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Postural control during reaching with the dominant arm was assessed in 58 preterm children with cerebral palsy (CP) aged 2 to 11 years, comprising 34 with spastic hemiplegia (17 males, 17 females) and 24 with bilateral spastic CP (bilateral CP; 15 male, 9 females). Assessments were made by multiple surface electromyogram (EMG) and kinematic recording. Mean gestational age at birth for the children with spastic hemiplegia and those with bilateral CP was 28.6 weeks (SEM 0.33) and 28.2 weeks (SEM 0.34) respectively; their mean birthweights were 1158 g (SEM 58) and 1190 g (SEM 59) respectively. All but one of the children with spastic hemiplegia could walk without restriction, the exception being a child who had self-mobility with limitations. In the group of children with bilateral CP, nine walked without assistive devices, 10 could walk with assistive devices, and five children needed a wheelchair for self-mobility. Comparison data of 29 typically developing children (10 males, 19 females) born at term with appropriate birthweight were available. Results indicated that in most children with CP the basic level of postural control ('direction-specificity', i.e. muscle activation on the side opposite to direction of body sway) was intact. However, the children with CP showed dysfunctions in: (1) recruitment order of the postural muscles, i.e. they exhibited a stereotyped top-down recruitment; and (2) the ability to modulate muscle contraction (that registers on EMG) to task-specific conditions. The latter dysfunction was more pronounced in children with bilateral CP than in those with spastic hemiplegia. Postural dysfunctions were correlated to some extent with the degree of disability in everyday activities as assessed by the Pediatric Evaluation of Disability Inventory. [ABSTRACT FROM AUTHOR]

Vici syndrome (OMIM 242840) is a very rare autosomal recessive multisystem disorder first described in 1988. In 2013, bi-allelic loss-of-function mutations in EPG5 were reported to cause Vici syndrome. Five principal diagnostic features of Vici syndrome have been proposed: agenesis of the corpus callosum, cataracts, cardiomyopathy, hypopigmentation, and combined immunodeficiency. We identified 15 patients carrying a homozygous founder missense variant in EPG5 who all exhibit a less severe clinical phenotype than classic Vici syndrome. All 15 show typical brain abnormalities on MRI. The homozygous founder variant in EPG5 they carry results in a shorter in-frame transcript and truncated, but likely still residual, EPG5 protein. We speculate that the residual EPG5 protein explains their attenuated phenotype, which is consistent with two previous observations that low expression of EPG5 can lead to an attenuated Vici syndrome phenotype. We propose renaming this condition EPG5-related neurodevelopmental disorder to emphasize the clinical variability of patients with bi-allelic mutations in EPG5., (© 2022 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.)

Background: The endoplasmic reticulum (ER)-membrane protein complex (EMC) is a multi-protein transmembrane complex composed of 10 subunits that functions as a membrane-protein chaperone. Variants in EMC1 lead to neurodevelopmental delay and cerebellar degeneration. Multiple families with biallelic variants have been published, yet to date, only a single report of a monoallelic variant has been described, and functional evidence is sparse., Methods: Exome sequencing was used to investigate the genetic cause underlying severe developmental delay in three unrelated children. EMC1 variants were modeled in Drosophila, using loss-of-function (LoF) and overexpression studies. Glial-specific and neuronal-specific assays were used to determine whether the dysfunction was specific to one cell type., Results: Exome sequencing identified de novo variants in EMC1 in three individuals affected by global developmental delay, hypotonia, seizures, visual impairment and cerebellar atrophy. All variants were located at Pro582 or Pro584. Drosophila studies indicated that imbalance of EMC1-either overexpression or knockdown-results in pupal lethality and suggest that the tested homologous variants are LoF alleles. In addition, glia-specific gene dosage, overexpression or knockdown, of EMC1 led to lethality, whereas neuron-specific alterations were tolerated., Discussion: We establish de novo monoallelic EMC1 variants as causative of a neurological disease trait by providing functional evidence in a Drosophila model. The identified variants failed to rescue the lethality of a null allele. Variations in dosage of the wild-type EMC1, specifically in glia, lead to pupal lethality, which we hypothesize results from the altered stoichiometry of the multi-subunit protein complex EMC., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Introduction: Lower urinary tract symptoms (LUTS) and gastrointestinal (GI) problems are common in Duchenne muscular dystrophy (DMD), but not systematically assessed in regular care. We aimed to determine the prevalence of bladder and bowel dysfunction (BBD) in DMD patients compared with healthy controls (HC)., Methods: The Childhood Bladder and Bowel Dysfunction Questionnaire (CBBDQ) based on the International Rome III criteria and the International Children's Continence Society was filled out by 57 DMD patients and 56 HC. Additionally, possible associations of BBD with, for example, medication use or quality of life were evaluated in an additional questionnaire developed by experts., Results: In 74% of patients versus 56% of HC ≥ 1 LUTS (n.s.) were reported, 68% of patients versus 39% of HC reported ≥1 bowel symptom ( p = 0.002) and 53% of patients versus 30% of HC reported combined LUTS and bowel symptoms ( p = 0.019). A negative impact of BBD on daily life functioning was reported by 42% of patients., Conclusions: These data underscore that standard screening for BBD is needed and that the CBBDQ could be of added value to optimize DMD care.

Congenital myopathies are early onset, slowly progressive neuromuscular disorders of variable severity. They are genetically and phenotypically heterogeneous and caused by pathogenic variants in several genes. Multi-minicore Disease, one of the more common congenital myopathies, is frequently caused by recessive variants in either SELENON, encoding the endoplasmic reticulum glycoprotein selenoprotein N or RYR1, encoding a protein involved in calcium homeostasis and excitation-contraction coupling. The mechanism by which recessive SELENON variants cause Multiminicore disease (MmD) is unclear. Here, we extensively investigated muscle physiological, biochemical and epigenetic modifications, including DNA methylation, histone modification, and noncoding RNA expression, to understand the pathomechanism of MmD. We identified biochemical changes that are common in patients harboring recessive RYR1 and SELENON variants, including depletion of transcripts encoding proteins involved in skeletal muscle calcium homeostasis, increased levels of Class II histone deacetylases (HDACs) and DNA methyltransferases. CpG methylation analysis of genomic DNA of patients with RYR1 and SELENON variants identified >3,500 common aberrantly methylated genes, many of which are involved in calcium signaling. These results provide the proof of concept for the potential use of drugs targeting HDACs and DNA methyltransferases to treat patients with specific forms of congenital myopathies., (© 2019 Wiley Periodicals, Inc.)

Background: The annual number of paediatric injury-related emergency visits and application of computed tomography (CT) has substantially increased, with associated higher risk of malignancies. In 2010, a guideline for CT-assessment based on risk factors for patients with mild traumatic brain injury (mTBI) became effective in all Emergency Departments (ED) in the Netherlands. This study evaluated the influence of this guideline on the frequency of CT-assessments, hospital admissions and factors that are related to guideline adherence., Methods: Retrospective cohort study of paediatric mTBI (<18 years), defined by Glasgow Coma Scale score of 13-15 admitted to the ED of the University Medical Center Groningen from 2008 to 2014. Data before (pre-GL) and after (post-GL) introduction of the guideline were evaluated. Primary outcome parameters were frequency of CT-assessments and hospital admissions after ED., Results: In total 633 patients were enrolled and data from pre-GL (n = 216) and post-GL (n = 315) were compared. Mean age was 7.9 years (SD 5.9), 59% were male. CT-assessments increased from 32% to 46% (p = .001), mostly in children aged 6-18 years. Hospital admissions increased from 38% to 54% (p < .001), mostly in children <6 years. No significant increase in CT-abnormalities is seen. Guideline adherence was 57%, although CT-assessments varied from 44 to 100% depending on presence of specific major risk factors., Conclusions: Introduction of a new guideline on management of paediatric mTBI showed significant increase in CT-assessments and more hospital admissions. In clinical practice, despite increase of guideline adherence the applications of cranial CT-scan varies within age groups and depends on the weighing of risk factors., (Copyright © 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Background: Annually 14.000 children with traumatic brain injury (TBI) are admitted to the Emergency Department (ED) in the Netherlands. Presentation varies and a specific entity comprises the juvenile head trauma syndrome (JHTS) with secondary deterioration after a mild trauma. As outcome of JHTS can be fatal, early recognition is essential., Aim: To outline the epidemiology and clinical features of JHTS, in comparison to paediatric mild TBI patients without JHTS., Methods: Retrospective study of 570 patients with mild TBI admitted to the ED of a level-one trauma centre from 2008 to 2014. Diagnosis of JHTS by experienced neurologists was compared with diagnosis by physicians at the ED., Results: Physicians at the ED diagnosed JHTS more frequently (14%) compared to experienced neurologists (8%). JHTS occurred after a lucid interval varying from 5 to 225 min (mean 44 (SD 64)) with changes in consciousness. JHTS patients were younger compared to mild TBI patients (4.1 (SD 2.4) vs. 7.3 (SD 5.7), p < 0.01), (range: 1-10 years). Falls occurred more often in JHTS (84% vs. 69%, p = 0.03) and at presentation, vomiting (42% vs. 22%, p < 0.01) and changed behaviour (29% vs. 1%, p = 0.03) were more present compared to the mild TBI group., Conclusion and Discussion: JHTS occurs more often in children up to 10 years with falls as major cause of injury. Clues for recognition of this syndrome comprise changes in consciousness and vomiting or changed behaviour on presentation at the ED. For clinical practice, these factors should guide the decision for hospital admission or discharge., (Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Objective: To describe the clinical and genetic characteristics of presynaptic congenital myasthenic syndrome secondary to biallelic variants in SLC18A3., Methods: Individuals from 2 families were identified with biallelic variants in SLC18A3, the gene encoding the vesicular acetylcholine transporter (VAChT), through whole-exome sequencing., Results: The patients demonstrated features seen in presynaptic congenital myasthenic syndrome, including ptosis, ophthalmoplegia, fatigable weakness, apneic crises, and deterioration of symptoms in cold water for patient 1. Both patients demonstrated moderate clinical improvement on pyridostigmine. Patient 1 had a broader phenotype, including learning difficulties and left ventricular dysfunction. Electrophysiologic studies were typical for a presynaptic defect. Both patients showed profound electrodecrement on low-frequency repetitive stimulation followed by a prolonged period of postactivation exhaustion. In patient 1, this was unmasked only after isometric contraction, a recognized feature of presynaptic disease, emphasizing the importance of activation procedures., Conclusions: VAChT is responsible for uptake of acetylcholine into presynaptic vesicles. The clinical and electrographic characteristics of the patients described are consistent with previously reported mouse models of VAChT deficiency. These findings make it very likely that defects in VAChT due to variants in SLC18A3 are a cause of congenital myasthenic syndrome in humans., (© 2016 American Academy of Neurology.)

Childhood meningiomas are rare. Recently, a new hereditary tumor predisposition syndrome has been discovered, resulting in an increased risk for spinal and intracranial clear cell meningiomas (CCMs) in young patients. Heterozygous loss-of-function germline mutations in the SMARCE1 gene are causative, giving rise to an autosomal dominant inheritance pattern. We report on an extended family with a pediatric CCM patient and an adult CCM patient and several asymptomatic relatives carrying a germline SMARCE1 mutation, and discuss difficulties in genetic counseling for this heritable condition. Because of the few reported cases so far, the lifetime risk of developing meningiomas for SMARCE1 mutation carriers is unclear and the complete tumor spectrum is unknown. There is no surveillance guideline for asymptomatic carriers nor a long-term follow-up recommendation for SMARCE1-related CCM patients as yet. Until more information is available about the penetrance and tumor spectrum of the condition, we propose the following screening advice for asymptomatic SMARCE1 mutation carriers: neurological examination and MRI of the brain and spine, yearly from diagnosis until the age of 18 and once every 3 years thereafter, or in between if there are clinical symptoms. This advice can also be used for long-term patient follow-up. More data is needed to optimize this proposed screening advice.

Leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL) is caused by autosomal recessive EARS2 mutations. Onset is most often in infancy, but in severe cases in the neonatal period. Patients typically have magnetic resonance imaging (MRI) signal abnormalities involving the thalamus, brainstem, and deep cerebral white matter. Most signal abnormalities resolve, but in severe cases at the expense of tissue loss. Here, we report a patient with an encephalopathy of antenatal onset. His early MRI at 8 months of age showed signal abnormalities in the deep cerebral white matter that improved over time. The thalami were absent with the configuration of a developmental anomaly, without evidence of a lesion. We hypothesized that this was a case of LTBL in which the thalamic damage occurred antenatally and was incorporated in the normal brain development. The diagnosis was confirmed by a novel homozygous EARS2 mutation. Our case adds to the phenotypic and genetic spectrum of LTBL., (Georg Thieme Verlag KG Stuttgart · New York.)

Hypomyelinating disorders of the central nervous system are still a diagnostic challenge, as many patients remain without genetic diagnosis. Using magnetic resonance imaging (MRI) pattern recognition and whole exome sequencing, we could ascertain compound heterozygous mutations in RARS in 4 patients with hypomyelination. Clinical features included severe spasticity and nystagmus. RARS encodes the cytoplasmic arginyl-tRNA synthetase, an enzyme essential for RNA translation. This protein is among the subunits of the multisynthetase complex, which emerges as a key player in myelination., (© 2014 American Neurological Association.)

Background: Duchenne muscular dystrophy (DMD) is a progressive muscle disease. No curative therapy is currently available, but in recent decades standards of care have improved. These improvements include the use of corticosteroids and mechanical ventilation., Objective: To present a detailed population based report of the DMD disease course in The Netherlands (1980-2006) and evaluate the effect of changes in care by comparing it with an historical Dutch DMD cohort (1961-1974)., Methods: Information about DMD patients was gathered through the Dutch Dystrophinopathy Database using a standardized questionnaire and information from treating physicians., Results: The study population involved 336 DMD patients (70% of the estimated prevalence), of whom 285 were still alive. Mean age at disease milestones was: diagnosis 4.3 years, wheelchair dependence 9.7 years, scoliosis surgery 14 years, cardiomyopathy (fractional shortening &lt;27%) 15 years, mechanical ventilation 17 years and death 19 years. Within our cohort, corticosteroid use was associated with an increased age of wheelchair dependence from 9.8 to 11.6 years (p &lt; 0.001). When comparing the recent cohort to the historical cohort, mean survival improved from 17 to 27 years (p &lt; 0.001)., Conclusion: The current study gives detailed information about the disease course of DMD patients, provides evidence for the positive effect of steroid treatment and mechanical ventilation and supports the use of patient registries as a valuable resource for evaluating improvements in care.

Background: Peroxisomes are organelles that proliferate continuously and play an indispensable role in human metabolism. Consequently, peroxisomal gene defects can cause multiple, often severe disorders, including the peroxisome biogenesis disorders. Currently, 13 different PEX proteins have been implicated in various stages of peroxisome assembly and protein import. Defects in any of these proteins result in a peroxisome biogenesis disorder. The authors present here a novel genetic defect specifically affecting the division of peroxisomes., Methods: The authors have studied biochemical and microscopical peroxisomal parameters in cultured patient fibroblasts, sequenced candidate PEX genes and determined the consequence of the identified PEX11β gene defect on peroxisome biogenesis in patient fibroblasts at different temperatures., Results: The patient presented with congenital cataracts, mild intellectual disability, progressive hearing loss, sensory nerve involvement, gastrointestinal problems and recurrent migraine-like episodes. Although microscopical investigations of patient fibroblasts indicated a clear defect in peroxisome division, all biochemical parameters commonly used for diagnosing peroxisomal disorders were normal. After excluding mutations in all PEX genes previously implicated in peroxisome biogenesis disorders, it was found that the defect was caused by a homozygous non-sense mutation in the PEX11β gene. The peroxisome division defect was exacerbated when the patient's fibroblasts were cultured at 40°C, which correlated with a marked decrease in the expression of PEX11γ., Conclusions: This novel isolated defect in peroxisome division expands the clinical and genetic spectrum of peroxisomal disorders and indicates that peroxisomal defects exist, which cannot be diagnosed by standard laboratory investigations.

Purpose: Our goal was to validate the hypothesis that the lumbosacral angle (LSA) increases in children with spinal dysraphism who present with progressive symptoms and signs of tethered cord syndrome (TCS), and if so, to determine for which different types and/or levels the LSA would be a valid indicator of progressive TCS. Moreover, we studied the influence of surgical untethering and eventual retethering on the LSA., Methods: We retrospectively analyzed the data of 33 children with spinal dysraphism and 33 controls with medulloblastoma. We measured the LSA at different moments during follow-up and correlated this with progression in symptomatology., Results: LSA measurements had an acceptable intra- and interobserver variability, however, some children with severe deformity of the caudal part of the spinal column, and for obvious reasons those with caudal regression syndrome were excluded. LSA measurements in children with spinal dysraphism were significantly different from the control group (mean LSA change, 21.0° and 3.1° respectively). However, both groups were not age-matched, and when dividing both groups into comparable age categories, we no longer observed a significant difference. Moreover, we did not observe a significant difference between 26 children with progressive TCS as opposed to seven children with stable TCS (mean LSA change, 20.6° and 22.4° respectively)., Conclusions: We did not observe significant differences in LSA measurements for children with clinically progressive TCS as opposed to clinically stable TCS. Therefore, the LSA does not help the clinician to determine if there is significant spinal cord tethering, nor if surgical untethering is needed.

Hypothermia can reduce seizure frequency in animal models of status epilepticus, and its effectiveness in human status epilepticus has been reported occasionally. We report an infant with hemimegalencephaly who presented with generalized status epilepticus. After high dose intravenous drug therapy, this converted to focal status epilepticus in the right occipital region. A sudden cessation of all seizure activity was found to coincide with accidental hypothermia. After application of mild continuous hypothermia, a marked reduction of seizure frequency occurred, which allowed reduction of intravenous drug doses and discharge from the IC unit. Ultimately, hemispherectomy was needed to achieve long term seizure control. The therapeutic effect of hypothermia should be further investigated in patients with refractory status epilepticus. When used in combination with anti-epileptic drugs, seizure control may be achieved at lower doses. Hypothermia may obviate the need for potentially dangerous barbiturate therapy. This case demonstrates that even a mild degree of hypothermia (+/-36 degrees C) can be remarkably effective., (Copyright (c) 2009. Published by Elsevier Ltd.)

Objective: To find out which patients with Duchenne muscular dystrophy are eligible for starting home mechanical ventilation and what the survival rate is., Design: Retrospective., Method: In 48 patients with Duchenne muscular dystrophy who were treated with home ventilation from 1987, the results were assessed in the follow-up visit in February 2005. Initially, ventilation was only given through a tracheotomy (TPPV), but after starting up a multidisciplinary neuromuscular consultation, non-invasive ventilation (NIPPV) was offered in an earlier stage of the disease. The following data were derived from the outpatient medical record: indication for ventilation, vital capacity (VC), arterial blood gas values, duration of ventilation up to February 2005, survival and causes of death., Results: 15 patients died. The 5-year survival rate was 75% from the start of mechanical ventilation and 67% (18/27) of the patients were still living at home at the time of the follow-up visit. The most important causes of death were cardiomyopathy (5/15) and tracheal bleeding (3/15). The group of patients who started ventilation before 1995 (n = 17) had a significantly smaller VC than the group (n = 31) who started after the neuromuscular consultation was set up. The PaCO2 during daytime was significantly higher in the group that started ventilation before 1995 compared to the group that started later., Conclusion: Home mechanical ventilation can be implemented effectively in patients with Duchenne dystrophy, with a 5-year survival of 75%.

Background and Purpose: Because it is debatable whether seat surface inclination improves motor function in children with cerebral palsy (CP), the effect of seat surface tilting on postural control and quality of reaching was studied., Subjects: The subjects were 58 children with CP aged 2 to 11 years (34 with unilateral spastic CP, 24 with bilateral spastic CP)., Methods: During the task of reaching movements, surface electromyographic and kinematic data were recorded for posture and reaching with the dominant arm in 3 sitting conditions: horizontal seat surface, seat surface tilted forward 15 degrees, and seat surface tilted backward 15 degrees., Results: In the children with unilateral spastic CP, forward tilting improved postural efficiency and quality of reaching. In the children with bilateral spastic CP, both forward and backward tilting of the seat surface was associated with more postural instability and did not affect the quality of reaching., Discussion and Conclusion: The results suggest that, in terms of postural control and quality of reaching, children with unilateral spastic CP benefit from a forward-tilted position and children with bilateral spastic CP benefit from a horizontal sitting position.

Brain magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) in one patient with merosin-deficient congenital muscular dystrophy (MDCMD) revealed significant metabolite (choline, creatine, N-acetyl aspartate) level reductions, fractional anisotropy (FA) reduction and increased apparent diffusion coefficient (ADC) in the white matter (p<0.01, all). In the gray matter, the MRS properties did not differ significantly from those in controls. The ADC and FA, however, differed significantly as in the white matter, although the differences were less pronounced. This is the first quantitative MR study of the brain in a patient with MDCMD, which revealed that the concentrations of all MRS measured metabolites were decreased only in the white matter. This observation, combined with the DTI observed ADC increases and FA decrease, indicated a presence of vasogenic edema in the white matter.

Mutation analysis was performed in four apparently unrelated Dutch families with pantothenate kinase-associated neurodegeneration, formerly known as Hallervorden-Spatz syndrome. A novel 3-bp deletion encompassing the nucleotides GAG at positions 1,142 to 1,144 of exon 5 of the PANK2 gene was found in all patients. One patient was compound heterozygous; she also carried a novel nonsense mutation (Ser68Stop). The other patients were homozygous for the 1142&#95;1144delGAG mutation. The 1142&#95;1144delGAG mutation was also found in a German patient of unknown descent. We used polymorphic microsatellite markers flanking the PANK2 gene (spanning a region of approximately 8 cM) for haplotype analyses in all these families. A conserved haplotype of 1.5 cM was found for the 1142&#95;1144delGAG mutation carriers. All the Dutch families originated from the same geographical region within the Netherlands. The results indicate a founder effect and suggest that the 1142&#95;1144delGAG mutation probably originated from one common ancestor. It was estimated that this mutation arose at the beginning of the ninth century, approximately 38 generations ago.

The relationships between kinematic characteristics of sitting posture during reaching movements of the dominant arm and 1) the kinematics of the reaching movement itself and 2) functional performance during daily life activities (PEDI) were assessed in 51 sitting preterm children with cerebral palsy (CP). The children were 2-11 y, 33 had spastic hemiplegia (SH) and 18 bilateral CP (Bi-CP). The data were compared with those of 26 typically developing children (TD). Sitting posture before the onset of reaching of children with CP differed from that of TD children: they sat with a more reclined pelvis and a more collapsed trunk. The more reclined pelvic position was associated with a better quality of reaching movements. The different sitting postures of pelvis and trunk were not related to functional performance during daily life activities. Displacement of the head, trunk, and pelvis of the children with CP did not differ from that of the TD children. Nevertheless, in the children with CP a more stable head, a more mobile trunk, and a more stable pelvis were related to better functional performance and/or a better quality of reaching. This suggests that physiotherapeutic guidance of children with CP should focus rather on the latter postural parameters than on the different sitting posture of pelvis and trunk.

Kinematic characteristics of reaching movements of the dominant arm were assessed in 51 sitting preterm children who were aged 2-11 y and had cerebral palsy (CP), including 33 with spastic hemiplegia and 18 with bilateral CP (Bi-CP). Reference data of 29 typically developing children were present. The results indicated that the quality of reaching movements from the dominant arm of children with CP was significantly worse than that of typically developing children. This held true in particular for the children with Bi-CP. For example, reaching movements of children with CP took more time and consisted less often of one movement unit. The quality of reaching was related to the severity of lesion present on the neonatal ultrasound scan of the brain, the severity of motor disorder, the degree of spasticity, and the ability to perform activities of daily life. The last indicates that movements of the dominant arm in children with spastic hemiplegia and Bi-CP deserve clinical attention.

Two previously healthy infants, a boy of 10 weeks and a girl of 4 months presented with apathy and muscle weakness. A third previously healthy child, a girl of 6 weeks old was admitted with respiratory insufficiency. None of the three had had a bowel movement for a number of days. After extensive investigations which revealed few abnormalities Clostridium botulinum toxin was obtained in serum from all three children. Type-B-toxin was shown in the faeces of the older girl and boy; both recovered quickly. The other girl had type-A toxin; she died. Two of the three children were given honey to comfort them. Infantile botulism must be considered in every infant with symptoms of constipation and hypotonia. The diagnosis can quickly be confirmed by electromyography with repetitive 50-Hz-stimulation. Honey is a well-known source of the C. botulinum spore and should not be given to children under the age of 12 months. These three children are the first cases to be described in the Netherlands.

Neuromuscular disorders are characterised by progressive muscle weakness, which in time causes functional impairment. To quantify the extent of disease progression, muscle force and functional ability can be measured. Which of these parameters changes most depends on the disease stage. In a previous study, we reported normal values for muscle force obtained by hand-held dynamometry in healthy children aged 4-16 years. In the present study, we report normal values for timed functional tests in healthy children aged 4-11 years. These normal values were compared with values obtained in 16 ambulant patients with Duchenne muscular dystrophy (DMD) aged 5-8 years to study the extent of functional impairment. In ambulant patients with DMD, we found that muscle function assessed by timed functional tests (running 9 m and rising up from the floor) and muscle force assessed by hand-held dynamometry were severely impaired. However, a small reduction of muscle force was accompanied by a large reduction in functional ability. Therefore, in our group of ambulant patients with DMD, timed functional testing was the most sensitive parameter to determine the extent of disease progression. Timed functional testing may therefore be considered as an additional outcome measure in drug trials to evaluate the effects of therapy in ambulant patients with DMD and possibly in other neuromuscular disorders.

Background: Prednisone treatment is used to prolong ambulation in patients with Duchenne muscular dystrophy (DMD). However, since severe adverse effects often accompany prednisone treatment, it is debatable whether the benefits of prednisone treatment outweigh its adverse effects., Objectives: To study the effects of prednisone on muscle function and to determine the extent of steroid-related adverse effects and their influence on the quality of life of ambulant patients with DMD., Design: A randomized, placebo-controlled, crossover trial with 6 months of treatment: prednisone or placebo (0.75 mg/kg daily) during the first 10 days of each month. After a washout period of 2 months, patients received the other regimen for an additional 6 months., Setting: University hospital and rehabilitation center in the Netherlands., Patients: Seventeen ambulant patients with DMD aged 5 to 8 years., Main Outcome Measure: Change in muscle function assessed by timed functional testing: running 9 m, climbing 4 standard-sized stairs, and rising from the floor to a standing position., Results: The increase in time needed to run 9 m (P = .005) and to climb 4 standard-sized stairs (P = .02) was significantly lower during the prednisone period., Conclusions: Prednisone slowed deterioration of muscle function and muscle force in ambulant patients with DMD. Although adverse effects were present, patient quality of life was not affected. Therefore, short-term prednisone treatment can be recommended to preserve motor functions in ambulant patients with DMD.

In this study, 105 healthy children (45 to 156 months old, 57 girls) were examined using ultrasound (US) imaging to obtain reference values of muscle dimensional and aspect parameters. We measured biceps and quadriceps sizes and subcutaneous tissue thickness. To quantify muscle aspect, we calculated muscle density, inhomogeneity and white-area index by digital image analysis. Age-, weight- and gender-dependencies were discussed. We demonstrated earlier that the complete set of parameters allows for differentiation between myopathies and neuropathies in adults, with high sensitivity. In this study, we investigated if these parameters have additional value in the diagnostic evaluation of 36 children with proven neuromuscular disease (20 Duchenne muscular dystrophy, 16 neuropathies). We found that density analysis provides a sensitive method for distinguishing between healthy children and children with neuromuscular disorders. We have also found that more detailed aspect analysis is necessary to further distinguish between these types of neuromuscular disorders in children. In conclusion, this set of normal muscle parameters can be used to help diagnose neuromuscular disorders in children. It will also facilitate follow-up in disease progression and therapy.

Amplitude-integrated EEG (aEEG) is used to select patients for neuroprotective therapy after perinatal asphyxia because of its prognostic accuracy within several hours after birth. We aimed to determine the natural course of aEEG patterns during the first 72 h of life, in relation to neurologic outcome, in a group of severely asphyxiated term infants. Thirty infants, admitted to our neonatal intensive care unit from October 1998 until February 2001, were studied retrospectively. The aEEG traces obtained during the first 72 h after birth were assessed by pattern recognition: continuous normal voltage (CNV), discontinuous normal voltage (DNV), burst suppression (BS), continuous low voltage, and flat trace. Epileptic activity was also determined. The course of aEEG patterns was examined in relation to neurologic findings at 24 mo. Initially, 17 of 30 infants had severely abnormal aEEG patterns (BS or worse), which changed spontaneously to normal voltage patterns (CNV, DNV) in 7 within 48 h. The sooner the abnormalities on aEEG disappeared, the better the prognosis. The likelihood ratio of BS or worse for adverse outcome was 2.7 (95% confidence interval 1.4-5.0) between 0 and 6 h and increased to a highest value of 19 (95% confidence interval 2.8-128) between 24 and 36 h; after 48 h, it was not significant. Normal voltage patterns (CNV and DNV) up to 48 h of life were predictive for normal neurologic outcomes (negative likelihood ratios <0.3). Our findings indicate that the course of aEEG patterns adds to the prognostic value of aEEG monitoring in asphyxiated infants. Spontaneous recovery of severely abnormal aEEG patterns is not uncommon.

Duchenne muscular dystrophy is clinically characterised by progressive muscle weakness and a gradual increase in the size of some affected muscles, especially calf muscles. The extent of calf enlargement is usually determined by subjective visual assessment. The purpose of this study was to determine the extent of calf muscle enlargement in Duchenne muscular dystrophy (DMD) patients compared with healthy age matched boys by quantifying calf circumference. Calf circumference in the group of DMD patients is significantly increased. However, in individual patients calf enlargement can be feigned by a discrepancy between calf circumference and circumference of the upper leg and arm muscles as part of a general muscle atrophy.

Background: During follow-up of children with a brain tumor, traditionally surveillance-imaging studies are done in addition to clinical evaluations. The purpose of this study was to determine the role of clinical evaluations by a multidisciplinary team for the detection of recurrent tumor., Procedure: We retrospectively assessed the predictive value of clinical evaluation, using subsequent neuroimaging as the gold standard. Ninety-eight children with a newly diagnosed primary brain tumor were included in the study. In these patients, 393 imaging studies were done, 75 because of clinical suspicion of recurrence, and 318 for routine surveillance only., Results: In 28 of these 75 imaging studies on clinical indications, a radiologic diagnosis of recurrence was made. Only 9 out of 318 routine surveillance imaging studies resulted in an unexpected diagnosis of recurrence. Thus, the overall positive predictive value of clinical evaluation was 37%; the overall negative predictive value was 97%. The negative predictive values for specific brain tumors varied from 91% (optical glioma) to 99% (primitive neuroectodermal tumors)., Conclusions: An accurate multidisciplinary clinical evaluation has a very high negative predictive value. Consequently, the added value of surveillance imaging studies is limited. The role of such studies during the follow-up of children with brain tumors should be reconsidered., (Copyright 2002 Wiley-Liss, Inc.)

Since muscle force and functional ability are not related linearly; maximum force can be reduced while functional ability is still maintained. For diagnostic and therapeutic reasons loss of muscle force should be detected as early and accurately as possible. Because of growth factors, maximum muscle force in children varies with age, which makes detection of force loss difficult. The purpose of this study was to establish reference values for muscle force in children aged 4-16 years, obtained by hand-held dynamometry in 11 muscle groups. In boys muscle force was predicted best by weight whereas in girls weight and age were best predictors. At age 14 boys become significantly stronger for nearly all tested muscle groups. These age-related reference values can be used to quantify muscle weakness in individual muscle groups in children aged 4-16 years and to evaluate the effects of therapy.

Perinatal asphyxia is one of the major causes of non-progressive neurological deficits seen in children. It is reported that currently no set of parameters allowing for accurate prediction of prognosis following severe perinatal asphyxia is available. Even electroencephalogram (EEG) recordings, which are known to give a fairly good prediction of long-term outcome, have their flaws. The aim of this prospective study was to evaluate the additional value of serial EEGs in full-term infants. In all, 36 infants were enrolled. All met strict entrance criteria, received standard treatment and underwent two EEGs according to a pre-set protocol: the first between 12 and 36 hours post-partum, the second between 7 and 9 days post-partum. It is clearly demonstrated that serial EEG recordings do enhance the prognostic value of the EEG. Moreover, distinct progression seen in serial EEGs is highly prognostic for a normal outcome and has even more prognostic value than one single severely abnormal EEG. A better indication of future outcome is obtained from serial EEGs.

An 8-year-old girl presented with a cerebral tumor and 3 recurrences within 15 months. The primary tumor was a low-grade astrocytoma, but the recurrences showed progressively malignant phenotypes with increasing mitotic activity and MIB-1 labeling indices. Radiotherapy was given between the first and the second recurrences. Cytogenetic analysis of the first and the second recurrences showed abnormal karyotypes. There seemed to be 2 common breakpoints in these 2 recurrences. TP53 gene mutation screening, using comprehensive denaturing gradient gel electrophoresis, revealed among others a possibly causative mutation of exon 5 in 3 of 4 tumor samples. The meaning of TP53 mutations in low-grade astrocytomas is still unclear, but the highly abnormal karyotypes, which are unusual in these tumors, probably provide genetic evidence for the unexpected aggressive behavior of the tumor in this patient.

Neurophysiological functioning was studied prospectively in children treated for acute lymphoblastic leukaemia with a low dose vincristine regime (8 x 1.5 mg/m2/dose), to obtain more insight into vincristine neuropathy. A WHO neurotoxicity score was estimated and vibration sense and electrophysiological measurements were taken at standardized times during vincristine treatment. The WHO neurotoxicity score showed decreased or disappearance of Achilles tendon reflexes, and mild sensory disturbances, but a grade 3-4 neurotoxicity was not demonstrated by any of the children. Vibration perception thresholds increased progressively during treatment and amplitudes of action potentials of peroneal and sensory ulnar and median nerves decreased, whereas nerve conduction velocities stayed unchanged. Both vibration perception thresholds and the electrophysiological findings hardly exceeded the limits of normality. We conclude that children treated for acute lymphoblastic leukaemia with a low dose vincristine regimen have mild axonal neuropathy which may be responsible for the motor problems in these children.

To establish normal values for flash visual evoked potentials (VEPs) in the preterm period, we analyzed 356 records from 63 neurologically normal infants (26-35 weeks gestation) followed longitudinally. Using both sleep and drowsy state recording within the same session and a mean of 5.7 weekly recording sessions per infant, we hypothesized that the prominent negative wave (N1) consisted of 2 negative components, N1a (early) and N1b (late). This hypothesis could explain the previously reported variability in VEP indices. With a precise definition of the N1a peak, we were able to establish reference ranges for N1a peak latencies at various postmenstrual ages (PMA) which, unlike those previously reported, are narrow enough to be clinically useful. From a cross-sectional analysis we found that the N1a peak latency decreased with maturation at about 4.6 msec/week between 30 and 40 weeks PMA (P < 0.001). We also analyzed the N1 wave form and demonstrated its developmental maturation during this period. There were significant decreases in the amplitudes of both the N1a and N1b peaks with maturation (P < 0.001), but the decrease of the N1a amplitude was steeper than that of N1b. The N1 wave form changed from a wave in which the early peak (N1a) was higher than the late peak (N1b) into the reverse with N1b higher than N1a. This wave change may be related to developmental processes in the visual system. Longitudinal follow-up revealed that extra-uterine life may accelerate the maturation of the N1 wave form but has no effect on the decrease of the absolute values of peak latencies.

In this case report we describe the coincidental finding of polyps in the gallbladder by ultrasound investigation in a six-year-old girl, known to have metachromatic leukodystrophy. The investigation was carried out because of suspicion of abdominal trauma after falling down the stairs and finding elevated serum amylase.