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