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Abstract Objective Self‐limited infantile epilepsy (SeLIE) has distinctive clinical features, and the PRRT2 gene is known to be a considerable genetic cause. There have been a few studies on PRRT2‐positive SeLIE only, and anti‐seizure medications are often required due to frequent seizures at initial seizure onset. This study aimed to provide clinical information for the early recognition of patients with PRRT2‐positive SeLIE and to propose effective anti‐seizure medications for seizure control. Methods We retrospectively reviewed 36 patients diagnosed with SeLIE with genetically confirmed pathogenic variants of PRRT2. In addition, six atypical cases with neonatal‐onset seizures and unremitting after 3 years of age were included to understand the expanded clinical spectrum of PRRT2‐related epilepsy. We analyzed the initial presentation, clinical course, and seizure control response to anti‐seizure medications. Results Patients with PRRT2‐related epilepsy had characteristic seizure semiology at the initial presentation, including all afebrile, clustered (n = 23, 63.9%), short‐duration (n = 33, 91.7%), and bilateral tonic–clonic seizures (n = 26, 72.2%). Genetic analysis revealed that c. 649dupC was the most common variant, and six patients had a 16p11.2 microdeletion containing the PRRT2 gene. One‐third of the patients were sporadic cases without a family history of epilepsy or paroxysmal movement disorders. In the 33 patients treated with anti‐seizure medications, sodium channel blockers, such as carbamazepine, were the most effective in seizure control. Significance Our results delineated the clinical characteristics of PRRT2‐positive SeLIE, differentiating it from other genetic infantile epilepsies and discovered the effective anti‐seizure medications for initial clustered seizure control. If afebrile bilateral tonic–clonic seizures develop in a normally developed infant as a clustered pattern, PRRT2‐positive SeLIE should be considered as a possible diagnosis, and sodium channel blockers should be administered as the first medication for seizure control.

IntroductionNusinersen is the first drug approved for spinal muscular atrophy (SMA) treatment. In this study, we aimed to evaluate the long-term safety and efficacy of nusinersen, assess the therapeutic effects based on the treatment initiation timing and baseline motor function, and explore the perception of functional improvement from either parents or patients, utilizing 3-year nationwide follow-up data in South Korea.MethodsWe enrolled patients with SMA who were treated with nusinersen under the National Health Insurance coverage, with complete motor score records available and a minimum treatment duration of 6 months. To evaluate the motor function of patients, the Hammersmith Infant Neurological Examination-2 (HINE-2) was used for type 1 and the Expanded Hammersmith Functional Motor Scale (HFMSE) was used for types 2 and 3 patients. A significant improvement was defined as a HINE-2 score gain ≥5 for patients with type 1 and an HFMSE score ≥ 3 for patients with types 2 and 3 SMA. Effects of treatment timing were assessed. Patients with type 2 were further categorized based on baseline motor scores for outcome analysis. We also analyzed a second dataset from five tertiary hospitals with the information on parents/patients-reported impressions of improvement.ResultsThe study comprised 137 patients, with 21, 103, and 13 patients representing type 1, 2, and 3 SMA, respectively. At the 3-year follow-up, the analysis encompassed 7 patients with type 1, 12 patients with type 2, and none with type 3. Nearly half of all enrolled patients across SMA types (42.8, 59.2 and 46.2%, respectively) reached the 2-year follow-up for analysis. Patients with type 1 SMA exhibited gradual motor function improvement over 1-, 2-, and 3-year follow-ups (16, 9, and 7 patients, respectively). Patients with type 2 SMA demonstrated improvement over 1-, 2-, and 3-year follow-ups (96, 61 and 12 patients, respectively). Early treatment from symptom onset resulted in better outcomes for patients with type 1 and 2 SMA. In the second dataset, 90.7% of 108 patients reported subjective improvement at the 1-year follow-up.ConclusionNusinersen treatment for types 1–3 SMA is safe and effective in long-term follow-up. Early treatment initiation was a significant factor affecting long-term motor outcome.

Herein, we describe the case of a 43-month-old girl who presented with clinical manifestations of dyskinetic cerebral palsy (CP), classified as the Gross Motor Function Classification System (GMFCS) V. The patient had no family history of neurological or perinatal disorders. Despite early rehabilitation, serial assessments using the Gross Motor Function Measure (GMFM) showed no significant improvements in gross motor function. Brain magnetic resonance imaging showed nonspecific findings that could not account for developmental delay or dystonia. Whole-genome sequencing identified a heterozygous NM_002074.5(GNB1):c.239T>C (p.Ile80Thr) mutation in guanine nucleotide-binding protein beta 1 (GNB1) gene. Considering this case and previous studies, genetic testing for the etiology of dyskinetic CP is recommended for children without relevant or with nonspecific brain lesions.

Purpose Frontal lobe epilepsy (FLE) has various clinical presentations depending on the anatomy involved. Seizures are brief and can mimic psychiatric conditions, and patients often cannot describe the aura. Therefore, it is difficult to characterize the semiology, especially in pediatric patients. This study investigated the characteristics of pediatric FLE. Methods We retrospectively reviewed the data of pediatric patients with FLE who underwent long-term video-electroencephalography (EEG) monitoring between January 2010 and June 2020. Patients’ demographic data, seizure-related clinical presentations, semiology, brain magnetic resonance imaging (MRI), and EEG data were analyzed. Results Fifty-six patients were included (31 males, 25 females). The age of seizure onset varied from 1 month to 14 years (mean±standard deviation, 6.1±4.4 years). Seizures were classified into nine categories, including focal tonic (30/56), aura (22/56), hypermotor (17/56), focal clonic (15/56), versive (13/56), and bilateral asymmetric tonic (4/56). Seventeen patients (30.4%) had abnormal MRI results, including focal cortical dysplasia, heterotopic gray matter, and neuroepithelial tumors. Ictal EEG changes were commonly observed in the dorsolateral premotor and central cortices. In focal tonic seizures, EEG changes often originated in the premotor cortex. The location of the lesions on MRI and EEG coincided in six cases. Conclusion In pediatric FLE, various seizure types occur depending on the ictal anatomic origin, and individual patients had multiple semiologies. Brain MRI was normal in two-thirds of patients, and interictal EEG did not reveal epileptiform discharges in approximately 25%. Semiology reported on the basis of home videos and interictal EEG will help localize the ictal onset zone.

Abstract The neural circuits of the infant brain are rapidly established near 6 months of age, but neurodevelopmental disorders can be diagnosed only at the age of 2–3 years using existing diagnostic methods. Early diagnosis is very important to alleviate life-long disability in patients through appropriate early intervention, and it is imperative to develop new diagnostic methods for early detection of neurodevelopmental disorders. We examined the serum level of secretogranin II (SCG2) in pediatric patients to evaluate its potential role as a biomarker for neurodevelopmental disorders. A plasmonic immunosensor performing an enzyme-linked immunosorbent assay (ELISA) on a gold nanodot array was developed to detect SCG2 in small volumes of serum. This nanoplasmonic immunosensor combined with tyramide signal amplification was highly sensitive to detect SCG2 in only 5 μL serum samples. The analysis using the nanoplasmonic immunosensor revealed higher serum SCG2 levels in pediatric patients with developmental delay than in the control group. Overexpression or knockdown of SCG2 in hippocampal neurons significantly attenuated dendritic arborization and synaptic formation. These results suggest that dysregulated SCG2 expression impairs neural development. In conclusion, we developed a highly sensitive nanoplasmonic immunosensor to detect serum SCG2, a candidate biomarker for the early diagnosis of neurodevelopmental disorders.

Purpose High-resolution vessel wall-magnetic resonance imaging (VW-MRI) has been used to detect regional vessel wall pathology, significantly contributing to the diagnosis of primary angiitis of the central nervous system (PACNS) from other arteriopathies. In this study, we aimed to describe three cases of PACNS initially presenting as acute ischemic stroke, diagnosed and followed up with VW-MRI. Methods The medical records of three patients diagnosed with PACNS were retrospectively reviewed. We also reviewed the clinical application of VW-MRI in published articles for the pediatric cases since 2016. Results The initial presenting symptoms were headache, diplopia, confused mentality, hemiplegia, dysarthria, and dizziness. All patients had acute infarction on brain MRI, with suspicion of vasculopathy on magnetic resonance angiography. VW-MRI revealed narrowing of vessels with concentric wall thickening and diffuse enhancement in the anterior cerebral artery (n=1), middle cerebral artery (n=1), posterior cerebral artery (n=2), lenticulostriate artery (n=1), anterior inferior cerebellar artery (n=1), and vertebral artery (n=1), suggestive of vascular wall pathology. After excluding the possible etiologies of vasculitis, the clinical diagnosis of PACNS was established. Three patients received high-dose steroid and cyclophosphamide therapy. Two patients were treated with long-term azathioprine based upon the findings of persistent vessel enhancement on VW-MRI. All patients were regularly followed up with VW-MRI for more than 1 year. We summarized the clinical and radiological features of the published pediatric cases using VW-MRI to date. Conclusion High-resolution VW-MRI plays an important role in diagnosing childhood PACNS, as results correlate with disease activity.

Purpose Hypothalamic hamartoma (HH), a rare congenital disorder, can cause intractable epilepsy and requires optimal surgical treatment. This study analyzed the clinical characteristics of HH and evaluated seizure outcomes and the safety of gamma-knife radiosurgery (GKS) in HH-related epilepsy to propose an optimal surgical treatment. Methods We reviewed the medical records of 18 patients with HH treated at Samsung Medical Center (1997 to 2018), and analyzed their presenting symptoms, brain magnetic resonance imaging (MRI) findings, treatment, and response. Results The median diagnostic age was 3.2 years. The first presenting symptom was a seizure in six (33.3%), precocious puberty in five (27.8%), both symptoms in six (33.3%), and no symptoms in one patient who was diagnosed incidentally on brain MRI. All mixed and intrahypothalamic types except one had seizures (n=12), while all five parahypothalamic types presented only precocious puberty. Eleven patients showed intractable epilepsy with medications and underwent surgical treatment (most commonly GKS). Eight patients underwent GKS, and two of them received repeated GKS for recurrent seizures. Six patients showed improved seizure control with GKS as the last treatment. Among them, two patients became seizure-free, and one patient had a decreased frequency of seizures after a single GKS. There was no adverse effect related to GKS. Conclusion Intractable epilepsy was the most common indication for surgical treatment of pediatric HH. GKS was effective in controlling seizures in 75% of HH patients without any adverse effects. Repeated GKS could also be considered as a safe option for intractable and disabling seizures.

Abstract SMA type 1 is the most severe type, characterized by early onset at

The membrane-bound O-acyltransferase domain-containing 7 (MBOAT7) gene is associated with intellectual disability, early onset seizures, and autism spectrum disorders. This study aimed to determine the pathogenetic mechanism of the MBOAT7 missense variant via molecular modeling. Three patients from a consanguineous family were found to have a homozygous c.757G>A (p.Glu253Lys) variant of MBOAT7. The patients showed prominent dysfunction in gait, swallowing, vocalization, and fine motor function and had intellectual disabilities. Brain magnetic resonance imaging showed signal changes in the bilateral globus pallidi and cerebellar dentate nucleus, which differed with age. In the molecular model of human MBOAT7, Glu253 in the wild-type protein is located close to the backbone carbonyl oxygens in the loop near the helix, suggesting that the ionic interaction could contribute to the conformational stability of the funnel. Molecular modeling showed that Lys253 in the mutant protein was expected to alter the surface charge distribution, thereby potentially affecting substrate specificity. Changes in conformational stability and substrate specificity through varied ionic interactions are the suggested pathophysiological mechanisms of the MBOAT7 variant found in patients with intellectual disabilities.

Background Most developmental screening tools in Korea are adopted from foreign tests. To ensure efficient screening of infants and children in Korea, a nationwide screening tool with high reliability and validity is needed. Purpose This study aimed to independently develop, standardize, and validate the Korean Developmental Screening Test for Infants and Children (K-DST) for screening infants and children for neurodevelopmental disorders in Korea. Methods The standardization and validation conducted in 2012–2014 of 3,284 subjects (4–71 months of age) resulted in the first edition of the K-DST. The restandardization and revalidation performed in 2015–2016 of 3.06 million attendees of the National Health Screening Program for Infants and Children resulted in the revised K-DST. We analyzed inter-item consistency and test-retest reliability for the reliability analysis. Regarding the validation of K-DST, we examined the construct validity, sensitivity and specificity, receiver operating characteristic curve analysis, and a criterion-related validity analysis. Results We ultimately selected 8 questions in 6 developmental domains. For most age groups and each domain, internal consistency was 0.73–0.93 and test-retest reliability was 0.77–0.88. The revised K-DST had high discriminatory ability with a sensitivity of 0.833 and specificity of 0.979. The test supported construct validity by distinguishing between normal and neurodevelopmentally delayed groups. The language and cognition domain of the revised K-DST was highly correlated with the K-Bayley Scales of Infant Development-II’s Mental Age Quotient (r=0.766, 0.739), while the gross and fine motor domains were highly correlated with Motor Age Quotient (r=0.695, 0.668), respectively. The Verbal Intelligence Quotient of Korean Wechsler Preschool and Primary Scales of Intelligence was highly correlated with the K-DST cognition and language domains (r=0.701, 0.770), as was the performance intelligence quotient with the fine motor domain (r=0.700). Conclusion The K-DST is reliable and valid, suggesting its good potential as an effective screening tool for infants and children with neurodevelopmental disorders in Korea.

Purpose Spinal muscular atrophy (SMA) is a genetic progressive neuromuscular disorder, and nusinersen has shown to improve its symptoms. Scoliosis is a frequent symptom in patients with SMA and complicates the intrathecal injection of nusinersen. The aim of this study was to investigate the safety and effectiveness of fluoroscopy-guided intrathecal injections in patients with SMA with severe scoliosis. Methods We retrospectively reviewed the medical records of 11 patients with SMA treated with nusinersen intrathecal injections at the Samsung Medical Center from 2018 to 2020. We assessed the type of SMA, genetic results, spine computed tomography or fluoroscopy findings, and adverse effects associated with the injection. Results Of 11 patients with SMA, six were diagnosed with severe scoliosis, four of whom underwent an operation for scoliosis. The six patients with severe scoliosis started receiving the nusinersen injection at a median age of 15.7 years. A total of 25 injections were completely performed with the interlaminar approach (ILA) at the lumbar level under C-arm fluoroscopy guidance. No adverse effects other than mild headache occurred. In one patient who underwent the complete fusion operation for scoliosis, laminectomy was performed for the nusinersen injection, and 3 doses were administered intrathecally via the interlaminar route at the lumbar level. Conclusion Fluoroscopy-guided ILA is a safe method for the intrathecal injection of nusinersen in patients with SMA with severe scoliosis. When defining the route, laminectomy might be necessary to open the window for the ILA route at the lumbar level.

Myostatin is a member of the transforming growth factor-beta superfamily and is an endogenous negative regulator of muscle growth. This study aimed to determine whether an oral administration of Lactobacillus casei expressing modified human myostatin (BLS-M22) could elicit sufficient levels of myostatin-specific antibody and improve the dystrophic features of an animal model of Duchenne muscular dystrophy (DMD; mdx mouse). BLS-M22 is a recombinant L. casei engineered to harbor the pKV vector and poly-gamma-glutamic acid gene linked to a modified human myostatin gene. Serological analysis showed that anti-myostatin IgG titers were significantly increased, and serum creatine kinase was significantly reduced in the BLS-M22-treated mdx mice compared to the control mice. In addition, treatment of BLS-M22 resulted in a significant increase in body weight and motor function (Rotarod behavior test). Histological analysis showed an improvement in the dystrophic features (fibrosis and muscle hypertrophy) of the mdx mice with the administration of BLS-M22. The circulating antibodies generated after BLS-M22 oral administration successfully lowered serum myostatin concentration. Myostatin blockade resulted in serological, histological, and functional improvements in mdx mice. Overall, the findings suggest the potential of BLS-M22 to treat DMD; however, further clinical trials are essential to ascertain its efficacy and safety in humans.

Microcephaly is a prevalent phenotype in patients with neurodevelopmental problems, often with genetic causes. We comprehensively investigated the clinical phenotypes and genetic background of microcephaly in 40 Korean patients. We analyzed their clinical phenotypes and radiologic images and conducted whole exome sequencing (WES) and analysis of copy number variation (CNV). Infantile hypotonia and developmental delay were present in all patients. Thirty-four patients (85%) showed primary microcephaly. The diagnostic yield from the WES and CNV analyses was 47.5%. With WES, we detected pathogenic or likely pathogenic variants that were previously associated with microcephaly in 12 patients (30%); nine of these were de novo variants with autosomal dominant inheritance. Two unrelated patients had mutations in the KMT2A gene. In 10 other patients, we found mutations in the GNB1, GNAO1, TCF4, ASXL1, SMC1A, VPS13B, ACTG1, EP300, and KMT2D genes. Seven patients (17.5%) were diagnosed with pathogenic CNVs. Korean patients with microcephaly show a genetic spectrum that is different from that of patients with microcephaly of other ethnicities. WES along with CNV analysis represents an effective approach for diagnosis of the underlying causes of microcephaly.

Lennox-Gastaut syndrome (LGS) is a severe type of childhood-onset epilepsy characterized by multiple types of seizures, specific discharges on electroencephalography, and intellectual disability. Most patients with LGS do not respond well to drug treatment and show poor long-term prognosis. Approximately 30% of patients without brain abnormalities have unidentifiable causes. Therefore, accurate diagnosis and treatment of LGS remain challenging. To identify causative mutations of LGS, we analyzed the whole-exome sequencing data of 17 unrelated Korean families, including patients with LGS and LGS-like epilepsy without brain abnormalities, using the Genome Analysis Toolkit. We identified 14 mutations in 14 genes as causes of LGS or LGS-like epilepsy. 64 percent of the identified genes were reported as LGS or epilepsy-related genes. Many of these variations were novel and considered as pathogenic or likely pathogenic. Network analysis was performed to classify the identified genes into two network clusters: neuronal signal transmission or neuronal development. Additionally, knockdown of two candidate genes with insufficient evidence of neuronal functions, SLC25A39 and TBC1D8, decreased neurite outgrowth and the expression level of MAP2, a neuronal marker. These results expand the spectrum of genetic variations and may aid the diagnosis and management of individuals with LGS.

Abstract Background Genetic testing is an emerging diagnostic approach in early‐onset epilepsy. Identification of the heterogeneous genetic causes of epilepsy may mitigate unnecessary evaluations and allow more accurate diagnosis and therapy. We aimed to uncover genetic causes of early‐onset epilepsy using next‐generation sequencing (NGS) to elucidate the diagnostic candidates and evaluate the diagnostic yield of targeted gene panel testing. Methods We evaluated 116 patients with early‐onset epilepsy developed before 2 years old and normal brain imaging using a NGS‐based targeted gene panel. Variants were classified according to their pathogenicity, and the diagnostic yield of the targeted genes and associated clinical factors were determined. Results We detected 40 disease‐causing variants with diagnostic yield of 34.5% (19 pathogenic, 21 likely pathogenic). Twelve variants were novel. The most commonly detected genes were SCN1A, associated with Dravet syndrome, and PRRT2, associated with benign familial infantile epilepsy. Other variants were identified in ARX, SCN2A, KCNQ2, PCDH19, STXBP1, DEPDC5, and SCN8A. The age of seizure onset and family history were associated with disease‐causing variants. Conclusion Next‐generation sequencing‐based targeted testing is an effective diagnostic test, with 30%–40% comparable diagnostic yield. Patients with earlier seizure onset and family history of epilepsy were the best candidates for testing. For pediatric patients with early‐onset epilepsy, genetic diagnosis is important for accurate prognosis and treatment.

The aim of this study was to evaluate the therapeutic effects and mechanisms of Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) in an animal model of Duchenne muscular dystrophy (DMD). Mdx mice (3–5 months old) were administered five different doses of WJ-MSCs through their tail veins. A week after injection, grip strength measurements, creatine kinase (CK) assays, immunohistochemistry, and western blots were performed for comparison between healthy mice, mdx control mice, and WJ-MSC-injected mdx mice. WJ-MSCs exerted dose-dependent multisystem therapeutic effects in mdx mice, by decreasing CK, recovering normal behavior, regenerating muscle, and reducing apoptosis and fibrosis in skeletal muscle. We also confirmed that miR-499-5p is significantly downregulated in mdx mice, and that intravenous injection of WJ-MSCs enhanced its expression, leading to anti-fibrotic effects via targeting TGFβR 1 and 3. Thus, WJ-MSCs may represent novel allogeneic “off-the-shelf” cellular products for the treatment of DMD and possibly other muscle disorders.

Malformations of cortical development are rare congenital anomalies of the cerebral cortex, wherein patients present with intractable epilepsy and various degrees of developmental delay. Cases show a spectrum of anomalous cortical formations with diverse anatomic and morphological abnormalities, a variety of genetic causes, and different clinical presentations. Brain magnetic resonance imaging has been of great help in determining the exact morphologies of cortical malformations. The hypothetical mechanisms of malformation include interruptions during the formation of cerebral cortex in the form of viral infection, genetic causes, and vascular events. Recent remarkable developments in genetic analysis methods have improved our understanding of these pathological mechanisms. The present review will discuss normal cortical development, the current proposed malformation classifications, and the diagnostic approach for malformations of cortical development.

Extracellular matrix (ECM) components play an important role in maintaining skeletal muscle function, but excessive accumulation of ECM components interferes with skeletal muscle regeneration after injury, eventually inducing fibrosis. Increased oxidative stress level caused by dystrophin deficiency is a key factor in fibrosis in Duchenne muscular dystrophy (DMD) patients. Mesenchymal stem cells (MSCs) are considered a promising therapeutic agent for various diseases involving fibrosis. In particular, the paracrine factors secreted by MSCs play an important role in the therapeutic effects of MSCs. In this study, we investigated the effects of MSCs on skeletal muscle fibrosis. In 2–5-month-old mdx mice intravenously injected with 1 × 105 Wharton’s jelly (WJ)-derived MSCs (WJ-MSCs), fibrosis intensity and accumulation of calcium/necrotic fibers were significantly decreased. To elucidate the mechanism of this effect, we verified the effect of WJ-MSCs in a hydrogen peroxide-induced fibrosis myotubes model. In addition, we demonstrated that matrix metalloproteinase-1 (MMP-1), a paracrine factor, is critical for this anti-fibrotic effect of WJ-MSCs. These findings demonstrate that WJ-MSCs exert anti-fibrotic effects against skeletal muscle fibrosis, primarily via MMP-1, indicating a novel target for the treatment of muscle diseases, such as DMD.

Genetic heterogeneity of common genetic generalized epilepsy syndromes is frequently considered. The present study conducted a focused analysis of potential candidate or susceptibility genes for common genetic generalized epilepsy syndromes using multi-gene panel testing with next-generation sequencing. This study included patients with juvenile myoclonic epilepsy, juvenile absence epilepsy, and epilepsy with generalized tonic-clonic seizures alone. We identified pathogenic variants according to the American College of Medical Genetics and Genomics guidelines and identified susceptibility variants using case-control association analyses and family analyses for familial cases. A total of 57 patients were enrolled, including 51 sporadic cases and 6 familial cases. Twenty-two pathogenic and likely pathogenic variants of 16 different genes were identified. CACNA1H was the most frequently observed single gene. Variants of voltage-gated Ca2+ channel genes, including CACNA1A, CACNA1G, and CACNA1H were observed in 32% of variants (n = 7/22). Analyses to identify susceptibility variants using case-control association analysis indicated that KCNMA1 c.400G>C was associated with common genetic generalized epilepsy syndromes. Only 1 family (family A) exhibited a candidate pathogenic variant p.(Arg788His) on CACNA1H, as determined via family analyses. This study identified candidate genetic variants in about a quarter of patients (n = 16/57) and an average of 2.8 variants was identified in each patient. The results reinforced the polygenic disorder with very high locus and allelic heterogeneity of common GGE syndromes. Further, voltage-gated Ca2+ channels are suggested as important contributors to common genetic generalized epilepsy syndromes. This study extends our comprehensive understanding of common genetic generalized epilepsy syndromes.

PurposeAcute necrotizing encephalopathy (ANE) is a fulminant disease of the brain characterized by bilateral thalamic lesions, and is prevalent among children in East Asia. The prognosis of ANE is usually poor with a high mortality rate and neurological sequelae. This study aimed to delineate the clinical characteristics and prognostic factors of ANE.MethodsWe retrospectively analyzed clinical data of 399 pediatric patients with encephalitis who were admitted to Samsung Medical Center from December 1998 to March 2011. We enrolled ten patients (11 cases) with ANE and analyzed their demographic, clinical, and neuroimaging data. The location and extent of the brain regions were checked based on fluid-attenuated inversion recovery, T1-, and T2-weighted imaging findings; the presence of contrast enhancement, restricted diffusion, and hemorrhage.ResultsTen patients were identified, including one patient with two episodes. The median age of onset was 1.5 years (0.4-8.4 years). The mortality rate was 40%, and only 30% of patients survived without neurological sequelae. The definite involvement of the brainstem on brain magnetic resonance imaging was significantly correlated with mortality (P=0.04).ConclusionBroad and extensive brainstem involvement suggested the fulminant course of ANE. Early diagnosis of ANE before brainstem involvement, through careful identification of symptoms of brain dysfunction, may be the best way to achieve better neurological outcomes.