Brain Dev. [JOURNAL]
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200 papers
Duchenne muscular dystrophy: Evolving therapeutic strategies and multidimensional evaluation approaches.
Komaki H
Brain Dev · 2025 Oct · PMID 40712356 · Publisher ↗
Duchenne muscular dystrophy (DMD) is a severe X-linked muscular disorder caused by the absence of dystrophin. Standard therapies prolong survival; however, there is an increasing need for disease-modifying approaches and...
Duchenne muscular dystrophy (DMD) is a severe X-linked muscular disorder caused by the absence of dystrophin. Standard therapies prolong survival; however, there is an increasing need for disease-modifying approaches and sensitive evaluation tools. This review presents a summary of the recent advances in DMD therapeutic strategies and multidimensional evaluation approaches, emphasizing their clinical applicability and future perspectives. In this study, a comprehensive review of the current literature was conducted focusing on mutation-specific therapies (exon skipping and gene therapy), non-mutation-specific pharmacological interventions (steroids, vamorolone, and histone deacetylase inhibitors), and emerging modalities such as cell-based therapy. The clinical outcome measures used across the disease stages were also examined, ranging from functional motor tests and imaging biomarkers to digital endpoints and quality of life (QOL) indices. Exon skipping and microdystrophin gene therapies have shown promising results in restoring partial dystrophin expression. Vamorolones and givinostat are alternative drugs with improved safety profiles. Time-based motor tests (such as time to sand, 10 m run) and digital biomarkers (Stride Velocity 95th Centile) enable the earlier detection of disease progression. Natural history data, including large registry-based datasets, enhance the interpretation of clinical trials. Patient-reported outcomes and disease-specific QOL measures, such as the DMD-QoL, are increasingly being incorporated to assess meaningful treatment benefits. The therapeutic landscape of DMD is evolving toward combination and personalized approaches. Multidimensional stage-specific evaluations are essential to capture functional changes and their therapeutic effects. Ongoing research on gene-, pharmacological-, and cell-based therapies, coupled with robust outcome assessments, may further improve patient care and QOL.
An atypical case of macrocephaly and severe intellectual disability associated with a missense variant in the guanine nucleotide exchange factor-1 domain of TRIO.
Hiraide T, Hayashi T, Yamoto K … +5 more , Masunaga Y, Asahina M, Ogata T, Saitsu H, Fukuda T
Brain Dev · 2025 Oct · PMID 40712355 · Publisher ↗
BACKGROUND: Trio rho guanine nucleotide exchange factor (TRIO), encodes a guanine nucleotide exchange factor (GEF) that is critical for neurodevelopment and regulates Rho guanosine triphosphatase. It has been shown that...
BACKGROUND: Trio rho guanine nucleotide exchange factor (TRIO), encodes a guanine nucleotide exchange factor (GEF) that is critical for neurodevelopment and regulates Rho guanosine triphosphatase. It has been shown that missense variants in the GEF1 or GEF2 domains or loss-of-function variants in TRIO are associated with microcephaly while gain-of-function variants in the spectrin repeat domain result in macrocephaly. Rare cases of macrocephaly linked to missense variants in the GEF1 domain have been reported; however, clinical details remain limited. CASE PRESENTATION: We describe the case of a Japanese boy with macrocephaly, severe intellectual disability, distinctive facial features, scoliosis, and growth hormone deficiency. Brain magnetic resonance imaging revealed a thin corpus callosum and pituitary hypoplasia. His occipitofrontal circumference was +2.5 standard deviations above the normal range, while his height and weight were below the average. He displayed many features characteristic of TRIO-related neurodevelopmental disorders caused by gain-of-function variants. However, trio-based exome sequencing identified a de novo missense variant (instead of gain-of-function variant) in the GEF1 domain of TRIO (NM_007118.4:c.4104T>A, p.(Asp1368Glu)). CONCLUSIONS: This case expands the phenotypic spectrum of TRIO-related neurodevelopmental disorders, highlighting macrocephaly associated with a missense variant in the GEF1 domain. Further studies are required to clarify the functional effects of TRIO variants and their phenotypic consequences.
Clinical features and prognostic factors of group B Streptococcus Meningitis in infants.
Li W, Xia X, Zhang L … +3 more , Peng X, Jiang L, Hu Y
Brain Dev · 2025 Oct · PMID 40712354 · Publisher ↗
PURPOSE: To summarize the clinical features of group B streptococcus (GBS) meningitis in infants and identify the risk factors for poor prognosis. METHODS: The clinical data of 52 infants with GBS meningitis treated at C...
PURPOSE: To summarize the clinical features of group B streptococcus (GBS) meningitis in infants and identify the risk factors for poor prognosis. METHODS: The clinical data of 52 infants with GBS meningitis treated at Children's Hospital of Chongqing Medical University from January 2012 to December 2021 were retrospectively analyzed. RESULTS: A total of 48 infants (48/52, 92.3 %) presented with symptom onset at ≤90 days of age. Among 52 patients, the most prevalent clinical manifestations were fever (98.1 %), altered mental status (84.6 %) and decreased appetite (63.5 %). Subdural effusion (30/52, 57.7 %) was the most common neurological complication. One patient (1.9 %) died from cerebral herniation. Positive blood culture alone was observed in 41 cases (78.8 %), isolated cerebrospinal fluid (CSF) culture positivity in 5 (9.6 %), and dual blood-CSF culture positivity in 6 (11.5 %). The median hospital stay was 33 days. The most frequently administered antibiotic regimens were vancomycin combined with carbapenems (18/52, 34.6 %) and vancomycin plus third-generation cephalosporins (15/52, 28.8 %). Univariate analysis indicated an association between glucocorticoid use and clinical outcomes; however, multivariate analysis yielded no statistically significant variables (P < 0.05). CONCLUSIONS: GBS meningitis is most common in infants below 3 months. Both clinical manifestations and ancillary tests may be nonspecific, and definitive diagnosis relies on etiological confirmation. The risk of neurological complications is high.
Immune dysregulation in new-onset refractory status epilepticus (NORSE): current insights and therapeutic perspectives.
Hanin A, Hirsch LJ
Brain Dev · 2025 Oct · PMID 40712353 · Publisher ↗
OBJECTIVE: Emerging evidence suggests that cryptogenic new-onset refractory status epilepticus (c-NORSE) arises from innate immunity dysfunction leading to exacerbated inflammation. While immunotherapies have been admini...
OBJECTIVE: Emerging evidence suggests that cryptogenic new-onset refractory status epilepticus (c-NORSE) arises from innate immunity dysfunction leading to exacerbated inflammation. While immunotherapies have been administered, their efficacy remains variable and unpredictable. METHODS: We conducted a comprehensive literature review of studies reporting inflammation biomarkers in patients with NORSE or evaluating targeted immunotherapies. Additionally, we discussed future research directions and therapeutic perspectives. RESULTS: A total of 29 studies reporting inflammation biomarkers in at least five patients were analyzed. Most focused on c-NORSE, frequently describing cerebrospinal fluid pleocytosis, often lymphocytic and usually mild, upon admission. Elevated levels of innate immunity-related pro-inflammatory cytokines were consistently reported in c-NORSE. A large international study further demonstrated significantly higher cytokine levels in c-NORSE compared to other refractory status epilepticus patients, suggesting the importance of innate immunity in c-NORSE pathophysiology. One recent study identified subgroups with distinct inflammatory profiles among c-NORSE, suggesting different treatment approaches. More than 30 case series or reports have documented the use of targeted immunotherapies in NORSE. The most commonly used are anakinra (IL1 antagonist) and tocilizumab (IL6 antagonist), both showing seemingly comparable efficacy in seizure control. Recently, intrathecal dexamethasone has gained interest, particularly in pediatric cases, showing promising efficacy with no reported side effects. Other emerging approaches include canakinumab (anti-IL1 antibody), Janus kinase (JAK) inhibitors, and tumor necrosis factor alpha (TNFα) inhibitors. CONCLUSIONS: Recent studies have advanced our understanding of innate immunity disturbances in c-NORSE onset and progression. Moreover, they highlight patient heterogeneity, emphasizing the need for personalized strategies targeting specific inflammatory pathways.
Letter to the editor: 'Prevalence and management of gastrointestinal complications of Duchenne muscular dystrophy: A retrospective cohort study'.
Atamanalp SS
Brain Dev · 2025 Aug · PMID 40695139 · Publisher ↗
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Association between epilepsy and attention deficit/hyperactivity disorder - correlation between interictal epileptiform discharges and behavioral disturbances.
Kanemura H
Brain Dev · 2025 Aug · PMID 40684609 · Publisher ↗
A relationship between epileptic activities and neuropsychological dysfunction has been indicated in epileptic children. Epileptic activities including frequent/prolonged seizures and severe EEG abnormalities could be as...
A relationship between epileptic activities and neuropsychological dysfunction has been indicated in epileptic children. Epileptic activities including frequent/prolonged seizures and severe EEG abnormalities could be associated with cognitive decline and behavioral disturbances. Frequent, prolonged seizures could induce growth disturbances in the prefrontal cortex, leading to behavioral disturbance. Meanwhile, frequent epileptic seizures or EEG abnormalities, including interictal epileptiform discharges (IEDs), are evident in attention deficit/hyperactivity disorder (ADHD). Subclinical IEDs could lead to neuropsychological dysfunction in epileptic and ADHD children. The concurrence of IED frequency and prolonged periods of high-frequency IEDs may predict the atypical evolution of self-limited epilepsy with centrotemporal spikes. In developmental and epileptic encephalopathy with spike-wave activation during sleep, cognitive/behavioral disturbances correlate with frequent IEDs such as secondary bilateral synchrony (SBS). On the other hand, EEG manifestations, particularly IED locations, could represent important predictors of optimal outcome in epilepsy and ADHD. Abnormal paroxysms in the frontal region could lead to neuropsychological dysfunctions, so frontal IEDs could be associated with cognitive/behavioral disturbances in epilepsy and ADHD. Frontal IEDs could predict atypical clinical features including behavioral disturbance and ultimate neuropsychological outcomes in epileptic/ADHD children. Early remission of clinical seizures and reduction of IEDs might be necessary to accomplish optimal outcomes for children presenting with behavioral disturbances. A therapeutic strategy comprising prompt suppression of IEDs (including frontal IEDs/SBS) could improve quality of life in at least some children with epilepsy and ADHD.
Recognition of Japanese kanji words in children with specific learning disorders: a preliminary study using magnetoencephalography.
Egashira Y, Kaga Y, Gunji A … +10 more , Kita Y, Kimura M, Hironaga N, Takeichi H, Hayashi S, Kaneko Y, Takahashi H, Hanakawa T, Okada T, Inagaki M
Brain Dev · 2025 Aug · PMID 40684608 · Publisher ↗
INTRODUCTION: In Western countries, reading disorders are believed to be caused by phonological processing problems. Conversely, Japanese children with developmental dyslexia (DD) and developmental dysgraphia often have...
INTRODUCTION: In Western countries, reading disorders are believed to be caused by phonological processing problems. Conversely, Japanese children with developmental dyslexia (DD) and developmental dysgraphia often have difficulty learning kanji that are ideographic characters. It is believed that kanji learning and alphabet learning have different pathologies, as the latter uses phonetic character. In this study, we aimed to clarify the characteristics of kanji word recognition in Japanese children with DD and developmental dysgraphia using magnetoencephalography with high spatial resolution. METHODS: Seven Japanese children with learning disorders, including 4 with DD and 3 with developmental dysgraphia, and 14 typically developing Japanese children (TDC) underwent magnetoencephalography while presented with kanji compounds and pseudo-kanji character sequences in their parafoveal visual fields, along with a foveal silent movie. RESULTS: No differences were found between conditions or groups, except significantly smaller source activation in the posterior transverse region of the collateral sulcus (ptCoS) in the patient group, when presenting pseudo-kanji than presenting kanji, or than TDC when presenting deviant pseudo-kanji. The ptCoS activity from kanji exhibited a positive correlation with writing skills in the patient group, independently of attention deficit hyperactivity disorder (ADHD) symptom scores. CONCLUSIONS: These results suggest that ptCoS activity during the presentation of kanji characters in Japanese children with DD and developmental dysgraphia reflects their writing ability, regardless of ADHD symptoms. Some forms of ptCoS dysfunction may be related to the neural basis of specific kanji writing functions in Japanese patients with DD and developmental dysgraphia.
Natural history of timed rise from floor in young individuals with Duchenne muscular dystrophy: A single-center retrospective study.
Yoneno S, Takeshita E, Shimizu-Motohashi Y … +4 more , Oba M, Hara T, Hirayama M, Komaki H
Brain Dev · 2025 Aug · PMID 40680325 · Publisher ↗
INTRODUCTION: Motor function in patients with Duchenne muscular dystrophy (DMD) is commonly evaluated using the 6-min walk test, North Star Ambulatory Assessment, and timed function tests. However, few reports have exami...
INTRODUCTION: Motor function in patients with Duchenne muscular dystrophy (DMD) is commonly evaluated using the 6-min walk test, North Star Ambulatory Assessment, and timed function tests. However, few reports have examined the progression of timed rise from floor (TRF) in patients with DMD undergoing steroid therapy in Japan. We investigated the natural history of TRF in patients with DMD treated in Japan. METHODS: We retrospectively assessed TRF by age group based on data collected from October 2010 to August 2023. We used Kaplan-Meier curves to analyze the loss of the ability to rise from the floor. Additionally, receiver operating characteristic analysis was performed to predict the loss of the ability to stand up after 1 year. RESULTS: In total, 165 males with DMD were enrolled. The median TRF peaked at 6 years of age and deteriorated thereafter. The median age of the loss of the ability to rise from the floor was 11.9 years (95 % confidence interval = 10.6-13.2). Using a TRF cutoff of 6.2 s, the sensitivity, specificity, and area under the curve for predicting loss of the ability to rise from the floor in 1 year were 71 %, 90 %, and 0.914, respectively. CONCLUSION: This study provided insights into the deterioration of TRF in patients with DMD receiving steroid treatment in Japan. As a simple and easily measurable parameter, TRF is a useful tool for predicting the progression of motor function.
Valproate and lamotrigine combination therapy in children with drug-resistant focal epilepsy: an observational analysis focusing on neuroimaging abnormalities.
Watanabe S, Enokizono T, Nishimura M … +11 more , Maruo K, Iwasaki T, Tsunoda Y, Ueno Y, Tanaka M, Takada Y, Tanaka R, Araki K, Masuda Y, Ishikawa E, Takada H
Brain Dev · 2025 Aug · PMID 40651106 · Publisher ↗
OBJECTIVE: This study aimed to investigate the efficacy of valproate and lamotrigine (VPA-LTG) combination therapy in pediatric patients with drug-resistant focal epilepsy (DRFE), focusing on the presence of neuroimaging...
OBJECTIVE: This study aimed to investigate the efficacy of valproate and lamotrigine (VPA-LTG) combination therapy in pediatric patients with drug-resistant focal epilepsy (DRFE), focusing on the presence of neuroimaging abnormalities. METHODS: Pediatric patients with epilepsy who visited the University of Tsukuba Hospital and Ibaraki Children's Hospital between October 2021 and September 2024 were included in this retrospective chart review. Patients with DRFE who received VPA-LTG combination therapy were enrolled. RESULTS: Data from 21 patients, including 16 males and 5 females, in the age range of 1.8-13.9 years were examined. The median numbers of previously failed anti-seizure medications (ASMs) and concurrent ASMs were 4 (range: 2-7) and 3 (range: 2-5), respectively. The overall responder rate (defined as the percentage of patients achieving ≥50 % seizure reduction over the last 12 months) was 38 %. The responder rate in patients without MRI abnormalities (67 %) was significantly higher than that in patients with MRI abnormalities (16 %). Patients with MRI abnormalities had more structural etiologies (42 %), whereas those without MRI abnormalities had more unknown etiologies (89 %). CONCLUSION: Our findings suggest that VPA-LTG combination therapy is a promising option for pediatric patients with DRFE without neuroimaging abnormalities.
Characteristics of withdrawal seizures in children with refractory status epilepticus who responded favorably to continuous midazolam therapy.
Takeuchi H, Kikuchi K, Takeda R … +5 more , Hirata Y, Matsuura R, Koichihara R, Ueta I, Hamano SI
Brain Dev · 2025 Aug · PMID 40651105 · Publisher ↗
BACKGROUND: This study investigates the characteristics of children with refractory status epilepticus (RSE) who experienced withdrawal seizures and responded favorably to continuous midazolam (cMDL) therapy. METHODS: Pa...
BACKGROUND: This study investigates the characteristics of children with refractory status epilepticus (RSE) who experienced withdrawal seizures and responded favorably to continuous midazolam (cMDL) therapy. METHODS: Patients who experienced RSE and achieved seizure cessation with cMDL were included in the study. Withdrawal seizure was defined as a seizure occurring from the initiation of cMDL tapering until 48 h after the discontinuation of cMDL. The patients were categorized into two groups: seizure cessation and withdrawal seizure groups. RESULTS: Nineteen patients with RSE achieved seizure cessation with cMDL. The seizure cessation group comprised 11 patients, while eight patients (42.1 %) were classified into the withdrawal seizure group. The median maintenance dose of cMDL were 0.1 mg/kg/h (interquartile range [IQR]: 0.1-0.2) for the seizure cessation group, and 0.25 mg/kg/h (IQR: 0.15-0.3) for the withdrawal seizure group. The median maintenance periods were 27 h (IQR: 12-32.5) for the seizure cessation group, and 52.5 h (IQR: 23-65.5) for the withdrawal seizure group. The seizure cessation group had a median cumulative MDL of 2.7 mg/kg (IQR: 1.6-4.9), while the withdrawal seizure group had 11.6 mg/kg (IQR: 4.5-24.5). CONCLUSION: Although statistical analysis was not conducted due to the small sample size, maintenance dose of cMDL is potentially correlated with withdrawal seizure. A multi-center study with large sample size and statistical analysis of this relationship may contribute to the establishment of an optimized cMDL tapering protocol.
Unraveling the connections between migraine and psychiatric comorbidities: A narrative review.
Yum J, Chu MK
Brain Dev · 2025 Aug · PMID 40633196 · Publisher ↗
The close association between migraine and psychiatric comorbidities is well documented. Migraine frequently co-occurs with mood disorders, particularly depression and anxiety, exhibiting a bidirectional relationship acr...
The close association between migraine and psychiatric comorbidities is well documented. Migraine frequently co-occurs with mood disorders, particularly depression and anxiety, exhibiting a bidirectional relationship across various populations, including children and adolescents. Emerging research has also highlighted significant associations between migraine and bipolar disorder, autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD). Shared pathophysiological mechanisms, including genetic predisposition, neurotransmitter imbalances, hormonal influences, and environmental factors, contribute to these comorbidities. Diagnosing migraine in individuals with ASD and ADHD presents unique challenges due to overlapping symptoms and communication barriers. Furthermore, psychiatric medications may influence migraine symptoms, necessitating careful management. This review explores the relationship between migraine and psychiatric disorders, emphasizing shared mechanisms, diagnostic considerations, and treatment strategies to optimize patient care. This review highlights the necessity for integrated clinical approaches that address both migraine and psychiatric comorbidities, ultimately improving health outcomes for affected individuals.
Biallelic novel CCDC186 loss-of-function variant disrupting the gene function causes neurodevelopmental phenotype and review of the literature.
Gezdirici A, Turk SB, Esen TE … +6 more , Yavas C, Akbulut E, Yilmaz HI, Dagdelen ZO, Arican P, Dogan M
Brain Dev · 2025 Aug · PMID 40633195 · Publisher ↗
BACKGROUND: Coiled-coil domain-containing protein 186 (CCDC186) is essential for the transport of secretory dense-core vesicles (DCVs), specialized organelles responsible for storing and releasing neurotransmitters and o...
BACKGROUND: Coiled-coil domain-containing protein 186 (CCDC186) is essential for the transport of secretory dense-core vesicles (DCVs), specialized organelles responsible for storing and releasing neurotransmitters and other modulatory molecules in neurons and endocrine cells, thereby playing a crucial role in physiological processes such as synaptic plasticity, neurotransmission, and hormonal regulation. Resent reports have suggested that biallelic loss-of-function (LOF) variants in CCDC186 may be associated with neurodevelopmental disorders and a range of systemic manifestations. METHODS: Whole exome sequencing (WES) was performed, and co-segregation analysis of the family was conducted using sanger sequencing. Additionally, five patients with CCDC186-associated phenotypes previously described in the literature were evaluated. Followed by cDNA synthesis and quantitative reverse transcription polymerase chain reaction (qRT-PCR) to analyze gene expression levels. Bioinformatics tools, including RoseTTAFold for protein modeling and STRING for protein-protein interaction networks, were employed to assess the structural and functional consequences of the mutation. RESULTS: We identified a homozygous NM_018017.4:c.535C>T (p.Arg179Ter) nonsense variant in the CCDC186 gene. This variant was associated with a marked downregulation of CCDC186 expression in the proband, with moderate reductions observed in heterozygous family members, suggesting dysregulated gene expression resulting from the mutation. Protein modeling indicated structural alterations, including a shift from intrinsically disordered regions to helix-loop-helix motifs in the mutant protein, as well as reduced binding probabilities for most interacting partners. CONCLUSION: In this study, we presented the comprehensive clinical and genetic profiles of a Turkish child with a novel CCDC186 variant, along with five previously reported patients from the literature. Our findings support that the homozygous LOF variants of the CCDC186 gene are associated with a novel neurodevelopmental phenotype.
Relationship between cerebrospinal fluid cytokines/chemokines and clinical impact of myelin oligodendrocyte glycoprotein antibody-associated disorders in children.
Lee S, Kong J, Lyu S … +7 more , Nam SO, Lim TJ, Song JY, Yeon GM, Kim YM, Ko A, Lee YJ
Brain Dev · 2025 Aug · PMID 40614442 · Publisher ↗
BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) has been increasingly reported in children at the first presentation of an acquired central nervous system (CNS) demyelinating dis...
BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) has been increasingly reported in children at the first presentation of an acquired central nervous system (CNS) demyelinating disorder and can have a relapsing course. This study aimed to evaluate cerebrospinal fluid (CSF) cytokine/chemokine profiles in children with acute-phase inflammatory demyelinating disorders according to MOG-IgG positivity and/or recurrent relapses. METHODS: A total of 24 cytokines/chemokines were measured using multiplex immunoassay in the CSF of 85 children, who were divided into serum MOG-IgG positive (MOG-P, n = 28) [acute disseminated encephalomyelitis (n = 19), optic neuritis (n = 8), neuromyelitis optica spectrum disorder (n = 1)] group, MOG-negative (MOGN, n = 27) demyelinating disorder group, and control (n = 30) group. RESULTS: All four CSF B-cell related (APRIL, BAFF, BLC/CXCL13, and MIP-3β/CCL19), Treg-related (IL-10), and the majority of CSF Th17-related (IL-6, IL-17 A, IL-21, G-CSF/CSF-3, and GM-CSF) cytokines/chemokines were significantly elevated during the acute phase in the MOG-P group compared to the MOG-N group. The mean values of B-cell-related and Treg-related (IL-10) molecules, as well as the seropositivity rate for MOG-IgG, were significantly higher in the relapse group than in the non-relapse group. Furthermore, the levels of all B-cell- and Treg-related IL-10, along with two Th17-related cytokines (IL-6, and IL-17 A), were positively correlated with the MOG-IgG titers in children with MOGAD. CONCLUSION: Children with MOG-IgG positivity exhibit a pronounced CNS inflammatory response characterized by elevated levels of humoral immunity-associated cytokines/chemokines, and selected Th17-related molecules. CSF cytokine/chemokine profiles may aid in predicting relapse, monitoring inflammation and disease activity, and identifying novel therapeutic targets in pediatric MOGAD.
A dilemma in pediatric migraine: Headache or school performance? - A comparison of topiramate and flunarizine.
Akca Ü, Akca G, Karatekin Ş
Brain Dev · 2025 Aug · PMID 40614441 · Publisher ↗
BACKGROUND: Migraine prophylaxis reduces pain severity and duration in pediatric patients, improving school and social adaptation. Topiramate (TPM) and flunarizine (FLN) are effective monotherapies for migraine preventio...
BACKGROUND: Migraine prophylaxis reduces pain severity and duration in pediatric patients, improving school and social adaptation. Topiramate (TPM) and flunarizine (FLN) are effective monotherapies for migraine prevention. This study compares their efficacy in pain management and impact on school and social life. METHODS: This two-group comparative study (2018-2023) included pediatric patients (aged 9-18 years) diagnosed with episodic or chronic migraine based on International Classification of Headache Disorders, 3rd edition (ICHD-3 beta) criteria. Patients were assessed for demographic characteristics, pain duration, pain frequency, pain intensity using the Visual Analogue Scale (VAS), Pediatric Migraine Disability Assessment Scale (PedMIDAS) scores, side effects, and treatment attitudes at baseline and after three months of TPM or FLN treatment. RESULTS: Among 226 patients, TPM showed a greater reduction in pain frequency than FLN (9.0 vs. 7.5; p = 0.007). The percentage reduction in monthly pain frequency was higher with TPM (83.5 % vs. 70.7 %; p = 0.022). Side effects were significantly lower in the FLN group. TPM caused weight loss, paresthesia, speech/memory impairment, and appetite reduction, while FLN caused weight gain (p < 0.001). TPM was more effective in reducing pain frequency (relative risk [RR] = 0.118; 95 % confidence interval [CI] -0.946 to -0.681; p = 0.011), pain duration (RR = 0.858, 95 % CI -2.640 to -1.350; p < 0.001), and pain intensity (RR = 0.729, 95 % CI -1.849 to -0.539; p < 0.001). However, FLN was superior in PedMIDAS scores, particularly in school attendance and participation (p < 0.001). No patients withdrew, but some were reluctant to use TPM due to concerns about stigmatization. Notably, substantial placebo effects have been observed in pediatric migraine trials, and the current evidence for the efficacy of preventive medications in this population remains limited. CONCLUSION: TPM and FLN are effective migraine treatments. TPM is superior for pain reduction, while FLN has fewer side effects and benefits school attendance and participation. Weight changes and stigma should be considered when prescribing TPM.
Early hypoglycemia is not an independent risk factor for 2-year neurodevelopmental impairment in appropriate-for-gestational age preterm infants < 32 weeks.
Palazzo M, Bonanni M, Correani A … +6 more , Ferretti E, D'Ascenzo R, Biagetti C, Burattini I, Cogo P, Carnielli V
Brain Dev · 2025 Aug · PMID 40609275 · Publisher ↗
OBJECTIVE: To evaluate whether hypoglycemia within the first 6 h of life (HOL) is an independent risk factor for 2-year neurodevelopmental impairment in appropriate-for-gestational age (AGA) preterm infants with a gestat...
OBJECTIVE: To evaluate whether hypoglycemia within the first 6 h of life (HOL) is an independent risk factor for 2-year neurodevelopmental impairment in appropriate-for-gestational age (AGA) preterm infants with a gestational age (GA) <32 weeks/days. METHODS: We retrospectively analyzed data of 598 AGA preterm infants (GA: 24-31 weeks/days). Infants with at least one episode of hypoglycemia within the first 6 HOL (blood glucose concentration below 40 mg/dL; Glyc<40) were compared with infants without any hypoglycemia (Glyc≥40). Propensity score matching analysis was conducted for comparisons. Logistic regression analyses were used to evaluate the association of Glyc<40 with 2-year cognitive (COG) and motor (MOT) impairments defined as a Bayley-III score < 85. RESULTS: Of the 598 AGA preterm infants, 129 (21.6 %) were classified as Glyc<40, and 469 (78.4 %) as Glyc≥40. Time from birth to intravenous glucose infusion did not significantly differ between Glyc<40 and Glyc≥40. After multiple adjustments, Glyc<40 infants did not have a significantly higher risk of both 2-year COG (ExpB: 1.150, p = 0.656) and MOT (ExpB: 0.982, p = 0.834) impairment compared to Glyc≥40. No differences in 2-year neurodevelopmental scores were found between the 79 matched infant pairs. CONCLUSION: In a clinical setting with strict glycemic monitoring and standardized glucose management, early hypoglycemia (≤6 HOL) was not identified as an independent risk factor for 2-year COG and MOT impairment in AGA preterm infants with a GA between 24 and 31 weeks/days.
L-NAME improves the morphology and necrosis of skeletal muscle by activating PINK1-PARKIN mediated mitophagy in mdx mice.
Li J, Wu W, Ji G … +3 more , Dong H, Wu H, Song X
Brain Dev · 2025 Aug · PMID 40602311 · Publisher ↗
BACKGROUND: This study investigates mitophagy in Duchenne muscular dystrophy (DMD, OMIM #310200), focusing on how nitric oxide synthase (NOS) inhibition improves muscle tissue pathology by affecting mitophagy, which is i...
BACKGROUND: This study investigates mitophagy in Duchenne muscular dystrophy (DMD, OMIM #310200), focusing on how nitric oxide synthase (NOS) inhibition improves muscle tissue pathology by affecting mitophagy, which is implicated in muscle weakness due to dystrophin deficiency and may affect DMD-related cardiomyopathy and respiratory problems. METHODS: Histopathological analysis, immunofluorescence staining, Western blot were used to study the mitophagy status of the tibialis anterior muscle in mdx mice without treatment or mdx mice administered L-NAME (L-N-nitro arginine methylester), an inhibitor of NOS. For in vitro experiment, the effect of S-nitrosylation enzyme, N6022, on mitophagy in C2C12 cells was assessed using TEM (transmission electron microscopy), and Western blot. RESULTS: Mdx mice showed dystrophic muscle pathology and elevated LC3 (microtubule-mssociated protein 1 light chain) and VDAC (voltage-dependent anion channel) expression, indicating increased mitophagy. Reduced PINK1 (PTEN-induced putative kinase 1) and PARKIN (E3 ubiquitin ligase PARK2) levels suggested incomplete mitochondrial clearance. L-NAME treatment improved muscle morphology and reduced necrosis, partially restoring mitophagy by increasing LC3 without matching VDAC upregulation. However, PINK1 and PARKIN were further reduced, suggesting mitophagic inefficiency. In C2C12 cells, GSNOR(S-nitrosoglutathione reductase) inhibition via N6022 elevated nitrosylation, impaired mitophagy, and caused mitochondrial accumulation with increased PINK1 but unchanged PARKIN, highlighting a critical role of nitrosylation balance in mitophagy regulation. CONCLUSIONS: NOS inhibition may serve as a key point for further research on the progression of DMD disease and as a potential therapeutic target for this incurable disease.
National study on pediatric acute encephalopathy in Japan (April 2020 to October 2023): Insights from the third study.
Omata T, Sakuma H, Nagase H … +9 more , Abe Y, Kuki I, Okumura A, Maegaki Y, Murayama K, Sakai Y, Hoshino A, Mizuguchi M, Takanashi JI
Brain Dev · 2025 Aug · PMID 40570505 · Publisher ↗
BACKGROUND: Previous national studies of acute encephalopathy in Japan were conducted in 2007-2010 and 2014-2017. In this third study (April 1, 2020-October 31, 2023), spanning the coronavirus disease 2019 (COVID-19) out...
BACKGROUND: Previous national studies of acute encephalopathy in Japan were conducted in 2007-2010 and 2014-2017. In this third study (April 1, 2020-October 31, 2023), spanning the coronavirus disease 2019 (COVID-19) outbreak, we compared results to assess trends in pediatric viral infections and therapeutic practices. METHODS: Questionnaires were sent to 430 hospitals of the Japanese Pediatric Society, yielding 241 responses and 1197 cases. A secondary survey to 151 facilities received 110 responses (72.8 %), identifying 622 eligible patients (604 for treatment, 544 for outcome analysis). Data on patient background, syndrome classification, causative virus, treatment, and prognosis were collected. RESULTS: Among 622 cases (54.6 % boys), the highest incidence was in 1-year-olds, with case numbers peaking during COVID-19 and influenza outbreaks. The frequency of clinical syndromes was: acute encephalopathy with biphasic seizures and late reduced diffusion, 35.1 %; clinically mild encephalitis/encephalopathy with a reversible splenial lesion, 17.8 %; hemorrhagic shock and encephalopathy syndrome (HSES), 6.9 %; acute encephalitis with refractory, repetitive partial seizures, 3.7 %; acute fulminant cerebral edema (AFCE), 2.2 %; acute necrotizing encephalopathy, 1.6 %; and unclassifiable, 31.4 %. Notably, the combined HSES/AFCE rate increased from 1.9 % in the 2014-2017 survey to 9.1 %, likely due to enhanced diagnosis and COVID-19 impact. Pathogens were exanthem subitum (16.1 %), severe acute respiratory syndrome coronavirus 2 (15.9 %), and influenza (7.7 %). Treatments included steroid pulse therapy (68.9 %), mitochondrial cocktails (42.5 %), and targeted temperature management (31.0 %). CONCLUSION: This study provides a comprehensive overview of pediatric acute encephalopathy during COVID-19 outbreaks, shows increases in the incidence of HSES/AFCE, and presents current treatment.
Hematopoietic stem cell gene therapy of neurometabolic lysosomal storage diseases.
Consiglieri G, Tucci F, Bernardo ME
Brain Dev · 2025 Aug · PMID 40570504 · Full text
Neurometabolic disorders are rare, inherited monogenic diseases arising from mutations in genes whose products are essential for brain functions and cause local accumulation of toxic substrates. Central nervous system in...
Neurometabolic disorders are rare, inherited monogenic diseases arising from mutations in genes whose products are essential for brain functions and cause local accumulation of toxic substrates. Central nervous system involvement can be severe, is progressive and frequently appears early in life. Current treatment options for neurometabolic disorders are represented mainly by enzyme replacement therapy (ERT) and allogeneic hematopoietic stem cell transplantation (HSCT) which do not sufficiently address clinical manifestations and leave patients with a substantial residual disease burden. Given this unmet medical need, alternative strategies based on genetic manipulation of patient's cells have been developed. Hematopoietic stem progenitor cells-gene therapy (HSPC-GT) entails the harvest autologous HSPCs which are ex-vivo manipulated by means of viral vectors to express the therapeutic gene and infused back into the patient after chemotherapy-based preparation. Modified HSPCs engraft and differentiate into the various hematopoietic cell lineages, producing the functional enzyme at either normal or supranormal levels. The number of clinical trials with HSPC-GT in neurometabolic disorders is rapidly increasing and some HSPC-GT products have recently received market approval. This review focuses on HSPC-GT strategies summarizing the most recent developments in the field of neurometabolic disorders.
Tuberous sclerosis complex: Clinical, genetic and 7T-MRI neuroimaging findings.
Campanario da Silva Pereira C, Gomes Dantas FD, da Rosa Baratela WA … +3 more , Antunes da Costa F, Tavares Lucato L, Kok F
Brain Dev · 2025 Aug · PMID 40554861 · Publisher ↗
BACKGROUND: Tuberous sclerosis complex (TSC) is a multisystemic disorder caused by monoallelic pathogenic variants in TSC1 or TSC2 genes. Neuropathological hallmark is the presence of cortical and subcortical tubers, amo...
BACKGROUND: Tuberous sclerosis complex (TSC) is a multisystemic disorder caused by monoallelic pathogenic variants in TSC1 or TSC2 genes. Neuropathological hallmark is the presence of cortical and subcortical tubers, among others. Epilepsy affects up to 85 %. AIMS: The objective was to correlate the number and location of tubers with neuropsychological and genetic characteristics in three groups of TSC patients: with active epilepsy, controlled epilepsy and without epilepsy. METHODS: Brain 7T-MRI study was performed in 30 subjects with TSC who had previously done brain conventional MRI. Molecular analysis of TSC1 and TSC2 was conducted post-enrollment. Data on epilepsy characteristics, neuropsychological performance and regional and total tuber counts as seen on 7T-MRI, were collected. RESULTS: Tuber counting in the frontal lobe was significantly higher in the group with active epilepsy compared to the groups with controlled or without epilepsy (p = 0.008). Total and frontal tuber count were significantly higher in individuals with TSC2 variants. Total, verbal and executive intelligence quotient (IQ) scores were significantly higher in the group without epilepsy compared to the controlled epilepsy group. Attention deficit/hyperactivity disorder (ADHD) was less frequent in the group without epilepsy. CONCLUSION: Severity of epilepsy in TSC correlates with the number of tubers, especially in the frontal lobe, and with the TSC2 deleterious variant. Future studies involving a larger number of patients may provide new insights into advanced imaging epilepsy biomarkers.
Hand-arm bimanual intensive therapy versus modified constraint-induced movement therapy in children with hemiparetic cerebral palsy: A randomized controlled trial.
Panda PK, Sharawat IK, Gupta D … +5 more , Palayullakandi A, Kumaran SS, Sherwani P, Sopanam S, Neyaz O
Brain Dev · 2025 Aug · PMID 40554137 · Publisher ↗
INTRODUCTION: Modified Constraint-Induced Movement Therapy (mCIMT) and Hand-Arm Bimanual Intensive Therapy (HABIT) are widely used for treating hemiparetic cerebral palsy (CP). Prior randomized controlled trials (RCTs) c...
INTRODUCTION: Modified Constraint-Induced Movement Therapy (mCIMT) and Hand-Arm Bimanual Intensive Therapy (HABIT) are widely used for treating hemiparetic cerebral palsy (CP). Prior randomized controlled trials (RCTs) comparing these approaches yielded mixed outcomes. METHODS: This RCT evaluated the efficacy of 12 weeks of mCIMT versus HABIT in children aged 5-18 years with hemiparetic CP. Primary objective was to compare improvements in upper limb function (quality of upper extremity skills test [QUEST] total score) in both groups. Secondary objectives were to compare speed of upper limb movements (nine-hole peg board test), muscle strength (thumb strength and hand grip strength), quality of life (CPQoL), compliance to advised therapy in both groups, sustenance of improvement 4 weeks after stopping supervised treatment, and to describe and compare diffusion tensor imaging (DTI) and resting functional magnetic resonance imaging (fMRI) changes. Both groups received 2-h supervised sessions, 8 sessions over 4 weeks, followed by weekly sessions for 8 more weeks. Participants practiced 2 h daily at home, monitored by activity logs and videos when feasible. RESULTS: Each group had 30 participants. Changes in QUEST total scores after 12 weeks were comparable between HABIT and mCIMT (12.00 ± 7.52 vs. 11.35 ± 7.10, p = 0.48). Individual QUEST domain scores, nine-hole peg test times, thumb and grip strength, and CPQoL improvements were also similar between groups (p>0.05 for all). Both groups showed significant improvements across all outcomes at 12 weeks (p<0.05), maintained at 16 weeks. DTI revealed comparable changes in apparent diffusion co-efficient and fractional anisotropy values in the contralateral corticospinal tract (p = 0.63 and 0.71, respectively). fMRI showed increased activation in the contralateral sensorimotor cortex in both groups at 12 weeks. CONCLUSION: HABIT and mCIMT demonstrate similar efficacy for upper limb function improvement in children with hemiparetic CP.
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