To determine if mexiletine is safe and effective in reducing myotonia in myotonic dystrophy type 1 (DM1).
Myotonia is an early, prominent symptom in DM1 and contributes to decreased dexterity, gait ...instability, difficulty with speech/swallowing, and muscle pain. A few preliminary trials have suggested that the antiarrhythmic drug mexiletine is useful, symptomatic treatment for nondystrophic myotonic disorders and DM1.
We performed 2 randomized, double-blind, placebo-controlled crossover trials, each involving 20 ambulatory DM1 participants with grip or percussion myotonia on examination. The initial trial compared 150 mg of mexiletine 3 times daily to placebo, and the second trial compared 200 mg of mexiletine 3 times daily to placebo. Treatment periods were 7 weeks in duration separated by a 4- to 8-week washout period. The primary measure of myotonia was time for isometric grip force to relax from 90% to 5% of peak force after a 3-second maximum grip contraction. EKG measurements and adverse events were monitored in both trials.
There was a significant reduction in grip relaxation time with both 150 and 200 mg dosages of mexiletine. Treatment with mexiletine at either dosage was not associated with any serious adverse events, or with prolongation of the PR or QTc intervals or of QRS duration. Mild adverse events were observed with both placebo and mexiletine treatment.
Mexiletine at dosages of 150 and 200 mg 3 times daily is effective, safe, and well-tolerated over 7 weeks as an antimyotonia treatment in DM1.
This study provides Class I evidence that mexiletine at dosages of 150 and 200 mg 3 times daily over 7 weeks is well-tolerated and effective in reducing handgrip relaxation time in DM1.
To quantitate improvement in hand‐grip myotonia and muscle strength (i.e., the “warm‐up” phenomenon) in myotonic dystrophy type 1 (DM1), six successive, standardized maximum voluntary isometric ...contractions (MVICs) were recorded on 2 separate days using a computerized isometric hand‐grip myometer in 25 genetically confirmed DM1 patients and in 17 normal controls. An automated computer program placed cursors along the declining (relaxation) phase of the MVICs at 90%, 50%, and 5% of peak force (PF) and calculated relaxation times (RTs) between these points. Mean 90% to 5% RT (a measure of myotonia) rapidly declined from 2.5 s in MVIC 1 to 0.8 s in MVIC 6 (warm‐up = 1.7 s) in DM1; in controls, it remained 0.4 s for all six MVICs (warm‐up = 0). In DM1, 70% of warm‐up occurred between MVIC 1 and 2, almost exclusively in the terminal 50% to 5% phase of muscle relaxation. Day 1 warm‐up was highly correlated with the severity of myotonia, and with day 2 warm‐up. Improvement in myotonia was not accompanied by either transient paresis or improvement in PF. We conclude that, with this testing paradigm: warm‐up of myotonia in DM1 can be reliably measured; is proportional to severity of myotonia; occurs rapidly, being most prominent between the first and second grips; mainly results from shortening of the terminal phase of muscle relaxation; and is not accompanied by significant warm‐up in force output. Muscle Nerve, 2005
To quantitate hand muscle myotonia and to assess the relationship between CTG repeat length and myotonia in myotonic dystrophy type 1 (DM1).
First dorsal interosseous twitch and tetanic contractions ...evoked by single and 10-Hz ulnar nerve stimulation were recorded with a force transducer in 15 patients with genetically confirmed DM1 and 15 control subjects. An automated computer program analyzed three single and three tetanic recordings per subject on 2 successive days by placing cursors along the declining (relaxation) phase of the force recordings at 90, 50, and 5% of peak force (PF) and calculating relaxation times (RT) between these points.
Tetanic and twitch RT was longer and PF lower in patients than subjects. RT (90 to 5%) was above the normal mean + 2.5 SD in 13 tetanic (87%) and 11 (73%) twitch patient recordings. In DM1, prolongation of RT was due mainly to delay in the terminal (50 to 5%), rather than the initial (90 to 50%) phase of relaxation, and was much greater in tetanic than single-twitch recordings. Mean test-retest variability was 19% for tetanic RT and 16% for tetanic PF. In DM1, both tetanic and twitch RT were positively correlated with leukocyte CTG repeat length.
In DM1, myotonia of intrinsic hand muscles can be quantitated reliably by automated analysis of tetanic and twitch RT, targeting, in particular, the terminal phase of muscle relaxation after tetanic stimulation. Severity of hand muscle myotonia depends on CTG repeat length consistent with a "triplet repeat dosage" effect on chloride channel mRNA splicing and function.
With the establishment of ceilometer networks by national weather services, a discussion commenced to which extent these simple backscatter lidars can be used for aerosol research. Though primarily ...designed for the detection of clouds it was shown that at least observations of the vertical structure of the boundary layer might be possible. However, an assessment of the potential of ceilometers for the quantitative retrieval of aerosol properties is still missing. In this paper we discuss different retrieval methods to derive the aerosol backscatter coefficient βp, with special focus on the calibration of the ceilometers. Different options based on forward and backward integration methods are compared with respect to their accuracy and applicability. It is shown that advanced lidar systems such as those being operated in the framework of the European Aerosol Research Lidar Network (EARLINET) are excellent tools for the calibration, and thus βp retrievals based on forward integration can readily be implemented and used for real-time applications. Furthermore, we discuss uncertainties introduced by incomplete overlap, the unknown lidar ratio, and water vapor absorption. The latter is relevant for the very large number of ceilometers operating in the spectral range around λ = 905–910 nm. The accuracy of the retrieved βp mainly depends on the accuracy of the calibration and the long-term stability of the ceilometer. Under favorable conditions, a relative error of βp on the order of 10% seems feasible. In the case of water vapor absorption, corrections assuming a realistic water vapor distribution and laser spectrum are indispensable; otherwise errors on the order of 20% could occur. From case studies it is shown that ceilometers can be used for the reliable detection of elevated aerosol layers below 5 km, and can contribute to the validation of chemistry transport models, e.g., the height of the boundary layer. However, the exploitation of ceilometer measurements is still in its infancy, so more studies are urgently needed to consolidate the present state of knowledge, which is based on a limited number of case studies.
The spatial structure and the progression speed of the first ash layer from the Icelandic Eyjafjallajökull volcano which reached Germany on 16/17 April is investigated from remote sensing data and ...numerical simulations. The ceilometer network of the German Meteorological Service was able to follow the progression of the ash layer over the whole of Germany. This first ash layer turned out to be a rather shallow layer of only several hundreds of metres thickness which was oriented slantwise in the middle troposphere and which was brought downward by large-scale sinking motion over Southern Germany and the Alps. Special Raman lidar measurements, trajectory analyses and in-situ observations from mountain observatories helped to confirm the volcanic origin of the detected aerosol layer. Ultralight aircraft measurements permitted the detection of the arrival of a second major flush of volcanic material in Southern Germany. Numerical simulations with the Eulerian meso-scale model MCCM were able to reproduce the temporal and spatial structure of the ash layer. Comparisons of the model results with the ceilometer network data on 17 April and with the ultralight aircraft data on 19 April were satisfying. This is the first example of a model validation study from this ceilometer network data.
1. The aim of this study was to investigate the role of the antagonist muscle in determining the accuracy of fast, single-joint motor responses to a target. We recently found that C5/C6 tetraplegic ...subjects, who lacked voluntary control of their triceps muscle, were less accurate than control subjects in producing fast flexion movements to a target. 2. Two hypotheses are proposed to account for these larger errors: 1) the ability of tetraplegic subjects to compensate for errors arising early in the motor response is impaired because of the lack of antagonist muscle activation; or 2) tetraplegic subjects lack antagonist (braking) force, so they must use much smaller accelerative forces when they move, in order to avoid overshooting their target. Because studies have shown that low levels of force are produced with less relative accuracy than larger forces, this relative inaccuracy of force generation by the motor control system at low force levels is responsible for the inaccuracy of tetraplegics' movements. To test these two hypotheses, we compared the variability of "fast and accurate as possible" force pulses in four control subjects and four C5/C6 tetraplegic subjects to targets at 15, 30, and 45% of maximum voluntary contraction. Multiple regression analyses were performed to look for patterns of agonist or antagonist muscle activation consistent with compensatory adjustments for early trajectory errors in both groups of subjects. 3. Force rise time was significantly prolonged in tetraplegic subjects, although there was some overlap between groups. At similar levels of effort, there were no significant differences in constant and variable errors of control and tetraplegic subjects. We also found no consistent statistical evidence for the presence of compensatory electromyographic activity in either group of subjects. Subjects who lacked the ability to make corrections involving the triceps muscle performed as well as subjects with normal triceps strength. This suggests that a corrective mechanism involving the triceps must have a weak role, if any, in these experiments. 4. Together with our observation that lower force targets are indeed associated with larger relative variable errors, in both control and tetraplegic subjects, the above results lead us to conclude that the second hypothesis listed above is more likely correct. The antagonist muscle clearly enables the production of briefer force pulses. In addition, the antagonist indirectly contributes to the accuracy of isotonic movements because antagonist braking allows larger agonist forces to be used. These larger agonist forces are less variable, and produce more accurate movements, than the smaller forces used by tetraplegic subjects.
Abstract Purpose To explore the relationship between pathologic tumor volume and volume estimated from different tumor segmentation techniques on18 F-fluorodeoxyglucose (FDG) positron emission ...tomography (PET) in oral cavity cancer. Materials and methods Twenty-three patients with squamous cell carcinoma of the oral tongue had PET–CT scans before definitive surgery. Pathologic tumor volume was estimated from surgical specimens. Metabolic tumor volume (MTV) was defined from PET–CT scans as the volume of tumor above a given SUV threshold. Multiple SUV thresholds were explored including absolute SUV thresholds, relative SUV thresholds, and gradient-based techniques. Results Multiple MTV’s were associated with pathologic tumor volume; however the correlation was poor ( R2 range 0.29–0.58). The ideal SUV threshold, defined as the SUV that generates an MTV equal to pathologic tumor volume, was independently associated with maximum SUV ( p = 0.0005) and tumor grade ( p = 0.024). MTV defined as a function of maximum SUV and tumor grade improved the prediction of pathologic tumor volume ( R2 = 0.63). Conclusions Common SUV thresholds fail to predict pathologic tumor volume in head and neck cancer. The optimal technique that allows for integration of PET–CT with radiation treatment planning remains to be defined. Future investigation should incorporate biomarkers such as tumor grade into definitions of MTV.
The smoothness with which movements are customarily performed has led Hogan (1984) to formulate a model for trajectory planning by the central nervous system in which the goal is to maximize ...smoothness, one measure of which is the integrated mean squared magnitude of jerk (jerk cost). We tested the applicability of this minimum-jerk model to one-joint goal directed movements performed by human subjects at different speeds and amplitudes, by comparing kinematic parameters and the jerk cost predicted by the mathematical model with values calculated from experimental data. We also tested a higher order, minimum-snap kinematic model. Normal subjects performed elbow flexions of 5 to 50 degrees "as rapidly and accurately as possible" and also at slower speeds. The boundary conditions of both models were adjusted to account for the failure of subjects to produce movements which reached equilibrium precisely at the target (so that acceleration and velocity reached zero together). Typically, fast movements (less than 300 ms duration) were fairly symmetric in that the durations and amplitudes of acceleration and deceleration were approximately equal; slower movements (greater than 300 ms) were asymmetric with strong, brief acceleration peaks and broad, slow deceleration peaks. In fast movements, the calculated jerk cost was consistently higher than predicted by the minimum-jerk model; a good fit to all kinematic parameters was provided by the minimum-snap model (a seventh-order polynomial). Neither model consistently predicted the trajectories of slower movements. We conclude that muscle/limb dynamics can account for the success of the minimum-snap model with fast movements, and that there is no evidence of planning for maximal smoothness in slower movements.
To evaluate an implanted neuroprosthesis that allows tetraplegic users to control grasp and release in 1 hand.
Multicenter cohort trial with at least 3 years of follow-up. Function for each ...participant was compared before and after implantation, and with and without the neuroprosthesis activated.
Tertiary spinal cord injury (SCI) care centers, 8 in the United States, 1 in the United Kingdom, and 1 in Australia.
Fifty-one tetraplegic adults with C5 or C6 SCIs.
An implanted neuroprosthetic system, in which electric stimulation of the grasping muscles of 1 arm are controlled by using contralateral shoulder movements, and concurrent tendon transfer surgery. Assessed participants' ability to grasp, move, and release standardized objects; degree of assistance required to perform activities of daily living (ADLs), device usage; and user satisfaction.
Pinch force; grasp and release tests; ADL abilities test and ADL assessment test; and user satisfaction survey.
Pinch force was significantly greater with the neuroprosthesis in all available 50 participants, and grasp-release abilities were improved in 49. All tested participants (49/49) were more independent in performing ADLs with the neuroprosthesis than they were without it. Home use of the device for regular function and exercise was reported by over 90% of the participants, and satisfaction with the neuroprosthesis was high.
The grasping ability provided by the neuroprosthesis is substantial and lasting. The neuroprosthesis is safe, well accepted by users, and offers improved independence for a population without comparable alternatives.
Fast isometric elbow flexor muscle contractions of specified amplitude in six normal subjects were compared with those of 11 patients with Parkinson's disease. Despite treatment, all patients ...exhibited deficits in this motor task. Three patients were able to produce rapid force pulses with normal contraction times, but the variability of their force responses was increased in comparison with the highly stereotyped responses produced by normal subjects. The other eight patients had prolonged contraction times and segmentation of the force profiles. The integrated area of the first agonist EMG burst and the rate of development of force (dF/dt) were less at any target level than what was needed to produce a fast response. The area of the EMG burst, however, did increase with target amplitude, and the relative increase of dF/dt, with target amplitude, was normal. It is concluded that the motor program subserving fast muscle contraction is preserved in Parkinson's disease, but its execution is characterised by improper scaling of motor output.
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