AIM: To examine the association between dystrophin isoform disruption and cognitive and behavioral outcomes, including autism spectrum disorder (ASD), in a large cohort of boys with Duchenne muscular dystrophy (DMD) and...AIM: To examine the association between dystrophin isoform disruption and cognitive and behavioral outcomes, including autism spectrum disorder (ASD), in a large cohort of boys with Duchenne muscular dystrophy (DMD) and related dystrophinopathies. METHOD: In this retrospective cohort study (2014-2025), 161 boys with genetically confirmed dystrophinopathy (145 DMD, 14 Becker muscular dystrophy, and 2 intermediate muscular dystrophy) were classified according to predicted involvement of the brain-expressed dystrophin isoforms Dp427, Dp140, and Dp71. Cognitive function was assessed using standardized intelligence measures (WISC-IV or WASI), complemented by comprehensive neuropsychological evaluation. ASD was diagnosed according to DSM-5 criteria and confirmed through multidisciplinary assessment. RESULTS: Intellectual disability (ID) was identified in 63 of 161 patients (39.1%), including 47 (29.1%) with mild and 16 (10.0%) with moderate ID. ASD was diagnosed in 16 patients (10%), and in 81% of cases ASD identification preceded or coincided with the diagnosis of dystrophinopathy. An isoform-dependent gradient was observed: patients with mutations restricted to exons 1-44 (Dp427-only) showed the highest frequency of normal cognition, whereas those with mutations affecting Dp140 or Dp71 exhibited progressively higher rates of ID and ASD. INTERPRETATION: Cognitive impairment and ASD are frequent non-muscular manifestations of childhood dystrophinopathies and correlate closely with disruption of brain-expressed dystrophin isoforms, particularly Dp140 and Dp71. Integrating genetic and neuropsychological assessment into routine clinical care is essential for early recognition and timely intervention.
Craiu D, Papadopoulou MT, Mrak JO
… +20 more, Butenko T, Saarela A, Cazacu C, Raluca N, Serdaroglu E, Malenica M, Vigevano F, Zafeiriou D, Gorman KM, Ming L, Bahi-Buisson N, Rostasy K, Kopyta IA, Sejersen T, Lin JP, Suppiej A, CNA-EPNS (Commission of National Advisors of the European Paediatric Neurology Society), GGCPWG-YEPNS (Guidelines & Good Clinical Practice Working Group – Young European Society of Paediatric Neurology), GC-EPNS (Guidelines Committee EPNS), Zuberi SM
INTRODUCTION: This study aimed to assess the availability of national transition guidelines in paediatric neurology across Europe and to provide a review of the existing literature. METHODS: A mixed-methods descriptive s...INTRODUCTION: This study aimed to assess the availability of national transition guidelines in paediatric neurology across Europe and to provide a review of the existing literature. METHODS: A mixed-methods descriptive study was conducted, combining a survey of national representatives of the European Paediatric Neurology Society and a scoping literature review. The survey, performed in 2021 with an update in 2026, assessed the existence of national or officially endorsed transition guidelines. The literature review (2002-2025) followed the Arksey and O'Malley framework and PRISMA-ScR recommendations. RESULTS: Thirty-six of 42 representatives responded to the 2021 survey; 66.7% reported no national transition guidelines in paediatric neurology, while 16.7% reported officially endorsed guidance. The literature search identified 23372 records, of which 132 publications were included in the final analysis. Most described centre-based transition models or general recommendations, while formal guidelines were rare. Drawing on the gaps identified through literature review and survey findings, this paper proposes a series of targeted recommendations to enhance the transition process in paediatric neurology. CONCLUSIONS: Transition guidance in paediatric neurology remains limited and heterogeneous across Europe. Specific recommendations are needed to provide guidance and enhance the effectiveness of this process. An EPNS-EAN Transition Task Force is currently developing a transition framework.
Brain involvement is a well-recognised feature of Duchenne muscular dystrophy (DMD), presenting with intellectual disability and/or behavioural manifestations. Cumulatively, associated neurodevelopmental comorbidities af...Brain involvement is a well-recognised feature of Duchenne muscular dystrophy (DMD), presenting with intellectual disability and/or behavioural manifestations. Cumulatively, associated neurodevelopmental comorbidities affect half of the DMD population but receive little attention in standards of care recommendations and clinical practice. Access to pharmacological interventions for emotional and behavioural symptoms is limited, despite the availability of drugs with well-established efficacy. We lack information on appropriate choice, efficacy and safety of psychopharmacological interventions in DMD. Neuromuscular clinicians and neuropsychologists from eight European countries held a series of meetings between 2024 and 2025 to review the range of behavioural and emotional comorbidities observed in their respective DMD clinics and treatment strategies implemented. Each centre provided empirical evidence of the efficacy and safety of psychopharmacological interventions based on their experience. This working group identified comorbidities for which there was full consensus on drug selection, efficacy, and apparent tolerability, as well as areas with inconsistent approaches, underscoring the need for additional evidence.
BACKGROUND: Cenobamate was approved in 2020 by the EMA for the adjunctive treatment of focal-onset seizures in adults. Based on data from clinical trials and early experience in adult patients, we used cenobamate in chil...BACKGROUND: Cenobamate was approved in 2020 by the EMA for the adjunctive treatment of focal-onset seizures in adults. Based on data from clinical trials and early experience in adult patients, we used cenobamate in children whose seizures were not controlled with available options. METHODS: We prospectively collected clinical data in patients who started treatment with cenobamate and report dosage, efficacy, retention rate, and adverse effects. RESULTS: Overall, 50 patients (median age 12.2 years, range 3.1-18.5, 19 patients below age 10 years; 44% female, median concomitant antiseizure medications 2) were treated with cenobamate for a median duration of 16 months (range 3-28). After gradually increasing cenobamate to clinical effect at a reduced dosage schedule, 60% (29/48) of children were responders (≥50% reduction) and 12% were free of major motor seizures. Patients were treated with an average daily dose of 3.7 mg/kg. During cenobamate treatment, 8 (16%) patients were able to discontinue at least one concomitant antiseizure medication. The retention rate at 12 months was 82%. The most common adverse events were somnolence (42%), nausea/vomiting (4%), and ataxia (4%). CONCLUSIONS: The findings of this single-center real-world study are in line with prior controlled studies and real-world experience in adult patients, as well as with the limited published experience in children. The efficacy and lack of serious side effects found in this study supports the use of cenobamate as a treatment for epilepsy also in children and infants.
OBJECTIVE: This study aims to evaluate the efficacy, safety and impact on growth of ketogenic diet therapy (KDT) in infants under two years of age with drug-resistant epilepsy. METHODS: A retrospective analysis was condu...OBJECTIVE: This study aims to evaluate the efficacy, safety and impact on growth of ketogenic diet therapy (KDT) in infants under two years of age with drug-resistant epilepsy. METHODS: A retrospective analysis was conducted on 36 infants who received KDT. Demographic data, seizure frequency, adverse effects, dietary adherence, and growth metrics were assessed at baseline and during follow-up intervals. RESULTS: In the intent-to-treat analysis, all patients who initiated the ketogenic diet were included, and the responder rates at 1, 3, 6, 12, 18, and 24 months were 52.8%, 58.3%, 58.3%, 52.8%, 38.9%, and 36.1%, respectively. Among those continuing KDT, one-third remained seizure-free at Month 24. Metabolic etiologies showed higher early responsiveness. Dyslipidemia was the most frequent adverse event but improved significantly over time. Adverse effects such as nephrolithiasis and gastrointestinal symptoms were common but manageable. Growth demonstrated a mild but statistically significant decline in Z-scores. Medication burden decreased over time, and 23.3% of patients who maintained long-term adherence ultimately became medication-free. CONCLUSION: KDT is an effective and generally well-tolerated treatment for drug-resistant epilepsy in infants, providing meaningful seizure control, reduced medication use, and an acceptable safety profile when carefully monitored.
INTRODUCTION: Tuberous sclerosis complex (TSC) is a rare autosomal dominant multi-systemic disease, leading to excessive cell proliferation and the formation of hamartomas affecting various organs. International and Fren...INTRODUCTION: Tuberous sclerosis complex (TSC) is a rare autosomal dominant multi-systemic disease, leading to excessive cell proliferation and the formation of hamartomas affecting various organs. International and French national guidelines emphasize the need for regular follow-up by different specialists with regular clinical evaluation, and biological and imaging investigations. This study aims to assess patient follow-up, its cost, and its adherence to the French National follow-up recommendations since the establishment of the day-hospital program tailored for pediatric patients with TSC. MATERIALS AND METHODS: Clinical and follow-up data were collected among 81 patients, aged from 3 to 18 years old, from the epilepsy reference center of Necker Hospital in Paris, with a confirmed diagnosis of TSC, retrospectively from January 1st, 2021 to January 1st, 2024. RESULTS: Patients had an average of 9.4 days of pathology-related follow-up events, and an average of 1.1 teleconsultation over 3 years. Patients attended 1.6 day hospital stays over the duration of follow-up. The mean annual cost per patient for consultations and hospitalizations was €1344. The level of disability significantly increases the cost of follow-up. However, home-hospital distance has no significant impact on overall follow-up costs, the number of teleconsultations, or day-hospital visits. DISCUSSION: While paraclinical imaging and neurological follow-up were consistent with national recommendations, compliance with TSC national guidelines for specialist consultations was more challenging to implement. Our findings suggest that a mixed day hospital model, centered on neuropediatrics and incorporating additional examinations and consultations, would facilitate compliance with follow-up recommendations. Reducing patient travel and optimizing costs should be considered key objectives for improving long-term care.
OBJECTIVE: To evaluate the effectiveness and safety of clonidine sedation for paediatric electroencephalography (EEG) in children unlikely to tolerate non-sedated recording. METHODS: We conducted a retrospective review o...OBJECTIVE: To evaluate the effectiveness and safety of clonidine sedation for paediatric electroencephalography (EEG) in children unlikely to tolerate non-sedated recording. METHODS: We conducted a retrospective review of all clonidine-sedated EEGs performed between September 2022 and September 2025 at our department. For each study, referral details and EEG reports were examined to record patient demographics, prior EEG history, sleep capture, study outcome, and any adverse events. EEGs were classified as successful if recording was completed and interpretable. Sleep was recorded as obtained or not. Descriptive statistics and Mann-Whitney U tests were used. RESULTS: Seventy-five clonidine-sedated EEGs were included. The mean age was eight years (range 2-17), and 75% were male. Almost all children had a neurodevelopmental or behavioural diagnosis, and most (69%) had previously undergone a non-sedated EEG. Overall, 82% of clonidine EEGs were successfully completed, including 76% of children who had previously failed a non-sedated study. Sleep was obtained in 68% of recordings, and 78% of those who had not achieved sleep previously, did so with clonidine. Median recording duration was 74 min (IQR 53-91). EEG abnormalities were identified in 60% of successful studies. No unplanned admissions or abandoned procedures occurred. CONCLUSIONS: Clonidine sedation is a safe and effective method for facilitating EEG acquisition and sleep capture in children with developmental or behavioural challenges who are unable to tolerate standard or sleep-deprived recordings. Use of clonidine in this population may reduce failed EEG attempts and support detection of EEG abnormalities in selected patients.
INTRODUCTION: Duchenne muscular dystrophy (DMD), an X-linked disorder due to dystrophin gene mutations leads to progressive muscle weakness and ambulation loss by adolescence. Autonomic dysfunction precedes dilated cardi...INTRODUCTION: Duchenne muscular dystrophy (DMD), an X-linked disorder due to dystrophin gene mutations leads to progressive muscle weakness and ambulation loss by adolescence. Autonomic dysfunction precedes dilated cardiomyopathy, a major cause of mortality. This study aimed to investigate early cardiovascular markers and their genotype - phenotype associations in young DMD patients. METHODS: Genetically confirmed ambulant DMD boys (n = 66) aged 5-10 years recruited from a quaternary care centre for neurological disorders in Southern India, were subjected to HRV, electrocardiography and compared with controls (n = 46 and n = 31 respectively) while echocardiography measures were compared with normative data. Relevant genotype - phenotype associations were evaluated. RESULTS: DMD subjects' HRV measures showed significantly higher LFnu, LF/HF and lower SDNN, RMSSD, total power compared to controls, and significantly shortened PR, prolonged QTc, greater Q, S, R wave amplitudes. Significantly higher E, E/A; and significantly lower LVEF, LVID (d), LVID(s), IVS (d) were found in DMD subjects. Further, HR and LF were positively correlated with time to rise from supine (p = 0.002 and p = 0.008 respectively) and HR with time to climb four standard stairs (p = 0.005). Genotype-phenotype correlations revealed more cardiac dysfunction with greater Q amplitude and lesser E, A velocities in proximal mutation group (exons1-44) than distal (exons45-79). DISCUSSION/CONCLUSIONS: Reduced HRV with increased sympathetic and decreased parasympathetic activity was found in DMD subjects. Significant abnormalities in cardiac investigations suggest initiation of early cardiac involvement in younger DMD patients. Significant associations between cardiac autonomic, functional and genotype highlight the need for further research to explore these relationships in depth.
INTRODUCTION: Ataxia Telangiectasia (A-T) is a rare neurodegenerative disease caused by mutations in the A-T Mutated (ATM) gene encoding the ATM protein. No curative treatments are available for A-T. Serum alpha fetoprot...INTRODUCTION: Ataxia Telangiectasia (A-T) is a rare neurodegenerative disease caused by mutations in the A-T Mutated (ATM) gene encoding the ATM protein. No curative treatments are available for A-T. Serum alpha fetoprotein (AFP) is a well known biomarker for A-T, but less is known about changes in serum AFP levels during the course of disease. The aim of this study is to obtain more insight in the serum AFP levels over time in individuals with classic and variant A-T, in order to better define its diagnostic potential. Furthermore, we hope that better understanding of the natural course of serum AFP levels in patients with A-T will contribute that the serum AFP level can be used as a valuable outcome measure in future clinical trials. METHOD: In this retrospective cohort study, we collected the initial and all follow-up serum AFP levels from the medical records of individuals (children and adults) with A-T who visit our multidisciplinary A-T outpatient clinic at the Radboud university medical center in Nijmegen, the Netherlands. RESULTS: In total, 336 serum AFP measurements in 45 individuals with A-T (36 with classic A-T and 9 with variant A-T) were included in this study. All patients showed increased serum AFP levels during the course of disease. In the first two years of life, however, serum AFP levels were found within the range of age-dependent reference values. Individuals with classic A-T showed the most rapid increase in serum AFP levels (on average 26.8 μg/l per year), between 2 and 12 years of life. Their serum AFP levels increased by 19.2 μg/l per year between the ages of 12 and 18 years and stabilized at a level ranging from 34 to 1000 μg/l thereafter. Serum AFP levels in adults with variant A-T (range: 95-680 μg/l) were remarkably similar to the levels in adults with classic A-T and remained stable over time. CONCLUSION: Serum AFP is a diagnostic biomarker for A-T, but levels may be normal in exceptional situations, especially in the first two years of life. Nevertheless, serum AFP levels increased over time in individuals with classic A-T until the age of approximately 18 years, when a plateau was reached. Caution is warranted when a rapid increase in serum AFP is observed. No normal AFP levels were observed in individuals with classic A-T over the age of 3 years and in individuals with variant A-T in this cohort.
BACKGROUND: PTEN Hamartoma Tumor Syndrome (PHTS) is an autosomal dominant syndrome caused by a mutation in the PTEN gene. Previous studies have suggested an association between PHTS and epilepsy, but the clinical charact...BACKGROUND: PTEN Hamartoma Tumor Syndrome (PHTS) is an autosomal dominant syndrome caused by a mutation in the PTEN gene. Previous studies have suggested an association between PHTS and epilepsy, but the clinical characteristics of epilepsy in PHTS remain unknown. OBJECTIVE: This study aims to expand knowledge of epilepsy in PHTS and provide insights into its clinical features. METHODS: A retrospective observational study was conducted at the Radboud University Medical Center, including 149 patients with clinically or genetically confirmed PHTS. Electronic patient records were reviewed for baseline characteristics, epileptic features, therapeutic interventions, and neuroimaging results. A cumulative risk analysis for developing epilepsy was performed. RESULTS: The prevalence of epilepsy among PHTS patients in this cohort was found to be 6%, with an estimated PHTS prevalence of 1:20 000 in the Netherlands. Autism spectrum disorder (ASD) was significantly associated with an increased risk of developing epilepsy (p = 0.002). A range of seizure semiologies was observed, with focal epilepsy being the most common, presenting as focal seizures with impaired awareness. EEG results predominantly showed (multi)focal discharges with variable localization. MRI abnormalities did not correlate with epileptic foci on EEG. CONCLUSION: This study highlights the clinical characteristics of epilepsy in pediatric patients with PHTS. Follow-up should include monitoring for characteristics of focal epilepsy, with EEG utilized selectively when such episodes are observed, rather than as a routine screening measure. Treatment strategies should be individualized based on the patient's characteristics. In cases of epilepsy, MRI is recommended to identify potential structural malformations amenable to surgical intervention.
Diodato D, Bosco L, Catteruccia M
… +14 more, Sancesario A, Jofrè J, Suarez B, Lacaux P, Tosi M, De Luca G, Mizzoni I, Pro S, Bellacchio E, Fattori F, Novelli A, Bertini E, Castiglioni C, D'Amico A
PURPOSE: Mechanosensation is the ability to detect dynamic mechanical stimuli and is essential for many processes, including sense of touch on the skin. PIEZO2 is a functional ion channel assembled by three monomers and...PURPOSE: Mechanosensation is the ability to detect dynamic mechanical stimuli and is essential for many processes, including sense of touch on the skin. PIEZO2 is a functional ion channel assembled by three monomers and is an essential mechanotransducer for touch, proprioception, and interoception. Heterozygous pathogenic variants in PIEZO2 gene are associated with distal arthrogryposis type 3 (MIM:114300) and type 5 (MIM:108145), and with Marden-Walker Syndrome (MIM:248700). Recessive pathogenic variants in PIEZO2 are associated with distal arthrogryposis with impaired proprioception and touch (DAIPT) (MIM:617146). Papers describing patient cohorts in literature are few. Here we described 9 patients from 8 families with a very similar clinical picture characterized by neonatal respiratory distress, hypotonia, delayed motor development, sensory ataxia, foot deformities, hyperlaxity, progressive scoliosis, and skeletal contractures. We also carried out a review of patients reported in literature with recessive PIEZO2 variants. METHODS: We retrospectively analyzed clinical and genetic results of 5 patients followed at Bambino Gesù Children Hospital and 4 patients followed at Neuropediatric Unit, Clinica Meds, Santiago, Chile. RESULTS: In our cohort, we identified nine patients harbouring PIEZO2 variants. Among them, eight patients carried single nucleotide variants (SNVs): three were compound heterozygous, two were homozygous, and two harboured two heterozygous variants of unknown allelic phase. Additionally, one other patient, who presented with a highly suggestive clinical phenotype, was found to harbour only a single heterozygous maternally inherited, frameshift variant. Only one patient was found to have a large homozygous copy number variant (CNV). CONCLUSIONS: Our cohort clinical phenotype, even though of variable severity, is highly concordant between the patients and literature data. To our knowledge this is one of the largest cohort of patients with recessive PIEZO2 variants so far.
BACKGROUND: Pediatric ovarian teratoma-associated anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) represents a clinically important but relatively uncommon subgroup, and evidence regarding factors associated wit...BACKGROUND: Pediatric ovarian teratoma-associated anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) represents a clinically important but relatively uncommon subgroup, and evidence regarding factors associated with acute severity and long-term functional outcome in this population remains limited. METHODS: We conducted a single-center retrospective cohort study of pediatric patients with surgically resected, histopathologically confirmed ovarian teratoma-associated NMDARE. Baseline and acute-phase characteristics were summarized in the full cohort (N = 97). Acute severity was defined by ICU admission with organ support and/or mechanical ventilation. Twelve-month functional outcome was assessed using the modified Rankin Scale (mRS) and dichotomized as good (mRS≤2) versus poor (mRS>2); outcome analyses were performed in the complete-case cohort (N = 71). Univariable and multivariable logistic regression identified factors independently associated with poor outcome. Discriminative performance was evaluated using ROC curve analysis. RESULTS: Among 97 patients, median age at onset was 14.2 years (IQR 12.3-16.5) and 95.9% were female. Mature teratoma accounted for 80.4%. The median onset-to-resection interval was 18 days (IQR 11-29), and 34.0% underwent resection >21 days after onset. Severe disease occurred in 29 patients (29.9%) and was associated with higher symptom burden (median symptom categories 5.0 vs 3.0, P < 0.001), more frequent MRI abnormalities (62.1% vs 33.8%, P = 0.009) and multifocal MRI lesions (27.6% vs 7.4%, P = 0.013), and higher rates of EEG background slowing (89.7% vs 61.8%, P = 0.014) and extreme delta-brush (44.8% vs 13.2%, P = 0.001). In the 12-month outcome cohort (N = 71), 76.1% achieved mRS≤2 and 23.9% had mRS>2; relapse occurred in 8.5% and death in 2.8%. Multivariable analysis identified central hypoventilation (aOR 4.18, 95%CI 1.62-10.78), symptom categories ≥4 (aOR 2.94, 1.14-7.61), multifocal MRI lesions (aOR 3.12, 1.01-9.65), extreme delta-brush (aOR 3.37, 1.18-9.63), and onset-to-resection >21 days (aOR 2.81, 1.05-7.49) as independent correlates of poor functional outcome. The combined clinical plus imaging-EEG model showed the highest discrimination (AUC 0.86, 95%CI 0.76-0.95), with sensitivity 88.2% and specificity 74.1% at the optimal cutoff. CONCLUSIONS: In pediatric ovarian teratoma-associated NMDARE, higher acute-phase clinical burden, multifocal MRI abnormalities, extreme delta-brush, central hypoventilation, and delayed tumor resection were independently associated with poor 12-month functional outcome.
OBJECTIVE: Evaluate the ability of ChatGPT for diagnostic guidance in patients with stroke suspicion and its ability to predict the likelihood of stroke. Additionally, to analyze its use as a scale calculator (Glasgow Co...OBJECTIVE: Evaluate the ability of ChatGPT for diagnostic guidance in patients with stroke suspicion and its ability to predict the likelihood of stroke. Additionally, to analyze its use as a scale calculator (Glasgow Coma Scale[GCS], Pediatric National Institute of Health Stroke Scale[PEDNIHSS]). METHODS: An observational, descriptive, retrospective, single-centre study was conducted in a Paediatric Emergency Department (PED). Standardised templates were created from the medical records of patients in whom the PSC had been activated and had been attended at the PED. These templates were introduced into independent conversations with ChatGPT. ChatGPT was instructed to: perform diagnostic guidance, predict stroke probability (in a 1-5 scale), calculate GCS and PEDNIHSS. Results were compared with the clinical diagnosis (stroke or stroke mimic) after assessment at the PED. RESULTS: 116 PSC activation case templates were analysed. ChatGPT's diagnostic guidance had weak concordance (k = 0.291), sensitivity 90.9%(95%CI78.9-100) and specificity 57.4%(95%CI47.5-67.4). The AUC of ChatGPT regarding the stroke probability scale, was 0.796 (95%CI:0.714-0.878). The optimal value for stroke detection on the stroke probability scale was 4, with sensitivity 88.24% (95%CI:77.41-99.07), and NPV 93.75% (95%CI:87.82-99.68). The concordance for the calculation of scales (GCS and PedNIHHS) with respect to the real value was weak (k = 0.227, k = 0.261 respectively). CONCLUSION: ChatGPT does not seem useful for diagnostic guidance nor scale calculation in patients with stroke suspicion. However, scores <4 on the stroke probability scale could help to rule out stroke, hence Chat-GPT could be a support tool in PSC activations.
George E, Braun M, Vassar R
… +7 more, Fox CK, Siegel DH, Mathes E, Frieden IJ, Hess CP, PHACE >10yr Study Group, Collaborators in PHACE >10yr Study Group
BACKGROUND: Posterior fossa anomalies, Hemangioma, Arterial anomalies, Cardiac anomalies and Eye anomalies (PHACE) is a neurocutaneous disorder characterized by various neuroimaging abnormalities, including cranio-cervic...BACKGROUND: Posterior fossa anomalies, Hemangioma, Arterial anomalies, Cardiac anomalies and Eye anomalies (PHACE) is a neurocutaneous disorder characterized by various neuroimaging abnormalities, including cranio-cervical arterial anomalies. The purpose of this multi-center study is to assess the long-term evolution of neuroimaging findings in PHACE, with focus on progressive arteriopathy and intracranial hemangioma. METHODS: Patients with definite PHACE who were ≥10 years of age were recruited from 16 sites. A pediatric neuroradiologist retrospectively reviewed clinical MRI/MRA or CTA reports collected from two timepoints: neuroimaging performed closest to 1 year of life and the latest available neuroimaging at the time of recruitment. Brain structural abnormalities (including intracranial hemangiomas), infarcts, cerebrovascular anomalies (including vascular risk score) and evidence of progressive arteriopathy were identified. RESULTS: Study included 83 patients with definite PHACE (median age at recruitment: 14 years (IQR: 12-18)) with a median of 9 years (IQR: 6-12) between scans. Progression of arteriopathy was identified in 20/68 (29.4%), including 5/68 (7%) with Moyamoya arteriopathy. The vascular risk score at initial imaging was not associated with progressive arteriopathy. Two children (2%) had infarcts; one of whom had a progressive arteriopathy. The presence of intracranial hemangioma was associated with Meckel's cave enlargement and follow-up imaging suggests Meckel's cave enlargement may at least partly be related to involution of an intracranial hemangioma. CONCLUSION: Almost one third of children with PHACE had a progressive cerebrovascular arteriopathy on long term follow-up imaging, but infarcts were rare. Further research is necessary to guide recommendations on duration and frequency of imaging surveillance.
This study presents the first reported case of a 3-year-old child with EIF2AK2-related dystonia treated with adjunctive luteolin supplementation. EIF2AK2-related dystonia, characterized by exacerbations during infections...This study presents the first reported case of a 3-year-old child with EIF2AK2-related dystonia treated with adjunctive luteolin supplementation. EIF2AK2-related dystonia, characterized by exacerbations during infections, is associated with disruptions in the integrated stress response (ISR). The ISR, a cellular signaling pathway activated in response to stress, culminates in the phosphorylation of eIF2α, which modulates protein synthesis and can induce cell death. Pathogenic variants in EIF2AK2 disrupt this pathway, contributing to the development of dystonia. Luteolin, a flavonoid possessing anti-inflammatory and neuroprotective properties, was hypothesized to modulate the ISR, thereby attenuating infection-induced dystonic exacerbations. The patient, exhibiting early-onset dystonia with clinical worsening during febrile episodes, harbored a de novo pathogenic variant in EIF2AK2. Following initial clinical improvement with trihexyphenidyl, adjunctive luteolin therapy was initiated, resulting in further clinical enhancements. Quantitative assessment using dystonia rating scales (UDRS, MSS, DSS) demonstrated sustained improvement, characterized by a reduction in the severity and frequency of infection-triggered relapses. The proposed mechanism of action involves luteolin disrupting the PACT-PKR interaction, a critical step in ISR activation, thus preventing excessive eIF2α phosphorylation and subsequent cellular dysfunction. This mechanism, supported by in vitro studies utilizing relevant disease models, suggests luteolin's potential to stabilize cellular homeostasis under stress. This case report indicates that luteolin may serve as a promising adjunctive therapeutic strategy for patients with infection-sensitive dystonic phenotypes, such as EIF2AK2-related dystonia. Further randomized controlled trials are warranted to validate these findings and establish the optimal dosing regimen and long-term safety profile of luteolin in vivo.