Polymicrogyria is a common malformation of cortical development whose etiology remains elusive. We conducted whole-exome sequencing for 124 patients with polymicrogyria and identified de novo ATP1A3 variants in eight patients. Mutated ATP1A3 causes functional brain diseases, including alternating hemiplegia of childhood (AHC), rapid-onset dystonia parkinsonism (RDP), and cerebellar ataxia, areflexia, pes cavus, optic nerve atrophy, and sensorineural deafness (CAPOS). However, our patients showed no clinical features of AHC, RDP, or CAPOS and had a completely different phenotype: a severe form of polymicrogyria with epilepsy and developmental delay. Detected variants had different locations in ATP1A3 and different functional properties compared with AHC-, RDP-, or CAPOS-associated variants. In the developing cerebral cortex of mice, radial neuronal migration was impaired in neurons overexpressing the ATP1A3 variant of the most severe patients, suggesting that this variant is involved in cortical malformation pathogenesis. We propose a previously unidentified category of polymicrogyria associated with ATP1A3 abnormalities.

There are various types of serious pediatric neurological diseases, although the absolute number of children with either of them is small. These children often have life-threatening conditions with severe disability and rely on medical technologies. Each child follows a different illness trajectory, which makes it difficult to predict his/her prognosis. Given the multiple treatment options, it becomes harder to know when "enough" is enough and what is best for the child. When it comes to critical decision-making, we, as healthcare providers, need to develop a trustful relationship with the parents and promote shared decision-making to fulfill their child's best interest. It is crucial to know what the parents hope and fear, and provide them with access to comprehensive, evidence-based information about their child's current and potential healthcare needs. In this article, four complex ethical issues are reviewed. A broad and constructive discussion is long awaited to ensure that these children's lives are enhanced to their best potential and treated with dignity in our society.

OBJECTIVE: To delineate the critical decision-making processes that paediatricians apply when treating children with life-threatening conditions and the psychosocial experience of paediatricians involved in such care. DESIGN: We conducted semistructured, individual face-to-face interviews for each participant from 2014 to 2015. The content of each interview was subjected to a comprehensive qualitative analysis. The categories of dilemma were extracted from a second-round content analysis. PARTICIPANTS: Participants were board-certified paediatricians with sufficient experience in making decisions in relation to children with severe illnesses or disabilities. We repeated purposive sampling and analyses until we reached saturation of the category data. RESULTS: We performed interviews with 15 paediatricians. They each reported both unique and overlapping categories of dilemmas that they encountered when making critical decisions. The dilemmas included five types of causal elements: (1) paediatricians' convictions; (2) the quest for the best interests of patients; (3) the quest for medically appropriate plans; (4) confronting parents and families and (5) socioenvironmental issues. Dilemmas occurred and developed as conflicting interactions among these five elements. We further categorised these five elements into three principal domains: the decision-maker (decider); consensus making among families, colleagues and society (process) and the consequential output of the decision (consequence). CONCLUSIONS: This is the first qualitative study to demonstrate the framework of paediatricians' decision-making processes and the complex structures of dilemmas they face. Our data indicate the necessity of establishing and implementing an effective support system for paediatricians, such as structured professional education and arguments for creating social consensus that assist them to reach the best plan for the management of severely ill children.

Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a childhood-onset encephalopathy, but the precise pathophysiology remains unclear. We encountered a child with Moyamoya syndrome and AESD. He exhibited left-predominant stenosis of the middle cerebral artery (MCA), and later developed broad lesions in the left hemisphere, raising the possibility that insufficient blood supply relates to formation of the lesions. To test the hypothesis, we investigated the relationship between MCA volume and lesion extent in seven AESD children without preexisting diseases. The MCA volume and lesion extent were quantified with time of flight images for construction of magnetic resonance angiography and apparent diffusion coefficient maps, respectively. Lateralization indices ([right - left]/[right + left]) of the MCA volume and lesion extent were calculated. We found that the lateralization indices were negatively correlated (r = -0.786, p = .036), that is, when the MCA volume was smaller in one side than the other side, the lesions were likely to develop more extensively in the ipsilateral side than the contralateral side. This indicates the association of insufficient blood supply with the lesions. The present study provides the first observation to suggest the involvement of vascular mechanism in AESD and has potential implications for novel therapeutic approach.

Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a newly defined clinicoradiologic syndrome characterized by biphasic seizures and altered consciousness followed by restricted diffusion in the white matter on magnetic resonance imaging in acute phase. Intractable epilepsy commonly occurs as the late complication. This study aimed to search predisposing factors to the development of epilepsy after AESD. Consecutively treated 22 patients with AESD in our institution from 2006 to 2016 were grouped into those with post-encephalopathic epilepsy (PEE, n = 10) or without PEE (n = 12). There was no difference between two groups in age at the onset of AESD, duration of the initial seizures, or the follow-up periods after discharge. PEE group patients more frequently showed coma or involuntary movements during the course of AESD than non-PEE group patients (36% vs. 8%, p = 0.008). The quantitative analysis of apparent diffusion coefficient (ADC) map revealed that PEE group showed broader areas with reduced diffusion in the posterior lobes at the onsets of AESD than non-PEE group (0.113 vs. 0.013, p = 0.035). On the other hand, the atrophy on day 30-ADC map did not correlate with the development or control of epilepsy. These results suggest that the clinical severity and ADC profiles in acute phase, rather than the brain atrophy in convalescent phase, may predict the development of post-AESD epilepsy.

BACKGROUND: Hypophosphatasia (HPP) is a rare genetic disorder characterized by rachitic bone manifestations and a low serum alkaline phosphatase (ALP) level. It is caused by mutations in the tissue non-specific alkaline phosphatase (TNSALP) gene, which encodes the tissue non-specific isozyme of ALP. HPP patients exhibit various presentations depending on their age at onset, such as infantile HPP combined with vitamin B6-responsive seizures. CASE PRESENTATION: A newborn with infantile HPP presented with tonic convulsions from day 5 after birth and received intravenous vitamin B6 (10mg/kg/day pyridoxal phosphate). Eleven days later, frequent apneic episodes occurred, and head magnetic resonance imaging (MRI) showed bilateral reticular formation lesions in the brain stem, including the medulla oblongata. After the pyridoxal phosphate dose was increased (to 40mg/kg/day), the patient's seizures and apnea resolved, and her MRI findings also improved. Genetic testing revealed that she was homozygous for the 1559delT mutation of TNSALP. CONCLUSIONS: High-dose pyridoxal phosphate is a useful treatment for HPP-induced seizures and might improve reticular formation lesions.

BACKGROUND: Botulism is a potentially fatal infection characterized by progressive muscle weakness, bulbar paralysis, constipation and other autonomic dysfunctions. A recent report suggested that cancer chemotherapy might increase the risk for the intestinal toxemia botulism in both adults and children. CASE PRESENTATION: We report a 5-year-old boy, who developed general muscle weakness, constipation, ptosis and mydriasis during the third induction therapy for relapsed acute myeloid leukemia. He had recent histories of multiple antibiotic therapy for bacteremia and intake of well water at home. Repeated bacterial cultures identified Clostridium botulinum producing botulinum neurotoxin A. Botulinum toxin A was isolated from his stools at 17, 21, and 23 days after the onset. Symptoms were self-limiting, and were fully recovered without anti-botulinum toxin globulin therapy. CONCLUSION: This is the second report of a pediatric case with cancer chemotherapy-associated intestinal toxemia botulism. Our case provides further evidence that the immunocompromised status due to anti-cancer treatments increases the risk for the development of botulism at all ages in childhood.

Huntington's disease (HD) and dentatorubral-pallidoluysian atrophy (DRPLA) are monogenic forms of neurodegenerative disorders with autosomal dominant inheritance. Compared with adult-onset HD and DRPLA, children with these disorders are more severely affected and are known to manifest the devastating symptoms of progressive myoclonic epilepsy (PME) syndrome. In this report, we present a 6-year-old girl with HD from a family, and 2 siblings with DRPLA from another unrelated family. Serial neuroimaging and electroencephalography (EEG) studies showed that periodic epileptiform discharges and synchronized paroxysmal activity became prominent with their disease progression. Periodic complexes in EEG may emerge at advanced stages of childhood PME as a consequence of rapidly degenerating processes of their brain functions.

BACKGROUND: Early-onset epileptic encephalopathy (EOEE) is a heterogeneous group of neurodevelopmental disorders characterised by infantile-onset intractable epilepsy and unfavourable developmental outcomes. Hundreds of mutations have been reported to cause EOEE; however, little is known about the clinical features of individuals with rare variants. CASE REPORT AND METHODS: We present a 10-year-old boy with severe developmental delay. He started experiencing recurrent focal seizures at 2 months old. Serial electroencephalograms persistently detected epileptiform discharges from the left hemisphere. Whole-exome sequencing and array-comparative genome hybridization were performed to search for de novo variations. Two-week-old C57Bl/6 mice were used for immunofluorescence studies. RESULTS: This case had a paternally inherited, 0.2-Mb duplication at chromosome 22q11.22. The whole-exome sequencing identified a de novo truncating mutation of tripartite motif containing 8 (TRIM8) (NM_030912:c.1099_1100insG:p.C367fs), one of the epileptic encephalopathy-associated genes. We verified that the murine homologues of these genes are expressed in the postnatal mouse brain. CONCLUSION: This is the second case of EOEE caused by a de novo truncating mutation of TRIM8. Further studies are required to determine the functional roles of TRIM8 in the postnatal development of the human brain and its functional relationships with other EOEE-associated genes.

A total of 40 patients (163 examinations) with severe motor and intellectual disabilities were enrolled for videofiberscopic investigation of granulation tissue in the trachea. Their ages ranged from 2 to 52 years (mean:23.2 years). Seven out of 11 patients (63.6%) with an endotracheal tube and 17 out of 21 patients (81.0%) with a tracheostomy tube had tracheal granulation tissue. The tracheal granulations were mainly located near the tip of the tube and tended to develop on the anterior wall of the trachea. For the treatment of the granulation tissue, the tube was changed to an adjustable cannula in 9 cases and laser ablation was done in 6, with relapse occurring in 5 and 4 cases, respectively. Local application of mitomycin C achieved a good outcome in 2 relapsing cases. Tracheal deformity due to torticollis, cervical lordosis, and thoracic deformity may cause tracheal granulation tissue in patients with severe motor and intellectual disabilities. In addition to changing the tube length and/or laser ablation, local application of mitomycin C may be a useful treatment for tracheal granulation tissue.

A total of 43 patients with severe motor and intellectual disabilities were enrolled in videofiberscopic investigation of laryngeal abnormalities. Their ages ranged from 2 to 41 years (mean: 19.9 years) and all of them had severe quadriplegia due to cerebral palsy or other conditions. Thirty-two out of the 43 patients (74.4%) had laryngeal abnormalities;laryngeal stenosis including that of iatrogenic origin, hypersecretion and laryngomalacia. Direct visualization of the occurrence of aspiration could be achieved in some patients. Seven (87.5%) out of 8 patients with tracheostomy and 25 (71.4%) out of 35 patients without tracheostomy had laryngeal abnormalities, showing no significant difference. The prevalence of abnormalities was significantly higher in patients with parenteral nutrition (30/33 = 90.9%) than in those with oral feeding (2/10 = 20%). Endoscopic investigation of the larynx is important, and videofiberscopy is especially effective for evaluation of laryngeal abnormalities in severely handicapped patients.