Establishing the role of muscle ultrasound as an imaging biomarker in facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is a hereditary muscle disease, that causes weakness and wasting of skeletal muscles. In this cross-sectional cohort-study on FSHD patients, we assessed muscle ultrasound findings and their relation to clinical outcome measures, evaluating the role of ultrasound as biomarker in FSHD. We included 115 genetically confirmed FSHD patients (52% males, age-range 22-80 years). They were subjected to a standardized muscle ultrasound protocol of seven truncal and upper- and lower extremity muscles bilaterally. Muscle images were scored using the Heckmatt scale. Muscle echogenicity was quantified using z-scores. Compound echogenicity and Heckmatt scores were calculated. Nearly all patients (94%) had one or multiple muscles with an increased echogenicity z-score. The trapezius muscle was most severely affected, followed by the rectus femoris muscle. Both compound ultrasound scores strongly with multiple clinical outcome measures (ρ 0.68-0.79, p < 0.001). While most muscles showed a high level of agreement between the echogenicity z-score and Heckmatt score (>95%), the tibialis anterior and gastrocnemius muscle showed lower levels of agreement (82 and 92%). In conclusion, our study confirms the use of muscle ultrasound as clinical severity biomarker and provides a solid base for future longitudinal studies to establish ultrasound as a monitoring biomarker in FSHD.

Tongue movements and teat compression during bottle feeding: A pilot study of a quantitative ultrasound approach.

Nutritive sucking is a complex process, essential to proper growth and development. The complexity of this oral sensorimotor activity includes movements of the tongue and jaw. Tongue movements during nutritive sucking can only be visualized with instrumented methods such as ultrasound. Until now, studies using ultrasound during nutritive sucking performed measurements on each individual ultrasound image frame, which was quite time-consuming. The aim of this pilot study was to automatically process ultrasound video recordings in healthy infants during bottle feeding to measure teat compression and tongue movements. Tongue movements and teat compression during bottle feeding were visualized and recorded using 2D dynamic ultrasound imaging. A custom-made semi-automated analysis-routine was developed. Teat compression was expressed as the median difference in teat diameter during the recording. Tongue movements were expressed as the displacement of the tongue along four evenly distributed image lines and the corresponding time-shifts between those lines. The recordings of 12 out of 14 participants were adequate for the analysis of tongue movements. Teat compression could be analysed in the recordings of 6 participants. The reliability of our analysis-routine was considered to be good, and the analysis-routine was more time-efficient than manual frame-by-frame analysis. This quantitative analysis-routine is a promising tool, that can be used efficiently and accurately in the future to collect normative data that can serve as reference values to distinguish normal from abnormal tongue movements in infants with feeding difficulties.

Correction to: Adaptive capacity of 2- to 5-month-old infants to the flow, shape, and flexibility of different teats during bottle feeding: a cross-sectional study.

Following the publication of the article [1], the authors noticed that Fig. 3 used is not the updated version. The correct version is shown below.

Adaptive capacity of 2- to 5-month-old infants to the flow, shape, and flexibility of different teats during bottle feeding: a cross-sectional study.

BACKGROUND: Nutritive sucking is a complex activity, the biomechanical components of which may vary in relation to respiratory phase, swallow-rate per minute, suck-swallow ratio, and swallow non-inspiratory flow (SNIF). Quantitative measurement of these components during nutritive sucking in healthy infants could help us to understand the complex development of sucking, swallowing, and breathing. This is important because the coordination between these components is often disturbed in infants with feeding difficulties. The aims of this study were to describe the biomechanical components of sucking and swallowing in healthy 2- to 5-month-old infants during bottle feeding, to assess whether infants adapt to the characteristics of two different teats, and to determine which independent variables influence the occurrence of SNIF. METHODS: Submental muscle activity, nasal airflow, and cervical auscultation were evaluated during bottle-feeding with two different teats. RESULTS: Sixteen term-born infants (6 boys) aged 2-5 months were included. All infants showed variable inhalation and exhalation after swallowing. The swallow rate per minute was significantly higher when infants fed with a higher flow teat (Philips Avent Natural 2.0™). Infants had suck:swallow ratios ranging from 1:1 to 4:1. A suck:swallow ratio of 1:1 occurred significantly more often when infants fed with a higher flow teat, whereas a suck:swallow ratio of 2:1 occurred significantly more often when infants fed with a low-flow teat (Philips Avent Classic+™). A suck:swallow ratio of 1:1 was negatively correlated with SNIF, whereas a suck:swallow ratio of 2:1 was positively correlated with SNIF. CONCLUSION: Healthy infants aged 2-5 months can adapt to the flow, shape, and flexibility of different teats, showing a wide range of biomechanical and motor adaptations.

The yield of diagnostic work-up of patients presenting with myalgia, exercise intolerance, or fatigue: A prospective observational study.

Myalgia, fatigue, and exercise intolerance are cause for referral to a neurologist. However, the diagnostic value of history, neurological examination, and ancillary investigations in patients with these symptoms is unknown. This study provides a sound footing for deciding which ancillary investigations should be conducted. A prospective observational study of the diagnostic approach in 187 patients with myalgia, exercise intolerance, or fatigue as their predominant symptom was performed. The primary outcomes were independent contribution of referral letter, history, examination, and ancillary investigations to a myopathy diagnosis. The secondary outcome was diagnostic value of combined ancillary investigations. 27% of patients had a myopathy. Positive family history (OR 3.2), progressive symptoms (OR 2.2), atrophy (OR 9.7), weakness (OR 10.9), and hyporeflexia (OR 4.4) were associated with a myopathy. Positive predictive values for myopathy were calculated for CK (0.32), EMG (0.66), ultrasound (0.47), and muscle biopsy (0.78). All contributed significantly in predicting myopathy. Multivariate analysis yielded a diagnostic algorithm facilitating a more efficient work-up in future patients. CK levels, EMG, ultrasound, and muscle biopsy independently contribute to predicting a myopathy. The diagnostic algorithm shows which combination of ancillary investigations should be employed in different subgroups and when to omit invasive techniques. This algorithm may drastically improve diagnostic efficiency.

Dystrophic changes in masticatory muscles related chewing problems and malocclusions in Duchenne muscular dystrophy.

Dysphagia in Duchenne muscular dystrophy (DMD) worsens with age, with increasingly effortful mastication. The aims of this study were to describe mastication problems in consecutive stages in a group of patients with DMD and to determine related pathophysiological aspects of masticatory muscle structure, tongue thickness, bite force and dental characteristics. Data from 72 patients with DMD (4.3 to 28.0 years), divided into four clinical stages, were collected in a cross sectional study. Problems with mastication and the need for food adaptations, in combination with increased echogenicity of the masseter muscle, were already found in the early stages of the disease. A high percentage of open bites and cross bites were found, especially in the later stages. Tongue hypertrophy also increased over time. Increased dysfunction, reflected by increasingly abnormal echogenicity, of the masseter muscle and reduced occlusal contacts (anterior and posterior open bites) were mainly responsible for the hampered chewing. In all, this study shows the increasing involvement of various elements of the masticatory system in progressive Duchenne muscular dystrophy. To prevent choking and also nutritional deficiency, early detection of chewing problems by asking about feeding and mastication problems, as well as asking about food adaptations made, is essential and can lead to timely intervention.

Facioscapulohumeral muscular dystrophy and respiratory failure; what about the diaphragm?

INTRODUCTION: We present a case of facioscapulohumeral muscular dystrophy (FSHD) with a diaphragm paralysis as the primary cause of ventilatory failure. FSHD is an autosomal dominant inherited disorder with a restricted pattern of weakness. Although respiratory weakness is a relatively unknown in FSHD, it is not uncommon. METHODS: We report on the clinical findings of a 68-year old male who presented with severe dyspnea while supine. RESULTS: Supplementing our clinical findings with laboratory, electrophysiological and radiological performances led to the diagnosis of diaphragm paralysis. Arterial blood gas in sitting position without supplemental oxygen showed a mild hypercapnia. His sleep improved after starting non-invasive ventilation and his daytime sleepiness disappeared. DISCUSSION: We conclude that in patients with FSHD who have symptoms of nocturnal hypoventilation, an adequate assessment of the diaphragm is recommended. This is of great importance as we know that nocturnal hypoventilation can be treated effectively by non-invasive ventilation.

Health-related quality of life and its relation to disease severity in boys with Duchenne muscular dystrophy: satisfied boys, worrying parents--a case-control study.

The progression of Duchenne muscular dystrophy is expected to negatively influence the patients' health-related quality of life, but knowledge of the relationship with disease severity is limited. We investigated the relationship between health-related quality of life (KIDSCREEN-52 questionnaire) and disease severity (clinical assessments of body functions and activities) in 40 boys with Duchenne muscular dystrophy (19 ambulant, 21 wheelchair dependent) who were in different phases of the disease and underwent life-limiting events such as the loss of the ability to ambulate and the ability to lift the arms. In addition, we compared boys' health-related quality of life perceptions with that of their parents. The participants' health-related quality of life was similar to healthy peers' and not influenced by disease severity, except for the physical domain. Parents scored much lower than the boys on the KIDSCREEN-52 domains Self Perception, Moods and Emotions, and Bullying. The latter finding needs attention in the management of Duchenne muscular dystrophy.

Congenital myopathy caused by a novel missense mutation in the CFL2 gene.

Nemaline myopathy and myofibrillar myopathy are heterogeneous myopathies that both comprise early-onset forms. We present two sisters from a consanguineous Iraqi Kurdish family with predominant axial and limb girdle weakness. Muscle biopsies showed features of both nemaline myopathy and myofibrillar myopathy. We performed homozygosity mapping in both siblings using an Affymetrix 250K Nspl SNP array. One of the overlapping homozygous regions harbored the gene CFL2. Because a mutation in CFL2 was identified in a family with nemaline myopathy, we performed sequence analysis of the gene and a novel homozygous missense mutation in exon 2 (c.19G>A, p.Val7Met) of CFL2 was identified in both siblings. CFL2 encodes the protein cofilin-2, which plays an important role in regulation of sarcomeric actin filaments. To our knowledge, this is the second family in which a mutation in CFL2 causes an autosomal recessive form of congenital myopathy with features of both nemaline and myofibrillar myopathy. Given the clinical variability and the multitude of histological features of congenital myopathies, CFL2 sequence analysis should be considered in patients presenting with an autosomal recessive form of congenital myopathy.

Myopathy in a 20-year-old female patient with D4ST-1 deficient Ehlers-Danlos syndrome due to a homozygous CHST14 mutation.

We here report on a 20-year-old female patient with EDS due to a homozygous CHST14 single nucleotide deletion resulting in D4ST-1 deficiency, accompanied by muscle hypoplasia and muscle weakness. Findings of muscle ultrasound, electromyography, and muscle biopsy pointed to a myopathy, similarly as in other EDS types. This myopathy probably contributes to the gross motor developmental delay in this type of EDS.

Skeletal muscle involvement in myotonic dystrophy type 2. A comparative muscle ultrasound study.

This study determines the presence and extent of muscle changes in 31 myotonic dystrophy type 2 (DM2) patients detected by muscle ultrasound. Results were compared to 31 adult-onset myotonic dystrophy type 1 patients (DM1) and healthy controls. Furthermore, we tested the hypothesis that structural muscle changes correlate with age, quantitative muscle force and serum creatine kinase in both disorders. In DM2 all seven examined muscles (right masseter muscle, right and left biceps brachii, right and left forearm flexors, right rectus femoris, and left tibialis anterior muscle) showed increased mean echo intensities (p ≤ 0.001). Atrophy of the masseter muscle and rectus femoris were both found in 23% of DM2 patients. Muscle thickness was significantly more decreased in the elbow flexors in DM2 compared to DM1. Echo intensity sum score correlated positively with age in DM2 (r=0.57, p=0.001) and negatively with muscle force (r=0.36, p=0.048). We conclude that all tested muscles are affected and structurally abnormal in DM2 patients. Proximal arm muscles are more affected in DM2 compared to DM1, which corresponds to clinical findings.

Normal height and weight in a series of ambulant Duchenne muscular dystrophy patients using the 10 day on/10 day off prednisone regimen.

Prednisone treatment delays the progressive course of Duchenne muscular dystrophy. The aim of this study was to determine the influence of the 10 day on/10 day off treatment on height and weight. We retrospectively reviewed the growth and weight charts of Duchenne patients born between 1988 and 2006 (patients between 4 and 9 years old, being able to walk in the home situation). Forty-seven patients were eligible for further analysis and divided into two groups: 33 patients treated with prednisone and 14 non-prednisone treated patients. Results of a median follow-up of 57 months (range 27-146) are described. By using linear mixed models this study demonstrates that height and body mass index in prednisone-treated patients with 10/10 regimen are not significantly different compared to untreated patients. We cautiously conclude that the alternating prednisone regimen has no apparent side effects on weight and height in the ambulatory phase of Duchenne muscular dystrophy.

Quantitative ultrasound of lower leg and foot muscles: feasibility and reference values.

BACKGROUND: Ultrasound is a non-invasive method to quantitatively measure various muscle parameters. Purpose of this study was to assess the feasibility of ultrasound of lower leg and foot muscles and to obtain reference values for muscle thickness (MT) and echo intensity (EI). METHODS: Ultrasound measurements of leg and foot muscles were performed in 60 healthy adults. MT and EI were quantitatively determined for the abductor hallucis (AH), extensor digitorum brevis (EDB), extensor hallucis longus (EHL) and peroneus longus (PER) muscles. Influence of age, height, weight and sex was determined using a multiple linear regression analysis. RESULTS: All muscles except the AH could easily be visualized with ultrasound. EI tended to be increased above 60 years and MT was significantly higher in men compared to women, necessitating age- and sex-dependent reference values. CONCLUSIONS: This study shows that muscle ultrasound is capable of visualizing lower leg and foot muscles and reference values for MT and EI can be obtained. Future research will focus on the use of these reference values to evaluate muscle abnormalities caused by neuromuscular disorders like hereditary motor and sensory neuropathy.

Radicular dysfunction due to spinal deformities in Marfan syndrome at older age: three case reports.

Marfan syndrome is a inherited connective tissue disorder due to mutations in fibrillin-1. It presents with cardiovascular, ocular, skeletal, pulmonary and dural signs and symptoms. Some of the symptoms of later onset are those associated with scoliosis and dural ectasia. This is the enlargement of the neural canal especially in the lower lumbar and sacral region and occurs in over 90% of Marfan patients. We here report three patients with lumbar and/or sacral radiculopathy due to (kypho)scoliosis and dural ectasia with spinal meningeal cysts. The pain, muscle weakness, muscle atrophy, and sensory disturbances illustrate the severe neurological complications which may occur in Marfan syndrome, especially at later age. Awareness of these complications and development of management protocols is essential since life expectancy of Marfan patients has increased. Marfan syndrome might gradually become recognized as an inherited connective tissue disorder with potentially severe neurological complications during ageing.

Neuromuscular features in Marfan syndrome.

Marfan syndrome is a clinically and allelic heterogeneous, heritable connective tissue disorder with infrequently reported neuromuscular features. This study is the first to delineate these symptoms in a non-selected population. Neuromuscular involvement was evaluated in 10 Marfan patients through a standardized questionnaire, physical examination, nerve conduction study (NCS), needle electromyography (EMG), muscle ultrasound, laboratory investigation, and muscle biopsy. Existing neuroimages were screened for dural ectasia and spinal meningeal cysts. Twenty healthy controls with similar age distribution completed the questionnaire. The results showed that various neuromuscular symptoms occur more frequently in the patients. Four older patients reported muscle weakness, five patients had a mild-to-moderate reduction in vibration sense, and all older patients mentioned mild functional impairments. NCS showed axonal polyneuropathy in four and EMG myopathic and neurogenic changes in all patients. Increased echo intensity and atrophy on muscle ultrasound was found in more than half of the patients. Muscle biopsies obtained in two patients showed myopathic changes in the older, female patient. In conclusion, the majority of Marfan patients exhibited neuromuscular symptoms characterized as myopathy or polyneuropathy or both, and signs of lumbosacral radiculopathy, with symptoms being most pronounced in the older patients. Although meriting corroboration, these findings indicate a need to further the awareness of neuromuscular involvement in this population.

Vestibular and proprioceptive influences on trunk movements during quiet standing.

We characterized upper trunk and pelvis motion in normal subjects and in subjects with vestibular or proprioceptive loss, to document upper body movement modes in the pitch and roll planes during quiet stance. Six bilateral vestibular loss (VL), six bilateral lower-leg proprioceptive loss (PL) and 28 healthy subjects performed four stance tasks: standing on firm or foam surface with eyes open or closed. Motion of the upper body was measured using two pairs of body-worn gyroscopes, one mounted at the pelvis and the other pair at the shoulders. Pitch and roll angular velocities recorded from the gyroscopes were analyzed separately for low-frequency (<0.7 Hz) and high-frequency (>3 Hz) motion. Low-frequency pitch motion was similar for all groups, consisting of in-phase pelvis and shoulder motion. High-frequency pitch motion in controls and VL subjects was dominated by pelvis motion with little shoulder motion, but vice versa in PL subjects. Low-frequency roll motion changed for all groups from mainly shoulder and little pelvis motion to in-phase pelvis and shoulder motion after moving from a firm to foam surface. In contrast, high-frequency roll motion changed from mainly shoulder motion to mainly pelvis motion with the change to a foam surface, except for PL subjects with eyes closed. Coherent low-frequency sway between pelvis and shoulder was only pronounced in VL patients. These results indicate that relative motion between the pelvis and shoulder depends on the support surface, the type of sensory loss, and whether the motion is in roll or pitch plane. Furthermore, relative motion between the pelvis and upper trunk is an integral part of movement modes used to control quiet stance. Vestibular loss patients showed very similar movement modes as controls, with larger amplitudes. Proprioceptive loss patients, however, used more shoulder motion and stabilized the pelvis for the high-frequency mode. We conclude that there is relative motion between the upper trunk and pelvis during quiet stance and suggest that it may contribute to balance control.

Evaluation of prednisolone treatment in the acute phase of neuralgic amyotrophy: an observational study.

BACKGROUND: Effective treatment for neuralgic amyotrophy (NA), a disabling brachial plexus syndrome of supposed immunomediated origin, is currently lacking. Given the circumstantial evidence of a beneficial effect of prednisolone on pain and paresis, this report evaluates the effects of prednisolone treatment administered in the acute phase in a retrospective case series of 50 NA patients. METHODS: Baseline variables (eg, age, sex, type of NA and number of attacks), treatment variables (eg, time until treatment, regimen and use of analgesics) and outcome measures (eg, duration and severity of pain, time course and severity of paresis and functional outcome) were statistically analysed and compared with a historical control group of 203 untreated NA patients. RESULTS: The baseline characteristics of the two patient groups were comparable. The median time until initial pain relief was lower in the study group (12.5 days vs 20.5 days), and a significantly higher percentage already recovered strength in the first month of treatment (18% vs 6.3%; p = 0.011). Twelve per cent had fully recovered within 1 year, while this was 1% for the controls (p<0.001), with the proportion reporting a "good" 12-month outcome also being higher (44% vs 10.7%; p<0.001). Side effects were reported by 20%, but none led to a discontinuation of treatment. CONCLUSION: Oral prednisolone seems effective in the acute phase of neuralgic amyotrophy with the current results supporting previous case reports. A regimen of oral prednisolone is therefore recommended in the acute phase of the syndrome pending a prospective, randomised trial verifying the results obtained.

Treatment for neonatal neuralgic amyotrophy.

We report a 15-day-old neonate with a brachial plexus neuropathy diagnosed as neuralgic amyotrophy concomitant with an osteomyelitis of the ipsilateral humerus. She was treated with intravenous antibiotics and oral dexamethasone and improved dramatically within days.