A nationwide survey of adenovirus-associated encephalitis/encephalopathy in Japan.

BACKGROUND: Adenovirus is a major pathogen causing febrile illness among children. It may also cause acute encephalitis/encephalopathy. This study aimed to elucidate the clinical features of adenovirus-associated encephalitis/encephalopathy (AdVE) among children in Japan. METHODS: A nationwide survey of children with AdVE was conducted. An initial survey was distributed among pediatricians to obtain information about children with AdVE treated between January 2014 and March 2019. A second survey was used to obtain the clinical information of children with AdVE from hospitals that responded to the initial survey and those identified from a literature search of the reported cases. We collected demographic data and information about symptoms of infection, neurological symptoms, laboratory parameters, treatment, and outcomes. Outcomes were determined using the Pediatric Cerebral Performance Category Score. RESULTS: Clinical information was available for 23 children with a median age of 39 months. Two had preexisting neurological disorders and six had a history of febrile seizures. The outcome was good in 15 patients and poor in eight patients. Serum lactate dehydrogenase, glucose, and ammonia levels were higher among children with a poor outcome compared to those with a good outcome. Clinically mild encephalitis/encephalopathy with a reversible splenial lesion was the most common type (n = 8), followed by acute encephalopathy with biphasic seizures and late reduced diffusion (n = 7). CONCLUSION: A prior history of febrile seizures was frequent in children with AdVE. Several different subtypes of acute encephalopathy were seen in children with AdVE, and the outcome was poor in those with acute encephalopathy with biphasic seizures and late reduced diffusion and hemorrhagic shock and encephalopathy syndrome. Elevated lactate dehydrogenase, glucose, and ammonia levels on admission were found to correlate with a poor outcome.

Case Report: Acquired Generalized Anhidrosis Caused by Brain Tumor: Review of the Literature.

Purpose: There has been limited focus on sweating failure in patients with brain tumor. We report two patients with generalized anhidrosis caused by germinoma. We also review previous reports of generalized anhidrosis due to brain tumor. Case Reports: Patient 1 was a 12-year-old boy with repetitive heat shock-like episodes even in winter. Based on Minor's test, he was diagnosed with generalized anhidrosis. Magnetic resonance imaging (MRI) revealed the absence of high signal intensity of the posterior pituitary. He was initially diagnosed with central diabetes insipidus. However, an MRI scan performed after 3 months revealed an enlarged pituitary stalk. He was finally diagnosed with germinoma by pituitary biopsy. After chemotherapy and radiation, sweating was partially resolved. Patient 2 was a 12-year-old girl with growth hormone deficiency and generalized anhidrosis. She was diagnosed with germinoma based on MRI and pituitary biopsy findings. After chemotherapy and radiation, the sweating resolved completely. Discussion: In our literature search, we identified four patients with anhidrosis due to brain tumor, including our cases. All patients had germinoma and continued to require hormone replacement therapy after treatment of germinoma. Two patients with incomplete recovery of sweating had the involvement in the hypothalamus, whereas one patient with complete recovery showed a lack of evident hypothalamic involvement. Improvement in sweating in one patient was not described. Conclusion: Germinoma can cause anhidrosis, and involvement in the hypothalamus may be relevant to incomplete recovery of sweating.

Hypersensitivity reaction to high-dose methotrexate and methotrexate-induced acral erythema in a child with acute lymphoblastic leukemia.

A 9-year-old boy with acute lymphoblastic leukemia experienced a hypersensitivity reaction (HSR) and acral erythema upon receiving high-dose methotrexate (HDMTX). Both HSR and acral erythema are uncommon adverse events of MTX therapy, and MTX has not been reported to cause HSRs in specific ethnic groups. We assessed the severity of each symptom and were successful in managing these adverse events for continuing subsequent HDMTX therapies. HSR appeared during the first and second HDMTX courses. Acral erythema occurred after the second and fourth courses. Desensitization by reducing the infusion rate and premedication allowed the continuation of HDMTX. Acral erythema improved with supportive care without dose reduction or interval lengthening. HSRs to MTX should be considered even during the first course. MTX-induced acral erythema is a self-limited reaction; therefore, the chemotherapeutic regimen should not be modified unless necessary.

Current medico-psycho-social conditions of patients with West syndrome in Japan.

OBJECTIVE: To unveil current medical and psychosocial conditions of patients with West syndrome in Japan. METHODS: A cross-sectional analysis was performed in patients with West syndrome registered in the Rare Epilepsy Syndrome Registry (RES-R) of Japan. Furthermore, new-onset patients registered in the RES-R were observed prospectively and their outcomes after one and two years of follow-up were compared with data at onset. RESULTS: For the cross-sectional study, 303 patients with West syndrome were included. Seizures (such as spasms, tonic seizures and focal seizures) occurred daily in 69.3% of the patients at registration. Seizure frequency of less than one per year was observed in cases of unknown etiology (22.6%), genetic etiology (23.8%) and malformation of cortical development (MCD; 19.1%). Neurological findings were absent in 37.0%, but a high rate of abnormality was seen in patients with Aicardi syndrome, hypoxic-ischemic encephalopathy (HIE), genetic etiology and MCD other than focal cortical dysplasia, accompanied by a >50% rate of bedridden patients. Abnormal EEG was found in 96.7%, and CT/MRI was abnormal in 62.7%. Treatments included antiepileptic drug therapy (94.3%), hormonal therapy (72.6%), diet therapy (8.3%) and surgery (15.8%). Intellectual/developmental delay was present in 88.4%, and was more severe in patients with Aicardi syndrome, genetic etiology and HIE. Autism spectrum disorder was found in 13.5%. For the longitudinal study, 27 new-onset West syndrome patients were included. The follow-up study revealed improved seizure status after two years in 66.7%, but worsened developmental status in 55.6%, with overall improvement in 51.9%. SIGNIFICANCE: The study reveals the challenging neurological, physical and developmental aspects, as well as intractable seizures, in patients with West syndrome. More than a half of the children showed developmental delay after onset, even though seizures were reduced during the course of the disease.

Neonatal intrahepatic cholestasis caused by citrin deficiency with no hepatic steatosis: a case report.

BACKGROUND: Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is a common form of neonatal jaundice. Histopathological examination of the liver in patients with NICCD typically shows fatty liver, steatohepatitis, and liver fibrosis. Jaundice and fatty liver often improve by 1 year of age. We herein describe a girl who was diagnosed with NICCD based on an SLC25A13 mutation, although no fatty deposits were found on pathologic examination of the liver. CASE PRESENTATION: The patient in this case was a 3-month-old girl. At 2 months of age, she presented with jaundice, discolored stools, and poor weight gain and was found to have hyperbilirubinemia. Cholangiography revealed that she did not have biliary atresia. A laparoscopic liver biopsy was performed, and liver histopathology showed no fatty deposits. Genetic analysis revealed a compound heterozygous mutation in SLC25A13, and she was diagnosed with NICCD. She was given medium-chain triglyceride milk and gained weight. She resumed consumption of normal milk and breast milk, and her stool color improved. She was discharged at 4 months of age with adequate weight gain and a lower total bilirubin concentration. She was in good condition after discharge and showed normal development at the time of outpatient follow-up. CONCLUSIONS: We experienced a case of NICCD in a patient without fatty liver. This case illustrates that the absence of hepatic steatosis in neonatal cholestasis does not rule out NICCD.

Evaluation of the Diagnostic Criteria for Anti-NMDA Receptor Encephalitis in Japanese Children.

OBJECTIVE: To evaluate the validity of the 2016 clinical diagnostic criteria proposed for probable anti-NMDA receptor (NMDAR) encephalitis in children, we tested the criteria in a Japanese pediatric cohort. METHODS: We retrospectively reviewed clinical information of patients with neurologic symptoms whose CSF was analyzed for NMDAR antibodies (NMDAR-Abs) in our laboratory from January 1, 2015, to March 31, 2019. RESULTS: Overall, 137 cases were included. Of the 41 cases diagnosed as probable anti-NMDAR encephalitis (criteria-positive) according to the 2016 criteria, 13 were positive and 28 were negative for anti-NMDAR-Abs. Of the 96 criteria-negative cases, 3 were positive and 93 were negative for anti-NMDAR-Abs. The sensitivity of the criteria was 81.2%, specificity was 76.9%, positive predictive value (PPV) was 31.7%, and negative predictive value was 96.9%. Compared with the true-positive group, the false-positive group contained more male than female patients (male:female, 4:9 in the true-positive vs 19:9 in the false-positive group, p = 0.0425). The majority of the cases with false-positive diagnoses were associated with neurologic autoimmunity. CONCLUSION: The clinical diagnostic criteria are reliable for deciding to start immunomodulatory therapy in the criteria-positive cases. Low PPV may be caused by a lower prevalence of NMDAR encephalitis or lower level of suspicion for encephalitis in the pediatric population. Physicians should therefore continue differential diagnosis, focusing especially on other forms of encephalitis. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that the proposed diagnostic criteria for anti-NMDAR encephalitis in children has a sensitivity of 81.2% and a specificity of 76.9%.

Acute encephalopathy in children with tuberous sclerosis complex.

OBJECTIVE: We examined the clinical manifestations of acute encephalopathy (AE) and identify risk factors for AE in children with tuberous sclerosis complex (TSC). METHODS: The clinical data of 11 children with clinically diagnosed TSC associated with AE and 109 children with clinically diagnosed TSC alone aged 4 years or older were collected from 13 hospitals. RESULTS: Of the 11 children with AE, 5 had histories of febrile seizures (FS), and all had histories of febrile status epilepticus (FSE). AE developed within 24 h after fever onset in all children with seizures lasting 30 min or longer. All children developed coma after seizure cessation. Head magnetic resonance imaging (MRI) revealed widespread abnormalities in the cerebral cortex, subcortical white matter, corpus callosum, basal ganglia, and thalamus. One child died; seven had severe neurological sequelae; and the other three, mild sequelae. Logistic regression analysis revealed that a history of FSE was correlated with the development of AE. SIGNIFICANCE: AE in children with TSC was characterized by sudden onset after fever, followed by coma, widespread brain edema evident on MRI, and poor outcomes. A history of FSE was a risk factor for the development of AE.

A nationwide questionnaire survey on accidental magnet ingestion in children in Japan.

AIM: The aim is to investigate the actual situation of accidental ingestion of magnets in children in Japan and the clinical features of the resulting gastrointestinal damage. METHODS: We developed a questionnaire and sent it to 496 board-certified training hospitals nationwide. Information was collected on the number of children with accidental magnet intake from 2015 to 2017, witnesses of magnet intake, number and type of magnets, presence or absence of gastrointestinal injury, treatment, etc RESULTS: The number of cases of accidental ingestion of magnets within the study period was 104, with a median age of 2 years. About half of the incidents were unwitnessed. There were 33 cases of accidental ingestion of multiple magnets. Among them, oesophagogastroduodenoscopy was performed in 4 children and surgery in 10, and significantly invasive treatment was required in comparison with single-magnet ingestion. Gastrointestinal injury was observed in 11 cases, 10 of which were caused by multiple-magnet ingestion. All 10 of these patients underwent surgical treatment. There was no mortality. CONCLUSION: The incidence of accidental magnet ingestion in Japan is estimated to be 50-70 per year. Unwitnessed cases are not uncommon. Multiple magnet ingestion often causes gastrointestinal injury. Many cases of gastrointestinal injury are caused by ingestion of magnetic toys.

Harlequin syndrome associated with ganglioneuroblastoma-induced Horner syndrome.

A 1-year-old boy presented with a 4-month history of hypertension, ptosis of the right upper eyelid, left hemifacial sweating, and flushing. He was diagnosed with Harlequin syndrome associated with Horner syndrome. Computed tomography revealed a mass lesion in the right superior mediastinum. Therefore, the patient underwent total tumor resection. Histological examination demonstrated ganglioneuroblastoma. The MYCN oncogene was not amplified, and the mitosis-karyorrhexis index was low. Accordingly, radiation and chemotherapy were not performed. No recurrence was observed within 8 months after surgery, and the patient's blood pressure was normalized. However, the ptosis, hemifacial sweating, and flushing persisted.

Procalcitonin as a Biomarker of Unresponsiveness to Intravenous Immunoglobulin for Kawasaki Disease.

OBJECTIVE: To investigate the usefulness of procalcitonin (PCT) as predictive factors of intravenous immunoglobulin (IVIG)-resistant Kawasaki disease patients. METHODS: We retrospectively analyzed the laboratory data from 215 children with Kawasaki disease treated with IVIG from 2014 to 2019. We analyzed the clinical and laboratory parameters just before the IVIG including serum levels of PCT with respect to the IVIG response. RESULTS: Eventually, 127 patients were analyzed. The median age was 2.4 years. IVIG was effective in 108 children (responders) and was ineffective in 19 (non-responders). Serum PCT concentration was higher in non-responders than those of responders (P < 0.001). Multivariate logistic regression analyses indicated that higher PCT concentration (odds ratio 1.34, 95% confidence interval 1.10-1.64) were associated with IVIG resistance. Analyses of the receiver operating characteristic curve showed that the cutoff value of PCT 2.18 ng/mL had 46.4% of sensitivity and 93.9% of specificity. Receiver operating characteristic analysis yielded an area under the curve of 0.82 (0.72-0.92) to predict IVIG resistance. CONCLUSIONS: Serum PCT value can be an excellent biomarker for predicting unresponsiveness to IVIG with a good discriminatory ability as well as the existing prediction scores.

A questionnaire survey on the efficacy of various treatments for dyskinetic cerebral palsy due to preterm bilirubin encephalopathy.

OBJECTIVES: Preterm children with severe dyskinetic cerebral palsy due to bilirubin encephalopathy often suffer from marked generalised hypertonus as they age. We performed a questionnaire survey to investigate patient-reported outcomes of treatments for improving their activities of daily life. METHODS: A mail questionnaire was administered to the caregivers of 67 children with preterm bilirubin encephalopathy aged >4 years. We asked about the type of treatments they received and their efficacy using a five-point subjective scale for the following five domains: motor function, postural stability, sleep, pain, and care burden. The names of oral drugs and their efficacies were also explored. RESULTS: The response rate of the questionnaires was 62.7% (42/67), and we analysed the results from 41 validated cases. All children underwent rehabilitation. A total of 30 children received oral drugs, 22 botulinum toxin, 12 orthopaedic surgery, and 3 intrathecal baclofen. Each of these treatments was subjectively reported to be effective in more than half of the recipients for each of the five domains, whereas 23 (56%) required more than two types of treatments other than rehabilitation. Chlordiazepoxide was the most commonly used oral drug, by 28 children (68%), and was discontinued in 7 patients (25%) only. In the sleep domain, the rate of a positive effect was significantly higher for oral drugs (92.7%) than the other treatments (p < 0.01). CONCLUSION: All treatments were partially effective, but their appropriate combination based on a multidisciplinary approach is essential for muscle tone management in children with preterm bilirubin encephalopathy.

Multiple Magnets Ingestion Followed by Intestinal Fistula With Mild Symptoms.

A healthy 3-year-old boy visited our hospital because of abdominal pain and vomiting, and abdominal X-ray revealed a 10 mm non-sharp foreign body in the lower abdomen. No one had witnessed accidental ingestion. Abdominal symptoms were mild. We followed-up with abdominal X-rays, but the foreign matter did not move. His grandfather remembered that he was playing with a posting magnet. Thus, the foreign matter was considered to be multiple magnets. No foreign body was excreted by laxative administration. There was no foreign matter revealed even by the colonoscopy. Because a fistula was found in the ileum, it was diagnosed as gastrointestinal perforation. Three magnets adhered from inside the fistula were removed by emergency laparotomy surgery. The final diagnosis was ileal sigmoid fistula due to damage of the mucous membrane sandwiched between the magnets. Multiple magnet ingestion often causes gastrointestinal injury. Even if the symptoms are mild, it should be removed promptly.

Gastric cancer in children and adolescents in Japan.

BACKGROUND: Very limited data are available on childhood gastric cancer. Using a retrospective survey and literature review, we assessed the clinical features of gastric cancer in children and adolescents. METHODS: We collected information on childhood gastric cancer from pediatricians of 518 hospitals that issue the title of "certified board pediatrician" approved by Japan Pediatric Society, using a questionnaire on background, diagnosis year, onset symptoms, tumor location, histology, nodular gastritis, Helicobacter pylori testing, treatment, and prognosis. Studies were collected using PubMed and the NPO Japan Medical Abstracts Society database. Data for childhood gastric cancer were abstracted from the Japanese Vital Statistics database. RESULTS: Of the 518 hospitals, 349 returned the questionnaire, which identified four patients. Literature review identified 77 cases of gastric cancer, and we analyzed data for 80 children <16 years old. Most patients were >10 years old, and there were no sex differences. Onset symptoms ranged from abdominal pain to non-localized. Sixteen of 44 children had a family history of cancer; 10 had a family history of gastric cancer. Histologically, approximately 80% had undifferentiated-type carcinoma. Prognosis was extremely poor, and two of three tested children were positive for H. pylori infection. Childhood gastric cancer death has been declining. CONCLUSIONS: Childhood gastric cancer is rare in Japan, and information on H. pylori in childhood gastric cancer patients is limited. Declining childhood gastric cancer rates may reflect the decreasing prevalence of infection but further study is necessary to clarify the relationship between H. pylori and gastric cancer.

Pseudoprogression successfully treated with bevacizumab in a child with spinal pilocytic astrocytoma.

CLINICAL CASE: We report on a 7-year-old female with spinal pilocytic astrocytoma complicated by pseudoprogression 1 month after completion of radiation therapy. Although she was initially treated with high-dose steroids, her clinical symptoms did not completely resolve, and magnetic resonance imaging (MRI) revealed extension of the lesions into the medulla oblongata. Treatment with bevacizumab was commenced, followed by rapid resolution of the clinical symptoms and improvements in the MRI findings. CONCLUSION: This case highlights the efficacy and tolerability of bevacizumab for the treatment of pseudoprogression in children with spinal low-grade gliomas.

Spontaneous adrenocorticotropic hormone (ACTH) normalisation due to tumour regression induced by metyrapone in a patient with ectopic ACTH syndrome: case report and literature review.

BACKGROUND: Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is caused by tumours releasing ACTH. Ectopic ACTH-producing tumour regression is rarely induced using steroidogenesis inhibitors. We presented a case of EAS in which ACTH production by a lung tumour was reduced by metyrapone (MTP) and also reviewed previous cases of ectopic ACTH production suppressed via steroidogenesis inhibition. CASE PRESENTATION: A 71-year-old female with general fatigue, central obesity and impaired glucose tolerance was diagnosed with Cushing's syndrome due to elevated ACTH (192.9 pg/mL; normal range, 7.2-63.3 pg/mL), cortisol (73.1 µg/dL; 6.4-21.0 µg/dL) and 24-h urinary free cortisol (UFC) (6160 µg/day; 11.2-80.3 µg/day) levels. Chest computed tomography identified a solid 26.6 × 22.9 × 30.0 mm tumour with a cavity in the upper lobe of the left lung. There was no adrenal gland enlargement. Tumour markers were not significantly elevated; ACTH levels were not suppressed by 8-mg dexamethasone. A corticotropin-releasing hormone stimulation test revealed blunted ACTH response (basal ACTH, 204.6 pg/mL; highest ACTH level during the 120-min stimulation test, 214.0 pg/mL). She was diagnosed with EAS due to a lung lesion. MTP treatment was started to reduce cortisol production. ACTH levels and cortisol and UFC levels were normalised and the ACTH-producing lung tumour was ablated after MTP treatment. In several reported cases, plasma ACTH levels reduced during steroidogenesis inhibitor treatment for EAS. Among the 10 patients, three cases of pheochromocytoma, one of thymic carcinoid and one of islet cell carcinoma were reported. In four cases, the tumour was not detected. In our case, the pathology of the lung tumour was unknown because of lack of tumour cells in biopsy. The patients were treated with ketoconazole (KTZ) and/or MTP and exhibited ACTH and cortisol/UFC suppression, but tumour regression was observed only in our case. CONCLUSION: MTP and/or KTZ may reduce ACTH and cortisol production. The tumour spontaneously regressed after MTP treatment, indicating that MTP may reduce the tumour size without surgery. The mechanisms of therapeutic effects of steroidogenesis inhibitors and prognosis of spontaneous remission should be elucidated further via molecular biology studies.

The efficacy of adrenocorticotropic hormone in a girl with anti-N-methyl-D-aspartate receptor encephalitis.

BACKGROUND: Immunomodulatory therapy has shown some therapeutic benefits in patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis. In this report, we describe the use of adrenocorticotropic hormone (ACTH) immunotherapy with good outcome in a patient with anti-NMDAR encephalitis. SUBJECT AND METHODS: A 4-year-old girl developed convulsions in her right arm and leg without impaired consciousness. These convulsions occurred frequently in clusters of 10-20 events of 10-20 s duration. She was admitted to our hospital on the 6th day following her initial series of convulsions. Flaccid paralysis of the right hand and leg was also found. Interictal electroencephalography showed high-amplitude slow waves. No abnormal findings were shown on MRI. 99mTc-ECD brain SPECT on the 14th day showed hyperperfusion in the left hemisphere, including the left basal ganglia. The convulsions ceased following the oral administration of valproic acid on the 10th day; however, paralysis associated with choreic dyskinesia of the right arm and leg remained. ACTH immunotherapy was then performed on the 15th day. We identified the presence of N-methyl-D-aspartate receptor antibody in CSF samples taken on the 6th day. After ACTH therapy, the patient fully recovered from the paralysis associated with choreic dyskinesia of the right arm and leg. She has not had a relapse and has not required medication for over a year. CONCLUSION: ACTH immunotherapy may be a useful treatment option for patients with anti-NMDAR encephalitis, although further evaluation is required.

Gastric perforation and critical illness polyneuropathy after steroid treatment in a patient with encephalitis/encephalopathy with transient splenial lesion.

The outcome of mild encephalitis/encephalopathy with reversible splenial lesion (MERS) is favorable whether or not specific treatment is performed. We report a patient with MERS treated with methylprednisolone, complicated by gastric perforation followed by critical illness polyneuropathy. The patient was a 14-year-old male with mildly impaired consciousness and hyponatremia who was treated with methylprednisolone pulse therapy. High fever appeared after methylprednisolone pulse therapy and free air was recognized on an abdomen roentgenogram. Gastric perforation was recognized on emergent endoscopic surgery and omental implantation repair was performed. His consciousness was fully recovered after surgery, whereas he was noted to have motor and sensory impairment of the lower extremities and vesico-rectal disturbance. Nerve conduction studies revealed decreased compound muscle action potentials with preserved motor conduction velocity and decreased sensory nerve action potentials. He was diagnosed as having critical illness polyneuropathy, and bedside physical rehabilitation was initiated. His neurological symptoms resolved within 6months. Our patient highlighted possible serious adverse events associated with steroid treatment for children with MERS.

Medulloblastoma with epithelioid features in the cerebellar vermis.

A 6-year-old girl was admitted with a mass lesion in the cerebellar vermis. She underwent subtotal tumor resection, and on immunohistopathology the tumor consisted of two different parts: typical medulloblastoma (MB) characteristics and atypical teratoid/rhabdoid tumor (AT/RT) features, despite positive integrase interactor 1 expression. The patient was diagnosed with MB with epithelioid features. Chemoradiation therapy was started because of tumor recurrence at the primary site and dissemination to the spinal cord, as determined on magnetic resonance imaging 2 weeks after surgery. The patient died due to tumor progression 13 months after initial diagnosis, although transient partial remission was achieved.

Bacteremia Caused by Raoultella ornithinolytica in Two Children.

We encountered 2 immunocompromised children complicated by Raoultella ornithinolytica bacteremia. One had received methylprednisolone pulse therapy for IgA nephropathy, and the other had leukopenia because of chemotherapy for leukemia. Both children had no specific symptoms, and R. ornithinolytica bacteremia was identified by routine blood culture. Both patients were successfully treated with antibiotic treatment.