. Replacing the summary scale, a 2-domains subtest measuring the higher-order construct of fatigue was created. Good test-retest reliability (Lin's concordance correlation coefficient of 0.86-0.90) and low floor and ceiling effects were demonstrated. The NFI-MS-G was found easily readable and invariant across groups of gender, age, disease duration, timepoint and centre. CONCLUSION: The German version of the NFI-MS comprehensively represents the construct of fatigue and has adequate psychometric properties. The German version differs from the English original version with respect to a lack of unidimensionality of the summary scale and minor local dependencies of the physical subscale that could be canceled out using a testlet analysis.

Measuring coping in multiple sclerosis: The Coping Index-MS.

BACKGROUND: Coping in multiple sclerosis (MS) refers to cognitive and behavioural efforts to manage stresses imposed by the illness. Existing generic and disease-specific coping scales do not meet modern guidelines for scale development and cannot produce interval-level metrics to allow for change scores. OBJECTIVE: The main aim of this study was to develop a brief patient-reported outcome measure for coping in MS, capable of interval-level measurement. METHODS: Qualitative work in 43 people with MS leads to a draft scale which was administered to 5747 participants, with longitudinal collection in 2290. A calibration sample of 1000 subjects split into development and validation sets was used to generate three scales consistent with Rasch model expectations. RESULTS: The total Coping Index-MS (CI-MS-T), CI-MS-Internal (CI-MS-I) and CI-MS-External (CI-MS-E) cover total, internal and externally focused coping. All three scales are capable of interval-level measurement. Trajectory analysis of 9000 questionnaires showed two trajectories in CI-MS-T: Group 1 showed a low level of coping with slight decline over 40 months, while Group 2 had a better and stable level of coping due to improving CI-MS-I which compensated for the deteriorating CI-MS-E over time. CI-MS-T < 30 identified group membership at baseline. CONCLUSION: The CI-MS-T, CI-MS-I and CI-MS-E, comprising 20 items, provide interval-level measurement and are free-for-use in not-for-profit settings.

German translation, cultural adaptation and validation of the unidimensional self-efficacy scale for multiple sclerosis.

BACKGROUND: Self-efficacy concerns individuals' beliefs in their capability to exercise control in specific situations and complete tasks successfully. In people with multiple sclerosis (PwMS), self-efficacy has been associated with physical activity levels and quality of life. As a validated German language self-efficacy scale for PwMS is missing the aims of this study were to translate the Unidimensional Self-Efficacy Scale for Multiple Sclerosis (USE-MS) into German, establish face and content validity and cultural adaptation of the German version for PwMS in Austria. A further aim was to validate the German USE-MS (USE-MS-G) in PwMS. METHODS: Permission to translate and validate the USE-MS was received from the scale developers. Following guidelines for translation and validation of questionnaires and applying Bandura's concept of self-efficacy, the USE-MS was forward-backward translated with content and face validity established. Cultural adaptation for Austria was performed using cognitive patient interviews. Reliability was assessed using Cronbach's alpha, Person separation index and Lin's concordance correlation coefficient. Rasch analysis was employed to assess construct validity. Comparison was made to scales for resilience, general self-efficacy, anxiety and depression, multiple sclerosis fatigue and health-related quality of life. Data were also pooled with an historic English dataset to compare the English and German language versions. RESULTS: The translation and cultural adaptation were successfully performed in the adaptation process of the USE-MS-G. Pretesting was conducted in 30 PwMS, the validation of the final USE-MS-G involved 309 PwMS with minimal to severe disability. The USE-MS-G was found to be valid against the Rasch model when fitting scale data using a bifactor solution of two super-items. It was shown to be unidimensional, free from differential item functioning and well targeted to the study population. Excellent convergent and known-groups validity, internal consistency, person separation reliability and test-retest reliability were shown for the USE-MS-G. Pooling of the English and German datasets confirmed invariance of item difficulties between languages. CONCLUSION: The USE-MS-G is a robust, valid and reliable scale to assess self-efficacy in PwMS and can generate interval level data on an equivalent metric to the UK version. TRIAL REGISTRATION: ISRCTN Registry; ISRCTN14843579 ; prospectively registered on 02. 01. 2019.

Psychosis in Alzheimer's Disease.

PURPOSE OF REVIEW: To review the incidence, treatment and genetics of psychosis in people with mild cognitive impairment (MCI) and Alzheimer's disease (AD). RECENT FINDINGS: Psychosis in Alzheimer's disease (AD) has an incidence of ~ 10% per year. There is limited evidence regarding psychological interventions. Pharmacological management has focused on atypical antipsychotics, balancing modest benefits with evidence of long-term harms. The 5HT2A inverse agonist pimavanserin appears to confer benefit in PD psychosis with initial evidence of benefit in AD. Cholinesterase inhibitors give modest benefits in DLB psychosis. The utility of muscarinic agonists, lithium, glutamatergic and noradrenergic modulators needs further study. Recent work has confirmed the importance of psychosis in MCI as well as AD. The lack of evidence regarding psychological therapies is an urgent knowledge gap, but there is encouraging evidence for emerging pharmacological treatments. Genetics will provide an opportunity for precision medicine and new treatment targets.

Test equating sleep scales: applying the Leunbach's model.

BACKGROUND: In most cases, the total scores from different instruments assessing the same construct are not directly comparable, but must be equated. In this study we aimed to illustrate a novel test equating methodology applied to sleep functions, a domain in which few score comparability studies exist. METHODS: Eight scales from two cross-sectional self-report studies were considered, and one scale was common to both studies. The International Classification of Functioning, Disability and Health (ICF) was used to establish content comparability. Direct (common persons) and indirect (common item) equating was assessed by means of Leunbach's model, which equates the scores of two scales depending on the same person parameter, taking into account several tests of fit and the Standard Error of Equating (SEE). RESULTS: All items were linked to the body functions category b134 of the ICF, which corresponds to 'Sleep functions'. The scales were classified into three sleep aspects: four scales were assessing mainly sleep disturbance, one quality of sleep, and three impact of sleep on daily life. Of 16 direct equated pairs, 15 could be equated according to Leunbach's model, and of 12 indirect equated pairs, 8 could be equated. Raw score conversion tables between each of these 23 equated pairs are provided. The SEE was higher for indirect than for direct equating. Pairs measuring the same sleep aspect did not show better fit indices than pairs from different aspects. The instruments mapped to a higher order concept of sleep functions. CONCLUSION: Leunbach's equating model has been successfully applied to a functioning domain little explored in test equating. This novel methodology, together with the ICF, enables comparison of clinical outcomes and research results, and facilitates communication among clinicians.

Use of coping strategies in MND/ALS: Association with demographic and disease-related characteristics.

OBJECTIVE: Understanding the use of coping strategies and which factors are associated with strategy utilization might help clinical staff anticipate which coping strategies individuals are more likely to utilize. In this study, we assess coping strategy use in the motor neuron disease (MND, also known as amyotrophic lateral sclerosis [ALS]) population and examine associations of demographic and disease variables with individual coping strategies. PARTICIPANTS AND METHODS: A total of 233 participants with MND/ALS were recruited into the ongoing Trajectories of Outcomes in Neurological Conditions study from MND clinics across the United Kingdom. Participants completed a questionnaire pack collecting data on demographics and a range of patient-reported measures including the Coping Orientations to Problems Experienced scale. Associations between demographic and clinical characteristics and coping strategies were examined by simple and multiple ordinal logistic regression. RESULTS: The most commonly used strategy was Acceptance, followed by Active Coping, Planning and Positive Re-interpretation and Growth. The least used strategies were Substance Use, Turning to Religion and Denial. Ten out of the fifteen strategies showed statistically significant associations with demographic and clinical characteristics. Most markedly, females were found to utilize many strategies more than males, namely Restraint, Seeking Instrumental Social Support, Seeking Emotional Social Support, Focus on and Venting of Emotions, Behavioural Disengagement and Mental Disengagement. CONCLUSION: Clinical staff should be aware that coping strategy use is associated with several demographic and disease characteristics. Targeted advice on coping may improve coping capacity and facilitate psychosocial adjustment.

Pharmacokinetics, Pharmacodynamics, and Safety of Single-Dose Rivaroxaban in Chronic Hemodialysis.

BACKGROUND: This study aimed to characterize the single-dose pharmacokinetic (PK) and pharmacodynamic (PD) profile of rivaroxaban 15 mg administered before and after dialysis in subjects with end-stage renal disease (ESRD), and to compare this profile in subjects with ESRD to that in healthy control subjects (creatinine clearance ≥80 ml/min). METHODS: This was an open-label, single-dose, single-center, parallel-group study of rivaroxaban in ESRD subjects who had been clinically stable on maintenance hemodialysis for ≥3 months. In 8 subjects with ESRD, a 15-mg dose of rivaroxaban was administered 2 ± 0.5 h before a hemodialysis session and repeated 7-14 days later at 3 h after a 4-h hemodialysis session. Eight healthy control subjects, matched for age, sex, and body mass index, received one 15-mg rivaroxaban dose. RESULTS: Compared to healthy subjects, area under the rivaroxaban plasma concentration versus time curve (AUC) increased by 56% following post-dialysis administration. Assuming similar bioavailability between groups, this reflects an approximate 35% decrease in overall drug clearance in ESRD subjects. Pre-dialysis dosing resulted in only 5% lowering of AUC versus post-dialysis dosing, confirming the minimal impact of dialysis on the PK of rivaroxaban. PD effects, as assessed by change in prothrombin time, percent factor Xa inhibition, and anti-Xa activity, were generally concordant with observed changes in plasma PK. CONCLUSIONS: Changes in PK and PD parameters in chronic dialysis patients were generally comparable to changes observed previously in patients with moderate-to-severe renal impairment who were not undergoing dialysis, and support use of a 15-mg dose in this patient population.

Urgent referral for suspected CNS cancer: which clinical features are associated with a positive predictive value of 3 % or more?

BACKGROUND: Urgent referral for suspected central nervous system (CNS) cancer is recommended, but little analysis of the referral criteria diagnostic performance has been conducted. New 2015 NICE guidance recommends direct brain imaging for patients with symptoms with positive predictive values (PPV) of 3 %, but further guidance is needed. METHODS: A 12-month retrospective evaluation of 393 patients referred under previous 2005 NICE 2-week rule criteria was conducted. Analysis was based on the three groups of symptoms forming the referral criteria, (1) CNS symptoms, (2) recent onset headaches, (3) rapidly progressive subacute focal deficit/cognitive/behavioural/personality change. Comparison was made with neuroimaging findings. RESULTS: Twelve (3.1 %) of 383 patients who attended clinic had CNS cancer suggesting the combination of clinical judgement and application of 2005 criteria matched the 2015 guideline's PPV threshold. PPVs for the three groups of symptoms were (1) 4.1 % (95 % CIs 2.0 to 7.4 %), (2) 1.2 % (0.1 to 4.3 %) and (3) 3.7 % (0.1 to 19.0 %). Sensitivities were (1) 83.3 % (95 % CIs 51.6 to 97.9 %), (2) 16.7 % (2.1 to 48.4 %), and (3) 8.3 % (0.2 to 38.5 %); specificities were (1) 37.2 % (32.3 to 42.3 %), (2) 55.5 % (50.3 to 60.7 %) and (3) 93.0 % (89.9 to 95.4 %). Of 288 patients who underwent neuroimaging, 59 (20.5 %) had incidental findings, most commonly cerebrovascular disease. CONCLUSIONS: The 2015 guidance is less prescriptive than previous criteria making clinical judgement more important. CNS symptoms had greatest sensitivity, while PPVs for CNS symptoms and rapidly progressive subacute deficit/cognitive/behavioural/personality change were closest to 3 %. Recent onset headaches had the lowest sensitivity and PPV.

Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial.

BACKGROUND: Parkinson's disease psychosis, which includes hallucinations and delusions, is frequent and debilitating in people with Parkinson's disease. We aimed to assess safety and efficacy of pimavanserin, a selective serotonin 5-HT2A inverse agonist, in this population. METHODS: In our 6 week, randomised, double-blind, placebo-controlled study, we enrolled adults (aged ≥40 years) with Parkinson's disease psychosis. Antipsychotic treatments were not permitted during the study, but controlled antiparkinsonian medication or deep brain stimulation was allowed. Eligible participants entered a 2 week non-pharmacological lead-in phase to limit the placebo response, after which they were randomly allocated (1:1) to receive pimavanserin 40 mg per day or matched placebo. The primary outcome was antipsychotic benefit as assessed by central, independent raters with the Parkinson's disease-adapted scale for assessment of positive symptoms (SAPS-PD) in all patients who received at least one dose of study drug and had a SAPS assessment at baseline and at least one follow-up. We assessed safety and tolerability in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01174004. FINDINGS: Between Aug 11, 2010, and Aug 29, 2012, we randomly allocated 199 patients to treatment groups. For 90 recipients of placebo and 95 recipients of pimavanserin included in the primary analysis, pimavanserin was associated with a -5·79 decrease in SAPS-PD scores compared with -2·73 for placebo (difference -3·06, 95% CI -4·91 to -1·20; p=0·001; Cohen's d 0·50). Ten patients in the pimavanserin group discontinued because of an adverse event (four due to psychotic disorder or hallucination within 10 days of start of the study drug) compared with two in the placebo group. Overall, pimavanserin was well tolerated with no significant safety concerns or worsening of motor function. INTERPRETATION: Pimavanserin may benefit patients with Parkinson's disease psychosis for whom few other treatment options exist. The trial design used in this study to manage placebo response could have applicability to other studies in neuropsychiatric disease. FUNDING: ACADIA Pharmaceuticals.

Associations between atrial fibrillation and early outcomes of patients with heart failure and reduced or preserved ejection fraction.

BACKGROUND: The relative impact of atrial fibrillation on early outcomes of patients with heart failure with reduced or preserved ejection fraction (EF) is unknown. METHODS: We conducted a retrospective cohort study of clinical registry data linked to Medicare claims for patients with heart failure with reduced or preserved EF stratified by presence of atrial fibrillation at admission. Outcomes of interest were all-cause mortality and readmission at 30days. We used Kaplan-Meier methods to estimate mortality and calculated cumulative incidence estimates of readmission. We used Cox proportional hazards models to examine associations between atrial fibrillation and 30-day outcomes. RESULTS: Among 66,357 patients admitted to 283 hospitals between January 2001 and March 2006, 46% had atrial fibrillation (44% of patients with reduced EF and 48% of patients with preserved EF). After adjustment for other patient characteristics, atrial fibrillation was associated with a modestly higher risk of 30-day mortality (HR, 1.08; 95% CI, 1.03-1.14) and readmission (HR, 1.06; 95% CI, 1.02-1.11). In subgroup analyses, atrial fibrillation was associated with a higher risk of 30-day mortality (HR, 1.16; 95% CI, 1.08-1.25) among patients with preserved EF but not among patients with reduced EF. The association of atrial fibrillation with readmission did not differ by heart failure type (P=.37 for the interaction). CONCLUSIONS: Atrial fibrillation was associated with higher 30-day mortality among patients with heart failure with preserved EF but not reduced EF. The association of atrial fibrillation with 30-day readmission was modest and did not differ by heart failure type.

On the discovery and development of pimavanserin: a novel drug candidate for Parkinson's psychosis.

Parkinson's disease psychosis (PDP) is a condition that may develop in up to 60 % of Parkinson's patients, and is a major reason for nursing home placement for those affected. There are no FDA approved drugs for PDP but low doses of atypical anti-psychotic drugs (APDs) are commonly prescribed off-label. Only low-dose clozapine has shown efficacy in randomized controlled trials, but all APDs have black box warnings related to the increased mortality and morbidity when used in elderly demented patients. Using molecular pharmacological profiling of a large collection of marketed drugs, we discovered that potent inverse agonist activity against 5-HT2A serotonin receptors was a common feature of atypical APDs, especially the atypical APDs used to treat PDP. Since low-dose clozapine therapy selectively blocks this receptor, it was hypothesized that a highly selective 5-HT2A receptor inverse agonist might provide good symptom control in patients suffering from PDP, with a greatly improved safety and tolerability profile. A high throughput screening and subsequent chemical lead optimization campaign to develop potent, selective 5-HT2A receptor inverse agonists was launched, eventually resulting in the discovery of pimavanserin. Pimavanserin displays nanomolar potency as a 5-HT2A receptor inverse agonist, selectivity for 5-HT2A over 5-HT2C receptors, and no meaningful activity at any other G-protein coupled receptor. It demonstrated robust activity in preclinical models of schizophrenia and PDP, and did not worsen motoric symptoms, in contrast to the APDs tested. In a Phase III clinical trial, pimavanserin showed highly significant benefits in the primary endpoint, the scale for assessment of positive symptoms-PD, a scale adapted for use in PDP. In addition, improvements in all other efficacy endpoints, including physician's clinical global impression, caregiver burden, night-time sleep quality and daytime wakefulness, were seen. Pimavanserin demonstrated good safety and tolerability and did not worsen motoric symptoms as assessed by the unified Parkinson's disease rating scale parts II and III. An open-label extension study has further demonstrated that pimavanserin is safe and well-tolerated with long-term use. Pimavanserin may therefore offer a viable treatment option for patients suffering from PDP.

Improving the measurement properties of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R): deriving a valid measurement total for the calculation of change.

BACKGROUND: The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score is a widely used measure of functional status in Amyotrophic Lateral Sclerosis/Motor Neuron Disease (ALS), but recent evidence has raised doubts about its validity. The objective was to examine the measurement properties of the ALSFRS-R, aiming to produce valid measurement from all 12 scale items. METHOD: Longitudinal ALSFRS-R data were collected between 2013-2020 from 1120 people with ALS recruited from 35 centers, together with other scales in the Trajectories of Outcomes in Neurological Conditions-ALS (TONiC-ALS) study. The ALSFRS-R was analyzed by confirmatory factor analysis (CFA), Rasch Analysis (RA) and Mokken scaling. RESULTS: No definite factor structure of the ALSFRS-R was confirmed by CFA. RA revealed the raw score total to be invalid even at the ordinal level because of multidimensionality; valid interval level subscale measures could be found for the Bulbar, Fine-Motor and Gross-Motor domains but the Respiratory domain was only valid at an ordinal level. All four domains resolved into a single valid, interval level measure by using a bifactor RA. The smallest detectable difference was 10.4% of the range of the interval scale. CONCLUSION: A total ALSFRS-R ordinal raw score can lead to inferential bias in clinical trial results due to its non-linear nature. On the interval level transformation, more than 5 points difference is required before a statistically significant detectable difference can be observed. Transformation to interval level data should be mandatory in clinical trials.

Dyspnea (breathlessness) in amyotrophic lateral sclerosis/motor neuron disease: prevalence, progression, severity, and correlates.

Objective: Dyspnea, or breathlessness, is an important symptom in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). We examined the measurement properties of the Dyspnea-12. Methods: Rasch analysis enabled conversion of raw Dyspnea-12 scores to interval level metric equivalents. Converted data were used to perform trajectory modeling; those following different trajectories were compared for demographic, clinical, symptom, and functioning characteristics. Logistic regression examined differences between distinct trajectories. Results: In 1022 people, at baseline, mean metric Dyspnea-12 was 7.6 (SD 9.3). 49.8% had dyspnea, severe in 12.6%. Trajectory analysis over 28 months revealed three breathlessness trajectories: group 1 reported none at baseline/follow-up (42.7%); group 2 significantly increased over time (9.4%); group 3 had a much higher level at baseline which rose over follow-up (47.9%). Group 3 had worse outcomes on all symptoms, functioning and quality of life; compared to group 1, their odds of: respiratory onset sixfold greater; King's stage ≥3 2.9 greater; increased odds of being bothered by choking, head drop, fasciculations, and muscle cramps; fatigue and anxiety also elevated (p < .01). Conclusion: Dyspnea is a cardinal symptom in ALS/MND and can be quickly measured using the Dyspnea-12. Raw scores can easily be converted to interval level measurement, for valid change scores and trajectory modeling. Dyspnea trajectories reveal different patterns, showing that clinical services must provide monitoring which is customized to individual patient need. Almost half of this large population had worsening dyspnea, confirming the importance of respiratory monitoring and interventions being integrated into routine ALS care.

Prevalence, treatment and correlates of depression in multiple sclerosis.

BACKGROUND: The prevalence of depression in Multiple Sclerosis (MS) is often assessed by administering patient reported outcome measures (PROMs) examining depressive symptomatology to population cohorts; a recent review summarised 12 such studies, eight of which used the Hospital Anxiety and Depression Scale-Depression (HADS-D). In clinical practice, depression is diagnosed by an individual structured clinical interview; diagnosis often leads to treatment options including antidepressant medication. It follows that an MS population will include those whose current depressive symptoms meet threshold for depression diagnosis, plus those who previously met diagnostic criteria for depression and have been treated such that depressive symptoms have improved below that threshold. We examined a large MS population to establish a multi-attribute estimate of depression, taking into account probable depression on HADS-D, as well as anti-depressant medication use and co-morbidity data reporting current treatment for depression. We then studied associations with demographic and health status measures and the trajectories of depressive symptoms over time. METHODS: Participants were recruited into the UK-wide Trajectories of Outcome in Neurological Conditions-MS (TONiC-MS) study, with demographic and disease data from clinical records, PROMs collected at intervals of at least 9 months, as well as co-morbidities and medication. Interval level conversions of PROM data followed Rasch analysis. Logistic regression examined associations of demographic characteristics and symptoms with depression. Finally, a group-based trajectory model was applied to those with depression. RESULTS: Baseline data in 5633 participants showed the prevalence of depression to be 25.3 % (CI: 24.2-26.5). There were significant differences in prevalence by MS subtype: relapsing 23.2 % (CI: 21.8- 24.5), primary progressive 25.8 % (CI: 22.5-29.3), secondary progressive 31.5 % (CI: 29.0-34.0); disability: EDSS 0-4 19.2 % (CI: 17.8-20.6), EDSS ≥4.5 31.9 % (CI: 30.2-33.6); and age: 42-57 years 27.7 % (CI: 26.0-29.3), above or below this range 23.1 % (CI: 21.6-24.7). Fatigue, disability, self-efficacy and self esteem correlated with depression with a large effect size (>0.8) whereas sleep, spasticity pain, vision and bladder had an effect size >0.5. The logistic regression model (N = 4938) correctly classified 80 % with 93 % specificity: risk of depression was increased with disability, fatigue, anxiety, more comorbidities or current smoking. Higher self-efficacy or self esteem and marriage reduced depression. Trajectory analysis of depressive symptoms over 40 months in those with depression (N = 1096) showed three groups: 19.1 % with low symptoms, 49.2 % with greater symptoms between the threshold of possible and probable depression, and 31.7 % with high depressive symptoms. 29.9 % (CI: 27.6-32.3) of depressed subjects were untreated, conversely of those treated, 26.1 % still had a symptom level consistent with a probable case (CI: 23.5-28.9). CONCLUSION: A multi-attribute estimate of depression in MS is essential because using only screening questionnaires, diagnoses or antidepressant medication all under-estimate the true prevalence. Depression affects 25.3 % of those with MS, almost half of those with depression were either untreated or still had symptoms indicating probable depression despite treatment. Services for depression in MS must be pro-active and flexible, recognising the heterogeneity of outcomes and reaching out to those with ongoing symptoms.

Atrial fibrillation in myocardial infarction patients: Impact on health care utilization.

BACKGROUND: Atrial fibrillation (AF) often complicates myocardial infarction (MI). While AF adversely impacts survival in MI patients, the impact of AF on health care utilization has not been studied. METHODS: The risk of hospitalizations, emergency department (ED) visits, and outpatient visits associated with prior, new-onset (<30 days post-MI), and late-onset (≥30 days post-MI) AF was assessed among incident MI patients from the Olmsted County, Minnesota, community. RESULTS: Of 1,502 MI patients, 237 had prior AF, 163 developed new-onset AF, 113 developed late-onset AF, and 989 had no AF. Over a mean follow-up of 3.9 years, 3,661 hospitalizations, 5,559 ED visits, and 80,240 outpatient visits occurred. After adjustment, compared with patients without AF, those with prior and new-onset AF exhibited a 1.6-fold and 1.3-fold increased risk of hospitalization, respectively. In contrast, late-onset AF carried a 2.2-fold increased risk of hospitalization. The hazard ratios were 1.4, 1.2, and 1.8 for ED visits and 1.4, 1.2, and 1.7 for outpatient visits for prior, new-onset, and late-onset AF. Additional adjustment for time-dependent recurrent MI and heart failure attenuated the results slightly for hospitalizations and ED visits; however, patients with late-onset AF still exhibited a >50% increased risk for both utilization measures. CONCLUSIONS: In MI patients, the risk of hospitalizations, ED visits, and outpatient visits differed by the timing of AF onset, with the greatest risk conferred by late-onset AF. Atrial fibrillation imparts an adverse prognosis after MI, underscoring the importance of its management in MI patients.