In the 66th annual meeting of the Japanese Society of Child Neurology (spring 2024), I gave an educational lecture on “Ethical Guidelines for Life-Science and Medical Research Involving Human Subjects” that were enacted in 2021 incorporating “Ethical Guidelines for Medical Research” and “Ethical Guidelines for Human Genomic Research,” and revised in 2022 and 2023. This article is a summary of what I spoke in the lecture.

  Emphasis is placed on the purpose and basic principles, definitions of newly introduced terms, responsibilities of researchers, requirements of informed consent, treatment of the results of research (especially those having personal implications for participant).

  As personal information protection legislation since 2004 influenced immensely the drafting of these Guidelines, its history and basic rules are also explained.

  Objective: To clarify the role of the autonomic nervous system (ANS) in autism spectrum disorder (ASD) using precise pupillary light reflex measurements. Methods: This study included 88 children with ASD diagnosed according to DSM-5, 121 typically developing (TD) children, and 105 TD adults. A pupillometer (NPi-200, NeurOptics) was used to measure the initial pupil diameter (R0), change in pupil diameter during constriction (RA), constriction velocity (CV), and dilation velocity (DV) under light conditions with light stimuli applied to one eye. No specific tasks were assigned during the measurements. Using the same parameters, we measured 32 children with TD and 20 children with ASD under dark conditions. Results: R0 reflected the sympathetic/parasympathetic tone ratio (SPR). Resting R0 was significantly smaller in children with ASD than in children with TD under both light and dark conditions, indicating a lower SPR. During pupillary light reflex, the RA, CV (of parasympathetic origin), and DV (of sympathetic origin) of children with ASD were significantly smaller, the CV/DV was significantly larger, and the SPR was higher under light conditions compared to TD children. These differences were no longer significant under dark conditions. Conclusion: The low SPR of R0 in children with ASD was independent of the environment (light/dark), indicating that they have a unique sympathetic/parasympathetic tone balance. In contrast, the SPR during the pupillary light reflex in children with ASD was higher under light conditions but decreased under dark conditions and was not significantly different from that of TD children, suggesting that the SPR varies depending on the environment (light or dark) and may represent an adaptive change in ASD.

  Myocarditis is an extremely rare complication of myasthenia gravis, particularly in adults, and has never been reported in children. Here, we present the case of a child in whom acute myocarditis preceded the diagnosis of systemic myasthenia gravis. A 3-year-old girl was initially hospitalized with acute myocarditis and responded well to high-dose intravenous immunoglobulins and prednisolone therapy. However, the myocarditis recurred when prednisolone was discontinued. The drug dose was then gradually tapered, and the patient was discharged from the hospital on the 86^th day of illness.

  Three days after discharge, the patient developed left excyclotropia, gait disorder, dysphagia, and right blepharoptosis, accompanied by elevated muscle enzyme levels. On the 96^th day, she was re-hospitalized. An edrophonium chloride test and repeated stimulation-induced electromyography confirmed the diagnosis of myasthenia gravis. Treatment with immunoglobulins and a gradual increase in the prednisolone dose improved proximal muscle weakness, although muscle enzyme levels remained elevated. Tacrolimus was subsequently administered, resulting in decreased muscle enzyme levels and discharge from the hospital.

  The clinical course and serological findings in this case differed from those typically seen in adult cases. However, the relationship between myocarditis and systemic myasthenia gravis remains poorly understood. A previous case report indicated that when the inflammation became chronic in an adult with acute myocarditis, the patient progressed to chronic myocarditis, possibly owing to Th17 cell activation. The clinical course suggested a potential link between myocarditis and myasthenia gravis. In this report, we discuss the clinical progression of the case in detail from the viewpoint of pediatric neurology. Further investigation into the immunological mechanisms underlying acute myocarditis in children with myasthenia gravis is warranted.

  Collagen type IV alpha 2 chain (COL4A2) is a gene that encodes the α2 chain of type IV collagen. It has been associated with brain lesions and other organ disorders. We experienced a family case in which a COL4A2 gene variant was identified in the patient following abnormal brain imaging findings in their sister. When the patient was 4 months old, it was noted that she could not grasp with her left hand and showed insufficient eye tracking to the left-hand side. Brain magnetic resonance imaging (MRI) identified ventriculomegaly and subependymal hemorrhage. Later, her older sister was admitted to hospital with seizures at 4 years of age. Her brain MRI revealed periventricular white matter lesions and subependymal hemorrhage. Hereditary cerebrovascular disease was suspected based on the abnormal brain imaging findings in the sister, and COL4A1/COL4A2 gene analysis was performed. Both sisters were heterozygous for a novel missense variant (c.1811G>T ; p.Gly604Val) in the COL4A2 gene. Their maternal aunt was found to have enlarged lateral ventricles when she had a brain MRI after experiencing headaches. Therefore, we considered the possibility of a similar gene mutation. After receiving genetic counseling, genetic analysis was performed on both parents and the maternal aunt. Similar gene variants were identified in both the mother and aunt. Because it is an autosomal dominant disorder, COL4A1/COL4A2 gene variants should be assumed if there is a family history of abnormal brain imaging.

  Adrenocorticotropic hormone (ACTH) therapy is one of the most effective treatments for infantile epileptic spasms syndrome (IESS), which was previously classified as West syndrome. In some cases, IESS can develop immediately before or after Bacillus Calmette-Guérin (BCG) vaccination. Vigabatrin, an alternative treatment, has limited availability and is associated with visual field defects in approximately one-third of cases. Additionally, delaying ACTH therapy may negatively impact long-term intellectual prognosis. Therefore, early consideration of ACTH therapy soon after BCG vaccination may be necessary in certain situations. We have experienced three cases involving patients diagnosed with IESS in whom ACTH therapy was administered 5, 6, and 14 days after BCG vaccination. In these cases, short-term seizure control was favorable. None of the patients developed BCG infection, and no BCG infection had occurred by 1 year post-treatment. Although early ACTH therapy after BCG vaccination carries a risk of BCG infection, early ACTH therapy may be an option if the clinician thinks it necessary and the family agrees. It is also recommended to ensure adequate follow-up for several years, collaborate with infectious disease specialists, and be prepared to administer anti-tuberculosis medication if necessary.

  Spinocerebellar ataxia (SCA) type 5 is an autosomal dominant disorder, characterized by spinocerebellar degeneration caused by the SPTBN2 variant. While SCA type 5 was originally considered to have an onset in adulthood, cases of infants with psychomotor delay have also been reported since 2012. Generally, the progression of SCA type 5 is mild, however, we encountered an infant SCA type 5 case with the SPTBN2 pathological variant NM_006946.4 : c.185C>T p. (T62I) d.n. which presented with severe generalized developmental delay and significant cerebellar atrophy. The child was still unable to hold his head up at 4 months of age and displayed generalized developmental delay. Although cerebellar symptoms were not prominent during infancy, and there was decreased muscle tone, predominantly affecting the trunk. A brain MRI scan revealed extensive cerebellar atrophy, which promoted genetic analysis and a diagnosis of SCA5. Clinically, the patient could be diagnosed with ataxic cerebral palsy, which should be differentiated by genetic analysis.

  The anti-myelin oligodendrocyte glycoprotein (MOG) antibodies are one of the autoantibodies associated with inflammatory demyelinating diseases of the central nervous system. Recently, a new disease concept, MOG-IgG-associated disease (MOGAD), has been established and is attracting attention. Although some patients with MOGAD exhibit peripheral neuropathy, pediatric MOGAD often presents as ADEM, and there have been no reports of pediatric MOGAD with peripheral neuropathy and anti-GM1 antibody positivity. Herein, we report a case of pediatric MOGAD with both central and peripheral neurological symptoms, which was positive for IgG anti-GM1 antibody. The patient, a healthy 13-year-old boy, presented with high fever and headache, followed by progressive impaired consciousness, respiratory muscle paralysis, and quadriplegia with loss of tendon reflexes, requiring long-term mechanical ventilation and temporary tracheotomy. A nerve conduction studies revealed transient conduction blocks of motor and sensory nerves in the extremities, and MRI revealed multiple lesions in the brainstem, subcortical area, and gray matter of spinal cord. After multiple steroid pulse therapy and intravenous immunoglobulin therapy, the patient was weaned from the ventilator and the tracheostomy was closed within 2 months, and he returned to his daily life without neurological sequelae by 6 months after onset. In severe cases of MOGAD with peripheral neuropathy in children, it may be useful to suspect the involvement of anti-ganglioside antibodies as well as anti-MOG antibodies in understanding the pathophysiology and selecting treatment.

  We report two cases in which a diagnosis of chronic appendicitis was challenging in children with orthostatic dysregulation (OD) and autism spectrum disorder (ASD). Case 1 : A 14-year-old boy developed headache, abdominal pain, and diarrhea at 13 years and 5 months of age. OD was diagnosed, and imaging studies initially suggested a functional abdominal pain. Eighteen months after symptom onset, abdominal CT scan revealed swollen wall thickening and fecalith formation. Symptoms improved after appendectomy. Case 2 : A 7-year-old boy with ASD developed abdominal pain at 6 years and 4 months of age. He was initially diagnosed with psychogenic abdominal pain. Fourteen months after symptom onset, he underwent appendectomy, which improved his symptoms. The two cases showed histopathological findings of submucosal fibrosis and lymphocyte infiltration. Chronic abdominal pain in children is often considered functional, which may delay the diagnosis of organic diseases. Children with OD or ASD often present with gastrointestinal symptoms from stress due to the effects of the brain-gut axis. In these two cases, the symptoms were thought to be psychosomatic because of underlying conditions, which delayed the diagnosis of chronic appendicitis. Chronic right lower quadrant pain in children with psychosomatic symptoms should include chronic appendicitis in the differential diagnosis.

  Molybdenum cofactor deficiency (MoCD) is a fatal inherited metabolic disorder characterized by neurological symptoms. The cause of death is often unclear. Herein, we present a case of a 1-month-old boy who presented with seizure clusters. Head magnetic resonance imaging revealed brain edema across the entire cerebrum. The uric acid level was low (0.3 mg/dL), and the urine sample was positive for sulfite. Echocardiography showed a coronary artery fistula. On day X+17, he became hypotensive and bradycardic and died. Genetic testing confirmed the diagnosis of MoCD. Pathological findings revealed a coronary artery fistula. Heart failure was determined to be the cause of death. It should be noted that MoCD can be complicated by cardiovascular diseases.

  X-linked hydrocephalus (XLH), the most common form of hereditary hydrocephalus, is caused by pathogenic variants in the L1 cell adhesion molecule. A 29-year-old male patient with XLH presented with recurrent vomiting for more than eleven years. Finally, when a cyclical vomiting syndrome was suspected as the cause of vomiting, gabapentin (GBP) was prescribed, which proved highly effective. Cyclical vomiting syndrome should be considered as a differential diagnosis when recurrent vomiting is encountered in individuals with severe cognitive and physical disabilities, who may have difficulty expressing pain. The patient’s diagnosis was confirmed by the identification of a novel variant of L1CAM, NM_001278116.2 : c.2929_2930del [p.H978Qfs*25], in a genetic analysis study.