scholarly journals Safety, Tolerability, and Effect of Nusinersen Treatment in Ambulatory Adults With 5q-SMA

2021 ◽  
Vol 12 ◽  
Author(s):  
Bakri Elsheikh ◽  
Steven Severyn ◽  
Songzhu Zhao ◽  
David Kline ◽  
Matthew Linsenmayer ◽  
...  
Keyword(s):  
Adverse Events ◽  
Motor Unit ◽  
Rating Scale ◽  
Muscular Atrophy ◽  
Compound Muscle Action Potential ◽  
Motor Unit Potential ◽  
Serious Adverse Events ◽  
Significant Treatment ◽  
Single Motor Unit ◽  
Isometric Muscle Contraction

Objective: To determine the safety and tolerability of nusinersen treatment in ambulatory adults with spinal muscular atrophy (SMA) and investigate the treatment effect on muscle strength, physical function, and motor unit physiology.Methods: Individuals aged 18 years or older with genetically confirmed 5q SMA, three or more copies of the SMN2 gene, and the ability to ambulate 30 feet were enrolled. Safety outcomes included the number of adverse events and serious adverse events, clinically significant vital sign or laboratory parameter abnormalities. Outcome assessments occurred at baseline (prior to the first dose of nusinersen) and then 2, 6, 10, and 14 months post-treatment.Results: Six women, seven men (mean age: 37 ± 11, range: 18–59 years) were included for analyses. The most common side effects were headache and back pain, but overall procedures and treatments were well-tolerated. No serious adverse events were reported. Maximal Voluntary Isometric Muscle Contraction Testing (MVICT) and 6-min walk test (6MWT) both showed overall stability with significant increases at 2, 6, and 10 months for the 6MWT. More consistent significant treatment effects were noted on the Hammersmith Functional Motor Scale Expanded, SMA-Functional Rating Scale, and forced vital capacity. Treatment resulted in progressively increased ulnar compound muscle action potential and average single motor unit potential amplitudes, but motor unit number estimation remained stable.Conclusions: Nusinersen treatment is safe and well-tolerated in ambulatory adults with SMA. Treatment resulted in improved motor function and electrophysiological findings suggest that this improvement may be occurring via improved motor unit reinnervation capacity.

scholarly journals Safety, Tolerability, and Effect of Nusinersen in Non-ambulatory Adults With Spinal Muscular Atrophy

2021 ◽  
Vol 12 ◽  
Author(s):  
Bakri Elsheikh ◽  
Steven Severyn ◽  
Songzhu Zhao ◽  
David Kline ◽  
Matthew Linsenmayer ◽  
...  
Keyword(s):  
Adverse Events ◽  
Spinal Muscular Atrophy ◽  
Motor Unit ◽  
Muscular Atrophy ◽  
Compound Muscle Action Potential ◽  
Motor Unit Potential ◽  
Single Motor Unit ◽  
Single Motor ◽  
Clinically Significant ◽  
Tract Infections

Objective: Investigation of the safety, tolerability, and treatment effect of nusinersen treatment in non-ambulatory adults with spinal muscular atrophy (SMA).Methods: Non-ambulatory individuals, aged 18 years or older with genetically confirmed 5q SMA were enrolled. In participants with spinal fusion, fluoroscopy guided cervical C1–C2 lateral approach was used. Outcomes at 2, 6, 10, and 14 months post-treatment were compared with baseline assessment. Forced vital capacity (FVC) was the primary outcome, and RULM, HFMSE, the modified SMA-FRS, and ulnar nerve electrophysiology [compound muscle action potential (CMAP), single motor unit size, and motor unit number] were secondary. Adverse and serious adverse events and clinically significant vital sign or lab abnormalities were recorded.Results: Results from 12 women and 7 men (mean age: 39.7 ± 13.9, range: 21–64 years) were analyzed. No clinically significant changes of vital signs or laboratory parameters were observed. Five participants were hospitalized for pneumonia. Other adverse events included headache, back pain, cervical injection site pain, and upper respiratory and urinary tract infections. High baseline protein/creatinine ratio without significant change on treatment noted in 4 participants. FVC was feasible in all participants. HFMSE and RULM were not feasible in the majority of participants. FVC and functional outcomes were stable without improvement. CMAP and single motor unit potential sizes showed enlargement while motor unit numbers were stable.Conclusions: Nusinersen, including C1/C2 delivery, was safe overall and well-tolerated. Several outcome measures were limited by floor effect. Overall, treatment resulted in stability of motor outcomes, but motor unit and CMAP size were increased.

scholarly journals Motor unit changes in children with symptomatic spinal muscular atrophy treated with nusinersen

2020 ◽  
Vol 92 (1) ◽  
pp. 78-85 ◽  
Author(s):  
Didu Kariyawasam ◽  
Arlene D'Silva ◽  
James Howells ◽  
Karen Herbert ◽  
Peter Geelan-Small ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Unit ◽  
Therapeutic Response ◽  
Muscular Atrophy ◽  
Compound Muscle Action Potential ◽  
Motor Unit Potential ◽  
Abductor Pollicis Brevis ◽  
Electrophysiological Response ◽  
Single Motor Unit ◽  
Motor Unit Number Estimation

ObjectivesTo elucidate the motor unit response to intrathecal nusinersen in children with symptomatic spinal muscular atrophy (SMA) using a novel motor unit number estimation technique.MethodsMScanFit MUNE studies were sequentially undertaken from the abductor pollicis brevis muscle after stimulation of the median nerve in a prospective cohort of symptomatic children with SMA, undergoing intrathecal treatment with nusinersen at a single neuromuscular centre from June 2017 to August 2019. Electrophysiological measures included compound muscle action potential (CMAP), motor unit number estimation (MUNE), motor unit number contributing to 50%–100% of CMAP (N50) and measures of collateral reinnervation including largest single motor unit potential (LSMUP) and amplitude of the smallest unit contributing to N50 (A50).ResultsTwenty children (median age 99 months, range 4–193) were followed for a median of 13.8 (4–33.5) months. Therapeutic intervention was an independent and significant contributor to an increase in CMAP (p = 0.005), MUNE (p = 0.001) and N50 (p = 0.04). The magnitude of this electrophysiological response was increased in children with shorter disease durations (p<0.05). Electrophysiological changes delineated children who were functionally stable from those who attained clinically significant gains in motor function.InterpretationNusinersen therapy facilitated functional innervation in SMA through recovery of smaller motor units. Delineation of biomechanisms of therapeutic response may be the first step in identifying potential novel targets for disease modification in this and other motor neuropathies. MScanFit MUNE techniques may have a broader role in establishing biomarkers of therapeutic response in similar adult-onset diseases.

A Controlled Trial of Extended-Release Guanfacine and Psychostimulants on Executive Function and ADHD

2018 ◽  
Vol 24 (2) ◽  
pp. 318-325 ◽  
Author(s):  
Judy P. M. van Stralen
Keyword(s):  
Executive Function ◽  
Adverse Events ◽  
Extended Release ◽  
Rating Scale ◽  
Controlled Trial ◽  
Severity Of Illness ◽  
P Value ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Stimulant Therapy

Objective: To evaluate the effectiveness of guanfacine extended-release (GXR) versus placebo as adjunct therapy to usual care stimulant therapy in improving executive function in children aged 6 to 12 years diagnosed with ADHD. Method: In this single center, double-blind placebo-controlled crossover trial, subjects continued to take their psychostimulant and were randomly assigned at baseline to receive active treatment or placebo first. Efficacy measures included Behavioural Rating Inventory of Executive Function (BRIEF-P), ADHD Rating Scale IV (ADHD-RS IV), and Clinical Global Impressions of Severity of Illness (CGI-S) and Improvement (CGI-I) scales. Safety measures included adverse events and vital signs. Results: Significant benefits of GXR plus psychostimulant were observed on BRIEF-P ( p value = .0392), ADHD-RS-IV ( p < .0001), CGI-S ( p = .0007), and CGI-I ( p = .003). There were no serious adverse events and no new safety signals. Conclusion: Use of GXR as adjunctive therapy to stimulant therapy significantly improves executive function in children with ADHD.

Combined treatment with reboxetine in depressed patients with no response to venlafaxine: a 6-week follow-up study

2007 ◽  
Vol 19 (5) ◽  
pp. 291-296 ◽  
Author(s):  
Cecilio Álamo ◽  
Francisco López-Muñoz ◽  
Gabriel Rubio ◽  
Pilar García-García ◽  
Antonio Pardo
Keyword(s):  
Adverse Events ◽  
Rating Scale ◽  
Combined Treatment ◽  
Open Label ◽  
Serious Adverse Events ◽  
Multicentric Study ◽  
Intent To Treat ◽  
Events Data ◽  
Clinical Global Impression Improvement

Objective:The purpose of present study was to evaluate the efficacy of the addition of reboxetine in patients that had not previously responded, or had done so only partially, over 6 weeks of conventional pharmacological treatment with venlafaxine.Methods:This open-label, prospective and multicentric study included 40 outpatients diagnosed with major depressive disorder according to the DSM-IV criteria. Efficacy was assessed using the 21-item Hamilton Depression Rating Scale (HAMD) and the Clinical Global Impression-Improvement (CGI-I). Safety was evaluated by recording spontaneously reported adverse events. Data were analysed on an intent-to-treat basis, using the last-observation-carried-forward method.Results:Mean HAMD reduction was 34.9% (P < 0.0001). The percentages of responders (≥50% reduction in HAMD) and patients considered as benefiting from complete remission (HAMD ≤ 10 points) at week 6 were 27.5 and 12.5%, respectively. By the end of the treatment, the score of CGI-I decreased 24.8% (P < 0.0001). Percentage of patient improving (CGI < 4 points) was 47.5%. The most common non-serious adverse events were constipation, nervousness, anxiety and insomnia.Conclusion:These findings suggest that the combined treatment of reboxetine and venlafaxine, in venlafaxine-resistant patients, may be an effective and well-tolerated strategy.

scholarly journals Application Value of the Motor Unit Number Index in Patients With Kennedy Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Shuo Zhang ◽  
Xin Yang ◽  
Yingsheng Xu ◽  
Yongmei Luo ◽  
Dongsheng Fan ◽  
...  
Keyword(s):  
Motor Unit ◽  
Rating Scale ◽  
Muscular Atrophy ◽  
Sum Score ◽  
Objective Parameter ◽  
Compound Muscle Action Potentials ◽  
Size Index ◽  
Axonal Collateral ◽  
Abductor Digiti Minimi ◽  
Sum Scores

The aim of this study was to evaluate the usefulness of the motor unit number index (MUNIX) technique in Kennedy disease (KD) and test the correlation between the MUNIX and other clinical parameters. The MUNIX values of the bilateral deltoid, abductor digiti minimi (ADM), quadriceps femoris (QF), and tibialis anterior (TA) were determined and compared with the course of the disease. The MUNIX sum score was calculated by adding the MUNIX values of these 8 muscles. Disability was evaluated using the spinal and bulbar muscular atrophy functional rating scale (SBMAFRS). The MUNIX scores of patients with KD were negatively correlated with the course of the disease (p &lt; 0.05), whereas their motor unit size index (MUSIX) scores were positively correlated with the course the of disease (p &lt; 0.05). MUNIX sum scores were correlated with SBMAFRS scores (r = 0.714, p &lt; 0.05). MUNIX was more sensitive than compound muscle action potentials or muscle strength as an indicator of neuron loss and axonal collateral reinnervation. The MUNIX sum score is an objective and a reliable indicator of disease progression, and it is a potential choice for therapeutic clinical trials. The MUNIX can assess the functional loss of motor axons and is correlated with disability. The MUNIX sum score may be especially suitable as an objective parameter.

scholarly journals Relationship of Anabolic Hormones With Motor Unit Characteristics in Quadriceps Muscle in Healthy and Frail Aging Men

2020 ◽  
Vol 105 (7) ◽  
pp. e2358-e2368 ◽  
Author(s):  
Agnieszka Swiecicka ◽  
Mathew Piasecki ◽  
Daniel Stashuk ◽  
David Jones ◽  
Frederick Wu ◽  
...  
Keyword(s):  
Motor Unit ◽  
Compound Muscle Action Potential ◽  
Free Testosterone ◽  
Quadriceps Muscle ◽  
Community Dwelling ◽  
Total Testosterone ◽  
Motor Unit Potential ◽  
Vastus Lateralis Muscle ◽  
Anabolic Hormones ◽  
Aging Men

Abstract Context Anabolic hormones are important factors in maintaining muscle mass for aging men, but their role in overall motor unit structure and function is unclear. Objective The objective of this work is to determine associations of anabolic and reproductive hormone levels with motor unit characteristics in quadriceps muscle in older healthy and frail men. Design This work is an observational cohort study of community-dwelling men. Participants Participants included healthy and frail men younger than 65 years. Intervention No intervention was performed. Outcome measure Quantitative assessments of electromyography-derived motor unit potential size (MUP) and compound muscle action potential size (CMAP) of the vastus lateralis muscle. Results We studied 98 men (mean ± SD: age 73 ± 6 years; body mass index [BMI] 25.7 ± 4.0 kg/m2; diabetes 11%) of whom 45% were prefrail and 18% frail. After adjusting for age, BMI, and prevalent diabetes, higher total and free testosterone levels were significantly related to larger CMAP (total testosterone: β [95% CI]: 0.3 [0.08-0.53]; free testosterone: 0.34 [0.13-0.56]). Exploratory analysis showed the relationship between free testosterone and CMAP was stronger in frail rather than robust men. In univariate analyses, estradiol was associated with CMAP size (0.37 [0.16-0.57]); and vitamin D was associated with MUP size (0.22 [0.01-0.43]) but these relationships were no longer significant after adjusting for potential confounders. Conclusion Our data highlight the associations between androgen levels and the electrophysiological characteristics of older men, particularly in the frail. Clinical trials involving administration of androgens will help to elucidate the potential benefits of intervention on neuromuscular function and/or frailty status.

Effects of motor unit losses on strength in older men and women

1993 ◽  
Vol 74 (2) ◽  
pp. 868-874 ◽  
Author(s):  
T. J. Doherty ◽  
A. A. Vandervoort ◽  
A. W. Taylor ◽  
W. F. Brown
Keyword(s):  
Motor Unit ◽  
Biceps Brachii ◽  
Compound Muscle Action Potential ◽  
Maximum Voluntary Contraction ◽  
Motor Units ◽  
Older Men ◽  
Single Motor Unit ◽  
Men And Women ◽  
Older Subjects ◽  
Older Men And Women

The influence of age-associated motor unit loss on contractile strength was investigated in a representative sample of healthy, active young and older men and women. In 24 younger subjects (22–38 yr) and 20 older subjects (60–81 yr) spike-triggered averaging was employed to extract a sample of surface-recorded single motor unit action potentials (S-MUAPs) from the biceps brachii and brachialis muscles. The amplitude of the maximum compound muscle action potential of the biceps brachii and brachialis muscles was divided by the mean S-MUAP amplitude to estimate the numbers of motor units present. The maximum isometric twitch contraction (MTC) and maximum voluntary contraction (MVC) of the elbow flexors were also recorded in 18 of the younger subjects and in all older subjects. The estimated numbers of motor units were significantly reduced (47%, P < 0.001) in older subjects with a mean value of 189 +/- 77 compared with a mean of 357 +/- 97 in younger subjects. The sizes of the S-MUAPs, however, were significantly larger in older subjects (23%, P < 0.01). Significant but less marked age-associated reductions in the MTC (33%, P < 0.05) and MVC (33%, P < 0.001) were also found and were similar for both men and women. These results suggest that motor unit losses, even in healthy active individuals, are a primary factor in the age-associated reductions in contractile strength.

Quantitative Motor Unit Number Estimates

2016 ◽  
pp. 361-381
Author(s):  
Eric J. Sorenson ◽  
Jasper R. Daube
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Unit ◽  
Muscular Atrophy ◽  
Compound Muscle Action Potential ◽  
Motor Units ◽  
Muscle Group ◽  
Muscle Action Potential ◽  
Mean Size ◽  
The Mean ◽  
Single Technique

Quantitative motor unit number estimates (MUNE) quantify the number of viable motor axons that innervate a muscle or muscle group. Various techniques have been developed to accomplish this, but no single technique has demonstrated superiority. The MUNE is calculated from the supramaximal compound muscle action potential (CMAP) by dividing the CMAP by the mean size of the motor unit potentials. The resulting unit-less number represents the number of motor units within a muscle or muscle group. MUNE has been applied most widely to disorders of the motor neuron such as ALS, spinal muscular atrophy, and polio, and it has been used in animal and human studies, and as an outcome measure in clinical trials for ALS and spinal muscular atrophy. Because of the limitations of MUNE (including patient discomfort, prolonged time to perform, and technical expertise for reliable results), it has not entered into routine clinical practice at this time.

scholarly journals Motor unit number estimation versus compound muscle action potential in the evaluation of motor unit loss in amyotrophic lateral sclerosis

2021 ◽  
Vol 57 (1) ◽  
Author(s):  
Arwa Khalid Ibrahem ◽  
Akram Mohammed Al-Mahdawi ◽  
Farqad Bader Hamdan
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Unit ◽  
Rating Scale ◽  
Compound Muscle Action Potential ◽  
Motor Units ◽  
Case Detection ◽  
Muscle Action ◽  
Compound Muscle Action Potentials ◽  
Rate Of Decline ◽  
Lateral Sclerosis

Abstract Introduction Motor neuron loss is the primary pathologic feature of amyotrophic lateral sclerosis (ALS). An estimate of the number of surviving motor units (MUs) represents a direct measure of the disease state in ALS. The objective of the study is to compare MU number estimation (MUNE) using the multipoint stimulation method (MPS) and compound muscle action potentials (CMAP) amplitude in patients with ALS. Methods Twenty-eight patients with ALS with a disease duration of 3–48 months were studied. Nerve conduction study of the median, ulnar, tibial, common peroneal, and sural nerves were done. Besides, electromyography (EMG) of cranio-bulbar, cervical, thoracic and lumbosacral muscles, and MPS-MUNE. Results MUNE is decreased in patients with ALS. MUNE was positively correlated with CMAP amplitude, medical research council (MRC) scale, and ALS functional rating scale (ALS-FRS). On the contrary, MUNE was negatively correlated with MUAP duration. Case detection by the MUNE methods was high as compared to that of CMAP amplitude. Conclusions MUNE is highly specific and more sensitive than CMAP amplitude in detecting the neurophysiologic abnormalities in patients with ALS. Case detection by MUNE is three times more than CMAP amplitudes. The rate of decline of motor units using the MPS-MUNE is more sensitive than the MRC score and ALSFRS-R when expressed as the percentage change from baseline.

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