Slowing of Peripheral Nerve Conduction Velocity in Children and Adolescents With Type 1 Diabetes Is Predicted by Glucose Fluctuations.

Nerve conduction velocity (NCV) abnormalities are the forerunners of diabetic peripheral neuropathy (DPN). Therefore, this study aimed to analyze the effect of glucose profile quality on NCV in children and young adults with type 1 diabetes. Fifty-three children age 5 to 23 years with type 1 diabetes were recruited to participate in the study, which was conducted prospectively at the Children's Hospital of Eastern Switzerland from 2016 to 2022. Glycemic targets were recorded, and a cross-sectional nerve conduction study analyzing the peroneal, tibial, median motor, and median sensory nerves was performed. Data were compared with those of a control group of 50 healthy children. In the age- and height-matched diabetes subgroup aged 10-16 years, all four nerves showed significantly slower NCV, most pronounced for the peroneal nerve. Because height has a retarding effect on peroneal NCV, NCV was adjusted for height (dNCV). Peroneal dNCV correlated negatively with long-term glycated hemoglobin and highly significantly with glucose variability. Because high glucose variability clearly increases the risk of neuropathy, together with but also independently of the mean glucose level, this aspect of glycemic control should be given more attention in the care of individuals with diabetes. ARTICLE HIGHLIGHTS: There is a strong need for the better identification of early subclinical manifestations of microvascular complications, such as diabetic peripheral neuropathy, in young individuals with diabetes. To identify peripheral neuropathy and contributing factors at an asymptomatic disease stage, and to exclude height as a known modifying factor, we performed association studies of height-adjusted nerve conduction velocity. We identified high glucose variability, especially the SD of mean glucose, as an unexpectedly strong predictor of slowed nerve conduction velocity. More attention should be paid to the goal of low glucose variability in the care of individuals with diabetes.

Etiology of Carpal Tunnel Syndrome in a Large Cohort of Children.

(1) Background: Carpal tunnel syndrome (CTS), a compressive mononeuropathy of the median nerve at the wrist, is rare in childhood and occurs most frequently due to secondary causes. (2) Methods: Medical history, electrodiagnostic findings, and imaging data of patients with CTS from two pediatric neuromuscular centers were analyzed retrospectively. The etiology of CTS was investigated and compared with the literature. (3) Results: We report on a cohort of 38 CTS patients (n = 22 females, n = 29 bilateral, mean age at diagnosis 9.8 years). Electrodiagnostic studies of all patients revealed slowing of the antidromic sensory or orthodromic mixed nerve conduction velocities across the carpal tunnel or lack of the sensory nerve action potential and/or prolonged distal motor latencies. Median nerve ultrasound was diagnostic for CTS and confirmed tumorous and vascular malformations. Etiology was secondary in most patients (n = 29; 76%), and mucopolysaccharidosis was the most frequent underlying condition (n = 14; 37%). Idiopathic CTS was rare in this pediatric cohort (n = 9; 24%). (4) Conclusion: Since CTS in childhood is predominantly caused by an underlying disorder, a thorough evaluation and search for a causative condition is recommended in this age group.

Change in cross-sectional area of the median nerve with age in neonates, infants and children analyzed by high-resolution ultrasound imaging.

AIM: To analyze age dependencies in the cross-sectional area (CSA) of the median nerve during early childhood. METHOD: A total of 43 participants (32 of whom were children younger than 2 years) were included in this cross-sectional study to analyze the age dependency of the CSA of the median nerve at three locations (wrist, forearm and upper arm) using high-resolution ultrasound images. RESULTS: A strong and highly significant correlation was found between age and CSA (p < 0.001). When plotted, the relationship followed a logarithmic curve (p < 0.001) with a growth rate that decreases with age. Based on the regression analysis, a temporally similar increase in CSA for all three locations was found. The nerve reaches 70% of its final CSA by 2 years of age at all three locations. INTERPRETATION: Similar to the nerve conduction speed, the increase in CSA is greatest during the first 2 years of life. Then, the rate gradually and synchronously slows at the proximal and distal locations. Measurement of the CSA in the clinical setting might offer a new method to assess the maturation of the nervous system in infants with minimal interference.

The clinical, histologic, and genotypic spectrum of SEPN1-related myopathy: A case series.

OBJECTIVE: To clarify the prevalence, long-term natural history, and severity determinants of SEPN1-related myopathy (SEPN1-RM), we analyzed a large international case series. METHODS: Retrospective clinical, histologic, and genetic analysis of 132 pediatric and adult patients (2-58 years) followed up for several decades. RESULTS: The clinical phenotype was marked by severe axial muscle weakness, spinal rigidity, and scoliosis (86.1%, from 8.9 ± 4 years), with relatively preserved limb strength and previously unreported ophthalmoparesis in severe cases. All patients developed respiratory failure (from 10.1±6 years), 81.7% requiring ventilation while ambulant. Histopathologically, 79 muscle biopsies showed large variability, partly determined by site of biopsy and age. Multi-minicores were the most common lesion (59.5%), often associated with mild dystrophic features and occasionally with eosinophilic inclusions. Identification of 65 SEPN1 mutations, including 32 novel ones and the first pathogenic copy number variation, unveiled exon 1 as the main mutational hotspot and revealed the first genotype-phenotype correlations, bi-allelic null mutations being significantly associated with disease severity (p = 0.017). SEPN1-RM was more severe and progressive than previously thought, leading to loss of ambulation in 10% of cases, systematic functional decline from the end of the third decade, and reduced lifespan even in mild cases. The main prognosis determinants were scoliosis/respiratory management, SEPN1 mutations, and body mass abnormalities, which correlated with disease severity. We propose a set of severity criteria, provide quantitative data for outcome identification, and establish a need for age stratification. CONCLUSION: Our results inform clinical practice, improving diagnosis and management, and represent a major breakthrough for clinical trial readiness in this not so rare disease.

High Prevalence and Incidence of Diabetic Peripheral Neuropathy in Children and Adolescents With Type 1 Diabetes Mellitus: Results From a Five-Year Prospective Cohort Study.

BACKGROUND: In this prospective cohort study, we investigated the prevalence of diabetic peripheral neuropathy at baseline and after five years of follow-up in children and adolescents with type 1 diabetes mellitus using both measurements of nerve conduction velocity and clinical neurological examination. METHODS: A total of 38 patients who underwent insulin pump or intensive insulin therapy were included. The subjects averaged 12.6 ± 2.4 years of age and their diabetes duration averaged 5.6 ± 3.2 years. All patients underwent a detailed physical, neurological, and electrophysiological examination, as well as laboratory testing at their annual checkup. RESULTS: At baseline, the prevalence of diabetic peripheral neuropathy diagnosed using neurological examination was 13.2%, whereas nerve conduction velocity testing revealed diabetic peripheral neuropathy in 31.6%, highlighting a high prevalence of subclinical diabetic peripheral neuropathy. During follow-up, there was a strong increase in the prevalence of clinically diagnosed diabetic peripheral neuropathy, which reached 34.2% (P = 0.039) after five years; the proportion of patients with subclinical diabetic peripheral neuropathy even reached 63.2% (P = 0.002). The most significant changes in electrophysiological parameters were observed in the tibial sensory nerve (P = 0.001). CONCLUSIONS: The prevalence of diabetic peripheral neuropathy in children and adolescents with type 1 diabetes mellitus was high, and there was a rapid increase in the prevalence of diabetic peripheral neuropathy during a five-year follow-up interval. Importantly, our data show that a mere clinical evaluation is not sensitive enough to diagnose diabetic peripheral neuropathy in these patients. Nerve conduction velocity measurement, which is regarded as the gold standard for the assessment of diabetic peripheral neuropathy, should be applied more broadly.

Validity of the neurological examination in diagnosing diabetic peripheral neuropathy.

The aim of this study was to evaluate the prevalence of diabetic peripheral neuropathy in children and adolescents with type 1 diabetes mellitus and examine whether the neurological examination validly diagnoses diabetic peripheral neuropathy as compared with the gold standard of nerve conduction velocity in these patients. Nerve conduction velocity was measured in an unselected consecutive series of patients aged 8-18 years who had been suffering from type 1 diabetes mellitus for at least 1 year. For the neurological examination, neuropathy disability scores and neuropathy sign scores were used. Of the 39 patients, six (15%) had clinically evident diabetic peripheral neuropathy, whereas nerve conduction velocity testing revealed diabetic peripheral neuropathy in 15 (38%) patients. Sensitivity and specificity of the neurological examination for the diagnosis of diabetic peripheral neuropathy were 40% and 100%, respectively. The corresponding positive and negative predictive values were 100% and 72.7%, respectively. This conclusions from this study are that in children and adolescents with type 1 diabetes mellitus, diabetic peripheral neuropathy is highly prevalent, but in the majority of patients it is subclinical. Sensitivity and negative predictive values of the neurological examination are low. Therefore, routine nerve conduction velocity measurement for the assessment of diabetic peripheral neuropathy appears to be warranted in these patients.

Mild head injury in pediatrics: algorithms for management in the ED and in young athletes.

Mild head injury is of interest because of a history of under diagnosis and underestimated clinical importance. Half of the patients with mild head injuries or concussions have sport-related injuries. Knowledge of symptoms and appropriate management can be improved and is a matter of practical interest. Several algorithms exist for discharge, admission or for cranial computed tomography (CT).These employ different risk factors and calculate their sensitivity of correctly identifying children with traumatic brain injury (TBI). In contrast, a multicenter, prospective study in the United States developed a prediction model to diagnose the absence of intracranial injury when certain symptoms are missing (negative prediction value). An acute concussion presents with a combination of physical, cognitive, and emotional symptoms, which are usually self-limited. In young athletes, a second impact before full recovery from the first may have deleterious consequences and should be avoided by strict "return to play" rules. Recent research suggests that repetitive minor hits may cause delayed brain damage (dementia pugilistica, "punch-drunk syndrome"). A link to neurodegenerative diseases such as dementia, Alzheimer's disease and parkinsonism (tauopathies) is described by amyloid ß plaques in the brain of such patients. A genetic predisposition (apolipoprotein) is discussed. This review focuses on the rules attempting to determine the need for cranial CT in the emergency department and the impact of mild head injuries in young athletes. We describe in detail standardized guidelines for appropriate diagnosis and treatment and discuss the association between repetitive minor injuries and chronic traumatic encephalopathy and neurodegenerative diseases.

Treatment of Duchenne muscular dystrophy with ciclosporin A: a randomised, double-blind, placebo-controlled multicentre trial.

BACKGROUND: Duchenne muscular dystrophy is a rare X-linked progressive disease characterised by loss of ambulation at about age 10 years, with death in early adulthood due to respiratory and cardiac insufficiency. Steroids are effective at slowing the progression of muscle weakness; however, their use is limited by side-effects, prompting the search for alternatives. We assessed the effect of ciclosporin A as monotherapy and in combination with intermittent prednisone for the treatment of ambulant patients with this disorder. METHODS: Our study was a parallel-group, placebo-controlled, double-blind, multicentre trial at trial sites of the German muscular dystrophy network, MD-NET, over 36 months. Ambulant patients with Duchenne muscular dystrophy who were aged 5 years or older were randomly assigned to receive either ciclosporin A (3·5-4·0 mg/kg per day) or matching placebo. Allocation was done centrally with computer-generated random numbers. Patients and investigators were masked to the allocated treatment. After 3 months of treatment, both groups were also given intermittent prednisone for a further 12 months (0·75 mg/kg, alternating 10 days on with 10 days off). All patients who received at least one dose of study drug or placebo were included in the primary analysis. The primary outcome measure was manual muscle strength measured on the Medical Research Council (MRC) scale. This trial is registered with the German clinical trial register DRKS, number DRKS00000445. FINDINGS: 77 patients were randomly assigned to the ciclosporin A group and 76 to the placebo group; 73 patients on ciclosporin A and 73 on placebo received at least one dose and were available for efficacy analyses. 3 months of treatment with ciclosporin A alone did not show any significant improvement in primary outcome measures (mean change in the proportion of a possible total MRC score [%MRC] was -2·6 [SD 6·0] for patients on ciclosporin A and -0·8 [4·9] for patients on placebo; adjusted group difference estimate -0·88, 97·5% CI -2·6 to 0·9; p=0·26). The combination of ciclosporin A with intermittent steroids was not better than intermittent steroids alone over 12 months (mean change in %MRC was 0·7 [7·1] for patients on ciclosporin A and -0·3 [7·9] for patients on placebo; adjusted group difference estimate -0·85, -3·6 to 1·9; p=0·48). Numbers of adverse events (75 in patients on ciclosporin A and 74 on placebo) and serious adverse events (four with ciclosporin A and four with placebo) did not differ significantly between groups. INTERPRETATION: Ciclosporin A alone or in combination with intermittent prednisone does not improve muscle strength or functional abilities in ambulant boys with Duchenne muscular dystrophy, but is safe and well tolerated. FUNDING: German Federal Ministry of Education and Research, Action Benni and co eV, Novartis Pharma AG, and Deutsche Gesellschaft für Muskelkranke eV.

Functional MRI, DTI and neurophysiology in horizontal gaze palsy with progressive scoliosis.

INTRODUCTION: Horizontal gaze palsy with progressive scoliosis (HGPPS) is an autosomal recessive disease due to a mutation in the ROBO3 gene. This rare disease is of particular interest because the absence, or at least reduction, of crossing of the ascending lemniscal and descending corticospinal tracts in the medulla predicts abnormal ipsilateral sensory and motor systems. METHODS: We evaluated the use of functional magnetic resonance imaging (fMRI) for the first time in this disease and compared it to diffusion tensor imaging (DTI) tractography and neurophysiological findings in the same patient with genetically confirmed ROBO3 mutation. RESULTS: As expected, motor fMRI, somatosensory evoked potentials (SSEP) and motor evoked potentials (MEP) were dominantly ipsilateral to the stimulation side. DTI tractography revealed ipsilateral ascending and descending connectivity in the brainstem yet normal interhemispheric connections in the corpus callosum. Auditory fMRI revealed bilateral auditory activation to monaural left-sided auditory stimulation. No significant cortical activation was observed after monaural right-sided stimulation, a hearing defect having been excluded. Prosaccades fMRI showed no activations in the eye-movement network. CONCLUSION: Motor fMRI confirmed the established findings of DTI and neurophysiology in the same patient. In suspected HGPPS, any technique appears appropriate for further investigation. Auditory fMRI suggests that a monaural auditory system with bilateral auditory activations might be a physiological advantage as compared to a binaural yet only unilateral auditory system, in analogy to anisometropic amblyopia. Moving-head fMRI studies in the future might show whether the compensatory head movements instead of normal eye movements activate the eye-movement network.

Methylphenidate-induced changes in cerebral hemodynamics measured by functional near-infrared spectroscopy.

The aim of the present preliminary study was to evaluate the feasibility of measuring cerebral hemodynamic effects of a clinical dose of methylphenidate by near-infrared spectroscopy in 10 boys (median age, 10.7 years; range, 8.6-11.8 years) with developmental attention-deficit/hyperactivity disorder (ADHD). Using a Trail Making Test known to activate the left dorsolateral prefrontal cortex, cerebral hemodynamic changes show a lower increase of cerebral blood volume in the right prefrontal cortex (P = .033) and a lower increase of the tissue oxygenation index in the left prefrontal cortex (P = .015) in the condition after intake of methylphenidate compared with a drug-naive situation. A lower increase of the tissue oxygenation index indicates a changing regional oxygen metabolism and consumption induced by methylphenidate. Near-infrared spectroscopy is a sensitive tool for measuring pharmacological effects of methylphenidate on the cerebral hemodynamics.

Fast improvement of verbal memory function after left temporal tumour resection.

CASE REPORT: A 7-y-old, right-handed girl presented at our clinic with complex partial seizures, behavioural problems and word-finding difficulties. Clinical examination was normal, but electroencephalogram revealed bilateral epileptic discharges in the temporal and paracentral leads. Magnetic resonance imaging showed an intracerebral mass in the left mesial temporal lobe in the areas of the gyrus temporooccipitalis medialis and gyrus parahippocampalis. Neuropsychological testing brought to light an above-average general intelligence, but the girl performed below average in verbal memory tests and average in figural memory tests. RESULTS: The tumour was completely removed by surgery. Neuropsychological testing 3 and 11 wk after tumour resection demonstrated above-average verbal learning and memory abilities and improved visual memory. The emotional disturbances, seizures and electroencephalogram abnormalities disappeared completely during the postoperative follow-up. CONCLUSION: After resection of a left temporal brain tumour, the patient was free of seizures, and neuropsychological functions recovered completely within weeks.

Sudden unexplained death in children with epilepsy: a cohort study with an eighteen-year follow-up.

AIM: Sudden unexplained death is a significant cause of mortality in adults with epilepsy. Only a few data exist about this risk in childhood. METHODS: Cases of sudden unexplained death in epilepsy (SUDEP) up to the age of 18 y occurring at our hospital between 1984 and 2001 were identified. The incidence rate was calculated on the basis of diagnosed epileptics registered with a statutory disability insurance scheme. RESULTS: Four cases of SUDEP were identified during the 18-y period. The incidence of SUDEP was 4.3 per 10,000 patient-years. All children showed polytherapy-refractory epilepsy, developmental retardation and early-onset epilepsy. Two witnessed cases had shown no previous signs of seizure. CONCLUSION: SUDEP is rare in childhood. Children with uncomplicated epilepsy seem not to be at risk.

Cerebral hemodynamic changes in response to an executive function task in children with attention-deficit hyperactivity disorder measured by near-infrared spectroscopy.

The aim of the present study was to evaluate the hemodynamic changes in both prefrontal regions induced by a cognitive task in children with a developmental attention-deficit disorder in comparison to normal controls using near-infrared spectroscopy (NIRS). A total of 11 boys with a mean age of 10.4 (+/-1.2) years that met the DSM-IV criteria for attention-deficit hyperactivity disorder (ADHD) participated in the study and were compared with 9 healthy age- and sex-matched controls. Using a trail-making test designed for the task of connecting numbers from 1-90 in four sets, changes in oxygenated (O2Hb) and deoxygenated (HHb) hemoglobin, tissue oxygenation index (TOI), and cerebral blood volume (CBV) were measured by near-infrared spectroscopy. During the first test set, designed as a short-attention task, the children with ADHD showed significant increases in O2Hb and CBV, whereas the controls showed no significant changes. During the 4 task cycles in which extended attention was demanded, both groups showed increases in O2Hb and CBV, but only the controls showed an additional increase in HHb in the left prefrontal region. In the ADHD group only, TOI showed an increase mainly on the left side. NIRS is a sensitive tool for measuring differences in hemodynamic changes between boys with ADHD and normal controls. Overall, the normal controls showed lateralized oxygen consumption in the left prefrontal cortex during an extended-attention task, whereas the boys with ADHD showed an imbalance between oxygenated and deoxygenated hemoglobin during the short- and extended-attention tasks.

Acceptance and timeliness of standard vaccination in children with chronic neurological deficits in north-western Switzerland.

UNLABELLED: There are no special recommendations for basic vaccinations in patients with chronic neurological deficits distinct from the nationwide advocated schedule in Switzerland. Reports describing adverse neurological events possibly related to vaccinations have attracted public attention. It is unclear if patients with chronic neurological deficits are more reluctantly vaccinated compared to healthy children. We therefore investigated the acceptance of vaccinations in such patients and healthy controls in a retrospective case-control study. At the University Children's Hospital, Basel, Switzerland we investigated 100 patients with chronic neurological deficits and 200 age-matched healthy controls regarding the issue of vaccination rates and ages. The total number of administered vaccinations against diphtheria, tetanus, pertussis, polio, Haemophilus influenzae type b (Hib), mumps, measles, rubella and hepatitis B were significantly lower in patients compared to healthy controls ( P < 0.01 for each of the respective vaccines). Patients had an increased risk to receive the third pertussis, diphtheria, and tetanus vaccinations (relative risks (RR) for late vaccination 1.53, 1.53, and 1.54 respectively, P < 0.01 for all comparisons), the second (RR = 1.60, P < 0.05) and third Hib vaccinations (RR = 1.52, P < 0.05), and the third polio vaccination (RR = 1.43, P < 0.05) later than controls. CONCLUSION: Children with chronic neurological deficits received fewer vaccinations than healthy controls. In addition, patients received vaccinations later than healthy children. Hence, it may be assumed that children with chronic neurological deficits are at an increased risk to acquire preventable infections. Therefore, vaccination should be promoted as part of the consultation during a routine appointment with the specialist.

Attention-induced frontal brain activation measured by near-infrared spectroscopy.

In eight right-handed healthy males aged 9.6-12.9 years, changes in the frontal cerebral concentrations of oxygenated, deoxygenated, and total hemoglobin, as well as in tissue oxygenation index and cytochrome oxidase aa(3) were measured by near-infrared spectroscopy. The males were evaluated using a trail-making test with four test cycles interrupted by relax breaks. During the first cycle of this task, a significant increase in deoxygenated hemoglobin was documented in the left frontal region. In the extended course of the test, a significant increase in oxygenated and total hemoglobin was observed on both sides, indicating an increase in cerebral blood volume. However, only on the left side was an increase in deoxygenated hemoglobin documented. In children, changes in cerebral oxygenation induced by a cognitive task could be measured by near-infrared spectroscopy. In a short and extended attention task, a lateralized increase in oxygen consumption was documented by an increase in deoxygenated hemoglobin. In an extended attention task, an increase in oxygenated and total hemoglobin was recorded additionally in both frontal brain regions, indicating a compensatory increase in cerebral perfusion. Further studies are required to examine the significance of this technique in testing differences in children with neurobehavioral disabilities.

Methylphenidate treatment.

Methylphenidate is the psychotropic drug most commonly used to treat individuals suffering from developmental attention-deficit-hyperactivity disorder. Additional attention deficit is part of numerous neurologic diseases in childhood. Despite the vast extent of scientific research on methylphenidate, the use of this stimulant in the treatment of cognitive and behavioral dysfunction in children with epilepsy, brain tumor, leukemia, closed brain injury, encephalitis, meningitis, or mental retardation continues to be controversial. Only few data exist about the efficacy and side effects of methylphenidate treatment in children with this neurologic illness or history. The aim of the present study is to provide a review of this important clinical topic and perhaps to stimulate further controlled investigations.