Neurologic Outcome Comparison between Fetal Open-, Endoscopic- and Neonatal-Intervention Techniques in Spina Bifida Aperta.

INTRODUCTION: In spina bifida aperta (SBA), fetal closure of the myelomeningocele (MMC) can have a neuroprotective effect and improve outcomes. In Europe, surgical MMC closure is offered by fetal-open (OSBAR), fetal-endoscopic (FSBAR), and neonatal (NSBAR) surgical techniques. Pediatric neurologists facing the challenging task of counseling the parents may therefore seek objective outcome comparisons. Until now, such data are hardly available. In SBA, we aimed to compare neurologic outcomes between OSBAR, FSBAR, and NSBAR intervention techniques. METHODS: We determined intervention-related complications, neuromuscular integrity, and neurologic outcome parameters after OSBAR (n = 17) and FSBAR (n = 13) interventions by age- and lesion-matched comparisons with NSBAR-controls. Neurological outcome parameters concerned: shunt dependency, segmental alterations in muscle ultrasound density (reflecting neuromuscular integrity), segmental motor-, sensory- and reflex conditions, and the likelihood of intervention-related gain in ambulation. RESULTS: Compared with NSBAR-controls, fetal intervention is associated with improved neuromuscular tissue integrity, segmental neurological outcomes, reduced shunt dependency, and a higher chance of acquiring ambulation in ≈20% of the operated children. Children with MMC-lesions with a cranial border at L3 revealed the most likely intervention-related motor function gain. The outcome comparison between OSBAR versus FSBAR interventions revealed no significant differences. CONCLUSION: In SBA, OSBAR- and FSBAR-techniques achieved similar neuroprotective results. A randomized controlled trial is helpful in revealing and compare ongoing effects by surgical learning curves.

Development of muscle ultrasound density in healthy fetuses and infants.

Muscle ultrasound density (MUD) is a non-invasive parameter to indicate neuromuscular integrity in both children and adults. In healthy fetuses and infants, physiologic MUD values during development are still lacking. We therefore aimed to determine the physiologic, age-related MUD trend of biceps, quadriceps, tibialis anterior, hamstrings, gluteal and calf muscles, from pre- to the first year of postnatal life. To avoid a bias by pregnancy-related signal disturbances, we expressed fetal MUD as a ratio against bone ultrasound density. We used the full-term prenatal MUD ratio and the newborn postnatal MUD value as reference points, so that MUD development could be quantified from early pre- into postnatal life. Results: During the prenatal period, the total muscle group revealed a developmental MUD trend concerning a fetal increase in MUD-ratio from the 2nd trimester up to the end of the 3rd trimester [median increase: 27% (range 16-45), p < .001]. After birth, MUD-values increased up to the sixth month [median increase: 11% (range -7-27), p = 0.025] and stabilized thereafter. Additionally, there were also individual MUD characteristics per muscle group and developmental stage, such as relatively low MUD values of fetal hamstrings and high values of the paediatric gluteus muscles. These MUD trends are likely to concur with analogous developmentally, maturation-related alterations in the muscle water to peptide content ratios.

Construct Validity and Reliability of the SARA Gait and Posture Sub-scale in Early Onset Ataxia.

Aim: In children, gait and posture assessment provides a crucial marker for the early characterization, surveillance and treatment evaluation of early onset ataxia (EOA). For reliable data entry of studies targeting at gait and posture improvement, uniform quantitative biomarkers are necessary. Until now, the pediatric test construct of gait and posture scores of the Scale for Assessment and Rating of Ataxia sub-scale (SARA) is still unclear. In the present study, we aimed to validate the construct validity and reliability of the pediatric (SARAGAIT/POSTURE) sub-scale. Methods: We included 28 EOA patients [15.5 (6-34) years; median (range)]. For inter-observer reliability, we determined the ICC on EOA SARAGAIT/POSTURE sub-scores by three independent pediatric neurologists. For convergent validity, we associated SARAGAIT/POSTURE sub-scores with: (1) Ataxic gait Severity Measurement by Klockgether (ASMK; dynamic balance), (2) Pediatric Balance Scale (PBS; static balance), (3) Gross Motor Function Classification Scale -extended and revised version (GMFCS-E&R), (4) SARA-kinetic scores (SARAKINETIC; kinetic function of the upper and lower limbs), (5) Archimedes Spiral (AS; kinetic function of the upper limbs), and (6) total SARA scores (SARATOTAL; i.e., summed SARAGAIT/POSTURE, SARAKINETIC, and SARASPEECH sub-scores). For discriminant validity, we investigated whether EOA co-morbidity factors (myopathy and myoclonus) could influence SARAGAIT/POSTURE sub-scores. Results: The inter-observer agreement (ICC) on EOA SARAGAIT/POSTURE sub-scores was high (0.97). SARAGAIT/POSTURE was strongly correlated with the other ataxia and functional scales [ASMK (rs = -0.819; p < 0.001); PBS (rs = -0.943; p < 0.001); GMFCS-E&R (rs = -0.862; p < 0.001); SARAKINETIC (rs = 0.726; p < 0.001); AS (rs = 0.609; p = 0.002); and SARATOTAL (rs = 0.935; p < 0.001)]. Comorbid myopathy influenced SARAGAIT/POSTURE scores by concurrent muscle weakness, whereas comorbid myoclonus predominantly influenced SARAKINETIC scores. Conclusion: In young EOA patients, separate SARAGAIT/POSTURE parameters reveal a good inter-observer agreement and convergent validity, implicating the reliability of the scale. In perspective of incomplete discriminant validity, it is advisable to interpret SARAGAIT/POSTURE scores for comorbid muscle weakness.

Muscle Ultrasound in Patients with Glycogen Storage Disease Types I and III.

In glycogen storage diseases (GSDs), improved longevity has resulted in the need for neuromuscular surveillance. In 12 children and 14 adults with the "hepatic" (GSD-I) and "myopathic" (GSD-III) phenotypes, we cross-sectionally assessed muscle ultrasound density (MUD) and muscle force. Children with both "hepatic" and "myopathic" GSD phenotypes had elevated MUD values (MUD Z-scores: GSD-I > 2.5 SD vs. GSD-III > 1 SD, p < 0.05) and muscle weakness (GSD-I muscle force; p < 0.05) of myopathic distribution. In "hepatic" GSD-I adults, MUD stabilized (GSD-I adults vs. GSD-I children, not significant), concurring with moderate muscle weakness (GSD-I adults vs. healthy matched pairs, p < 0.05). In "myopathic" GSD-III adults, MUD increased with age (MUD-GSD III vs. age: r = 0.71-0.83, GSD-III adults > GSD-III children, p < 0.05), concurring with pronounced muscle weakness (GSD-III adults vs. GSD-I adults, p < 0.05) of myopathic distribution. Children with "hepatic" and "myopathic" GSD phenotypes were both found to have myopathy. Myopathy stabilizes in "hepatic" GSD-I adults, whereas it progresses in "myopathic" GSD-III adults. Muscle ultrasonography provides an excellent, non-invasive tool for neuromuscular surveillance per GSD phenotype.

Visual screening of muscle ultrasound images in children.

In children, non-invasive muscle ultrasound (MU) imaging has become increasingly important for the detection of neuromuscular pathology, by either quantitative or visual assessment. MU quantification requires time, expertise and equipment. If application of visual MU screening provides reliable results, ubiquitous application could be advocated. Previously, we found that visual MU screening can reliably detect segmental neuromuscular alterations within a patient. Analogously, we reasoned that visual MU screening could discern pathologic MU images from healthy controls. We therefore investigated visual screening results by 20 clinical observers (involving 100 MU images, with [n = 53] and without [n = 47] neuromuscular pathology). MU screening revealed adequate sensitivity, specificity and negative predictive value (85%, 75% and 82%, respectively). MU-experienced observers revealed higher specificity than MU-inexperienced observers (86% vs. 69%, p = 0.005). We conclude that clinical observers can identify neuromuscular pathology by visual screening. To enhance specificity, a secondary view by an expert appears advisory.

Muscle ultrasound quantifies segmental neuromuscular outcome in pediatric myelomeningocele.

In pediatric spina bifida aperta (SBA), non-invasive assessment of neuromuscular integrity by muscle ultrasound density (MUD) could provide important information about the clinical condition. We therefore aimed to determine the association between pediatric SBA MUD and segmental neurologic function. We included 23 children (age range: 1-18 y) with SBA with L4-5 lesions, and we associated SBA MUD with control values and segmental neuromuscular function. Results revealed that MUD outcomes in the lower extremities: (i) are independent of age, (ii) exceed control values, (iii) differ intra-individually (i.e., between the left and right sides in the same individual) in association with segmental neuromuscular function. We concluded that SBA leg MUD can quantify the segmental neuromuscular condition throughout childhood.

Visual assessment of segmental muscle ultrasound images in spina bifida aperta.

In spina bifida aperta (SBA), spinal MRI provides a surrogate marker to estimate muscle damage caudal to the myelomeningocele (MMC). This muscle damage by the MMC can be quantified by intra-individual comparison of muscle ultrasound density (MUD) caudal versus cranial to the MMC (dMUD = [MUD(caudal-to-the-MMC)] - [MUD(cranial-to-the-MMC)]). Quantitative dMUD assessment requires time, equipment and expertise, whereas it could also be visually determined by differences in muscle echodensity caudal vs. cranial to the MMC (visual-dMUD). If visual and quantitative dMUD correspond, visual dMUD assessment could provide a clinical screening parameter. In 100 SBA muscle ultrasound recordings of patients with various MMC levels, we aimed to compare quantitative dMUD (dMUD = [MUD(calf-muscle/S1)] - [MUD(quadriceps-muscle/L2-L4)]) with visual dMUD assessments by 20 different observers. Results indicate that quantitative dMUD can be visually detected (sensitivity 86%; specificity 57%), implicating that visual dMUD screening could provide a quick, clinical screening tool for muscle impairment by the MMC.

Fetal endoscopic myelomeningocele closure preserves segmental neurological function.

AIM: Our aim was to compare the effect of prenatal endoscopic with postnatal myelomeningocele closure (fetally operated spina bifida aperta [fSBA]) versus neonatally operated spina bifida aperta [nSBA]) on segmental neurological leg condition. METHOD: Between 2003 and 2009, the fetal surgical team (Department of Obstetrics, University of Bonn, Germany) performed 19 fetal endoscopic procedures. Three procedures resulted in fetal death, three procedures were interrupted by iatrogenic hemorrhages and 13 procedures were successful. We matched each successfully treated fSBA infant with another nSBA infant of the same age and level of lesion, resulting in 13 matched pairs (mean age 14 mo; SD 16 mo; f/m=1.6; female-16, male-10). Matched fSBA and nSBA pairs were compared in terms of segmental neurological function and leg muscle ultrasound density (MUD). We also determined intraindividual difference in MUD (dMUD) between myotomes caudal and cranial to the myelomeningocele (reflecting neuromuscular damage by the myelomeningocele) and compared dMUD between fSBA and nSBA infants. Finally, we correlated dMUD with segmental neurological function. RESULTS: We found that, on average, the fSBA group were born at a lower gestational age than the nSBA group (median 32 wks [range 25-34 wks] vs 39 wks [34-41 wks]; p=0.001) and experienced more complications (chorioamnionitis, premature rupture of the amniotic membranes, oligohydramnios, and infant respiratory distress syndrome necessitating intermittent positive-pressure ventilation). Neurological function was better preserved after fSBA than after nSBA (median motor and sensory gain of two segments; better preserved knee-jerk [p=0.006] and anal [p=0.032] reflexes). The dMUD was smaller in fSBA than in nSBA infants (mean difference 24, 95% confidence interval [CI] 15-33; p<0.05), which was associated with better preserved segmental muscle function. INTERPRETATION: Fetal endoscopic surgery is associated with spinal segmental neuroprotection, but it results in more complications. Before considering clinical implementation of fetal endoscopic myelomeningocele closure as standard care, the frequency of complications should be appropriately reduced and results assessed in larger groups over a longer period of time.

In children with Friedreich ataxia, muscle and ataxia parameters are associated.

AIM: In children with Friedreich ataxia (FRDA), ataxia is assessed using the surrogate marker the International Cooperative Ataxia Rating Scale (ICARS). We aimed to determine whether ICARS scores in children with FRDA are confounded by muscle weakness. METHOD: In 12 children with FRDA (10 males, two females; mean age 13 y 6 mo, SD 2 y 6 mo) and 12 age-matched children without FRDA (nine males; three females), we determined the association between muscle and ataxia parameters (i.e. muscle ultrasound density (MUD), muscle force, sensory evoked potentials, and ICARS scores). Children with FRDA were included on the basis of FXN gene analysis. Children in the comparison group were included on basis of uneventful pregnancy and normal cognitive and neurological development. RESULTS: In children with FRDA, muscle ultrasound density was homogeneously increased in the biceps, quadriceps, and tibialis anterior muscles (median 4SD). FRDA muscle weakness was significantly more pronounced in proximal than in distal muscles (-2SD vs -0.5SD respectively; p=0.004), with a stronger impairment of leg muscles than of arm muscles (-2SD vs -0. SD respectively; p=0.001). Comparing MUD between children with FRDA and an age-matched comparison group revealed a relatively strong increase in MUD in the proximal leg muscles in the FRDA group. Under the condition of persistently absent sensory evoked potentials, leg ICARS subscores in the FRDA group appeared to be positively associated with leg muscle force until a maximal plateau level of ICARS subscores was reached. INTERPRETATION: In children with FRDA, ataxia scales based on ICARS are confounded by muscle weakness. Longitudinal ICARS evaluations in children with FRDA do not necessarily indicate altered ataxia.