Infantile Hypoxic Encephalopathy Mimicking Acute Encephalopathy with Biphasic Seizures and Late Reduced Diffusion (AESD) Identified as an Episode of Brief Resolved Unexplained Event (BRUE).

Acute encephalopathy with biphasic seizures and reduced diffusion (AESD) is characterized by biphasic seizures following febrile viral infections and delayed reduced diffusion of the cerebral white matter on magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI) (bright tree appearance, BTA). However, hypoxic encephalopathy with biphasic seizures and AESD-mimicking imaging findings has not been reported. We report a case of hypoxic encephalopathy due to suffocation with concomitant biphasic seizures and BTA, mimicking AESD. On day 1, a healthy 5-month-old girl was found face down with decreased breathing and a deteriorating consciousness level, suggesting a brief resolved unexplained event (BRUE). Electroencephalography (EEG) revealed periodic epileptic discharges, suggesting possible nonconvulsive status epilepticus. Despite improvements in consciousness level and EEG abnormalities on day 2, her consciousness level deteriorated again with generalized tonic-clonic seizures on day 3, and a head MRI-DWI revealed restricted diffusion predominantly in the subcortical areas, suggesting BTA. Treatment for acute encephalopathy resolved the clinical seizures and EEG abnormalities. Persistence of abnormal EEG, reflecting abnormal excitation and accumulation of neurotoxic substances caused by hypoxia, may have contributed to the development of AESD-like findings. As hypoxic encephalopathy causes AESD-like biphasic seizures, monitoring consciousness level, seizure occurrence, and EEG abnormalities even after acute symptoms have temporarily improved following hypoxia is essential.

Post coronavirus disease 2019 condition in children at a children's hospital in Japan.

BACKGROUND: Acute coronavirus disease 2019 (COVID-19) is associated with chronic symptoms. These have been termed the "post COVID-19 condition." The data on this condition in children are still limited. We therefore aimed to elucidate the characteristics of this post COVID-19 condition. METHODS: Children referred to a long COVID-19 clinic were included at Tokyo Metropolitan Children's Medical Center between October 2021 and July 2022. Children with another diagnosis and those who failed to meet criteria for post COVID-19 condition were excluded. Demographic and clinical data were collected retrospectively. RESULTS: Of 33 referrals, nine were excluded, and 24 fulfilled the criteria for post COVID-19 condition. The median age and percentage of girls were 12.5 (IQR: 11-13) years and 29.2%, respectively. All the patients had mild, acute COVID-19. Dysgeusia and brain fog was observed more frequently during the Delta and Omicron variant periods, respectively. School absenteeism >4 weeks was observed in 41.6% of the patients. Common symptoms included malaise, headache, dysgeusia, and dysosmia. The median duration of post COVID-19 condition was 4.5 (IQR: 2.8-5.2) months. Pain management and counseling using the pacing approach were the most commonly offered treatments. Symptom resolution and improvement was observed in 29.2% and 54.2% of the patients, respectively. CONCLUSIONS: One third of the patients referred for long COVID did not fit the definition of the post COVID-19 condition. After a median follow up of 4.5 months, the majority of the cases resolved or improved.

The Utility of Limited-Montage Electroencephalography for Seizure Detection in Children.

BACKGROUND: The primary objective of this study was to investigate the utility of limited-montage electroencephalography (EEG) for seizure detection in children. We also aimed to determine whether the detection rate differed among different montage patterns. METHODS: This study was carried out between November 2019 and October 2020 at a tertiary children's hospital in Japan. The subjects were inpatients in the pediatric intensive care unit who had an epileptic seizure during EEG monitoring. Each patient's EEG record, consisting of a 15-minute recording during an epileptic seizure and a 15-minute recording in the absence of an epileptic seizure, was extracted from the medical charts. The EEG data were then analyzed using six, limited-montage coverage patterns: (1) Fp1-C3, Fp2-C4, (2) Fp1-O1, Fp2-O2, (3) Fp1-T3, Fp2-T4, (4) C3-O1, C4-O2, (5) C3-T3, C4-T4, and (6) O1-T3, O2-T4. The sensitivity and specificity of each montage for seizure detection was analyzed. RESULTS: One hundred thirty-two EEG data points from 11 patients were examined. Sensitivity and specificity were the highest for Fp1-O1 and Fp2-O2 at 73% and 91%, respectively. Overall, the montage covering the frontopolar area had the highest detection rate, followed by the montage covering the occipital, central, and temporal areas. CONCLUSION: Limited-montage EEG identified seizures in children hospitalized in the intensive care unit, but the detection rate differed by montage coverage. The detection rate was highest in the montage covering the frontopolar area.

Sinus pericranii associated with syntelencephaly: a case report.

BACKGROUND: Sinus pericranii is a rare cranial venous malformation resulting in a subcutaneous mass due to abnormal communication between intracranial and subperiosteal/interperiosteal veins. To date, to the best of our knowledge, there are no reports of sinus pericranii associated with syntelencephaly, a subtype of lobar holoprosencephaly. We herein report a case of sinus pericranii associated with syntelencephaly. This report can provide us better understanding of the etiology of sinus pericranii, the potential risks, and the treatment options for these patients. CASE PRESENTATION: A 2-year-4-month old female patient who received the diagnosis of syntelencephaly as a neonate presented with a subcutaneous mass in the parietal region. The mass was soft, nonpulsatile, 3 × 2 cm in size, and showed enlargement in the lying position. Color cranial Doppler ultrasound, head magnetic resonance imaging (MRI), and cerebral angiography revealed a dilated vessel passing through the parietal bone and forming a communication between the superior sagittal sinus and scalp veins. Based on these findings, sinus pericranii was diagnosed. The head MRI also showed coronal craniosynostosis, a tight posterior fossa. At age 2 years and 7 months, the patient underwent a transection of the sinus pericranii and the mass resolved without any complications or recurrences for more than 2.5 years to date. CONCLUSION: Sinus pericranii is a rare cranial and venous malformation sometimes accompanied by brain malformations or craniosynostosis that may become more apparent as the brain and skull develop. Since this condition can be complicated by intracranial hemorrhage and sinus thrombosis, early detection is necessary to determine the treatment options. Physicians should be alert to the possibility of this condition if they observe a soft cranial mass that appears to decrease in size in the sitting position and bulge in the lying position.

Classification of pediatric headache cases referred to a neurology department.

BACKGROUND: Headaches are very common in children. The patients often have mild symptoms, but on occasion may have severe, secondary headaches. The present study aimed to clarify the details of children with headaches seen at the outpatient clinic of a pediatric neurological department. METHODS: The present, retrospective observational study was conducted at a tertiary pediatric hospital in Japan and enrolled children referred to the neurology department outpatient clinic for headache between April 2018 and March 2021. RESULTS: In total, 113 cases of headache were examined; of these, 99 (87.6%) were primary headaches, one case (0.9%) was a secondary headache, and 13 (11.5%) were unclassified or unspecified. There were 46 cases (40.7%) of tension-type headache (TTH), both confirmed and suspected, 30 cases (26.5%) of migraine, and 23 cases (20.4%) of a combination of the TTH and migraine. One case of secondary headache was attributed to an infection. Arachnoid cysts were found in seven patients (7.8%). Acute drug treatments were administered to 93 patients (82.3%), with acetaminophen being the most common drug, followed by ibuprofen. Prophylactic drug treatments were administered to 39 patients (34.5%), with goreisan (a Chinese herbal medicine containing Alisma orientale, Poria cocos, Polyporus umbellatus, Atractylodes lancea, and Cinnamomum cassia) being the most common (41%). CONCLUSIONS: Few cases of secondary headache and none of emergency headache were diagnosed. The prevalence of arachnoid cysts was higher than in the general pediatric population, suggesting that arachnoid cysts might be associated with headache.

Retrospective Echocardiographic Analysis of West Syndrome During Adrenocorticotropic Hormone Therapy.

Background: Ventricular hypertrophy is a well-known side effect of adrenocorticotropic hormone (ACTH) therapy in patients with West syndrome (WS), but there are only a few reports of echocardiographic evaluation of these patients' diastolic function. Methods: The present, retrospective study analyzed echocardiographic findings in 24 patients with WS treated with ACTH therapy between April 2010 and December 2014. The therapy protocol involved administering tetracosactide acetate 0.01-0.0125 mg/kg via intramuscular injection once a day for weeks 1-2, then gradually tapering off. Echocardiographic evaluation was done before treatment initiation and at weeks 1, 2, and 4 after the initiation of treatment. Results: The systolic and diastolic blood pressure values were elevated at week 1 after commencement of the therapy and remained elevated throughout its duration. Both the interventricular septal end-diastolic thickness and left ventricular posterior wall end-diastolic diameter increased in thickness at week 1 and remained thickened. None of the patients experienced heart failure or systolic dysfunction. Early diastolic mitral flow velocity (E)/early diastolic mitral annular velocity (E') increased at week 1 and remained high at weeks 2 and 4. The E wave deceleration time (DcT) was prolonged at week 2 and returned to the baseline at week 4. Conclusion: Increased ventricular wall thickness, decreased diastolic capacity, and elevated BP were noted in children with WS during ACTH therapy. Cardiac function, including ventricular wall thickness and diastolic function, should be monitored during ACTH therapy. E/E' and DcT are useful in evaluating diastolic function.

Symptomatic enophthalmos due to sphenoid wing dysplasia appearing over 12 years in a patient with neurofibromatosis type 1: a case report and literature review.

Sphenoid wing dysplasia (SWD) is a common orbital complication of neurofibromatosis type 1 (NF1). However, enophthalmos associated with SWD is extremely rare, and details of its natural history are unclear. We present the case of a 14-year-old boy with an early childhood diagnosis of NF1 presenting with left blepharophimosis and enophthalmos for several months. Imaging demonstrated enlargement of the left lateral SWD, progression of the posteromedial deviation of the orbital contents, and sphenoid/ethmoid sinus deformation due to left temporal lobe compression over 12 years. Two characteristic changes were revealed on imaging: enlargement of the middle cranial fossa and deformation of the sphenoid/ethmoid sinuses. The orbital contents were compressed by the intracranial pressure of the temporal lobe and were displaced posteromedially into the space created by the deformed sphenoid/ethmoid sinuses. Because orbital symptoms can gradually become apparent over years with the progression of SWD and skeletal growth, long-term follow-up of orbital symptoms is recommended in patients with NF1.

Status Epilepticus due to Asfotase Alfa Interruption in Perinatal Severe Hypophosphatasia.

BACKGROUND: Hypophosphatasia (HPP), an inherited, metabolic disorder caused by loss-of-function mutations in the ALPL gene, affects not only bone and tooth mineralization but also central nervous system (CNS) function, resulting in vitamin B6/pyridoxine-responsive seizures. Asfotase alfa treatment mainly improves the skeletal manifestations of HPP. As of yet, there are no reports demonstrating seizure exacerbation caused by asfotase alfa interruption. CASE: The patient was a 2-year and 8-month-old female with clinical and genetic diagnosis of perinatal severe HPP. Genetic analysis of ALPL identified compound heterozygous variants. Asfotase alfa and pyridoxine administration begun on postnatal day 2 restored normal development and suppressed seizures except for simple febrile seizures. From age 2 years when her asfotase alfa injections became irregular, she began experiencing seizure exacerbation, including status epilepticus, leading to acute encephalopathy and severe sequelae. The seizure exacerbations always coincided with low alkaline phosphatase (ALP) activity caused by the interruption of asfotase alfa administration. DISCUSSION: The clinical course of the present case demonstrated the effect of asfotase alfa on CNS symptoms and a clear correlation between low serum ALP activity and seizure exacerbation. Serum ALP activity measurements were useful as a therapeutic marker in the present case. Furthermore, the risk of seizure exacerbation in the patient could have been predicted, given the genotype-phenotype correlation related to the ALPL gene in the Japanese population. CONCLUSION: Regular asfotase alfa injections are needed to prevent seizure exacerbation in patients with HPP. Educating patients and their family about the need for regular asfotase alfa treatment is crucial to preventing disease exacerbation.

Refractory cerebral infarction in a child with an ACTA2 mutation.

INTRODUCTIONS: A specific mutation in the ACTA2 gene is known to cause multisystemic smooth muscle dysfunction syndrome, which is associated with cerebrovascular diseases and various organ disorders. Cerebral infarctions resulting from severe vasculopathy can be refractory; however, there are no previous reports describing the detailed clinical course of recurrent cerebral infarctions due to an ACTA2 mutation. Herein, we report a patient with an ACTA2 mutation who experienced multiple refractory cerebral infarctions in early childhood. PATIENT DESCRIPTION: The patient was aged 1 year and 5 months at her first episode of cerebral infarction. Arteriopathy due to an ACTA2 mutation was diagnosed based on the characteristic cerebrovascular findings and abnormal physical findings, such as bilateral dilated pupils. Bilateral encephaloduroarteriosynangiosis and encephalogaleosynangiosis were performed after the first episode. Because the cerebral infarctions recurred postoperatively, administration of cilostazol followed by bosentan was started. However, despite these treatments she experienced seven cerebral infarctions by age 2 years and 6 months. INTERPRETATION: Cerebral infarctions in patients with a specific ACTA2 mutation can occur even in early childhood, recur frequently, and cause severe motor and cognitive impairment. Physicians should be highly aware of this disease and be ready to provide the medical and surgical interventions necessary to minimize the disabling sequelae.

Coloboma may be a shared feature in a spectrum of disorders caused by mutations in the WDR37-PACS1-PACS2 axis.

We report a male adult with early infantile-onset epilepsy, facial dysmorphism, and iridal and choroidal coloboma who had a de novo heterozygous mutation in PACS2, that is, c.625G > A p.(Glu209Lys). This specific mutation was previously reported in a patient with PACS2-related disorder (early infantile epileptic encephalopathy 66). De novo heterozygous mutations in WDR37 have been shown to cause a novel human disorder, neurooculocardiogenitourinary syndrome (NOCGUS syndrome) (OMIM #618652), characterized by intellectual disability, facial dysmorphism, and coloboma. According to large-scale interactome data, WDR37 interacts most strongly, by far, with PACS1 and PACS2. Clinically, coloboma has been described as a feature in a WDR37-related disorder and a PACS1-related disorder (Schuurs-Hoeijmakers syndrome), but not in a PACS2-related disorder. Our review of the phenotypes of three human disorders caused by WDR37, PACS1, and PACS2 mutations showed a significant overlap of epilepsy, intellectual disability, cerebellar atrophy, and facial features. The present observation of coloboma as a shared feature among these three disorders suggests that this group of genes may be involved in ocular development. We propose that dysregulation of the WDR37-PACS1-PACS2 axis results in a spectrum that is recognizable by intellectual disability, distinctive facial features, and coloboma.

Nonsense variants of STAG2 result in distinct congenital anomalies.

Herein, we report two female cases with novel nonsense mutations of STAG2 at Xq25, encoding stromal antigen 2, a component of the cohesion complex. Exome analysis identified c.3097 C>T, p.(Arg1033*) in Case 1 (a fetus with multiple congenital anomalies) and c.2229 G>A, p.(Trp743*) in Case 2 (a 7-year-old girl with white matter hypoplasia and cleft palate). X inactivation was highly skewed in both cases.

White matter abnormality in Jacobsen syndrome assessed by serial MRI.

INTRODUCTION: Jacobsen syndrome (JS) is caused by a deletion at the terminus of the long arm of chromosome 11. There are few reports of JS associated with cerebral white matter abnormalities (WMA), and the etiology, pathophysiology, and time-dependent changes in WMA with JS still remain unclear. CASE REPORT: The patient was a 2-month-old female with several morphological anomalies, including trigonocephaly, ectropion, flat nasal bridge, low-set ears, and sparse eyebrows. Chromosome analysis (G-banding karyotyping) of 46,XX,del(11)(q23.3) led to the diagnosis of JS. Head MRI performed at age 9 months indicated diffuse WMA with hyperintense signals on T2-weighted imaging. MRI at age 2.5 years demonstrated a decrease in the WMA and progressive myelination. DISCUSSION: These findings suggested that the WMA in the present patient were due to chronic white matter edema associated with a deletion in the 11q terminal region of HEPACAM/GlialCAM, a causative gene for megalencephalic leukoencephalopathy with subcortical cysts type 2B (MLC2B). As with some of MLC2B patients, the WMA in the present patient improved over time. The present report is the first to document dramatic changes in WMA in JS visualized by serial MRI examinations from the neonatal period through early childhood. CONCLUSION: The findings of the present study suggested that WMA in JS are due to chronic white matter edema associated with HEPACAM/GlialCAM deletion and show gradual improvement over time, as seen in some MLC2B patients.

Retraction Note to: Nonsense variants in STAG2 result in distinct sex-dependent phenotypes.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Nonsense variants in STAG2 result in distinct sex-dependent phenotypes.

We herein report two individuals with novel nonsense mutations in STAG2 on Xq25, encoding stromal antigen 2, a component of the cohesion complex. A male fetus (Case 1) clinically presented with holoprosencephaly, cleft palate and lip, blepharophimosis, nasal bone absence, and hypolastic left heart by ultrasonography at 15 gestational weeks. Another female patient (Case 2) showed a distinct phenotype with white matter hypoplasia, cleft palate, developmental delay (DD), and intellectual disability (ID) at 7 years. Whole-exome sequencing identified de novo nonsense mutations in STAG2: c.3097C>T, p.(Arg1033*) in Case 1 and c.2229G>A, p.(Trp743*) in Case 2. X-inactivation was highly skewed in Case 2. To date, only 10 STAG2 pathogenic variants (four nonsense, four missense, and two frameshift) have been reported in patients with multiple congenital anomalies, ID, and DD. Although Case 2 showed similar clinical features to the reported female patients with STAG2 abnormalities, Case 1 showed an extremely severe phenotype, which could be explained by the first detected truncating variant in males.

Diagnostic use of computational retrotransposon detection: Successful definition of pathogenetic mechanism in a ciliopathy phenotype.

Among more than 5,000 human monogenic disorders with known causative genes, transposable element insertion of a Long Interspersed Nuclear Element 1 (LINE1, L1) is known as the mechanistic basis in only 13 genetic conditions. Meckel-Gruber syndrome is a rare ciliopathy characterized by occipital encephalocele and cystic kidney disease. Here, we document a boy with occipital encephalocele, post-axial polydactyly, and multicystic renal disease. A medical exome analysis detected a heterozygous frameshift mutation, c.4582_4583delCG p.(Arg1528Serfs*17) in CC2D2A in the maternally derived allele. The further use of a dedicated bioinformatics algorithm for detecting retrotransposon insertions led to the detection of an L1 insertion affecting exon 7 in the paternally derived allele. The complete sequencing and sequence homology analysis of the inserted L1 element showed that the L1 element was classified as L1HS (L1 human specific) and that the element had intact open reading frames in the two L1-encoded proteins. This observation ranks Meckel-Gruber syndrome as only the 14th disorder to be caused by an L1 insertion among more than 5,000 known human genetic disorders. Although a transposable element detection algorithm is not included in the current best-practice next-generation sequencing analysis, the present observation illustrates the utility of such an algorithm, which would require modest computational time and resources. Whether the seemingly infrequent recognition of L1 insertion in the pathogenesis of human genetic diseases might simply reflect a lack of appropriate detection methods remains to be seen.

[Irreversible cerebral ischemia caused by febrile status epilepticus in Sturge-Weber syndrome type III].

We report a 9-year-old girl with Sturge-Weber syndrome (SWS) type III, whose motor function deteriorated after an episode of febrile status epilepticus. The patient had leptomeningeal angiomas in the left temporal, occipital, and parietal lobes. Complex partial seizures, which started at 8 months, were controlled by antiepileptic medications. At 9 years of age, she developed irreversible ischemic lesions in the left temporal and occipital regions after the febrile status epilepticus and her motor function deteriorated. In addition to antiepileptic medications, aspirin therapy was started.SWS type III is a rare disorder characterized by leptomeningeal angiomatosis without facial nevus. In addition to the chronic ischemia in the affected cortex, epileptic seizures result in a phased progression of ischemia in SWS. Although the patient's complex partial seizures had been well-controlled, a single episode of febrile status epilepticus resulted in permanent brain lesions. The impairment of appropriate hemodynamic response to status epilepticus, together with venous hypertension in the affected side in SWS may have caused the cerebral infarction in our case. Seizure control is crucial to improving the neurological prognosis of SWS.