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Clinical scales represent an important tool not only for the initial grading/scoring of disease and assessment of progression, but also for the quantification of therapeutic effects in clinical trials. There are several scales available for the clinical evaluation of cerebellar symptoms. While some scales have been developed and evaluated for specific cerebellar disorders such as Friedreich ataxia, others reliably capture cerebellar symptoms with no respect to the underlying etiology. Each scale has its strengths and weaknesses. Extensive scales are certainly useful for thorough documentation of specific features of certain phenotypes, but this gain of information is not always essential for the purpose of a study. Therefore, compact and manageable scales like the Scale for the Assessment and Rating of Ataxia (SARA) or Brief Ataxia Rating Scale (BARS) are often preferred compared to more complex scales in observational and therapeutic studies., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Polymicrogyria (PMG) is a brain malformation due to abnormal cortical organisation. It is a heterogeneous disorder associated with 22q11.2 deletion syndrome (also known as velocardiofacial (VCF) syndrome) amongst others. Since this association was first recognised in 1996, over 30 patients with PMG and 22q11.2 deletion have been described. In 22q11.2 deletion syndrome, PMG is mainly located in the perisylvian areas; it frequently has an asymmetrical presentation with a striking predisposition for the right hemisphere. Neurological features of perisylvian PMG include developmental delay/mental retardation, seizures, microcephaly, spasticity and oromotor dysfunction. Thus in children diagnosed with 22q11.2 deletion syndrome, a finding of PMG has important prognostic value. We present a seven-month old boy with microcephaly, short stature and developmental delay. A cerebral MRI showed slightly enlarged ventricles and symmetrical perisylvian polymicrogyria. A 22q11.2 deletion was revealed by array-based comparative genomic hybridization. Remarkably the boy had no other manifestations of VCF syndrome. Paediatricians, child neurologists and clinical geneticists should be aware that the presence of PMG (especially in the perisylvian areas) needs investigating for 22q11.2 deletion, even if other more common VCF syndrome features are absent., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Introduction: In children with Friedreich's ataxia (FRDA children), clinical ataxia outcomes are hardly substantiated by underlying neurophysiological parameters. In young FRDA children, some reports (based upon International Cooperative Ataxia Rating Scale scores (ICARS)) mention transient neurological improvement upon idebenone treatment. However, these outcomes are obtained with adult instead of pediatric reference values. It is unknown whether age-related neurophysiological parameters can really substantiate neurologic improvement., Aim: In young FRDA children, we aimed to determine longitudinal neurophysiological parameters during idebenone treatment., Methods: During a two-year study period, 6 genetically proven FRDA children with cardiomyopathy (6-18years) were longitudinally assessed for neurophysiological parameters [sensory evoked potentials (SEPs), F response, peripheral nerve conduction and dynamometry] in association with age-matched ICARS-scores., Results: In all FRDA children, SEPs remained absent during the two-year study period. Peroneal nerve conduction velocity declined (from -1SD to -2SD; p<.05), whereas F responses remained essentially unaltered. Total muscle force and leg muscle force decreased (from -2 to -3SD and -2.5 to -3.5SD; both p<.05) and age-related ICARS-scores deteriorated (median increase +41%; p<.05)., Conclusion: In FRDA children, age-related neurophysiological and ataxia parameters deteriorate during idebenone treatment. Although we cannot exclude some (subjective) disease stabilization, age-related neurophysiological parameters do not substantiate neurologic improvement.

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.

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.

Purpose: In infants with frequent therapy resistant seizures (TRS-infants), clinical detection of pyridoxine-dependency (PD) or -responsiveness (PR) occurs by empirical intravenous (IV) pyridoxine administration during recording of the EEG. However, in undiagnosed TRS-infants it is still unclear to what extent EEG alterations by pyridoxine-IV are attributable to PD/PR or to non-specific responses. Before EEG alterations by pyridoxine-IV can be ascribed to PD/PR, these non-specific responses should be excluded first., Methods: In 10 TRS-infants under 1 year of age, we determined the EEG effect by pyridoxine-IV on the EEG-recording., Results: After pyridoxine-IV administration, our data indicate declined (10-15%; p<0.05) EEG-amplitudes and total power (magnitude/frequency-band) at frontal, central and centro-temporal electrodes., Conclusion: In TRS-infants, pyridoxine-IV affects EEG-amplitude and -total power in a non-specific way, which does not identify PD/PR.

In this study, we investigated whether the Achilles tendon reflex (ATR) in healthy infants is modulated by changes in body position (prone vs. supine). The amplitude of the ATR was compared at postnatal day 1, months 2, 3 and 6, while infants were placed in prone and supine position. The ATR was considered "positive" when at least 1 of 20 tendon taps evoked a visible contraction of the ankle plantar flexor muscles. At 6 months, the amplitude and latency of the ATR were evaluated by electromyographic (EMG) recordings of the (lateral and medial) gastrocnemius muscle, with the infant in prone and supine position. At postnatal day 1, the clinical ATR response was more frequently present in prone than supine position (14/16 or 88% vs. 4/16 or 25%, respectively, p < 0.01). From 2 months onwards, the frequencies of positive ATRs were no longer significantly different between prone (14/14 or 100%) and supine position (10/14 or 67%). However, based on the EMG recordings at 6 months, the ATR amplitude was higher in prone compared to supine position (n=8, median 5.5 mV, range 4.7-6.6 mV; and median 3.8 mV, range 2.3-5.6 mV, p < 0.05). We conclude that the ATR response in healthy infants is more pronounced in prone than in supine position, either when clinically (visually) assessed during routine tendon tapping or when neurophysiologically assessed during surface EMG recording.

Introduction: In neonates with spina bifida aperta (SBA), leg movements by myotomes caudal to the meningomyelocele (MMC) are transiently observed. It is unclear whether these leg movements relate to functional neural conduction through the MMC. For optimal therapeutical intervention, pathophysiological insight in these transient leg movements seems relevant. If leg movements by myotomes caudal to the MMC concur with the execution of general movements (GMs), functional neural conduction through the MMC is implicated., Objective: In neonates with SBA, we aimed to determine whether the transiently present leg movements caudal to the MMC indicate functional neural conduction through the MMC., Methods: During the perinatal period, fetuses and neonates with SBA (n = 7 and n = 13, respectively) were longitudinally analysed for concurrency between leg movements caudal to the MMC and GMs. To address the integrity of the reflex arc in spinal segments (at, or) caudal to the MMC, tendon leg reflexes were assessed during the first postnatal week., Results: At postnatal day 1, leg movements caudal to the MMC concurred with GMs in 12 of 13 infants. Isolated leg movements were observed in only 3 of these 12 infants (isolated vs. concurrent; p < 0.005). Leg movements concurring with GMs lasted longer than isolated leg movements (median duration = 11 s vs. 2 s; p < 0.05). Between days 1 and 7, tendon leg reflexes (at, or) caudal to the MMC had disappeared in all but 1 neonate. However, leg movements caudal to the MMC remained concurrently present with GMs in all five neonates available for follow-up after day 7. Comparing these leg movements between days 1 and 7 indicated a decreased duration (-44%, p < 0.05)., Conclusions: In neonates with SBA, leg movements caudal to the MMC concur with GMs, indicative of functional neural conduction through the MMC. The disappearance of these leg movements is caused by lower motor neuron dysfunction at the reflex arc, whereas neural conduction through the MMC is still functional.

Aim of the Study: In the present longitudinal study we investigated the relationship between prenatal motor behaviour and the postnatal neurological sequelae of infants with spina bifida aperta., Methods and Patients: Prenatal isolated leg movements and general movements of 13 fetuses/infants with spina bifida aperta were assessed by means of ultrasound recordings, and were compared with: 1. the spinal level of morphological defect (meningo-myelocele), 2. the postnatal motor behaviour, 3. the postnatal sensory function, and 4. the final motor outcome., Results: In all 13 cases studied, the spinal defect was either at thoracic (n = 8) or at lumbal (n = 5) level. All fetuses displayed active leg movements corresponding to the functioning of low lumbal myelum segments (L4-5 in two cases or L5-S1 in 11 cases), despite vertebral defects at high localisation. These leg movements were of normal quality (normal in appearance) and endogenously generated, since no external stimulus was exerted to elicit them. This implies that in fetuses with spina bifida aperta active leg movements can be generated at spinal segments which are located at (n = 1), or under (n = 12) the meningo-myelelocele. Postnatally, for a short period of time (mostly during the first few hours), leg movements related to myelum function at (n = 1) or lower than (n = 7) the spinal defect were detected. However, only in two infants these early leg movements were of normal quality and corresponded with the final motor outcome. In contrast to these early neonatal leg movements, early sensory function was strongly related to the spinal defect (r = 0.76; P = 0.005) and to the final motor outcome (sensory function predicted outcome in all infants of whom follow-up was performed)., Conclusion: These data on fetuses/infants with spina bifida aperta strongly indicate that a discrepancy exists between the occurrence of prenatal leg movements and the spinal localisation of the meningo-myelocele on the one hand, and between the occurrence of pre- and postnatal leg movements on the other hand (quantity and quality).

The possibility of studying fetal motor behaviour by ultrasound techniques has provoked research on its potential application for assessment of prenatal neurological conditions. The characteristics ('quality') of one particular movement pattern, the 'general movement', has been shown to be discriminative between uncomplicated pregnancy and major pathology of the developing central nervous system. Some recent studies have investigated whether the quality and/or the quantity of fetal movements correlated with other clinical variables during complicated pregnancies, and whether they provided prognostic information for the neurological outcome. Longitudinal research encompassing the pre- and postnatal periods was performed on uncomplicated pregnancies and on pregnancies complicated by intrauterine growth retardation, oligohydramnios (due to premature rupture of the amniotic membranes), or fetal breech position. Although the quantity of both fetal general movements and fetal breathing movements were found to be related to clinical variables of the fetal condition (such as heart rate variability, heart rate decelerations), clinical application seems limited due to large inter- and intra-individual variabilities. In contrast, the quality of fetal general movements appeared highly correlated with parameters of fetal clinical condition in individual cases and fulfilled several prerequisites for serving as a reliable diagnostic tool for prediction of the fetal condition and for assessment of the integrity of the central nervous system.

The effect of intra-uterine movement restriction on the development of motor functions was studied longitudinally by comparing infants born after uncomplicated breech position (n = 13) with control infants (vertex position, n = 5-10). Before birth, fetal leg posture was studied at regular intervals by means of real time ultrasound observations, and classified as complete (n = 1), inconsistent (n = 6), or incomplete (n = 6) breech position. Limited extension of the hips, preference posture and joint position in percentage of time (each until 12 weeks), withdrawal reflex and magnet response (until 26 weeks) and posture while sitting, standing and walking without support (up to 12-18 months) were assessed longitudinally. The results showed statistically significant, positive relationships between intra-uterine breech position and neonatal limited extension of the hip-joint, between limited extension of the hip-joint and the percentage of time that the hips are in flexion during the first 12 weeks, between this flexion of the hips (in percentage of time) and an abnormally 'flexed' walking pattern at 12-18 months, and finally, between a positive magnet response at 6 months and an abnormal walking pattern at 12-18 months. These findings suggest that intra-uterine movement restriction of the legs can cause long term alterations in the development of motor functions (leg posture, reflexes and posture while walking), possibly mediated by alterations in proprioceptive feedback mechanisms.

In 17 fetuses with intrauterine growth retardation (IUGR), we studied the quantity of general movements and fetal breathing movements both cross-sectionally and longitudinally. In IUGR fetuses, cross-sectional comparisons were made between the quantity of fetal movements and (1) the fetal clinical condition and (2) the quality of general movements. In addition, the quantity of fetal movements in IUGR was compared with that in uncomplicated pregnancies and in pregnancies complicated by premature rupture of the amniotic membranes. In IUGR, the quantity of general movements declined from 25 weeks gestation onwards, whereas the quantity of fetal breathing movements increased. Longitudinal assessment of these parameters was obtained in four cases and showed a decline of general movements. No relationship between prenatal longitudinal data and neonatal outcome could be observed. Relating the quantity of general movements and breathing movements to the fetal condition, growth retarded fetuses were divided into three groups according to fetal deterioration. 1. Normal amount of amniotic fluid and normal fetal heart rate patterns. 2. Reduced amount of amniotic fluid. 3. Abnormal fetal heart rate patterns. The quantity of general movements as well as that of breathing movements was low in group 3, compared to group 1. In group 2 only the quantity of breathing movements and not of general movements was low. A similar pattern was found in the relation with the quality of general movements observed during fetal deterioration. Cross-sectional analysis of median values (28-31 weeks gestation) did not reveal differences in the quantity of general movements when IUGR, normal pregnancies and premature rupture of the membranes (with or without oligohydramnios) were compared. The quantity of fetal breathing movements was significantly lower in pregnancies complicated by IUGR and by premature rupture of the membranes with oligohydramnios compared to those of normal pregnancies and premature rupture of the membranes without oligohydramnios. In uncomplicated IUGR, the quantity of general movements and breathing movements is in the same range as in normal uncomplicated pregnancies. Similar to the quality of general movements, the quantitative variables were related to the fetal condition. However, in contrast to the quality of general movements, the quantity of general movements and breathing movements showed a high inter- and intraindividual variation. Therefore, the results of this study discourage the use of quantitative aspects of general movements and breathing movements as reliable indicators of the neurological condition in the individual fetus.

The effect of severe intrauterine growth retardation on the quality of general movements was studied longitudinally in 17 human fetuses. During the prenatal and postnatal periods, fetal movements were recorded by means of weekly 1 h ultrasound and video registrations. Neurological examinations were performed at 1, 3, 6 and 12 months after birth. No clear effect of uncomplicated intrauterine growth retardation could be detected on the quality of general movements. General movements became slow and small in amplitude (4/5) in cases where there was a reduction in the amount of amniotic fluid. Parallel to the onset of abnormal fetal heart rate patterns, general movements became poor in repertoire (7/7), while they were hardly discernible after further deterioration of the fetal condition (5/7). With the exception of 3 infants with cerebral haemorrhages, the quality of general movements observed just before and after birth was identical (13/16). In these infants, the quality of general movements as well as the results of the standardized neurological examination tended to normalize at 3 months and 1 year, respectively. Uncomplicated IUGR had no marked effect on the quality of general movements or on the results of the neurological examination at the age of 1 year.

The effect of severe oligohydramnios (due to prolonged premature rupture of the membranes (PROM)) on breathing movements and lung development was studied longitudinally in 11 human fetuses. Prenatally, fetal breathing movements (FBM) were scored off-line from weekly, 1 h during ultrasound recordings (n = 47). In each recording, the incidence of FBM was scored according to 4 different methods. Postnatally, the cases were retrospectively assigned to a group with normal (n = 4), partially hypoplastic (n = 3), or hypoplastic (n = 4) lungs. Compared to control fetuses, the percentage of time spent breathing (%FBM) was low (2-5%) and did not increase with gestational age. Large inter-individual and intra-individual variations in the %FBM were found in all 3 diagnostic groups. Evaluation of the %FBM according to the 4 different methods revealed no significant differences between the 3 groups. We conclude that lung development is, at least partly, independent of the incidence of FBM. Furthermore, the analysis of FBM cannot reliably predict lung development in fetuses with oligohydramnios due to PROM.

The effect of the amount of amniotic fluid on the form of fetal general movements was studied longitudinally in 19 pregnancies complicated by premature rupture of the amniotic membranes (PROM). Before birth, general movements were studied weekly by means of 1-h ultrasound observations, performed under standardized conditions. In the early postnatal period, 11 of these infants were followed with video recordings of their spontaneous movements. In the fetus, speed and amplitude of general movements were directly related to the reduction in amniotic fluid. A moderate reduction of amniotic fluid was associated with a decrease in amplitude, while a more severe reduction of amniotic fluid caused a decrease in speed as well. Postnatally, the small amplitude and low speed showed a marked tendency to normalize between 1 and 5 weeks. These results are important for the qualitative assessment of motor behaviour in pregnancies with obstetrical complications that are associated with oligohydramnios (such as PROM or intra-uterine growth retardation).