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.

RYR1-related myopathies: a wide spectrum of phenotypes throughout life.

BACKGROUND AND PURPOSE: Although several recent studies have implicated RYR1 mutations as a common cause of various myopathies and the malignant hyperthermia susceptibility (MHS) trait, many of these studies have been limited to certain age groups, confined geographical regions or specific conditions. The aim of the present study was to investigate the full spectrum of RYR1-related disorders throughout life and to use this knowledge to increase vigilance concerning malignant hyperthermia. METHODS: A retrospective cohort study was performed on the clinical, genetic and histopathological features of all paediatric and adult patients in whom an RYR1 mutation was detected in a national referral centre for both malignant hyperthermia and inherited myopathies (2008-2012). RESULTS: The cohort of 77 non-related patients (detection rate 28%) included both congenital myopathies with permanent weakness and 'induced' myopathies such as MHS and non-anaesthesia-related episodes of rhabdomyolysis or hyperCKemia, manifested throughout life and triggered by various stimuli. Sixty-one different mutations were detected, of which 24 were novel. Some mutations are present in both dominant (MHS) and recessive modes (congenital myopathy) of inheritance, even within families. Histopathological features included an equally wide spectrum, ranging from only subtle abnormalities to prominent cores. CONCLUSIONS: This broad range of RYR1-related disorders often presents to the general paediatric and adult neurologist. Its recognition is essential for genetic counselling and improving patients' safety during anaesthesia. Future research should focus on in vitro testing by the in vitro contracture test and functional characterization of the large number of RYR1 variants whose precise effects currently remain uncertain.

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.

Dysphagia in spinal muscular atrophy type II: more than a bulbar problem?

OBJECTIVE: In patients with spinal muscular atrophy (SMA) type II, feeding problems and dysphagia are common, but the underlying mechanisms of these problems are not well defined. This case control study was designed to determine the underlying mechanisms of dysphagia in SMA type II. METHODS: Six children with SMA type II and 6 healthy matched controls between 6.4 and 13.4 years of age were investigated during swallowing liquid and solid food in 2 different postures using surface EMG (sEMG) of the submental muscle group (SMG) and a video fluoroscopic swallow study (VFSS). RESULTS: The VFSS showed postswallow residue of solid food in the vallecula and above the upper esophageal sphincter (UES), which can be responsible for indirect aspiration. Better results in swallowing were achieved in a more forward head position. These findings were supported by the sEMG measurements of the SMG during swallowing. CONCLUSIONS: Dysphagia in spinal muscular atrophy type II is due to a neurologic dysfunction (lower motor neuron problems from the cranial nerves in the brainstem) influencing the muscle force and efficiency of movement of the tongue and the submental muscle group in combination with a biomechanical component (compensatory head posture). The results suggest an integrated treatment with an adapted posture during meals and the advice of drinking water after meals to prevent aspiration pneumonias.

Quantitative skeletal muscle ultrasound: diagnostic value in childhood neuromuscular disease.

UNLABELLED: In this study we investigated the diagnostic value of quantitative skeletal muscle ultrasonography in 150 consecutively referred children with symptoms suspect for a neuromuscular disorder. Muscle thickness and quantitatively determined echo intensity of four muscles and the distribution of these variables within the body were examined. RESULTS: Patients with and without a neuromuscular disorder could be discriminated with a positive predictive value of 91% and a negative predictive value of 86%. Patients with a neurogenic disorder could be distinguished from myopathies and non-neuromuscular disorders with a positive predictive value of 86% and a negative predictive of 84%, using the pattern of distribution of pathology within the body. CONCLUSIONS: Skeletal muscle ultrasound is a good, practical and non-invasive aid in the diagnosis of neuromuscular disorders in children, that is able to discriminate between children with and without a neuromuscular disorder and between neurogenic disorders and myopathies with high predictive values.

Predictive value of neonatal MRI with respect to late MRI findings and clinical outcome. A study in infants with periventricular densities on neonatal ultrasound.

PURPOSE: The aim of this study was to correlate hypoxic-ischemic white matter damage on neonatal MRI with MRI appearance and neurological outcome at the age of 1 1/2 years. PATIENTS AND METHODS: A sequential cohort of infants with periventricular densities on neonatal ultrasound was studied with neonatal MRI. Images of 46 infants with a mean gestational age of 31 weeks were obtained at a mean age of 20 days after birth and at 1 1/2 years. To establish agreement between the neonatal and follow-up MRI (general, motor, and visual scores), the weighted Cohen's kappa test was used. To establish the predictive power of neonatal MRI with respect to the neurologic indices at the age of 1 1/2 years, the sensitivity, specificity, and positive and negative predictive values were calculated. RESULTS: There was a moderately good to good agreement between the general, motor, and visual neonatal and follow-up MRI scores: weighted kappa = 0.59 (95% CI: 0.44 - 0.74), 0.82 (95% CI: 0.72 - 0.93), and 0.70 (95% CI: 0.56 - 0.84), respectively. Neonatal MRI scores provided a good prediction of the three neurological outcome measures (developmental delay, cerebral palsy, and cerebral visual impairment): sensitivity, specificity, and predictive values were high, with little difference between the three MRI scores. The 32 patients with (nearly) normal neonatal MRI scores were neurologically (nearly) normal at 1 1/2 years on all three outcome measures, whereas 8 patients with seriously abnormal neonatal MRI scores were neurologically abnormal at 1 1/2 years on all three outcome measures. CONCLUSION: Neonatal MRI is able to predict the precise localization and size of perinatal leukomalacia on follow-up MRI and provides a good prediction of neurological outcome at 1 1/2 years.

Predictive value of EEG in neonates with periventricular leukomalacia.

The aim of this study was to evaluate whether EEG (i.e. positive Rolandic sharp waves) can be used to predict neurodevelopment in newborn infants with periventricular leukomalacia and compare the predictive value with that of MRI. A sequential cohort of neonates (n=45; 33 males, 12 females; mean gestational age 31.2 weeks, SD 2.7, range 27 to 37.8 weeks; mean birthweight 1592 g, SD 601 g) with periventricular hyperechogenicities on cranial ultrasound was recruited for this study. EEGs were analyzed for positive Rolandic sharp waves. Neurodevelopment was evaluated at the ages of 12 and 18 months. In the whole group the probability of a poor outcome was 24% and the probability of any impairment was 33%. If the number of positive Rolandic sharp waves was no more than 0.1 per minute, the probability of a poor outcome was reduced to 9% (95% confidence interval [95%CI] 2 to 27%) and the probability of any impairment was reduced to 13% (95%CI 4 to 32%). In all infants with more than 0.1 positive Rolandic sharp waves per minute the probability of a poor outcome was 41% (95%CI 23 to 61%) and of any impairment was 55% (95%CI 34 to 73%). In these infants MRI identified infants with a poor outcome with a sensitivity of 1.00 (95%CI 0.70 to 1.00) and a specificity of 0.92 (95%CI 0.67 to 0.99), and infants with any impairment with a sensitivity of 0.83 (95%CI 0.55 to 0.95) and a specificity of 1.00 (95%CI 0.72 to 1.00). Results suggest that if an EEG of an infant with periventricular leukomalacia contains no more than 0.1 positive Rolandic sharp waves per minute the probability of a normal or mildly delayed development is high (0.91, 95%CI 0.73 to 0.98). MRI enhances the accuracy of the outcome prediction slightly; however, owing to a wide confidence interval, this advantage is negligible. However, if the frequency of the positive Rolandic sharp waves exceeds 0.1per minute, MRI can significantly enhance the precision of the prediction of outcome.

Development of spontaneous leg movements in infants with and without periventricular leukomalacia.

The main question asked in the present study was whether support could be found for the notion that supraspinal influences on the generation of spontaneous kicking movements become increasingly apparent in the first half-year after birth. In comparing groups of infants with and without damage in tracts connected with the cortex surrounding the central sulcus, such support would consist of the finding that similar patterns of spontaneous kicking are observed early in development, whereas differences between groups should occur with increasing age. Using 3-D registrations, the spontaneous kicking movements of 19 infants with differing degrees of periventricular, lobar, and subcortical leukomalacia based on white matter (WM) abnormalities on ultrasound were compared to those of 10 healthy control infants at 6, 12, 18, and 26 weeks of corrected age. Magnetic resonance imaging recordings were used to identify the location and severity of the brain lesions. Infants with extensive lesions in the periventricular and lobar WM with or without diffuse lesions in the subcortical WM showed a decreased variability on some spatial and temporal parameters of kicks. More importantly, these infants showed a different developmental course for intralimb couplings when compared to the other infants; they were unable to dissociate tight intralimb couplings at 18 and 26 weeks. As all of these infants had substantial damage of the corticospinal tracts, these findings suggest that these tracts are involved in the regulation of intralimb joint dissociations between 4 and 6 months of age. However, caution is needed as areas outside those in which the corticospinal tracts are located could be damaged as well and most of the infants with moderate to severe lesions in the corticospinal tract had additional psychomotor problems. For interlimb couplings and most of the spatial and temporal parameters of kicks, no differences were found between groups. This strengthens the claim that inter- and intralimb couplings are organized in fundamentally different ways.

Value of fluid-attenuated inversion recovery sequences in early MRI of the brain in neonates with a perinatal hypoxic-ischemic encephalopathy.

The aim of our study was to assess the usefulness of fluid-attenuated inversion recovery (FLAIR) sequences in comparison with conventional spin-echo and inversion MR imaging in neonates for evaluation of myelination and for detection of hypoxic-ischemic brain injury. We reviewed early MR scans of 18 neonates with suspected hypoxic-ischemic brain damage. Myelination could be evaluated with confidence using conventional MR imaging in all but 2 infants; however, the presence of myelin was very difficult to assess on FLAIR images. Overall, 53 lesions or groups of lesions were identified. The FLAIR technique was more sensitive in 11 of the lesions; especially (pre)cystic lesions could be identified much better and more cysts were found. Conventional MR imaging failed to identify 2 of the lesions and was more sensitive in 14 of the lesions; especially punctate hemorrhages and lesions in basal ganglia or thalami could be better determined. The FLAIR technique missed 3 of these lesions. In the remaining 28 lesions conventional MR and FLAIR images were equally diagnostic. The FLAIR technique and conventional MR imaging are complementary in detecting early sequelae of hypoxic-ischemic brain injury in neonates. The FLAIR technique is not suitable for assessing myelination of the neonatal brain; therefore, FLAIR cannot replace conventional MR imaging.

MR patterns of hypoxic-ischemic brain damage after prenatal, perinatal or postnatal asphyxia.

The relationship between MR patterns of brain damage and type or timing of perinatal hypoxia-ischemia was studied. MR images of 104 children with evidence of bilateral posthypoxic-ischemic brain damage and neonatal records were reviewed. Three different MR patterns were found. Periventricular leukomalacia occurred in 73 children, in 82% after a history of subacute or chronic hypoxia-ischemia, in 71% after preterm birth. Predominant lesions of basal ganglia and thalamus occurred in 21 children, in 95% preceded by acute profound asphyxia, in 85% after term birth. Multicystic encephalopathy occurred in 10 infants, in 70% preceded by mild signs of hypoxia-ischemia, followed by an unexpectedly severe encephalopathy, in 60% after term birth. Statistical analysis showed that the patterns of injury were primarily related to the type of hypoxia-ischemia. We conclude that the type of hypoxia-ischemia, rather than the postconceptional age at occurrence determines the pattern of brain injury.

Early MR features of hypoxic-ischemic brain injury in neonates with periventricular densities on sonograms.

BACKGROUND AND PURPOSE: In the early 1980s, diagnosing periventricular leukomalacia (PVL) in neonates by using cranial sonography was possible for the first time. Our purpose was to investigate the possibility of diagnosing PVL in the acute stage by using MR imaging. We evaluated early MR features of hypoxic-ischemic brain injury in neonates with periventricular densities (flares) on cranial sonograms to determine the added value of MR imaging over sonography alone for early diagnosis of brain damage. METHODS: In a prospective study, infants who showed flares and/or cysts on sonograms underwent MR imaging during the (sub)acute stage. RESULTS: Fifty infants were classified according to the highest sonographic grade up to the day of MR imaging: 23 infants had sonographic grade 1 (flares < 1 week), 15 had sonographic grade 2 (flares > or = 1 week), four had sonographic grade 3 (small localized cysts), and eight had sonographic grade 4 (extensive periventricular cysts); none had sonographic grade 5 (multicystic leukomalacia) on the day of MR imaging. Overall, the additional information provided by MR imaging (over sonography alone) consisted of the depiction of hemorrhagic lesions in 64% of the infants. Extent and severity of the hemorrhages varied from isolated punctate lesions to extensive hemorrhages throughout the white matter; the latter were followed by cystic degeneration at autopsy in two infants. In nine of the 12 infants with cystic PVL, MR images showed more numerous or more extensive cysts. In addition, in two infants, MR images showed cysts not present on sonograms. In 32% of the infants, MR imaging provided no additional information; in these children, all but one had flares on sonograms whereas MR images showed no abnormalities or a zone of mild periventricular signal change. CONCLUSION: MR imaging can depict the precise site and extent of hypoxic-ischemic brain injury at an earlier stage and allows a wider differentiation of lesions as compared with sonography alone. Hemorrhagic PVL is considered to be rare, but was present in 64% of our study population.

Predictive value of neonatal MRI as compared to ultrasound in premature infants with mild periventricular white matter changes.

A follow-up study was performed in 42 premature infants in whom serial neonatal ultrasound and a single neonatal MRI of the brain was normal, or showed mild periventricular white matter changes. The aim of the study was to evaluate the clinical significance of periventricular signal intensity changes on MRI and to compare the predictive value of neonatal MRI with that of ultrasound. The infants underwent repeated standardised motor assessments and developmental tests. MRI was repeated at the corrected age of 12 months. Pronounced periventricular signal intensity changes on neonatal MRI and periventricular echodensities (flaring) on ultrasound were associated with a high incidence of transient motor problems during infancy. The degree of echogenicity carried the highest predictive value, as compared to duration of flaring on ultrasound and degree of periventricular signal intensity change on MRI. It is concluded that signal intensity changes on neonatal MRI represent the same ischaemic change of the periventricular white matter as flaring on ultrasound and that routine neonatal MRI screening is not warranted in premature infants without clinical evidence of neurological problems and with normal or mildly abnormal ultrasound scans. Recording of the degree of echogenicity should become a routine procedure in neonatal cerebral ultrasonography.

Unilateral thalamic lesions in premature infants: risk factors and short-term prognosis.

The aim of the study was to assess incidence, risk factors, clinical symptomatology and short-term outcome of unilateral thalamic lesions in preterm infants, as detected by ultrasound. Sixteen preterm infants, born after a gestational age of less than 35 weeks, with a unilateral thalamic lesion, but without additional significant cerebral lesions, were included. Their follow-up data were compared to those of a selected control group consisting of healthy premature infants. In addition, the neonatal clinical data of the patients with a thalamic lesion were compared to data of the healthy control group and of a general control group, consisting of a non-selected year-cohort of preterm infants. During the study period, the incidence of unilateral thalamic lesions was 5.3% among preterm infants. Ultrasound was not able to distinguish between hemorrhagic and ischemic lesions. The infants with a unilateral thalamic lesion had a more complicated respiratory course and were ventilated significantly longer than infants without such a lesion. The infants with a thalamic lesion had disturbances in tone, persisting throughout infancy, while the healthy control group showed only transient disturbances in tone.

Magnetic resonance imaging of the brain in premature infants during the neonatal period. Normal phenomena and reflection of mild ultrasound abnormalities.

An MRI study was performed in 34 preterm infants who were clinically and neurologically normal and whose cranial ultrasound revealed no or only mild abnormalities. The postconceptional age at MRI varied between 30.6 and 37 weeks. The purpose of the study was to evaluate the significance of periventricular changes in signal intensity on MRI, comparing MRI with ultrasound. T1-weighted and T2-weighted images were assessed for changes in signal intensity of the periventricular white matter relative to the remainder of the cerebral hemispheric white matter. Cerebral MRIs of 13 postterm infants were additionally investigated. In all preterm infants small localized areas of high signal intensity on T1-weighted images and low signal intensity on T2-weighted images were seen adjacent to the frontal horns of the lateral ventricles. They faded with increasing age and were no longer seen one month after term in the group of postterm infants. The areas were considered normal before term age and probably represent remnants of the germinal matrix. Periventricular echodensities corresponded with a zone of changed signal intensity within the periventricular white matter on MRI. MRI signal change correlated with the presence and location of echodensities; the MRI signal changes slowly faded away after the echodensities disappeared.

MRI assessment of myelination of motor and sensory pathways in the brain of preterm and term-born infants.

A study was performed in 48 neurologically normal preterm and term-born infants, with a postconceptional age at MRI varying between 30 2/7 and 46 weeks and a mean age of 34 2/7 weeks. The purpose of the study was to determine the normal progress of myelination on MRI in that age range. T1- and T2-weighted images of the brain were assessed for changes in signal intensity of white matter relative to gray matter. Multiple sites in the brainstem, cerebellum and cerebral hemispheres were assessed separately. The findings were correlated with the ages of the infants. As judged from relative signal intensities, myelin was present at the post-conceptional age of 30-34 weeks in the following structures: tegmentum pontis (in particular medial lemniscus), superior and inferior colliculi, decussation of the superior cerebellar peduncles, crura cerebri, ventrolateral thalamus, lateral globus pallidus, dorsolateral putamen, dentate nucleus, middle and superior cerebellar peduncles, vermis cerebelli, cortex bordering the central sulcus and hippocampus. Little progress in myelination was noticed up to the post-conceptional age of 46 weeks. Between 34 and 46 weeks, myelin appeared in the lateral part of the posterior limb of the internal capsule and in the central part of the corona radiata and became more prominently visible in the cortex bordering the central sulcus.