Hyperkinetic Movements in Patients With Disease of Motor Neurons and Their Response to Treatment With Nusinersen

Study Overview
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Brief Summary
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Hyperkinetic movement disorders in patients with diseases of motor neurons will be studied. Patients with spinal muscular atrophy (SMA) and motor neuron disease patients will be studied. Involuntary movements will be video recorded and accelerometry with electromyography (EMG) will be recorded in a subset of patients. Hyperkinetic involuntary movements studied will be tremor and minipolymyoclonus. Tremor is defined as involuntary, rhythmic, oscillatory movements of a body part, and minipolymyoclonus are intermittent and irregular movements, with amplitudes sufficient to produce visible movements of the joints. Hyperkinetic movement disorders may be of central or peripheral origin and using accelerometry with EMG may help distinguish the two mechanisms. In patients with SMA the investigators will explore the effect of Nusinersen treatment on phenomenology and amplitude of tremor and minipolymyoclonus. Aims: To explore the prevalence and phenomenology of hyperkinetic movement disorders in patients with MND and SMA and to study the underlying pathological mechanisms with the use of accelerometry and EMG. To explore the effect of Nusinersen treatment on phenomenology and amplitude of involuntary movements. Hypotheses: Based on clinical observations the investigators believe it will proven that hyperkinetic movement disorders are common in patients with disease of motor neurons. The investigators hypothesize that hyperkinetic movement disorders in MND and SMA patients are of peripheral origin, being caused by uneven graduation of contraction in the wasted muscles with large motor units being active with no sufficient previous recruitment of small units to smooth contraction of large motor units. If tremor and minipolymyoclonus in SMA are due to the activation of enlarged motor units which are caused by reinnervation of muscle fibers, the treatment with Nusinersen will increase the amplitude of tremor and minipolymyoclonus. Methods: Presence, quality, and regularity of hyperkinetic movement disorders will be defined using clinical examination, accelerometry and EMG. Hyperkinetic movements will be classified as minipolymyoclonus or tremor. In patients with SMA, the measurements will be repeated 6-12 months after initiation of treatment with Nusinersen.

Detailed Description
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Background: Minipolymyoclonus and tremor are frequently mentioned as part of the clinical picture of spinal muscular atrophy, but the precise mechanism of the occurrence of tremor and minipolymyoclonus in these patients remains unknown. In the 1970s it was suggested minipolymyoclonus and tremor are caused by reinnervation that follows denervation of muscle fibers in neuropathies. The investigators are not aware of any later or more systematic study on the frequency of minipolymyoclonus and tremor occurrence in SMA patients or its evolution during the disease course. Nusinersen, an antisense oligonucleotide, is a medicine registered for treating SMA. Nusinersen increases the production of the functional survival motor neuron protein by regulating gene expression and thus slows down or stops alpha-motor neuron degradation. MND is considered a disease of upper and lower motor neuron and movement disorders are not considered part of its typical clinical picture. Movement disorders are only reported in MND in association with extrapyramidal or cerebellar degeneration or dysfunction. Contrary to this, the investigators have encountered anecdotal evidence from a number of patients with otherwise typical MND who manifested involuntary jerks and tremor. Aims: To explore the prevalence and phenomenology of hyperkinetic movement disorders in patients with SMA and MND, to explore the effect of Nusinersen treatment on phenomenology and amplitude of tremor and minipolymyoclonus, and to elucidate the underlying pathological mechanisms by using accelerometry and EMG. Patients and inclusion/exclusion criteria: All genetically proven SMA patients who will be treated with Nusinersen and consecutive patients followed in MND outpatient clinic will be recruited. Patients with SMA type I, II, III, and IV and patients with ''clinically definite ALS'' or ''clinically probable ALS'' or ''clinically probable ALS - laboratory supported'' according to the revised El Escorial diagnostic criteria or with the diagnosis of PMA or PLS will be included. There will be no exclusion criteria. Study protocol: All patients will be clinically examined and video-recorded. SMA patients will be examined and video-recorded for the second time 6-12 months after initiation of treatment with Nusinersen. The presence, quality, and regularity of involuntary movements will be evaluated while subjects will be sitting in a chair with hands resting in their lap (usual posture when examining rest tremor), during forward horizontal reach posture, and during finger to nose task. Based on regularity and distribution, hyperkinetic movements will be classified as minipolymyoclonus (MPMC) or tremor. Accelerometry with EMG will be recorded in a subset of patients with hyperkinetic movements. Methods: Accelerometry with electromyography: With accelerometry tremor (frequency and amplitude) in the subjects will be objectively evaluated. A triaxle accelerometer will be attached to the 3rd metacarpal bone bilaterally. Simultaneously EMG will be recorded. Bipolar Ag / AgCl surface EMG electrodes will be placed over the flexor carpi radialis and the extensor carpi radialis muscle bilaterally. Electromyography and accelerometry will be recorded while subjects will be sitting in an armchair/wheelchair or lying in a hospital bed (a) at rest position (b) with arms outstretched (postural condition) (c) at the postural condition with 500 g mass attached to the hand (weight loading) and (d) while performing a goal-directed task (action). Statistical analysis: Clinical measures before and after Nusinersen treatment will be compared using two-related-samples T-test or repeated-measures ANOVA. To assess possible causative mechanisms (disease factors) that determine the presence of involuntary movements, separate multilevel binary logistic analyses will be performed.

Official Title
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Hyperkinetic Movements in Patients With Motor Neuron Disease and in Patients With Spinal Muscular Atrophy and Their Response to Treatment With Nusinersen

Conditions
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Tremor, SMA, Involuntary Movements, MND (Motor Neurone DIsease)

Intervention / Treatment
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* Drug: Nusinersen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Genetically proven SMA patients treated with Nusinersen ''clinically definite ALS'' or ''clinically probable ALS'' or ''clinically probable ALS - laboratory supported'' according to the revised El Escorial diagnostic criteria or diagnosis of PMA or PLS Exclusion Criteria: No.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| MND patients<br>Patients with ''clinically definite ALS'' or ''clinically probable ALS'' or ''clinically probable ALS - laboratory supported'' according to the revised El Escorial diagnostic criteria or with the diagnosis of PMA or PLS will be included. | |
| SMA patients<br>SMA patients type I, II, III, and IV will be included. | Drug: Nusinersen<br>* Patients with SMA who will be treated with nusinersen will be included.<br>* Other names: Spinraza;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevalence of involuntary movements in patients with SMA before starting treatment with nusinersen | All patients will be clinically examined and video-recorded before starting treatment with nusinersen. The presence of involuntary movements will be evaluated as present or not present while subjects will be sitting in a chair with hands resting in their lap (usual posture when examining rest tremor), during forward horizontal reach posture and during finger to nose task. | Baseline (before starting nusinersen treatment) | 
| The effect of nusinersen on the prevalence of involuntary movements in patients with SMA | All patients will be clinically examined and video-recorded 6-12 months after starting treatment with nusinersen. The presence of involuntary movements will be evaluated as present or not present while subjects will be sitting in a chair with hands resting in their lap (usual posture when examining rest tremor), during forward horizontal reach posture and during finger to nose task. | 6-12 months after starting nusinersen | 
| Characteristics of involuntary movements in patients with SMA before starting treatment with nusinersen | The quality and regularity of involuntary movements will be evaluated in the standard positons before starting treatment with nusinersen. Based on regularity and distribution, movements observed will be classified as minipolymyoclonus or tremor. | Baseline (before starting nusinersen treatment) | 
| The effect of nusinersen on the characteristics of involuntary movements in patients with SMA | The quality and regularity of involuntary movements will be evaluated in the standard positons 6-12 moths after starting treatment with nusinersen. Based on regularity and distribution, movements observed will be classified as minipolymyoclonus or tremor. | 6-12 months after starting nusinersen | 
| Amplitude of involuntary movements in patients with SMA before starting treatment with nusinersen | The quality and regularity of involuntary movements will be evaluated in the standard positons before starting treatment with nusinersen. Accelerometry with EMG will be recorded in all patients with hyperkinetic movements. Amplitude of involuntary movements will be graded on a scale from 0 to 3. | Baseline (before starting nusinersen treatment) | 
| The effect of nusinersen on the amplitude of involuntary movements in patients with SMA | The quality and regularity of involuntary movements will be evaluated in the standard positons 6-12 moths after starting treatment with nusinersen. Accelerometry with EMG will be recorded in all patients with hyperkinetic movements. Amplitude of involuntary movements will be graded on a scale from 0 to 3. | 6-12 months after starting nusinersen | 
| Prevalence of involuntary movements in patients with MND | Patients will be clinically examined by movement disorders experts and video-recorded. The presence of involuntary movements will be evaluated while subjects will be sitting in a chair with hands resting in their lap (usual posture when examining rest tremor), during forward horizontal reach posture and during finger to nose task. | Day 1 | 
| Characteristics of involuntary movements in patients with MND | The quality and regularity of involuntary movements will be evaluated while subjects will be sitting in a chair with hands resting in their lap (usual posture when examining rest tremor), during forward horizontal reach posture and during finger to nose task. Based on regularity and distribution, hyperkinetic movements will be classified as minipolymyoclonus or tremor. | Day 1 | 
| Amplitude of involuntary movements in patients with MND | In 10 patients accelerometry with electromyography will be recorded at standard positions. | Day 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tremor, Minipolymyoclonus, Nusinersen, SMA, MND, ALS