José Castro

Motor Unit Number Index (MUNIX) : A novel neurophysiological marker for neuromuscular disorders; test-retest reliability in healthy volunteers

OBJECTIVEnTo investigate the intra-rater and inter-rater test-retest reliability of the Motor Unit Number Index (MUNIX) in healthy subjects in a multicentre setting.nnnMETHODSnSix study centres applied the MUNIX technique in 66 healthy subjects. Five to six muscles (biceps brachii, BB; abductor digiti minimi, ADM; abductor pollicis brevis, APB; tibialis anterior, TA; extensor digitorum brevis, EDB and abductor hallucis, AH) were measured in each volunteer four times by two independent examiners.nnnRESULTSnThe method was easy to perform and well tolerated. The intraclass correlation coefficient (ICC) varied between centres and muscles. Intra-rater reliability was greatest for the AH (ICC 0.83) and EDB (ICC 0.81). Inter-rater reliability was greatest for the AH (ICC 0.69) and ADM muscles (ICC 0.69). The most critical muscle was the APB muscle (ICC 0.52, total variability). This was mostly due to variability in the compound muscle action potential (CMAP) measurements. MUNIX values of the APB, ADM and TA fell into the same range as in other motor unit number estimation (MUNE) studies.nnnCONCLUSIONnMUNIX measurements in multiple muscles show good inter- and intra-rater reliability in healthy subjects. CMAP amplitude must be controlled to optimize reliability.nnnSIGNIFICANCEnResults suggest that MUNIX could serve as a reliable marker for motor neuron loss in diseases like amyotrophic lateral sclerosis.

Tracking motor neuron loss in a set of six muscles in amyotrophic lateral sclerosis using the Motor Unit Number Index (MUNIX): a 15-month longitudinal multicentre trial

Background Motor Unit Number Index (MUNIX) is a novel neurophysiological measure that provides an index of the number of functional lower motor neurons in a given muscle. So far its performance across centres in patients with amyotrophic lateral sclerosis (ALS) has not been investigated. Objective To perform longitudinal MUNIX recordings in a set of muscles in a multicentre setting in order to evaluate its value as a marker of disease progression. Methods Three centres applied MUNIX in 51 ALS patients over 15u2005months. Six different muscles (abductor pollicis brevis, abductor digiti minimi, biceps brachii, tibialis anterior, extensor dig. brevis, abductor hallucis) were measured every 3u2005months on the less affected side. The decline between MUNIX and ALSFRS-R was compared. Results 31 participants reached month 12. For all participants, ALSFRS-R declined at a rate of 2.3%/month. Using the total score of all muscles, MUNIX declined significantly faster by 3.2%/month (p≤0.02). MUNIX in individual muscles declined between 2.4% and 4.2%, which differed from ASLFRS-R decline starting from month 3 (p≤0.05 to 0.002). Subgroups with bulbar, lower and upper limb onset showed different decline rates of ALSFRS-R between 1.9% and 2.8%/month, while MUNIX total scores showed similar decline rates over all subgroups. Mean intraclass correlation coefficient for MUNIX intra-rater reliability was 0.89 and for inter-rater reliability 0.80. Conclusion MUNIX is a reliable electrophysiological biomarker to track lower motor neuron loss in ALS.

Motor Unit Number Index (MUNIX): reference values of five different muscles in healthy subjects from a multi-centre study.

Motor Unit Number Index (MUNIX) : Reference values of five different muscles in healthy subjects from a multi-centre study

Neurophysiological markers in familial amyloid polyneuropathy patients: Early changes

OBJECTIVEnFamilial amyloid polyneuropathy-type I (FAP-I) is a hereditary, axonal, sensory-motor and autonomic polyneuropathy, with early involvement of small fibres. Liver transplantation is the only effective therapy in FAP, but should be performed early in the course of the disease. Reliable quantitative methods that could allow the determination of early changes in the peripheral nerve function are essential. Our aim was to find sensitive neurophysiological markers in FAP-I.nnnMETHODSnEighty-one FAP-I patients were included in this study. They were divided into two groups (G1, asymptomatic FAP-I mutation carriers; G2, early symptomatic). Seventy-six healthy controls formed a control group (G3). Nerve conduction studies, needle electromyography with motor unit potential analysis of the extensor digitorum brevis, RR interval and sympathetic skin response (SSR) were analyzed.nnnRESULTSnThe amplitudes of the motor response of the peroneus nerve and of the plantar SSR were significantly lower in G1 compared to G3. No other differences were found between those two groups. With a cut-off point of 0.2mV for plantar SSR, its sensitivity and specificity are 0.53 and 0.95, respectively. The positive predictive value and the negative predictive value are 0.82.nnnCONCLUSIONSnSSR response at foot is a useful measurement to detect early dysfunction of peripheral nerve fibres in FAP-I. Its abnormality should be considered a warning sign and lead to a careful clinical assessment.nnnSIGNIFICANCEnSSR is a useful neurophysiological marker in FAP-I.

Acquired amyloid neuropathy in a Portuguese patient after domino liver transplantation.

Familial amyloid polyneuropathy (FAP) is a progressive neuropathy with autonomic dysfunction. Domino liver transplantation (DLT), in which the liver of an FAP patient is transplanted into another patient, is routinely applied to compensate for the shortage of available organs. We report a patient who developed a clinical picture of FAP 9 years after a DLT from an FAP donor. Electrophysiological, neuropathological, and autonomic tests were administered. The patient presented with typical clinical features of FAP. Electrophysiological investigation confirmed a moderate sensorimotor axonal and autonomic neuropathy. Sural nerve biopsy confirmed the presence of amyloid deposits in the endoneurium. Skin biopsy at the ankle showed reduced intraepidermal nerve fiber density. Our report shows that FAP can develop in a recipient of an FAP liver. This suggests that careful longitudinal study is required to evaluate the risk of FAP polyneuropathy in patients who undergo domino liver transplantation. Muscle Nerve, 2010

Quality Control of Motor Unit Number Index (MUNIX) Measurements in 6 Muscles in a Single-Subject “Round-Robin” Setup

Background Motor Unit Number Index (MUNIX) is a neurophysiological measure that provides an index of the number of lower motor neurons in a muscle. Its performance across centres in healthy subjects and patients with Amyotrophic Lateral Sclerosis (ALS) has been established, but inter-rater variability between multiple raters in one single subject has not been investigated. Objective To assess reliability in a set of 6 muscles in a single subject among 12 examiners (6 experienced with MUNIX, 6 less experienced) and to determine variables associated with variability of measurements. Methods Twelve raters applied MUNIX in six different muscles (abductor pollicis brevis (APB), abductor digiti minimi (ADM), biceps brachii (BB), tibialis anterior (TA), extensor dig. brevis (EDB), abductor hallucis (AH)) twice in one single volunteer on consecutive days. All raters visited at least one training course prior to measurements. Intra- and inter-rater variability as determined by the coefficient of variation (COV) between different raters and their levels of experience with MUNIX were compared. Results Mean intra-rater COV of MUNIX was 14.0% (±6.4) ranging from 5.8 (APB) to 30.3% (EDB). Mean inter-rater COV was 18.1 (±5.4) ranging from 8.0 (BB) to 31.7 (AH). No significant differences of variability between experienced and less experienced raters were detected. Conclusion We provide evidence that quality control for neurophysiological methods can be performed with similar standards as in laboratory medicine. Intra- and inter-rater variability of MUNIX is muscle-dependent and mainly below 20%. Experienced neurophysiologists can easily adopt MUNIX and adequate teaching ensures reliable utilization of this method.

The diagnostic accuracy of Sudoscan in transthyretin familial amyloid polyneuropathy

OBJECTIVEnTransthyretin familial amyloid polyneuropathy (TTR-FAP) is an axonal sensory-motor and autonomic neuropathy. Reliable quantification of sudomotor function could prove essential in the diagnosis and early treatment management. We aim to assess the diagnostic value of a new sudomotor test (Sudoscan) in TTR-FAP.nnnMETHODSnOne hundred and thirty-three TTR-FAP Val30Met carriers, divided in asymptomatic and symptomatic stage 1, were compared with 37 healthy controls. We analyzed the right sural sensory nerve action potential (SNAP), the plantar sympathetic skin response (SSR) and the electrochemical skin conductance (ESC) measured by Sudoscan in both hands and feet.nnnRESULTSnAll neurophysiological measures were significantly worse in the symptomatic group. However, feet ESC was the only test distinguishing symptomatic patients with autonomic dysfunction from those without autonomic dysfunction, and both groups from asymptomatic subjects and healthy controls. Feet ESC was a significant independent predictor for the presence of symptoms and autonomic failure, after adjusting for demographic characteristics, sural SNAP and SSR amplitudes (p<0.05). Feet ESC showed 76% sensitivity and 85% specificity for detection of dysautonomia.nnnCONCLUSIONnFeet ESC is a sensitive test to assess early autonomic dysfunction in TTR-FAP subjects. This investigation should be considered for routine assessment in this population.nnnSIGNIFICANCEnAbnormal feet responses on Sudoscan support early diagnosis in TTR-FAP.

Neurophysiological techniques to detect early small-fiber dysfunction in transthyretin amyloid polyneuropathy

Introduction: Transthyretin familial amyloid polyneuropathy (TTR‐FAP) is characterized by early selective involvement of small nerve fibers. Initial clinical diagnosis is complicated by psychosocial factors. We evaluated diagnostic accuracy of sural sensory nerve action potentials, plantar sympathetic skin response (SSR), and cortical laser‐evoked potentials (LEP) to dorsal foot stimulation in the early diagnosis of TTR‐FAP.Methods: Sixty‐three subjects with TTR‐FAP (Val30Met) mutation were split into 2 groups (asymptomatic carriers and early‐symptomatic patients) and compared with 33 healthy controls. Results: The diagnostic accuracy of plantar SSR amplitude and LEP N2 latency was similar; all had very high specificity (94 to 97%) but low sensitivity (22 to 32%) in distinguishing controls from carriers and early‐symptomatic patients. No control had abnormal results on both tests. Conclusions: Plantar SSR and LEPs have similar diagnostic performance in detecting small‐fiber dysfunction in early TTR‐FAP; we propose that both tests should be used to investigate this population. Muscle Nerve 49: 181–186, 2014

Motor Unit Number Index (MUNIX) detects motor neuron loss in pre-symptomatic muscles in Amyotrophic Lateral Sclerosis

OBJECTIVEnMotor Unit Number Index (MUNIX) is a quantitative neurophysiological measure that provides an index of the number of lower motor neurons supplying a muscle. It reflects the loss of motor neurons in patients with Amyotrophic Lateral Sclerosis (ALS). However, it is unclear whether MUNIX also detects motor unit loss in strong, non-wasted muscles.nnnMETHODSnThree centres measured MUNIX in 49 ALS patients every three months in six different muscles (abductor pollicis brevis, abductor digiti minimi, biceps brachii, tibialis anterior, extensor digitorum brevis, abductor hallucis) on the less affected side. The decline of MUNIX in initially non-wasted, clinically strong muscles (manual muscle testing, MMT grade 5) was analysed before and after onset of weakness.nnnRESULTSnIn 49 subjects, 151 clinically strong muscles developed weakness and were included for analysis. The average monthly relative loss of MUNIX was 5.0% before and 5.6% after onset of weakness. This rate of change was significantly higher compared to ALS functional rating scale (ALSFRS-R) and compound muscle action potential (CMAP) change over 12months prior to the onset of muscle weakness (p=0.024).nnnCONCLUSIONnMUNIX is an electrophysiological marker that detects lower motor neuron loss in ALS, before clinical weakness becomes apparent by manual muscle testing.nnnSIGNIFICANCEnThis makes MUNIX a good biomarker candidate for disease progression and possibly pharmacodynamics responds.

Voluntary control of a plegic limb during yawning

Yawning is a phylogenetically ancient phenomenon coordinated by a network of supratentorial and infratentorial centres located in brainstem, hypothalamus, and limbic regions [1]. Movements of plegic limbs during yawning in patients with stroke are common [2]. The first descriptions come from the 18th and 19th centuries by Darwin and by Abercrombie, respectively [3, 4]. These movements have always been described as involuntary and stereotyped, however [5]. We report a novel phenomenon: a stroke patient who could voluntarily control the movements of his plegic limb during yawning. A 59-year-old right-handed male was admitted in the emergency department presenting right facial palsy, dysarthria, right hemiplegia, and right pain anesthesia of sudden onset. The relevant medical antecedents were diabetes mellitus and arterial hypertension. The presentation suggested a sensorimotor lacunar syndrome due to a subcortical stroke. The diagnosis of acute left Middle Cerebral Artery infarct was made and he was submitted to endovenous thrombolysis. The inferior limb deficit improved; however, the right superior limb remained plegic—grade 0 (MRC scale) in all segments, including abduction/adduction, flexion/extension, and medial/lateral rotation of the shoulder and flexion/extension and supination/pronation of the elbow. The only exception was the elevation of the shoulder, in which the patient could perform a full range of motion if the force gravity was eliminated (grade 2). Since the first hours of stroke onset, the patient presented a reflexive, stereotyped movement of flexion of the right elbow while yawing. Remarkably, at day 6, the patient started to have voluntary control over that movement. Ability to touch the chin or the left arm with the right hand according to the request of the observer was documented (Online Resource 1). The patient noticed an association between the duration of yawning and the range of movements that he was able to do, such that during more sustained yawning, he could even perform more complex movements of distal joints—grabbing objects purposely, for instance. These movements could also be volitionally suppressed. They were impossible without yawning or when he simulated yawning. He did not notice an increase in the frequency of yawning, fatigue of the movement during multiple episodes of yawning, and his limb was not spastic. MRI showed an infarct involving lenticular nucleus, anterior and posterior limbs of internal capsule, body of caudate nucleus, and corona radiata (Fig. 1a). Tractography and transcranial magnetic stimulation confirmed the disruption on the left pyramidal tract (Fig. 2). The topography of his lesion was compared to controls. The controls were selected prospectively and had: (a) an acute ischemic lesion on brain MRI of the left lenticulocapsulo-radiate region; (b) an upper limb paresis ≤ 2; (c) yawned during admission. Of the four controls selected, two did not present any movement during yawning and two presented involuntary movements exclusively. Brain images were normalized to MNI152 space. The volume of lesion of the case was 8461 mm3 and that of the controls ranged from 3747 to 9858 mm3. The overlay of lesions of case and controls showed that some areas of Electronic supplementary material The online version of this article (http s://doi.org/10.1007 /s004 15-017-8729 -z) contains supplementary material, which is available to authorized users.