Pediatric Neurological Disorders Research Articles

Resolving unsolved whole-genome sequencing data in paediatric neurological disorders: a cohort study

ObjectiveTo resolve unsolved whole-genome sequencing (WGS) data in individuals with paediatric neurological disorders.DesignA cohort study method using updated bioinformatic tools, new analysis targets, clinical information and literature databases was employed...

Utility of next generation sequencing in paediatric neurological disorders: experience from South Africa.

Next generation sequencing (NGS)-based tests have become routine first-line investigative modalities in paediatric neurology clinics in many high-income countries (HICs). Studies from these countries show that these tests are both cost-effective and reliable in diagnosing many complex childhood neurological diseases. However, NGS-based testing in low-and middle-income countries (LMICs) is limited due to affordability constraints. The primary objective of this study was to evaluate the diagnostic yield and impact of targeted gene panel sequencing in a selected paediatric cohort attending a tertiary paediatric neurology clinic in the Western Cape Province of South Africa. This retrospective study included 124 consecutive paediatric patients with neurological disease, aged 6 weeks to 17 years, referred for NGS-based multi-gene panel testing over a 41-month period. Twenty-four different disease group-specific panels were utilized. A caregiver experience questionnaire was administered when a pathogenic variant was identified. The overall study diagnostic yield (DY) was 45% (56/124 patients). The diagnostic yield in this study is similar to previously reported paediatric cohorts in HICs. The high yields for neuromuscular disorders (52%) and early epileptic encephalopathies (41%) suggest that NGS-based panels may be more cost-effective as first-line testing in well-defined phenotypes. The latter finding argues for early inclusion of all children with developmental epileptic encephalopathies (DEE), as early diagnosis leads to better treatment and avoidance of unnecessary investigations.

Agreement and disagreement in pediatric functional neurological symptom disorders: Comparing patient reported outcome measures (PROMs) and clinician assessments

Youth with functional neurological symptom disorder (FNSD) often perceive themselves as having limited capabilities, which may not align with clinical evaluations. This study assessed the disparities between clinician evaluations and patient-reported outcome measures (PROMs) regarding pain, motor function, and learning difficulties in youth with FNSD. Sixty-two youths with FNSD participated in this study, all of whom reported experiencing pain, motor problems, and/or learning difficulties. Clinicians also assessed these domains, resulting in a two-by-two categorization matrix: (1) agreement: child and clinician report "problems"; (2) agreement: child and clinician report "no problems"; (3) disagreement: child reports "problems" while the clinician does not; and (4) disagreement: clinician reports "problems" while the child does not. Agreement/disagreement differences were analyzed. No significant differences in prevalence were observed between the evaluators regarding pain (clinician-85%, child-88%), motor (clinician-98%, child-95%), or learning problems (clinician-69%, child-61%). More than 80% of the children and clinicians report pain and motor disorders. Instances in which children and clinicians reported learning problems (40.3%) exceeded cases in which both reported no problems (9.6%) or only the child reported problems (20.9%). Overall, the agreement between pain and motor function assessments was high (>90%), whereas that concerning learning difficulties was moderate (49.9%). Disagreement in pain/motor assessments was minimal (<5%), whereas for learning difficulties, disagreement rates were high (>20%). In conclusion, a significant concordance exists between PROMs and clinician assessments of pain and motor problems. However, the higher frequency of disagreements regarding learning difficulties emphasizes the importance of incorporating patient and clinician evaluations in pediatric FNSD treatment.

Pediatric Functional Neurological Disorder Triggered by Concussion: Physical Therapy Intervention with a 12-year-old male and 2-year follow up

Pediatric Functional Neurological Disorder Triggered by Concussion: Physical Therapy Intervention with a 12-year-old male and 2-year follow up

A rare pediatric neurometabolic disorder: Leigh syndrome

Subacute necrotizing encephalomyelopathy called Leigh Disease is a rare inherited pediatric neurological disorder generally involving infants. The condition primarily involves the central nervous system and the most involved structures are basal ganglia, thalamus, and brainstem. In this disorder, there is a progressive loss of mental and movement abilities associated with abnormal muscle tones, weakness, visual loss, respiratory failure, and strikingly, we got raised lactate levels in the blood, cerebral spinal fluid, and other body fluids. The prognosis of this condition is bad as there is no effective treatment and finally, the patient succumbs to death mostly due to respiratory failure. Here, we present a case of Leigh disease in an 8-month-old boy having chief complaints of delayed motor (weakness), and cognitive development with a previous history of recurrent respiratory infection. Upon recent radiological imaging, gross neurological abnormalities were seen which suggested the possibility of Leigh disease which was further confirmed by raised body fluid lactate levels.

Mesenchymal Stem Cell-Induced Neuroprotection in Pediatric Neurological Diseases: Recent Update of Underlying Mechanisms and Clinical Utility.

Pediatric neurological diseases refer to a group of disorders that affect the nervous system in children. These conditions can have a significant impact on a child's development, cognitive function, motor skills, and overall quality of life. Stem cell therapy is a new and innovative approach to treat various neurological conditions by repairing damaged neurons and replacing those that have been lost. Mesenchymal stem cells (MSCs) have gained significant recognition in this regard due to their ability to differentiate into different cell types. MSCs are multipotent self-replicating stem cells known to render promising results in the treatment of stroke and spinal cord injury in adults. When delivered to the foci of damage in the central nervous system, stem cells begin to differentiate into neural cells under the stimulation of paracrine factors and secrete various neurotrophic factors (NTFs) like nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) that expedite the repair process in injured neurons. In the present review, we will focus on the therapeutic benefits of the MSC-based therapies in salient pediatric neurological disorders including cerebral palsy, stroke, and autism.

Association between red blood cell transfusion and mortality in critically ill children: a single-center pediatric intensive care experience

Aims: Our study aimed to evaluate the association of erythrocyte transfusion with mortality and morbidity in critically ill children and to emphasize the importance of the risk it carries. Methods: A retrospective evaluation of 524 pediatric patients aged 1 month to 18 years who had been admitted between February 2022 to March 2023 at Sancaktepe Şehit Prof. Dr. İlhan Varank Training and Research Hospital, were performed. Children with hemoglobinopathies, and chronic anemia (defined as the presence of anemia for more than 6 weeks) were excluded. Demographic data, clinical variables, and outcome data were analyzed. Results: The median age was 36.5 (1.0-272.0) months, and 56.1% of the patients were male. The median duration of a pediatric intensive care unit stay was 5 (1-114) days. Respiratory diseases (44.7%) were the most common reasons for admission to the pediatric intensive care unit, followed by, neurological diseases (12.8%)and sepsis (11.3%). Mortality rate was 5.7%. The median baseline hemoglobin level upon admission was 10.5 g/dl (3.2-18.8). Severe anemia (hemoglobin &amp;lt; 7 g/dl was present in 6.1% of all patients. One hundred and sixteen (22.1%) patients were transfused; 61 (11.6%) were transfused only once. A total of 292 packed red blood cells transfusions were administered. Transfused patients required prolonged hospital stays, support for inotropic agents, invasive mechanical ventilation, and extracorporeal treatment and had an excessive mortality rate (p&amp;lt;0.001, p&amp;lt;0.001, p&amp;lt;0.001, p&amp;lt;0.001, p&amp;lt;0.001). Conclusion: Clinicians should consider that the administration of packed red blood cells transfusions in critically ill patients may have the potential to both raise mortality and provide life-saving benefits during their pediatric intensive care unit stay. As with any treatment with potential side effects, it is essential to reduce the use of unnecessary blood products.

Neurofilament light protein as a biomarker for spinal muscular atrophy: a review and reference ranges.

Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality, characterized by progressive neuromuscular degeneration resulting from mutations in the survival motor neuron (SMN1) gene. The availability of disease-modifying therapies for SMA therapies highlights the pressing need for easily accessible and cost-effective blood biomarkers to monitor treatment response and for better disease management. Additionally, the wide implementation of newborn genetic screening programs in Western countries enables presymptomatic diagnosis of SMA and immediate treatment administration. However, the absence of monitoring and prognostic blood biomarkers for neurodegeneration in SMA hinders effective disease management. Neurofilament light protein (NfL) is a promising biomarker of neuroaxonal damage in SMA and reflects disease progression in children with SMA undergoing treatment. Recently, the European Medicines Agency issued a letter of support endorsing the potential utilization of NfL as a biomarker of pediatric neurological diseases, including SMA. Within this review, we comprehensively assess the potential applications of NfL as a monitoring biomarker for disease severity and treatment response in pediatric-onset SMA. We provide reference ranges for normal levels of serum based NfL in neurologically healthy children aged 0-18 years. These reference ranges enable accurate interpretation of NfL levels in children and can accelerate the implementation of NfL into clinical practice.

Study of lncRNAs in Pediatric Neurological Diseases: Methods, Analysis of the State-of-Art and Possible Therapeutic Implications.

Long non-coding RNAs (lncRNAs) have emerged as crucial regulators in various cellular processes, and their roles in pediatric neurological diseases are increasingly being explored. This review provides an overview of lncRNA implications in the central nervous system, both in its physiological state and when a pathological condition is present. We describe the role of lncRNAs in neural development, highlighting their significance in processes such as neural stem cell proliferation, differentiation, and synaptogenesis. Dysregulation of specific lncRNAs is associated with multiple pediatric neurological diseases, such as neurodevelopmental or neurodegenerative disorders and brain tumors. The collected evidence indicates that there is a need for further research to uncover the full spectrum of lncRNA involvement in pediatric neurological diseases and brain tumors. While challenges exist, ongoing advancements in technology and our understanding of lncRNA biology offer hope for future breakthroughs in the field of pediatric neurology, leveraging lncRNAs as potential therapeutic targets and biomarkers.

Parents' Knowledge, Awareness, and Attitude Toward Children With Epilepsy in the Al Baha Region, Saudi Arabia: A Cross-Sectional Study.

Background Epilepsy is a prevalent pediatric neurological disorder, with widespread implications globally. Parents' knowledge and attitudes toward their epileptic children play a pivotal role in the well-being and management of the condition. Despite its prevalence in Saudi Arabia, awareness and perceptions vary across communities. Objective This study aimed to assess parents' knowledge, awareness, and attitudes toward children with epilepsy in the Al Baha region of Saudi Arabia. Methods A descriptive, cross-sectional study was conducted in the Al Baha region from November 2022 to January 2023. An anonymous, self-administered questionnaire was distributed among 390 parents, targeting those aged 18-60 years. Results While the majority recognized that epilepsy is not contagious, misconceptions persisted. Nearly 67.7% of families lacked clarity on the causes of epilepsy. Most believed in the potential curability of epilepsy, favoring medication as the primary treatment. A significant association was identified between having an epileptic child and knowledge of seizure-first aid. The majority held an optimistic view regarding the academic and extracurricular achievements of epileptic children. Conclusion The study highlights a mix of informed and misinformed beliefs among parents in the Al Baha region. While many perspectives were encouraging, certain misconceptions underlined the need for continued awareness campaigns and educational initiatives. Addressing these gaps is essential for providing comprehensive care and inclusion of children with epilepsy in the community.

The microstructural change of the brain and its clinical severity association in pediatric Tourette syndrome patients

BackgroundGilles de la Tourette syndrome (GTS) is a prevalent pediatric neurological disorder. Most studies point to abnormalities in the cortico-striato-thalamocortical (CSTC) circuits. Neuroimaging studies have shown GTS’s extensive impact on the entire brain. However, due to participant variability and potential drug and comorbidity impact, the results are inconsistent. To mitigate the potential impact of participant heterogeneity, we excluded individuals with comorbidities or those currently undergoing medication treatments. Based on the hypothesis of abnormality within the CSTC circuit, we investigated microstructural changes in white matter using diffusion spectrum imaging (DSI). This study offers the first examination of microstructural changes in treatment-naïve pediatric patients with pure GTS using diffusion spectrum imaging.MethodsThis single-center prospective study involved 30 patients and 30 age- and gender-matched healthy volunteers who underwent sagittal T1-weighted MRI and DSI. We analyzed generalized fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity.ResultsNo significant differences were observed in mean diffusivity and axial diffusivity values between the two groups. However, the patient group exhibited significantly higher generalized fractional anisotropy values in the right frontostriatal tract of the dorsolateral prefrontal cortex, the right frontostriatal tract of the precentral gyrus, and bilateral thalamic radiation of the dorsolateral prefrontal cortex. Additionally, the generalized fractional anisotropy value of the right frontostriatal tract of the precentral gyrus is inversely correlated with the total tic severity scores at the most severe condition.ConclusionTreatment-naïve pediatric GTS patients demonstrated increased connectivity within the CSTC circuit as per diffusion spectrum imaging, indicating possible CSTC circuit dysregulation. This finding could also suggest a compensatory change. It thus underscores the necessity of further investigation into the fundamental pathological changes in GTS. Nevertheless, the observed altered connectivity in GTS patients might serve as a potential target for therapeutic intervention.

Clinical application of magnetic resonance elastography in pediatric neurological disorders.

Magnetic resonance elastography is a relatively new, rapidly evolving quantitative magnetic resonance imaging technique which can be used for mapping the viscoelastic mechanical properties of soft tissues. MR elastography measurements are akin to manual palpation but with the advantages of both being quantitative and being useful for regions which are not available for palpation, such as the human brain. MR elastography is noninvasive, well tolerated, and complements standard radiological and histopathological studies by providing in vivo measurements that reflect tissue microstructural integrity. While brain MR elastography studies in adults are becoming frequent, published studies on the utility of MR elastography in children are sparse. In this review, we have summarized the major scientific principles and recent clinical applications of brain MR elastography in diagnostic neuroscience and discuss avenues for impact in assessing the pediatric brain.

Postural control in pediatric neuromuscular and neurological diseases

Postural control in pediatric neuromuscular and neurological diseases

A Case Series of Transgender and Gender-Nonconforming Patients in a Pediatric Functional Neurologic Disorder Clinic.

Youth who identify as transgender and gender nonconforming (TGNC) are at increased risk of anxiety, depression, bullying, and loss of social and family support. These factors may increase the risk of developing functional neurologic disorder (FND). If the risk of FND is increased in TGNC youth, then identifying which youth are at increased risk, and the particular times when risk is increased, may allow for earlier diagnosis and treatment of FND. Better awareness of functional symptoms among clinicians who care for TGNC youth may prevent disruption of gender-affirming care if FND symptoms emerge. Patients diagnosed with FND who are TGNC may require different forms of intervention than other youth with FND. We present 4 cases from our multidisciplinary pediatric FND program of TGNC youth who developed FND. In all individuals for whom follow-up information was available, access to gender-affirming health care was associated with marked improvement or resolution of FND symptoms.

The PANDAS/PANS disorders. Is it time for more allergist-immunologists to get involved?

Background: The pediatric autoimmune neurologic disorders associated with streptococcal infections (PANDAS) comprise a group of patients who, after infection with group A β-hemolytic streptococci (GAS), exhibit a spectrum of neuropsychiatric symptoms that include obsessive thoughts, compulsive behaviors, tics, hyperactivity, inattention, and mild choreiform movements. More recently, a group of patients with a symptom complex similar to PANDAS without evidence of streptococcal etiology was given the acronym pediatric acute-onset neuropsychiatric syndrome (PANS). Despite more than several decades of study and increasing numbers of patients being identified with PANDAS and PANS, there are ongoing controversies, which range from disagreements about specific pathogenetic mechanisms to whether these entities actually exist. Objective: The purpose of this report was to examine the current body of evidence that deals with the relationship(s) of immunologic host responses to infection and putative immunologic mechanisms involved in the pathogenesis of these disorders, to evaluate the effectiveness of anti-inflammatory and immunomodulatory therapies with intravenous immunoglobulin (IVIG), and to consider the extent to which allergist/immunologists might be involved in their management. Methods: An extensive literature review was conducted in medical literature data bases by applying terms such as PANDAS, PAN, autoimmune encephalitis, neuroinflammation, and autoimmune obsessive-compulsive disorders. Results: PANDAS and its later iterative form, PANS, continue to challenge clinicians, patients, and their families. Although the precise reason why these disorders develop remains unknown, both are considered to have an autoimmune basis related to the production of antibodies directed at antigens of the putative causative infectious disease agents that are cross-reactive with antigenic epitopes on selected brain nuclei, which lead to the neuroinflammatory sequelae responsible for the neuropsychiatric symptoms of these conditions, a phenomenon referred to as molecular mimicry. Conclusion: The PANDAS/PANS disorders are a continuing burden for growing numbers of patients, health-care providers, and the global health-care systems, and are a particular challenge for the allergist/immunologist who is increasingly being called upon for their management. Because of the importance of immunologic factors in the pathogenesis and treatment of these conditions with anti-inflammatory and immune-modulating treatments, the allergist/immunologist is well poised to offer consultative care.

Epileptic Channelopathies and Neuromuscular Disorders in Newborns: A Narrative Review.

Neonates can have ion channel abnormalities known as channelopathies, which can impact any organ system. These abnormalities cause seizures, which can result in developmental delays and lead to early death. For a child's long-term neurodevelopment, early identification as a channelopathy is essential to avoid any brain damage. Therefore, this review aims to focus on early diagnostic criteria. Since it might be difficult for doctors to interpret the presenting symptoms of channelopathies, a thorough diagnostic examination that follows a methodical step-by-step procedure is essential. Skeletal muscle fiber and neuron excitability depend on voltage-gated sodium channels. It is now known that mutations in voltage-gated sodium channel genes can cause a growing variety of fatal or debilitating pediatric neurological diseases. Episodic paralysis, myotonia, newborn hypotonia, respiratory impairment, laryngospasm/stridor, congenital myasthenia, and myopathy are examples of muscle phenotypes. There may be a connection between sodium channel malfunction and abrupt infant death, according to recent findings. Numerous epilepsy syndromes and complex encephalopathies are among the manifestations of different channelopathies that are becoming more widely recognized.

Genetic etiology of progressive pediatric neurological disorders

BackgroundThe aim of the study was to characterize molecular diagnoses in patients with childhood-onset progressive neurological disorders of suspected genetic etiology.MethodsWe studied 48 probands (age range from newborn to 17 years old) with progressive neurological disorders of unknown etiology from the largest pediatric neurology clinic in Finland. Phenotypes included encephalopathy (54%), neuromuscular disorders (33%), movement disorders (11%), and one patient (2%) with hemiplegic migraine. All patients underwent whole-exome sequencing and disease-causing genes were analyzed.ResultsWe found 20 (42%) of the patients to have variants in genes previously associated with disease. Of these, 12 were previously reported disease-causing variants, whereas eight patients had a novel variant on a disease-causing gene: ATP7A, CHD2, PURA, PYCR2, SLC1A4, SPAST, TRIT1, and UPF3B. Genetics also enabled us to define atypical clinical presentations of Rett syndrome (MECP2) and Menkes disease (ATP7A). Except for one deletion, all findings were single-nucleotide variants (missense 72%, truncating 22%, splice-site 6%). Nearly half of the variants were de novo.ConclusionsThe most common cause of childhood encephalopathies are de novo variants. Whole-exome sequencing, even singleton, proved to be an efficient tool to gain specific diagnoses and in finding de novo variants in a clinically heterogeneous group of childhood encephalopathies.ImpactWhole-exome sequencing is useful in heterogeneous pediatric neurology cohorts.Our article provides further evidence for and novel variants in several genes.De novo variants are an important cause of childhood encephalopathies.

Syncope and unresponsiveness in an adolescent with comorbid cardiac disease: an illustrative case report and literature review of Functional Neurologic Symptom Disorder.

This case report with associated literature review explores the challenges, opportunities, and current evidence in creating a thoughtful diagnostic and management plan for an adolescent with Functional Neurologic Symptom Disorder and comorbid cardiac disease. We perform a literature review utilizing PubMed to identify the current evidence base related to Pediatric Functional Neurologic Symptom Disorder in the setting of comorbid cardiac disease. Ultimately, 25 manuscripts were identified for inclusion in this study. We report the recent epidemiology, screening, diagnostic, and treatment measures utilized in pediatric syncope with a focus on differentiating psychogenic causes from serious cardiac and benign etiologies. We further describe how psychiatric and psychological factors influence assessment, management, and outcomes. This study provides current, evidence-based suggestions for the assessment, diagnosis, and management of pediatric syncope with emphasis on recognizing psychogenic causes of syncope. It includes description of a novel case of Functional Neurologic Symptom Disorder in a pediatric patient with structural cardiac disease. The study highlights how the absence of standardized guidelines, heterogeneity in care delivery, and lack of concurrent mental health management led to worse outcomes.

Biochimie du liquide cérébrospinal

AbstractBasic biochemical analysis of cerebrospinal fluid (CSF) is limited to the dosages of proteins (proteinorrhachia) and glucose (glycorrhachia), always completed with cytological and bacteriological examination of CSF and with notation of its aspect. They form the basic examination of CSF for the diagnosis of infectious meningitidis or sub-arachnoid haemorrhage. A number of other biochemical analyses were developed with electrophoresis, the study of immunoglobulins, and application of index for transudation or intrathecal synthesis, also isoelectric focalisation searching for oligoclonal bands characteristic of multiple sclerosis as well as the development of biomarkers of inflammatory neurological diseases and in particular neurodegenerative diseases. Tau and phosphorylated-tau proteins help in the differential diagnosis of Alzheimer’s disease. The elevation of angiotensin-converting enzyme activity in CSF helps in the diagnosis of neurosarcoidosis. Neurotransmitters allow the study of paediatric neurological diseases with abnormal movements.

Pediatric Functional Neurologic Disorders

Functional neurologic disorders are common in the pediatric population. Recently, there has been a renewed focus on functional neurologic disorders, leading to improvements in diagnosis and management. This review focuses on updates in clinical presentation, diagnosis, pathophysiology (including neuroimaging), and treatment of functional neurologic disorders in the pediatric population.