Epidemiology of seropositive myasthenia gravis in Sardinia: A population-based study in the district of Sassari.

INTRODUCTION/AIMS: The global incidence and prevalence of myasthenia gravis (MG) range between 6-31/million and 10-37/100,000, respectively. Sardinia is a high-risk region for different immune-mediated disorders, but the epidemiology of MG remains unclear. We determined the epidemiology of MG with acetylcholine receptor (AChR)-immunoglobulin G (IgG) and muscle-specific tyrosine kinase (MuSK)-IgG in the district of Sassari (North-Western Sardinia; population, 325,288). METHODS: From the laboratory of the University Hospital of Sassari (reference for AChR/MuSK-IgG testing in Sardinia since 1998) and the main neurology units in Sardinia, we retrospectively identified MG patients with (1) AChR-IgG and/or MuSK-IgG positivity by radioimmunoprecipitation assay; and (2) residency in the district of Sassari. Incidence (January 2010-December 2019) and prevalence (December 31, 2019) were calculated. RESULTS: A total of 202 patients were included (incident, 107; prevalent, 180). Antibody specificities were AChR (n = 187 [93%]) and MuSK (n = 15 [7%]). The crude MG incidence (95% confidence interval) was 32.6 (26.8-39.2)/million, while prevalence was 55.3 (47.7-63.9)/100,000. After age-standardization to the world population, incidence decreased to 18.4 (14.3-22.5)/million, while prevalence decreased to 31.6 (26.1-37.0)/100,000. Among incident cases, age strata (years) at MG onset were: <18 (2%), 18-49 (14%), 50-64 (21%), and ≥65 (63%). DISCUSSION: Sardinia is a high-risk region for MG, with a prevalence that exceeds the European threshold for rare disease. Identification of the environmental and genetic determinants of this risk may improve our understanding of disease pathophysiology.

Resistance Training for Muscle Weakness in Multiple Sclerosis: Direct Versus Contralateral Approach in Individuals With Ankle Dorsiflexors' Disparity in Strength.

OBJECTIVE: To compare effects of contralateral strength training (CST) and direct strength training of the more affected ankle dorsiflexors on muscle performance and clinical functional outcomes in people with multiple sclerosis (MS) exhibiting interlimb strength asymmetry. DESIGN: Randomized controlled trial. SETTING: University hospital. PARTICIPANTS: Individuals with relapsing-remitting MS (N=30) and mild-to-moderate disability (Expanded Disability Status Scale score ≤6) presenting with ankle dorsiflexors' strength disparity. INTERVENTIONS: Participants were randomly assigned to a CST (n=15) or direct strength training (n=15) group performing 6 weeks of maximal intensity strength training of the less or more affected dorsiflexors, respectively. MAIN OUTCOME MEASURES: Maximal strength, endurance to fatigue, and mobility outcomes were assessed before, at the intervention end, and at 12-week follow-up. Strength and fatigue parameters were measured after 3 weeks of training (midintervention). RESULTS: In the more affected limb of both groups, pre- to postintervention significant increases in maximal strength (P≤.006) and fatigue endurance (P≤.04) were detected along with consistent retention of these improvements at follow-up (P≤.04). At midintervention, the direct strength training group showed significant improvements (P≤.002), with no further increase at postintervention, despite training continuation. Conversely, the CST group showed nonsignificant strength gains, increasing to significance at postintervention (P≤.003). In both groups, significant pre- to postintervention improvements in mobility outcomes (P≤.03), not retained at follow-up, were observed. CONCLUSIONS: After 6 weeks of training, CST proved as effective as direct strength training in enhancing performance of the more affected limb with a different time course, which may have practical implications in management of severely weakened limbs where direct strength training is not initially possible.

Effects of volitional contraction on intracortical inhibition and facilitation in the human motor cortex.

Short-interval intracortical inhibition (SICI), intracortical facilitation (ICF) and short-interval intracortical facilitation (SICF) were assessed in the cortical motor area of the first dorsal interosseous muscle (FDI) of 16 healthy subjects. Paired-pulse TMS was delivered to the left hemisphere at the following interstimulus intervals (ISIs): 2 and 3 ms for SICI, 10 and 15 ms for ICF and 1-5 ms for SICF. Motor-evoked potentials were recorded from the resting and active right FDI. The effects exerted on SICI and ICF by four intensities (60-90% of active motor threshold, AMT) of the conditioning stimulus (S1) and by three levels of muscle contraction (10%, 25%, 50% of maximal voluntary contraction, MVC) were evaluated. The effects exerted on SICF were evaluated with two intensities (90% and 70% of AMT) of the test stimulus (S2) and with the same levels of muscle contraction. Results showed that: (i) during 10% MVC, maximum SICI was observed with S1 = 70% AMT; (ii) the amount of SICI obtained with S1 = 70% AMT was the same at rest as during 10% MVC, but decreased at higher contraction levels; (iii) ICF was observed only at rest with S1 = 90% AMT; (iv) SICF was facilitated at 10% and 25% MVC, but not at 50% MVC. We conclude that during muscle activation, intracortical excitability reflects a balance between activation of SICI and SICF systems. Part of the reduction in SICI during contraction is due to superimposed recruitment of SICF. Low intensity (70% AMT) conditioning stimuli can test SICI independently of effects on SICF at low contraction levels.

Intracortical modulation of cortical-bulbar responses for the masseter muscle.

Short interval intracortical inhibition (SICI) and intracortical facilitation (ICF) were evaluated in the masseter muscles of 12 subjects and the cortical silent period (SP) in nine subjects. Motor evoked potentials (MEPs) were recorded from contralateral (cMM) and ipsilateral (iMM) masseters, activated at 10% of maximal voluntary contraction (MVC). Interstimulus intervals (ISIs) were 2 and 3 ms for SICI, 10 and 15 ms for ICF. TMS of the left masseteric cortex induced MEPs that were larger in the cMM than the iMM; stimulation of right masseteric cortex produced a similar asymmetry in response amplitude. SICI was only observed using a CS intensity of 70% AMT and was equal in both cMM and iMM. SICI was stronger at higher TS intensities, was abolished by muscle activation greater than 10% MVC, and was unaffected by coil orientation changes. Control experiments confirmed that SICI was not contaminated by any inhibitory peripheral reflexes. However, ICF could not be obtained because it was masked by bilateral reflex depression of masseter EMG caused by auditory input from the coil discharge. The SP was bilateral and symmetric; its duration ranged from 35 to 70 ms depending on TS intensity and coil orientation. We conclude that SICI is present in the cortical representation of masseter muscles. The similarity of SICI in cMM and iMM suggests either that a single pool of inhibitory interneurons controls ipsi- and contralateral corticotrigeminal projections or that inhibition is directed to bilaterally projecting corticotrigeminal fibres. Finally, the corticotrigeminal projection seems to be weakly influenced by inhibitory interneurons mediating the cortical SP.

Effect of Contralateral Strength Training on Muscle Weakness in People With Multiple Sclerosis: Proof-of-Concept Case Series.

BACKGROUND: The contralateral strength training (CST) effect is a transfer of muscle performance to the untrained limb following training of the contralateral side. OBJECTIVE: The aim of this study was to explore, in individuals with multiple sclerosis (MS) presenting marked lower limb strength asymmetry, the effectiveness of CST on management of muscle weakness of the more-affected limb following training of the less-affected limb. DESIGN: A single-subject research design was used. METHODS: Eight individuals with MS underwent 16 to 18 high-intensity training sessions of the less-affected ankle dorsiflexor muscles. The primary outcome measure of this single-system case series was maximal strength expressed as peak moment and maximal work. Secondary outcome measures were: Six-Minute-Walk Test, Timed "Up & Go" Test, 10-Meter Timed Walk Test, and Multiple Sclerosis Quality of Life-54 questionnaire. RESULTS: After the 6-week intervention, the contralateral more affected (untrained) limb showed a 22% to 24% increase in maximal strength. From pretest-posttest measurements, participants also performed significantly better on the clinical and functional secondary outcome measures. At the 12-week follow-up, the strength levels of the weaker untrained limb remained significantly superior to baseline levels in the majority (5 out of 8) of the outcome parameters. LIMITATIONS: Considering the design used, the absence of a control group, and the sample size, these findings should be cautiously generalized and will need confirmation in a properly planned randomized controlled trial. CONCLUSIONS: The present proof-of-concept study shows, for the first time, the occurrence of the CST effect on muscle performance of ankle dorsiflexor muscles in people with MS. These preliminary findings reveal new potential implications for CST as a promising rehabilitation approach to those conditions where unilateral muscle weakness does not allow or makes difficult performing conventional strength training of the weaker limb.

A comprehensive assessment of the cross-training effect in ankle dorsiflexors of healthy subjects: A randomized controlled study.

PURPOSE: To investigate the cross-training effect, induced on ankle dorsiflexors (AD) by unilateral strength-training of the contralateral muscles, as transfer of peak torque (PT) and muscle work (MW) and their relative contributions to muscle performance. METHODS: Thirty healthy volunteers were randomly assigned to a training or control group. The trained group sustained a 4-week maximal isokinetic training of the stronger AD at 90 and 45°/s. At both angular velocities, PT, MW and MW/PT ratio were measured from both legs at baseline and after intervention (trained group) or no-intervention (controls). The familiarization/learning-effect was calculated and subtracted by PT and MW measures to obtain their net changes. RESULTS: Net PT increased in both legs (untrained: +27.5% at 90°/s and +17.9% at 45°/s; trained: +15% at 90°/s and +16.3% at 45°/s). Similarly, net MW increased in both the untrained (90°/s: +29.6%; 45°/s: +37%) and trained (90°/s: +23.4%; 45°/s: +18.3%) legs. PT and MW gains were larger in the untrained than trained AD (p<0.0005), with MW improving more than PT at 45°/s (p=0.04). The MW/PT ratio increased bilaterally only in the trained group (p<0.05), depending on the angular velocity. CONCLUSIONS: The cross-training effect occurred in AD muscles in terms of both PT and MW, with MW adding valuable information to PT-analysis in describing muscle performance. Moreover, the MW/PT ratio allowed estimating the contributions of these parameters to muscle capability and may represent a novel index in isokinetic testing. The greater improvements in the untrained than trained limb raises interesting clinical implications in asymmetric conditions.

Primary motor cortex hyperexcitability in Fabry's disease.

OBJECTIVE: Involvement of pyramidal cells and/or changes in excitability of brain areas remote from an ischemic stroke has been demonstrated. Since in Fabry disease (FD), specific cerebrovascular lesions are present, we thought to investigate motor cortex excitability, using transcranial magnetic stimulation. METHODS: Resting (RMT) and active (AMT) motor threshold, input-output curve (IN-OUT), central motor conduction time (CMCT), cortical silent period (cSP), short and long interval intracortical inhibition (SICI and LICI), intracortical facilitation (ICF), short interval intracortical facilitation (SICF) and short afferent inhibition (SAI) were measured in the cortical representation of the right first dorsal interosseous muscle in 11 patients with FD and 11 sex- and age matched healthy subjects. RESULTS: FD patients showed a significant increase of steepness in IN-OUT, ICF and SICF curves. RMT, AMT, CMCT, SICI, LICI and SAI were normal. CONCLUSIONS: Our data documented an increased activity of motor cortex glutamatergic excitatory circuits in FD, evident also in patients without brain MRI lesions. Following enzyme replacement treatment, this abnormality was partly reversed. SIGNIFICANCE: We suggest that our findings are expression of subtle "biochemical brain lesions", due to an early involvement of neurons and/or astrocytes by the cascade of pathologic events leading to brain damage in FD.

Amyotrophic lateral sclerosis in Sardinia, insular Italy, 1995-2009.

Recent genetic studies suggest a Sardinian type of amyotrophic lateral sclerosis (ALS). Thus, ALS incidence, prevalence and survival were investigated in a large population of Sardinians aimed to disclose population-specific patterns and their temporal changes. This is a population-based incidence and prevalence study in northern and central Sardinia, insular Italy (over 700,000 population). Incidence rates were computed for the time interval 1995-2009 and by quinquennia. Prevalence was computed for prevalence days 31 December 2004 and 2009. Onset-based survival for 1995-2009 is also reported. All ALS patients (El Escorial Criteria) in the study area were retrospectively included. The ALS crude incidence from 2005-2009 was 2.5 (95 % CIs: 0.1, 4.9), 3.4 in men and 1.6 in women. Onset occurred most often between the age of 65-74 years in men and 55-64 years in women. The ALS incidence tended to increase over the period 1995-2009. The mean age at onset was 61.7 years with no difference based on gender, varying significantly from 59.9 years in 1995-1999 to 63.9 years in 2005-2009. On December 31, 2009, the ALS crude prevalence was 10.8 per 100,000 (95 % CIs: 8.6, 13.1), 13.8 in men and 8.0 in women, whereas it was 6.3 per 100,000 (95 % CIs: 4.1, 8.6) on December 31, 2004 (M:F ratio of 0.95). Mean survival from onset was 37.0 months, with no difference based on gender, and a tendency to decrease during the period 1995-2009, in relation to type and age of onset. The population-based incidence and prevalence data of ALS in Sardinians indicate an increase of the disease occurrence over the past 40 years, providing support for a population-specific variant of ALS in Sardinia.

Theta Burst Stimulation over the human primary motor cortex modulates neural processes involved in movement preparation.

OBJECTIVE: To test whether inhibitory continuous Theta Burst (cTBS) transcranial magnetic stimulation (TMS) can alter neural activity involved in planning and execution of a self-paced movement. METHODS: In seven subjects, cTBS was applied over either the left or right primary motor cortex (left M1 and right M1) and the left dorsal premotor cortex (left PMd) in different experimental sessions. Motor evoked potentials (MEP) at rest were measured as well as the two main components of the movement related cortical potential (MRCP), the Bereitschaftspotential (BP) and the negative slope (NS'), prior to self-paced right thumb opposition. RESULTS: cTBS suppressed contralateral MEPs when it was applied over left M1, right M1 and left PMd. In addition, cTBS over left M1, but not at any other location, reduced the amplitude of the NS' and tended to shorten the BP onset without changing EMG activity associated with voluntary muscular output. There was a significant correlation between the percent suppression of the MEP and the reduction in amplitude of the total MRCP (BP+NS'). CONCLUSIONS: cTBS can produce long-lasting effects on brain activity involved in the preparation and execution of a volitional movement. SIGNIFICANCE: The fact that movement was not compromised while brain activity changed suggests that the motor system of healthy subjects operates with a safety factor that can adjust patterns of activation to compensate for the partial disruption caused by cTBS.

Origin of sound-evoked EMG responses in human masseter muscles.

Sound is a natural stimulus for both cochlear and saccular receptors. At high intensities it evokes in active masseter muscles of healthy subjects two overlapping reflexes: p11/n15 and p16/n21 waves, whose origin has not yet been demonstrated. Our purpose was to test which receptor in the inner ear is responsible for these reflexes. We compared masseter EMG responses induced in normal subjects (n = 9) by loud clicks (70-100 dB normal hearing level (NHL), 0.1 ms, 3 Hz) to those evoked in subjects with a selective lesion of the cochlea (n = 5), of the vestibule (n = 1) or with mixed cochlear-vestibular failure (n = 5). In controls, 100 dB clicks induced bilaterally, in the unrectified mean EMG (unrEMG), a clear p11 wave followed by a less clear n15 wave and a subsequent n21 wave. Lowering the intensity to 70 dB clicks abolished the p11/n15 wave, while a p16 wave appeared. Rectified mean EMG (rectEMG) showed, at all intensities, an inhibitory deflection corresponding to the p16/n21 wave in the unrEMG. Compared to controls, all deaf subjects had a normal p11 wave, together with more prominent n15 wave; however, the p16/n21 waves, and their corresponding inhibition in the rectEMG, were absent. The vestibular patient had bilaterally clear p11 waves only when 100 dB clicks were delivered bilaterally or to the unaffected ear. Stimulation of the affected ear induced only p16/n21 waves. Data from mixed patients were consistent with those of deaf and vestibular patients. We conclude that click-induced masseter p11/n15 waves are vestibular dependent, while p16/n21 waves depend on cochlear integrity.

Prevalence of primary blepharospasm in Sardinia, Italy: a service-based survey.

We performed a service-based epidemiological study of primary blepharospasm in the island of Sardinia (Italy). Due to its favorable geographical location, we are confident we will provide reliable data from patients seeking botulinum toxin treatment. A total of 53 patients were assessed. Prevalence was estimated to be 32.2 per 1 million (95% confidence interval, 23.0-40.8). These results are in line with those obtained in other similar surveys, that is, record-based, and performed in various European regions such as Northern England, the Munich area, as well as the Epidemiologic Study of Dystonia in Europe.

Non-nociceptive upper limb afferents modulate masseter muscle EMG activity in man.

Recent electrophysiological data obtained in anaesthetized rats evidenced jaw muscle excitatory responses to the electrical stimulation of type II limb somatosensory afferents. In the present work, we describe an inhibitory reflex evoked in human masseter muscles by stimulation of non-nociceptive fibres travelling in the median and radial nerves (MED and RAD, respectively). Eighteen healthy volunteers participated in the study. Subjects were seated on a comfortable chair, with the complex head-mandible-neck-trunk and the limbs securely fixed to the chair. Attempts were made to minimize possible interferences due to the activation of afferents other than the stimulated ones. The subjects were instructed to contract masseter muscles at a submaximal level and to maintain a stable level of muscle contraction during all trials. EMG voluntary activity was recorded from both masseter muscles by means of coaxial needle electrodes before and after the electrical stimulation of MED and/or RAD at intensities below pain threshold. In all subjects, MED stimulation induced bilaterally a marked depression of masseter EMG activity, which occurred at a latency of 23.6 +/- 2.1 ms and lasted 27.8 +/- 6.6 ms. RAD stimulation also induced a marked reduction in masseter EMG activity, but this effect was clearly observed in 9 out of 18 subjects, and it showed latency (30.2 +/- 7.5 ms) and duration (44.9 +/- 5.4 ms) significantly longer in comparison with the MED-induced effect. All subjects exhibited the inhibitory period in masseter EMG following the simultaneous stimulation of both nerves; this one appeared at a latency not significantly different (25.3 +/- 5.9 ms) and lasted much more (37.4 +/ - 8.2 ms) than EMG depression evoked by MED stimulation. The duration of masseter muscle inhibition, induced by MED and/or RAD stimulation, was inversely related to the level of EMG activity, while latency was not related to it. Significant increases in the inhibitory period duration were also observed by increasing stimulus intensity, within a subthreshold range for the activation of nociceptive fibres. In all cases, the inhibitory period was followed by a later excitatory rebound activity, whose latency and duration depended on the duration of the preceding EMG inhibition and on the background level of masseter activation. In conclusion, results evidenced that the activation of arm somatosensory fibres modulates masseter muscle activity in normal man. This might lead to a coordination between limb and masticatory muscle activity, which is required in several complex motor acts.

Modulation of masseter exteroceptive suppression by non-nociceptive upper limb afferent activation in humans.

The effects induced by non-noxious electrical stimulation of upper limb nerves on exteroceptive suppression (ES) of masseter muscle EMG activity were studied in 15 healthy subjects. EMG activity of masseter muscles was recorded bilaterally and great care was taken to minimise the activation of afferents other than the stimulated ones. Masseter ES was elicited by applying a non-noxious electrical stimulus to the skin above the mental nerve (Mt) of one side, during a voluntary contraction of masseter muscles at a prescribed steady clenching level. Onset and offset latencies and duration of early and late components of masseter ES (ES1 and ES2, respectively) were evaluated in control conditions and compared to those obtained when a non-noxious electrical stimulation was delivered separately to Med or Rad or simultaneously to both nerves (Med-Rad) of one side. Upper limb nerve stimulation could be simultaneous or it could precede or follow Mt stimulation by various time intervals. In control conditions, ES1 latency onset and duration values (mean +/- SD) were 11.3+/-2.9 ms and 16.9+/-2.1 ms, respectively, and ES2 latency onset and duration values were 44.5+/-6.0 ms and 28.6+/-11.1 ms, respectively. No significant differences were observed which were related to the side being recorded. Two types of effects, opposite in nature, were shown on masseter ES, depending on the time intervals between Mt and upper limb nerve stimulation. The first effect, which was facilitatory, consisted of a significant increase in ES1 and ES2 duration. A maximal increase in ES1 duration (134-155% compared to control value) occurred when upper limb nerve stimulation preceded that of Mt by 18-30 ms. Maximal ES2 lengthening (115-145%) was observed when upper limb nerve stimulation followed that of the Mt by 10 ms. The second effect was inhibitory and affected only ES2, which appeared completely eliminated when Med stimulation preceded that of Mt by 40-80 ms. By contrast, ES1 was never suppressed at any interstimulus interval. These data might reflect the different action of the central outflow, following the upper limb-induced effects, on the different neuronal circuits mediating ES1 and ES2.