José Manuel Matamala

Differentiating lower motor neuron syndromes

Lower motor neuron (LMN) syndromes typically present with muscle wasting and weakness and may arise from pathology affecting the distal motor nerve up to the level of the anterior horn cell. A variety of hereditary causes are recognised, including spinal muscular atrophy, distal hereditary motor neuropathy and LMN variants of familial motor neuron disease. Recent genetic advances have resulted in the identification of a variety of disease-causing mutations. Immune-mediated disorders, including multifocal motor neuropathy and variants of chronic inflammatory demyelinating polyneuropathy, account for a proportion of LMN presentations and are important to recognise, as effective treatments are available. The present review will outline the spectrum of LMN syndromes that may develop in adulthood and provide a framework for the clinician assessing a patient presenting with predominantly LMN features.

Detection of fasciculations in amyotrophic lateral sclerosis: The optimal ultrasound scan time.

This study seeks to elucidate the optimal scan time to detect fasciculations by using ultrasound in the diagnosis of amyotrophic lateral sclerosis (ALS).

Cortical function and corticomotoneuronal adaptation in monomelic amyotrophy

OBJECTIVE To evaluate corticomotoneuronal integrity in monomelic amyotrophy using threshold tracking transcranial magnetic stimulation (TT-TMS). METHODS Cortical excitability studies were prospectively performed in 8 monomelic amyotrophy patients and compared to 21 early-onset amyotrophic lateral sclerosis (ALS) patients and 40 healthy controls. Motor evoked potentials responses were recorded over abductor pollicis brevis. RESULTS Maximal motor evoked potential (MEP/CMAP ratio) was significantly increased in monomelic amyotrophy compared with controls (monomelic amyotrophy 51.2±12.4%; control 22.7±2.1%, p=0.04). Averaged short-interval intracortical inhibition (SICI, ISI 1-7ms) in monomelic amyotrophy patients was similar to controls (monomelic amyotrophy 9.6±2.1%; control 10.0±0.9%, p=0.98). However, it was significantly reduced in early-onset ALS in comparison with monomelic amyotrophy patients (monomelic amyotrophy 9.6±2.1%; ALS 2.3±1.7%, p<0.001). Averaged SICI is a good parameter (area under the curve 0.79, p=0.02) to discriminate between monomelic amyotrophy and early-onset ALS patients. CONCLUSIONS TT-TMS technique has identified normal cortical function in monomelic amyotrophy, a feature that distinguishes it from early-onset ALS. The greater corticomotoneuronal projections to spinal motoneurons may represent central nervous system adaptive change in monomelic amyotrophy. SIGNIFICANCE Corticomotoneuronal dysfunction does not drive the lower motor neurone loss presented in monomelic amyotrophy.

Quantitative muscle ultrasound as a biomarker in Charcot-Marie-Tooth neuropathy

OBJECTIVE The utility of quantitative muscle ultrasound as a marker of disease severity in Charcot-Marie-Tooth (CMT) disease subtypes was investigated. METHODS Muscle ultrasound was prospectively performed on 252 individual muscles from 21 CMT patients (9 CMT1A, 8 CMTX1, 4 CMT2A) and compared to 120 muscles from 10 age and gender-matched controls. Muscle ultrasound recorded echogenicity and thickness in representative muscles including first dorsal interosseus (FDI) and tibialis anterior (TA). RESULTS Muscle volume of FDI and thickness of TA correlated with MRC strength. Muscle echogenicity was significantly increased in FDI (65.05 vs 47.09; p<0.0001) and TA (89.45 vs 66.30; p<0.0001) of CMT patients. In TA, there was significantly higher muscle thickness (23 vs 18 vs 16mm; p<0.0001) and lower muscle echogenicity (80 vs 95 vs 108; p<0.0001) in CMT1A compared to CMTX1 and CMT2A. This corresponded to disease severity based on muscle strength (MRC grading CMT1A vs CMTX1 vs CMT2A: 59 vs 48 vs 44; p=0.002). CONCLUSION In CMT, quantitative muscle ultrasound of FDI and TA is a useful marker of disease severity. SIGNIFICANCE The current findings suggest that quantitative muscle ultrasound has potential as a surrogate marker of disease progression in future interventional trials in CMT.

Dynamic muscle ultrasound identifies upper motor neuron involvement in amyotrophic lateral sclerosis

Abstract Objective: The aim of the present study was to elucidate the pattern of change in bulbar muscles using ultrasound in patients diagnosed with amyotrophic lateral sclerosis (ALS). Methods: Changes in the mylohyoid and geniohyoid muscle complex (mylohyoid-geniohyoid-muscle-complex) thickness were recorded while swallowing 5 ml of water using M-mode ultrasound in 30 ALS patients compared to 20 healthy controls. The ratio of mylohyoid-geniohyoid-muscle-complex thickness as determined by the maximum thickness of mylohyoid-geniohyoid-muscle-complex during swallowing divided by thickness at rest, was compared between ALS patients and controls, with the correlation between thickness ratio, echogenicity and clinical parameters assessed. Results: Overall, the thickness ratio in ALS patients was 1.39 ± 0.23 (mean ± SD) compared to 1.55 ± 0.17 in controls (p < 0.05). In sub-analysis, the thickness ratio was significantly decreased in ALS patients with bulbar-onset disease compared to those with limb-onset disease (p < 0.01) and controls (p < 0.01). Thickness ratio negatively correlated with the severity of upper motor neuron involvement in the bulbar region (p < 0.05). Conclusions: Bulbar muscle ultrasound represents a novel method to detect impaired mobility and thereby provides an objective assessment of upper motor neuron involvement in the bulbar region of ALS patients.

Inter-session reliability of short-interval intracortical inhibition measured by threshold tracking TMS

Paired-pulse transcranial magnetic stimulation (TMS) using fixed test stimuli suffers from marked variability of the motor evoked potential (MEP) amplitude. Threshold tracking TMS (TT-TMS) was introduced to overcome this problem. The aim of this work was to describe the absolute and relative reliability of short-interval intracortical inhibition (SICI) using TT-TMS. Cortical excitability studies were performed on twenty-six healthy subjects over three sessions (two recordings on the same day and one seven days apart), with MEPs recorded over abductor pollicis brevis. Reliability was established by calculating the standard error of the measurements (SEm), minimal detectable change (MDC) and intraclass correlation coefficient (ICC). Resting motor threshold and averaged SICI presented the lowest SEm and highest ICCs. SICI at 1 ms showed a higher SEm than SICI at 3 ms, suggesting different physiological processes, but averaging SICI over a number of intervals greatly increases the reproducibility. The variability was lower for tests undertaken at the same time of day seven days apart compared to tests performed on the same day, and in both instances the ICC for averaged SICI was ≥0.81. The MDC in averaged SICI was reduced from 6.7% to 2% if the number of subjects was increased from one to eleven. In conclusion, averaged SICI is the most reproducible variable across paired-pulse TT-TMS measures, showing an excellent ICC. It is recommended that, in longitudinal studies, testing be performed at the same time of day and that changes in cortical excitability should be measured and averaged over a number of interstimulus intervals to minimise variability.

Laterality of motor cortical function measured by transcranial magnetic stimulation threshold tracking.

Introduction: Threshold tracking paired‐pulse transcranial magnetic stimulation (TTTMS) examines cortical function and is useful for diagnosis of motor neuron disorders. Differences in cortical function have been identified between dominant and non‐dominant limbs using constant stimulus methods, but they remain unclear, potentially due to methodological differences. In this study we aimed to clarify differences in cortical function between dominant and non‐dominant limbs using TTTMS. Methods: Single‐pulse TMS, TTTMS, and nerve conduction studies were performed in 25 healthy, right‐handed participants by recording from the abductor pollicis brevis muscle. Results: There were no side‐to‐side differences observed in resting motor threshold, motor evoked potential (MEP) amplitude, MEP latency, central motor conduction time, cortical silent period, short‐interval intracortical inhibition and facilitation, compound muscle action potential (CMAP) amplitude, CMAP latency, F‐wave latency, or neurophysiological index. Conclusions: These findings suggest that, when using TTTMS, there are no differences in cortical function between dominant and non‐dominant hemispheres. Muscle Nerve 55: 424–427, 2017

Prognostic factors in C9orf72 amyotrophic lateral sclerosis

The discovery of the C9orf72 hexanucleotide repeat expansion heralded significant advancement in the understanding of amyotrophic lateral sclerosis (ALS).1 ,2 Critically, the C9orf72 mutation represents the most common genetic cause of ALS (up to 50% of familial and 20% of sporadic ALS), responsible for the majority of motor and cognitive manifestations across the ALS–frontotemporal dementia (FTD) continuum.3–5 Pathologically, the C9orf72 mutation is associated with TDP-43 protein aggregation, the hallmark of ALS cases and is also present in 50% of FTD. The exact function of the normal C9orf72 protein remains undefined; however, it seems to play a major role in cellular trafficking, specifically in neurons. The loss of function …

Treatment approaches in motor neurone disease.

PURPOSE OF REVIEW Although there is no cure for motor neurone disease (MND), the advent of multidisciplinary care and neuroprotective agents has improved treatment interventions and enhanced quality of life for MND patients and their carers. RECENT FINDINGS Evidence-based multidisciplinary care, respiratory management and disease-modifying therapy have improved the outcomes of patients diagnosed with MND. Supportive approaches to nutritional maintenance and optimization of symptomatic treatments, including management of communication and neuropsychiatric issues, improve the quality of life for MND patients. SUMMARY Recent progress in the understanding of the clinical, pathophysiological and genetic heterogeneity of MND has improved the approach of clinicians to treatment. Notwithstanding improvement to care and quality of life, survival benefit has become evident with the advent of a multidisciplinary care framework, early treatment with riluzole and noninvasive ventilation. Weight maintenance remains critical, with weight loss associated with more rapid disease progression. The end-of-life phase is poorly defined and treatment is challenging, but effective symptom control through palliative care is achievable and essential. Encouragingly, current progress of clinical trials continues to close the gap towards the successful development of curative treatment in MND.

T41. Ectopic impulse generation in peripheral nerve hyperexcitability syndromes and amyotrophic lateral sclerosis

OBJECTIVE To elucidate differences in the distribution and firing frequency of fasciculations between peripheral nerve hyperexcitability syndromes and amyotrophic lateral sclerosis (ALS) and to explore the generator site of fasciculations. METHODS Ultrasound of 14 preselected muscles was performed in patients with peripheral hyperexcitability and ALS. The distribution and firing frequency of fasciculations were calculated. Cortical excitability assessment was also done by threshold tracking transcranial magnetic stimulation. RESULTS In total, 518 muscles from 37 peripheral hyperexcitability patients and 756 muscles from 54 ALS patients were examined. Regarding the detection rate, 74% of muscles in ALS patients demonstrated fasciculations, compared with 34% of muscles in peripheral hyperexcitability patients (P < 0.001). The number of unique repeating focal muscle fasciculation movements per muscle and firing frequency of individual fasciculations in ALS were both significantly higher than those in peripheral hyperexcitability (P < 0.001). Furthermore, cortical silent period duration negatively correlated with the number and firing frequency of fasciculations in ALS (P < 0.05). A similar relationship was not evident in peripheral hyperexcitability. CONCLUSIONS In ALS patients, fasciculations were more widespread, greater in number and higher in firing frequency than in peripheral hyperexcitability patients. SIGNIFICANCE A significant proportion of fasciculations in ALS may be influenced by changes in central excitability.