Impact of subcutaneous immunoglobulin on quality of life in patients with chronic inflammatory demyelinating polyneuropathy previously treated with intravenous immunoglobulin.

INTRODUCTION/AIMS: Intravenous immunoglobulin (IVIg) is a common therapy for patients with chronic inflammatory demyelinating polyneuropathy (CIDP). IVIg may cause systemic adverse events (AEs); therefore, infusion of subcutaneous immunoglobulin (SCIg) may be preferred by some patients. In this study we document the experiences of patients transitioning from IVIg to SCIg. METHODS: Transitioning subjects with CIDP were followed in a 6-month prospective, open-label study. The primary endpoint was percentage of subjects who withdrew for any reason (including significant AEs). The secondary endpoint was symptom progression or relapse requiring a change in management. Quality of life (QOL) and treatment satisfaction were assessed using the Short Form 36-item Health Survey (SF-36), Treatment Satisfaction Questionnaire for Medication (TSQM), and Chronic Acquired Polyneuropathy Patient-Reported Index (CAP-PRI). Efficacy was assessed using the Inflammatory Rasch-built Overall Disability Scale, hand-held dynamometry, limb motor strength testing (LMST), and timed 25-ft walk (T25-FW). RESULTS: Fifteen CIDP subjects transitioned from IVIg to SCIg. Of these, three (20%) met the primary endpoint and one (7%) met the secondary endpoint. The SF-36 showed a statistically significant improvement for the domain of role limitations-physical after 24 weeks (P = .03), with no significant differences observed in other domains. TSQM and CAP-PRI showed significant differences in favor of SCIg (P = .003 and .02, respectively). No significant differences were observed in efficacy after 24 weeks, except for LMST, which favored SCIg (P = .003). Eight of the 12 study completers (67%) continued with SCIg. DISCUSSION: Transition to SCIg was associated with maintained efficacy and improved QOL.

Clinical features of LRP4/agrin-antibody-positive myasthenia gravis: A multicenter study.

INTRODUCTION: Our aim in this study was to identify the prevalence and clinical characteristics of LRP4/agrin-antibody-positive double-seronegative myasthenia gravis (DNMG). METHODS: DNMG patients at 16 sites in the United States were tested for LRP4 and agrin antibodies, and the clinical data were collected. RESULTS: Of 181 DNMG patients, 27 (14.9%) were positive for either low-density lipoprotein receptor-related protein 4 (LRP4) or agrin antibodies. Twenty-three DNMG patients (12.7%) were positive for both antibodies. More antibody-positive patients presented with generalized symptoms (69%) compared with antibody-negative patients (43%) (P ≤ .02). Antibody-positive patients' maximum classification on the Myasthenia Gravis Foundation of America (MGFA) scale was significantly higher than that for antibody-negative patients (P ≤ .005). Seventy percent of antibody-positive patients were classified as MGFA class III, IV, or V compared with 39% of antibody-negative patients. Most LRP4- and agrin-antibody-positive patients (24 of 27, 89%) developed generalized myathenia gravis (MG), but with standard MG treatment 81.5% (22 of 27) improved to MGFA class I or II during a mean follow-up of 11 years. DISCUSSION: Antibody-positive patients had more severe clinical disease than antibody-negative patients. Most DNMG patients responded to standard therapy regardless of antibody status.

Impact of expiratory strength training in amyotrophic lateral sclerosis: Results of a randomized, sham-controlled trial.

INTRODUCTION: The purpose of this study was to determine the impact of an in-home expiratory muscle strength training (EMST) program on pulmonary, swallow, and cough function in individuals with amyotrophic lateral sclerosis (ALS). METHODS: EMST was tested in a prospective, single-center, double-blind, randomized, controlled trial of 48 ALS individuals who completed 8 weeks of either active EMST (n = 24) or sham EMST (n = 24). The primary outcome to assess treatment efficacy was change in maximum expiratory pressure (MEP). Secondary outcomes included: cough spirometry; swallowing; forced vital capacity; and scoring on the ALS Functional Rating Scale-Revised. RESULTS: Treatment was well tolerated with 96% of patients completing the protocol. Significant differences in group change scores were noted for MEP and Dynamic Imaging Grade of Swallowing Toxicity scores (P < 0.02). No differences were noted for other secondary measures. DISCUSSION: This respiratory training program was well-tolerated and led to improvements in respiratory and bulbar function in ALS. Muscle Nerve 59:40-46, 2019.

Impact of expiratory strength training in amyotrophic lateral sclerosis.

INTRODUCTION: We evaluated the feasibility and impact of expiratory muscle strength training (EMST) on respiratory and bulbar function in persons with amyotrophic lateral sclerosis (ALS). METHODS: Twenty-five ALS patients participated in this delayed intervention open-label clinical trial. Following a lead-in period, patients completed a 5-week EMST protocol. Outcome measures included: maximum expiratory pressure (MEP); physiologic measures of swallow and cough; and penetration-aspiration scale (PAS) scores. RESULTS: Of participants who entered the active phase of the study (n = 15), EMST was well tolerated and led to significant increases in MEPs and maximum hyoid displacement during swallowing post-EMST (P < 0.05). No significant differences were observed for PAS scores or cough spirometry measures. CONCLUSIONS: EMST was feasible and well tolerated in this small cohort of ALS patients and led to improvements in expiratory force-generating pressures and swallow kinematics. Further investigation is warranted to confirm these preliminary findings. Muscle Nerve 54: 48-53, 2016.

Muscle-Specific Receptor Tyrosine Kinase (MuSK) Myasthenia Gravis.

Autoimmune myasthenia gravis (MG) is the prototypic, antibody-mediated neuromuscular disease and is characterized by a decrease in the number of functional acetylcholine receptors (AChR) within the muscle end plate zone of the neuromuscular junction (NMJ). Although the pathophysiology of AChR-mediated myasthenia gravis has been extensively studied over the last 40 years since its original description by Patrick and Lindstrom (Science 180:871-872, 1973), less is known about the much more recently described muscle-specific kinase (MuSK) antibody-mediated MG. MuSK-MG has features clinically distinct from Ach-R MG, as well as a different pattern of response to treatment and a unique immunopathogenesis.

Voluntary Cough Airflow Differentiates Safe Versus Unsafe Swallowing in Amyotrophic Lateral Sclerosis.

Dysphagia and aspiration are prevalent in amyotrophic lateral sclerosis (ALS) and contribute to malnutrition, aspiration pneumonia, and death. Early detection of at risk individuals is critical to ensure maintenance of safe oral intake and optimal pulmonary function. We therefore aimed to determine the discriminant ability of voluntary cough airflow measures in detecting penetration/aspiration status in ALS patients. Seventy individuals with ALS (El-Escorial criteria) completed voluntary cough spirometry testing and underwent a standardized videofluoroscopic swallowing evaluation (VFSE). A rater blinded to aspiration status derived six objective measures of voluntary cough airflow and evaluated airway safety using the penetration-aspiration scale (PAS). A between groups ANOVA (safe vs. unsafe swallowers) was conducted and sensitivity, specificity, area under the curve (AUC) and likelihood ratios were calculated. VFSE analysis revealed 24 penetrator/aspirators (PAS ≥3) and 46 non-penetrator/aspirators (PAS ≤2). Cough volume acceleration (CVA), peak expiratory flow rise time (PEFRT), and peak expiratory flow rate (PEFR) were significantly different between airway safety groups (p < 0.05) and demonstrated significant discriminant ability to detect the presence of penetration/aspiration with AUC values of: 0.85, 0.81, and 0.78, respectively. CVA <45.28 L/s/s, PEFR <3.97 L/s, and PEFRT >76 ms had sensitivities of 91.3, 82.6, and 73.9 %, respectively, and specificities of 82.2, 73.9, and 78.3 % for identifying ALS penetrator/aspirators. Voluntary cough airflow measures identified ALS patients at risk for penetration/aspiration and may be a valuable screening tool with high clinical utility.

Humoral factors in ALS patients during disease progression.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons in the CNS and leading to paralysis and death. There are currently no effective treatments for ALS due to the complexity and heterogeneity of factors involved in motor neuron degeneration. A complex of interrelated effectors have been identified in ALS, yet systemic factors indicating and/or reflecting pathological disease developments are uncertain. The purpose of the study was to identify humoral effectors as potential biomarkers during disease progression. METHODS: Thirteen clinically definite ALS patients and seven non-neurological controls enrolled in the study. Peripheral blood samples were obtained from each ALS patient and control at two visits separated by 6 months. The Revised ALS Functional Rating Scale (ALSFRS-R) was used to evaluate overall ALS-patient functional status at each visit. Eleven humoral factors were analyzed in sera. Cytokine levels (GM-CSF, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and TNF-α) were determined using the Bio-Rad Bio-Plex® Luminex 200 multiplex assay system. Nitrite, a breakdown product of NO, was quantified using a Griess Reagent System. Glutathione (GSH) concentrations were measured using a Glutathione Fluorometric Assay Kit. RESULTS: ALS patients had ALSFRS-R scores of 30.5 ± 1.9 on their first visit and 27.3 ± 2.7 on the second visit, indicating slight disease progression. Serum multiplex cytokine panels revealed statistically significant changes in IL-2, IL-5, IL-6, and IL-8 levels in ALS patients depending on disease status at each visit. Nitrite serum levels trended upwards in ALS patients while serum GSH concentrations were drastically decreased in sera from ALS patients versus controls at both visits. CONCLUSIONS: Our results demonstrated a systemic pro-inflammatory state and impaired antioxidant system in ALS patients during disease progression. Increased levels of pro-inflammatory IL-6, IL-8, and nitrite and significantly decreased endogenous antioxidant GSH levels could identify these humoral constituents as systemic biomarkers for ALS. However, systemic changes in IL-2, IL-5, and IL-6 levels determined between visits in ALS patients might indicate adaptive immune system responses dependent on current disease stage. These novel findings, showing dynamic changes in humoral effectors during disease progression, could be important for development of an effective treatment for ALS.

Motor unit number estimation: a technology and literature review.

INTRODUCTION: Numerous methods for motor unit number estimation (MUNE) have been developed. The objective of this article is to summarize and compare the major methods and the available data regarding their reproducibility, validity, application, refinement, and utility. METHODS: Using specified search criteria, a systematic review of the literature was performed. Reproducibility, normative data, application to specific diseases and conditions, technical refinements, and practicality were compiled into a comprehensive database and analyzed. RESULTS: The most commonly reported MUNE methods are the incremental, multiple-point stimulation, spike-triggered averaging, and statistical methods. All have established normative data sets and high reproducibility. MUNE provides quantitative assessments of motor neuron loss and has been applied successfully to the study of many clinical conditions, including amyotrophic lateral sclerosis and normal aging. CONCLUSIONS: MUNE is an important research technique in human subjects, providing important data regarding motor unit populations and motor unit loss over time.

The motor neuron response to SMN1 deficiency in spinal muscular atrophy.

INTRODUCTION: The purpose of this study was to measure and analyze motor unit number estimation (MUNE) values longitudinally in spinal muscular atrophy (SMA). METHODS: Sixty-two children with SMA types 2 and 3 were observed prospectively for up to 42 months. Longitudinal electrophysiological data were collected, including compound motor action potential (CMAP), single motor unit action potential (SMUP), and MUNE. RESULTS: Significant motor neuron loss and compensatory collateral reinnervation were noted at baseline. Over time, there was a significant mean increase in MUNE (4.92 units/year, P = 0.009), a mean decrease in SMUP amplitude (-6.32 µV/year, P = 0.10), and stable CMAP amplitude. CONCLUSIONS: The unexpected longitudinal results differ from findings in amyotrophic lateral sclerosis studies, perhaps indicating that compensatory processes in SMA involve new motor unit development. A better understanding of the mechanisms of motor unit decline and compensation in SMA is important for assessing novel therapeutic strategies and for providing key insights into disease pathophysiology.

Respiratory Strength Training in Amyotrophic Lateral Sclerosis: A Double-Blind, Randomized, Multicenter, Sham-Controlled Trial.

BACKGROUND AND OBJECTIVE: The objective of this study was to evaluate the short-term physiologic effect and one-year functional effect of a 12-week inspiratory and expiratory respiratory strength training (RST) program in individuals with amyotrophic lateral sclerosis (ALS). METHODS: A double-blinded, randomized, sham-controlled trial was conducted in 45 individuals with early-stage ALS. Participants were randomized into 12 weeks of active RST (30% load, n = 23) or sham RST (0% load, n = 22). An intent-to-treat analysis was conducted. Linear regression of pre-post change with group status and pretest scores as predictors was conducted. Primary outcomes included maximum expiratory and inspiratory pressure (MEP, MIP), and secondary outcomes were cough spirometry and forced vital capacity. Exploratory follow-up outcomes included one-year global and bulbar decline (ALS Functional Rating Scale-Revised [ALSFRS-R] total and bulbar subscale slope), oral intake status, and time to noninvasive ventilation (NIV). RESULTS: TheRST completion rate was 91% with no RST-related adverse events. A 12-week RST program led to increases in MEP (p = 0.004), but not MIP (p = 0.33). On average, MEP increased by 20.8 cm H2O after active RST (95% CI +7.6 to +33.9) and decreased by 1.0 cm H2O (95% CI -9.1 to +7.2) after sham RST. Mean MIP increased by 8.9 cm H2O (95% CI +1.5 to +16.3) and 4.8 cm H2O (95% CI -0.6 to +10.2) for the active and sham groups, respectively. Regarding secondary outcomes, RST led to significant increases in cough peak inspiratory flow (p = 0.02); however, it did not affect cough expiratory flow (p = 0.06) or FVC (p = 0.60). Regarding 12-month outcomes, a significant difference in the ALSFRS-R bulbar subscale slope was observed across treatment groups, with a more than two-fold faster rate of bulbar decline in the sham vs active RST groups observed (-0.29 vs -0.12 points/month, p = 0.02). Total ALSFRS-R slope, feeding status, and time to NIV did not differ across treatment groups (p > 0.05). DISCUSSION: RST was well tolerated and led to improvements in some, but not all, short and long-term outcomes. RST represents a proactive rehabilitative intervention that could increase physiologic capacity of specific breathing and airway clearance functions during the early stages of ALS. Further work is needed to determine optimal training intensity, resistance load specifications, and potential long-term functional outcomes. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that a mild-intensity respiratory strength training program improves maximum expiratory pressure, but not maximum inspiratory pressure, in patients with early-stage ALS.

Therapies, Research Funding, and Racial Diversity in Essential Tremor: A Systematic Review of the Literature.

Background: Essential tremor (ET) is one of the most common tremor disorders in the world. Despite this, only one medication, propranolol, is approved by the Food and Drug Administration to treat it. Objectives: We analyzed controlled clinical trials in ET, spanning the last 50 years, to identify potential shortcomings in the therapeutic clinical pipeline. Methods: Outcomes reviewed included demographics (specifically gender and race), therapeutic modalities, funding information, location of research, and trends over time. Clinical trials published in English were identified in scientific databases (Pubmed, SCOPUS, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform from 1970 through December 2021. Included trials were prospective, either single- or double-blinded (including blinded video assessments for surgical trials), with change in limb, head, or voice tremor as the primary outcome measure. Results: One hundred and eighty-six controlled clinical trials were accepted for extraction, including 4207 patients. Of the 145 trials that included gender, males comprised 59% of the patient population. Only 6.4% of studies provided racial demographics; in these studies, 70.5% of patients were Caucasian. The most common therapeutic modality over the past 50 years was "pharmaceutical" (56%), and the most common pharmaceutical studied was propranolol (32%). 41% of clinical trials reported no specific funding. Conclusions: Future efforts should focus on increasing funding for clinical trial research in ET worldwide, and trials should be designed to be more inclusive of disadvantaged minorities.

Eculizumab during Pregnancy in a Patient with Treatment-Refractory Myasthenia Gravis: A Case Report.

The recombinant humanized monoclonal antibody eculizumab has been shown to be effective and well tolerated in patients with anti-acetylcholine receptor antibody-positive, treatment-refractory generalized myasthenia gravis (gMG). Myasthenia gravis (MG) often affects women of child-bearing potential. However, management can be challenging during pregnancy, and current treatment options are limited due to potential teratogenicity. Data are currently lacking on the use of eculizumab in pregnant women with gMG. This case report describes a successful pregnancy in a young woman with treatment-refractory gMG treated with eculizumab before, during, and after pregnancy. Eculizumab appeared to have a favorable benefit-risk profile in this setting, with no treatment-related adverse effects noted in either the patient or the neonate. The patient remains neurologically stable on eculizumab, which she has now been receiving for 5 years. This first report of the use of eculizumab during pregnancy in a patient with treatment-refractory gMG suggests a potential role for eculizumab in this setting, although further clinical experience is necessary to support its use during pregnancy in women with MG.

Radicava/Edaravone Findings in Biomarkers From Amyotrophic Lateral Sclerosis (REFINE-ALS): Protocol and Study Design.

OBJECTIVES: To identify putative biomarkers that may serve as quantifiable, biological, nonclinical measures of the pharmacodynamic effect of edaravone in amyotrophic lateral sclerosis (ALS) and to report real-world treatment outcomes. METHODS: This is a prospective, observational, longitudinal, multicenter (up to 40 sites) US study (Clinicaltrials.gov; NCT04259255) with at least 200 patients with ALS who will receive edaravone for 24 weeks (6 cycles; Food and Drug Administration-approved regimen). All participants must either be treatment naive for edaravone or be more than 1 month without receiving any edaravone dose before screening. Biomarker quantification and other assessments will be performed at baseline (before cycle 1) and during cycles 1, 3, and 6. Selected biomarkers of oxidative stress, inflammation, neuronal injury and death, and muscle injury, as well as biomarker discovery panels (EpiSwitch and SOMAscan), will be evaluated and, when feasible, compared with biobanked samples. Clinical efficacy assessments will include the ALS Functional Rating Scale-Revised, King's clinical staging, ALS Assessment Questionnaire-40, Appel ALS Score (Rating Scale), slow vital capacity, hand-held dynamometry and grip strength, and time to specified states of disease progression or death. DNA samples will also be collected for potential genomic evaluation. The predicted rates of progression and survival, and their potential correlations with biomarkers, will be evaluated. Adverse events related to the study will be reported. RESULTS: The study is estimated to be completed in 2022 with an interim analysis planned. CONCLUSIONS: Findings may help to further the understanding of the pharmacodynamic effect of edaravone, including changes in biomarkers, in response to treatment.

Vascular endothelial growth factor gene transfer for diabetic polyneuropathy: a randomized, double-blinded trial.

OBJECTIVE: Randomized, blinded trial of intramuscular gene transfer using plasmid vascular endothelial growth factor (VEGF) to treat diabetic polyneuropathy. METHODS: Diabetic patients with polyneuropathy were randomized to receive a VEGF-to-placebo ratio of 3:1. Three sets of injections were given at eight standardized sites adjacent to the sciatic, peroneal, and tibial nerves of one leg. Primary outcomes were change in symptom score at 6 months and a prespecified overall clinical and electrophysiological improvement score. Secondary outcomes were differences in symptoms, examination scores, visual analog pain scale, nerve conduction, and quantitative sensory testing. RESULTS: Thirty-nine patients received plasmid VEGF and 11 received placebo. Mean symptom score improved in both legs at 6 months, favoring VEGF over placebo (-1.2 +/- 0.5 vs -0.9 +/- 0.5; p < 0.01 after adjustment for change in the untreated leg) and compared with the untreated leg (-0.7 +/- 0.5; p = 0.02). The region of sensory loss and visual analog pain scale improved in the treated group (-1.5 vs -0.5; p = 0.01). Twelve of 39 VEGF versus 2 of 11 placebo patients met criterion for overall improvement. Other measures including nerve conduction potentials did not improve. There were 84 adverse events in VEGF patients, and 22 were serious; there were 51 events in placebo patients, and 2 were serious. INTERPRETATION: Intramuscular plasmid VEGF gene transfer improved diabetic neuropathic symptoms, meeting primary end-point criteria for efficacy but not affecting most secondary measures. Treatment was associated with more serious adverse events that did not reach statistical significance. These results are not conclusive but may justify further clinical study.