A Likely Pathogenic variant in the KBTBD13 Gene: A Case Series of Three Patients with Nemaline Myopathy Type 6.

Background: Nemaline myopathy type 6 (NEM6) or KBTBD13-related congenital myopathy is the most prevalent type of nemaline myopathy in the Netherlands and is characterised by mild childhood-onset axial, proximal and distal muscle weakness with prominent neck flexor weakness combined with slowness of movements. The most prevalent variant in the Netherlands is the c.1222C > T p.(Arg408Cys) variant in the KBTBD13 gene, also called the Dutch founder variant. Objective: To provide a comprehensive clinical and functional characterisation of three patients to assess the pathogenicity of a newly identified variant in the KBTBD13 gene. Results: We present three cases (Patient 1: female, 76 years old; Patient 2: male, 63 years old; and his brother Patient 3: male, 61 years old) with a c.1222C > A p.(Arg408Ser) variant in the KBTBD13 gene. Patient 1 was also included previously in a histopathological study on NEM6. Symptoms of muscle weakness started in childhood and progressed to impaired functional abilities in adulthood. All three patients reported slowness of movements. On examination, they have mild axial, proximal and distal muscle weakness. None of the patients exhibited cardiac abnormalities. Spirometry in two patients showed a restrictive lung pattern. Muscle ultrasound showed symmetrically increased echogenicity indicating fatty replacement and fibrosis in a subset of muscles and histopathological analyses revealed nemaline rods and cores. Slower muscle relaxation kinetics with in vivo functional tests was observed. This was confirmed by in vitro functional tests showing impaired relaxation kinetics in isolated muscle fibres. We found a genealogic link between patient 1, and patient 2 and 3 nine generations earlier. Conclusions: The c.1222C > A p.(Arg408Ser) variant in the KBTBD13 gene is a likely pathogenic variant causing NEM6.

A cross-sectional study in 18 patients with typical and mild forms of nemaline myopathy in the Netherlands.

Nemaline myopathy (NM) is a congenital myopathy with generalised muscle weakness, most pronounced in neck flexor, bulbar and respiratory muscles. The aim of this cross-sectional study was to assess the Dutch NM patient cohort. We assessed medical history, physical examination, quality of life (QoL), fatigue severity, motor function (MFM), and respiratory muscle function. We included 18 of the 28 identified patients (13 females (11-67 years old); five males (31-74 years old)) with typical or mild NM and eight different genotypes. Nine patients (50 %) used a wheelchair, eight patients (44 %) used mechanical ventilation, and four patients (22 %) were on tube feeding. Spinal deformities were found in 14 patients (78 %). The median Medical Research Council (MRC) sum score was 38/60 [interquartile range 32-51] in typical and 48/60 [44-50] in mild NM. The experienced QoL was lower and fatigue severity was higher than reference values of the healthy population. The total MFM score was 55 % [49-94] in typical and 88 % [72-93] in mild NM. Most of the patients who performed spirometry had a restrictive lung function pattern (11/15). This identification and characterisation of the Dutch NM patient cohort is important for international collaboration and can guide the design of future clinical trials.

Improving Heckmatt muscle ultrasound grading scale through Rasch analysis.

The 4-point Heckmatt grading scale can easily be used to analyze muscle ultrasound images. The scale is used in an expanding set of muscles and neuromuscular disorders. This prompted the need for evaluation of the measurement properties of the scale in its current form. In this retrospective observational study we included muscle ultrasound images from patients who were undergoing an ultrasound exam for either clinical or research purposes. The primary outcome of this study was to investigate and improve the measurement properties of the Heckmatt scale using Rasch analysis. We investigated whether observers consistently used the 4 response categories. Data was available of 30.967 muscle ultrasound images from 1783 patients and 43 different individual muscles. In 8 of the 43 muscles, observers had difficulty to discriminate between the response categories, especially in bulbar muscles. After rescoring to a 3-point scale, the response categories were consistently used in all 43 muscles. In conclusion, a 3-point Heckmatt grading scale leads to improved accurate scoring compared to the original 4-point Heckmatt grading scale. Using the 3-point Heckmatt grading scale will not only simplify the use of the scale but also enhance its application in clinical practice and research purposes.

Future Directions for Respiratory Muscle Training in Neuromuscular Disorders: A Scoping Review.

BACKGROUND: Respiratory muscle training (RMT) aims to improve inspiratory and/or expiratory muscle function in neuromuscular disorders (NMDs). A comprehensive overview of the available literature is lacking. This scoping review explores methodological characteristics, (adverse) effects, and adherence of RMT studies in NMDs. Moreover, it identifies limitations and research gaps in the literature and provides future research directions. SUMMARY: Eligible studies were identified using MEDLINE, Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials databases. Three reviewers independently selected articles. Inclusion criteria were English language, original research articles on RMT using a device, patients with an NMD, and pulmonary function tests or respiratory muscle strength as outcome measures. We included NMDs with slow, intermediate and fast progression. Exclusion criteria were critically ill patients, weaning from mechanical ventilation, other neurological disorders, and RMT combined with non-respiratory interventions. One reviewer extracted the data on patients' characteristics, methodological characteristics, results of outcome measures, adverse events, and patient adherence. Forty-five studies were identified. We found a large diversity in study designs and training protocols. The effects of RMT on respiratory muscle strength and/or endurance are variable. Patient adherence was high and no serious adverse events were reported. KEY MESSAGES: The diversity in studies across the available literature precludes definitive conclusions regarding the effects of RMT on respiratory muscle function and clinically relevant outcomes in NMDs. Therefore, well-powered and -designed studies that focus on clinically relevant outcomes and assess whether RMT can improve or offset deterioration of respiratory muscle weakness in NMDs are needed.

24 Hours Ex-vivo Hypothermic Acellular Perfusion of Porcine Forelimb: A 7-day Follow-up Study.

BACKGROUND: One of the limiting factors for vascularized composite allograft (VCA) storage is the short viable ischemic time (4-6 hours). Hypothermic machine perfusion (MP) enables near-physiological preservation, avoiding the deleterious effects of hypoxia and static cooling. This study aims to compare muscle injury after 24-hour acellular perfusion with static cold storage (SCS) in a porcine limb replantation model, examining outcomes for up to 7 days after reperfusion. METHODS: Sixteen procured porcine forelimbs were perfused hypothermic for 24 hours with Histidine-Tryptophan-Ketoglutarate (HTK, n=8) or preserved on ice for 4 hours (SCS, n=8) before orthotopic replantation. Muscle injury was assessed using biochemical markers and muscle biopsies were analyzed using the Histologic Injury Severity Score (HISS). RESULTS: During preservation, limb weight decreased by 2% in the SCS group and increased by 44% in the perfusion group (p<0.001). Twelve limbs (HTK, n=6; SCS, n=6) survived for 7 days. Three days after replantation, increased creatinine kinase levels were observed in the perfusion group (33781 mmol/liter versus 2163 mmol/liter; p<0.001). Mean endpoint HISS was 3.8 (SD 0.7) in the perfusion group and 1.8 (SD 0.7) in the SCS group (p=0.008), mostly due to increased edema (p=0.004). CONCLUSION: 24 hours of hypothermic MP and 4 hours of SCS of VCA demonstrated both minimal degenerated muscle tissue seven days after replantation.

Comparison of muscle ultrasound and needle electromyography findings in neuromuscular disorders.

INTRODUCTION/AIMS: Needle electromyography (EMG) and muscle ultrasound can be used to evaluate patients with suspected neuromuscular disorders. The relation between muscle ultrasound pathology and the corresponding needle EMG findings is unknown. In this study we compared the results of concurrent ultrasound and needle EMG examinations in patients suspected of a neuromuscular disorder. METHODS: Retrospective data from 218 patients with pairwise ultrasound and EMG results of 796 muscles were analyzed. We compared overall quantitative and visual muscle ultrasound results to EMGs with neurogenic and myopathic abnormalities and assessed the congruency of both methods in the different clinical diagnosis categories. RESULTS: In muscles of patients with a neuromuscular disorder, abnormalities were found with EMG in 71.8%, and quantitative and visual muscle ultrasound results were abnormal in 19.3% and 35.4% respectively. In muscles with neurogenic EMG abnormalities, quantitative and visual muscle ultrasound results were abnormal in 18.9% versus 35.6%, increasing up to 43.7% versus 87.5% in muscles with the most pronounced signs of denervation. Congruency of EMG and ultrasound was better for more proximal and cranial muscles than for muscles in the hand and lower limb. DISCUSSION: Needle EMG and muscle ultrasound typically produce disparate results and identify different aspects of muscle pathology. Muscle ultrasound seems less suited for detecting mild neurogenic abnormalities. As the severity of neurogenic needle EMG abnormalities increased, muscle ultrasound abnormalities were also increasingly found. Visual analysis seems better suited than grayscale quantification for detecting neurogenic abnormalities.

Respiratory function in LAMA2-related muscular dystrophy and SELENON-related congenital myopathy, a 1.5-year natural history study.

INTRODUCTION: LAMA2-related muscular dystrophy (LAMA2-MD) and SELENON(SEPN1)-related congenital myopathy (SELENON-RM) are rare neuromuscular diseases with respiratory impairment from a young age. Prospective natural history studies are needed for prevalence estimations, respiratory characterization, optimizing clinical care and selecting outcome measures for trial readiness. METHODS: Our prospective 1.5-year natural history study included spirometry (forced vital capacity (FVC); difference between upright and supine vital capacity (dVC)), respiratory muscle strength tests (sniff nasal inspiratory pressure (SNIP)) (age≥5 years), and diaphragm ultrasound (thickness; thickening; echogenicity; all ages). RESULTS: Twenty-six LAMA2-MD patients (M = 8, median 21 [9; 31] years) and 11 SELENON-RM patients (M = 8, 20 [10; 33] years) were included. At baseline, 17 (85 %) LAMA2-MD (FVC%: 59 % [33; 68]) and all SELENON-RM patients (FVC%: 34 % [31; 46]) had an impaired respiratory function (FVC%<80 %). Nine (35 %) LAMA2-MD and eight (73 %) SELENON-RM patients received mechanical ventilation at baseline, and two additional SELENON-RM patients started during follow-up. Contrarily to LAMA2-MD, SELENON-RM patients had severe diaphragm atrophy (diaphragm thickness z-score: 2.5 [-3.1; -2.1]) and dysfunction (diaphragm thickness ratio: 1.2 [1.0; 1.7]; dVC: 30 % [7.7; 41]). SNIP was low in both neuromuscular diseases and correlated with motor function. In SELENON-RM, respiratory function decreased during follow-up. CONCLUSION: The majority of LAMA2-MD and all SELENON-RM patients had respiratory impairment. SELENON-RM patients showed lower respiratory function which was progressive, more prevalent mechanical ventilation, and more severe diaphragm atrophy and dysfunction than LAMA2-MD patients. Spirometry (FVC%, dVC) and respiratory muscle strength tests (SNIP) are useful in clinical care and as outcome measure in clinical trials. CLINICAL TRIAL NUMBER: NCT04478981.

SELENON-Related Myopathy Across the Life Span, a Cross-Sectional Study for Preparing Trial Readiness.

BACKGROUND: SELENON(SEPN1)-related myopathy (SELENON-RM) is a rare congenital neuromuscular disease characterized by proximal and axial muscle weakness, spinal rigidity, scoliosis and respiratory impairment. No curative treatment options exist, but promising preclinical studies are ongoing. Currently, natural history data are lacking, while selection of appropriate clinical and functional outcome measures is needed to reach trial readiness. OBJECTIVE: We aim to identify all Dutch and Dutch-speaking Belgian SELENON-RM patients, deep clinical phenotyping, trial readiness and optimization of clinical care. METHODS: This cross-sectional, single-center, observational study comprised neurological examination, functional measurements including Motor Function Measurement 20/32 (MFM-20/32) and accelerometry, questionnaires, muscle ultrasound, respiratory function tests, electro- and echocardiography, and dual-energy X-ray absorptiometry. RESULTS: Eleven patients with genetically confirmed SELENON-RM were included (20±13 (3-42) years, 73% male). Axial and proximal muscle weakness were most pronounced. The mean MFM-20/32 score was 71.2±15.1%, with domain 1 (standing and transfers) being most severely affected. Accelerometry showed a strong correlation with MFM-20/32. Questionnaires revealed impaired quality of life, pain and problematic fatigue. Muscle ultrasound showed symmetrically increased echogenicity in all muscles. Respiratory function, and particularly diaphragm function, was impaired in all patients, irrespective of the age. Cardiac assessment showed normal left ventricular systolic function in all patients but abnormal left ventricular global longitudinal strain in 43% of patients and QRS fragmentation in 80%. Further, 80% of patients showed decreased bone mineral density on dual-energy X-ray absorptiometry scan and 55% of patients retrospectively experienced fragility long bone fractures. CONCLUSIONS: We recommend cardiorespiratory follow-up as a part of routine clinical care in all patients. Furthermore, we advise vitamin D supplementation and optimization of calcium intake to improve bone quality. We recommend management interventions to reduce pain and fatigue. For future clinical trials, we propose MFM-20/32, accelerometry and muscle ultrasound to capture disease severity and possibly disease progression.

LAMA2-Related Muscular Dystrophy Across the Life Span: A Cross-sectional Study.

Background and Objectives: LAMA2-related muscular dystrophy (LAMA2-MD) is a rare neuromuscular disease characterized by proximal and axial muscle weakness, rigidity of the spine, scoliosis, and respiratory impairment. No curative treatment options exist, yet promising preclinical studies are ongoing. Currently, there is a paucity on natural history data, and appropriate clinical and functional outcome measures are needed. We aim for deep clinical phenotyping, establishment of a well-characterized baseline cohort for prospective follow-up and recruitment for future clinical trials, improvement of clinical care, and selection of outcome measures for reaching trial readiness. Methods: We performed a cross-sectional, single-center, observational study. This study included neurologic examination and functional measurements among others the Motor Function Measure 20/32 (MFM-20/32) as primary outcome measure, accelerometry, questionnaires, muscle ultrasound, respiratory function tests, electrocardiography and echocardiography, and dual-energy X-ray absorptiometry. Results: Twenty-seven patients with genetically confirmed LAMA2-MD were included (21 ± 13 years; M = 9; ambulant = 7). Axial and proximal muscle weakness was most pronounced. The mean MFM-20/32 score was 42.0% ± 29.4%, with domain 1 (standing and transfers) being severely affected and domain 3 (distal muscle function) relatively spared. Physical activity as measured through accelerometry showed very strong correlations to MFM-20/32 (Pearson correlation, -0.928, p < 0.01). Muscle ultrasound showed symmetrically increased echogenicity, with the sternocleidomastoid muscle most affected. Respiratory function was impaired in 85% of patients without prominent diaphragm dysfunction and was independent of age. Ten patients (37%) needed (non)invasive ventilatory support. Cardiac assessment revealed QRS fragmentation in 62%, abnormal left ventricular global longitudinal strain in 25%, and decreased left ventricular ejection fraction in 14% of patients. Decreased bone quality leading to fragility fractures was seen in most of the patients. Discussion: LAMA2-MD has a widely variable phenotype. Based on the results of this cross-sectional study and current standards of care for congenital muscular dystrophies, we advise routine cardiorespiratory follow-up and optimization of bone quality. We propose MFM-20/32, accelerometry, and muscle ultrasound for assessing disease severity and progression. For definitive clinical recommendations and outcome measures, natural history data are needed. Clinical Trials Registration: This study was registered at clinicaltrials.gov (NCT04478981, 21 July 2020). The first patient was enrolled in September 2020.

Inspiratory Muscle Training in Nemaline Myopathy.

BACKGROUND: Respiratory muscle weakness is a common feature in nemaline myopathy. Inspiratory muscle training (IMT) is an intervention that aims to improve inspiratory muscle strength. OBJECTIVE: The aim of this controlled before-and-after pilot study was to investigate if IMT improves respiratory muscle strength in patients with nemaline myopathy. METHODS: Nine patients (7 females; 2 males, age 36.6±20.5 years) with respiratory muscle weakness and different clinical phenotypes and genotypes were included. Patients performed eight weeks of sham IMT followed by eight weeks of active threshold IMT. The patients trained twice a day five days a week for 15 minutes at home. The intensity was constant during the training after a gradual increase to 30% of maximal inspiratory pressure (MIP). RESULTS: Active IMT significantly improved MIP from 43±15.9 to 47±16.6 cmH2O (p = 0.019). The effect size was 1.22. There was no significant effect of sham IMT. Sniff nasal inspiratory pressure, maximal expiratory pressure, spirometry, and diaphragm thickness and thickening showed no significant improvements. CONCLUSIONS: This pilot study shows that threshold IMT is feasible in patients with nemaline myopathy and improves inspiratory muscle strength. Our findings provide valuable preliminary data for the design of a larger, more comprehensive trial.

Respiratory features of centronuclear myopathy in the Netherlands.

Centronuclear myopathy (CNM) is a heterogeneous group of muscle disorders primarily characterized by muscle weakness and variable degrees of respiratory dysfunction caused by mutations in MTM1, DNM2, RYR1, TTN and BIN1. X-linked myotubular myopathy has been the focus of recent natural history studies and clinical trials. Data on respiratory function for other genotypes is limited. To better understand the respiratory properties of the CNM spectrum, we performed a retrospective study in a non-selective Dutch CNM cohort. Respiratory dysfunction was defined as an FVC below 70% of predicted and/or a daytime pCO2 higher than 6 kPa. We collected results of other pulmonary function values (FEV1/FVC ratio) and treatment data from the home mechanical ventilation centres. Sixty-one CNM patients were included. Symptoms of respiratory weakness were reported by 15/47 (32%) patients. Thirty-three individuals (54%) with different genotypes except autosomal dominant (AD)-BIN1-related CNM showed respiratory dysfunction. Spirometry showed decreased FVC, FEV1 & PEF values in all but two patients. Sixteen patients were using HMV (26%), thirteen of them only during night-time. In conclusion, this study provides insight into the prevalence of respiratory symptoms in four genetic forms of CNM in the Netherlands and offers the basis for future natural history studies.

Detecting impaired muscle relaxation in myopathies with the use of motor cortical stimulation.

Impaired muscle relaxation is a notable feature in specific myopathies. Transcranial magnetic stimulation (TMS) of the motor cortex can induce muscle relaxation by abruptly halting corticospinal drive. Our aim was to quantify muscle relaxation using TMS in different myopathies with symptoms of muscle stiffness, contractures/cramps, and myalgia and explore the technique's diagnostic potential. In men, normalized peak relaxation rate was lower in Brody disease (n = 4) (-3.5 ± 1.3 s-1), nemaline myopathy type 6 (NEM6; n = 5) (-7.5 ± 1.0 s-1), and myotonic dystrophy type 2 (DM2; n = 5) (-10.2 ± 2.0 s-1) compared to healthy (n = 14) (-13.7 ± 2.1 s-1; all P ≤ 0.01) and symptomatic controls (n = 9) (-13.7 ± 1.6 s-1; all P ≤ 0.02). In women, NEM6 (n = 5) (-5.7 ± 2.1 s-1) and McArdle patients (n = 4) (-6.6 ± 1.4 s-1) had lower relaxation rate compared to healthy (n = 10) (-11.7 ± 1.6 s-1; both P ≤ 0.002) and symptomatic controls (n = 8) (-11.3 ± 1.8 s-1; both P ≤ 0.008). TMS-induced muscle relaxation achieved a high level of diagnostic accuracy (area under the curve = 0.94 (M) and 0.92 (F)) to differentiate symptomatic controls from myopathy patients. Muscle relaxation assessed using TMS has the potential to serve as a diagnostic tool, an in-vivo functional test to confirm the pathogenicity of unknown variants, an outcome measure in clinical trials, and monitor disease progression.

Longitudinal Analysis of Quadriceps Muscle Strength in Patients with Previous COVID-19 Hospitalization and in Patients with Post-Acute Sequelae following Mild COVID-19.

Muscle weakness is a prominent symptom in post-acute sequelae of COVID-19 (PASC). However, few studies have objectively and longitudinally assessed muscle strength after varying COVID-19 severity grades. This observational study aimed to explore the prevalence, determinants, and 1.5 years change of quadriceps muscle weakness in 98 patients discharged from COVID-19 hospitalization and in 50 patients with PASC following mild COVID-19. Isometric quadriceps maximal voluntary contraction (MVC) was assessed on a computerized dynamometer at three visits. Also, in a subgroup of 14 post-COVID-19 patients with quadriceps muscle weakness, muscle thickness and echo intensity were determined by muscle ultrasound of nine upper and lower extremity muscles. Muscle weakness was found in 59% of post-hospitalized patients and in 65% of those with PASC following mild COVID-19 at ~14 weeks after acute COVID-19. Whereas during ~1.5 years follow-up MVC modestly improved, muscle weakness prevalence remained unchanged. Hospital length of stay and diabetes mellitus were identified as possible predictors of muscle weakness following COVID-19 hospitalization. No predictors could be identified in those with PASC following mild COVID-19. Ultrasound outcomes revealed no large structural abnormalities. In conclusion, clinically relevant muscle weakness is common after COVID-19 and its long-term improvement is poor. Future studies with relevant control groups are warranted to confirm our data.

Reproducibility and robustness of motor cortical stimulation to assess muscle relaxation kinetics.

Transcranial magnetic stimulation (TMS) of the motor cortex can be used during a voluntary contraction to inhibit corticospinal drive to the muscle and consequently induce involuntary muscle relaxation. Our aim was to evaluate the reproducibility and the effect of varying experimental conditions (robustness) of TMS-induced muscle relaxation. Relaxation of deep finger flexors was assessed in 10 healthy subjects (5 M, 5 F) using handgrip dynamometry with normalized peak relaxation rate as main outcome measure, that is, peak relaxation rate divided by (voluntary plus TMS-evoked)force prior to relaxation. Both interday and interrater reliability of relaxation rate were high with intraclass correlation coefficient of 0.88 and 0.92 and coefficient of variation of 3.8 and 3.7%, respectively. Target forces of 37.5% of maximal voluntary force or higher resulted in similar relaxation rate. From 50% of maximal stimulator output and higher relaxation rate remained the same. Only the most lateral position (>2 cm from the vertex) rendered lower relaxation rate (mean ± SD: 11.1 ± 3.0 s-1 , 95% CI: 9.0-13.3 s-1 ) compared to stimulation at the vertex (12.8 ± 1.89 s-1 , 95% CI: 11.6-14.1 s-1 ). Within the range of baseline skin temperatures, an average change of 0.5 ± 0.2 s-1 in normalized peak relaxation rate was measured per 1°C change in skin temperature. In conclusion, interday and interrater reproducibility and reliability of TMS-induced muscle relaxation of the finger flexors were high. Furthermore, this technique is robust with limited effect of target force, stimulation intensity, and coil position. Muscle relaxation is strongly affected by skin temperature; however, this effect is marginal within the normal skin temperature range. We deem this technique well suited for clinical and scientific assessment of muscle relaxation.

Respiratory muscle function in patients with nemaline myopathy.

In this cross-sectional study, we comprehensively assessed respiratory muscle function in various clinical forms of nemaline myopathy (NM) including non-volitional tests for diaphragm function. Forty-two patients with NM were included (10 males (25-74 y/o); 32 females (11-76 y/o)). The NM forms were typical (n=11), mild (n=7), or childhood-onset with slowness of movements (n=24). Forced vital capacity (FVC) and maximal inspiratory pressure were decreased in typical NM in comparison with childhood-onset NM with slowness (32.0 [29.0-58.5] vs 81.0 [75.0-87.0]%, p<0.01, and 35.0 [24.0-55.0] vs 81.0 [65.0-102.5] cmH2O, p<0.01). Eight patients with childhood-onset NM with slowness had respiratory muscle weakness. There was a low correlation between FVC and Motor Function Measure scores (r=0.48, p<0.01). End-inspiratory diaphragm thickness and twitch mouth pressure were decreased in patients requiring home mechanical ventilation compared to non-ventilated patients with normal lung function (1.8 [1.5-2.4] vs 3.1 [2.0-4.6] mm, p=0.049, and -7.9 [-10.9- -4.0] vs -14.9 [-17.3- -12.6], p=0.04). Our results show that respiratory muscle weakness is present in all NM forms, including childhood-onset NM with slowness, and may be present irrespective of the degree of general motor function impairment. These findings highlight the importance for screening of respiratory function in patients with NM to guide respiratory management.

Muscle ultrasound is a sensitive biomarker in oculopharyngeal muscular dystrophy.

INTRODUCTION/AIMS: Oculopharyngeal muscular dystrophy (OPMD) is a late-onset, progressive muscle disease. Quantitative muscle ultrasound (QMUS) assesses structural changes in muscles and is a sensitive biomarker in neuromuscular disorders. Our aim of this study was to determine whether QMUS can detect muscle pathology and can be used as longitudinal imaging biomarker in OPMD. METHODS: Genetically confirmed OPMD patients, recruited by their treating physicians or from the national neuromuscular database, were examined twice, 20 months apart, using QMUS of orofacial and limb muscles, and measurements of functional capacity and muscle strength. Absolute echo intensity (AEI) and muscle thickness of all muscles were analyzed and correlated with clinical data. RESULTS: The tongue, deltoid, iliopsoas, rectus femoris, and soleus muscles showed increased AEI at baseline compared with normal values in 43 OPMD patients, with the rectus femoris being most often affected (51%).The AEI and muscle thickness of 9 of 11 muscles correlated significantly with the motor function measure, 10-step stair test, swallowing capacity, dynamometry, Medical Research Council grade, tongue strength, and bite force (r = 0.302 to -0.711). Between baseline and follow-up, deterioration in AEI was found for the temporalis, tongue, and deltoid muscles, and decreased muscle thickness was detected for the temporalis, masseter, digastric, tongue, deltoid, iliopsoas, and soleus muscles (P < .05). No relation was found between the change in AEI and repeat length or disease duration. DISCUSSION: QMUS detected muscle pathology and disease progression in OPMD over 20 months. We conclude that QMUS should be considered as a biomarker in treatment trials.

Visual versus quantitative analysis of muscle ultrasound in neuromuscular disease.

INTRODUCTION/AIMS: Visual and quantitative muscle ultrasound are both valid diagnostic tools in neuromuscular diseases. To optimize muscle ultrasound evaluation and facilitate its use in neuromuscular disease, we examined the correlation between visual and quantitative muscle ultrasound analysis and their pitfalls. METHODS: Retrospective data from 994 patients with 13,562 muscle ultrasound images were analyzed. Differences in echogenicity z-score distribution per Heckmatt grade and corresponding correlation coefficients were calculated. RESULTS: Overall, there was a correlation of 0.60 between the two scoring systems, with a gradual increase in z-score with increasing Heckmatt grades and vice versa. Patients with a neuromuscular disorder had higher Heckmatt grades (p < 0.001) and z-scores (median z-score = 0.30, p < 0.001) than patients without. The highest Heckmatt grades and z-scores were found in patients with either a dystrophy or inflammatory myopathy (both median Heckmatt grade of 2 and median z score of 0.74 and 1.20, respectively). Discrepant scores were infrequent (<2%), but revealed important pitfalls in both grading systems. DISCUSSION: Visual and quantitative muscle ultrasound are complementary techniques to evaluate neuromuscular disease and have a moderate positive correlation. Importantly, we identified specific pitfalls for visual and quantitative muscle ultrasound and how to overcome them in clinical practice.

Association of diaphragm thickness and echogenicity with age, sex, and body mass index in healthy subjects.

INTRODUCTION/AIMS: Diaphragm ultrasound is increasingly used in the diagnosis of diaphragm dysfunction and to guide respiratory management in patients with neuromuscular disorders and those who are critically ill. However, the association between diaphragm ultrasound variables and demographic factors like age, sex, and body mass index (BMI) are understudied. Such relationships are important for correct interpretation of normative values and comparison with selected patients groups. The aim of this study was to determine the associations between diaphragm ultrasound variables and subject characteristics. METHODS: B-mode ultrasound was used to image the diaphragm at the zone of apposition in 83 healthy subjects. Diaphragm thickness at resting end-expiration (Tend-exp ), diaphragm thickness at maximal end-inspiration (Tmax-insp ), diaphragm thickening ratio (Tmax-insp /Tend-exp ), and diaphragm echogenicity were measured. Multivariate linear regression was used to explore the associations between diaphragm ultrasound variables and subject characteristics. RESULTS: Tend-exp , Tmax-insp , and thickening ratio do not change with age whereas diaphragm echogenicity increases with age. The thickening ratio had a weak negative association with BMI, while Tend-exp was positively associated with BMI. Men had a larger Tend-exp and Tmax-insp than women (Tend-exp 1.6 ± 0.5 and 1.4 ± 0.3 mm; p = .011, Tmax-insp 3.8 ± 1.0 and 3.2 ± 0.9 mm; p = .004), but similar thickening ratios. DISCUSSION: Diaphragm thickness, thickening, and echogenicity measured with ultrasound are associated with factors such as age, BMI, and sex. Therefore, subject characteristics should be considered when interpreting diaphragm ultrasound measurements. In the absence of normative values, matched control groups are a prerequisite for research and in clinical practice.

The Role of Microelectrode Recording and Stereotactic Computed Tomography in Verifying Lead Placement During Awake MRI-Guided Subthalamic Nucleus Deep Brain Stimulation for Parkinson's Disease.

BACKGROUND: Bilateral deep brain stimulation of the subthalamic nucleus (STN-DBS) has become a cornerstone in the advanced treatment of Parkinson's disease (PD). Despite its well-established clinical benefit, there is a significant variation in the way surgery is performed. Most centers operate with the patient awake to allow for microelectrode recording (MER) and intraoperative clinical testing. However, technical advances in MR imaging and MRI-guided surgery raise the question whether MER and intraoperative clinical testing still have added value in DBS-surgery. OBJECTIVE: To evaluate the added value of MER and intraoperative clinical testing to determine final lead position in awake MRI-guided and stereotactic CT-verified STN-DBS surgery for PD. METHODS: 29 consecutive patients were analyzed retrospectively. Patients underwent awake bilateral STN-DBS with MER and intraoperative clinical testing. The role of MER and clinical testing in determining final lead position was evaluated. Furthermore, interobserver variability in determining the MRI-defined STN along the planned trajectory was investigated. Clinical improvement was evaluated at 12 months follow-up and adverse events were recorded. RESULTS: 98% of final leads were placed in the central MER-track with an accuracy of 0.88±0.45 mm. Interobserver variability of the MRI-defined STN was 0.84±0.09. Compared to baseline, mean improvement in MDS-UPDRS-III, PDQ-39 and LEDD were 26.7±16.0 points (54%) (p < 0.001), 9.0±20.0 points (19%) (p = 0.025), and 794±434 mg/day (59%) (p < 0.001) respectively. There were 19 adverse events in 11 patients, one of which (lead malposition requiring immediate postoperative revision) was a serious adverse event. CONCLUSION: MER and intraoperative clinical testing had no additional value in determining final lead position. These results changed our daily clinical practice to an asleep MRI-guided and stereotactic CT-verified approach.