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Background Early diagnosis is of substantial benefit for patients with Pompe disease. Yet underdiagnosing and substantial diagnostic delay are still frequent and the determinants of this are unknown. This study is the first to systematically investigate the diagnostic odyssey in Pompe disease from patients', parents', and physicians' perspectives. Methods Patients with infantile or late onset Pompe disease, their parents as well as their metabolic experts were invited to fill in respective surveys. The survey addressed perceived disease symptoms at onset and during the course of the disease, specialties of involved physicians, activities of patient-initiated search for diagnosis and the perceived impact of time to diagnosis on outcome. Results of experts' and patients'/parents' surveys were compared and expressed by descriptive statistics. Results and Discussion We collected data on 15 males and 17 females including 9 infantile and 23 late onset Pompe patients. All received the correct diagnosis at a metabolic or musculoskeletal expert center. Patients with direct referral to the expert center had the lowest diagnostic delay, while patients who were seen by several physicians, received the correct diagnosis after 44%-200% longer delay. The proportion of direct referral varied strongly between pediatricians (57%) and other disciplines (18%-36%). Conclusion Our study highlights a substantially larger diagnostic delay in Pompe patients that are not directly referred to expert centers for diagnostic work. Our findings may be used to develop more successful strategies for early diagnosis. Synopsis Diagnostic delay in Pompe disease is substantial particularly in patients that are not directly referred to expert centers for diagnostic workup, so facilitating direct referral may be a new strategy for early diagnosis.

Objective To estimate non-invasively the amount, recruitment pattern and discharge frequency of spinal motor neurons (MN) at contraction strength >20% of maximal voluntary contraction (MVC) of small hand muscles. Methods A peripheral collision technique was used and consisted of supramaximal electrical stimuli at Erb's point and at the wrist, synchronizing descending volleys of action potential during voluntary isometric contractions of the abductor digiti minimi muscle at 20–80% of MVC strength and 1–8 s of contraction duration. Responses of 13 healthy volunteers were quantified and analysed using a recently described model of MN behaviour. Results A linear relationship between MN discharge and force generation was noticed with R2 = 0.996, and was confirmed using the simulation results (R2 = 0.997) for contraction durations up to 8 s. For each investigated force level, discharge frequency and recruitment pattern were calculated for individual MN. Conclusions Using this method, MN discharge properties during voluntary activity can be estimated non-invasively. Significance This method provides new opportunities for the non-invasive study of MN behaviour, and could be expanded to patients with conduction failure and during fatigue.

Pompe disease is a rare autosomal-recessive disorder characterised by limb-girdle myopathy and respiratory weakness in the late-onset form (LOPD). Various mutations in the acid alpha-glucosidase gene lead to toxic lysosomal and extra-lysosomal glycogen accumulation in all organs due to ineffective glycogen clearance by the encoded enzyme. Only one randomized trial demonstrated beneficial effects of respiratory function and meters walked in the 6-min walking test with enzyme replacement therapy (ERT). These results were confirmed in several retrospective and prospective observations and in meta-analyses. Due to a potential lifelong therapy, moderate efficacy and high treatment costs time of ERT initiation and cessation is an ongoing matter of debate. So far, several national and international recommendations have been published with different criteria concerning diagnosis, initiation and cessation of ERT in LOPD. We therefore formally analysed recent published recommendations and consensus statements of LOPD using diagnostic nodes (DODES) as a special software tool. With DODES, an objective analysis becomes possible if the content of the recommendations is represented as algorithms using cross-compatible elements. This analysis formally disclosed both, areas of great heterogeneity and concordance for the diagnosis and management of LOPD and paved the way for a Pompe disease burden scale focussing on ERT initiation. According to this investigation further clinical research should concentrate on ERT in pre-symptomatic and severely affected LOPD patients and on cessation criteria for ERT as these issues are areas of international uncertainty and discordance.

Supplemental Digital Content is available in the text, Introduction: Intensive care unit-acquired weakness (ICU-AW) is often observed in critically ill patients with prolonged intensive care unit (ICU) stay. We hypothesized that evolving metabolic abnormalities during prolonged ICU stay are reflected by changing nutrient patterns in blood, urine and skeletal muscle, and that these patterns differ in patients with/without ICU-AW and between patients with/without sepsis. Methods: In a prospective single-center observational trial, we aim to recruit 100 critically ill patients (ICU length of stay ≥ 5 days) with severe sepsis/septic shock (“sepsis group”, n = 50) or severe head trauma/intracerebral hemorrhage (“CNS group”, n = 50). Patients will be sub-grouped for presence or absence of ICU-AW as determined by the Medical Research Council sum score. Blood and urine samples will be collected and subjected to comprehensive nutrient analysis at different time points by targeted quantitative mass spectrometric methods. In addition, changes in muscular tissue (biopsy, when available), muscular architecture (ultrasound), electrophysiology, body composition analyses (bioimpedance, cerebral magnetic resonance imaging), along with clinical status will be assessed. Patients will be followed-up for 180 and 360 days including assessment of quality of life. Discussion: Key objective of this trial is to assess changes in nutrient pattern in blood and urine over time in critically ill patients with/without ICU-AW by using quantitative nutrient analysis techniques. Peer-reviewed published NAChO data will allow for a better understanding of metabolic changes in critically ill patients on standard liquid enteral nutrition and will likely open up new avenues for future therapeutic and nutritional interventions.

INTRODUCTION The aim of this study was to compare orthodromic sural nerve conduction study (NCS) results using ultrasound-guided needle positioning (USNP) to surface electrode recordings. METHODS 51 healthy subjects aged 24 - 80 years, divided into 5 age groups, were examined. Electrical stimuli were applied behind the lateral malleolus. Sensory nerve action potentials (SNAPs) were recorded 8 and 15 cm proximally with surface and needle electrodes. RESULTS Mean SNAP amplitudes in µV (surface/needle electrodes) averaged 12.7 (SD 7.6)/40.6 (SD 20.8), P 60 years. SNAP amplitudes were smaller at the proximal recording location. DISCUSSION NCS using USNP yield higher amplitude responses than surface electrodes in all age groups at all recording sites. SNAP amplitudes are smaller at proximal recording locations due to sural nerve branching. This article is protected by copyright. All rights reserved.

Although not curative, enzyme replacement therapy (ERT) with recombinant human acid alpha-glucosidase enzyme has shown to be effective in the treatment of late-onset Pompe disease (LOPD). For this potentially life-long treatment, little is known on the clinical effect of cessation and resuming ERT. Due to a Swiss supreme court decision on ERT reimbursement, a temporary stop of ERT occurred in our study population. The aim of this study was to report the 36-months follow-up assessments after resuming ERT. After resuming ERT, seven patients suffering from genetically and enzymatically confirmed LOPD had periodic, mandatory, prospective assessments of pulmonary function tests, muscle strength summary scores, distances walked in timed walking tests, and patient-reported questionnaires. Data were statistically analyzed for significant differences between time points at ERT cessation, at ERT resuming, and 36 months thereafter. After resuming ERT forced vital capacity (p = 0.007) and distance walked in the 6 min walk test (6-MWT, p = 0.011) significantly increased at 36 months. Compared to before ERT cessation, distance walked in 6-MWT at 36 months still remained significantly lower (p = 0.005). Self-reported scores in the fatigue severity scale significantly declined at 36 months after resuming ERT (p = 0.019). No other functional or reported parameter significantly changed at 36 months after resuming ERT. Our data suggests that long-term interruption of ERT in LOPD may lead to deterioration of clinical meaningful parameters and quality of life. In addition, a clinical restoration after ERT cessation is possible for most of the LOPD patients within a 36 months follow-up.

Enzyme replacement therapy (ERT) with recombinant human alglucosidase alfa (rhGAA) in late-onset Pompe disease is moderately effective. Little is known about the clinical course after treatment termination and the resumption of ERT. In Switzerland, rhGAA therapy for Pompe disease was temporarily withdrawn after the federal court judged that the treatment costs were greatly out of proportion compared to the benefits. Re-treatment was initiated after the therapy was finally licensed. We retrospectively analysed seven Pompe patients, who underwent cessation and resumption of ERT (median age 43 years). The delay from first symptoms to final diagnosis ranged from 4 to 20 years. The demographics, clinical characteristics, assessments with the 6-min walking test (6-MWT), the predicted forced vital capacity (FVC) and muscle strength were analysed. Before initiation of ERT, all patients suffered from proximal muscle weakness of the lower limbs; one was wheelchair-bound and two patients received night-time non-invasive ventilation. Initial treatment stabilised respiratory function in most patients and improved their walking performance. After treatment cessation, upright FVC declined in most and the 6-MWT declined in all patients. Two patients needed additional non-invasive ventilatory support. Twelve months after resuming ERT, the respiratory and walking capacity improved again in most patients. However, aside for one patient, none of the patients reached the same level of respiratory function or distance walked in 6 min, as at the time of ERT withdrawal. We conclude that cessation of ERT in Pompe disease causes a decline in clinical function and should be avoided. Resuming treatment only partially recovers respiratory function and walking capacity.

HYPOTHESIS Facial nerve monitoring can be used synchronous with a high-precision robotic tool as a functional warning to prevent of a collision of the drill bit with the facial nerve during direct cochlear access (DCA). BACKGROUND Minimally invasive direct cochlear access (DCA) aims to eliminate the need for a mastoidectomy by drilling a small tunnel through the facial recess to the cochlea with the aid of stereotactic tool guidance. Because the procedure is performed in a blind manner, structures such as the facial nerve are at risk. Neuromonitoring is a commonly used tool to help surgeons identify the facial nerve (FN) during routine surgical procedures in the mastoid. Recently, neuromonitoring technology was integrated into a commercially available drill system enabling real-time monitoring of the FN. The objective of this study was to determine if this drilling system could be used to warn of an impending collision with the FN during robot-assisted DCA. MATERIALS AND METHODS The sheep was chosen as a suitable model for this study because of its similarity to the human ear anatomy. The same surgical workflow applicable to human patients was performed in the animal model. Bone screws, serving as reference fiducials, were placed in the skull near the ear canal. The sheep head was imaged using a computed tomographic scanner and segmentation of FN, mastoid, and other relevant structures as well as planning of drilling trajectories was carried out using a dedicated software tool. During the actual procedure, a surgical drill system was connected to a nerve monitor and guided by a custom built robot system. As the planned trajectories were drilled, stimulation and EMG response signals were recorded. A postoperative analysis was achieved after each surgery to determine the actual drilled positions. RESULTS Using the calibrated pose synchronized with the EMG signals, the precise relationship between distance to FN and EMG with 3 different stimulation intensities could be determined for 11 different tunnels drilled in 3 different subjects. CONCLUSION From the results, it was determined that the current implementation of the neuromonitoring system lacks sensitivity and repeatability necessary to be used as a warning device in robotic DCA. We hypothesize that this is primarily because of the stimulation pattern achieved using a noninsulated drill as a stimulating probe. Further work is necessary to determine whether specific changes to the design can improve the sensitivity and specificity.

Background Current state-of-the-art to diagnose peripheral neuropathy are neurological examination and electrodiagnostic studies. However, deeply situated nerves and plexus remain difficult to assess using these techniques, hence magnetic resonance neurography (MRN) emerged as a complementary method. MRN remains a qualitative approach and quantification, in terms of extraction of imaging biomarkers is needed to facilitate diagnosis and for follow-up examinations. Towards a multi-parametric quantitative imaging approach, accurate nerve segmentation needs to be performed first. Hampered by time-consuming manual annotation, we developed a semi-automatic, time-effective, hence clinically feasible segmentation approach based on machine-learning algorithms. In this study, we compared its performance on low- and high-resolution MRN. Materials and methods We acquired images of 9 healthy volunteers at the upper leg using 3 MRN sequences: lower resolution turbo inversion recovery magnitude (TIRM, voxel size of 78 × 78 × 4.0 mm3), lower resolution spin echo T2-weighted (T2, voxel size .52 × .52 × 4.0 mm3), and high resolution, fat-suppressed spin echo T2-weighted (hrT2, voxel size .25 × .25 × 3.3 mm3). An expert manually segmented the sciatic nerve on the T2 and hrT2 images (ground truth, GT). Our segmentation algorithm is based on a decision forest with context- and intensity-based descriptors. We split the images into two sets: a multi-modal low-resolution (TIRM and T2), and a mono-modal high-resolution (hrT2). We perform a leave-one-out cross-validation for both sets and calculate the Dice coefficient to the manually annotated GT. Cross-sectional areas (CSA) were calculated from the middle slice of the image stack. Results Dice coefficients of 0.723 ± 0.202 and 0.735 ± 0.080 are achieved for the low- and high-resolution MRN images (p = 0.858, CI 95 %). Segmentation results and 3-D renderings of the same nerve segmented in low- and high-resolution are shown in Fig. 1 . CSA for GT were 34.0 ± 5.5 mm2 (T2), and 35.4 ± 8.5 mm2 (hrT2), using semi-automatic segmentation 24.8 ± 7.6 mm2 (T2), and 25.7 ± 10.6 mm2 (hrT2). Discussion and conclusion Semi-automatic, hence fast peripheral nerve segmentation is feasible in both low- and high-resolution MRN images of the upper leg, providing image-based quantitative morphometric data. The equal performance of the low-resolution images might be due to the multi-modal setting, which possibly provides more discriminative descriptors for nerve. The lower CSA using semi-automatic segmentation is due to more rigorous segmentation constraints. Future work will include the application of our method to localize and quantify nerve lesions in images of patients diagnosed with peripheral neuropathy.

Objective To compare the individual latency distributions of motor evoked potentials (MEP) in patients with multiple sclerosis (MS) to the previously reported results in healthy subjects ( Firmin et al., 2011 ). Methods We applied the previously reported method to measure the distribution of MEP latencies to 16 patients with MS. The method is based on transcranial magnetic stimulation and consists of a combination of the triple stimulation technique with a method originally developed to measure conduction velocity distributions in peripheral nerves. Results MEP latency distributions in MS typically showed two peaks. The individual MEP latency distributions were significantly wider in patients with MS than in healthy subjects. The mean triple stimulation delay extension at the 75% quantile, a proxy for MEP latency distribution width, was 7.3 ms in healthy subjects and 10.7 ms in patients with MS. Conclusions In patients with MS, slow portions of the central motor pathway contribute more to the MEP than in healthy subjects. The bimodal distribution found in healthy subjects is preserved in MS. Significance Our method to measure the distribution of MEP latencies is suitable to detect alterations in the relative contribution of corticospinal tract portions with long MEP latencies to motor conduction.

HYPOTHESIS A multielectrode probe in combination with an optimized stimulation protocol could provide sufficient sensitivity and specificity to act as an effective safety mechanism for preservation of the facial nerve in case of an unsafe drill distance during image-guided cochlear implantation. BACKGROUND A minimally invasive cochlear implantation is enabled by image-guided and robotic-assisted drilling of an access tunnel to the middle ear cavity. The approach requires the drill to pass at distances below 1 mm from the facial nerve and thus safety mechanisms for protecting this critical structure are required. Neuromonitoring is currently used to determine facial nerve proximity in mastoidectomy but lacks sensitivity and specificity necessaries to effectively distinguish the close distance ranges experienced in the minimally invasive approach, possibly because of current shunting of uninsulated stimulating drilling tools in the drill tunnel and because of nonoptimized stimulation parameters. To this end, we propose an advanced neuromonitoring approach using varying levels of stimulation parameters together with an integrated bipolar and monopolar stimulating probe. MATERIALS AND METHODS An in vivo study (sheep model) was conducted in which measurements at specifically planned and navigated lateral distances from the facial nerve were performed to determine if specific sets of stimulation parameters in combination with the proposed neuromonitoring system could reliably detect an imminent collision with the facial nerve. For the accurate positioning of the neuromonitoring probe, a dedicated robotic system for image-guided cochlear implantation was used and drilling accuracy was corrected on postoperative microcomputed tomographic images. RESULTS From 29 trajectories analyzed in five different subjects, a correlation between stimulus threshold and drill-to-facial nerve distance was found in trajectories colliding with the facial nerve (distance 95%) at distances to the facial nerve below 0.5 mm. However, reduction in stimulus threshold to 0.3 mA or lower resulted in a decrease of facial nerve distance detection range below 0.1 mm (>95% sensitivity). Subsequent histopathology follow-up of three representative cases where the neuromonitoring system could reliably detect a collision with the facial nerve (distance

In this study we sought to evaluate the reproducibility of sensory nerve conduction studies (NCS) using ultrasound-guided needle positioning (USNP).

Der Patient prasentierte sich mit einer akut aufgetretenen, hochstgradigen, axonalen Radialisparese, die initial von starksten Schmerzen begleitet war. Differentialdiagnostisch wurde zunachst neben einer Kompressionsneuropathie zunachst auch an eine neuralgische Schulteramyotophie gedacht, doch bewies die am 1. Tag nach Auftreten der Paresen durchgefuhrte Neurographie eine Radialislasion am Oberarm. Nach langer Verlaufsbeobachtung, und nachdem anamnestisch, klinisch, elektrophysiologisch und bildgebend keine befriedigende Ursachenklarung gelungen war, wurde die Indikation zur chirurgischen Exploration gestellt. Intraoperativ zeigte sich eine Torquierung des N. radialis am Oberarm, welche reponiert werden konnte. Der weitere Verlauf war gunstig, heute, 2 Jahre nach Operation besteht eine zufriedenstellende Funktionalitat der betroffenen Hand.

To evaluate the usefulness of ultrasound imaging to improve the positioning of the recording needle for nerve conduction studies (NCS) of the sural nerve.Orthodromic NCS of the sural nerve was performed in 44 consecutive patients evaluated for polyneuropathy. Ultrasound-guided needle positioning (USNP) was compared to conventional "blind" needle positioning (BNP), electrically guided needle positioning (EGNP), and to recordings with surface electrodes (SFN).The mean distance between the needle tip and the nerve was 1.1 mm with USNP compared to 5.1 mm with BNP (p0.0001). The mean amplitude of the sensory nerve action potential (SNAP) was 21 microV with USNP and 11 microV with BNP (p0.0001). Compared to BNP, nerve-needle distances and SNAP amplitudes did not improve with EGNP. SNAP amplitudes recorded with SFN were significantly smaller than with BNP, EGNP and USNP.Ultrasound increases the precision of needle positioning markedly, compared to conventional methods. The amplitude of the recorded SNAP is usually clearly greater using USNP. In addition, USNP is faster, less painful and less dependent on the patient.USNP is superior to BNP, EGNP, and SFN in accurate measurement of SNAP amplitude. It has a potential use in the routine near-nerve needle sensory NCS of pure sensory nerves.

Objective To quantify repetitive discharges of spinal motor neurons (repMNDs) in response to single transcranial magnetic stimuli (TMS). To assess their contribution to the size of motor evoked potentials (MEPs). Methods We combined the triple stimulation technique (TST) with an additional nerve stimulus in the periphery (=quadruple stimulation; QuadS). The QuadS eliminates the first action potential descending on each axon after TMS, and eliminates effects on response size induced by desynchronization of these discharges, thereby allowing a quantification of motor neurons (MNs) discharging twice. In some instances, a quintuple stimulation (QuintS) was used, to quantify the number of MNs discharging three times. Recordings were from the abductor digiti minimi of 14 healthy subjects, using two different stimulation intensities and three different levels of facilitatory muscle precontractions. Results The threshold to obtain repMNDs was high. Their maximal size differed markedly between subjects, ranging from 8 to 52% of all MNs. Stimulation intensity and facilitatory muscle contraction, but not resting motor threshold, correlated with the amount of repMNDs. QuintS never yielded discernible responses, hence all observed repMNDs were double discharges. RepMNDs contributed to the MEP areas, but did not influence MEP amplitudes. Conclusions QuadS and QuintS allow precise quantification of repMNDs. The threshold of repMNDs is high and varies considerably between subjects. Significance repMNDs have to be considered when MEP areas are measured. Their analysis may be of interest in neurological disorders, but standardized stimulation parameters appear essential.

Objective : To establish the triple stimulation technique (TST) for recordings from the first dorsal interosseus (FDI) and the abductor pollicis brevis muscles (APB), and to analyse the test–retest repeatability of the TST measurements in APB. Methods : The recently developed TST was slightly modified for recordings from small hand muscles to account for volume conducted activity from surrounding muscles. The TST combines transcranial magnetic stimulation (TMS) with a peripheral collision technique [Magistris et al. Brain 121 (1998) 437]. In contrast to conventional motor-evoked potentials (MEPs), it quantifies the number of conducting central motor neurons (expressed by the TST amplitude ratio, TST–AR). MEPs and TST were performed in 30 sides of 25 healthy subjects (target muscle FDI), and in 29 sides of 21 healthy subjects (target muscle APB). All APB recordings were repeated after 25±5.9 days. Results : The TST–AR averaged 97.4±2.5% in FDI and 95.9±4.7% in APB. There was a mean difference of the TST–AR ratio of 2.9±3.1% between the repeated APB recordings (95% limits of agreement±6.3%). Conclusions : TMS allows activation of virtually all motor neurons supplying FDI and APB, when effects of volume conduction are eliminated. Its test–retest repeatability is excellent. Significance : The TST is well suited for follow-up examinations of central motor conduction failures. The greater number of established target muscles widens its clinical applicability.

Objective : To quantify temperature induced changes (=Uhthoff phenomenon) in central motor conduction and their relation to clinical motor deficits in 20 multiple sclerosis (MS) patients. Methods : Self-assessment of vulnerability to temperature and clinical examination were performed. We used motor evoked potentials to measure central motor conduction time (CMCT) and applied the triple stimulation technique (TST) to assess conduction failure. The TST allows an accurate quantification of the proportion of conducting central motor neurons, expressed by the TST amplitude ratio (TST-AR). Results : Temperature induced changes of TST-AR were significantly more marked in patients with prolonged CMCT ( P =0.037). There was a significant linear correlation between changes of TST-AR and walking velocity ( P =0.0002). Relationships were found between pronounced subjective vulnerability to temperature and (i) abnormal CMCT ( P =0.02), (ii) temperature induced changes in TST-AR ( P =0.04) and (iii) temperature induced changes in walking velocity ( P =0.04). CMCT remained virtually unchanged by temperature modification. Conclusions : Uhthoff phenomena in the motor system are due to varying degrees of conduction block and associated with prolonged CMCT. In contrast to conduction block, CMCT is not importantly affected by temperature. Significance : This is the first study quantifying the Uhthoff phenomenon in the pyramidal tract of MS patients. The results suggest that patients with central conduction slowing are particularly vulnerable to develop temperature-dependent central motor conduction blocks.

To characterize central motor conduction in relation to the clinical deficits and to the disease duration in 90 patients with acute relapsing-remitting MS (RR-MS) and in 51 patients with chronic primary or secondary progressive MS (P-MS).The triple stimulation technique (TST) was used to quantify the central motor conduction failure (expressed by the TST amplitude ratio) and conventional motor evoked potentials (MEPs) were used to measure the central motor conduction time (CMCT).The TST amplitude ratio was reduced in presence of a clinical motor deficit (p=0.02 for RR-MS, p0.01 for P-MS), but did not significantly differ in RR-MS and P-MS (p0.05) when patients with similar clinical motor deficit were compared. The CMCT was not related to the clinical motor deficit in both RR-MS and P-MS. However, the CMCT was markedly prolonged in P-MS, when patients with similar clinical motor deficit and with similar disease duration were compared (p0.01). The differences were not attributable to differential involvement of the spinal cord, which was similar in RR-MS and P-MS.Our results disclose differences between the central motor conduction in RR-MS and P-MS that are not related to disease severity, spinal cord involvement or disease duration.

Objective : To quantify the percentage of motor units of a foot muscle that can be activated by transcranial magnetic stimulation (TMS) in normal subjects and patients. Methods : We adapted the recently described triple stimulation technique (TST) for recordings from abductor hallucis (AH). Conventional motor evoked potentials (MEPs) of this muscle are usually small and variable in shape, because of an important temporal desynchronization of the TMS induced spinal motor neuron discharges. The TST allows ‘resynchronization’ of these discharges and thereby a quantification of the proportion of motor units activated by TMS. The lower limb (LL-) TST was applied to 33 sides of 18 normal subjects and 51 sides of 46 patients with multiple sclerosis, amyotrophic lateral sclerosis, or spinal cord disorders. Results : In healthy subjects, the LL-TST demonstrated that TMS achieves activation of virtually all motor neurons supplying the AH. In 33 of 51 patient sides, abnormal LL-TST responses suggested corticospinal conduction failures of various degrees. The LL-TST was 2.54 times more sensitive to detect central conduction failures than the conventional LL-MEPs. Combining the LL-TST with TST of the upper limbs further increased the sensitivity to detect a conduction failure by 1.50 times. Conclusion : The LL-TST markedly improves the examination of corticospinal pathways.

Objective : To quantitatively estimate upper motor neuron (UMN) loss in ALS. Methods : We used the recently developed triple stimulation technique (TST) to study corticospinal conduction to 86 abductor digiti minimi muscles of 48 ALS patients. This method employs a collision technique to estimate the proportion of motor units activated by a transcranial magnetic stimulus. At the same time, it yields an estimate of lower motor neuron (LMN) integrity. Results : The TST disclosed and quantified central conduction failures attributable to UMN loss in 38 sides of 24 patients (subclinical in 15 sides), whereas conventional motor evoked potentials detected abnormalities in only 18 sides of 12 patients (subclinical in two sides). The increased sensitivity of the TST to detect UMN dysfunction was particularly observed in early cases. Increased central motor conduction times (CMCT) occurred exclusively in sides with conduction failure. In sides with clinical UMN syndromes, the TST response size (but not the CMCT) correlated with the muscle weakness. In sides with clinical LMN syndromes, the size of the peripherally evoked compound muscle action potentials correlated with the muscle weakness. Conclusion : The TST is a sensitive method to detect UMN dysfunction in ALS. It allows a quantitative estimate of the UMN loss, which is related to the functional deficit. Therefore, the TST has a considerable impact on diagnostic certainty in many patients. It will be suited to follow the disease progression and therapeutic trials.

Thirty-two patients with a peripheral neuropathy and paraproteinemia were tested for IgM antibodies against myelin-associated protein (MAG) and sulfatide by means of enzyme-linked immunosorbent assay. Nine patients (28 %) had increased anti-sulfatide IgM antibodies and showed a chronic, slowly progressive, distally pronounced, and symmetric polyneuropathy with sensory to sensory-motor impairment, ataxia, hyporeflexia, and axonal involvement in electrophysiological studies. Ten patients (31 %) with increased anti-MAG antibodies had a similar, homogeneous polyneuropathy syndrome but presented with demyelinating features. A weak cross-reactivity between anti-MAG and anti-sulfatide antibodies was present in only three patients. In conclusion, although the two neuropathy groups clearly differed in their electrophysiological features, their clinical presentation was rather similar.

Objective : We report an electrophysiological method to differentiate amyotrophic lateral sclerosis (ALS) from cervical spondylotic myelopathy (CSM). Methods : Motor evoked potentials (MEPs) by transcranial magnetic stimulation were investigated in patients with ALS ( n =10) and CSM ( n =9). In addition to limb MEPs using the triple stimulation technique (TST) at upper limbs, MEPs recorded from trapezius muscles were compared with those obtained from 23 normal subjects. The parameters studied were: central motor conduction time, amplitude ratio and, for the trapezius, the interside asymmetry. Results : Whereas limb MEPs were abnormal in most ALS and CSM patients (17/19), trapezius MEPs were abnormal in all ALS patients, and normal in 8 out of 9 CSM patients. Conclusion : Recording of trapezius MEPs is a valuable addition to the limb MEPs study, since it distinguishes ALS from SCM in most patients.

We examined the effect of facial muscle contraction and eye movements on motor evoked potentials (MEPs) from the abductor pollicis brevis muscle (APB) evoked by transcranial magnetic stimulation (TMS). The hypothesis was that activity of large cortical regions (face) influences the excitability of spinal motoneurons via cortical or subcortical pathways. MEPs were recorded in 12 healthy subjects during the following conditions: (1) rest; (2) facial muscle contraction; (3) eye movements; (4) 10% precontraction of the target muscle; and (5) simultaneous target muscle precontraction and facial muscle contraction. In 9 subjects, spinal motoneuron excitability was assessed by measurements of F waves during the same facilitation maneuvers. Activation of eye and facial muscles clearly facilitated MEPs from the APB. The facilitation of MEP size during nonspecific maneuvers was almost similar to that obtained by target muscle precontraction, whereas shortening of latencies was significantly smaller. The occurrence and amplitude of F waves increased in parallel with MEP size during specific and nonspecific facilitation, pointing to spinal motoneuronal threshold changes as a potential facilitatory mechanism by facial and eye muscle activation. The different MEP latencies during specific and nonspecific facilitation were not explained by different spinal motoneuron excitability, but raise the possibility that supraspinal mechanisms contributed to nonspecific facilitation.

The amplitudes of motor evoked potentials (MEPs) were mapped by transcranial magnetic stimulation (TMS) using the triple stimulation technique (TST) in 11 normal individuals. Stimuli were given while the subjects were (a) distracted, (b) concentrating on their target (recorded) hand, and (c) concentrating on their contralateral hand. Within seconds, the proportion of excited motor units increased, similarly in all subjects, by an average of 70% from (a) to (b), and by 48% from (a) to (c). At the optimal stimulation site, results obtained with the TST were compared to those of conventional MEPs. The TST proved superior in detecting the rapid changes of the motor output caused by the non-specific mental tasks studied.

Amplitudes of motor evoked potentials (MEPs) are usually much smaller than those of motor responses to maximal peripheral nerve stimulation, and show marked variation between normal subjects and from one stimulus to another. Consequently, amplitude measurements have low sensitivity to detect central motor conduction failures due to the broad range of normal values. Since these characteristics are mostly due to varying desynchronization of the descending action potentials, causing different degrees of phase cancellation, we applied the recently developed triple stimulation technique (TST) to study corticospinal conduction to 489 abductor digiti minimi muscles of 271 unselected patients referred for possible corticospinal dysfunction. The TST allows resynchronization of the MEP, and thereby a quantification of the proportion of motor units activated by the transcranial stimulus. TST results were compared with those of conventional MEPs. In 212 of 489 sides, abnormal TST responses suggested conduction failure of various degrees. By contrast, conventional MEPs detected conduction failures in only 77 of 489 sides. The TST was therefore 2.75 times more sensitive than conventional MEPs in disclosing corticospinal conduction failures. When the results of the TST and conventional MEPs were combined, 225 sides were abnormal: 145 sides showed central conduction failure, 13 sides central conduction slowing and 67 sides both conduction failure and slowing. It is concluded that the TST is a valuable addition to the study of MEPs, since it improves detection and gives quantitative information on central conduction failure, an abnormality which appears to be much more frequent than conduction slowing. This new technique will be useful in following the natural course and the benefit of treatments in disorders affecting central motor conduction.

Task-dependent differences in the facilitation of motor evoked potentials (MEPs) following cortex stimulation were studied in a proximal (deltoid) and a distal muscle (abductor digiti minimi; ADM) in 23 healthy subjects during both dynamic and steady contractions of the target muscle under isometric and under nonisometric conditions. In the deltoid, MEP amplitudes were significantly greater if stimulation was performed during dynamic contractions than during steady contractions, despite equal background electromyographic levels just prior to the stimulus. The same task-specific extra facilitation of deltoid MEP amplitudes was also found with magnetic stimulation of the brain stem instead of the cortex in 3 subjects. In the ADM, no such task-dependent extra facilitation of MEPs during dynamic contractions was found. It is concluded that in the deltoid, during dynamic contractions, a greater proportion of the spinal motoneurons is close to depolarization threshold (greater “subliminal fringe”) whereas the number of firing motoneurons is similar to that during steady contraction. The lack of task-dependent extra facilitation of MEPs in the ADM is explained by the predominant recruitment principle for force gradation in small hand muscles, which is in contrast to the predominant frequency principle used in proximal muscles. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:1309–1316, 1998.

Transcranial stimulation has become an established method in the evaluation of corticospinal tract function. Clinical studies mainly address slowing of conduction through measurement of increased central conduction time (CCT) and 'failures' of conduction through observation of marked reductions in the size of the motor evoked potential (MEP). While CCT is of great interest in detecting subclinical slowing of conduction, the method discloses only gross failures of conduction, since the size of the MEP varies markedly between normal subjects and from one stimulus to another, leading to a broad range of normal values. Furthermore, transcranial stimulation does not appear to achieve depolarization of all spinal motor neurons leading to the target muscles, since in most normal subjects MEPs are smaller in amplitude than the responses evoked by peripheral nerve stimulation. We have developed a triple stimulation technique (TST) which, through two collisions, links central to peripheral conduction and suppresses desynchronization of MEPs. This technique shows that transcranial stimulation does achieve depolarization of all, or nearly all, spinal motor neurons supplying the target muscle in healthy subjects. Our data thus demonstrate that the amplitudes of MEPs are (i) smaller than those of peripheral responses, mostly due to phase cancellation of the action potentials caused by the desynchronization occurring within the corticospinal tract or at spinal cell level and (ii) variable between normal subjects and from one stimulus to another, mostly due to variability of this desynchronization. This technique provides new insights into normal corticospinal tract conduction. It will improve detection and quantification of central motor conduction failures.

Glycogen storage disease type II is a rare multi-systemic disorder characterised by an intracellular accumulation of glycogen due a mutation in the acid alpha glucosidase (GAA) gene. The level of residual enzyme activity, the genotype and other yet unknown factors account for the broad variation of the clinical phenotype. The classical infantile form is characterised by severe muscle hypotonia and cardiomyopathy leading to early death. The late-onset form presents as a limb girdle myopathy with or without pulmonary dysfunction. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) in infants is life saving. In contrast, therapeutic efficacy of rhGAA in the late-onset form is modest. High expenses of rhGAA, on-going infusions and poor pharmacokinetic efficacy raised a discussion of the cost effectiveness of ERT in late-onset Pompe disease in Switzerland. This discussion was triggered by a Swiss federal court ruling which confirmed the reluctance of a health care insurer not to reimburse treatment costs in a 67-year-old female suffering from Pompe disease. As a consequence of this judgement ERT was stopped by all insurance companies in late-onset Pompe patients in Switzerland regardless of their clinical condition. Subsequent negotiations lead to the release of a national guideline of the management of late-onset Pompe disease. Initiation and limitation of ERT is outlined in a national Pompe registry. Reimbursement criteria are defined and individual efficacy of ERT with rhGAA is continuously monitored.

The excitability of the late component of the blink reflex was measured in 19 patients with periodic leg movements in sleep (PLMS) and in 18 control patients with other sleep complaints. PLMS patients were not different from controls regarding age, body mass index, and apneas and hypopneas per hour of sleep. The latencies of the R1 and R2 components of the blink reflex were not different between the groups. However, in PLMS, the excitability of the R2 response was markedly enhanced: The second R2 response to a pair of stimuli given at an interval of 500 ms was in PLMS 59.5% (range 21–87%) of the first R2 response and in controls 18.8% (range 2–79%) (p < 0.0001, Mann-Whitney U test). These results provide further evidence of an altered motor control in PLMS, which is likely to be located subcortically and possibly related to the dopaminergic striaitopallidal system.

This article discusses parameters influencing the size of motor-evoked potentials (MEPs) in normal and pathological conditions, and the methods of meaningful quantification of the MEPs. MEPs are widely used to study the physiology of corticospinal conduction in healthy subjects and in patients with diseases of the central nervous system. The characteristics of MEP size are, stimulus intensity, coil positioning, and facilitation. MEPs show variability in size and shape from one stimulus to the next, even if the stimulus parameters are kept constant. This article describes the triple stimulation technique (TST), which was developed to eliminate the effects of phase cancellation from the MEPs, to allow for a better quantification. Pathological conditions may modify the parameters discussed in the article and influence the size of the MEPs by lesions of motor neurons or of their axons, central conduction velocity slowing, or conduction block.

Using magnetic stimulation techniques in addition to conventional electrical stimulation, the entire facial motor pathway can be assessed electrophysiologically. To study the diagnostic yield of these examinations, 174 patients with facial palsies of a variety of etiologies were examined (85 Bell's palsies, 24 Guillain-Barré syndrome (GBS), 19 Lyme borreliosis, 17 zoster oticus, 12 meningeal affections, 10 brain-stem disorders and 7 HIV-related facial palsies). The facial nerve was stimulated electrically at the stylomastoid fossa and magnetically within its canalicular portion. Additionally, the face-associated contralateral motor cortex was stimulated magnetically. Recordings were from the nasalis or mentalis muscle, or both, using surface electrodes. Bell's palsy patients showed typically a unilateral local hypoexcitability of the facial nerve to canalicular stimulation. In GBS, bilateral latency prolongations were frequent, as expected for a myelinic disorder. In contrast, in zoster, predominant axonotmesis was unilateral, and in HIV infection sometimes bilateral. The method was very sensitive to detect subclinical dysfunctions in meningo-radiculitis and malignant meningeal diseases, either prior to the onset of palsy, or on the contralateral (clinically unaffected) side. It also distinguished reliably between central and peripheral facial motor pathway lesions. In our experience, these inexpensive and non-invasive electrophysiological techniques contribute substantially to the differential diagnosis of facial palsies.

During REM sleep, a powerful postsynaptic inhibition of spinal motoneurons induces a generalized muscle hypotonia. Despite this inhibition, it has been shown that by transcranial magnetic stimulation of the brain (TMS), muscle responses of normal amplitude can be evoked in small hand muscles of humans. Tonic innervation during sleep is different in postural vs. limb muscles, and the spinal inhibition differs during tonic vs. phasic REM episodes, Both phenomena may affect muscle responses to TMS. In this study, muscle responses of 14 healthy subjects were compared to TMS in abductor digiti minimi, lumbar erector spinae, trapezius, and diaphragm during phasic and tonic REM sleep. In all four muscles, the amplitudes of the muscle responses were extremely variable, ranging for example in trapezius from -100% to +473% as compared to wakefulness. There was no systematic difference between the muscles. Moreover, no differences were found for TMS during phasic REM events compared to tonic REM sleep. Thus, responses to TMS during REM sleep may be preserved, with a decreased or increased amplitude. As a likely explanation, the cortical excitability and/or the spinal inhibition fluctuates during REM sleep in humans.

In this prospective study, automated interference pattern analysis (IPA, "Willison analysis", modified by Stålberg et al. 1983) was compared to the quantitative evaluation of mean motor unit potential duration (QMUP) in 239 muscles from consecutive, unselected patients. The sensitivity and specificity of both methods were calculated with respect to the clinically derived final neurological diagnosis, with histology available for 120 examinations. Whereas specificities were not different for the methods, the sensitivity for detection of abnormal vs. normal was 49% for QMUP and 74% for IPA (P0.001). The sensitivity for detection of myopathy or neuropathy was 46% or 38% for QMUP and 75% (P0.001) or 53% (P0.05) for IPA. Thus, in all instances, IPA had superior sensitivity with unchanged specificity as compared to QMUP. The results of a rapid and purely qualitative visual MUP assessment were statistically not different from QMUP. Although widely used, neither of these methods has been evaluated for its reliability in unselected patients with various grades of disease. Our results indicate that in a routine setting, the best diagnostic strategy might be the automated IPA, which can be quickly obtained in several muscles, followed by muscle biopsy in unclear cases.

Background: In multiple sclerosis (MS), fatigue is a common and often disabling symptom. It has multiple causes with central motor fatigue playing an important role. Objective: The objective of this study was to analyse the central motor conduction changes in relation to muscle contraction force during muscle fatigue and recovery in MS patients compared to healthy controls. Methods: A total of 23 MS patients with fatigue and 13 healthy subjects were assessed during 2 minutes of fatiguing exercise of the abductor digiti minimi muscle of the hand and the subsequent 7 minutes of recovery. Central motor conduction was quantified by transcranial magnetic stimulation using the triple stimulation protocol and calculating a central conduction index (CCI). Results: Force declined to 36% of the pre-exercise level (SD 16%; p < 0.01) in MS patients and to 44% (SD 9%, p < 0.01) in healthy subjects (group differences, not statistically significant). The decline of the CCI was significantly less marked in patients (–20%, SD 26%, p < 0.05) than in healthy subjects (–57%, SD 15%, p < 0.05; group differences, p < 0.05). The decline of force and CCI were not correlated in either group. Conclusions: During a fatiguing exercise, the decline in central motor conduction is significantly less pronounced in MS patients than healthy subjects, although the reduction of force is similar.

To study motor pathways to masticatory muscles, a new recording technique using surface electrodes was developed. The recording electrode was mounted on a spatula and inserted enorally into the pterygomandibular plica over the belly of m. masseter. Using this technique, mean latencies/amplitudes of the compound action potentials (CMAPs) in 18 healthy subjects were 1.2 ms/4.9 mV after electrical stimulation of the trigeminal nerve below the zygomatic arch, and 5.5 ms/1.1 mV after magnetic stimulation of the cortex. In 15 patients with unilateral lesions of the facial nerve, masticatory CMAPs had virtually symmetrical configuration, latency, and amplitude, excluding a major contribution of volume conducted activity from other cranial muscles. The technique was evaluated in patients after surgical treatment for trigeminal neuralgia. Patients with with retrogasserian thermocoagulation and central demyelinating lesions were consistently identified. © 1994 John Wiley & Sons, Inc.

Magnetic brain stimulation was performed in a patient with the narcolepsy-cataplexy syndrome during and after a cataplectic status. Amplitudes and thresholds of responses in six muscles (diaphragm, lumbar erector spinae, trapezius, biceps, tibialis anterior and abductor digiti V) remained unchanged during cataplexy as compared to the normal state. Our data suggest that, similar to rapid eye movement (REM) sleep, an enhanced cortical excitability to magnetic brain stimulation may compensate for the postsynaptic spinal inhibition of muscle tone during cataplexy, and that there is no difference in this respect between axial and distal muscles. Our data agree well with other evidence of increased cortex activity during cataplexy and REM sleep.

Facial nerve function was examined in patients who underwent posterior fossa surgery for unilateral acoustic neuroma. Examinations took place prior to surgery (n = 47 patients), early after surgery (0-12 days, n = 16 of 47 patients), and late after surgery (187-1505 days, n = 29 of 47 patients). Clinical signs of facial palsy were present to a variable extent in 13 of 47 patients before, in 12 of 16 patients early, and in 18 of 29 patients later after surgery. Electrophysiologically, the facial nerve was stimulated electrically at the stylomastoid fossa and magnetically at its proximal intracanalicular segment. In addition, the face-associated motor cortex was stimulated magnetically. In patients with facial palsy, any of these stimulation methods resulted in a decreased amplitude of the response in the nasalis muscle. The decrease showed a linear relationship to the clinical grade of palsy, pre- and postoperatively. Corticomuscular latencies remained unchanged. We conclude that: (i) the electrophysiological characteristics of facial nerve lesions due to compression by acoustic neuromas or due to a complication of neuroma removal are those of a purely axonal neuropathy; (ii) the three stimulation techniques have a similar diagnostic yield, thus making the use of all three of them redundant; and (iii) the electrophysiological techniques allowed no prediction of the final facial nerve function.

In this study we sought to evaluate the reproducibility of sensory nerve conduction studies (NCS) using ultrasound-guided needle positioning (USNP).Orthodromic NCS of the sural nerve using needle electrodes with USNP as well as surface electrodes were conducted twice in 20 healthy volunteers.The mean sensory nerve action potential (SNAP) amplitude in the initial examination was 39.5 μV using needle electrodes with USNP, and 12.5 μV using surface electrodes (P0.0001). The mean SNAP amplitude in the follow-up examination was 39.2 μV using needle electrodes with USNP, and 12.4 μV using surface electrodes (P0.0001). The mean intraindividual change in SNAP amplitude (test-retest) was 21.2% using needle electrodes with USNP, and 24.8% using surface electrodes (P = 0.6).Sensory NCS of the sural nerve using needle electrodes with USNP have reliable test-retest reproducibility and yield greater SNAP amplitudes than sensory NCS using surface electrodes.

Objective To measure the intra-individual distribution of the latencies of motor evoked potentials (MepL) using transcranial magnetic stimulation. Methods We used the triple stimulation technique (TST) to quantify the proportion of excited spinal motor neurons supplying the abductor digiti minimi muscle in response to a maximal magnetic brain stimulus (Magistris et al., 1998). By systematically manipulating the TST delay, we could quantify the contribution of slow-conducting motor tract portions to the TST amplitude. Results Our method allowed the establishment of a MepL distribution for each of the 29 examined healthy subjects. MepLs of 50% of the motor tract contributing to the motor evoked potential laid between the intra-individually minimal MepL (MepL min ) and MepL min +4.9ms (range 1.6–9.2). The individual MepL distributions showed two peaks in most subjects. The first peak appeared at a MepL that was 3.0ms longer on average (range 0.7–6.0) than MepL min ; the second peak appeared at MepL min +8.1ms on average (range 3.7–13.0). Conclusions Slow-conducting parts of the motor pathway contribute notably to the motor evoked potential. Our data suggest a bimodal distribution of central conduction times, which might possibly relate to different fibre types within the pyramidal tract. Significance We present a non-invasive method to assess slow-conducting parts of the human central motor tract.

To date, obesity affects a substantial population in industrialised countries. Due to the increased awareness of obesity-related morbidity, efficient dietary regimens and the recent successes with bariatric surgery, there is now a high demand for body contouring surgery to correct skin abundancies after massive weight loss. The known risks for this type of surgery are mainly wound-healing complications, and, more rarely, thromboembolic or respiratory complications. We present two female patients (23 and 39 years of age) who, in spite of standard positioning and precautions, developed sciatic neuropathy after combined body contouring procedures, including abdominoplasty and inner thigh lift. Complete functional loss of the sciatic nerve was found by clinical and electroneurographic examination on the left side in patient one and bilaterally in patient two. Full nerve conductance recovery was obtained after 6 months in both patients. Although the occurrence of spontaneous neuropathies after heavy weight loss is well documented, this is the first report describing the appearance of such a phenomenon following body contouring surgery. One theoretical explanation may be the compression of the nerve during the semirecumbent positioning combined with hip flexion and abduction, which was required for abdominal closure and simultaneous access to the inner thighs. We advise to avoid this positioning and to include the risk of sciatic neuropathy in the routine preoperative information of patients scheduled for body contouring surgery after heavy weight loss.

Background: Mutations in SCN4A may lead to myotonia. Methods: Presentation of a large family with myotonia, including molecular studies and patch clamp experiments using human embryonic kidney 293 cells expressing wild-type and mutated channels. Results: In a large family with historic data on seven generations and a clear phenotype, including myotonia at movement onset, with worsening by cold temperature, pregnancy, mental stress, and especially after rest after intense physical activity, but without weakness, the phenotype was linked with the muscle sodium channel gene ( SCN4A ) locus, in which a novel p.I141V mutation was found. This modification is located within the first transmembrane segment of domain I of the Na v 1.4 α subunit, a region where no mutation has been reported so far. Patch clamp experiments revealed a mutation-induced hyperpolarizing shift (−12.9 mV) of the voltage dependence of activation, leading to a significant increase (approximately twofold) of the window current amplitude. In addition, the mutation shifted the voltage dependence of slow inactivation by −8.7 mV and accelerated the entry to this state. Conclusions: We propose that the gain-of-function alteration in activation leads to the observed myotonic phenotype, whereas the enhanced slow inactivation may prevent depolarization-induced paralysis.

Transcranial magnetic stimulation allows to study the properties of the human corticospinal tract non-invasively. After a single transcranial magnetic stimulus, spinal motor neurons (MNs) sometimes fire not just once, but repetitively. The biological significance of such repetitive MN discharges (repMNDs) is unknown. To study the relation of repMNDs to other measures of cortico-muscular excitability and to physiological measures of the skill for finely tuned precision movements, we used a previously described quadruple stimulation (QuadS) technique (Z'Graggen et al. 2005) to quantify the amount of repMNDs in abductor digiti minimi muscles (ADMs) on both sides of 20 right-handed healthy subjects. Skillfulness for finger precision movements of both hands was assessed using a finger tapping task. In 16 subjects, a follow-up examination was performed after training of either precision movements (n = 8) or force (n = 8) of the left ADM. The size of the QuadS response (amplitude and area ratios) was greater in the dominant right hand than in the left hand (QuadS amplitude ratio: 47.1 +/- 18.1 versus 37.7 +/- 22.0%, Wilcoxon test: P0.05; QuadS area ratio: 49.7 +/- 16.2% versus 36.9 +/- 23.0%, Wilcoxon test: P0.05), pointing to a greater amount of repMNDs. Moreover, the QuadS amplitude and area increased significantly after finger precision training, but not after force training. This increase of repMNDs correlated significantly with the increase in performance in the finger tapping task. Our results demonstrate that repMNDs are related to handedness and therefore probably reflect supraspinal excitability differences. The increase of repMNDs after skills training but not after force training supports the hypothesis of a supraspinal origin of repMNDs.