Leukodystrophies, a group of genetic disorders primarily affecting brain white matter, were once considered untreatable. Advances in MRI and genetic diagnostics now allow most patients to receive a genetic diagnosis, and...Leukodystrophies, a group of genetic disorders primarily affecting brain white matter, were once considered untreatable. Advances in MRI and genetic diagnostics now allow most patients to receive a genetic diagnosis, and emerging treatments are shifting the field from therapeutic nihilism to cautious optimism. Allogenic haematopoietic stem cell transplantation (HSCT), used since the 1980s, has shown efficacy in specific leukodystrophies, such as adrenoleukodystrophy and metachromatic leukodystrophy, when administered early. Gene therapy has become a viable option, with ex vivo approaches like atidarsagene autotemcel providing promising outcomes for early-onset MLD. Trials for gene replacement and antisense oligonucleotide therapies are ongoing for several leukodystrophies, including Canavan disease and Alexander disease. Certain treatments, such as guanabenz for Vanishing White Matter, target disease-specific dysregulated molecular pathways. Despite these advances, challenges remain, including the ultrarare nature of most leukodystrophies, limited natural history data, high treatment costs, and barriers to accessibility. Future developments, including newborn screening and close international collaboration, aim to enhance early diagnosis, refine treatment timing, and expand access to innovative therapies.
Mercante A, Nardocci N, Fernández-Alvarez E
… +12 more, Lumsden DE, Hauer J, Bernadá M, Drake R, Kreicbergs U, Palomo-Carrión R, Gemma M, Coubes P, Fasano A, Lin JP, Benini F, Pediatric Dystonia and Palliative Care Group and the European Paediatric Neurology Society (EPNS)
BACKGROUND: Pediatric dystonias are associated with a broad spectrum of etiologies, resulting in a heterogeneous patient population in whom clinical presentation, evolution, and therapeutic needs may differ. These neurol...BACKGROUND: Pediatric dystonias are associated with a broad spectrum of etiologies, resulting in a heterogeneous patient population in whom clinical presentation, evolution, and therapeutic needs may differ. These neurological symptoms are particularly common in children and adolescents with life-limiting and life-threatening conditions requiring pediatric palliative care (PPC). The impact on the child's quality of life is significant, as is distress for caregivers. Addressing and alleviating dystonia is key to providing good palliative care; however, there is limited evidence. A greater recognition and management of dystonia in this setting is urgently needed to provide appropriate interventions and care. OBJECTIVES: To develop a standardized approach to dystonia in PPC. MATERIALS AND METHODS: A two-round Delphi process explored the views of experts on the definition, assessment, monitoring, and treatment of dystonia in PPC. Professionals from different backgrounds and disciplines were invited worldwide. The final panel comprised 71 participants who completed a multi-statement online questionnaire. RESULTS: Fifty-three items were endorsed, providing expert, consensus-based recommendations. CONCLUSIONS: The limited clinical knowledge of childhood dystonia represents a challenge, especially in children with palliative care needs. This study is a first international consensus on dystonia in PPC and offers novel approaches to improving the dystonia-related burden and advancing clinical practice in this vulnerable population.
BACKGROUND: knowledge about lasting effects of continuous intrathecal baclofen (CITB) therapy during development into adulthood in non-ambulant individuals with cerebral palsy (CP) is limited. AIM: we assessed individual...BACKGROUND: knowledge about lasting effects of continuous intrathecal baclofen (CITB) therapy during development into adulthood in non-ambulant individuals with cerebral palsy (CP) is limited. AIM: we assessed individual goals including ease of care, pain reduction, at long term. Also, we aimed to gauge burden of CITB through hospitalization rates, orthopedic surgeries, pump-related complications, pump refills, and satisfaction levels among individuals and caregivers. METHODS: a prospective cohort of 17 individuals with CP (pump implantation 2002-2005) was assessed in 2022. Visual Analogue Scale (VAS) scores, Child Health Questionnaire Parent Form-50 (CHQ-PF50), and a Likert-scale questionnaire, were employed. Data was gathered through interviews with individuals or caregivers. RESULTS: fifteen individuals were alive at initial follow-up (mean age 31.8 years). Statistically significant improvements in VAS scores for individual goals, ease of care, and pain observed six months post-therapy initiation persisted into adulthood. Mental health and change in health decreased back to baseline at long-term follow-up, other domains of quality in life did not differ significantly. Treatment-related hospital admission was one per 3.6 years, of which 13.2 % were due to complications. The number of patients with scoliosis increased during the years. Despite, the majority (80 %) expressed continued preference for CITB treatment. CONCLUSION: improvements of CITB on domains of body function, activities and social participation, and quality of life persist into adulthood. Although there are some side effects of CITB therapy, both patients and their caregivers report high satisfaction.
γ-aminobutyric acid (GABA) serves as the main inhibitory cortical neurotransmitter and is involved in crucial functions of neural circuitry affecting cognition, communication, movement, behavior, and the seizure threshol...γ-aminobutyric acid (GABA) serves as the main inhibitory cortical neurotransmitter and is involved in crucial functions of neural circuitry affecting cognition, communication, movement, behavior, and the seizure threshold. GABAergic neurons and interneurons contribute to essential aspects of cortical dynamic organization and regulatory processes and mediate aspects of synaptic development. Inherited metabolic disorders affecting the metabolic pathways of GABA, its transport, and its receptors lead to a wide array of neurodevelopmental manifestations. Presentation typically ensues at early ages but could occur later in life and range in severity. This group of disorders warrants increased suspicion, as their early identification and management may lead to clinical improvement and shorten the diagnostic odyssey often associated with affected individuals. We provide an overview of the scientific basis, clinical presentation, and ongoing therapeutic advances of the main disorders of GABA metabolism stemming from deficiencies of succinic semialdehyde dehydrogenase (SSADH), GABA-transaminase, GABA transporter, and GABA receptor subunits.
Pediatric-onset multiple sclerosis (POMS) accounts for up to 10 % of the affected population. However, it remains an unexplored field in Greece, as no national registry or disease's atlas are currently available. Because...Pediatric-onset multiple sclerosis (POMS) accounts for up to 10 % of the affected population. However, it remains an unexplored field in Greece, as no national registry or disease's atlas are currently available. Because of that, we conducted a single-center study. We searched the registries of our hospital during the period January 2010-September 2023 and catalogued 23 children that were under 16 years old when they were first hospitalized in our department and diagnosed with POMS. We compared our data collected to the available literature regarding demographics and the risk factors, and our findings in general meet the acquired POMS knowledge. Most of our children have vitamin D deficiency, previous EBV infection, whilst some of them have personal or family history of autoimmunity. The mean age of first diagnosis is 12.3 years, similar to the global mean age of POMS. Despite the findings obtained, more studies are essential in this field.
BACKGROUND: Charcot-Marie-Tooth disease type 1 (CMT1) is a prevalent inherited neuropathy characterized by progressive sensory and motor deficits affecting the peripheral nervous system. Although muscle weakness is commo...BACKGROUND: Charcot-Marie-Tooth disease type 1 (CMT1) is a prevalent inherited neuropathy characterized by progressive sensory and motor deficits affecting the peripheral nervous system. Although muscle weakness is commonly seen in the hands, weakness of more proximal muscles has been observed in adults. In childhood, the muscle strength of the upper limbs must be explored to understand the natural history of the disease. OBJECTIVE: This study assessed differences in the muscle strength of elbow flexors and extensors between typically developing children and adolescents (as controls) and those with CMT1 using isometric and isokinetic contractions. METHOD: Eighteen children and adolescents with CMT1 participated and were matched with 36 controls in this case control study (1:2). The peak torque of elbow flexors (EFL) and extensors (EEX) was assessed using an isokinetic dynamometer through isometric and isokinetic contractions at a speed of 120°.s-. Descriptive, t-tests and ANOVA were used for the statistical analysis. RESULTS: The CMT group exhibited significantly lower peak torque values across all assessed muscles and contraction types compared to the control group (p ≤ 0.05). Additionally, the isokinetic peak torque comparing the values of the elbow flexors with elbow extensors showed a significant difference to the control group (p ≤ 0.05). The intra-group analysis considering types of contractions showed no statistical difference. CONCLUSION: Children with CMT1 presented proximal weakness in the muscles of the upper limbs, not only in the distal hand muscles. Health professionals should pay attention to the assessment and rehabilitation procedures with the aim of contributing to quality of life in the subsequent stages of life.
Hubert J, Schmidt V, Wittmann E
… +10 more, Melder A, Lomidze A, Smit N, Bulubas L, Campana M, Vogelmann U, Dornheim B, Padberg F, Heinen F, Landgraf MN
OBJECTIVE: To determine whether pulmonary hypertension (PH) is associated with higher risk of adverse neurodevelopmental outcome at age 5 in a population-based cohort of 22-31 preterm children. STUDY DESIGN: In the EPIPA...OBJECTIVE: To determine whether pulmonary hypertension (PH) is associated with higher risk of adverse neurodevelopmental outcome at age 5 in a population-based cohort of 22-31 preterm children. STUDY DESIGN: In the EPIPAGE-2 French prospective population-based cohort of preterm children born in 2011, the neurodevelopmental outcome of children with PH was collected at 5 years. The primary outcome was a composite measure with four levels of neurodevelopmental disabilities: severe, moderate, mild, no disability, based on cerebral palsy, visual, hearing or cognitive deficiencies, behavioral difficulties and developmental coordination disorders. Secondary outcomes were autism spectrum disorders and school attendance. Missing data were multiply imputed. Developmental measures were compared using generalized estimating equations models. RESULTS: Of the 3007 eligible children, 1825 were analyzed, of whom 79 (4.3 %) were PH+. At age 5, 36.9 % (95 % CI, 26.0-47.8) of PH + children had moderate to severe overall neurodevelopmental disabilities compared with 17.9 % (95 % CI, 16.1-19.8) of PH-children, P < 0.001. Significant differences at 5 years between the PH+ and PH- groups were observed for cerebral palsy (CP) (6 % versus 2.3 % for severe CP, P = 0.003), cognitive deficiency (31.7 % versus 15.0 %, P < 0.001) and developmental coordination disorders (27.1 % versus 11.7 %, P < 0.001). There were no significant differences in behavioral difficulties and autism spectrum disorders. Normal school was attended by 69.2 % of PH + children versus 88.3 % of PH- children. CONCLUSION: In this nationwide population-based cohort of extremely preterm and very preterm infants, moderate to severe overall neurodevelopmental disability at age 5 was significantly associated with neonatal PH.
INTRODUCTION: Fetal surgery for spina bifida aperta has achieved great advancement in last decade offering three possible methods for surgical repair. Open fetal microsurgical repair still remains the gold standard consi...INTRODUCTION: Fetal surgery for spina bifida aperta has achieved great advancement in last decade offering three possible methods for surgical repair. Open fetal microsurgical repair still remains the gold standard considering long-term results available. Since 2016, we established a program offering this modality of treatment in Germany. PATIENTS AND METHODS: All patients who underwent interdisciplinary prenatal evaluation following a standardized protocol between June 2016-June 2024. Sacral lesions were excluded. The surgical technique and protocol used were similar to that described in Management Of Myelomeningocele Study (MOMS). RESULTS: Sixteen patients underwent surgery for spina bifida aperta without fetal nor maternal deaths. Microsurgical fetal repair was performed between 24th and 25th week of gestation age (GA) (Mean: 24 + 5 weeks GA). Lesion levels were mainly lumbosacral (n = 15) and one thoracolumbar (n = 1). Repair was successful in all 16 cases and with reversible hindbrain herniation at time of birth in 13/16 patients (81.3 %). Average time of delivery was 33 + 5 weeks GA, with 8 preterm deliveries occurring before 37 weeks GA; average birth weight was 2193 g. Maternal complications included 2 patients with uterine scar thinning. Hydrocephalus management was needed in 5/16 patiens (31.25 %) via ventriculo-peritoneal shunting. CONCLUSION: Open fetal repair of spina bifida aperta in selected fetuses is safe and offers the unborn child a better quality of life but does not cure the disease and is not without risks or complications. Collaboration within the pediatric community is recommended to compile data in a common registry to develop standardized treatment and follow-up protocols.
BACKGROUND: Paroxysmal movement disorders (PxMD) are characterized by episodic involuntary movements and include paroxysmal dyskinesias (PD) and episodic ataxias (EA). Although reported in the medical literature since 18...BACKGROUND: Paroxysmal movement disorders (PxMD) are characterized by episodic involuntary movements and include paroxysmal dyskinesias (PD) and episodic ataxias (EA). Although reported in the medical literature since 1892, the exact prevalence in children is unknown. OBJECTIVES: To determine the prevalence and clinical characteristics of PxMD in the pediatric population in the Republic of Ireland. METHODS: Cross-sectional cohort study across pediatric neurology services in the Republic of Ireland incorporating retrospective chart, telephone and clinical reviews. RESULTS: Seventy-nine cases met the inclusion criteria (PD = 37, EA = 38, Alternating Hemiplegia of Childhood = 4). Point prevalence for all PxMD was 6.5 cases per 100,000 persons aged less than 18 years (PD 3/100,000, EA 3.1/100,000, Alternating Hemiplegia of Childhood 0.3/100,000). Sixty-four cases were clinically reviewed by the research team (PD = 33, EA = 31). A cause was identified in 38 % (24/64). The highest investigation yield was from single-gene testing (38 %, 9/24) followed by gene panels (25 %, 11/44). Variable evolution patterns were seen. In PD, 55 % (18/33) resolved and 30 % (10/33) improved. This was due to medication in 61 % (20/33), trigger avoidance in 6 % (2/33) and spontaneous remission in 18 % (6/33). In EA, 45 % (14/31) resolved and 42 % (13/31) improved, with spontaneous remission or improvement in 48 % (17/33). DISCUSSION: This study adds to the PxMD knowledge base by determining PxMD prevalence in a pediatric population for the first time. This prevalence is higher than previous adult population estimates. An aetiology was identified in one-third. A large proportion can expect symptom improvement either with medications, trigger avoidance or spontaneous remission over time.
INTRODUCTION: Headaches are becoming increasingly common in children and adolescents, leading to a rise in emergency department visits and hospitalizations. This study explores alternative therapeutic options, focusing o...INTRODUCTION: Headaches are becoming increasingly common in children and adolescents, leading to a rise in emergency department visits and hospitalizations. This study explores alternative therapeutic options, focusing on the anesthetic blockade of the greater occipital nerve (GON) for paediatric migraines. MATERIALS AND METHODS: A prospective study assessing the utility of the anesthetic blockade in the GON zone with 0.5 % Bupivacaine in adolescents with refractory migraines. Inclusion criteria involve adolescents aged 12 to 17 with a diagnosis of migraine status. The study outlines the infiltration technique, efficacy assessment, and sustained utility evaluation, aiming to determine the safety, effectiveness, and patient satisfaction associated with the procedure. RESULTS: Out of 24 patients with migraine status, 92 % were females, with an average age of 14 years. Two-thirds reported incapacitating pain, and associated symptoms included nausea, vomiting, dizziness, syncope, phonophobia, and photophobia. The anesthetic blockade resulted in statistically significant total or partial improvement in the majority of patients, with sustained effectiveness observed at the 7-day follow-up. High satisfaction with the treatment was reported, and no adverse effects were documented. CONCLUSION: The anesthetic blockade in the GON zone emerges as a safe and effective strategy for the treatment of paediatric migraines in the emergency department. High patient satisfaction and sustained effectiveness support its consideration, emphasizing the need for consensus and clinical trials to standardize procedures and indications across diverse populations.
INTRODUCTION: The development of children with NF1 has so far been primarily studied in school-age children with various subtests showing heterogeneous profiles. The aim of this study is to characterise the development o...INTRODUCTION: The development of children with NF1 has so far been primarily studied in school-age children with various subtests showing heterogeneous profiles. The aim of this study is to characterise the development of infants with NF1 across all areas of early childhood development. MATERIAL AND METHODS: 32 infants with NF1, aged 12-47 months, participated in this cross-sectional cohort study. Development was assessed with the MFED 1-4 comprising 7 test categories. Items measuring visual abilities (colour and visuospatial items) from all subcategories were selected and compared to the normal population. RESULTS: Infants with NF1 showed a global developmental delay, more pronounced in application of memorised knowledge. A particular deficit was found in items requiring spatial vision. DISCUSSION: The present study is the first to examine the global development of children with NF1 under 48 months. Consistent with animal data, we found significant deficits in visuospatial abilities, which may significantly contribute to the perceived global developmental delay. These findings underline the need for early and specific developmental therapy in this patient group in order to train the development early in infancy and to achieve the best neurodevelopmental outcome.
Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy in children. Impairment of masticatory function and swallowing disorders, potentially leading to aspiration and gastrostomy, are linked to fatty inf...Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy in children. Impairment of masticatory function and swallowing disorders, potentially leading to aspiration and gastrostomy, are linked to fatty infiltration in the masticatory muscles, as previously observed in muscle ultrasound. This study aims to quantify muscle volume and fat fraction in muscle magnetic resonance imaging (MRI) in the masticatory muscles in non-ambulant DMD patients compared to healthy controls and evaluate their correlation with maximum bite force (MBF), which has not been previously described. Fifteen patients with DMD and 16 controls were included. MBF was measured with an oral dynamometer and total muscle volume (TMV) and fat signal fraction (FSF) were quantified using MRI with the Dixon technique. Four DMD patients presented with masticatory or swallowing difficulties. DMD patients had a significantly lower median MBF (141.8 N) compared with healthy controls (481.6 N, p < 0.0001). Additionally, median FSF was significantly higher in DMD patients (47.07 %) compared to controls (5.31 %, p < 0.0001). A strong negative correlation between TMV and MBF was observed in DMD patients (ρ = -0.70, p = 0.0048). A significant negative correlation between MBF and normalized FSF was observed in healthy controls (ρ = -0.5487, p = 0.300) and DMD patients (ρ = -0.5893, p = 0.0224). A non-significant positive correlation between age and FSF in DMD was detected (ρ = 0.38, p = 0.17). MBF, TMV and FSF quantified with the Dixon MRI are sensitive measures to evaluate masticatory function in DMD patients and may serve as biomarkers for clinical follow up. Studies in older patients are needed to evaluate the predictive role of MBF, TMV and FSF in the nutritional status of patients and the need for therapeutic interventions such as gastrostomy.
OBJECTIVE: The aim of this study was to investigate the changes in interictal paroxysmal fast activity and functional connectivity before and after steroid pulse therapy in patients with Lennox-Gastaut syndrome (LGS). ME...OBJECTIVE: The aim of this study was to investigate the changes in interictal paroxysmal fast activity and functional connectivity before and after steroid pulse therapy in patients with Lennox-Gastaut syndrome (LGS). METHODS: The medical records of patients who visited the pediatric neurology clinics with LGS as their primary complaint and completed intravenous methylprednisolone therapy were reviewed. Effects of steroid therapy on clinical seizures and scalp EEG were analyzed. Generalized paroxysmal fast activity (GPFA) burden were detected and compared before and after treatment. As a measure of global functional connectivity, we calculated mutual information (MI) between all channels, which was then used to assess network topology. RESULTS: Steroid pulse therapy improved seizure control in 20 (27 %) patients. Fourteen (18.9 %) children became complete seizure-free, but 8 patients experienced relapses subsequently. The later age of disease onset, shorter duration of epilepsy, and definite cerebral structural etiology were found to advantageous for hormone response. A significant correlation was observed between GPFA burden and diary seizure number. Patients with higher GPFA burdens and higher MI values exhibited a poor response to steroid treatment. Patients who respond positively to steroids therapy demonstrated longer characteristic path length, higher modularity and lower global efficiency in high beta and gamma bands. CONCLUSION: Add-on steroid therapy can be considered as an optional adjunct for LGS. GPFA could be utilized as a parameter to predict treatment effects and prognosis for LGS. The group that responded to steroids showed a high level of local clustering and low long-range network connectivity. This study provides real-world evidence regarding the effectiveness of steroid in refractory LGS.
UNLABELLED: Tumefactive lesions (TDL) are larger than 2 cm in diameter on T2-weighted brain MRI. They are distinguished from other types of demyelinating lesions by their size and degree of perilesional edema and/or rim...UNLABELLED: Tumefactive lesions (TDL) are larger than 2 cm in diameter on T2-weighted brain MRI. They are distinguished from other types of demyelinating lesions by their size and degree of perilesional edema and/or rim enhancement, which can make diagnosis challenging. AIM: To study the clinical and radiological features, follow-up and final diagnosis of patients presenting with TDL. METHOD: Medical records of children seen at the Pediatric neurology and radiology department between 1992 and 2017 were reviewed. 15 patients younger than 18 years of age who had at least one TDL on their first magnetic resonance imaging (MRI) were included. Clinical and radiological features and evolution of imaging findings were studied. RESULTS: First, all patients were admitted acutely with a polysymptomatic presentations (86,6 %) mainly affecting the motor system (92,8 %). The largest diagnostic group was MS (n = 10, 66,6 %) with 9 out of 10 individual's diagnosed during follow up. At least one new clinical or radiological relapse was observed in 12 patients with a mean occurrence of 9 and 14 months respectively. All cases who developed a radiological relapse and most (n: 9, 75 %) of those who experienced a clinical relapse were diagnosed with MS and all had new lesions at the time of diagnosis. All children with MS had positive OCBs. Most TDLs (21/24, 87,5 %) were localized in the supratentorial area. TDL + other demyelinating lesions were observed in most 12/15 (80 %) patients and the size of TDL was between 2 and 4 cm (20/24, 83.3 %). All patients with MS, whether they had a single TDL or multiple TDLs, had accompanying small demyelinating lesions. On follow-up all TDLs became smaller (14/15, 93,3 %) or resolved (n = 1). CONCLUSION: The non-infiltratind pattern, presence of multiple small demyelinating lesions and CSF oligoclonal band positivity may suggest MS, which is one of the most common causes. However, for a definitive diagnosis, patients should continue to be monitored with radiological imaging even in the absence of clinical relapses.
Vitamins are essential cofactors of various enzyme reactions in amino acid, neurotransmitter, nucleotide and energy metabolism. Over the past decade a number of inborn errors of metabolism have been identified, that affe...Vitamins are essential cofactors of various enzyme reactions in amino acid, neurotransmitter, nucleotide and energy metabolism. Over the past decade a number of inborn errors of metabolism have been identified, that affect different steps in vitamin absorption, transport, activation or recycling and repair of active vitamin cofactors. According to the respective cofactor function this may result in acute or chronic multisystem disease or in disorders that selectively affect the nervous system. Most of these disorders are amenable to specific treatment with excellent results, but diagnostic delay can lead to rapid, irreversible damage or even death. Therefore, especially in case of acute and severe neurologic presentations compatible with one of the here discused disorders, a vitamin trial should be considered while awaiting results of biochemical and genetic testing. Diagnosis of these disorders is especially rewarding, as treatment is often per oral, available worldwide and comparably cheap. This article will review current knowledge of the clinical presentation, biomarkers and specific treatment of inborn errors of vitamin metabolism and illustrates why child neurologists should have vitamins in their pockets.