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

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.

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

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2020-324254 ◽

2020 ◽

Vol 92 (1) ◽

pp. 78-85 ◽

Cited By ~ 1

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.

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

Frontiers in Neurology ◽

10.3389/fneur.2021.650535 ◽

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.

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Quantitative Motor Unit Number Estimates

Clinical Neurophysiology ◽

10.1093/med/9780190259631.003.0022 ◽

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.

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Evaluation of Metabolic Effects of Nusinersen in Patients with Spinal Muscular Atrophy

Journal of Pediatric Neurology ◽

10.1055/s-0041-1731395 ◽

2021 ◽

Author(s):

Lena-Luise Becker ◽

Claudia Weiss ◽

René Günther ◽

Andreas Hermann ◽

Manuela Theophil ◽

...

Keyword(s):

Spinal Muscular Atrophy ◽

Motor Function ◽

Muscular Atrophy ◽

Metabolic Effects ◽

Height Velocity ◽

Multicentric Study ◽

Specific Effects ◽

Altered Glucose ◽

Clinically Significant ◽

Few Data

AbstractNusinersen is the first disease-modifying therapy for spinal muscular atrophy (SMA), but there are few data on potential long-term endocrinological and metabolic systemic effects of this novel treatment as well as metabolic alterations in SMA itself. In this retrospective and multicentric study, we analyzed anthropometric, endocrinological, and motor function data of 81 pediatric and adult patients with SMA1 to 3 undergoing treatment with nusinersen. In 39 patients (51%), we observed a slight increase in body mass index (BMI) centiles under treatment with nusinersen, especially in patients with SMA2 and in pediatric patients between 3.1 and 12 years. A correlation to the SMN2 copy number or motor function was not found. Additionally, length centiles decreased significantly under treatment. The results of longitudinal endocrinological assessments were interpreted as not clinically significant in most patients; in three patients, the signs of an altered glucose metabolism were present. Our study indicates a putative effect of treatment with nusinersen on BMI, which might be due to a conjoint effect of weight gain and reduction of height velocity, without evidence of correlation to increased muscle function. Further studies need to address specific effects of targeted therapies such as nusinersen or onasemnogene abeparvovec on body composition including fat and muscle mass.

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Rectification is required to extract oscillatory envelope modulation from surface electromyographic signals

Journal of Neurophysiology ◽

10.1152/jn.00296.2014 ◽

2014 ◽

Vol 112 (7) ◽

pp. 1685-1691 ◽

Cited By ~ 19

Author(s):

Christopher J. Dakin ◽

Brian H. Dalton ◽

Billy L. Luu ◽

Jean-Sébastien Blouin

Keyword(s):

Motor Unit ◽

Stimulus Frequency ◽

Motor Units ◽

Surface Emg ◽

Medial Gastrocnemius ◽

Single Motor Unit ◽

Single Motor ◽

Single Motor Units ◽

Emg Signal ◽

Envelope Modulation

Rectification of surface electromyographic (EMG) recordings prior to their correlation with other signals is a widely used form of preprocessing. Recently this practice has come into question, elevating the subject of EMG rectification to a topic of much debate. Proponents for rectifying suggest it accentuates the EMG spike timing information, whereas opponents indicate it is unnecessary and its nonlinear distortion of data is potentially destructive. Here we examine the necessity of rectification on the extraction of muscle responses, but for the first time using a known oscillatory input to the muscle in the form of electrical vestibular stimulation. Participants were exposed to sinusoidal vestibular stimuli while surface and intramuscular EMG were recorded from the left medial gastrocnemius. We compared the unrectified and rectified surface EMG to single motor units to determine which method best identified stimulus-EMG coherence and phase at the single-motor unit level. Surface EMG modulation at the stimulus frequency was obvious in the unrectified surface EMG. However, this modulation was not identified by the fast Fourier transform, and therefore stimulus coherence with the unrectified EMG signal failed to capture this covariance. Both the rectified surface EMG and single motor units displayed significant coherence over the entire stimulus bandwidth (1–20 Hz). Furthermore, the stimulus-phase relationship for the rectified EMG and motor units shared a moderate correlation ( r = 0.56). These data indicate that rectification of surface EMG is a necessary step to extract EMG envelope modulation due to motor unit entrainment to a known stimulus.

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