The Role of Ultrasound for the Personalized Botulinum Toxin Treatment of Cervical Dystonia.

The visualization of the human body has frequently been groundbreaking in medicine. In the last few years, the use of ultrasound (US) imaging has become a well-established procedure for botulinum toxin therapy in people with cervical dystonia (CD). It is now undisputed among experts that some of the most relevant muscles in this indication can be safely injected under visual US guidance. This review will explore the method from basic technical considerations, current evidence to conceptual developments of the phenomenology of cervical dystonia. We will review the implications of introducing US to our understanding of muscle function and anatomy of common cervical dystonic patterns. We suggest a flow chart for the use of US to achieve a personalized treatment of people with CD. Thus, we hope to contribute a resource that is useful in clinical practice and that stimulates the ongoing development of this valuable technique.

[Treatment satisfaction in patients with cervical dystonia : Subgroup analysis of INTEREST-IN-CD-2]. / Behandlungszufriedenheit bei Patienten mit zervikaler Dystonie : Subgruppenanalyse von INTEREST-IN-CD-2.

BACKGROUND: Even though treatment guidelines recommend botulinum neurotoxin A (BoNT-A) as first line treatment for primary cervical dystonia (CD), there are only limited data on how BoNT-A-injections are administered in routine clinical practice. OBJECTIVE: This subgroup analysis evaluated patient satisfaction and symptom control under consideration of BoNT­A treatment modalities in German and Austrian CD patients (DE/AT, n = 79) compared to the full international cohort (n = 995). MATERIAL AND METHODS: The INTEREST-IN-CD2 was a prospective, multicenter, longitudinal observational study. Course of treatment in adult primary CD patients under BoNT­A treatment was assessed over a time period of 3 years. Primary outcome measure was the long-term satisfaction of patients with treatment, measured as maximum satisfaction between two consecutive injections as well as satisfaction at the time of reinjection. RESULTS: Treatment satisfaction at the maximum effect was stable and comparably good in both populations during the study (82.3-92.7% and 85.0-89.9%). Satisfaction decreased with decreasing BoNT­A effect at the end of the treatment interval: it was comparable at the start of the study in both groups (54.2% vs. 51.4%), decreased numerically in the DE/AT group to 32.7% but remained stable in the total population. Analysis of Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and Tsui scores did not reveal any substantial differences between the DE/AT subgroup and total cohort. CONCLUSION: Overall, the study confirmed good clinical symptom control by BoNT­A. The numerical differences in the current satisfaction seen in the comparison of DE/AT to the total cohort are possibly due to different proportions of BoNT­A naïve patients in both groups, as they expressed different levels of satisfaction than previously treated patients.

Detection radius of EMG for fasciculations: Empiric study combining ultrasonography and electromyography.

OBJECTIVE: The aims of this study were to investigate the detection radius and sensitivity of EMG for fasciculations. METHODS: Muscle ultrasonography was performed simultaneously to EMG recordings in patients with fasciculations in the context of amyotrophic lateral sclerosis. Ultrasonography and EMG parameters were analyzed for selected fasciculations. RESULTS: A total of 381 fasciculations were detected by ultrasonography in 18 muscles of 10 patients. Out of these, 125 (33%) were EMG-negative. In contrast, none of the fasciculations detected by EMG were ultrasonography-negative. EMG detection probability decreased significantly with increasing distance from the center of the fasciculation. EMG detection rate was 98% when the EMG needle was located within the fasciculation and 50% at 7.75 mm distance from the fasciculation center. In addition, EMG detection depended significantly on cross-sectional area of the fasciculation and presence of neurogenic changes. CONCLUSIONS: For detecting the same fasciculations, EMG is less sensitive than ultrasonography. EMG detection probability decreases sharply at a distance comparable to motor unit size. SIGNIFICANCE: These results extend previous knowledge about superior sensitivity of ultrasonography for fasciculations. Moreover, our novel bimodal detection method provides first in vivo data about the EMG detection radius for fasciculations in a clinical setting.

Evaluation of a laser-based sensor for the diagnosis of neurological disorders.

Involuntary muscle activities like fasciculations or tremor are an indication for several neurological disorders. However, currently used techniques for measuring those activities are limited due to their invasiveness, the unsuitability for measuring a whole body simultaneously and the lack of an objective measurement of amplitude and duration of muscle activity. Hence, we developed a new laser-based sensor for the remote quantification of muscle activity. In the present paper we show a basic evaluation of our system by reference to ultrasound measurements. Our results show the detection limits of our remote sensor technology in terms of fasciculation size and depth within the muscle. Those results will help us for a better interpretation of our measurement results and hold promise for the future development of our system.

Combined accelerometer and EMG analysis to differentiate essential tremor from Parkinson's disease.

In this study, we intended to differentiate patients with essential tremor (ET) from tremor dominant Parkinson disease (PD). Accelerometer and electromyographic signals of hand movement from standardized upper extremity movement tests (resting, holding, carrying weight) were extracted from 13 PD and 11 ET patients. The signals were filtered to remove noise and non-tremor high frequency components. A set of statistical features was then extracted from the discrete wavelet transformation of the signals. Principal component analysis was utilized to reduce dimensionality of the feature space. Classification was performed using support vector machines. We evaluated the proposed method using leave one out cross validation and we report overall accuracy of the classification. With this method, it was possible to discriminate 12/13 PD patients from 8/11 patients with ET with an overall accuracy of 83%. In order to individualize this finding for clinical application we generated a posterior probability for the test result of each patient and compared the misclassified patients, or low probability scores to available clinical follow up information for individual cases. This non-standardized post hoc analysis revealed that not only the technical accuracy but also the clinical accuracy limited the overall classification rate. We show that, in addition to the successful isolation of diagnostic features, longitudinal and larger sized validation is needed in order to prove clinical applicability.

Ultrasound and electrophysiologic findings in patients with Guillain-Barré syndrome at disease onset and over a period of six months.

OBJECTIVE: To investigate cross-sectional areas (CSAs) of several peripheral nerves including the vagus nerve and the diameter of spinal nerves as measured by nerve ultrasound (NUS) and nerve conduction studies (NCS) in Guillain-Barré syndrome (GBS) patients over at least six months compared to healthy controls. METHODS: NUS and/or NCS of several nerves, the vagus nerve, and the 5th/6th cervical spinal nerves were performed in patients with GBS at days 2-3 after symptom onset, at days 10-14 after immunoglobulin therapy and after six months compared to healthy controls. RESULTS: 27 GBS-patients and 31 controls were included. Using NUS significant enlargement was found in all measured nerves (P<0.001), except the sural nerve (P=0.086) compared to the controls at onset. The vagus (median 3.0 mm(2) vs. 2.0 mm(2), P<0.0001) and the cervical spinal nerves were significantly enlarged (median 3.5/4.0 mm vs. 2.6/3.2 mm, p<0.0001), the vagus most obviously in patients with autonomic dysregulation (AD, 4.0 mm(2)). Six months later, NCS showed persisting pathology in CMAP-amplitudes with amelioration of F-wave pathology. NUS showed restitution in the spinal nerves (median 2.6/3.2 mm) and the vagus (median 2.0 mm(2)) in all patients excluding the vagus in those with persistent AD (median 4.0 mm(2)). The peripheral nerves did not change significantly (P>0.05). CONCLUSION: Ultrasonographic detection of cervical spinal nerve enlargement supports the diagnosis of GBS in the early phase. Its regression may be a good parameter for the clinical restitution over time. Vagus enlargement may be a risk marker for development of AD. SIGNIFICANCE: Ultrasound is a reliable diagnostic follow-up tool in early GBS.

Increased intima-media thickness in rayon workers after long-term exposure to carbon disulfide.

INTRODUCTION: Long-term exposure to carbon disulfide (CS2) is associated with increased cardiovascular mortality. However, previous studies on actual vascular changes showed heterogeneous results. Intima-media thickness of the carotid arteries (IMT) represents an established marker of atherosclerosis and a reasonable surrogate marker for cardiovascular risk. IMT was examined in a large cohort of CS2 exposed workers and the association with cumulative CS2 exposure analysed. METHODS: In a cross-sectional examination, 290 exposed and 137 non-exposed workers in a German rayon-manufacturing plant were assessed. Individual cumulative exposure was calculated from this assessment combined with the results of two cross-sectional studies in 1992 and 1999 and department-specific annual means of ambient (CECS2) and individual biological (CETTCA) monitoring results obtained 1992-2009. Furthermore, cumulative duration of working in CS2-exposed departments (CEYEARS) was calculated. Examination included assessment of a broad set of known cardiovascular risk factors and IMT measurement of the carotid arteries on both sides. Multiple linear regression analyses were performed with IMT as outcome and three variants of cumulative exposure (duration of exposure, cumulative CS2, and cumulative TTCA) as well as categorised maximum CS2 exposure, all adjusted for cardiovascular risk factors. RESULTS: All models of cumulative exposure showed a significant increase in IMT in the group with the highest level of exposure: CEYEARS > 20 years, ß = 0.045 mm; CECS2 > 270 ppm × years, ß = 0.052 mm; CETTCA > 33 mg/g creatinine × years, ß = 0.038 mm. Alternatively, addressing maximum exposure, workers with CS2 exposure of >10 ppm in at least 3 years exhibited a significant IMT increase (ß = 0.068 mm). CONCLUSION: Long-term CS2 exposure is an independent risk factor concerning IMT changes. The amount of IMT increase, in a similar range as that associated with other cardiovascular risk factors, might be clinically relevant.

Assessing viability of extracorporeal preserved muscle transplants using external field stimulation: a novel tool to improve methods prolonging bridge-to-transplantation time.

Preventing ischemia-related cell damage is a priority when preserving tissue for transplantation. Perfusion protocols have been established for a variety of applications and proven to be superior to procedures used in clinical routine. Extracorporeal perfusion of muscle tissue though cumbersome is highly desirable since it is highly susceptible to ischemia-related damage. To show the efficacy of different perfusion protocols external field stimulation can be used to immediately visualize improvement or deterioration of the tissue during active and running perfusion protocols. This method has been used to show the superiority of extracorporeal perfusion using porcine rectus abdominis muscles perfused with heparinized saline solution. Perfused muscles showed statistically significant higher ability to exert force compared to nonperfused ones. These findings can be confirmed using Annexin V as marker for cell damage, perfusion of muscle tissue limits damage significantly compared to nonperfused tissue. The combination of extracorporeal perfusion and external field stimulation may improve organ conservation research.

Ultrasound in dual nerve impairment after proximal radial nerve lesion.

INTRODUCTION: Sonography in classical nerve entrapment syndromes is an established and validated method. In contrast, few publications highlight lesions of the radial nerve, particularly of the posterior interosseus nerve (PIN). METHOD: Five patients with a radial nerve lesion were investigated by electromyography, nerve conduction velocity and ultrasound. Further normative values of 26 healthy subjects were evaluated. RESULTS: Four patients presented a clinical and electrophysiological proximal axonal radial nerve lesion and one patient showed a typical posterior interosseous nerve syndrome (PINS). The patient with PINS presented an enlargement of the PIN anterior to the supinator muscle. However four patients with proximal lesions showed an unexpected significant enlargement of the PIN within the supinator muscle. CONCLUSION: High-resolution sonography is a feasible method to demonstrate the radial nerve including its distal branches. At least in axonal radial nerve lesions, sonography might reveal abnormalities far distant from a primary proximal lesion site clearly distinct from the appearance in classical PINS.

Relevance of sonography for botulinum toxin treatment of cervical dystonia: an expert statement.

Botulinum neurotoxin A (BoNT A) is the first-line treatment for cervical dystonia. However, although BoNT A has a favorable safety profile and is effective in the majority of patients, in some cases the treatment outcome is disappointing or side effects occur when higher doses are used. It is likely that in such cases either the target muscles were not injected accurately or unintended weakness of non-target muscles occurred. It has been demonstrated in clinical trials for spastic movement disorders that sonography-guided BoNT A injections could improve treatment outcome. As the published evidence for a benefit of sonography-guided BoNT injection in patients with cervical dystonia is scarce, it is the aim of this review to discuss the relevance of sonography in this indication and provide a statement from clinical experts for its use. The clear advantage of sonography-guided injections is non-invasive, real-time visualization of the targeted muscle, thus improving the precision of injections and potentially the treatment outcomes as well as avoiding adverse effects. Other imaging techniques are of limited value due to high costs, radiation exposure or non-availability in clinical routine. In the hands of a trained injector, sonography is a quick and non-invasive imaging technique. Novel treatment concepts of cervical dystonia considering the differential contributions of distinct cranial and cervical muscles can reliably be implemented only by use of imaging-guided injection protocols.

Spasticity treatment with onabotulinumtoxin A: data from a prospective German real-life patient registry.

This study aimed at providing real-life baseline, injection and outcome data for the treatment of various forms of spasticity with onabotulinumtoxin A in Germany. Prospective data were collected in an open multicenter patient registry from 2005 until 2010, encompassing the experience of ten specialized German centers in the treatment of spasticity using onabotulinumtoxin A in 508 patients with a total of 2005 treatment sessions. Disease entities comprised spasticity following stroke (both ischemic and hemorrhagic), traumatic brain injury, multiple sclerosis, cerebral palsy, and anoxia. Sustained improvement was observed in a variety of outcome parameters including goal attainment and motor performance scores for up to five repeated injection sessions. No significant differences between disease entities or between upper and lower limb treatment were observed with regard to efficacy and safety following onabotulinumtoxin A treatment. Minor to moderate side effects were reported in <1 % of the study population. We conclude that repetitive treatment of focal and multifocal spasticity with onabotulinumtoxin A provides a safe and efficacious therapeutic strategy for patients with different disease entities of the central nervous system.

Current and historical individual data about exposure of workers in the rayon industry to carbon disulfide and their validity in calculating the cumulative dose.

INTRODUCTION: The objective of the study was to investigate how exposure to carbon disulfide (CS2) in a rayon-manufacturing plant has changed within two decades and whether it is possible to calculate valid data for the individual cumulative exposure. METHODS: The data for CS2 concentration in air and biological exposure monitoring (2-thio-1,3-thiaxolidine-4-carboxylic acid (TTCA) in urine) from two cross-sectional studies, performed in 1992 (n = 362) and 2009 (n = 212) in a German rayon-manufacturing plant, were compared to data obtained from company-internal measurements between the studies. RESULTS: Using the data from the cross-sectional studies and company-internal data, cumulative external exposure and the cumulative internal exposure were calculated for each worker. External and internal CS2 exposure of the employees decreased from 1992 (medians 4.0 ppm and 1.63 mgTTCA/g creatinine) to 2009 (medians 2.5 ppm and 0.86 mg/g). However, company-internal CS2 data do not show a straight trend for this period. The annual medians of the company-internal measurement of external exposure to CS2 have varied between 2.7 and 8.4 ppm, in which median values exceeded 5 ppm generally since 2000. The annual medians for the company-internal biomonitoring assessment ranged between 1.2 and 2.8 mg/g creatinine. The cumulative CS2 exposure ranged from 8.5 to 869.5 ppm years for external exposure and between 1.30 and 176.2 mg/g creatinine years for the internal exposure. Significant correlations were found between the current air pollution and the internal exposure in 2009 but also between the cumulative external and internal CS2 exposure. CONCLUSIONS: Current exposure data, usually collected in cross-sectional studies, rarely allow a reliable statement on the cumulative dose, because of higher exposure in the past and of fluctuating courses of exposure. On the other hand, company-internal exposure data may be affected by non-representative measurement strategies. Some verification of the reliability of cumulative exposure data may be possible by testing the correlation between cumulative exposure data of external assessment and biological monitoring.

Subjective outcome, neurophysiological investigations, postoperative complications and recurrence rate of partial medial epicondylectomy in cubital tunnel syndrome.

The aim of the study was to evaluate the clinical outcome with subjective and neurophysiological parameters following partial medial epicondylectomy (pME) and to evaluate complications and recurrence rates. A retrospective analysis was performed in 29 patients (18 males and 11 females) with cubital tunnel syndrome (CuTS) who underwent pME. Mean time follow-up was 41.4 months. For subjective parameters, DASH (Disabilities of Arm, Shoulder and Hand), a self-created questionnaire about postoperative satisfaction and a visual pain scale (VAS) have been used. All patients were classified according to the Mc Gowan Classification (McG) and Wilson & Krout Classification (WKC). The patients were examined by nerve conduction velocity. Total mean of the DASH score was 24.8 points. In a questionnaire with integrated pain score (1-5), 96% of the patients declared a postoperative improvement, whereas 41.4% patients of the latter group were very contented with the results, 37.9% were contented, 17.2% were less contented and 3.4% were discontented. The VAS for evaluation of postoperative pain showed an average of 2.36 (0-5.9) out of 10. Of the patients, 68.0% were classified as grade I according to McG and 68.0% as excellent or good according to WKC. Motor nerve conduction velocity improved from 34.8 m/s preoperatively to 48.2 m/s postoperatively. One patient developed a haematoma and three patients (10.3%) had to be classified as recurrence. High postoperative rates of patient satisfaction and improved neurophysiological results could be achieved by pME.

Loss of topographic specificity of LTD-like plasticity is a trait marker in focal dystonia.

In focal hand dystonia, long-term potentiation (LTP) and depression (LTD)-like neuronal plasticity, as assessed by paired associative stimulation (PAS) targeting the hand-associated motor cortex, is enhanced and the topographic organization of plasticity is lost. However, if any of these abnormalities alone is sufficient to cause focal dystonia (FD) remains unknown. Ten patients with cervical dystonia (CD), 9 with blepharospasm (BS) and 16 age- and sex-matched controls were examined. PAS was performed by combining repetitively electric stimulation of the median nerve with subsequent transcranial magnetic stimulation of the contralateral motor cortex at 21.5ms (PAS21.5) and 10ms (PAS10). Corticospinal excitability was indexed by the magnitude of motor evoked potentials (MEPs) recorded from abductor pollicis brevis (APB) and abductor digiti minimi (ADM) muscles. In controls, MEP size of the homotopically conditioned APB increased after PAS21.5 whereas the MEP size of the heterotopically conditioned ADM remained stable. PAS10 led to a decrease of MEP size of the APB and to an increase of the heterotopic ADM. In contrast, after PAS21.5 and PAS10 in CD and BS MEP size increased and decreased, respectively, in both muscles. The magnitude of excitability changes, however, did not differ between dystonic patients and healthy controls. In FD the topographic organization of PAS21.5 and PAS10-induced plasticity is deranged in cortical areas not involved in the control of the dystonic body part. Somatotopical disorganization of plasticity may represent an endophenotypic trait in FD but may not be sufficient to generate a dystonic phenotype. Development of a dystonic phenotype may require that the gain of plasticity is additionally enhanced. This article is part of a Special Issue entitled "Advances in dystonia".

Objective outcome of partial medial epicondylectomy in cubital tunnel syndrome.

AIM: Goal of the study was to evaluate the clinical outcome in cubital tunnel syndrome (CuTS) after partial medial epicondylectomy (pME) with objective parameters. METHOD: A retrospective analysis was performed in 29 (18 male/11 female) patients with CuTS who underwent pME. Mean time follow-up was 41.4 months. Parameters assessed sensibility (two point discrimination (2PD) and Semmes Weinstein Monofilaments (SW)) of the fifth finger and grip and pinch strength. In addition, elbow range of motion, elbow instability, medial elbow pain, Froment sign and Tinel`s sign were evaluated. RESULTS: Postoperative static 2PD of the fifth finger was 12.6 mm. SW values on the operated side (mean 3.58; 2.44-6.65) were comparable to the non-operated side (mean 3.28; 2.44-4.93). Tinel's sign over the ulnar sulcus was positive in 13 cases preoperative and in 16 cases postoperatively. Range of motion of the elbow joint achieved normal values in flexion/extension and pronation/supination with no significant difference in comparison to the non-operated side. Froment sign was positive in 2 cases, negative in 23 cases. Grip strength averaged 48.1 kg in man versus 24.4 kg in women. Pinch strength was 8.6 versus 5.3 kg. Grip strength on the operated side reached up to 91.0% values of the opposite arm. CONCLUSION: Good postoperative objective results were reached by pME. pME is an adequate treatment option in CuTS.

Task-specific craniocervical dystonia.

The pathophysiology of dystonia is incompletely understood. Unlike many other focal dystonias, cervical dystonia, a frequent dystonia leading to twisting of the head, does not appear to be related to overuse or acquisition of a demanding motor skill. Here, we report development of task-specific dystonia of the neck muscles in a 67-year-old patient following bilateral traumatic arm amputation at the age of 15. To compensate for the amputation, the patient learned to write with a pen held in his mouth. After several years of practicing this unusual and demanding skill, symptoms of task-specific cervical dystonia (CD) developed. This dystonia later became permanent, and independent of the motor activity that initially triggered the dystonic muscular contractions. This singular case raises the possibility that the pathophysiology of CD may share common elements with that of focal dystonias in different body regions.

LTP-like changes induced by paired associative stimulation of the primary somatosensory cortex in humans: source analysis and associated changes in behaviour.

Paired associative stimulation (PAS), which combines repetitive peripheral nerve stimulation with transcranial magnetic stimulation (TMS), may induce neuroplastic changes in somatosensory cortex (S1), possibly by long-term potentiation-like mechanisms. We used multichannel median nerve somatosensory evoked potential (MN-SSEP) recordings and two-point tactile discrimination testing to examine the location and behavioural significance of these changes. When TMS was applied to S1 near-synchronously to an afferent signal containing mechanoreceptive information, MN-SSEP changes (significant at 21-31 ms) could be explained by a change in a tangential source located in Brodmann area 3b, with their timing and polarity suggesting modification of upper cortical layers. PAS-induced MN-SSEP changes between 28 and 32 ms were linearly correlated with changes in tactile discrimination. Conversely, when the near-synchronous afferent signal contained predominantly proprioceptive information, PAS-induced MN-SSEP changes (20-29 ms) were shifted medially, and tactile performance remained stable. With near-synchronous mechanoreceptive stimulation subtle differences in the timing of the two interacting signals tended to influence the direction of tactile performance changes. PAS performed with TMS delivered asynchronously to the afferent pulse did not change MN-SSEPs. Hebbian interaction of mechanoreceptive afferent signals with TMS-evoked activity may modify synaptic efficacy in superficial cortical layers of Brodmann area 3b and is associated with timing-dependent and qualitatively congruent behavioural changes.

Characteristics of sensory trick-like manoeuvres in jaw-opening dystonia.

We evaluated the effect of different manipulations on the performance of a standardized counting task in 7 patients with idiopathic jaw-opening dystonia. Patients used a small stick as sensory stimulus. Following conditions were examined: stick placed between teeth and cheek (CHEEK), biting on stick (TEETH), voluntary jaw occlusion without stick (OCCLUSION). Articulation was rated by patients and experimenters and surface electromyographic activity (EMG) was recorded. Patient-rating (CHEEK - 36.6%, TEETH - 48.1%) and EMG (-18.1%; -17.3%) were significantly improved for conditions using the stick, whereas experimenter-rating showed a trend for TEETH (-16.2%). Although jaw occlusion during speaking deteriorates articulation in healthy subjects, there was no further deterioration in patients and EMG was even significantly reduced (-18.6%). Comparable results were obtained in 1 patient using a special dental device. We conclude that sensory tricks significantly improve subjective and objective parameters. Besides tactile stimulation, altered proprioceptive feedback and antagonist activation may modulate hyperactive dystonic networks.