Myasthenia gravis (MG) is an autoimmune neuromuscular disorder characterized by muscle weakness and fatigue due to autoantibodies impairing neuromuscular transmission. With a global prevalence of 40–180 per million, Taiwan has seen a rise in MG cases from 4476 in 2013 to 5752 in 2019, with generalized MG (GMG) prevalence increasing significantly, whereas GMG patients incur substantially higher medical costs and resource utilization compared to non-MG patients. To standardize MG management, the Society formed an expert committee of 37 MG specialists and a patient representative, tasked with developing evidence-based guidelines. The committee, organized into 11 thematic subgroups, conducted a systematic review of literature from 2015 to 2024 and employed a Modified Delphi method to achieve consensus on clinical guidance statements. Recommendations cover diagnosis (e.g., antibody testing and electrophysiological tests), treatment (e.g. thymectomy, steroids, and novel biologics), and management of specific MG subtypes, including ocular, early- and late-onset, muscle-specific tyrosine kinase-related, and refractory MG, as well as myasthenic crisis and neonatal MG. The guidelines emphasize early diagnosis, integrated management of comorbidities, and long-term care strategies, including patient support and tailored exercise programs. These consensus statements aim to enhance care quality, improve patient outcomes, and guide future research and pharmaceutical development in Taiwan’s medical community.

Respiratory syncytial virus (RSV)-associated encephalopathy is an uncommon but potentially devastating complication in children. Increasing evidence suggests that infection-triggered neuroinflammation rather than direct viral invasion underlies neurologic injury in a subset of patients. We describe 2 previously healthy, unrelated children who developed rapidly progressive encephalopathy after RSV infection. Initial brain magnetic resonance imaging scan results were normal, but follow-up imaging results showed multifocal white matter lesions consistent with an acute disseminated encephalomyelitis-like pattern. Both patients were given refractory to high-dose corticosteroids, intravenous immunoglobulin, and interleukin (IL)-6 blockade. Markedly elevated serum IL-1β levels were documented in one patient. Treatment with the IL-1 receptor antagonist, anakinra, was temporally associated with neurologic and radiologic recovery in both cases. These observations suggest that an IL-1-driven autoinflammatory phenotype may contribute to disease severity in selected children with RSV-associated encephalopathy and highlight the importance of repeat neuroimaging and consideration of targeted immunomodulation in refractory cases.

Neurofibromatosis type 1 (NF1) is a genetic disorder resulting from pathogenic variants in the tumor suppressor NF1 gene, which encodes neurofibromin. Its clinical manifestations are age-related and affect multiple systems, ranging from the characteristic café-au-lait macules, visible on the skin from birth, to plexiform neurofibromas (PNs), which have the potential to transform into malignant tumors during adolescence and adulthood. The Taiwan Child Neurology Society convened a series of meetings with experts from various specialties to review the latest evidence and updates related to NF1, including the recent approval of selumetinib for pediatric patients with symptomatic and inoperable PN in Taiwan. A consensus on diagnosis and management was established with the goal of enhancing disease understanding and providing guidance to local clinicians. Emphasis was placed on the importance of early recognition, diagnosis, and continuous health supervision, with the use of a multidisciplinary team (MDT) approach. It is recommended that a comprehensive benefit-risk assessment, considering all available treatment options, be conducted by the MDT to develop personalized management plans and ensure optimal care for pediatric NF1 patients.

Recent findings indicate that infants with spinal muscular atrophy (SMA) treated early through newborn screening (NBS) have better outcomes. This study aimed to investigate the long-term outcomes of a 5-year SMA NBS program in Taiwan. From September 2017 to August 2022, two NBS centers screened patients for SMN1 homozygous deletion using quantitative real-time polymerase chain reaction (RT-PCR) or the Sequenom MassARRAY platform and subsequently confirmed the findings using multiplex ligation-dependent probe amplification (MLPA). Implementation of SMA NBS using RT-PCR or MassARRAY platform efficiently led to the detection of neonates with homozygous survival motor neuron 1 (SMN1) deletions at a median age of 9 (range 4–14) days. Among the 446,966 newborns screened, 22 were detected to have a homozygous deletion of SMN1, followed by MLPA confirmation. One patient initially showed negative screening results but was later confirmed to have a compound heterozygous mutation. Among the 23 confirmed cases, 8 patients had two SMN2 copies (all classified as SMA type 1), 11 patients had three SMN2 copies (including 4 with SMA type 1, 2 with SMA type 2, 3 with SMA type 3, and 2 asymptomatic cases), and 4 patients had four SMN2 copies (all asymptomatic). The mean (median) follow-up duration for 19 survivors was 4.2 (5.0) years. All patients with two SMN2 copies developed symptoms within 62 days; those with three SMN2 copies experienced disease onset within 1 year. After diagnosis, most patients were on a watch and wait to receive disease-modifying therapy (DMT) due to initial lack of insurance coverage and limitations on indications after coverage was granted. Of the 19 children who received DMT, the outcomes included 12 walkers, 1 walker requiring support, 3 sitters, 1 non-sitter, and 2 patients with SMA type 1b with two SMN2 copies who succumbed to acute respiratory failure. This 5-year SMA NBS study using RT-PCR or the MassARRAY platform, along with an extended follow-up, demonstrates that early diagnosis and prompt treatment can enhance SMA clinical outcomes and change its natural progression in the therapeutic era. Infants with NBS who received presymptomatic DMT had better clinical outcomes than those who received symptomatic DMT.

BackgroundThe clinical presentations of abusive head trauma can abruptly worsen, so the occurrence of seizures and changes of EEG can be variable according to patients' conditions. Since the changes of EEG background waves reflect the cortical function of children, we aimed to find out whether the timing of EEG background, epileptiform discharges and seizure patterns were associated with the outcomes of patients with AHT.Material and methodsUsing seizure type and acute stage electroencephalographic (EEG) characteristics to assess adverse neurological outcomes in children with seizures secondary to abusive head trauma (AHT). Children who were hospitalized with AHT at a tertiary referral hospital from October 2000 to April 2010 were evaluated retrospectively. A total of 50 children below 6 years of age admitted due to AHT were included. KOSCHI outcome scale was used to evaluate the primary outcome and neurological impairment was used as secondary outcome after 6 months discharge.ResultsChildren with apnea, cardiac arrest, reverse blood flow and skull fracture in clinic had a higher mortality rate even in the no-seizure group (3/5 [60%] vs. 3/45 [6.7%], odds ratio [OR] = 11; 95% CI = 2.3–52; p = 0.025). Seizure occurrence reduced mostly at the second day after admission in seizure groups; but children with persistent seizures for 1 week showed poor neurological outcomes. The occurrence of initial seizure was frequency associated with younger age; focal seizure, diffuse cortical dysfunction in acute-stage EEG, and low Glasgow Coma Scale (GCS) score were significantly related to poor outcomes after 6 months. Diffuse cortical dysfunction was also associated with motor, speech, and cognitive dysfunction.ConclusionsDiff use cortical dysfunction in acute-stage EEG combined with low GCS score and focal seizure may related to poor outcomes and neurological dysfunctions in children with AHT.

Objective: Protocadherin-19 (PCDH19) epilepsy is a rare female restricted epilepsy syndrome with early onset seizures and developmental delay caused by a change or mutation of the PCDH19 gene on the X chromosome. SCN1A-negative patients with a Dravet-like phenotype may have a gene mutation in PCDH19. The aim of this case series was to characterize the phenotype of epileptic patients according to PCDH19 mutations, antiseizure medications, brain images and mutation types in Taiwan. Methods: We retrospectively reviewed the medical records of patients with PCDH19 epilepsy from July 2017 to December 2021 from multiple centers in Taiwan. We analyzed the patients' clinical data and genetic reports. Results: Fifteen female patients (age 3-23 years) were enrolled. Seizure onset was at 4 months to 2 years 7 months of age with generalized tonic-clonic or focal seizures. Seizure frequency tended to be in clusters rather than single longer seizures. The patients had varying degrees of intellectual disability, however 3 had no impairment. Two patients had abnormal brain images including mesial temporal sclerosis, subcortical and periventricular white matter lesions. On average, the patients received 4 antiseizure medications (range 3-6), including 9 patients who were seizure free, and 3 who received sodium channel blockers without aggravation. Missense and truncating variants (frameshift and nonsense variants) accounted for 40% and 46.7% of all mutations. The mutations of 13 patients were located on EC1 to EC4, and EC5 to cytoplasmic domain in 2 patients. Significance: PCDH19 epilepsy has distinct phenotypes and an unusual X-linked pattern of expression in which females manifest core symptoms. Psychiatric and behavioral problems are frequently part of the clinical picture. Patients are usually treated with a wide array of standard antiseizure medications, with no preferred antiseizure medication class. No strong correlations between phenotype and location of variant mutations were found in our patients.

Identifying genetic risk factors for highly heterogeneous disorders such as epilepsy remains challenging. Here we present, to our knowledge, the largest whole-exome sequencing study of epilepsy to date, with more than 54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets and four copy number variants at exome-wide significance. Genes encoding ion channels show strong association with multiple epilepsy subtypes, including epileptic encephalopathies and generalized and focal epilepsies, whereas most other gene discoveries are subtype specific, highlighting distinct genetic contributions to different epilepsies. Combining results from rare single-nucleotide/short insertion and deletion variants, copy number variants and common variants, we offer an expanded view of the genetic architecture of epilepsy, with growing evidence of convergence among different genetic risk loci on the same genes. Top candidate genes are enriched for roles in synaptic transmission and neuronal excitability, particularly postnatally and in the neocortex. We also identify shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our data can be accessed via an interactive browser, hopefully facilitating diagnostic efforts and accelerating the development of follow-up studies.

Natalizumab (NTZ), a monoclonal antibody against the integrin α4β1 (VLA-4) found on activated T cells and B cells, blocks the interaction of this integrin with adhesion molecules of central nervous system (CNS) endothelial cells and lymphocyte migration through the blood–brain barrier, effectively preventing new lesion formation and relapses in multiple sclerosis (MS). Whether NTZ treatment has additional effects on the peripheral immune system cells, and how its actions compare with other MS disease-modifying treatments, have not been extensively investigated. In particular, its effect on the proportions of circulating regulatory T cells (Treg) is unclear. In this study, we investigated the effect of NTZ treatment in 12 patients with relapsing MS, at 6 and 12 months after the start of treatment. We evaluated the proportions of regulatory T cells (Treg), defined by flow cytometry as CD4+ CD25++ FoxP3+ cells and CD4+ CD25++ CD127– cells at these intervals. As an exploratory study, we also investigated the NTZ effects on the proportions of bulk T and B lymphocyte populations, and of those expressing novel the markers CD195 (CCR5), CD196 (CCR6), or CD161 (KLRB1), which are involved in MS pathogenesis but have been studied less in the context of MS treatment. The effects of NTZ were compared to those obtained with 11 patients under interferon-beta-1a (IFN-β1a) treatment, and against 9 healthy volunteers. We observed a transient increment in the proportion of Treg cells at 6 months, which was not sustained at 12 months. We observed a reduction in the proportion of T cells expressing CD195 (CCR5) and CD161 (KLRB1) subsets of T cells. We conclude that NTZ does not have an effect on the proportion of Treg cells over 1 year, but it may affect the expression of molecules important for some aspects MS pathogenesis, in a manner that is not shared with IFN-β1a.

Phosphofurin Acidic Cluster Sorting Protein 2 (PACS2)-related early infantile developmental and epileptic encephalopathy (EIDEE) is a rare neurodevelopmental disorder. EIDEE is characterized by seizures that begin during the first three months of life and are accompanied by developmental impairment over time. In this article, we present three patients with EIDEE who experienced neonatal-onset seizures that developed into intractable seizures during infancy. Whole exome sequencing revealed a de novo heterozygous missense variant in all three patients in the p.Glu209Lys variant of the PACS2 gene. We conducted a literature review and found 29 cases to characterize the seizure patterns, neuroimaging features, the usage of anticonvulsants, and the clinical neurodevelopmental outcomes of PACS2-related EIDEE. The seizures were characterized by brief, recurring tonic seizures in the upper limbs, sometimes accompanied by autonomic features. Neuroimaging abnormalities were observed in the posterior fossa region, including mega cisterna magna, cerebellar dysplasia, and vermian hypoplasia. The long-term prognosis ranges from low-average intelligence to severe developmental retardation, emphasizing the importance of early recognition and accurate diagnosis by pediatric neurologists to provide personalized patient management.

Anti-glutamic acid decarboxylase (anti-GAD) antibodies are associated with different types of syndromes. However, few studies have investigated the correlation between anti-GAD antibody titers with clinical severity and outcomes in children with encephalitis/encephalopathy. In this single-center retrospective cohort study, we consecutively enrolled hospitalized children who had encephalitis and/or encephalopathy with positive anti-GAD antibodies in serum and/or cerebrospinal fluid (CSF) from February 2010 to October 2021. Thirty-seven patients were included and divided into high-titer and low-titer groups. The patients with high anti-GAD antibody titers were associated with initial symptoms of language difficulty and ataxia. The level of titers was not associated with severity or outcomes. Anti-GAD antibody titers decreased after immunotherapy, however, the clinical response to immunotherapy was variable. A transient elevation in anti-GAD antibody titers during immunotherapy was noted. Further studies are warranted to investigate the role of anti-GAD antibodies in the pathogenesis and immune mechanisms of encephalitis/encephalopathy.

IntroductionSjogren’s syndrome is an autoimmune disease that commonly involves exocrinopathy. Although studies have reported psychiatric manifestations resulting from Sjogren’s syndrome, few studies have focused on such manifestations in pediatric patients. Herein, we present a case of an adolescent girl with depression and involuntary self-harm behaviors related to Sjogren’s syndrome with central nervous system involvement.Case presentationA 15-year-old girl, with an underlying history of epilepsy, developed depressive symptoms of a year’s duration, accompanied by three seizure episodes and involuntary self-harm behaviors. The self-harm behaviors, which included head banging and arm scratching, were sudden onset, involuntary, and unable to be recalled afterwards. After admission to our ward, the patient was positive for serum antinuclear antibodies and Schirmer’s test. Moreover, 24-hour electroencephalography revealed epileptiform discharges during the mood swing episodes. Positive findings for antinuclear antibodies and anti-SSA antibodies in both serum and cerebrospinal fluid, suggested central nervous system involvement in Sjogren’s syndrome. After rituximab treatment, her mood became euthymic, and her involuntary self-harm behaviors ceased.ConclusionCentral nervous system involvement leading to psychiatric presentations has rarely been reported in adolescents with Sjogren’s syndrome. When treating adolescent patients with involuntary self-harm behaviors and neurological symptoms, it is crucial to consider autoimmune encephalitis related to Sjogren’s syndrome in the differential diagnosis.

PURPOSE:Our objective was to assess the adverse outcomes during pregnancy, as well as for the fetus and neonates, in women with epilepsy, both with and without the use of antiseizure medications (ASMs).METHODS:A cohort of singleton pregnancies between January 1, 2004 and December 31, 2014 was identified using the Taiwan National Health Database. The pregnancies were categorized into ASM exposure, ASM nonexposure, and control (consisting of women without an epilepsy diagnosis) groups. We recorded adverse outcomes in neonates and documented pregnancy complications. The generalized estimating equation with logit link was used to estimate adjusted odds ratios.RESULTS:There were 629 singleton pregnancies in the group exposed to ASMs, 771 in the epilepsy group without ASM exposure, and 2,004,479 in the control group. Women with epilepsy had a significantly higher risk of puerperal cerebrovascular diseases (adjusted odds ratios in the exposure and nonexposure groups = 54.46 and 20.37, respectively), respiratory distress syndrome (5.1 and 2.99), mortality (3.15 and 3.22), sepsis (2.67 and 2.54), pregnancy-related hypertension (1.71 and 1.8), preeclampsia (1.87 and 1.79), cesarean delivery (1.72 and 2.15), and preterm labor (1.38 and 1.56). The use of ASMs may increase the risk of eclampsia (adjusted odds ratio = 12.27). Compared to controls, fetuses/neonates born to women with epilepsy had a higher risk of unexplained stillbirth (adjusted odds ratios in the exposure and nonexposure groups = 2.51 and 2.37, respectively), congenital anomaly (1.37 and 1.33), central nervous system malformation (3.57 and 2.25), low birth weight (1.90 and 1.97), and a low Apgar score at 5 min (2.63 and 1.3). The use of ASMs may introduce an additional risk of small for gestational age; the adjusted odds ratio was 1.51.CONCLUSION:Women with epilepsy, irrespective of their exposure to ASMs, had a slightly elevated risk of pregnancy and perinatal complications. Puerperal cerebrovascular diseases may be a hidden risk for women with epilepsy.

(1) Background: Natalizumab dramatically reduces relapses and MRI inflammatory activity (new lesions and enhancing lesions) in multiple sclerosis (MS). Chemical exchange saturation transfer (CEST) MRI can explore brain tissue in vivo with high resolution and sensitivity. We investigated if natalizumab can prevent microstructural tissue damage progression measured with MRI at ultra-high field (7 Tesla) over the first year of treatment. (2) Methods: In this one-year prospective longitudinal study, patients with active relapsing–remitting MS were assessed clinically and scanned at ultra-high-field MRI at the time of their first natalizumab infusion, at 6 and 12 months, with quantitative imaging aimed to detect microstructural changes in the normal-appearing white matter (NAWM), including sequences sensitive to magnetisation transfer (MT) effects from amide proton transfer (MTRAPT) and the nuclear Overhauser effect (MTRNOE). (3) Results: 12 patients were recruited, and 10 patients completed the study. The difference in the T1 relaxation times at month 6 and month 12 of natalizumab treatment was not significant, suggesting the lack of accumulation of tissue damage, while improvements were seen in MTR (MTRAPT and MTRNOE measures) at month 12, suggesting a tissue repair effect. This paralleled the expected lack of clinical and radiological worsening of conventional MRI measures of disease activity (new lesions or gadolinium-enhancing lesions). (4) Conclusion: Natalizumab prevents microstructural brain damage and has effects suggesting an improved white matter microstructure measured at ultra-high field during the first year of treatment.

Objectives Systemic lupus erythematosus (SLE) is a female-dominated autoimmune disease that can occur at any age and has a diverse course. The clinical manifestation of this disease can vary depending on the patient’s age at onset. The aim of this study was to characterise the comorbidities at the time of SLE diagnosis and after in different age groups. Methods A total 1042 incident cases of SLE with a Catastrophic Illness Card in 2005 and 10,420 age- and sex-matched controls from the general population registered in the National Health Insurance Research Database in Taiwan were enrolled in the study. The risk of comorbidities before (adjusted odds ratio, [aOR]) and after (adjusted hazard ratio, [aHR]) of SLE was analysed. The burden of these SLE-associated comorbidities was weight by the Charlson comorbidity index (CCI). We used the cumulative incidence to evaluate the impact of comorbidities on different age onset groups. Results In this study, musculoskeletal diseases had the highest positive association (aOR, 5.29; 95% confidence interval [CI]: 4.25–6.57) prior to the diagnosis of SLE and they were also the most common developing incident comorbidity after the diagnosis (HR, 13.7; 95% CI: 11.91–15.77). It only took less than 1 year for 50% of the late-onset SLE patients to develop any increase in CCI score. The developing comorbidities attributed to 16.3% all-cause mortality and they had the greatest impact on late-onset SLE patients, with 33.3% cumulative incidence to all-cause mortality. There is no difference in the incidence of infectious diseases across different age groups. The herpes zoster infection had the greatest cumulative incidence among the category of infection diseases in child-onset SLE patients. Conclusion SLE patients had increased risks of multiple pre-existing comorbidities at diagnosis. The developed comorbidity after diagnosis could contribute to all-cause mortality. The herpes zoster infection is primarily an issue in child-onset SLE patients.

PURPOSE:The incidence of Tourette syndrome and chronic tic disorders has seldom been evaluated in Asia.METHODS:Using the National Taiwan Insurance Research Database, the annual standardized incidence and prevalence of Tourette syndrome (TS) and chronic tic disorders were estimated from 2007 to 2015. The pre-existing comorbidity at disease diagnosis was also evaluated.RESULTS:From 2007 to 2015, the age- and sex-standardized incidence increased from 5.34 (95% confidence interval [CI] 5.06-5.62) per 100,000 person-years to 6.87 (95% CI 6.53-7.21) per 100,000 person-years. In children and adolescents, the age- and sex-standardized incidence increased from 19.58 (95% CI 18.42-20.75) per 100,000 person-years to 31.79 (95% CI 30.09-33.49) per 100,000 person-years. In adults, the age- and sex-standardized incidence decreased from 2.01 (95% CI 1.79-2.23) per 100,000 person-years to 1.24 (95% CI 1.07-1.42) per 100,000 person-years. The incidence rate ratio (IRR) between males and females was 3.74 (95% CI 3.32-4.22). The age- and sex-standardized prevalence increased from 37.51 (95% CI 36.75-38.27) per 100,000 people in 2007 to 84.18 (95% CI 83.02-85.35) per 100,000 people in 2015. The rate risk (RR) between males and females was 3.65 (95% CI 3.53-3.78).CONCLUSION:The annual incidence rates of TS and chronic tic disorders increased in childhood and adolescence but decreased in adulthood from 2007 to 2015. The prevalence rates increased over the same period.

Background: No previous study has investigated the relationship between middle cerebral artery (MCA) flow velocity and the severity of hypoxic ischemic encephalopathy (HIE) evaluated by magnetic resonance imaging (MRI). The aim of this study was to assess the correlation between cerebral blood flow as assessed by transcranial Doppler sonography and the severity of MRI brain injury in asphyxiated neonates with clinical HIE who received therapeutic hypothermia. Methods: This retrospective cohort study was conducted in the neonatal intensive care unit at Chang Gung Memorial Hospital between April 2011 and May 2014. All neonates with HIE who received therapeutic hypothermia, transcranial Doppler examinations, and brain MRI were eligible. Brain MRI was performed at 11 days of age (interquartile range: 8.5-15 days) and the severity of MRI brain injuries was evaluated using the MR scoring system proposed by Barkovich et al. Serial transcranial Doppler examinations were performed in prehypothermia, hypothermia, and post-hypothermia phases. Results: Twenty-six neonates met the eligibility criteria for this study. Neonates with an abnormal MCA mean flow velocity (MFV) during the hypothermia phase had a higher risk of brain MRI abnormalities (77.8% vs. 22.2%, p = 0.017) and neonates with abnormal high MFV of MCA had higher MR scores of basal ganglia (p = 0.022). However, there were no statistical differences between abnormal MFV of MCA and brain MRI abnormalities during pre- and post-hypothermia phases. Conclusions: During therapeutic hypothermia, mean cerebral blood flow velocity of the MCA was associated with the severity of MRI brain injury in the neonates with clinical HIE.