Magnetic resonance reveals mitochondrial dysfunction and muscle remodelling in spinal muscular atrophy.

Genetic therapy has changed the prognosis of hereditary proximal spinal muscular atrophy, although treatment efficacy has been variable. There is a clear need for deeper understanding of underlying causes of muscle weakness and exercise intolerance in patients with this disease to further optimize treatment strategies. Animal models suggest that in addition to motor neuron and associated musculature degeneration, intrinsic abnormalities of muscle itself including mitochondrial dysfunction contribute to the disease aetiology. To test this hypothesis in patients, we conducted the first in vivo clinical investigation of muscle bioenergetics. We recruited 15 patients and 15 healthy age and gender-matched control subjects in this cross-sectional clinico-radiological study. MRI and 31P magnetic resonance spectroscopy, the modality of choice to interrogate muscle energetics and phenotypic fibre-type makeup, was performed of the proximal arm musculature in combination with fatiguing arm-cycling exercise and blood lactate testing. We derived bioenergetic parameter estimates including: blood lactate, intramuscular pH and inorganic phosphate accumulation during exercise, and muscle dynamic recovery constants. A linear correlation was used to test for associations between muscle morphological and bioenergetic parameters and clinico-functional measures of muscle weakness. MRI showed significant atrophy of triceps but not biceps muscles in patients. Maximal voluntary contraction force normalized to muscle cross-sectional area for both arm muscles was 1.4-fold lower in patients than in controls, indicating altered intrinsic muscle properties other than atrophy contributed to muscle weakness in this cohort. In vivo31P magnetic resonance spectroscopy identified white-to-red remodelling of residual proximal arm musculature in patients on the basis of altered intramuscular inorganic phosphate accumulation during arm-cycling in red versus white and intermediate myofibres. Blood lactate rise during arm-cycling was blunted in patients and correlated with muscle weakness and phenotypic muscle makeup. Post-exercise metabolic recovery was slower in residual intramuscular white myofibres in patients demonstrating mitochondrial ATP synthetic dysfunction in this particular fibre type. This study provides the first in vivo evidence in patients that degeneration of motor neurons and associated musculature causing atrophy and muscle weakness in 5q spinal muscular atrophy type 3 and 4 is aggravated by disproportionate depletion of myofibres that contract fastest and strongest. Our finding of decreased mitochondrial ATP synthetic function selectively in residual white myofibres provides both a possible clue to understanding the apparent vulnerability of this particular fibre type in 5q spinal muscular atrophy types 3 and 4 as well as a new biomarker and target for therapy.

Prospective Evaluation of Sleep Apnea as Manifestation of Heart Failure in Children.

In adults with heart failure, central sleep apnea (CSA), often manifested as Cheyne-Stokes respiration, is common, and has been associated with adverse outcome. Heart failure in children is commonly caused by dilated cardiomyopathy (DCM). It is unknown whether children with heart failure secondary to DCM have CSA, and whether CSA is related to the severity of heart failure. In this prospective observational study, 37 patients (<18 year) with heart failure secondary to DCM were included. They underwent polysomnography, clinical and laboratory evaluation and echocardiographic assessment. After a median follow-up time of 2 years, eight patients underwent heart transplantation. CSA (apnea-hypopnea index [AHI] ≥1) was found in 19 % of the patients. AHI ranged from 1.2 to 4.5/h. The occurrence of CSA was not related to the severity of heart failure. Three older patients showed a breathing pattern mimicking Cheyne-Stokes respiration, two of whom required heart transplantation. CSA was found in 19 % of the children with heart failure secondary to DCM. No relation was found with the severity of heart failure. In a small subset of children with severe DCM, a pattern mimicking Cheyne-Stokes respiration was registered.

Arterial spin labeling measurement of cerebral perfusion in children with sickle cell disease.

PURPOSE: To evaluate the applicability of arterial spin labeling (ASL) cerebral blood flow (CBF) measurements in children with sickle cell disease (SCD). MATERIALS AND METHODS: We included 12 patients and five controls. Conventional magnetic resonance imaging (MRI) (T2, fluid attenuated inversion recovery [FLAIR], and MR angiography) was performed to diagnose silent infarcts, vasculopathy, or leukoencephalopathy. Pseudo-continuous ASL was performed to measure CBF using two postlabeling delays to identify transit-time effects. Perfusion estimates were corrected for hematocrit and blood velocity in the labeling plane and compared to phase-contrast MR. CBF asymmetries between the flow maps of the left and right internal carotid arteries were tested for significance using paired t-tests. Significant asymmetries were expressed in terms of an asymmetry ratio (AR = absolute difference/mean). An AR >10% was considered clinically relevant. RESULTS: Mean CBF was higher in patients than in controls. Agreement between CBF and flow improved after applying hematocrit and velocity corrections. At a 2100 msec postlabeling delay one patient had a clinically relevant asymmetry. No association was observed between CBF asymmetries and silent infarcts. CONCLUSION: Care must be taken in the interpretation of ASL-CBF measurements in SCD patients. A long postlabeling delay with blood velocity correction anticipates overestimation of CBF asymmetries.

Reproducibility of diffusion tensor imaging in human forearm muscles at 3.0 T in a clinical setting.

The aim of the present study was to evaluate a fast clinical protocol to enable diffusion tensor imaging of the human forearm and assess the reproducibility of six diffusion tensor imaging parameters, i.e., the tensor eigenvalues (λ(1), λ(2), and λ(3)), mean diffusivity, fractional anisotropy, and ellipsoid eccentricity. The right forearms of 10 healthy volunteers were scanned twice, with a 1-week interval. Reproducibility of the diffusion tensor imaging parameters was interpreted using Bland-Altman plots, coefficient of repeatability, repeatability index, and the intraclass correlation coefficient. Analysis was done for three regions of interest: the whole muscle volume, flexor digitorum profundus, and extensor digitorum. The Bland-Altman analysis showed that there is good agreement between the two measurements. Based on the intraclass correlation coefficients, agreement was substantial (0.59 < intraclass correlation coefficient < 0.92) for all six parameters of the whole muscle volume and flexor digitorum profundus but only fair (0.18 < intraclass correlation coefficient < 0.64) for the extensor digitorum. Using a 7 min 40 sec scan protocol, which was well tolerated by the volunteers, the reproducibility of diffusion tensor imaging parameters was demonstrated. However, repeatability varies, depending on the region of interest and diffusion tensor imaging parameters. This should be taken into account when a longitudinal study is designed.

Comparison of four MR carotid surface coils at 3T.

BACKGROUND: The quality of carotid wall MRI can benefit substantially from a dedicated RF coil that is tailored towards the human neck geometry and optimized for image signal-to-noise ratio (SNR), parallel imaging performance and RF penetration depth and coverage. In last decades, several of such dedicated carotid coils were introduced. However, a comparison of the more successful designs is still lacking. OBJECTIVE: To perform a head-to-head comparison over four dedicated MR carotid surface coils with 4, 6, 8 and 30 coil elements, respectively. MATERIAL AND METHODS: Ten volunteers were scanned on a 3T scanner. For each subject, multiple black-blood carotid vessel wall images were measured using the four coils with different parallel imaging settings. The performance of the coils was evaluated and compared in terms of image coverage, penetration depth and noise correlations between elements. Vessel wall of a common carotid section was delineated manually. Subsequently, images were assessed based on vessel wall morphology and image quality parameters. The morphological parameters consisted of the vessel wall area, thickness, and normalized wall index (wall area/total vessel area). Image quality parameters consisted of vessel wall SNR, wall-lumen contrast-to-noise ratio (CNR), the vessel g-factor, and CNRindex ((wall-lumen signal) / (wall+lumen signal)). Repeated measures analysis of variance (rmANOVA) was applied for each parameter for the averaged 10 slices for all volunteers to assess effect of coil and SENSE factor. If the rmANOVA was significant, post-hoc comparisons were conducted. RESULTS: No significant coil effect were found for vessel wall morphological parameters. SENSE acceleration affected some morphological parameters for 6- and 8-channel coils, but had no effect on the 30-channel coil. The 30-channel coil achieved high acceleration factors (10x) with significantly lower vessel g-factor values (ps ≤ 0.01), but lower vessel wall SNR and CNR values (ps ≤ 0.01). CONCLUSION: All four coils were capable of high-quality carotid MRI. The 30-channel coil is recommended when rapid image acquisition acceleration is required for 3D measurements, whereas 6- and 8-channel coils demonstrated the highest SNR performance.

REPRODUCIBILITY OF THE MODIFIED STAR EXCURSION BALANCE TEST COMPOSITE AND SPECIFIC REACH DIRECTION SCORES.

BACKGROUND: The mSEBT is a screening tool used to evaluate dynamic balance. Most research investigating measurement properties focused on intrarater reliability and was done in small samples. To know whether the mSEBT is useful to discriminate dynamic balance between persons and to evaluate changes in dynamic balance, more research into intra- and interrater reliability and smallest detectable change (synonymous with minimal detectable change) is needed. PURPOSE: To estimate intra- and interrater reliability and smallest detectable change of the mSEBT in adults at risk for ankle sprain. STUDY DESIGN: Cross-sectional, test-retest design. METHODS: Fifty-five healthy young adults participating in sports at risk for ankle sprain participated (mean ± SD age, 24.0 ± 2.9 years). Each participant performed three test sessions within one hour and was rated by two physical therapists (session 1, rater 1; session 2, rater 2; session 3, rater 1). Participants and raters were blinded for previous measurements. Normalized composite and reach direction scores for the right and left leg were collected. Analysis of variance was used to calculate intraclass correlation coefficient values for intra- and interrater reliability. Smallest detectable change values were calculated based on the standard error of measurement. RESULTS: Intra- and interrater reliability for both legs was good to excellent (intraclass correlation coefficient ranging from 0.87 to 0.94). The intrarater smallest detectable change for the composite score of the right leg was 7.2% and for the left 6.2%. The interrater smallest detectable change for the composite score of the right leg was 6.9% and for the left 5.0%. CONCLUSION: The mSEBT is a reliable measurement instrument to discriminate dynamic balance between persons. Most smallest detectable change values of the mSEBT appear to be large. More research is needed to investigate if the mSEBT is usable for evaluative purposes. LEVEL OF EVIDENCE: Level 2.

Evaluation of a new device for home cardiorespiratory recording in children.

OBJECTIVE: To evaluate the feasibility of using a new home cardiorespiratory recording device (HCRD) in children. DESIGN: Cross-sectional study. PATIENTS: Consecutive children scheduled for adenotonsillectomy to treat habitual snoring and/or apneas at otorhinolaryngology clinics in 2 academic and 7 general hospitals. INTERVENTION: Single-night unattended home cardiorespiratory recording prior to adenotonsillectomy using the HCRD. MAIN OUTCOME MEASURES: Number of technically acceptable recordings and successful recordings with artifact-free signals (respiration, saturation, and nasal flow) present for sufficient duration to allow scoring of the polysomnogram and to make a diagnosis. RESULTS: Of 53 eligible children, 24 participated in the study. The main reason for nonparticipation was refusal of caregivers (n = 16). Mean (SD) age of participants was 4.2 (1.6) years; median Brouillette obstructive sleep apnea score was 2.54. Technically acceptable recordings were obtained in 18 children (75%). Only 7 recordings (29%) were classified as successful. The poorest signal quality was obtained from the nasal cannula. CONCLUSION: Based on strict scoring criteria in this study, the results of single-night unattended recordings at home with the HCRD fell short of expectations.

The relationship between central adrenal insufficiency and sleep-related breathing disorders in children with Prader-Willi syndrome.

BACKGROUND: The annual death rate of patients with Prader-Willi syndrome (PWS) is high (3%). Many deaths of children are sudden and unexplained. Sleep apneas have been suggested to play a role in sudden deaths. Recently, we discovered that 60% of patients with PWS suffer from central adrenal insufficiency (CAI) during stress. OBJECTIVE: The aim was to study the relationship between CAI and sleep-related breathing disorders. DESIGN: In 20 children with PWS who underwent a metyrapone test (30 mg/kg at 2330 h), sleep-related breathing was evaluated by polysomnography before the metyrapone test. In addition, we recorded sleep-related breathing in 10 children with PWS during their metyrapone test. CAI was diagnosed when ACTH levels during the metyrapone test were below 33 pmol/liter at 0730 h. All tests were performed during healthy condition. SETTING: The study was conducted in a pediatric intensive care unit and specialized sleep center. RESULTS: Median (interquartile range) age was 8.4 yr (6.5-10.2). After metyrapone administration, median (interquartile range) central apnea index (number/hour) increased significantly from 2.2 (0.4-4.7) to 5.2 (1.5-7.9) (P = 0.007). The increase tended to be higher in children with CAI [2.8 (2.0-3.9) vs. 1.0 (-0.2 to 2.6); P = 0.09]. During polysomnography before the metyrapone test, sleep-related breathing was worse in children with CAI, who had a significantly higher central apnea index and tended to have a lower minimum oxygen saturation compared to those without CAI (P = 0.03 and P = 0.07). CONCLUSIONS: In children with PWS, the central apnea index increased significantly after metyrapone administration, particularly in those with CAI during stress. In addition, children with CAI had a higher central apnea index compared to those without several months before the metyrapone test.

Undiagnosed obstructive sleep apnea syndrome in children with syndromal craniofacial synostosis.

Children with syndromal craniofacial synostosis have a high risk for obstructive sleep apnea syndrome. Early diagnosis and treatment can relieve symptoms and morbidity. Little is known about the development and natural history of obstructive sleep apnea syndrome through life. The aim of this study was to investigate our experience of clinical history and treatment modalities concerning obstructive sleep apnea syndrome from birth until the current age in children with syndromal craniofacial synostosis. Children with one of the three syndromal craniofacial synostoses (Apert, Crouzon, or Pfeiffer) born between 1984 and 2001 were evaluated. The medical history and symptoms of obstructive sleep apnea syndrome were assessed by retrospective analysis of the medical records. The present and past complaints were explored by means of a questionnaire. Retrospective analysis of the medical records showed a suspicion for obstructive sleep apnea syndrome in 26% of the children compared with 53% in the questionnaire. The severity and presentation of obstructive sleep apnea syndrome were not related to the age of the child. Obstructive sleep apnea syndrome symptoms occurred in almost half of the children during colds. Several symptoms were significantly more common in children with a high suspicion for obstructive sleep apnea syndrome. Treatment modalities consisted of adenotonsillectomies, continuous positive airway pressure, and Le Fort III surgery. Use of a standard questionnaire showed that the suspicion for obstructive sleep apnea syndrome in children with syndromal craniofacial synostosis is much higher than reported in the medical records. Regular screening for obstructive sleep apnea syndrome with a standard questionnaire could be of additional value for the detection of obstructive sleep apnea syndrome in children with syndromal craniofacial synostosis.