A Randomized, Double-Blinded, Placebo-Controlled, Cross Over Study Evaluating the Efficacy and Safety of Timolol Ophthalmic Solution as an Acute Treatment of Migraine

Introduction. Daily oral beta-adrenoreceptor antagonist has been shown to be effective in preventing migraine headaches. Timolol 0.5% ophthalmic solution is a non-selective beta-adrenoreceptor antago- nist, where the primary use is for glaucoma. There have been case reports that timolol is effective in aborting or improving an acute migraine headache. The objective of this study was to assess the efficacy (decrease of ≥ 50% in pain scale at 120 minutes) of timolol 0.5% ophthalmic solution compared to placebo in acute treatment of migraine headache. Methods.We performed a randomized, double-blind, crossover, placebo-controlled, study. Study entry criteria required subjects to have one to eight migraine episodes per month. The primary outcome was comparison of the change in a visual analog pain scale (VAS) at 120 minutes after taking the study medication. Study subjects were given a pain scale with a range of 1 (no pain) to 10 (most severe pain) to complete after onset of migraine but before administration of study drops and 120 minutes after administration of study drops. Improve- ment was defined as a ≥ 50% decrease in pain scale. Results. Nineteen subjects completed the study and were used for analysis. The primary outcome changes in pain scale, 120 minutes after dose, showed a similar decrease for placebo and drug with a slightly wider 95% CI for placebo. Six subjects in each arm experi- enced a ≥ 50% decrease in pain scale. Conclusion. These results support that timolol 0.5% ophthalmic solution is not an efficacious treatment for acute migraine headache

Quantitative sensory testing in a large cohort of neuropathy patients: QST in Neuropathy

Background: Quantitative sensory testing (QST) is a subjective but reliable and quantifiable method to detect patient thresholds to different sensory stimuli. QST is used to measure small- and large-fiber nerve function and can be used in conjunction with other diagnostic modalities in the evaluation of peripheral neuropathy (PN). The utility of QST to distinguish among different types of PN, however, has not been explored. The objective of the study was to evaluate if different patterns of QST abnormalities could distinguish between PN types. Methods: This single-center retrospective cohort study evaluated the frequency of QST abnormalities to vibratory, cold and heat detection thresholds in a large population of PN cases evaluated at the University of Texas Southwestern Medical Center peripheral neuropathy clinic between 1995-2000. PN was categorized by etiology. Results: A total of 559 QST studies were performed in this study. The average age of patients (n=557) was 60 years with a male-to-female ratio of 1:1. The most common diagnosis was cryptogenic sensory polyneuropathy (CSPN, n=294), followed by Charcot–Marie–Tooth disease (n=84)). Meta-regression of vibration and cold indicate that the expected proportion of abnormal responses is less for the vibration test (p = 0.0002), relative to the cold test. However, no differences were observed between diagnoses. Conclusions: Though abnormal QST thresholds were seen in most patients with PN, patterns of QST abnormalities do not distinguish between different types of PN. The routine clinical utility of QST is likely limited

Methotrexate Polyglutamation in a Myasthenia Gravis Clinical Trial

Introduction. Methotrexate (MTX) is an immunosuppressive and anti-inflammatory drug used to treat rheumatoid arthritis (RA) and other autoimmune conditions. MTX is transported into cells, where glutamate moieties are added and is retained as methotrexate polyglutamates (MTXPGs). In the RA literature, it has been reported that the degree of polyglutamation correlates with the anti-inflammatory effect of MTX in RA. There are no prior studies evaluating the relationship between MTXPGs and myasthenia gravis (MG) outcome measures. The objective of this study was to assess the correlation between methotrexate (MTX) polyglutamates (MTXPGs) with Myasthenia Gravis (MG) outcome measures. Methods.xAn analysis was done of blood drawn from patients enrolled in the 12-month randomized, placebo-controlled study of MTX in MG study. Red blood cell MTXPGs were measured via ultraperformance liquid chromatography and tandem mass spectrometry. MTXPG was correlated to MG outcome measures using Spearman Correlation Coefficient. A two-group t-test was used to determine the difference in MTXPG based on clinical outcome responder definitions. Results. Twenty-one polyglutamate samples were analyzed of subjects on MTX while eight samples were analyzed from subjects on placebo. Pentaglutamate had the strongest correlation with the MG-ADL (0.99), while tetraglutamate had the strongest correlation with the QMG (0.54). Triglutamate had the strongest correlation with MGC (0.76). Conclusion. There were variable correlations between MTXPG1-5 and MG outcomes (rho range: 0.08 to 0.99). There are strong correlations between MTXPG and the MG-ADL, QMG, and MGC. Long chain methotrexate polyglutamates correlate better with MG outcomes

A Patient Activities of Daily Living Scale for Amyotrophic Lateral Sclerosis

Background: Motor neuron disorders are rare, progressive neurodegenerative diseases which affect multiple domains of motor function. The ability to assess function from home using an electronic medical record (EMR) would facilitate pragmatic studies. Objective: To develop a Patient Activity of Daily Living scale for Amyotrophic Lateral Sclerosis and other motor neuron disorders (PADL-ALS) to support large pragmatic trials. Methods: The Greater Plains Collaborative Clinical Data Research Network (GPC) developed and tested the feasibility of using the PADL-ALS.  We convened patient and caregiver focus groups and in-person meetings to recommend changes to the ALS Functional Rating Scale-Revised (ALSFRS-R), which clarified language and added questions about pseudobulbar affect, pain, and faith.  Feasibility was determined by conducting a survey of participants identified using EMR-computable phenotypes and returned via patient-preferred modalities. Results: Surveys were distributed to 1079 participants at nine GPC health systems.  The survey response rate was 44.4% (range 12.9-57.66%): male to female ratio 1.56; 84% self-identified as a patient with ALS.  Patient respondents used computers or tablets more frequently than caregivers responding on their behalf.  The PADL-ALS correlated to clinic-performed ALSFRS-R within 4 weeks of survey completion (n=33, rho=0.93, Kansas only).  The pseudobulbar affect question correlated to functional motor burden.  Over 80% agreed to be contacted for future research opportunities. Conclusion:  We demonstrated the feasibility of determining functional burden with the PADL-ALS using an EMR-computable phenotype.  Future directions include implementing the PADL-ALS to answer pragmatic questions about ALS care

Timing of Decremental Response During Repetitive Nerve Stimulation in Myasthenia Gravis

Background: A decrement >10% detected during repetitive nerve stimulation (RNS) is supportive of considering a diagnosis of myasthenia gravis (MG). Several studies have found that most of this decrement is seen between 4 to 6 min post-exercise. However, there are not available studies analyzing if shorter timing would be sufficient.   Objective: The objective of this study was to evaluate if RNS up to 2 min post-exercise is sufficient to detect a decrement response >10%. Methods: We performed a retrospective chart review study of patients referred to our neuromuscular clinic at The University of Kansas Medical Center with symptoms suggestive of MG from 2013 to 2017. Results: A total of 76 patients with MG and 100 controls were identified.  A significant decrement was detected in 95% of MG patients with abnormal RNS within 2 minutes post-exercise. Conclusion: RNS up to 2 min post-exercise might be sufficient to detect a significant decrement in MG patients.&nbsp

Amyloid Myopathy as an Inclusion Body Myositis Mimic

Introduction: Amyloid myopathy is a rare presentation of systemic amyloidosis. Amyloid myopathy can be initially misdiagnosed as sporadic inclusion body myositis (IBM). Methods: We report 4 cases of amyloid myopathy clinically mimicking inclusion body myositis and initially thought to be phenotypically IBM by neuromuscular experts. Results: Case 1 is an 81-year-old woman who presented with distal arm and proximal leg asymmetric weakness (myopathy pattern 4). Case 2 is a 76-year-old man with primary systemic amyloidosis who presented with myopathy pattern 4 and progressive dysphagia for four years. Case 3 is an 82-year-old man with progressive myopathy pattern 4 weakness and swallowing difficulty. Case 4 is a 62-year-old man with progressive bilateral finger flexor weakness. Muscle biopsies in all 4 cases showed perivascular amyloid deposits Discussion: Amyloid myopathy may be clinically indistinguishable from IBM. Muscle biopsy is of critical importance in the evaluation of patients suspected to have IBM

A Bayesian comparative effectiveness trial in action: developing a platform for multisite study adaptive randomization

A grant from the One-University Open Access Fund at the University of Kansas was used to defray the author's publication fees in this Open Access journal. The Open Access Fund, administered by librarians from the KU, KU Law, and KUMC libraries, is made possible by contributions from the offices of KU Provost, KU Vice Chancellor for Research & Graduate Studies, and KUMC Vice Chancellor for Research. For more information about the Open Access Fund, please see http://library.kumc.edu/authors-fund.xml.Background In the last few decades, the number of trials using Bayesian methods has grown rapidly. Publications prior to 1990 included only three clinical trials that used Bayesian methods, but that number quickly jumped to 19 in the 1990s and to 99 from 2000 to 2012. While this literature provides many examples of Bayesian Adaptive Designs (BAD), none of the papers that are available walks the reader through the detailed process of conducting a BAD. This paper fills that gap by describing the BAD process used for one comparative effectiveness trial (Patient Assisted Intervention for Neuropathy: Comparison of Treatment in Real Life Situations) that can be generalized for use by others. A BAD was chosen with efficiency in mind. Response-adaptive randomization allows the potential for substantially smaller sample sizes, and can provide faster conclusions about which treatment or treatments are most effective. An Internet-based electronic data capture tool, which features a randomization module, facilitated data capture across study sites and an in-house computation software program was developed to implement the response-adaptive randomization. Results A process for adapting randomization with minimal interruption to study sites was developed. A new randomization table can be generated quickly and can be seamlessly integrated in the data capture tool with minimal interruption to study sites. Conclusion This manuscript is the first to detail the technical process used to evaluate a multisite comparative effectiveness trial using adaptive randomization. An important opportunity for the application of Bayesian trials is in comparative effectiveness trials. The specific case study presented in this paper can be used as a model for conducting future clinical trials using a combination of statistical software and a web-based application. Trial registration ClinicalTrials.gov Identifier: NCT02260388, registered on 6 October 201