A lissencephaly-associated BAIAP2 variant causes defects in neuronal migration during brain development.

Lissencephaly is a neurodevelopmental disorder characterized by a loss of brain surface convolutions caused by genetic variants that disrupt neuronal migration. However, the genetic origins of the disorder remain unidentified in nearly one-fifth of people with lissencephaly. Using whole-exome sequencing, we identified a de novo BAIAP2 variant, p.Arg29Trp, in an individual with lissencephaly with a posterior more severe than anterior (P>A) gradient, implicating BAIAP2 as a potential lissencephaly gene. Spatial transcriptome analysis in the developing mouse cortex revealed that Baiap2 is expressed in the cortical plate and intermediate zone in an anterior low to posterior high gradient. We next used in utero electroporation to explore the effects of the Baiap2 variant in the developing mouse cortex. We found that Baiap2 knockdown caused abnormalities in neuronal migration, morphogenesis and differentiation. Expression of the p.Arg29Trp variant failed to rescue the migration defect, suggesting a loss-of-function effect. Mechanistically, the variant interfered with the ability of BAIAP2 to localize to the cell membrane. These results suggest that the functions of BAIAP2 in the cytoskeleton, cell morphogenesis and migration are important for cortical development and for the pathogenesis of lissencephaly in humans.

Clinical features and lymphocyte immunophenotyping analysis in primary immunodeficiency patients with non-transplant lymphoproliferative disorders.

Lymphoproliferative disorders (LPD) comprise a heterogeneous group and are originally classified into the "Disease of immune dysregulation" category. Of 96 Taiwanese patients during 2003-2022, 31 (median 66, range 0.03-675 months) developed LPD, mainly including palpable lymphadenopathy (in 10 patients), intestinal lymphadenopathy associated with refractory inflammatory bowel disease (IBD in 8) and hepatosplenomegaly (in 7) during long-term follow-up (median 144, range 3-252 months). They distributed in the categories of antibody deficiency (2 CVID, 2 TTC37, PIK3CD, PIK3R1 and AICDA each), phagocyte (4 CYBB, 1 STAT1 and 1 IFNRG1), immune dysregulation (2 FOXP3, 2 XIAP and 2 HLH), combined immunodeficiencies (2 IL2RG; CD40L, ZAP70 and unknown each), syndromic features (2 STAT3-LOF, 1 WAS and 1 ATM) and three with anti-IFN-γ autoantibodies. An increased senescent (CD8 + CD57+) and CD21-low, disturbed transitional B (CD38 + IgM++), plasmablast B (CD38++IgM-), memory B (CD19 + CD27+) and TEMRA (CD27-IgD-) components were often observed in cross-sectional immunophenotyping and trended to develop LPD.

Improving social cognition following theta burst stimulation over the right inferior frontal gyrus in autism spectrum: an 8-week double-blind sham-controlled trial.

BACKGROUND: The right inferior frontal gyrus (RIFG) is a potential beneficial brain stimulation target for autism. This randomized, double-blind, two-arm, parallel-group, sham-controlled clinical trial assessed the efficacy of intermittent theta burst stimulation (iTBS) over the RIFG in reducing autistic symptoms (NCT04987749). METHODS: Conducted at a single medical center, the trial enrolled 60 intellectually able autistic individuals (aged 8-30 years; 30 active iTBS). The intervention comprised 16 sessions (two stimulations per week for eight weeks) of neuro-navigated iTBS or sham over the RIFG. Fifty-seven participants (28 active) completed the intervention and assessments at Week 8 (the primary endpoint) and follow-up at Week 12. RESULTS: Autistic symptoms (primary outcome) based on the Social Responsiveness Scale decreased in both groups (significant time effect), but there was no significant difference between groups (null time-by-treatment interaction). Likewise, there was no significant between-group difference in changes in repetitive behaviors and exploratory outcomes of adaptive function and emotion dysregulation. Changes in social cognition (secondary outcome) differed between groups in feeling scores on the Frith-Happe Animations (Week 8, p = 0.026; Week 12, p = 0.025). Post-hoc analysis showed that the active group improved better on this social cognition than the sham group. Dropout rates did not vary between groups; the most common adverse event in both groups was local pain. Notably, our findings would not survive stringent multiple comparison corrections. CONCLUSIONS: Our findings suggest that iTBS over the RIFG is not different from sham in reducing autistic symptoms and emotion dysregulation. Nonetheless, RIFG iTBS may improve social cognition of mentalizing others' feelings in autistic individuals.

Distinct Lymphocyte Immunophenotyping and Quantitative Anti-Interferon Gamma Autoantibodies in Taiwanese HIV-Negative Patients with Non-Tuberculous Mycobacterial Infections.

PURPOSE: The presence of anti-interferon-γ autoantibodies (AutoAbs-IFN-γ) is not rare in patients suffering from persistent non-tuberculous mycobacterial (NTM) infections that are characteristic of adult-onset immunodeficiency syndrome. The immune disturbances in this distinct disorder remain to be elucidated. METHODS: Patients with NTM infections but without effective response over 3 months' treatment were referred to our institute to quantify their level of AutoAbs-IFN-γ after excluding defective IL12/23-IFN-γ circuit and reactive oxygen species production. The AutoAbs-IFN-γ and percentage of lymphocyte subpopulations most relevant to T and B cell pools were assessed and compared with age-matched healthy controls. RESULTS: A total of 31 patients were enrolled during the 15-year study period (2008-2022), 20 patients with > 50% suppression of IFN-γ detection at 1:100 serum dilution were classified into the Auto-NTM group. The remaining 11 with negligible suppression were assigned to the No Auto-NTM group. Mycobacterium chimaera-intracellulare group (MAC), M. kansasii, and M. abscessus were the most common pathogens. Pneumonia (19 vs 7), lymphadenitis (11 vs 5), Salmonella sepsis (6 vs 2), osteomyelitis (5 vs 1), and cutaneous herpes zoster (4 vs 4) were the main manifestations in both the Auto-NTM and No Auto-NTM groups who had similar onset-age (55.3 vs 53.6 years; p = 0.73) and follow-up duration (71.9 vs 54.6 months; p = 0.45). The Auto-NTM group had significantly higher transitional (IgM + + CD38 + +), CD19 + CD21-low, and plasmablast (IgM-CD38 + +) in the B cell pool, with higher effector memory (CD4 + /CD8 + CD45RO + CCR7 -), senescent CD8 + CD57 + , and Th17 cells, but lower naïve (CD4 + /CD8 + CD45RO - CCR7 +) and Treg cells in the T cell pool when compared to the No Auto-NTM and healthy groups. NTM patients with/without AutoAbs-IFN-γ had lower Th1-like Tfh (CD4 + CXCR5 + CXCR3 + CCR6 -) cells. All Auto-NTM patients still had non-remitted mycobacterial infections and higher AutoAbs-IFN-γ despite anti-CD20 therapy in 3 patients. CONCLUSION: In patients with suspected adult-onset immunodeficiency syndrome, two thirds (20/31) were recognized as having significantly inhibitory AutoAbs-IFN-γ with higher antibody-enhancing transitional, CD19 + CD21-low and plasmablast B cells; as well as higher effector memory, senescent CD8 + CD57 + and Th17 cells, but lower naïve T and Treg cells in contrast to those with negligible AutoAbs-IFN-γ. Such immunophenotyping disturbances might correlate with the presence of AutoAbs-IFN-γ. However, the mutual mechanisms need to be further clarified.

Incidence and prevalence of Tourette syndrome and chronic tic disorders in Taiwan: a nationwide population-based study.

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.

Correlation of anti-acetylcholine receptor antibody levels and long-term outcomes of juvenile myasthenia gravis in Taiwan: a case control study.

BACKGROUND: Myasthenia gravis is the most common disease affecting the neuromuscular junction. The most common etiology among patients with juvenile myasthenia gravis is the production of antibodies against the acetylcholine receptor. However, the clinical outcome in relation to serum levels of anti-acetylcholine receptor antibodies in juvenile myasthenia gravis has rarely been discussed. We aimed to analyze the correlation between the presence of anti-acetylcholine receptor antibodies and outcome in juvenile myasthenia gravis. METHODS: Patients diagnosed with juvenile myasthenia gravis younger than of 20 years of age were retrospectively recruited from January 1995 to February 2017 in a tertiary referral medical center. According to the Myasthenia Gravis Foundation of America outcome scale, the primary outcome was complete symptom remission and cessation of medications for at least 1 year measured 2 years after diagnosis. Secondary outcome was complete symptom remission at the last outpatient clinic. RESULTS: A total of 54 patients were followed up for over 2 years. Nine patients (9/54, 16.7%) achieved complete remission without medication use at 2 years after diagnosis. Thirteen (24.1%) patients achieved complete remission during longer follow-up periods. Those with negative anti-acetylcholine receptor antibodies were more likely to achieve complete remission at 2 years (6/15 [40%] vs. 3/39 [7.7%], 95% Confidence interval [CI] 1.670 to 38.323) and at the last outpatient clinic follow-up (8/15 [53.3%] vs. 5/39 [12.8%], 95% CI 2.367 to 20.704). Thirteen patients with comorbid autoimmune thyroid diseases were older than those without disease (11.8 ± 5.8 years old vs. 8.0 ± 6.3 years old, 95% CI 0.018 to 7.33). Moreover, patients negative for anti-acetylcholine receptor antibodies were less likely comorbid with autoimmune thyroid disease (1/35 [2.9%] vs. 12/71 [16.9%], 95% CI 0.018 to 1.161). CONCLUSIONS: Juvenile myasthenia gravis patients without anti-acetylcholine antibodies exhibited significantly increased complete remission rates and a reduced likelihood of comorbid autoimmune thyroid diseases compared with those with anti-acetylcholine receptor antibodies among Chinese.

Efficacy and tolerability of perampanel in children and adolescents with pharmacoresistant epilepsy: The first real-world evaluation in Asian pediatric neurology clinics.

AIM: This study investigated the efficacy and safety of perampanel (PER) adjunctive therapy in pediatric patients with epilepsy whose seizures are pharmacoresistant to existing antiepileptic drugs. METHODS: A clinical retrospective study was conducted from 2016 to 2017 in the pediatric neurology clinic at a tertiary children's hospital. We reviewed the data obtained from 66 children whose seizures were pharmacoresistant to more than two antiepileptic drugs, and could be followed up for a minimum of 3 months after PER adjunctive therapy initiation. The efficacy was estimated by the PER response rate at 3-, 6-, and 12-month follow-up evaluations, and adverse events were also recorded. RESULTS: The rate of seizure reduction of >50% was 30.3%, 37.5%, and 34.7% for all seizure types at 3, 6, and 12 months, in which 7.6%, 8.9%, and 14.3% of the patients became seizure-free at these time points, respectively. No significant differences were found between enzyme-inducing and nonenzyme-inducing antiepileptic drugs in combination with PER with regard to the responder rate. Five patients with Dravet syndrome were included in the study. Four of them (80%) exhibited 50% seizure reduction at the last visit, at which point, two patients (40.0%) were seizure-free. The retention rate was 51% at 12 months. Adverse events were documented in 25 patients (35.7%) and led to PER discontinuation in eight patients (12.1%). The most common adverse events comprised irritability, skin rash, dizziness, and somnolence; however, all were transient and successfully managed after PER dose reduction or discontinuation. CONCLUSION: The current data support the value of adjunctive PER in child and adolescent patients with pharmacoresistant epilepsy in daily clinical practice. Perampanel was efficacious and generally well-tolerated as an add-on treatment for epilepsy.

Electroencephalogram pattern predicting neurological outcomes of children with seizures secondary to abusive head trauma.

BACKGROUND: The 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 METHODS: Using 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. RESULTS: Children 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. CONCLUSIONS: Diffuse 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.

Acute disseminated encephalomyelitis in children: a single institution experience of 28 patients.

The aim of this study is to describe the clinical, laboratory, and neuroimaging features, treatment and outcome of acute disseminated encephalomyelitis (ADEM) in Taiwanese children to compare with two series from United States of America and Japan. We retrospectively reviewed the medical records and magnetic resonance images of 28 children, 23 boys and 5 girls, with ADEM between January 2001 and December 2009. Their mean age at disease onset was 6 years 9 months. Twenty four children experienced a prodromal illness. There was no special seasonal distribution in our patients. They presented mostly with impaired consciousness and headache. Cerebrospinal fluid samples of 21 patients were analyzed and none showed intrathecal oligoclonal bands. Magnetic resonance imaging showed variable findings: lesions with abnormal signal changes frequently found in the subcortical white matter of frontal and parietal lobes. No patient showed cortical gray matter involvement. We also found a high rate of deep gray matter involvement including thalami and basal ganglia. Treating with steroids was usually associated with a rapid recovery and both intravenous high dose methylprednisolone and dexamethasone had the same effect. All patients survived. Twenty three patients recovered completely with only mild sequelae in the remaining five children.

The clinical relevance of anti-glutamic acid decarboxylase antibodies in children with encephalitis/encephalopathy.

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.

Clinical aspects and genetic analysis of Taiwanese patients with the phenotype of hyper-immunoglobulin E recurrent infection syndromes (HIES).

BACKGROUND: Hyper-immunoglobulin E recurrent infection syndromes (HIES) has characteristic features and identified mutations. This study investigated clinical features and causal candidate mutations in Taiwanese patients with the HIES phenotype on referral base over 23 million inhabitants. PATIENTS AND METHODS: Clinical manifestations of the HIES phenotype, severity scoring, immunological functions and candidate genes of signal transducer and activator of transcription 3 (STAT3), tyrosine kinase 2 (TYKZ), and dedicator of cytokineses 8 (DOCK8) were analyzed. RESULTS: Between 1985 and 2009, six sporadic and two siblings met HIES criteria (onset age: 2-54 months; severity score: 31-65) out of 187 patients with primary immunodeficiencies. Five patients with the autosomal dominant (AD)-HIES phenotype presented as pneumatocoele, bronchiectasis, retained primary teeth, minor trauma fracture, scoliosis, coronary aneurysm, and lymphoma. Three with the autosomal recessive (AR)-HIES phenotype and impaired lymphocyte proliferation function had herpes simplex virus infection, molluscum contagiosum, and cerebral vasculitis. Notably in one patient with the AR-HIES phenotype, unintentional lead component in traditional application herbs for accelerating wound healing deposited in basal ganglia and aggravated involuntary movement relative to cerebral vacculitis. Those with mildly elevated memory T cells and decreased memory B cells trended to develop arteritis. Of five AD-HIES patients, three were mortalities from acute myocardial infarction, Proteus mirabilis, and Staphylococcus aureus sepsis. Only one had de novo novel STAT3 (Gln 469 Arg) mutation with "relative" lower HIES STAT3 score. CONCLUSIONS: Known genetic defects responsible for the HIES phenotype are not so common in Taiwan. This may infer genetic variations in different ethnicities although selection bias and under-diagnosis for HIES with known genetic defects could be contribution factors.

Risk assessment for adverse outcome in term and late preterm neonates with bilirubin values of 20 mg/dL or more.

The aim of this study is to identify clinical, etiologic, and laboratory factors that potentiate adverse outcome of hyperbilirubinemia among term and late preterm neonates in logistic regression analysis. A retrospective cohort of infants with total serum bilirubin (TSB) ≥ 20 mg/dL from 1995 to 2007 was surveyed. Eighteen infants had adverse outcome. Controls were 270 infants without sequelae. Risks were significantly higher in infants with six etiologies causing hyperbilirubinemia: sepsis (odds ratio [OR] = 161.7, 95% confidence interval [CI] = 11.7 to 2242.8), gastrointestinal obstruction (OR = 39.2, 95% CI = 2.7 to 567.3), Rh incompatibility (OR = 31.0, 95% CI = 5.1 to 188.9), hereditary spherocytosis (OR = 19.6, 95% CI = 1.6 to 235.5), ABO incompatibility (OR = 5.1, 95% CI = 1.3 to 19.7), and glucose-6-phosphate dehydrogenase deficiency (OR = 4.7, 95% CI = 1.3 to 16.7). Infants with acute bilirubin encephalopathy were more likely to have adverse outcome than subjects without acute bilirubin encephalopathy (OR = 281.7, 95% CI = 25.8 to 3076.7). Adverse outcome was more common in infants with a positive direct Coombs test (OR = 4.5, 95% CI = 1.3 to 15.4). Infants with hemoglobin < 10 g/dL tended to have adverse outcome more often than those with hemoglobin ≥ 13 g/dL (OR = 11.8, 95% CI = 3.3 to 42.9). Infants with TSB of 35 mg/dL or more (OR = 472.5, 95% CI = 47.8 to 4668.8) and of 30 to 34.9 mg/dL (OR = 9.5, 95% CI = 1.6 to 57.9) carry greater risks as compared with those with TSB of 20 to 24.9 mg/dL. In conclusion, this study quantitatively verified the potential risks for adverse outcome of neonatal hyperbilirubinemia.

Genetics and clinical correlation of Dravet syndrome and its mimics - experience of a tertiary center in Taiwan.

BACKGROUND: Dravet syndrome is a severe developmental and epileptic encephalopathy characterized by the onset of prolonged febrile and afebrile seizures in infancy and SCN1A gene mutations. In some cases, non-SCN1A gene mutations can present with a phenotype very similar to that of Dravet syndrome. The aim of this study was to compare phenotypes of patients with SCN1A and non-SCN1A gene mutation-related Dravet syndrome. METHODS: Thirty-six patients with Dravet syndrome-like phenotypes were followed from July 2017 to December 2019. We retrospectively analyzed their clinical profiles and genetic surveys. RESULTS: Of the 36 enrolled patients, 15 (41.7%) had SCN1A mutations, one (2.8%) had an SCN8A mutation, one (2.8%) had an STX1B mutation, and five females (13.9%) had PCDH 19 mutations. The median age at first seizure onset was 7 months in those with SCN1A mutations, 1.3 years in those with PCDH19 mutations, and 10 months for the remaining patients. The majority of the patients with SCN1A mutations had status epilepticus (80% vs. 20%) and fever-sensitive seizures (76% vs. 31%) compared to those with PCDH19 mutations. The patients with SCN1A-related seizures had a higher rate of focal seizures as first seizure type than those without SCN1A mutations. Three of five (60%) patients with PCDH19 mutations had brain magnetic resonance imaging abnormalities. The three most commonly used antiseizure medications were sodium valproate, levetiracetam, and clobazam. Seven of the 15 patients with SCN1A mutations used stiripentol. The median time from seizure onset to genetic diagnosis was 6.6 years (range 4 months-22.3 years). CONCLUSION: The patients with SCN1A mutations in this study had high rates of fever-sensitive seizures, status epilepticus, seizure onset with focal seizure type, and relatively young age at seizure onset. The patients with PCDH19 mutations had a relatively high rate of abnormal brain magnetic resonance imaging findings.

Immunologic analysis and serum heavy metal levels in exacerbated Tourette syndrome.

Tourette syndrome (TS) is a childhood-onset and relapsing disorder characterized by involuntary simple or complex tics and high co-morbidity with behavioral anomalies. Its pathophysiologic mechanisms remain unclarified. We investigated immunologic alternations and serum heavy metal levels in patients with TS to elucidate the unclarified mechanisms. Based on the Yale Global Tic Severity Scale, fifteen TS subjects (four females) aged 8-34 (mean: 15.4 +/- 6.7) in exacerbation with mean severity score 40.3 +/- 14.6 were enrolled in this study. The immunoglobulin levels were normal except for higher immunoglobulin E levels (in 10 patients) with atopy. In exacerbation, there were reverse CD4/CD8 (in two), higher percentages of natural killer cells (in five) and memory T cells (in eight), diminished lymphocyte activation CD69 marker (in three) and impaired NK cytotoxicity (in six) that showed a trend of lower inhibitory CD94 (NKG2A), activating NKp46, and perforin expression compared to those of patients with stable TS and healthy controls, but similar granzyme expression. Serum ASLO, mycoplasma antibody and the levels of heavy metals were not significantly different. All aforementioned immune alterations returned to the normal ranges except for the consistently higher memory T cells. Our study demonstrated that, in some patients with TS, consistently higher memory T cells and lower cytotoxicity in exacerbation status reflect immune alterations and underscore the potential for immunomodulation or immunosuppressive treatment.

Craniocervical arterial dissection: a cause of childhood arterial ischemic stroke in Taiwan.

BACKGROUND/PURPOSE: To describe the clinical characteristics and imaging findings of craniocervical dissection in childhood ischemic stroke, in a tertiary medical center. METHODS: In this retrospective study, we investigated children (aged 1 month to 18 years) with symptoms and radiographic confirmation of ischemic stroke from January 1996 to January 2007. Stroke work-up included neuroimaging (magnetic resonance imaging, computed tomography, conventional angiography, and magnetic resonance angiography), cardiac assessment, prothrombotic assays, immunoassays, infection screening, and metabolic screening. RESULTS: Among 95 children with arterial ischemic stroke, arterial dissection was identified as the underlying risk factor in nine patients (7 boys and 2 girls; age range, 1.9 17.2 years). All the patients had focal neurological signs and two had warning symptoms. A history of trauma was noted in two patients and another two had stroke during physical exertion. The other five patients had spontaneous dissection. Six patients had anterior circulation arterial dissection. Three patients had posterior circulation arterial dissection, and the most common location was in the vertebral artery. Antiplatelet treatment was given to five patients and anticoagulants to one. Endovascular treatment was given to one patient with dissecting aneurysm. One patient died at the acute stage and another seven had neurological deficits after 9 months to 8 years follow-up. The ninth patient had no residual neurological impairment. No patients had recurrent stroke. CONCLUSION: Arterial dissection should be considered in childhood ischemic stroke. Spontaneous arterial dissection is an important factor in this group. Early investigation and treatment can improve the outcome.

Intravenous valproate for seizures in 137 Taiwanese children - valproate naive and non-naive.

PURPOSE: Valproate has been widely used in controlling various kinds of seizures. Intravenous forms of valproate control seizures in a more rapid and efficacious pattern than oral forms. We evaluated the effectiveness and adverse effects of intravenous valproate for controlling seizures in Taiwanese children under 18 years old. METHODS: Retrospective chart reviews were performed on 137 pediatric patients receiving valproate infusion from January 2003 to December 2006. Patients were divided into 4 groups as follows: (1) previous use of other antiepileptic drugs (AEDs) (n=59), (2) previous use of oral valproate (n=8), (3) previous use of other AEDs and valproate (n=32), (4) first time use of valproate (n=38). The indications for using intravenous valproate include status epilepticus, repetitive seizures, prophylactic use for brain operations or in cases where oral administration was not feasible due to medical problems. RESULTS: The mean age was 8±6.22 years old and the average dose was 31.2±26.45 mg/kg/day. The mean duration of usage was 7.8±6.99 days. Eight patients failed to respond to intravenous valproate and the AED was shifted to other drugs. Thirty-two patients achieved successful seizure control after adding other AEDs following intravenous valproate. The seizure control rate in our study was 71%, and six patients died of complications associated with an underlying disorder. An allergic reaction (skin rash) was found in 1 patient, while no serious adverse effects were noted in our patients. CONCLUSION: Intravenous valproate is effective and safe in controlling seizures in children who are either valproate naive or not.

Diminished toll-like receptor response in febrile infection-related epilepsy syndrome (FIRES).

BACKGROUND: Defective human TLR3 signaling causes recurrent and refractory herpes simplex encephalitis/encephalopathy. Children with febrile infection-related epilepsy syndrome with refractory seizures may have defective TLR responses. METHODS: Children with febrile infection-related epilepsy syndrome were enrolled in this study to evaluate TLR1-9 responses (IL-6, IL-8, IL-12p40, INF-α, INF-γ, and TNF-α) in their peripheral blood mononuclear cells (PBMCs) and monocyte-derived dendritic cells (MDDCs), compared to those with febrile seizures and non-refractory epilepsy with/without underlying encephalitis/encephalopathy. RESULTS: Adenovirus and enterovirus were found in throat cultures of enrolled patients (2-13 years) as well as serologic IgM elevation of mycoplasma pneumonia and herpes simplex virus, although neither detectable pathogens nor anti-neural autoantibodies in the CSF could be noted. Their PBMCs and MDDCs trended to have impaired TLR responses and significantly lower in cytokine profiles of TLR3, TLR4, TLR7/8, and TLR9 responses but not other TLRs despite normal TLR expressions and normal candidate genes for defective TLR3 signaling. They also had decreased naïve T and T regulatory cells, and weakened phagocytosis. CONCLUSION: Children with febrile infection-related epilepsy syndrome (FIRES) could have impaired TLR3, TLR4, TLR7/8, and TLR9 responses possibly relating to their weakened phagocytosis and decreased T regulatory cells.

Distinct Clinical Features and Novel Mutations in Taiwanese Patients With X-Linked Agammaglobulinemia.

Background: X-linked agammaglobulinemia (XLA) is caused by a mutation of the Bruton's tyrosine kinase (BTK) gene and is the most common genetic mutation in patients with congenital agammaglobulinemia. The aim of this study was to analyze the clinical features, genetic defects, and/or BTK expression in patients suspected of having XLA who were referred from the Taiwan Foundation of Rare Disorders (TFRD). Methods: Patients with recurrent bacterial infections in the first 2 years of life, serum IgG/A/M below 2 standard deviations of the normal range, and ≦2% CD19+B cells were enrolled during the period of 2004-2019. The frequency of infections, pathogens, B-lymphocyte subsets, and family pedigree were recorded. Peripheral blood samples were sent to our institute for BTK expression and genetic analysis. Results: Nineteen (from 16 families) out of 29 patients had BTK mutations, including 7 missense mutations, 7 splicing mutations, 1 nonsense mutation, 2 huge deletions, and 2 nucleotide deletions. Six novel mutations were detected: c.504G>T [p.K168N], c.895-2A>G [p.Del K290 fs 23*], c.910T>G [p.F304V], c.1132T>C [p.T334H], c.1562A>T [p.D521V], and c.1957delG [Del p.D653 fs plus 45 a.a.]. All patients with BTK mutations had obviously decreased BTK expressions. Pseudomonas sepsis developed in 14 patients and led to both Shanghai fever and recurrent hemophagocytic lymphohistiocytosis (HLH). Recurrent sinopulmonary infections and bronchiectasis occurred in 11 patients. One patient died of pseudomonas sepsis and another died of hepatocellular carcinoma before receiving optimal treatment. Two patients with contiguous gene deletion syndrome (CGS) encompassing the TIMM8A/DDP1 gene presented with early-onset progressive post-lingual sensorineural Deafness, gradual Dystonia, and Optic Neuronopathy syndrome (DDON) or Mohr-Tranebjaerg syndrome (MTS). Conclusion: Pseudomonas sepsis was more common (74%) than recurrent sinopulmonary infections in Taiwanese XLA patients, and related to Shanghai fever and recurrent HLH, both of which were prevented by regular immunoglobulin infusions. Approximately 10% of patients belonged to CGS involving the TIMM8A/DDP1 gene and presented with the DDON/MTS phenotype in need of aggressive psychomotor therapy.

Shifting Valproic Acid to Levetiracetam in Women of Childbearing Age With Epilepsy: A Retrospective Investigation and Review of the Literature.

Objective: Valproic acid is the most high-risk teratogenic antiepileptic drug, and it may lead to fetal major congenital malformations. However, it is still used in women of childbearing age with epilepsy. The aim of this study was to report our experience of discontinuing or lowering valproic acid by adding levetiracetam, a low-risk teratogenic antiepileptic drug. Methods: We reviewed the medical records of childbearing age female patients with epilepsy who were treated with valproic acid initially and then switched to levetiracetam. The clinical profiles were recorded. The primary outcome was successful switching, which was defined as a decrease in the daily valproic acid dosage, after levetiracetam had been added. Results: Twenty-four female patients were enrolled (median age 22 years). The successful switching rate was 83.3% (20/24), and 55% (11/20) discontinued valproic acid after levetiracetam had been added. There were no significant differences between the successful and unsuccessful groups in etiology, electroencephalogram, and magnetic resonance imaging findings. Pharmacoresistant to levetiracetam was much higher in the unsuccessful group (45 vs. 100%). The median switching duration was 19.5 months in the successful group. There were improvements in metrorrhagia and alopecia in all of the patients in the successful group after valproic acid had been tapered. Conclusions: Our experience supports switching valproic acid to levetiracetam in childbearing age women with epilepsy as an effective strategy to lower the teratogenic rate and adverse effects. A long switching period was noted in this study. We suggest starting early in childbearing age women with epilepsy.

Chinese patients with defective IL-12/23-interferon-gamma circuit in Taiwan: partial dominant interferon-gamma receptor 1 mutation presenting as cutaneous granuloma and IL-12 receptor beta1 mutation as pneumatocele.

BACKGROUND: IL-12/23-interferon-gamma circuit enhances reactive oxygen species (ROS) synthesis in macrophage to attack intracellular pathogens such as mycobacteria and salmonella. Defective ROS in patients with chronic granulomatous disease (CGD) have increased susceptibility to these pathogens. However, patients with defective IL-12/23-interferon-gamma circuit rather than CGD are not recognized in Taiwan, endemic for tuberculosis and salmonella. AIM: The purpose of this study was to identify Taiwanese patients with defective IL-12/23-IFN-gamma circuit. PATIENTS AND METHODS: In a long-term molecular study of primary immunodeficiency diseases (PIDD), the tentative CGD patients presenting with Bacille Calmette-Guerin (BCG)-induced infection, refractory atypical mycobacterial cutaneous granuloma and osteomyelitis, recurrent salmonella sepsis, and pneumatocele were studied for the IL-12/23-IFN-gamma circuit. ROS was first measured to exclude CGD. Candidate genes of IL12RB1, IFNRG1, IL12p40, IFNRG2, signal transducer and activator of transcription-1, and NF-kappaB essential modulator and their encoding protein expressions were analyzed. RESULTS: Of the 175 Taiwanese PIDD patients during a 28-year period, three patients from two unrelated families were identified with the hotspot INFRG1 deletion mutation (818del4) and had CGD features, presenting as cutaneous granuloma, and multiple osteomyelitis infected by non-tuberculosis mycobacteria, Mycobacteria avium complex and Mycobacterium scrofulaceum. Another with mis-sense IL12RB1 mutation (Arg211Pro) was noted as recurrent Salmonella enteritidis D sepsis and pneumatocele. CONCLUSION: Patients with defective IL-12/23-IFN-gamma circuit may resemble or overlap CGD manifestations of refractory cutaneous atypical mycobacterial granuloma and salmonella pneumatocele.