R.J. Verbeek

Does fetal endoscopic closure of the myelomeningocele prevent loss of neurologic function in spina bifida aperta

Background Spina bifida aperta (SBA) is associated with shuntdependent hydrocephalus and with meningomyelocele (MMC). Fetal endoscopic closure of the MMC may reduce shunt-dependency, but the benefit upon motor function in individual patients is still unclear. An increase in differentiated muscle ultrasound density (dMUD) provides an objective parameter for the extent of muscle damage caudal to the MMC. In this perspective, we aimed to compare dMUD and neurological function between SBA children treated by fetal endoscopic closure (fSBA) and by neonatal closure (nSBA) of 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.

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.

Spinal hemorrhages are associated with early neonatal motor function loss in human spina bifida aperta

BACKGROUND In spina bifida aperta (SBA), leg movements caudal to the meningomyelocele are present in utero, but they disappear shortly after birth. It is unclear whether leg movements disappear by impact of the neuro-developmental malformation or by superimposed traumatic damage. If superimposed traumatic damage is involved, targeted fetal intervention could improve motor outcome. AIM To characterize neuromuscular pathology in association with perinatal motor function loss in SBA. PATIENTS/METHODS In fetal SBA (n=8; 16-40 weeks GA), the median time interval between ultrasound registrations of fetal motor behavior and post-mortem histology was 1 week. Histology was assessed cranial, at and caudal to the meningomyelocele and compared with findings in fetal controls (n=4). RESULTS Despite fetal movements caudal to the meningomyelocele (5/6), histology indicated muscle fiber alterations (6/6) that concurred with neuro-developmental and traumatic spinal defects [Neuro-developmental defects: spinal ependymal denudation (3/8), reduced amount of (caspase3-negative) lower motor neurons (LMNs; 8/8), aberrant spinal vascularization (8/8). Traumatic defects: gliosis (7/8), acute/fresh spinal hemorrhages near LMNs (8/8)]. CONCLUSION In all delivered SBA patients, recent spinal hemorrhages were superimposed upon pre-existing defects. If early therapeutic strategies can prevent these superimposed secondary spinal hemorrhages, motor outcome may improve.

Muscle ultrasound density in human fetuses with spina bifida aperta

BACKGROUND In fetal spina bifida aperta (SBA), leg movements caudal to the meningomyelocele (MMC) are transiently present, but they disappear shortly after birth. Insight in the underlying mechanism could help to improve treatment strategies. In fetal SBA, the pathogenesis of neuromuscular damage prior to movement loss is still unknown. We reasoned that prenatal assessment of muscle ultrasound density (fetal-MUD) could help to reveal whether progressive neuromuscular damage is present in fetal SBA, or not. AIM To reveal whether prenatal neuromuscular damage is progressively present in SBA. PATIENTS/METHODS In SBA fetuses (n=6; 22-37 weeks gestational age), we assessed fetal-MUD in myotomes caudal to the MMC and compared measurements between myotomes cranial to the MMC and controls (n=11; 17-36 weeks gestational age). Furthermore, we intra-individually compared MUD and muscle histology between the pre- and postnatal period. RESULTS Despite persistently present fetal leg movements caudal to the MMC, fetal-MUD was higher caudal to the MMC than in controls (p<0.05). Fetal-MUD caudal to the MMC did not increase with gestational age, whereas fetal-MUD in controls and cranial to the MMC increased with gestational age (p<0.05). In 5 of 6 patients assessed, comparison between pre- and postnatal MUD and/or muscle histology indicated consistent findings. CONCLUSIONS In fetal SBA, persistent leg movements concur with stable, non-progressively increased fetal-MUD. These data may implicate that early postnatal loss of leg movements is associated with the impact of additional neuromuscular damage after the prenatal period.

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.

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.

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.

P25-17 Muscle ultrasound in pre-birth and early life: an application in spina bifida aperta

partial seizures when they brushed their teeth by themselves. We saw a severely disabled girl who developed tooth-brushing-induced seizures when her mother brushed her teeth. The aim of our study was to clarify the epileptogenic features of the tooth-brushing-induced seizures in our case. Patient: We diagnosed an 11-year-old girl who had severe mental retardation, hypotonic cerebral palsy, and epilepsy with tooth-brushing epilepsy. As she could not brush her teeth by herself due to the disabilities, her mother brushed her teeth daily. She had spontaneous simple partial seizures at the age of 1 year and 2 months, and developed the same type of seizures induced by tooth-brushing at the age of 8 years. The patient developed spontaneous simple partial seizures several times a day and the tooth-brusing-induced seizures consistently twice a day. Methods: We performed ictal EEG and [Tc-99m]HMPAO-SPECT at the time of the seizure induced by the tooth-brushing as well as interictal [F18]FDG and [C-11]FMZ-PET to identify the epileptogenic focus. Results: The ictal EEG showed rhythmic alpha waves for 2 seconds in the frontal regions bilaterally, followed by diffuse polyspikes. The ictal [Tc-99m]HMPAO-SPECT demonstrated hyperperfusion in the left parietal region, including the somatosensory cortex, where the interictal [F18]FDG and [C-11]FMZ showed low uptake of each radiotracer. Conclusions: Our results show that the epileptogenic focus during the tooth-brushing-induced seizures is located in the somatosensory cortex.

Can muscle ultrasound density in early life predict motor outcome in spina bifida aperta

Background Spina bifida aperta (SBA) is associated with neurological function loss caudal to the meningomyelocele (MMC). At birth, leg movements are transiently present, but they do not reliably predict motor outcome. Pediatric neuromuscular studies have shown that muscle ultrasound density (MUD) reflects neuromuscular condition. In the present study, we investigated whether MUD assessment can predict motor outcome in SBA.