Altered action potential waveform and shorter axonal initial segment in hiPSC-derived motor neurons with mutations in VRK1.

We recently described new pathogenic variants in VRK1, in patients affected with distal Hereditary Motor Neuropathy associated with upper motor neurons signs. Specifically, we provided evidences that hiPSC-derived Motor Neurons (hiPSC-MN) from these patients display Cajal Bodies (CBs) disassembly and defects in neurite outgrowth and branching. We here focused on the Axonal Initial Segment (AIS) and the related firing properties of hiPSC-MNs from these patients. We found that the patient's Action Potential (AP) was smaller in amplitude, larger in duration, and displayed a more depolarized threshold while the firing patterns were not altered. These alterations were accompanied by a decrease in the AIS length measured in patients' hiPSC-MNs. These data indicate that mutations in VRK1 impact the AP waveform and the AIS organization in MNs and may ultimately lead to the related motor neuron disease.

Electromyographic findings in primary lateral sclerosis during disease progression.

OBJECTIVE: To characterize electromyographic (EMG) findings in patients with primary lateral sclerosis (PLS) during the disease course. METHODS: In PLS patients we scored spontaneous activity and motor unit action potential (MUP) pattern on EMG. We compared patients according to lower (group A) and higher (group B) EMG scores. EMG studies were repeated at intervals longer than 11 months; two or three repeat studies were required for inclusion in the analysis. RESULTS: We studied 22 patients. Fasciculation potentials were found in 13 and fibrillations/positive sharp waves (fibs/sw) in 3 patients. Both were stable over time. Most patients had MUP abnormalities (n = 17), with worsening in the lower limbs in patients with three evaluations (p = 0.010). Compared to group A (n = 12), patients of group B (n = 10) had a significant shorter disease duration (median 10.9 vs 15.2 years, p < 0.001), lower functional score at both first (39 vs 45, p = 0.034) and last (29 vs 38, p = 0.003) evaluations, and had a faster functional decline (0.19 vs 0.08, p = 0.004). CONCLUSIONS: Most PLS patients showed minor and stable EMG abnormalities, without progression to ALS. Patients with more EMG abnormalities have a faster progression. SIGNIFICANCE: EMG abnormalities in most PLS patients are minor and stable.

Bradykinesia in motoneuron diseases.

OBJECTIVE: Only few studies investigated voluntary movement abnormalities in patients with motoneuron diseases (MNDs) or their neurophysiological correlates. We aimed to kinematically assess finger tapping abnormalities in patients with amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS), as compared to healthy controls (HCs), and their relationship with motoneuron involvement. METHODS: Fourteen ALS and 5 PLS patients were enrolled. Finger tapping was assessed by a motion analysis system. Patients underwent a central motor conduction time assessment, a motor nerve conduction study, and needle electromyography. Data were compared to those of 79 HCs using non-parametric tests. Possible relationships between clinical, kinematic, and neurophysiological data were assessed in patients. RESULTS: As a major finding, ALS and PLS patients performed finger tapping slower than HCs. In both conditions, movement slowness correlated with muscle strength. In ALS, movement slowness also correlated with the amplitude of the compound muscle action potential recorded from the muscles involved in the task and with denervation activity. No correlations were found between slowness, measures of upper motoneuron involvement, and other clinical and neurophysiological data. CONCLUSIONS: This study provides novel information on voluntary movement abnormalities in MNDs. SIGNIFICANCE: The results highlight the pathophysiological role of motoneurons in generating movement slowness.

Assessing the upper motor neuron in amyotrophic lateral sclerosis using the triple stimulation technique: A multicenter prospective study.

OBJECTIVE: To evaluate the relevance of transcranial magnetic stimulation (TMS) using triple stimulation technique (TST) to assess corticospinal function in amyotrophic lateral sclerosis (ALS) in a large-scale multicenter study. METHODS: Six ALS centers performed TST and conventional TMS in upper limbs in 98 ALS patients during their first visit to the center. Clinical evaluation of patients included the revised ALS Functional Rating Scale (ALSFRS-R) and upper motor neuron (UMN) score. RESULTS: TST amplitude ratio was decreased in 62% of patients whereas conventional TMS amplitude ratio was decreased in 25% of patients and central motor conduction time was increased in 16% of patients. TST amplitude ratio was correlated with ALSFRS-R and UMN score. TST amplitude ratio results were not different between the centers. CONCLUSIONS: TST is a TMS technique applicable in daily clinical practice in ALS centers for the detection of UMN dysfunction, more sensitive than conventional TMS and related to the clinical condition of the patients. SIGNIFICANCE: This multicenter study shows that TST can be a routine clinical tool to evaluate UMN dysfunction at the diagnostic assessment of ALS patients.

Impact of Upper Extremity Impairment and Trunk Control on Self-Care Independence in Children With Upper Motor Neuron Lesions.

OBJECTIVE: The purpose of this study was to evaluate the relative importance of different approaches to measure upper extremity selective voluntary motor control (SVMC), spasticity, strength, and trunk control for explaining self-care independence in children affected by upper motor neuron lesions. METHODS: Thirty-one patients (mean [SD] age = 12.5 [3.2] years) with mild to moderate arm function impairments participated in this observational study. Self-care independence was evaluated with the Functional Independence Measure for children (WeeFIM). Upper extremity SVMC was quantified with the Selective Control of the Upper Extremity Scale (SCUES), a similarity index (SISCUES) calculated from simultaneously recorded surface electromyography muscle activity patterns, and an accuracy and involuntary movement score derived from an inertial-measurement-unit-based assessgame. The Trunk Control Measurement Scale was applied and upper extremity spasticity (Modified Ashworth Scale) and strength (dynamometry) were assessed. To determine the relative importance of these factors for self-care independence, 3 regression models were created: 1 included only upper extremity SVMC measures, 1 included upper extremity and trunk SVMC measures (overall SVMC model), and 1 included all measures (final self-care model). RESULTS: In the upper extremity SVMC model (total variance explained 52.5%), the assessgame (30.7%) and SCUES (16.5%) were more important than the SISCUES (4.5%). In the overall SVMC model (75.0%), trunk SVMC (39.0%) was followed by the assessgame (21.1%), SCUES (11.0%), and SISCUES (4.5%). In the final self-care model (82.1%), trunk control explained 43.2%, upper extremity SVMC explained 23.1%, spasticity explained 12.3%, and strength explained 2.3%. CONCLUSION: Although upper extremity SVMC explains a substantial portion of self-care independence, overall trunk control was even more important. Whether training trunk control and SVMC can translate to improved self-care independence should be the subject of future research. IMPACT: This study highlights the importance of trunk control and selective voluntary motor control for self-care independence in children with upper motor neuron lesions.

Combining structural and metabolic markers in a quantitative MRI study of motor neuron diseases.

OBJECTIVE: To assess the performance of a combination of three quantitative MRI markers (iron deposition, basal neuronal metabolism, and regional atrophy) for differential diagnosis between amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS). METHODS: In total, 33 ALS, 12 PLS, and 28 healthy control (HC) subjects underwent a 3T MRI study including single- and multi-echo sequences for gray matter (GM) volumetry and quantitative susceptibility mapping (QSM) and a pseudo-continuous arterial spin labeling (ASL) sequence for cerebral blood flow (CBF) measurement. Mean values of QSM, CBF, and GM volumes were extracted in the motor cortex, basal ganglia, thalamus, amygdala, and hippocampus. A generalized linear model was applied to the three measures to binary discriminate between groups. The diagnostic performances were evaluated via receiver operating characteristic analyses. RESULTS: A significant discrimination was obtained: between ALS and HCs in the left and right motor cortex, where QSM increases were respectively associated with disability scores and disease duration; between PLS and ALS in the left motor cortex, where PLS patients resulted significantly more atrophic; between ALS and HC in the right motor cortex, where GM volumes were associated with upper motor neuron scores. Significant discrimination between ALS and HC was achieved in subcortical structures only combining all three parameters. INTERPRETATION: While increased QSM values in the motor cortex of ALS patients is a consolidated finding, combining QSM, CBF, and GM volumetry shows higher diagnostic potential for differentiating ALS patients from HC subjects and, in the motor cortex, between ALS and PLS.

Macrophage roles in peripheral nervous system injury and pathology: Allies in neuromuscular junction recovery.

Peripheral nerve injuries remain challenging to treat despite extensive research on reparative processes at the injury site. Recent studies have emphasized the importance of immune cells, particularly macrophages, in recovery from nerve injury. Macrophage plasticity enables numerous functions at the injury site. At early time points, macrophages perform inflammatory functions, but at later time points, they adopt pro-regenerative phenotypes to support nerve regeneration. Research has largely been limited, however, to the injury site. The neuromuscular junction (NMJ), the synapse between the nerve terminal and end target muscle, has received comparatively less attention, despite the importance of NMJ reinnervation for motor recovery. Macrophages are present at the NMJ following nerve injury. Moreover, in denervating diseases, such as amyotrophic lateral sclerosis (ALS), macrophages may also play beneficial roles at the NMJ. Evidence of positive macrophages roles at the injury site after peripheral nerve injury and at the NMJ in denervating pathologies suggest that macrophages may promote NMJ reinnervation. In this review, we discuss the intersection of nerve injury and immunity, with a focus on macrophages.

Long non-coding RNAs in motor neuron development and disease.

Long non-coding RNAs (lncRNAs) are RNAs that exceed 200 nucleotides in length and that are not translated into proteins. Thousands of lncRNAs have been identified with functions in processes such as transcription and translation regulation, RNA processing, and RNA and protein sponging. LncRNAs show prominent expression in the nervous system and have been implicated in neural development, function and disease. Recent work has begun to report on the expression and roles of lncRNAs in motor neurons (MNs). The cell bodies of MNs are located in cortex, brainstem or spinal cord and their axons project into the brainstem, spinal cord or towards peripheral muscles, thereby controlling important functions such as movement, breathing and swallowing. Degeneration of MNs is a pathological hallmark of diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy. LncRNAs influence several aspects of MN development and disruptions in these lncRNA-mediated effects are proposed to contribute to the pathogenic mechanisms underlying MN diseases (MNDs). Accumulating evidence suggests that lncRNAs may comprise valuable therapeutic targets for different MNDs. In this review, we discuss the role of lncRNAs (including circular RNAs [circRNAs]) in the development of MNs, discuss how lncRNAs may contribute to MNDs and provide directions for future research.

Pyramidal weakness: Is it time to retire the term?

Pyramidal weakness, that is, the weakness that preferentially spares the antigravity muscles, is considered an integral part of the upper motor neuron syndrome. Despite its name, pyramidal weakness has very little to do with the pyramidal tract, and preeminent texts on neurology, neuroanatomy, and clinical examination differ considerably in their descriptions and localization of this enigmatic finding. Evidence from human and nonhuman primate studies demonstrates that lesions confined only to the corticospinal (pyramidal) tract cause significant deficits in fine motor control of the hand, but do not cause posturing or patterned weakness of the extremities. Lesioning of the corticofugal fibers, particularly the corticoreticular and corticopontine tracts, leads to dysbalanced output from reticulospinal, and vestibulospinal systems, which along with changes in rubrospinal tract output balance, probably accounts for the pyramidal weakness pattern. Importantly, this would delineate that pyramidal weakness could only be incited by lesions above the brainstem. It has also been suggested that the inherently greater strength of the antigravity musculature is the substrate for pyramidal weakness, independent of any preferential motor innervation. These hypotheses require further testing in myometric studies with carefully selected participants.

Sensitivity and specificity of single and combined clouds analyses compared with quantitative motor unit potential analysis.

INTRODUCTION: Turns-amplitude, number of small segments (NSS)-activity, and envelope-activity clouds are three methods of electromyography (EMG) interference pattern analysis. Our objective was to evaluate the sensitivity and specificity of each individual cloud analysis and combined clouds analysis to compare with that of quantitative motor unit potential (QMUP) analysis. METHODS: A total of 379 muscles from 100 patients were analyzed by both QMUP and clouds analyses. Calculation of sensitivity and specificity was based on the clinical diagnosis as the "gold standard." RESULTS: For discrimination of abnormal vs normal and neuropathic vs non-neuropathic, combined clouds analysis had greater sensitivity than QMUP analysis and any single cloud analysis, but there were no differences in specificity. For discrimination of myopathic vs non-myopathic, combined clouds analysis and single cloud analysis had greater sensitivity than QMUP analysis, but there were no differences in specificity. DISCUSSION: Combined clouds analysis was superior to QMUP and each single cloud analysis for distinguishing normal, myopathic, and neuropathic muscles.

Exploring the use of educational materials for increasing participation in a stretching program: a quality improvement project in people with motor neuron disease.

BACKGROUND: Decreased range of motion is a common secondary complication of motor neuron disease (MND) that can contribute to functional decline and decreased participation in daily activities. AIM: The purpose of this study was to develop and assess the effectiveness of educational brochures and videos aimed at improving knowledge regarding the importance of a regular stretching program. DESIGN: This was a quality improvement (QI) project. SETTING: Participants were seen in an outpatient multidisciplinary neuromuscular clinic. POPULATION: Individuals with motor neuron disease were invited to participate in this QI study. METHODS: Individuals were asked to complete surveys asking questions regarding current stretching program, pain levels, and knowledge of benefits of stretching before and after receiving the stretching brochures or videos. RESULTS: A total of 53 participants completed the pre-intervention survey, 28 in the brochure group and 25 in the video group. Of those, 86% and 88% completed the post-intervention survey in the brochure and video groups, respectively. The video group increased stretching frequency significantly more than the brochure group (2.04 and 0.62 days/week respectively, P=0.004). Significantly more participants in the video group reported usage of stretches from the educational materials on a regular basis (54% for brochure group and 86% for video group, P=0.024). CONCLUSIONS: Educational brochures and videos are two different strategies to improve knowledge of benefits of stretching for individuals with MND. Both groups increased frequency of stretching. Videos may be better able to improve frequency of stretching when compared to brochures. CLINICAL REHABILITATION IMPACT: The brochures and videos developed for this study can be used by clinicians treating individuals with MND. By improving knowledge regarding the benefits of stretching, individuals with MND may choose to prioritize stretching as a part of their routine. This in turn may help to prevent or address potential joint or muscle length issues or assist patients to incorporate preventative measures into their treatment plans.

A Structured Approach to the Diagnosis of Peripheral Nervous System Disorders.

PURPOSE OF REVIEW: Neuroanatomic localization and pattern recognition can be used to diagnose both focal lesions and generalized disorders of the peripheral nervous system. This article describes the nature and pattern of sensory and motor deficits associated with lesions of specific spinal nerve roots, plexus, or peripheral nerves. It also describes the patterns of sensory and motor deficits that suggest multifocal or generalized disorders of the motor neurons, sensory neurons, and peripheral nerves. RECENT FINDINGS: The pattern of sensory and motor deficits may be used to distinguish lesions of the peripheral nervous system from those of the central nervous system. The spinal roots, nerve plexus, and peripheral nerves supply specific muscles and receive sensory input from distinctive cutaneous regions. Focal lesions of these structures therefore produce characteristic patterns of sensory and motor deficits. Multifocal or generalized disorders of the peripheral nervous system may be distinguished by categorizing their sensory and motor involvement, proximal and distal predominance, and degree of symmetry. Serum tests, CSF analysis, electrodiagnostic studies, MRI, ultrasound, nerve biopsy, and skin biopsy have unique roles in the diagnosis of suspected neuromuscular disorders. SUMMARY: A structured approach to the diagnosis of nerve and motor neuron disorders can lead to hypothesis-driven diagnostic testing. Ancillary tests should be reserved for cases in which confirming or refuting a diagnosis will change patient management.

Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases.

PURPOSE OF REVIEW: This article reviews the clinical features, diagnostic approach, and treatments available for amyotrophic lateral sclerosis (ALS) and other motor neuron diseases. The article also provides an update on the genetics and pathophysiology of ALS. RECENT FINDINGS: ALS remains a clinical diagnosis without a unique biomarker. The areas of greatest progress include a large expansion in the number of genes associated with familial and sporadic ALS. The discovery of these genes, along with other work, has provided a deeper understanding of the mechanisms of motor neuron failure in ALS. Areas of particular interest include the role of transactive response DNA-binding protein 43 and other RNA-processing proteins in the development of disease. SUMMARY: ALS remains a relentlessly progressive disorder with an elusive core pathophysiology. The current mainstay of treatment remains symptom management and palliation, particularly in the setting of a multidisciplinary clinic. The future holds potential for targeted therapies based on an ever-evolving understanding of the pathophysiology of both familial and sporadic ALS.

Clinical outcomes in multifocal motor neuropathy: A combined cross-sectional and follow-up study.

OBJECTIVE: To assess the clinical course of multifocal motor neuropathy (MMN) in a large cohort of patients and to identify predictive factors of a progressive disease course. METHODS: Between May 2015 and February 2016, we collected clinical data from 100 patients with MMN, of whom 60 had participated in a nationwide cross-sectional cohort study in 2007. We documented clinical characteristics using standardized questionnaires and performed a standardized neurologic examination. We used multiple linear regression analysis to identify factors that correlated with worse outcome. RESULTS: We found that age at diagnosis (45.2 vs 48.6 years, p < 0.02) was significantly increased between 2007 and 2015-2016, whereas diagnostic delay decreased by 15 months. Seven out of 10 outcome measures deteriorated over time (all p < 0.01). Patients who had a lower Medical Research Council (MRC) sumscore and absence of 1 or more reflexes at the baseline visit showed a greater functional loss at follow-up (p = 0.007 and p = 0.016). CONCLUSIONS: Our study shows that MMN is a progressive disease. Although 87% of patients received maintenance treatment, muscle strength, reflexes, vibration sense, and the Self-Evaluation Scale score significantly deteriorated over time. Lower MRC sumscore and absence of reflexes predicted a more progressive disease course. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that lower MRC sumscore and the absence of reflexes predict a more progressive disease course in patients with MMN.

Therapeutic Interventions to Improve Mobility with Spinal Cord Injury Related Upper Motor Neuron Syndromes.

Mobility is essential for quality of life and social participation. Some individuals with spinal cord injury have sufficient residual lower extremity motor control to walk. Improving walking function incorporates practice and training, and assistive devices or stimulation to augment function and balance. Overground robotic exoskeletons may have the potential to transform upright mobility in the future. Most individuals with spinal cord injury use a wheelchair for at least some of their mobility needs. Wheelchair skills training can open up new possibilities for participation. Regardless of the means of mobility, developing habits that protect joint health are essential for optimal lifelong mobility.

Validity and reliability of an accelerometer-based assessgame to quantify upper limb selective voluntary motor control.

INTRODUCTION: Current clinical assessments measure selective voluntary motor control (SVMC) on an ordinal scale. We introduce a playful, interval-scaled method to assess SVMC in children with brain lesions and evaluate its validity and reliability. METHODS: Thirty-one neurologically intact children (median [1st-3rd quartile]: 11.6 years [8.5-13.9]) and 33 patients (12.2 years [8.8-14.9]) affected by upper motor neuron lesions with mild to moderate impairments participated. Using accelerometers, they played a movement tracking game (assessgame) with isolated joint movements (shoulder, elbow, lower arm [pro-/supination], wrist, and fingers), yielding an accuracy score. Involuntary movements were recorded simultaneously and resulted in an involuntary movement score. Both scores were normalized to the performance of 33 neurologically intact adults (32.5 years [27.9; 38.3]), which represented physiological movement patterns. We correlated the assessgame outcomes with the Manual Ability Classification System, Selective Control of the Upper Extremity Scale, and a therapist rating of involuntary movements. Furthermore, a robust ANCOVA was performed with age as covariate, comparing patients to their healthy peers at the age levels of 7.5, 9, 10.5, 12, and 15 years. Intraclass correlation coefficients and smallest real differences indicated relative and absolute reliability. RESULTS: Correlations (Kendall/Spearman) for the accuracy score were τ = 0.29 (p = 0.035; Manual Ability Classification System), ρ = - 0.37 (p = 0.035; Selective Control of the Upper Extremity Scale), and ρ = 0.64 (p < 0.001; therapist rating). Correlations for the involuntary movement metric were τ = 0.37 (p = 0.008), ρ = - 0.55 (p = 0.001), and ρ = 0.79 (p < 0.001), respectively. The robust ANCOVAs revealed that patients performed significantly poorer than their healthy peers in both outcomes and at all age levels except for the dominant/less affected arm, where the youngest age group did not differ significantly. Robust intraclass correlation coefficients and smallest real differences were 0.80 and 1.02 (46% of median patient score) for the accuracy and 0.92 and 2.55 (58%) for involuntary movements, respectively. CONCLUSION: While this novel assessgame is valid, the reliability might need to be improved. Further studies are needed to determine whether the assessgame is sensitive enough to detect changes in SVMC after a surgical or therapeutic intervention.

Rotator drift: A sign of upper motor neuron leg weakness.

OBJECTIVE: There are techniques for eliciting subtle arm weakness (pronator drift), but the accompanying abnormal reflex response (Hoffmann's sign) is of limited value; conversely, in the leg there are no techniques for eliciting subtle weakness equivalent to pronator drift, but there is a robust abnormal reflex response (Babinski's sign). Thus, there is a need to devise a simple and rapid technique for detecting leg weakness capable of being used in either cooperative or comatose patients. PATIENTS AND METHODS: Using three patient groups (discovery set, training set, test set) a technique for detecting upper motor neuron (UMN) lesion leg weakness was devised. RESULTS: With the patient supine, the examiner grasps both big toes, pointing them towards the ceiling with the long axis of the foot perpendicular to the bed; the patient is asked to maintain this position for 30 s. People with pyramidal tract weakness show external rotator drift on their weak side: on the normal side the foot is deviated 20-25° from the perpendicular, on the paretic side the foot is deviated more than 30°. CONCLUSION: This rotator drift sign is a simple method for detecting subtle UMN leg weakness. When combined with the pronator drift sign, these two signs constitute "pyramidal drift" signs for the bedside detection of UMN hemiparetic weakness.