Abstract Primary torsion dystonia (PTD) is a chronic movement disorder manifested clinically by focal or generalized sustained muscle contractions, postures, and/or involuntary movements. The most ...common inherited form of PTD is associated with the DYT1 mutation on chromosome 9q34. A less frequent form is linked to the DYT6 locus on chromosome 8q21-22. Both forms are autosomal dominant with incomplete (∼30%) clinical penetrance. Extensive functional and microstructural imaging with positron emission tomography (PET) and diffusion tensor MRI (DTI) has been performed on manifesting and non-manifesting carriers of these mutations. The results are consistent with the view of PTD as a neurodevelopmental circuit disorder involving cortico-striatal-pallido-thalamocortical (CSPTC) and related cerebellar–thalamo-cortical pathways. Studies of resting regional metabolism have revealed consistent abnormalities in PTD involving multiple interconnected elements of these circuits. In gene carriers, changes in specific subsets of these regions have been found to relate to genotype, phenotype, or both. For instance, genotypic abnormalities in striatal metabolic activity parallel previously reported reductions in local D2 receptor availability. Likewise, we have identified a unique penetrance-related metabolic network characterized by increases in the pre–supplementary motor area (SMA) and parietal association areas, associated with relative reductions in the cerebellum, brainstem, and ventral thalamus. Interestingly, metabolic activity in the hypermetabolic areas has recently been found to be modified by the penetrance regulating D216H polymorphism. The DTI data raise the possibility that metabolic abnormalities in mutation carriers reflect adaptive responses to developmental abnormalities in the intrinsic connectivity of the motor pathways. Moreover, findings of increased motor activation responses in these subjects are compatible with the reductions in cortical inhibition that have been observed in this disorder. Future research will focus on clarifying the relationship of these changes to clinical penetrance in dystonia mutation carriers, and the reversibility of disease-related functional abnormalities by treatment.
Surface electromyography (sEMG) can be used to measure the electrical activity of the respiratory muscles. The possible applications of sEMG span from patients suffering from acute respiratory ...failure to patients receiving chronic home mechanical ventilation, to evaluate muscle function, titrate ventilatory support and guide treatment. However, sEMG is mainly used as a monitoring tool for research and its use in clinical practice is still limited-in part due to a lack of standardization and transparent reporting. During this round table meeting, recommendations on data acquisition, processing, interpretation, and potential clinical applications of respiratory sEMG were discussed. This paper informs the clinical researcher interested in respiratory muscle monitoring about the current state of the art on sEMG, knowledge gaps and potential future applications for patients with respiratory failure.
Neuromuscular electrical stimulation (NMES) has been investigated as a preventative measure for intensive care unit-acquired weakness. Trial results remain contradictory and therefore inconclusive. ...As it has been shown that NMES does not necessarily lead to a contractile response, our aim was to characterise the response of critically ill patients to NMES and investigate potential outcome benefits of an adequate contractile response.
This is a sub-analysis of a randomised controlled trial investigating early muscle activating measures together with protocol-based physiotherapy in patients with a SOFA score ≥ 9 within the first 72 h after admission. Included patients received protocol-based physiotherapy twice daily for 20 min and NMES once daily for 20 min, bilaterally on eight muscle groups. Electrical current was increased up to 70 mA or until a contraction was detected visually or on palpation. Muscle strength was measured by a blinded assessor at the first adequate awakening and ICU discharge.
One thousand eight hundred twenty-four neuromuscular electrical stimulations in 21 patients starting on day 3.0 (2.0/6.0) after ICU admission were included in this sub-analysis. Contractile response decreased from 64.4% on day 1 to 25.0% on day 7 with a significantly lower response rate in the lower extremities and proximal muscle groups. The electrical current required to elicit a contraction did not change over time (day 1, 50.2 31.3/58.8 mA; day 7, 45.3 38.0/57.5 mA). The electrical current necessary for a contractile response was higher in the lower extremities. At the first awakening, patients presented with significant weakness (3.2 2.5/3.8 MRC score). When dividing the cohort into responders and non-responders (> 50% vs. ≤ 50% contractile response), we observed a significantly higher SOFA score in non-responders. The electrical current necessary for a muscle contraction in responders was significantly lower (38.0 32.8/42.9 vs. 54.7 51.3/56.0 mA, p < 0.001). Muscle strength showed higher values in the upper extremities of responders at ICU discharge (4.4 4.1/4.6 vs. 3.3 2.8/3.8 MRC score, p = 0.036).
Patients show a differential contractile response to NMES, which appears to be dependent on the severity of illness and also relevant for potential outcome benefits.
ISRCTN ISRCTN19392591 , registered 17 February 2011.
Background
Characterizing patient–ventilator interaction in critically ill patients is time-consuming and requires trained staff to evaluate the behavior of the ventilated patient.
Methods
In this ...study, we recorded surface electromyography (
sEMG
) signals from the diaphragm and intercostal muscles and esophageal pressure (
P
es
) in mechanically ventilated patients with ARDS. The sEMG recordings were preprocessed, and two different algorithms (triangle algorithm and adaptive thresholding algorithm) were used to automatically detect inspiratory patient effort. Based on the detected inspirations, major asynchronies (ineffective, auto-, and double triggers and double efforts), delayed and synchronous triggers were computationally classified. Reverse triggers were not considered in this study. Subsequently, asynchrony indices were calculated. For the validation of detected efforts, two experts manually annotated inspiratory patient activity in
P
es
, blinded toward each other, the
sEMG
signals, and the algorithmic results. We also classified patient–ventilator interaction and calculated asynchrony indices with manually detected inspirations in
P
es
as a reference for automated asynchrony classification and asynchrony index calculation.
Results
Spontaneous breathing activity was recognized in 22 out of the 36 patients included in the study. Evaluation of the accuracy of the algorithms using 3057 inspiratory efforts in
P
es
demonstrated reliable detection performance for both methods. Across all datasets, we found a high sensitivity (triangle algorithm/adaptive thresholding algorithm: 0.93/0.97) and a high positive predictive value (0.94/0.89) against expert annotations in
P
es
. The average delay of automatically detected inspiratory onset to the
P
es
reference was
-
79 ms/29 ms for the two algorithms. Our findings also indicate that automatic asynchrony index prediction is reliable. For both algorithms, we found the same deviation of
0.06
±
0.13
to the
P
es
-based reference.
Conclusions
Our study demonstrates the feasibility of automating the quantification of patient–ventilator asynchrony in critically ill patients using noninvasive sEMG. This may facilitate more frequent diagnosis of asynchrony and support improving patient–ventilator interaction.
Abstract
Background
The objective was to investigate the role of gene expression and plasma levels of the muscular protein myostatin in intensive care unit-acquired weakness (ICUAW). This was ...performed to evaluate a potential clinical and/or pathophysiological rationale of therapeutic myostatin inhibition.
Methods
A retrospective analysis from pooled data of two prospective studies to assess the dynamics of myostatin plasma concentrations (day 4, 8 and 14) and myostatin gene (
MSTN
) expression levels in skeletal muscle (day 15) was performed. Associations of myostatin to clinical and electrophysiological outcomes, muscular metabolism and muscular atrophy pathways were investigated.
Results
MSTN
gene expression (median IQR fold change: 1.00 0.68–1.54 vs. 0.26 0.11–0.80;
p
= 0.004) and myostatin plasma concentrations were significantly reduced in all critically ill patients when compared to healthy controls. In critically ill patients, myostatin plasma concentrations increased over time (median IQR fold change: day 4: 0.13 0.08/0.21 vs. day 8: 0.23 0.10/0.43 vs. day 14: 0.40 0.26/0.61;
p
< 0.001). Patients with ICUAW versus without ICUAW showed significantly lower
MSTN
gene expression levels (median IQR fold change: 0.17 0.10/0.33 and 0.51 0.20/0.86;
p
= 0.047). Myostatin levels were directly correlated with muscle strength (correlation coefficient 0.339;
p
= 0.020) and insulin sensitivity index (correlation coefficient 0.357;
p
= 0.015). No association was observed between myostatin plasma concentrations as well as
MSTN
expression levels and levels of mobilization, electrophysiological variables, or markers of atrophy pathways.
Conclusion
Muscular gene expression and systemic protein levels of myostatin are downregulated during critical illness. The previously proposed therapeutic inhibition of myostatin does therefore not seem to have a pathophysiological rationale to improve muscle quality in critically ill patients.
Trial registration
:
ISRCTN77569430
—13th of February 2008 and
ISRCTN19392591
17th of February 2011.
Graphical abstract
Background
Early mobilization improves physical independency of critically ill patients at hospital discharge in a general intensive care unit (ICU)‐cohort. We aimed to investigate clinical and ...molecular benefits or detriments of early mobilization and muscle activating measures in a high‐risk ICU‐acquired weakness cohort.
Methods
Fifty patients with a SOFA score ≥9 within 72 h after ICU admission were randomized to muscle activating measures such as neuromuscular electrical stimulation or whole‐body vibration in addition to early protocol‐based physiotherapy (intervention) or early protocol‐based physiotherapy alone (control). Muscle strength and function were assessed by Medical Research Council (MRC) score, handgrip strength and Functional Independence Measure at first awakening, ICU discharge, and 12 month follow‐up. Patients underwent open surgical muscle biopsy on day 15. We investigated the impact of muscle activating measures in addition to early protocol‐based physiotherapy on muscle strength and function as well as on muscle wasting, morphology, and homeostasis in patients with sepsis and ICU‐acquired weakness. We compared the data with patients treated with common physiotherapeutic practice (CPP) earlier.
Results
ICU‐acquired weakness occurs within the entire cohort, and muscle activating measures did not improve muscle strength or function at first awakening (MRC median IQR: CPP 3.3 3.0–4.3; control 3.0 2.7–3.4; intervention 3.0 2.1–3.8; P > 0.05 for all), ICU discharge (MRC median IQR: CPP 3.8 3.4–4.4; control 3.9 3.3–4.0; intervention 3.6 2.8–4.0; P > 0.05 for all), and 12 month follow‐up (MRC median IQR: control 5.0 4.3–5.0; intervention 4.8 4.3–5.0; P = 0.342 for all). No signs of necrosis or inflammatory infiltration were present in the histological analysis. Myocyte cross‐sectional area in the intervention group was significantly larger in comparison with the control group (type I +10%; type IIa +13%; type IIb +3%; P < 0.001 for all) and CPP (type I +36%; type IIa +49%; type IIb +65%; P < 0.001 for all). This increase was accompanied by an up‐regulated gene expression for myosin heavy chains (fold change median IQR: MYH1 2.3 1.1–2.7; MYH2 0.7 0.2–1.8; MYH4 5.1 2.2–15.3) and an unaffected gene expression for TRIM63, TRIM62, and FBXO32.
Conclusions
In our patients with sepsis syndrome at high risk for ICU‐acquired weakness muscle activating measures in addition to early protocol‐based physiotherapy did not improve muscle strength or function at first awakening, ICU discharge, or 12 month follow‐up. Yet it prevented muscle atrophy.
Measurement of oxygen uptake (VO 2 ) and carbon dioxide removal (VCO 2 ) on membrane lungs (MLs) during extracorporeal membrane oxygenation (ECMO) provides potential for improved and safer therapy. ...Real-time monitoring of ML function and degradation, calculating caloric needs as well as cardiac output, and weaning algorithms are among the future possibilities. Our study compared the continuous measurement of the standalone Quantum Diagnostics System (QDS) with the published Measuring Energy Expenditure in ECMO patients (MEEP) approach, which calculates sequential VO 2 and VCO 2 values via blood gas analysis and a physiologic gas content model. Thirty-nine datasets were acquired during routine venovenous ECMO intensive care treatment and analyzed. VO 2 was clinically relevant underestimated via the blood-sided measurement of the QDS compared to the MEEP approach (mean difference -42.61 ml/min, limits of agreement LoA -2.49/-87.74 ml), which could be explained by the missing dissolved oxygen fraction of the QDS equation. Analysis of VCO 2 showed scattered values with wide limits of agreement (mean difference 54.95 ml/min, LoA 231.26/-121.40 ml/min) partly explainable by a calculation error of the QDS. We described potential confounders of gas-sided measurements in general which need further investigation and recommendations for enhanced devices.
Background: Impaired cortical inhibiton and maladaptive cortical plasticity are functional hallmarks of sporadic focal dystonias. Whether or not these mechanisms translate to generalized dystonias ...and whether these features reflect state or trait characteristics are topics of research in hereditary dystonias.
Methods: We present a series of studies using a multitracer approach with positron emission tomography (PET) and diffusion tensor MRI (DTI) in the DYT1 and the DYT6 genotype.
Results: In these hereditary dystonias functional and microstructural abnormalities were found in cortico‐striatal‐pallido‐thalamocortical (CSPTC) and cerebellar‐thalamo‐cortical circuits. Genotype‐specific abnormalities were localized to the basal ganglia, SMA and cerebellum. Functional changes, as potential correlates of maladaptive sensorimotor plasticity were found throughout the sensorimotor system and were more pronounced in affected mutation carriers than in their non‐manifesting counterparts. In both genotypes, striatal metabolic abnormalities were paralleled by genotype‐specific reductions in D2 receptor availability. However, these reductions failed to show a clear association with clinical or functional markers of the disease. By contrast, microstructural changes of cerebellar pathways clearly related to penetrance and may thus represent the main intrinsic abnormality underlying cortical downstream effects, such as increased sensorimotor responsivity.
Conclusions: These studies are consistent with the view of primary torsion dystonia as a neurodevelopmental circuit disorder involving CSPTC and related cerebellar pathways.
To identify metabolic brain networks that are associated with Tourette syndrome (TS) and comorbid obsessive-compulsive disorder (OCD).
We utilized (18)F-fluorodeoxyglucose and PET imaging to examine ...brain metabolism in 12 unmedicated patients with TS and 12 age-matched controls. We utilized a spatial covariance analysis to identify 2 disease-related metabolic brain networks, one associated with TS in general (distinguishing TS subjects from controls), and another correlating with OCD severity (within the TS group alone).
Analysis of the combined group of patients with TS and healthy subjects revealed an abnormal spatial covariance pattern that completely separated patients from controls (p < 0.0001). This TS-related pattern (TSRP) was characterized by reduced resting metabolic activity of the striatum and orbitofrontal cortex associated with relative increases in premotor cortex and cerebellum. Analysis of the TS cohort alone revealed the presence of a second metabolic pattern that correlated with OCD in these patients. This OCD-related pattern (OCDRP) was characterized by reduced activity of the anterior cingulate and dorsolateral prefrontal cortical regions associated with relative increases in primary motor cortex and precuneus. Subject expression of OCDRP correlated with the severity of this symptom (r = 0.79, p < 0.005).
These findings suggest that the different clinical manifestations of TS are associated with the expression of 2 distinct abnormal metabolic brain networks. These, and potentially other disease-related spatial covariance patterns, may prove useful as biomarkers for assessing responses to new therapies for TS and related comorbidities.
To determine whether changes in D(2) receptor availability are present in carriers of genetic mutations for primary dystonia.
Manifesting and nonmanifesting carriers of the DYT1 and DYT6 dystonia ...mutations were scanned with (11)C raclopride (RAC) and PET. Measures of D(2) receptor availability in the caudate nucleus and putamen were determined using an automated region-of-interest approach. Values from mutation carriers and healthy controls were compared using analysis of variance to assess the effects of genotype and phenotype. Additionally, voxel-based whole brain searches were conducted to detect group differences in extrastriatal regions.
Significant reductions in caudate and putamen D(2) receptor availability were evident in both groups of mutation carriers relative to healthy controls (p < 0.001). The changes were greater in DYT6 relative to DYT1 carriers (-38.0 +/- 3.0% vs -15.0 +/- 3.0%, p < 0.001). By contrast, there was no significant difference between manifesting and nonmanifesting carriers of either genotype. Voxel-based analysis confirmed these findings and additionally revealed reduced RAC binding in the ventrolateral thalamus of both groups of mutation carriers. As in the striatum, the thalamic binding reductions were more pronounced in DYT6 carriers and were not influenced by the presence of clinical manifestations.
Reduced D(2) receptor availability in carriers of dystonia genes is compatible with dysfunction or loss of D(2)-bearing neurons, increased synaptic dopamine levels, or both. These changes, which may be present to different degrees in the DYT1 and DYT6 genotypes, are likely to represent susceptibility factors for the development of clinical manifestations in mutation carriers.
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