Coronavirus disease 2019-associated acute necrotizing encephalopathy in a 9-year-old boy

Coronavirus disease 2019 (COVID-19) is associated with a variety of neurologic manifestations. Acute necrotizing encephalopathy (ANE) is a rare, life-threatening complication characterized by rapid deterioration of neurologic status following viral infection, such as influenza or human herpesvirus 6. Since the COVID-19 pandemic, a rise in ANE cases associated with the infectious disease has been reported in adult patients. We present a case of COVID-19-associated ANE in a 9-year-old boy. The patient experienced 3 days of fever and mild respiratory symptoms, followed by lethargy. Magnetic resonance imaging on day 4 showed hyperintensity in the bilateral thalami, midbrain, pons, hypothalamus, and cerebellum, along with some areas of hemorrhage. From the imaging findings, ANE was strongly suspected, leading to the initiation treatment involving a 5-day course of remdesivir and multiple immunomodulator therapies, including high-dose corticosteroids, intravenous immunoglobulin, tocilizumab, and 10 cycles of therapeutic plasma exchange. Subsequently, the patient gradually improved, experiencing only minor neurological sequelae and showing favorable radiologic improvement. In COVID-19-infected patients presenting neurologic symptoms, it is crucial to promptly suspect and investigate unexplained encephalopathy using neuroimaging. Early administration of immunomodulator therapy is vital for the diagnosis and optimizing clinical outcomes.

The Early Response to Dietary Therapy can Predict the Late Outcome in Children with Intractable Epilepsy

Background@#and Purpose Dietary therapy (DT), including the ketogenic diet (KD), is one of the nonpharmacological treatment options for patient with drug-resistant epilepsy. However, maintaining DT in patients without seizure reduction is very difficult, so it is critical for clinicians to decide when to stop this intervention. @*Methods@#We retrospectively analyzed early clinical and laboratory findings and the clinical characteristics of children who received DT. The maintenance of DT and the clinical seizure frequency were assessed at 1, 3, 6, 12, and 24 months after KD initiation. Responders were defined as patients showing an overall reduction in seizure frequency of >50% relative to the baseline. @*Results@#We included 67 patients who received DT, but only 23 (34.3%) of these patients remained on DT at 6 months. Only 1 (5%) of the 20 responders at 1 month became a nonresponder at 6 months. The response rate at 6 months was significantly higher among patients under 2 years of age (15/17, 88.2%) than older patients (2/6, 33.3%; p=0.021). Moreover, the 6-month responders were significantly younger (29.4±38.6 months, mean±SD) than the nonresponders (98.9±84.6 months, p=0.012) at the initiation of the diet. A high blood β-hydroxybutyrate (BHB) level at 1 month predicted a good DT response at 6 months. @*Conclusions@#Most 1-month responders maintained their response on DT for up to 6 months.The blood BHB level at 1 month was significantly correlated with the 6-month seizure outcome.Confirming clinical and laboratory biomarkers for the efficacy of DT requires further studies with larger cohorts.

Pediatric Sedation in the Emergency Department: Trends from a Nationwide Population-based Study in Korea, 2007–2018

Background@#Pediatric sedation in the emergency department (ED) is widely performed in Korea; thus exploring the trends of its use is necessary. This study aimed to investigate the characteristics of patients and sedatives use in the ED and verify their changes over recent years. @*Methods@#A nationwide population-based retrospective study was conducted including pediatric patients aged ≤ 15 years who received sedative medication in the ED and were discharged during 2007–2018, using the Korean Health Insurance Review and Assessment Service database. Patient characteristics (age, sex, level of ED, and diagnosis) and type of sedative used were analyzed. @*Results@#Sedation was performed in total 468,221 visits during 2007–2018 (399,320 visits, at least 3.8% of overall ED visits during 2009–2018). Among these, 71.0% were children aged 1–3 years and 93.5% were sedated to support diagnosis of injury. An increase in total sedation was observed in patients aged 4–6 years during the study period (from 13.8% to 21.8%). A gradual decrease in the use of chloral hydrate (CH) compared with an increase in ketamine use was observed (CH, from 70.6% to 28.6%; ketamine, from 23.8% to 60.7%). Therefore, ketamine was the most used sedative since 2014. The most frequently used sedatives over the study period differed according to age groups (CH in <1 year and 1–3 years; ketamine in 4–6 years and 7–10 years; and midazolam in 11–15 years). @*Conclusions@#The characteristics of patients related to sedatives use in the ED have changed over time. These changes should be considered in the development of future Korean guidelines regarding pediatric sedation in the ED.

Pediatric Sedation in the Emergency Department: Trends from a Nationwide Population-based Study in Korea, 2007–2018

Background@#Pediatric sedation in the emergency department (ED) is widely performed in Korea; thus exploring the trends of its use is necessary. This study aimed to investigate the characteristics of patients and sedatives use in the ED and verify their changes over recent years. @*Methods@#A nationwide population-based retrospective study was conducted including pediatric patients aged ≤ 15 years who received sedative medication in the ED and were discharged during 2007–2018, using the Korean Health Insurance Review and Assessment Service database. Patient characteristics (age, sex, level of ED, and diagnosis) and type of sedative used were analyzed. @*Results@#Sedation was performed in total 468,221 visits during 2007–2018 (399,320 visits, at least 3.8% of overall ED visits during 2009–2018). Among these, 71.0% were children aged 1–3 years and 93.5% were sedated to support diagnosis of injury. An increase in total sedation was observed in patients aged 4–6 years during the study period (from 13.8% to 21.8%). A gradual decrease in the use of chloral hydrate (CH) compared with an increase in ketamine use was observed (CH, from 70.6% to 28.6%; ketamine, from 23.8% to 60.7%). Therefore, ketamine was the most used sedative since 2014. The most frequently used sedatives over the study period differed according to age groups (CH in <1 year and 1–3 years; ketamine in 4–6 years and 7–10 years; and midazolam in 11–15 years). @*Conclusions@#The characteristics of patients related to sedatives use in the ED have changed over time. These changes should be considered in the development of future Korean guidelines regarding pediatric sedation in the ED.

Clinical Implications of Ketosis in Children with Benign Convulsions with Mild Gastroenteritis

Altered Structural Network in Newly Onset Childhood Absence Epilepsy

Background@#and Purpose: Recent quantitative neuroimaging studies of childhood absence epilepsy (CAE) have identified various structural abnormalities that might be involved in the onset of absence seizure and associated cognitive and behavioral functions. However, the neuroanatomical alterations specific to CAE remain unclear, and so this study investigated the regional alterations of brain structures associated with newly diagnosed CAE. @*Methods@#Surface and volumetric magnetic resonance imaging data of patients with newly diagnosed CAE (n=18) and age-matched healthy controls (n=18) were analyzed using FreeSurfer software. A group comparison using analysis of covariance was performed with significance criteria of p<0.05 andp<0.01 in global and regional analyses, respectively. @*Results@#Compared with control subjects, the patients with CAE had smaller total and regional volumes of cortical gray-matter (GM) in the right rostral middle frontal, right lateral orbitofrontal, and left rostral middle frontal regions, as well as in the right precentral, right superior, middle, left middle, and inferior temporal gyri. The cortex in the right posterior cingulate gyrus and left medial occipital region was significantly thicker in patients with CAE than in controls. @*Conclusions@#Patients with CAE showed a reduced bilateral frontotemporal cortical GM volume and an increased posterior medial cortical thickness, which are associated with the default mode network. These structural changes can be suggested as the neural basis of the absence seizures and neuropsychiatric comorbidities in CAE.

Treatment of Children and Adolescents with Epilepsy with Atomoxetine

Objective@#The objective of this study was to assess the effectiveness and safety of atomoxetine in Korean children and adolescents with epilepsy. @*Methods@#We retrospectively reviewed the electronic medical records of 105 children and adolescents with epilepsy treated with atomoxetine. Effectiveness was measured with the Clinical Global Impressions-Severity (CGI-S) and/or Clinical Global Impressions-Improvement (CGI-I) scales at baseline, and after 4 and 12 weeks. We defined response to atomoxetine as a CGI-I score less than three at week 12. Safety was evaluated at each visit, based on clinical assessment by a child and adolescent psychiatrist and reports from participants or their caregivers. @*Results@#In total participants (n=105), 33 (31.4%) showed a response to treatment: a significant decrease in CGI-S scale score was observed over 12 weeks of atomoxetine treatment. The most common adverse event (AE) was decreased appetite (n=16, 15.2%), and life-threatening AEs were not observed. Seizure aggravation due to atomoxetine was observed in 7.6% (n=8) of total participants, and one of them discontinued atomoxetine. @*Conclusion@#Our results provide preliminary evidence of the effectiveness and safety of atomoxetine in children and adolescents with epilepsy.

Psychological Impact of Quarantine on Caregivers at a Children's Hospital for Contact with Case of COVID-19

Quarantine often provokes negative psychological consequences. Thus, we aimed to identify the psychological and behavioral responses and stressors of caregivers quarantined with young patients after a close contact to a coronavirus disease 2019 case at a children's hospital. More than 90% of the caregivers reported feelings of worry and nervousness, while some of them reported suicidal ideations (4.2%), and/or homicidal ideations (1.4%). Fear of infection of the patient (91.7%) and/or oneself (86.1%) were most frequently reported stressors. A multidisciplinary team including infection control team, pediatrician, psychiatrist, nursing staff and legal department provided supplies and services to reduce caregiver's psychological distress. Psychotropic medication was needed in five (6.9%), one of whom was admitted to the psychiatry department due to suicidality. Quarantine at a children's hospital makes notable psychological impacts on the caregivers and a multidisciplinary approach is required.

A long-term subacute sclerosing panencephalitis survivor treated with intraventricular interferon-alpha for 13 years / 소아과

Subacute sclerosing panencephalitis (SSPE) is a rare, progressive, and fatal central nervous system disorder resulting from persistent measles virus infection. Long-term data are scarce, with a maximum follow-up period of 10 years. Interferon-alpha (IFN-α) is a protein that exerts its antiviral activity via enhancement of cellular immune response and is reported to be an effective drug for the treatment of SSPE. However, there is currently no consensus regarding the optimal duration of IFN-α therapy. Here, we present a case report of a patient with SSPE treated with long-term intraventricular IFN-α therapy, which facilitated clinical improvement and neurological stabilization without causing serious adverse effects. To the best of our knowledge, this is one of the longest follow-up studies investigating a patient with SSPE receiving intraventricular INF-α treatment. Further studies are necessary to validate the benefits and safety of long-term intraventricular IFN-α treatment in patients with SSPE.

Efficacy and Tolerability of Low-Dose Perampanel in Patients with Childhood-Onset Intractable Epilepsy / 대한소아신경학회지

PURPOSE@#The aim of this study was to evaluate the efficacy and tolerability of perampanel as adjunctive therapy in childhood-onset refractory epilepsy.@*METHODS@#We retrospectively reviewed the medical records of 110 patients who were treated with perampanel in Asan Medical Center children's hospital. Two patients with poor compliance were excluded and 108 patients were enrolled. The clinical characteristics were reviewed, and the total seizure frequency before and after the add-on of perampanel was analyzed.@*RESULTS@#The mean age of the patients (64 males) was 20.2 years (range, 10.5 to 35.6). The mean maintenance dose was 4.8 mg/day (2 to 10 mg). Eight patients (7.4%) achieved seizure freedom and 35 (32.4%) achieved a seizure reduction of ≥50%. Among them, three patients achieved seizure freedom with only 2 mg/day of perampanel. There was no significant difference in sex, age at seizure onset, duration of epilepsy, use of concomitant enzyme-inducing antiepileptic drugs, number of concomitant antiepileptic drugs, and adverse events between responders and non-responders. The retention rate was up to 68.0% in the first year and 59.5% in the second year of the study. Thirty-four patients (31.5%) reported adverse events: violence, somnolence, dizziness, drooling, weight gain, insomnia, and vomiting. There was no contributing factor for the adverse events, including sex, age, and the number of concomitant antiepileptic drugs and enzyme-inducing antiepileptic drugs when comparing the adverse event present group with the adverse event absent group.@*CONCLUSION@#Low-dose perampanel showed reasonable efficacy and tolerability in patients with refractory childhood-onset epilepsy. Further validation with pharmacokinetic studies is needed.

Two Cases of Hirayama Disease in a Pediatric Clinic / 대한소아신경학회지

We report two pediatric cases with Hirayama disease—a 16-year-old boy with a left wrist drop and a 14-year-old-boy with weakness and muscle atrophy of right hand. Motor nerve conduction study revealed decreased motor nerve action potential amplitudes in the ulnar nerve and radial nerve of the affected hands. The former patient showed normal magnetic resonance imaging (MRI) of the cervical spine, but the latter showed mild, asymmetric thinning of the anterior spinal cord at levels C5 to C7. Following active rehabilitation and avoidance of neck flexion, no further progression of neurological findings was noticed. These clinical findings were typical of Hirayama disease. We show that timely and accurate diagnosis for Hirayama disease is possible with awareness of disease history, careful physical examination, and the use of neurophysiological studies and MRI studies.

Moyamoya disease in a 3-year-old boy presenting with a focal motor seizure provoked by hyperventilation

A previously healthy, 3-year-old boy presented to the emergency department with an afebrile focal motor seizure. He was found crying and having a seizure 30 minutes earlier. During this seizure, he was jerking his head and right extremities. Subsequent magnetic resonance imaging showed acute infarction in the bilateral frontal lobes, chiefly in the left. After hospitalization, conventional angiography demonstrated bilateral stenosis of the distal internal carotid arteries with development of lenticulostriate collaterals, which confirmed the diagnosis of moyamoya disease. It is vital to recognize focal motor seizures and situations related to hyperventilation in children with a seizure, which imply a structural lesion and a provoked cerebral ischemia in preexisting moyamoya disease, respectively.

Rufinamide in Patients with Childhood Onset Intractable Epilepsy

PURPOSE: This study is aimed to evaluate the effectiveness and tolerability of rufinamide as add-on therapy in patients with intractable epilepsies. METHODS: We retrospectively reviewed the medical records of 70 patients treated with rufinamide in Asan Medical Center, children's hospital. Two cases with incomplete medical records were excluded and total sixty-eight cases were enrolled. Rufinamide was added on the existing antiepileptic drugs and the total seizure frequency at pre-medication, 3 months and 12 months were examined. RESULTS: The mean age of 68 patients (43 male) was 10.5 yrs (range, 1-24 yrs). At 3 months after rufinamide initiation, 5 patients achieved freedom from seizures and 28 (41.2%) achieved a ≥50% seizure reduction. At 12 months, 7 patients achieved seizure freedom and 29 (42.6%) achieved ≥50% seizure reduction. The retention rate was hold up to 75.0% at 3 months and 66.2% at 12 months of study. Total 29 patients reported adverse events in order of seizure aggravation, somnolence, insomnia, common cold, nausea and vomiting. CONCLUSION: In this study, rufinamide is effective and tolerable in patients with other intractable epilepsy of childhood onset as well as the patients with LGS. Further research is required to define the efficacy of rufinamide in intractable epilepsy other than LGS.

Clinical Characteristics of Transplant-associated Encephalopathy in Children

We aimed to analyze characteristics of encephalopathy after both hematopoietic stem cell and solid organ pediatric transplantation. We retrospectively reviewed medical records of 662 pediatric transplant recipients (201 with liver transplantation [LT], 55 with heart transplantation [HT], and 67 with kidney transplantation [KT], 339 with allogeneic hematopoietic stem cell transplantation [HSCT]) who received their graft organs at Asan Medical Center between January 2000 and July 2014. Of the 662 patients, 50 (7.6%) experienced encephalopathy after transplantation. The incidence of encephalopathy was significantly different according to the type of organ transplant: LT, 16/201 (8.0%), HT, 13/55 (23.6%), KT, 5/67 (7.5%), and HSCT, 16/339 (4.7%) (P < 0.001). Drug-induced encephalopathy (n = 14) was the most common encephalopathy for all transplant types, but particularly after HSCT. Hypertensive encephalopathy was the most common after KT and HT, whereas metabolic encephalopathy was the most common after LT. The median time to encephalopathy onset also differed according to the transplant type: 5 days after KT (range 0–491 days), 10 days after HT (1–296 days), 49.5 days after HSCT (9–1,405 days), and 39 days after LT (1–1,092 days) (P = 0.018). The mortality rate among patients with encephalopathy was 42.0% (n = 21/50). Only 5 patients died of neurologic complications. Transplant-associated encephalopathy presented different characteristics according to the type of transplant. Specialized diagnostic approach for neurologic complications specific to the type of transplant may improve survival and quality of life in children after transplantation.

Identification of two novel Duchenne muscular dystrophies mutations in patients with Becker muscular dystrophy

Duchenne and Becker muscular dystrophies (DMD and BMD, respectively) are X-linked neuromuscular disorders characterized by progressive muscle weakness and severe skeletal muscle degeneration. BMD is a milder form with a later onset. Patients with BMD tend to survive much longer than those with DMD. The differentiation between DMD and BMD is important in the genetic counseling of affected patients and their families. Since muscle biopsies are invasive procedures, the differential diagnosis of BMD and DMD is often dependent on the mutation identified in the DMD gene in affected patients. However, when a novel DMD mutation is identified, the differential diagnosis should be based on muscle biopsy findings with other clinical findings. Here we describe two Korean patients with BMD confirmed by muscle biopsy and genetic testing. Two novel exonic deletions in the DMD gene were identified.

Genotype-Phenotype Correlation of SMN1 and NAIP Deletions in Korean Patients with Spinal Muscular Atrophy

BACKGROUND AND PURPOSE: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by progressive muscle weakness and atrophy. Most SMA patients have a homozygous deletion in survival of motor neuron 1 (SMN1) gene, and neuronal apoptosis inhibitory protein (NAIP) gene is considered a phenotype modifier. We investigated the genotype-phenotype correlation of SMN1 and NAIP deletions in Korean SMA patients. METHODS: Thirty-three patients (12 males and 21 females) treated at the Asan Medical Center between 1999 and 2013 were analyzed retrospectively. The polymerase chain reaction (PCR), restriction-fragment-length polymorphism analysis, and multiplex PCR were used to detect deletions in SMN1 (exons 7 and 8) and NAIP (exons 4 and 5). We reviewed clinical presentations and outcomes and categorized the patients into three clinical types. NAIP deletion-driven differences between the two genotypes were analyzed. RESULTS: Deletion analysis identified homozygous deletions of SMN1 exons 7 and 8 in 30 patients (90.9%). Among these, compared with patients without an NAIP deletion, those with an NAIP deletion showed a significantly lower age at symptom onset (1.9±1.7 months vs. 18.4±20.4 months, mean±SD; p=0.007), more frequent type 1 phenotype (6/6 vs. 8/24, p=0.005), and worse outcomes, with early death or a requirement for ventilator support (4/4 vs. 2/12, p=0.008). CONCLUSIONS: Homozygous deletion in SMN1 and a concurrent NAIP deletion were associated with an early onset, severe hypotonia, and worse outcome in SMA patients. Deletion analysis of NAIP and SMN1 can help to accurately predict prognostic outcomes in SMA.

Epileptic Spasms, a Journey to Find Therapeutics Based on Pathophysiology

After the first description of infantile spasms (IS) in 1841, extensive clinical and laboratory investigations have been done to find the pathophysiology and the optimal treatments. The concept of the “infantile spasms” has been evolved to the “epileptic spasms”, which includes the spasms outside the infancy the pathophysiology of IS, however, is still unknown. There have been a few randomized trials that proved the efficacy of the anecdotally used drugs in IS including hormonal therapy and vigabatrin. Due to its relative low incidence (1/2000) and the variable etiologies, clinical studies have difficulties in making a clear conclusion. Thus, animal models were eagerly sought to find the pathophysiology based treatments with definite efficacy and several models are now available. In this paper, the current understandings of the epileptic spasms as well as the translational researches using the animal models of IS are reviewed. The latest evidences of therapeutics in IS are discussed shortly.

Epilepsy and Other Neuropsychiatric Manifestations in Children and Adolescents with 22q11.2 Deletion Syndrome

BACKGROUND AND PURPOSE: 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome. Epilepsy and other neuropsychiatric (NP) manifestations of this genetic syndrome are not uncommon, but they are also not well-understood. We sought to identify the characteristics of epilepsy and other associated NP manifestations in patients with 22q11.2DS. METHODS: We retrospectively analyzed the medical records of 145 child and adolescent patients (72 males and 73 females) with genetically diagnosed 22q11.2DS. The clinical data included seizures, growth chart, psychological reports, development characteristics, school performance, other clinical manifestations, and laboratory findings. RESULTS: Of the 145 patients with 22q11.2DS, 22 (15.2%) had epileptic seizures, 15 (10.3%) had developmental delay, and 5 (3.4%) had a psychiatric illness. Twelve patients with epilepsy were classified as genetic epilepsy whereas the remaining were classified as structural, including three with malformations of cortical development. Patients with epilepsy were more likely to display developmental delay (odds ratio=3.98; 95% confidence interval=1.5-10.5; p=0.005), and developmental delay was more common in patients with structural epilepsy than in those with genetic epilepsy. CONCLUSIONS: Patients with 22q11.2DS have a high risk of epilepsy, which in these cases is closely related to other NP manifestations. This implies that this specific genetic locus is critically linked to neurodevelopment and epileptogenesis.

Erratum to: Epilepsy and Other Neuropsychiatric Manifestations in Children and Adolescents with 22q11.2 Deletion Syndrome

The publisher wishes to apologize for incorrectly displaying acknowledgement.

Two cases of familial cerebral cavernous malformation caused by mutations in the CCM1 gene / 소아과

Cerebral cavernous malformation (CCM) is a vascular malformation characterized by abnormally enlarged capillary cavities without any intervening neural tissue. We report 2 cases of familial CCMs diagnosed with the CCM1 mutation by using a genetic assay. A 5-year-old boy presented with headache, vomiting, and seizure-like movements. Brain magnetic resonance imaging (MRI) revealed multiple CCM lesions in the cerebral hemispheres. Subsequent mutation analysis of his father and other family members revealed c.940_943 del (p.Val314 Asn315delinsThrfsX3) mutations of the CCM1 gene. A 10-month-old boy who presented with seizure-like movements was reported to have had no perinatal event. His aunt was diagnosed with cerebral angioma. Brain and spine MRI revealed multiple angiomas in the cerebral hemisphere and thoracic spinal cord. Mutation analysis of his father was normal, although that of the patient and his mother revealed c.535C>T (p.Arg179X) mutations of the CCM1 gene. Based on these studies, we suggest that when a child with a familial history of CCMs exhibits neurological symptoms, the physician should suspect familial CCMs and consider brain imaging or a genetic assay.