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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Immunotherapy for anti-NMDA receptor encephalitis: Experience from a single center in Taiwan.

BACKGROUND: Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an anti-neuronal antibody-mediated inflammatory brain disease that causes severe psychiatric and neurological deficits in previously healthy patients. The aims of this study were to demonstrate the clinical characteristics of patients diagnosed with anti-NMDA receptor encephalitis and to compare the different treatment strategies among these patients. METHODS: Patients presenting with newly acquired psychiatric and/or neurological deficits were studied retrospectively from 2009 to 2017. Patients with evidence of anti-NMDA receptor antibodies in serum and/or cerebrospinal fluid were enrolled. The modified Rankin scale was used to assess the initial status and outcomes of the enrolled patients. Details of the clinical presentations and results of investigations were analyzed. RESULTS: All (n = 24) of the patients received first-line immunotherapy (steroids, and/or intravenous immunoglobulin, and/or plasma exchange), and 14 patients received second-line immunotherapy (rituximab and/or cyclophosphamide). The mean time between the first- and second-line treatment was 13 days. During the first 6 months, 20 patients (20/24, 83%) achieved a good outcome (modified Rankin Scale score ≤2) and 15 patients (15/24, 62.5%) completely recovered. Four patients (17.7%) relapsed, and three patients (12.5%) had associated tumors. CONCLUSION: Immunotherapy is an effective treatment for anti-NMDA receptor encephalitis. Rituximab and/or cyclophosphamide are treatment options for those who cannot tolerate or do not respond to first-line immunotherapy. Prospective studies are necessary to investigate the role of rituximab and cyclophosphamide in anti-NMDA receptor encephalitis.

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.

Combination of intravenous immunoglobulin and steroid pulse therapy improves outcomes of febrile refractory status epilepticus.

BACKGROUND: Febrile infections are an important cause of paediatric refractory status epilepticus, and immune-mediated mechanisms and inflammatory processes have been associated with neurological manifestations in such patients. The aim of this study was to investigate the effects of immunotherapy as adjuvant treatment for febrile refractory status epilepticus. METHODS: We retrospectively reviewed cases of febrile refractory status epilepticus in a paediatric intensive care unit between January 2000 and December 2013 and analysed their clinical characteristics. Patients positive for antineuronal antibodies against surface antigens were excluded. RESULTS: We enrolled 63 patients (38 boys), aged 1-18 years, all of whom received multiple antiepileptic drugs. Twenty-nine (46%) of the patients received intravenous immunoglobulin alone, 16 (25.4%) received a combination of intravenous immunoglobulin and methylprednisolone pulse therapy, and 18 (28.6%) did not receive immunotherapy treatment. Overall, 12 (19%) patients died within 1 month. After 6 months, 12 (20%) patients had good neurological outcomes, including two who returned to baseline and 13 (29.5%) who had favourable seizure outcomes. We compared the outcomes of the different treatments, and found that a combination of intravenous immunoglobulin and methylprednisolone pulse therapy had the best neurological and seizure outcomes at 6 months compared to intravenous immunoglobulin alone and no immunotherapy. CONCLUSIONS: Our observational study showed that a combination of intravenous immunoglobulin and methylprednisolone pulse therapy as adjuvant treatment for febrile refractory status epilepticus was associated with better neurological and seizure outcomes. Further prospective studies are needed to confirm these findings.

Schizencephaly in children: A single medical center retrospective study.

BACKGROUND: The aim of this study was to evaluate the clinical, and neuroimaging features, outcomes, and other associated systemic disorders in children with schizencephaly at a single medical center in Taiwan. METHODS: We retrospectively reviewed the medical records and magnetic resonance images (MRI) of children with schizencephaly between January 2000 and December 2014. The MRI findings of schizencephaly were recorded along with the presence of associated cerebral disorders. Clinical, electroencephalographic and additional systemic disorders were also recorded. RESULTS: A total of 21 patients (13 males and 8 females) were included in the study. According to the location of schizencephaly, the patients were classified into two groups: unilateral (n = 16) and bilateral (n = 5). The majority of the patients with neurological deficits were detected before 1 year of age, especially in bilateral clefts. The most common initial presentation was hemiparesis in unilateral schizencephaly, and seizures in bilateral schizencephalies. Ventriculomegaly was the most common associated cerebral disorder, and the most common additional systemic disorders included congenital heart disease, hydronephrosis, and strabismus. Seventeen patients suffered from epileptic seizures with generalized tonic-clonic seizures being the most common. Eight patients developed refractory epilepsy. The majority of the patients had motor deficits, intellectual disabilities, and language deficits, especially in bilateral clefts. CONCLUSIONS: This study demonstrates that the clinical features of schizencephaly vary widely, with their severity closely related to the cleft. Determining the type, size, and extent of schizencephaly is useful to plan management and predict the prognosis.

Clinical and neuroimaging findings in children with gray matter heterotopias: A single institution experience of 36 patients.

OBJECTIVE: To describe the clinical spectrum and neuroimaging features of childhood gray matter heterotopias in a single tertiary hospital in Taiwan. METHODS: We retrospectively reviewed the medical records and magnetic resonance images (MRI) of 36 patients with gray matter heterotopias, 19 females and 17 males, between July 1999 and June 2014. The MRI morphologic findings of gray matter heterotopias were recorded along with the presence of associated cerebral malformations. The clinical, electrophysiological and associated systemic malformation data were also recorded. RESULTS: A total of 36 patients were included in the study. Their ages ranged from 1 month to 18 years with a mean age of 3 years 6 months. According to the location of gray matter heterotopias, patients were classified into two groups: periventricular (26) and band (10). The phenotypic spectrum in our population differed from that described previously. In the periventricular group, additional cerebral malformations were found in 18/26 (69%) and systemic malformations in 14/26 (54%). In the band group, additional cerebral malformations were found in 5/10 (50%) and systemic malformations in 2/10 (20%). The majority of patients had developmental delay and intellectual deficit. Twenty-two patients suffered from epileptic seizures with 12 developing refractory epilepsy. CONCLUSIONS: In periventricular heterotopias, the most common associated cerebral malformation was ventriculomegaly, followed by agenesis of corpus callosum. Congenital heart disease was the most common additional systemic malformation. However, the most common associated cerebral malformation was pachygyria in band form. The majority of patients had developmental delay, intellectual deficit, especially in band heterotopias.

Anti-N-methyl-D-aspartate receptor encephalitis in Taiwan--a comparison between children and adults.

BACKGROUND: Since the discovery of antibodies against the N-methyl-D-aspartate receptor in 2007, anti-N-methyl-D-aspartate receptor encephalitis is increasingly recognized worldwide. We compare the clinical features of adults and children with this disorder in Taiwan. METHODS: Patients admitted to Chang Gung Memorial Hospital and Chang Gung Children's Hospital and those who were referred from other institutions because of unknown encephalitis from 2009 to 2013 were enrolled, and their clinical features were analyzed. Data on cases from a review of the literature were also included in the analysis. RESULTS: Twelve patients (10 females) aged between 7 years and 28 years with anti-N-methyl-D-aspartate receptor encephalitis were identified. Six patients (50%) were <18 years old, one of whom was male and three of whom had an underlying tumor. Overall, 91.6% of the patients presented with mood, behavioral, or personality changes; 91.6% developed seizures; 100% had stereotyped movements; 83.3% had autonomic instability; and 66.7% had hypoventilation. Responses to immunotherapy were slow and variable. Overall, 63.6% of the patients had a substantial recovery after immunotherapy or removal of the tumor, and one patient experienced neurological relapses. There were no significant differences in clinical manifestations between children and adults. CONCLUSIONS: Anti-N-methyl-D-aspartate receptor encephalitis is increasingly recognized in Taiwan. It is characterized by its clinical features, predominantly affects females with and/or without an ovarian tumor, and it is a potentially treatable disorder. It is important for neurologists to be familiar with the clinical presentations of the disease in children and young adults.

Immunologic difference between hypersensitivity to mosquito bite and hemophagocytic lymphohistiocytosis associated with Epstein-Barr virus infection.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening, virus-triggered immune disease. Hypersensitivity to mosquito bite (HMB), a presentation of Chronic Active Epstein-Barr Virus infection (CAEBV), may progress to HLH. This study aimed to investigate the immunologic difference between the HMB episodes and the HLH episodes associated with EBV infection. Immunologic changes of immunoglobulins, lymphocyte subsets, cytotoxicity, intracellular perforin and granzyme expressions, EBV virus load and known candidate genes for hereditary HLH were evaluated and compared. In 12 HLH episodes (12 patients) and 14 HMB episodes (4 patients), there were both decreased percentages of CD4+ and CD8+ and increased memory CD4+ and activated (CD2+HLADR+) lymphocytes. In contrast to HMB episodes that had higher IgE levels and EBV virus load predominantly in NK cells, those HLH episodes with virus load predominantly in CD3+ lymphocyte had decreased perforin expression and cytotoxicity that were recovered in the convalescence period. However, there was neither significant difference of total virus load in these episodes nor candidate genetic mutations responsible for hereditary HLH. In conclusion, decreased perforin expression in the HLH episodes with predominant-CD3+ EBV virus load is distinct from those HMB episodes with predominant-NK EBV virus load. Whether the presence of non-elevated memory CD4+ cells or activated lymphocytes (CD2+HLADR+) increases the mortality rate in the HLH episodes remains to be further warranted through larger-scale studies.

Limbic encephalitis in Taiwanese children and adolescence: a single center study.

BACKGROUND: Non-viral limbic encephalitis, which may be paraneoplastic or idiopathic, is increasingly recognized in adults and children. Early identification of potential patients, who have neuronal autoantibodies to intracellular or neuronal surface antigens in order to give appropriate immunotherapy, is key to improving the prognosis. This cross-sectional study describes the clinical manifestation and the serological evidence of the presence of neuronal antibodies in Taiwanese children with limbic encephalitis. METHOD: We enrolled children and adolescents who had been hospitalized due to nonviral limbic encephalitis. Serum samples from these patients were collected to screen antibodies against intracellular antigens [amphiphysin, Ma2, Ri, Yo, Hu and antiglutamic acid decarboxylase (GAD)] and neuronal surface antigens [N-methyl-d-aspartate (NMDA) receptor, γ-amino butyric acid (GABAB) receptor and voltage-gated potassium channel complexes (VGKCs)]. RESULTS: All of the 10 enrolled patients had acute onset of fever and rapid clinical deterioration. They had persistent neuropsychiatric symptoms and 90% developed refractory epilepsy, despite six patients having been treated with methylprednisolone pulse therapy or intravenous immunoglobulin (IVIG) at the acute stage. In the laboratory findings, half of the cases were positive for antibodies with regards to intracellular antigens (amphiphysin or GAD). The general outcomes, assessed by Glasgow Outcome Scale, were similar between patients with and those without the antibodies (Mann-Whitney U test, p = 0.43). One patient, who was positive for antibodies to amphiphysin 10 years after disease onset, still had a significant response to oral prednisolone therapy. At the end of the follow-up period, no cancer or insulin-dependent diabetes mellitus was detected in any of the patients. CONCLUSION: This study provides evidence for a potential association between antibodies and limbic encephalitis. The presence of antibodies, especially antibodies to GAD, may serve as an indicator for immunotherapy.