A Case of X-Linked Adrenal Hypoplasia Congenital (AHC) Due to Large Deletion of NR0B1 (DAX1) and Contiguous Gene.

X-linked adrenal hypoplasia congenita (AHC) is caused predominantly by mutations in the NR0B1 (DAX1) gene. Among these, X-linked AHC due to a large deletion of NR0B1 is extremely rare. In Korea, the first case was reported in 2005, and there have been no further documented cases since then. Herein, we report a unique case of X-linked AHC caused by an entire gene deletion that includes the NR0B1 gene and seven other genes. A seven-day-old boy presented to a pediatric endocrine clinic with prolonged postnatal jaundice, skin hyperpigmentation, hyponatremia, and hyperkalemia, suggestive of an adrenal crisis. In genetic analysis, next-generation sequencing panel for congenital adrenal hyperplasia (CAH) showed no variants. However, chromosomal microarray results revealed large deletion of Xp21.2 (29,655,007_30,765,126) including eight protein-coding genes (NR0B1, IL1RAPL1, GK, MAGEB1-4, TASL). In cases of atypical adrenal insufficiency and genetically undiagnosed CAH, NR0B1-related AHC should be suspected, as Xp21 deletion is very rare and not detected in NGS, making microarray the best option for genetic diagnosis.

Increased pulsatility index of the basilar artery is a risk factor for neurological deterioration after stroke: a case control study.

BACKGROUND: Higher pulsatility of the middle cerebral artery (MCA) is known to be associated with stroke progression. We investigated whether pulsatility index (PI) of the basilar artery (BA) can predict neurological deterioration (ND) after acute cerebral infarction. METHODS: A total of 708 consecutive patients with acute ischemic stroke who had undergone transcranial Doppler (TCD) ultrasonography were included. ND was defined as an increase in the National Institutes of Health Stroke Scale scores by two or more points after admission. The patients were categorized into quartiles according to BA PI. Multivariable logistic regression analysis was performed to examine whether BA PI is independently associated with ND. RESULTS: BA PI was well correlated with the right (n = 474, r2 = 0.573, P < 0.001) by Pearson correlation analysis although MCA PI could not be measured from right MCA (n = 234, 33.05%) and left MCA (n = 252, 35.59%) by TCD owing to insufficient temporal bone window. Multivariable logistic regression analysis including age, sex, cerebral atherosclerosis burden, National Institutes of Health Stroke Scale at admission, and the proportion of patients with current smoking status, hypertension, diabetes mellitus, atrial fibrillation revealed that the higher BA PI (odds ratio, 3.28; confidence interval, 1.07-10.17; P = 0.038) was independently associated with ND. CONCLUSIONS: BA PI, which would be identified regardless of temporal window, could predict ND among acute stroke patients.

The diagnostic values of red flags in pediatric patients with headache.

BACKGROUND: Headache is a common complaint in childhood and adolescence. Differentiating benign primary headaches from ominous secondary headaches is often difficult. Clinicians usually seek red flags to determine the need for neuroimaging. We aimed to evaluate the diagnostic values of red flags in pediatric headaches. METHODS: We retrospectively reviewed the medical records of 1510 pediatric patients (1470 with primary headache, 40 with secondary headache) presenting with headache and underwent neuroimaging from two centers between March 2010 and December 2019. RESULTS: The secondary-headache group exhibited significantly higher frequencies of abnormal neurologic signs/symptoms (40.0% vs 6.8%, p < 0.001), Valsalva maneuver/exercise-induced headache (15.0% vs 4.9%, p = 0.004), headache with vomiting (35.0% vs 17.9%, p = 0.006), and onset under age 6 (25.0% vs 10.3%, p = 0.003) than the primary-headache group, with the following positive likelihood ratio (PLR): 5.88, 3.06, 1.96, and 2.42, respectively. The sensitivity values were as follows: abnormal neurologic signs/symptoms (16/40, 40.0%), headache with vomiting (14/40, 35.0%), onset under age 6 (10/40, 25.0%), and Valsalva maneuver/exercise-induced headache (6/40, 15.0%). The overall sensitivity for ominous secondary headaches requiring surgical treatment was 86.2% (25/29). CONCLUSIONS: Certain red flags, including abnormal neurologic signs/symptoms, Valsalva maneuver/exercise-induced headache, headache with vomiting, and onset under age 6, were more prevalent in the secondary-headache group; nonetheless, their sensitivity values and PLR were relatively low. Notwithstanding, considering these red flags' high overall sensitivity for ominous secondary headaches, neuroimaging in patients presenting these red flags should rely on careful follow-up of symptom progression.

Changes in the Epidemiology and Causative Pathogens of Meningitis in Children After the Outbreak of the Coronavirus Disease 2019: A Multicenter Database Study.

Background: With the outbreak of the COVID-19 pandemic, non-pharmaceutical interventions such as social distancing have been implemented worldwide, and a decrease in other infectious diseases has been reported as an unexpected benefit. However, to date, studies are lacking regarding the effects of the COVID-19 pandemic on neuroinfectious diseases; therefore, we aimed to determine the effects of the COVID-19 pandemic on the incidence of meningitis, which is the most common infectious disease in children. Methods: This retrospective study used electronic medical record data from five university hospitals located in the metropolitan cities in Korea. This study included patients aged <18 years who were diagnosed with meningitis between January 2017 and December 2020. We analyzed the clinical characteristics of patients with meningitis and changes in the incidence and causative pathogens of meningitis before and after the COVID-19 outbreak. Results: The study included 677 patients with meningitis. Following the outbreak of COVID-19 in Korea in January 2020, the incidence of childhood meningitis significantly decreased and seasonal changes noted yearly disappeared. There was a difference in the age distribution of patients with meningitis. The incidence of meningitis decreased significantly in children aged >5 years, and the incidence in children <5 years of age relatively increased (p < 0.001). In addition, there was a notable decrease in the cases of suspected meningitis (p < 0.001). The incidence of enteroviral meningitis, the most common cause of meningitis, significantly decreased. Conclusion: After the COVID-19 outbreak, the incidence of childhood meningitis significantly decreased with the implementation of non-pharmaceutical interventions. Absence of enteroviral meningitis and decrease in the proportion of patients aged ≥5 years with meningitis having mild symptoms were noted. Consequently, it can be concluded that the non-pharmaceutical interventions (NPIs) instituted to prevent the spread of COVID-19 had some effect on reducing the incidence of meningitis.

One-year changes in the pediatric emergency department caused by prolonged coronavirus disease 2019 pandemic.

BACKGROUND: With the coronavirus disease 2019 (COVID-19) pandemic lasting for more than a year, it is imperative to identify the associated changes in the use of emergency medical care for efficient operation of the pediatric emergency department (PED). This study was conducted to determine the long-term impact of the COVID-19 pandemic on patterns of PED visits. METHODS: This is a retrospective observational study of visits to the PED of six hospitals, between January 1, 2017, and December 31, 2020. We compared changes in the characteristics of patients before and during the COVID-19 pandemic. RESULTS: A total of 245 022 visits were included in this analysis. After the first case of COVID-19 was reported in Korea, we observed a significant decrease (54.2%) in PED visits compared with the annual average number of visits in the previous 3 years. Since then, the weekly number of PED visits decreased by 11.9 person/week (95% CI: -15.3--8.4, P < 0.001), which included an increase of 0.21% (95% CI: 0.15%-0.26%, P < 0.001) per week in high acuity patients. From 2017 to 2020, the proportion of infectious respiratory diseases by year was 25.9%, 27.0%, 28.6%, and 16.3%, respectively, demonstrating a significant decrease in 2020 (P < 0.001). CONCLUSIONS: During the COVID-19 pandemic, the number of patient visits to PEDs continues to decline, especially among those with infectious diseases. However, the disease severity of patients has gradually increased. There has been a change in the characteristics of visits to PEDs after COVID-19 which will require an appropriate response from a long-term perspective.

The Role of Focal Epilepsy Features in Defining SCN1A Mutation-positive Dravet Syndrome as Generalized and Focal Epilepsy.

BACKGROUND AND PURPOSE: This study was aimed to describe focal epilepsy features of SCN1A mutation-positive Dravet syndrome patients. METHODS: A total of 82 SCN1A mutation-positive patients were reviewed retrospectively (39 boys and 43 girls). Seizure type and electroencephalography (EEG) findings were investigated according to the stage, disease onset, and steady state (after age 2 years). Long-term video EEG data were used to classify the seizure type. RESULTS: Focal seizures at onset and the steady state were found in 54.9% (45/82) and 90% (63/70) of patients, respectively. Afebrile focal seizures were an initial seizure in about one fourth of the patients (22/82, 26.8%). Of 48 seizures captured during long-term video EEG monitoring of 30 patients, 19 seizures were classified as focal onset (39.6%). Of the 19 focal seizures, 12 were either focal motor or focal non-motor seizures, and seven were focal onset bilateral tonic-clonic seizure. Focal epileptiform discharges were more frequent than generalized epileptiform discharges at seizure onset and during the clinical course on conventional EEG (3.7% vs. 0%, 52.9% vs. 32.9%, respectively). CONCLUSIONS: Our study provides a comprehensive description of focal epilepsy features of SCN1A mutation-positive Dravet syndrome patients. Recognizing these features as defining the clinical spectrum of Dravet syndrome may lead to earlier genetic diagnosis and tailored management.

Clinical Spectrum of Myelin Oligodendrocyte Glycoprotein-Immunoglobulin G-Associated Disease in Korean Children.

BACKGROUND AND PURPOSE: The myelin oligodendrocyte glycoprotein (MOG) antibody is detected at a high rate in childhood acquired demyelinating syndrome (ADS). This study aimed to determine the diagnostic value of the MOG antibody in ADS and the spectrum of MOG-antibody-positive demyelinating diseases in children. METHODS: This study included 128 patients diagnosed with ADS (n=94) or unexplained encephalitis (n=34). The MOG antibody in serum was tested using an in-house live-cell-based immunofluorescence assay. RESULTS: The MOG antibody was detected in 48 patients (46 ADS patients and 2 encephalitis patients, comprising 23 males and 25 females). Acute disseminated encephalomyelitis (ADEM) (35.4%) was the most-common diagnosis, followed by the unclassified form (17.4%), isolated optic neuritis (ON) (15.2%), neuromyelitis optica spectrum disorder (13.0%), multiple sclerosis (MS) (10.8%), other clinically isolated syndromes [monophasic event except ADEM, isolated ON, or transverse myelitis (TM)] (8.7%), and unexplained encephalitis (4.3%). At the initial presentation, 35 out of the 46 patients with ADS had brain lesions detected in magnetic resonance imaging, and 54% of these 35 patients had encephalopathy. Nine of the 11 patients without brain lesions exhibited only ON. Thirty-nine percent of the patients experienced a multiphasic event during the mean follow-up period of 34.9 months (range 1.4-169.0 months). Encephalopathy at the initial presentation was frequently confirmed in the monophasic group (p=0.011). CONCLUSIONS: MOG antibodies were identified in all pediatric ADS phenotypes except for monophasic TM. Therefore, the MOG antibody test is recommended for all pediatric patients with ADS, especially before a diagnosis of MS and for patients without a clear diagnosis.

Erratum to: Elevated Serum Uric Acid in Benign Convulsions with Mild Gastroenteritis in Children.

This corrects the article on p. 496 in vol. 15, PMID: 31591838.

Elevated Serum Uric Acid in Benign Convulsions with Mild Gastroenteritis in Children.

BACKGROUND AND PURPOSE: To identify whether serum uric acid levels are significantly higher in patients with benign convulsion associated with mild gastroenteritis (CwG) than in patients with acute gastroenteritis. METHODS: This retrospective study compared the serum levels of uric acid between CwG, acute gastroenteritis, and febrile seizure after correcting for the varying degree of mild dehydration using serum HCO3- levels. We also compared the serum uric acid levels between patients with CwG and febrile seizures in order to exclude the effect of seizures on uric acid. RESULTS: This study included 154 CwG patients (age range 0.73-3.19 years), 2,938 patients with acute gastroenteritis, and 154 patients with febrile seizure. The serum uric acid level was significantly higher in CwG patients than in patients with acute gastroenteritis [9.79±2.16 mg/dL vs. 6.04±2.3 mg/dL (mean±SD), p<0.001]. This difference was also significant after correcting for dehydration. The serum uric acid level was significantly higher in CwG patients than in dehydration-corrected acute gastroenteritis patients (9.79±2.16 mg/dL vs. 6.67±2.48 mg/dL, p<0.001). The serum uric acid level was not elevated in patients with febrile seizure. CONCLUSIONS: We have confirmed that serum uric acid is elevated in CwG patients even after correcting for their dehydration status, and that this was not a postictal phenomenon. Highly elevated serum uric acid in CwG could be a useful clinical indicator of CwG in patients with acute gastroenteritis.

The Anti-Inflammatory Effect of Sulforaphane in Mice with Experimental Autoimmune Encephalomyelitis.

BACKGROUND: Multiple sclerosis (MS) is an immune-associated inflammatory disorder of the central nervous system and results in serious disability. Although many disease-modifying therapy drugs have been developed, these drugs have shown limited clinical efficacy and some adverse effects in previous studies, therefore, there has been reasonable need for less harmful and cost-effective therapeutics. Herein, we tested the anti-inflammatory effect of sulforaphane (SFN) in a mouse model of experimental autoimmune encephalomyelitis (EAE). METHODS: The EAE mice were randomly assigned into two experimental groups: the phosphate-buffered saline (PBS)-treated EAE group and SFN-treated EAE group. After EAE mice induction by auto-immunization against the myelin oligodendrocyte glycoprotein peptide, we evaluated EAE symptom scores and biochemical analyses such as infiltration of inflammatory cells and demyelination of the spinal cord. Furthermore, western blotting was performed using the spinal cords of EAE mice. RESULTS: In the behavioral study, the SFN-treated EAE mice showed favorable clinical scores compared with PBS-treated EAE mice at the 13th day (1.30 ± 0.15 vs. 1.90 ± 0.18; P = 0.043) and 14th day (1.80 ± 0.13 vs. 2.75 ± 0.17; P = 0.003). Additionally, the biochemical studies revealed that SFN treatment inhibited the inflammatory infiltration, demyelinating injury of the spinal cords, and the up-regulation of inducible nitric oxide synthase in the EAE mice. CONCLUSION: The SFN treatment showed anti-inflammatory and anti-oxidative effects in the EAE mice. Conclusively, this study suggests that SFN has neuroprotective effects via anti-inflammatory processing, so it could be a new therapeutic or nutritional supplement for MS.

Incidence and mechanism of early neurological deterioration after endovascular thrombectomy.

BACKGROUND: We investigated the prevalence and mechanisms of neurological deterioration after endovascular thrombectomy. METHODS: Between January 2011 and October 2017, acute ischemic stroke patients treated by endovascular thrombectomy in a tertiary university hospital were included. Early neurological deterioration (END) was defined as an increase of 2 or more National Institute of Health Stroke Scale (NIHSS) compared to the best neurological status after stroke within 7 days. The END mechanism was categorized into ischemia progression, symptomatic hemorrhage, and brain edema. RESULTS: A total of 125 acute ischemic stroke patients received endovascular thrombectomy. Neurological deterioration was detected in 44 patients, and 38 cases (86.4% of END) occurred within 72 h. The END mechanism included 20 ischemia progression, 16 brain edema and 8 hemorrhagic transformation cases. Multivariable logistic regression analysis revealed that the patients who experienced END were more likely to have poor functional outcome defined as modified Rankin scale 3-6 at 90 days than neurologically stable patients (odds ratio (OR) = 4.06, confidence interval (CI) = 1.39-11.9). The risk factor of END due to ischemia progression was stroke subtype of large artery atherosclerosis (OR = 6.28, CI = 1.79-22.0). Successful recanalization (OR = 0.11, CI = 0.03-0.39) and NIHSS after endovascular thrombectomy (OR = 1.15 per one-point increase, CI = 1.06-1.24) were significantly associated with END due to hemorrhage or brain edema. CONCLUSION: Neurological deterioration frequently occurs after endovascular thrombectomy, and the risk factors of END differ according to the mechanism of END.

Factors Associated with Favorable Outcome of Topiramate Migraine Prophylaxis in Pediatric Patients.

BACKGROUND AND PURPOSE: There are few studies that have investigated predictive factors related to migraine prophylaxis of which produced inconsistent results. The aim of this study was to identify factors that can predict the treatment response to topiramate prophylaxis in pediatric patients with migraine. METHODS: One hundred and thirteen patients who were older than 7 years and received topiramate for at least 3 months were recruited from the Seoul National University Bundang Hospital outpatient clinic from 2005 to 2014. A positive response was defined as a reduction of more than 50% in the number of migraine episodes after topiramate treatment. Proposed predictive factors such as migraine characteristics including severity and frequency were assessed, as were other data on sex, disease duration, associated symptoms, family history, and impairment of daily activities. RESULTS: Seventy patients (61.9%) responded to prophylactic treatment with topiramate. Patients who experienced significant impairment in daily activities showed significant benefit from the treatment (p=0.004). Sex, the severity, frequency, and duration of migraine episodes, disease duration, treatment duration, age at onset, and associated symptoms were not significantly related to a response to topiramate treatment. CONCLUSIONS: Migraine characteristics and associated symptoms were not significantly related to a response to topiramate treatment. However, patients with significant impairment in daily activities showed significant benefit from the treatment, and so prophylactic topiramate treatment should be strongly encouraged in this patient group.

Large-scale structural alteration of brain in epileptic children with SCN1A mutation.

OBJECTIVE: Mutations in SCN1A gene encoding the alpha 1 subunit of the voltage gated sodium channel are associated with several epilepsy syndromes including genetic epilepsy with febrile seizures plus (GEFS +) and severe myoclonic epilepsy of infancy (SMEI). However, in most patients with SCN1A mutation, brain imaging has reported normal or non-specific findings including cerebral or cerebellar atrophy. The aim of this study was to investigate differences in brain morphometry in epileptic children with SCN1A mutation compared to healthy control subjects. METHODS: We obtained cortical morphology (thickness, and surface area) and brain volume (global, subcortical, and regional) measurements using FreeSurfer (version 5.3.0, https://surfer.nmr.mgh.harvard.edu) and compared measurements of children with epilepsy and SCN1A gene mutation (n = 21) with those of age and gender matched healthy controls (n = 42). RESULTS: Compared to the healthy control group, children with epilepsy and SCN1A gene mutation exhibited smaller total brain, total gray matter and white matter, cerebellar white matter, and subcortical volumes, as well as mean surface area and mean cortical thickness. A regional analysis revealed significantly reduced gray matter volume in the patient group in the bilateral inferior parietal, left lateral orbitofrontal, left precentral, right postcentral, right isthmus cingulate, right middle temporal area with smaller surface area and white matter volume in some of these areas. However, the regional cortical thickness was not significantly different in two groups. SIGNIFICANCE: This study showed large-scale developmental brain changes in patients with epilepsy and SCN1A gene mutation, which may be associated with the core symptoms of the patients. Further longitudinal MRI studies with larger cohorts are required to confirm the effect of SCN1A gene mutation on structural brain development.

Eosinophilic Granulomatosis with Polyangiitis Presented as Acute Polyneuropathy and Cerebral Vasculitis.

Eosinophilic granulomatosis with polyangiitis (EGPA) is an immune related systemic disease that is caused by vasculitis affecting multiple organ systems. It is characterized by asthma, fever, eosinophilia, cardiac problems, renal injury, and peripheral neuropathy. In this report, we describe a patient with EGPA with concurrent cerebral infarction and acute polyneuropathy mimicking a Guillain-Barre syndrome (GBS). A 46-year-old man presented with rapidly progressing gait disturbance, muscular weakness, and tingling sensation in all four limbs. A nerve conduction study revealed sensorimotor polyneuropathy in all four limbs, and a test of the cerebrospinal fluid showed an albumin-cytologic dissociation. In addition, brain magnetic resonance imaging (MRI) using fluid-attenuated inversion recovery and diffusion weighted MRI revealed high signal intensity lesions with gadolinium enhancement on T1-weighted MRI in the right caudate nucleus. After performing laboratory tests, paranasal sinus computed tomography, and a nasal smear, the patient was diagnosed with EGPA and treated with high dose glucocorticoid and oral cyclophosphamide. In conclusion, our findings indicate that a diagnosis of EGPA should be considered when a patient presents with rapidly progressing polyneuropathy mimicking a GBS along with unusual systemic symptoms or brain lesions.

Averaged EEG spike dipole analysis may predict atypical outcome in Benign Childhood Epilepsy with Centrotemporal Spikes (BCECTS).

PURPOSE: Benign Childhood Epilepsy with Centrotemporal Spikes (BCECTS) is the most common childhood idiopathic focal epilepsy with a good outcome. However, an increasing number of reports suggest a 'not so benign' outcome showing atypical evolution. METHODS: We analyzed the electroencephalographic (EEG) spike source dipoles of BCECTS patients to compare patients with confirmed typical and atypical outcome showing intractable epilepsy and cognitive decline. Thirty-seven patients that were diagnosed for BCECTS and whose clinical information was sufficient enough to confirm long-term outcome were included in the study. Eight patients (22%, 7 patients for poor seizure control and 1 patient for cognitive decline) were classified as showing atypical outcome. Forty-seven averaged spike dipole sources were analyzed using the single equivalent current dipole (ECD) method. The inverse problem was solved using the 4 shells ellipsoidal model. RESULTS: The coordinate value of yori differed significantly between the two groups (mean±standard deviation, 0.32±0.33 for the typical group and -0.33±0.77 for the atypical group, P<0.001). These findings suggest that the averaged spike source dipoles were oriented anteriorly in patients with typical outcome and posteriorly in patients with atypical outcome. Spike source dipoles seemed to be located higher in patients with atypical presentation but this finding was insignificant. CONCLUSION: We can conclude that there are significant differences in spike source dipole in patients with BCECTS that shows atypical outcome, and we can use this finding as a marker for predicting an outcome at the time of diagnosis.