Publications by authors named "Ichiro Kuki"

57 Publications

Preliminary report for Epilepsia Open A case of West syndrome with severe global developmental delay and confirmed KIF5A gene variant.

Epilepsia Open 2021 03 7;6(1):230-234. Epub 2021 Jan 7.

Department of Human Genetics Yokohama City University Graduate School of Medicine Yokohama Japan.

Objective: Kinesin family member 5A (KIF5A) is a molecular motor protein responsible for intracellular transport, specifically in neurons. While abnormalities in the gene have been reported in the onset of various neurological diseases, there are no studies demonstrating an association between this gene and West syndrome.

Methods: In the case presented here, epileptic spasms appeared at 7 months; electroencephalogram (EEG) investigation confirmed hypsarrhythmia, resulting in a diagnosis of West syndrome. The patient exhibited peculiar facies, hypotonia, failure to thrive, and severe global developmental delay.

Results: Cranial magnetic resonance imaging (MRI) revealed severe delayed myelination. I-iomazenil SPECT image at 7 months demonstrated decreased accumulation in bilateral areas, including the primary somatosensory and motor cortices, and the primary and association visual areas compared to an age-matched control. Whole exome sequencing analysis demonstrated a novel de novo heterozygous missense variant in , (NM_004984.4:c.710A>T: p. Glu237Val).

Significance: It was concluded that the variant impaired the transport of GABA receptors to the cell membrane surface, thus leading to an imbalance of these receptors between regions of the cerebrum and resulting in the onset of epilepsy.
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http://dx.doi.org/10.1002/epi4.12431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918309PMC
March 2021

Phase-amplitude coupling of interictal fast activities modulated by slow waves on scalp EEG and its correlation with seizure outcomes of disconnection surgery in children with intractable nonlesional epileptic spasms.

J Neurosurg Pediatr 2021 Feb 26:1-9. Epub 2021 Feb 26.

4Department of Neurology, The Hospital for Sick Children, Toronto, Ontario, Canada.

Objective: Epileptic spasms (ESs) are classified as focal, generalized, or unknown onset ESs. The classification of ESs and surgery in patients without lesions apparent on MRI is challenging. Total corpus callosotomy (TCC) is a surgical option for diagnosis of the lateralization and possible treatment for ESs. This study investigated phase-amplitude coupling (PAC) of fast activity modulated by slow waves on scalp electroencephalography (EEG) to evaluate the strength of the modulation index (MI) before and after disconnection surgery in children with intractable nonlesional ESs. The authors hypothesize that a decreased MI due to surgery correlates with good seizure outcomes.

Methods: The authors studied 10 children with ESs without lesions on MRI who underwent disconnection surgeries. Scalp EEG was obtained before and after surgery. The authors collected 20 epochs of 3 minutes each during non-rapid eye movement sleep. The MI of the gamma (30-70 Hz) amplitude and delta (0.5-4 Hz) phase was obtained in each electrode. MIs for each electrode were averaged in 4 brain areas (left/right, anterior/posterior quadrants) and evaluated to determine the correlation with seizure outcomes.

Results: The median age at first surgery was 2.3 years (range 10 months-9.1 years). Two patients with focal onset ESs underwent anterior quadrant disconnection (AQD). TCC alone was performed in 5 patients with generalized or unknown onset ESs. Two patients achieved seizure freedom. Three patients had residual generalized onset ESs. Disconnection surgeries in addition to TCC consisted of TCC + posterior quadrant disconnection (PQD) (1 patient); TCC + AQD + PQD (1 patient); and TCC + AQD + hemispherotomy (1 patient). Seven patients became seizure free with a mean follow-up period of 28 months (range 5-54 months). After TCC, MIs in 4 quadrants were significantly lower in the 2 seizure-free patients than in the 6 patients with residual ESs (p < 0.001). After all 15 disconnection surgeries in 10 patients, MIs in the 13 target quadrants for each disconnection surgery that resulted in freedom from seizures were significantly lower than in the 26 target quadrants in patients with residual ESs (p < 0.001).

Conclusions: In children with nonlesional ESs, PAC for scalp EEG before and after disconnection surgery may be a surrogate marker for control of ESs. The MI may indicate epileptogenic neuronal modulation of the interhemispheric corpus callosum and intrahemispheric subcortical network for ESs. TCC may be a therapeutic option to disconnect the interhemispheric modulation of epileptic networks.
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http://dx.doi.org/10.3171/2020.9.PEDS20520DOI Listing
February 2021

gAChR antibodies in children and adolescents with acquired autoimmune dysautonomia in Japan.

Ann Clin Transl Neurol 2021 04 23;8(4):790-799. Epub 2021 Feb 23.

Department of Molecular Neurology and Therapeutics, Kumamoto University Hospital, Kumamoto, Japan.

Objective: Patients with acquired autonomic dysfunction may have antibodies specific to the ganglionic nicotinic acetylcholine receptor (gAChR). However, the clinical features of children and adolescents with acquired autonomic dysfunction (AAD) remain unclear. This study aimed to determine the clinical features of pediatric patients with acquired autonomic dysfunction.

Methods: This study retrospectively examined a series of patients of AAD with serum gAChR antibodies who were referred to our laboratory for antibody testing between January 2012 and April 2019. The study included 200 patients (<20 years, 20 cases; ≥20 years, 175 cases) with clinical features of AAD.

Results: Upon comparing pediatric and adult patients, we found that antecedent infection and autonomic symptoms at onset with gastrointestinal symptoms occurred more frequently in children with AAD. We confirmed that four children (20.0%) met the diagnostic criteria for postural orthostatic tachycardia syndrome (POTS). A significantly higher number of children than adults had POTS (P = 0.002). In addition, upper GI dysfunction was more prevalent in children than in adults (P = 0.042). In particular, nausea and vomiting occurred in 60.0% of children with AAD and in 21.1% of adults (P < 0.001). The frequency of paralytic ileus was significantly higher in children with AAD (20.0%) relative to adults (6.3%) (P = 0.030). Regarding extra-autonomic manifestations, encephalopathy was more frequent in children (15.0%) than in adults (1.1%) (P < 0.001).

Interpretation: Pediatric AAD patients have their own clinical characteristics, and these features may be unique to children and adolescents.
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http://dx.doi.org/10.1002/acn3.51317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045944PMC
April 2021

Distinct dual cortico-cortical networks successfully identified between supplemental and primary motor areas during intracranial EEG for drug-resistant frontal lobe epilepsy.

Epilepsy Behav Rep 2021 19;15:100429. Epub 2021 Jan 19.

Division of Neurology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X3, Canada.

We present a case of drug-resistant focal motor seizures in which separate cortico-cortical epileptic networks within the supplementary motor area (SMA) proper and primary motor area (PMA) were proven by ictal high-frequency oscillation (HFO) and cortico-cortical evoked potential (CCEP). A 12-year-old girl presented with two types seizures: type A, tonic extension and subsequent clonic movements of the right arm; and type B, tonic and clonic movements of the right leg. MRI was normal and karyotype genetic analysis revealed 46,X,t(X;14)(q13;p12). She underwent placement of chronic subdural electrodes over the left hemisphere. We recorded a total of nine seizures during 10 days of epilepsy monitoring. Type A seizures started from the lower part of the left SMA proper and early spread to the hand motor area of the PMA. Type B seizures started from the upper part of the SMA proper and early spread to the leg motor area of the PMA. CCEPs of both SMA proper and PMA activated two identical routes for evoked potentials correlating with separate pathways. Corticectomy of the left SMA proper and PMA achieved seizure-free without hemiparesis. Within a small homunculus of the SMA proper, separate epileptic networks were proven and validated by seizure semiology, ictal HFO, and CCEP.
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http://dx.doi.org/10.1016/j.ebr.2021.100429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851778PMC
January 2021

Intrathecal dexamethasone therapy for febrile infection-related epilepsy syndrome.

Ann Clin Transl Neurol 2021 03 5;8(3):645-655. Epub 2021 Feb 5.

Department of Brain and Neuroscience, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

Objective: Increasing reports suggest a role for immunological mechanisms in febrile infection-related epilepsy syndrome (FIRES). The objective of this study was to elucidate the efficacy and safety of intrathecal dexamethasone therapy (IT-DEX).

Methods: We assessed six pediatric patients with FIRES who were administered add-on IT-DEX in the acute (n = 5) and chronic (n = 1) phases. We evaluated clinical courses and prognosis. We measured cytokines/chemokines in cerebrospinal fluid (CSF) from FIRES patients at several points, including pre- and post-IT-DEX, and compared them with control patients with chronic epilepsy (n = 12, for cytokines/chemokines) or with noninflammatory neurological disease (NIND, n = 13, for neopterin).

Results: Anesthesia was weaned after a median of 5.5 days from IT-DEX initiation (n = 6). There was a positive correlation between the duration from the disease onset to the introduction of IT-DEX and the length of ICU stay and the duration of mechanical ventilation. No patient experienced severe adverse events. Seizure spreading and background activities on electroencephalography were improved after IT-DEX in all patients. The levels of CXCL10, CXCL9, IFN-γ, and neopterin at pre-IT-DEX were significantly elevated compared to levels in epilepsy controls, and CXCL10 and neopterin were significantly decreased post-IT-DEX, but were still higher compared to patients with chronic epilepsy. IL-6, IL-8, and IL-1β were significantly elevated before IT-DEX compared to epilepsy controls, though there was no significant decrease post-treatment.

Interpretation: IT-DEX represents a therapeutic option for patients with FIRES that could shorten the duration of the critical stage of the disease. The effect of IT-DEX on FIRES might include cytokine-independent mechanisms.
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http://dx.doi.org/10.1002/acn3.51308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951105PMC
March 2021

A case of infantile Tay-Sachs disease with late onset spasms.

Brain Dev 2021 May 20;43(5):661-665. Epub 2021 Jan 20.

Division of Pediatric Neurology, Children's Medical Center, Osaka City General Hospital, Osaka, Japan.

Background: Epilepsy is known to be associated with Tay-Sachs disease (TSD); however, no detailed reports are available. This case report aimed to present the clinical features of late onset spasms (LOS) in a patient with infantile TSD, and to elucidate the pathophysiology leading to LOS, using proton magnetic resonance spectroscopy (MRS).

Case Presentation: At 11 months old, our patient had an afebrile seizure. At 14 months, he showed developmental stagnation and an increase in the frequency of epileptic seizures. Magnetic resonance imaging (T2-weighted images) showed high signal intensities in the thalamus bilaterally, and in the head of the caudate nucleus. Serum β-hexosaminidase enzyme activity was reduced, and he was diagnosed with TSD with a homozygous pathogenic variant of the HEXA gene (c. 571-1 G > T [IVS5, -1 G > T]), confirmed using direct sequence analysis. At 20 months, epileptic spasms in series around times of drowsiness and waking were observed on long-term video-electroencephalogram monitoring, in which ictal findings were different from those of startle seizures and non-epileptic myoclonus. Therefore, the epilepsy was classified as LOS. Epileptic spasms stopped following adrenocorticotropic hormone therapy, after which his vitality and consciousness improved. Serial MRS results showed a progressive decline in N-acetyl aspartate, and an increase in myoinositol in the grey matter over time.

Discussion And Conclusion: Our patient's MRS results suggested that cortical and subcortical axonal and neuronal degeneration with widespread gliosis in the cerebrum might lead to the development of LOS, and that LOS might be underestimated in patients with TSD.
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http://dx.doi.org/10.1016/j.braindev.2020.12.016DOI Listing
May 2021

Thyroid crisis mimicking clinically mild encephalitis/encephalopathy with a reversible splenial lesion: A pediatric case report.

Brain Dev 2021 Apr 4;43(4):596-600. Epub 2021 Jan 4.

Department of Pediatric Neurology, Osaka City General Hospital, Osaka, Japan.

Background: Reversible lesions in the splenium of the corpus callosum (SCC) with viral infections are associated mainly with clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS). We report a pediatric patient in thyroid crisis with reversible SCC lesions.

Case Description: We diagnosed a 9-year-old girl with thyroid crisis. She had presented with fever, tachycardia, and impaired consciousness. Magnetic resonance imaging revealed hyperintense signals in the splenium and genu of the corpus callosum and a white matter lesion of the left hemisphere in diffusion-weighted imaging. The initial, tentative diagnosis was clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS). We initiated intravenous methylprednisolone pulse therapy; thereafter, her level of consciousness rapidly improved. On admission, thyroid function studies revealed elevation of free thyroxine and a low level of thyroid stimulating hormone with thyroid-related autoantibodies. She was begun on thiamazole and was discharged without neurological sequelae.

Conclusion: Thyroid crisis is similar to acute encephalitis or encephalopathy associated with viral infection, especially with MERS, because the clinical and radiological features resemble those of thyroid crisis; therefore, thyroid diseases should be considered as a possible cause of reversible lesions in the splenium of the corpus callosum.
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http://dx.doi.org/10.1016/j.braindev.2020.12.007DOI Listing
April 2021

Acute encephalopathy in children with tuberous sclerosis complex.

Orphanet J Rare Dis 2021 01 6;16(1). Epub 2021 Jan 6.

Department of Pediatrics, Aichi Medical University, 1-1 Yazako Karimata, Nagakute, Aichi, 480-1195, Japan.

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.
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http://dx.doi.org/10.1186/s13023-020-01646-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789140PMC
January 2021

[Convulsive syncope then convulsive seizure occurred in the long clinical course: a case report].

Rinsho Shinkeigaku 2020 Sep 8;60(9):627-630. Epub 2020 Aug 8.

Department of Neurology, Ijinkai Takeda General Hospital.

A 17-year-old woman presented with transient consciousness impairment attack and convulsion after bathing and prolonged standing since age 12. EEG showed WHAM ( wake, high amplitude, anterior, male) type of phantom spikes that usually carry the high risk of epilepsy at age 13. At age 17, EEG wise generalized spike and wave complex was recorded once, and head-up tilt test was positive. She was carefully observed without antiepileptic drugs since convulsive syncope due to neurally mediated syncope was most likely. During the follow-up period, she had eventually unprovoked generalized tonic-clonic seizures (convulsive seizure) twice and thus she was started with antiepileptic drug with success. Although both convulsive syncope and convulsive seizure differ in nature and effects on quality of life, in this patient, the latter occurred later and both occurs together. It is important to distinguish them by means of the degree of convulsion and EEG finding.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001451DOI Listing
September 2020

Prenatal clinical manifestations in individuals with variants.

J Med Genet 2020 Jul 30. Epub 2020 Jul 30.

Department of Pediatric Neurology, Bobath Memorial Hospital, Osaka, Osaka, Japan.

Background: Variants in the type IV collagen gene () cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with variants remain unclear.

Methods: We examined in 218 individuals with suspected /2-related brain defects. Among those arising from variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail.

Results: Pathogenic variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly.

Conclusions: Prenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and gene testing should be considered when pathogenic variants are strongly suspected.
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http://dx.doi.org/10.1136/jmedgenet-2020-106896DOI Listing
July 2020

DWI scoring system for prognosis of acute encephalopathy with biphasic seizures and late reduced diffusion.

Jpn J Radiol 2020 Sep 8;38(9):860-869. Epub 2020 May 8.

Departments of Diagnostic and Interventional Radiology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahi-cho, Abeno-ku, Osaka, Japan.

Purpose: The aim of this study was to predict neurological outcomes for acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) using diffusion-weighted imaging (DWI), and assess relationships between anatomical sites of lesions and their outcomes.

Materials And Methods: We assessed DWI abnormalities and neurological outcomes in 30 patients with AESD, and classified patients into severe and non-severe groups according to their neurological outcomes. We also established a DWI scoring system as follows: zero for normal, and one for lesion at each location. Differences between the severe and non-severe groups were examined, and receiver operating characteristic (ROC) curve analysis was performed.

Results: Nine (30%) patients were classified into the severe group. On DWI, patients in the severe group were more likely to have temporal lobe (P = 0.014), perirolandic (P = 0.008), and corpus callosum (P = 0.0008) lesions than those in the non-severe group. The total DWI scores were significantly higher in the severe group than those in the non-severe group (P = 0.0002). ROC curve showed an area under the curve of 0.929, with a cutoff value of five, sensitivity of 88.9%, and specificity of 81.0%.

Conclusion: Patients with severe AESD had more extensive DWI abnormalities than those with non-severe AESD. Our DWI scoring system may be useful for the prediction of outcomes of AESD. Widespread lesions seemed to have stronger influence on outcomes than each lesion location.
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http://dx.doi.org/10.1007/s11604-020-00984-8DOI Listing
September 2020

Neurocritical care and target immunotherapy for febrile infection-related epilepsy syndrome.

Biomed J 2020 06 21;43(3):205-210. Epub 2020 Apr 21.

Department of Pediatric Neurology, Children's Medical Center, Osaka City General Hospital, Osaka, Japan.

Febrile infection-related epilepsy syndrome (FIRES) is an intractable neurological disease characterized by an unexplained refractory status epilepticus triggered by febrile infection. A Consensus definition of FIRES was proposed in 2018, and its clinical features and prognosis are gradually being clarified. However, the development of effective treatments has been hindered as the etiology of this rare disease is as yet unelucidated. The basic approach to the management of FIRES, like other forms of epilepsy, is based on the control of seizures, however seizures are extremely intractable and require intravenous administration of large doses of anticonvulsants, mainly barbiturates. This treatment strategy produces various complications including respiratory depression and drug hypersensitivity syndrome, which make it more difficult to control seizures. Consequently, it is crucial to predict these events and to formulate a planned treatment strategy. As well, it is important to grow out of conventional treatment strategies that rely on only anticonvulsants, and alternative therapies are gradually being developed. One such example is the adoption of a ketogenic diet which may lead to reduced convulsions as well as improve intellectual prognosis. Further, overproduction of inflammatory cytokines in the central nervous system has been shown to be strongly related to the pathology of FIRES which has led to attempts at immunomodulation therapy including anti-cytokine therapy.
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http://dx.doi.org/10.1016/j.bj.2020.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424090PMC
June 2020

Anatomic Understanding of Subtotal Hemispherotomy Using Cadaveric Brain, 3-Dimensional Simulation Models, and Intraoperative Photographs.

Oper Neurosurg (Hagerstown) 2020 06;18(6):E209-E218

Department of Neurosurgery, Osaka City University Graduate School of Medicine, Osaka, Japan.

Background: When the epileptogenic foci skip the motor area, the epilepsy can be cured by surgery while preserving the motor function. This surgery has been reported as subtotal hemispherectomy. The disconnective variant of this surgery, subtotal hemispherotomy, is described.

Objective: To demonstrate each step clearly, a cadaveric brain, 3-dimensional reconstruction and simulation model, and intraoperative photographs were used.

Methods: A formalin-fixed cadaveric brain was dissected to show each step of this surgery. For the 3-dimensional model, several brain structures were reconstructed from preoperative images, and the surgery was simulated. Intraoperative photographs and postoperative magnetic resonance images were taken from the representative cases.

Results: Temporo-parieto-occipital disconnection is performed to disconnect these lobes and the insula, limbic system, and splenium of the corpus callosum. The postcentral sulcus is the anterior border of the disconnection. Next, prefrontal disconnection is performed to disconnect the frontal lobe and the insula, frontal lobe and basal ganglia, and the anterior part of the corpus callosum. The precentral sulcus is the posterior border of the disconnection. Finally, corpus callosotomy of the central part is performed. After these steps, subtotal hemispherotomy, with preservation of the pre- and postcentral gyrus, is achieved. The 3-dimensional model clearly shows the anatomic relationships between deep brain structures. In the representative cases, postoperative motor deterioration was transient or none, and seizure-free status was achieved after surgery.

Conclusion: Subtotal hemispherotomy is generally difficult because of the complicated anatomy and narrow and deep surgical corridors. Combined use of these methods facilitates a clearer understanding of this surgery.
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http://dx.doi.org/10.1093/ons/opz354DOI Listing
June 2020

Reply to the letter: "Acute encephalopathy with brain swelling".

Brain Dev 2020 01 20;42(1):100-101. Epub 2019 Sep 20.

Department of Pediatrics, Aizenbashi Hospital, Osaka, Japan.

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http://dx.doi.org/10.1016/j.braindev.2019.08.010DOI Listing
January 2020

Thermolabile polymorphism of carnitine palmitoyltransferase 2: A genetic risk factor of overall acute encephalopathy.

Brain Dev 2019 Nov 24;41(10):862-869. Epub 2019 Jul 24.

Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Objectives: Acute encephalopathy is an acute brain dysfunction after preceding infection, consisting of multiple syndromes. Some syndromes, such as acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), are severe with poor outcome, whereas others, such as clinically mild encephalitis/encephalopathy with reversible splenial lesion (MERS), are mild with favorable outcome. Previous study reported the association of the thermolabile polymorphism in Carnitine Palmitoyltransferase 2 (CPT2) gene and severe syndromes of acute encephalopathy. To further explore the pathogenetic role of CPT2 in acute encephalopathy, we conducted a case-control association study of a typical thermolabile CPT2 polymorphism, rs2229291, in 416 patients of acute encephalopathy, including both severe and mild syndromes.

Methods: The case cohort consisted of 416 patients, including AESD, MERS, and other syndromes. The control subjects were 100 healthy Japanese. rs2229291 was genotyped by Sanger sequencing. Genetic distribution was compared between the patients and controls using Cochran-Armitage trend test.

Results: Minor allele frequency of rs2229291 was significantly higher in AESD (p = 0.044), MERS (p = 0.015) and entire acute encephalopathy (p = 0.044) compared to the controls. The polymorphism showed no significant association with influenza virus, or with outcome.

Conclusions: This study provided evidence that CPT2 is a susceptibility gene for overall acute encephalopathy, including both severe and mild syndromes, and suggested that impairment of mitochondrial metabolism is common to various syndromes of acute encephalopathy.
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http://dx.doi.org/10.1016/j.braindev.2019.07.008DOI Listing
November 2019

Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy.

Nat Commun 2019 06 7;10(1):2506. Epub 2019 Jun 7.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.

Although there are many known Mendelian genes linked to epileptic or developmental and epileptic encephalopathy (EE/DEE), its genetic architecture is not fully explained. Here, we address this incompleteness by analyzing exomes of 743 EE/DEE cases and 2366 controls. We observe that damaging ultra-rare variants (dURVs) unique to an individual are significantly overrepresented in EE/DEE, both in known EE/DEE genes and the other non-EE/DEE genes. Importantly, enrichment of dURVs in non-EE/DEE genes is significant, even in the subset of cases with diagnostic dURVs (P = 0.000215), suggesting oligogenic contribution of non-EE/DEE gene dURVs. Gene-based analysis identifies exome-wide significant (P = 2.04 × 10) enrichment of damaging de novo mutations in NF1, a gene primarily linked to neurofibromatosis, in infantile spasm. Together with accumulating evidence for roles of oligogenic or modifier variants in severe neurodevelopmental disorders, our results highlight genetic complexity in EE/DEE, and indicate that EE/DEE is not an aggregate of simple Mendelian disorders.
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http://dx.doi.org/10.1038/s41467-019-10482-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555845PMC
June 2019

Chronological dynamic changes in cortico-subcortical imbalance of cerebral blood flow in a boy with CAPOS syndrome.

Brain Dev 2019 Aug 20;41(7):625-629. Epub 2019 Mar 20.

Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

Background: Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy and Sensorineural hearing loss (CAPOS) syndrome is a known ATP1A3-related disorder, but little has been elucidated regarding its pathophysiology. We now report two new patients, a Japanese boy and his mother with a pathogenic mutation (c.2452G>A) in ATP1A3, who were diagnosed with CAPOS syndrome.

Methods: After febrile illnesses at 7 months of age, and again at 22 months of age, the boy had a reduced level of consciousness, truncal ataxia and eye movement-disorders. The patient's 32-year-old mother may have experienced an episode of acute encephalopathy in her childhood and sustained sensorineural hearing loss. In the present study, we demonstrated chronological dynamic changes in cerebral blood flow (CBF) in the son, using serial single-photon emission computed tomography (SPECT).

Results: The serial CBF-SPECT findings using statistical methods showed progressive hyperperfusion in the frontal lobes, basal ganglia and thalamus, and hypoperfusion in the occipital and temporal lobes during the acute and subacute phases. Thereafter, the dynamic changes of CBF improved in the chronic but hypoperfusion in thalamus appeared to the chronic phase.

Conclusion: The abnormal cortico-subcortical CBF may contribute to an acute encephalopathy-like condition in the acute stage of CAPOS syndrome. CAPOS syndrome is not often reported, and is possibly an under-recognized syndrome in clinically mild cases.
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http://dx.doi.org/10.1016/j.braindev.2019.03.003DOI Listing
August 2019

Biallelic KARS pathogenic variants cause an early-onset progressive leukodystrophy.

Brain 2019 03;142(3):560-573

Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL, USA.

The leukodystrophies cause severe neurodevelopmental defects from birth and follow an incurable and progressive course that often leads to premature death. It has recently been reported that abnormalities in aminoacyl t-RNA synthetase (ARS) genes are linked to various unique leukodystrophies and leukoencephalopathies. Aminoacyl t-RNA synthetase proteins are fundamentally known as the first enzymes of translation, catalysing the conjugation of amino acids to cognate tRNAs for protein synthesis. It is known that certain aminoacyl t-RNA synthetase have multiple non-canonical roles in both transcription and translation, and their disruption results in varied and complicated phenotypes. We clinically and genetically studied seven patients (six male and one female; aged 2 to 12 years) from five unrelated families who all showed the same phenotypes of severe developmental delay or arrest (7/7), hypotonia (6/7), deafness (7/7) and inability to speak (6/7). The subjects further developed intractable epilepsy (7/7) and nystagmus (6/6) with increasing age. They demonstrated characteristic laboratory data, including increased lactate and/or pyruvate levels (7/7), and imaging findings (7/7), including calcification and abnormal signals in the white matter and pathological involvement (2/2) of the corticospinal tracts. Through whole-exome sequencing, we discovered genetic abnormalities in lysyl-tRNA synthetase (KARS). All patients harboured the variant [c.1786C>T, p.Leu596Phe] KARS isoform 1 ([c.1702C>T, p.Leu568Phe] of KARS isoform 2) either in the homozygous state or compound heterozygous state with the following KARS variants, [c.879+1G>A; c.1786C>T, p.Glu252_Glu293del; p.Leu596Phe] ([c.795+1G>A; c.1702C>T, p.Glu224_Glu255del; p.Leu568Phe]) and [c.650G>A; c.1786C>T, p.Gly217Asp; p.Leu596Phe] ([c.566G>A; c.1702C>T, p.Gly189Asp; p.Leu568Phe]). Moreover, similarly disrupted lysyl-tRNA synthetase (LysRS) proteins showed reduced enzymatic activities and abnormal CNSs in Xenopus embryos. Additionally, LysRS acts as a non-canonical inducer of the immune response and has transcriptional activity. We speculated that the complex functions of the abnormal LysRS proteins led to the severe phenotypes in our patients. These KARS pathological variants are novel, including the variant [c.1786C>T; p.Leu596Phe] (c.1702C>T; p.Leu568Phe) shared by all patients in the homozygous or compound-heterozygous state. This common position may play an important role in the development of severe progressive leukodystrophy. Further research is warranted to further elucidate this relationship and to investigate how specific mutated LysRS proteins function to understand the broad spectrum of KARS-related diseases.
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http://dx.doi.org/10.1093/brain/awz001DOI Listing
March 2019

Seizure freedom from temporal lobe epilepsy with mesial temporal lobe tumor by tumor removal alone without hippocampectomy despite remaining abnormal discharges on intraoperative electrocorticography: Report of two pediatric cases and reconsideration of the surgical strategy.

Surg Neurol Int 2018 10;9:181. Epub 2018 Sep 10.

Department of Neurosurgery, Osaka City University Graduate School of Medicine, Osaka, Japan.

Background: In the surgical treatment of temporal lobe epilepsy with mesial temporal lobe tumor, whether to remove the hippocampus aiming for a better seizure outcome in addition to removing the tumor is a dilemma. Two pediatric cases treated successfully with tumor removal alone are presented.

Case Description: The first case was an 11-year-old girl with a ganglioglioma in the left uncus, and the second case was a 9-year-old girl with a pleomorphic xanthoastrocytoma in the left parahippocampal gyrus. In both cases, the hippocampus was not invaded, merely compressed by the tumor. Tumor removal was performed under intraoperative electrocorticography (ECoG) monitoring. After tumor removal, abnormal discharges remained at the hippocampus and adjacent temporal cortices, but further surgical interventions were not performed. The seizures disappeared completely in both cases.

Conclusions: When we must decide whether to remove the hippocampus, the side of the lesion, the severity and chronicity of the seizures, and the presence of invasion to the hippocampus are the factors that should be considered. Abnormal discharges on ECoG at the hippocampus or adjacent cortices are one of the factors related to epileptogenicity, but it is simply a result of interictal irritation, and it is not an absolute indication for additional surgical intervention.
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http://dx.doi.org/10.4103/sni.sni_61_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6157038PMC
September 2018

An unusual manifestation of Sjögren syndrome encephalitis.

Brain Dev 2019 Feb 28;41(2):217-220. Epub 2018 Aug 28.

Department of Pediatric Emergency Medicine, Osaka City General Hospital, Osaka, Japan.

Sjögren syndrome (SS) is a systemic inflammatory and autoimmune disease characterized by systemic disorders of the exocrine glands, predominantly the salivary and lacrimal glands. Here, we report a 4-year-old boy who presented with the repetition of generalized tonic-clonic seizures for 1-2 min. Initially, he was diagnosed with idiopathic autoimmune encephalitis and was treated with steroids. He was eventually diagnosed with SS based on the examination results, such as inflammatory cell infiltration into the minor salivary glands and positive serum anti-SSA/Ro antibody. Although central nervous system complications are rare in pediatric SS, this condition should be considered in the differential diagnosis when a patient presents with idiopathic autoimmune encephalitis of unknown cause. Furthermore, SS can occur in relatively young children and can present without imaging abnormalities.
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http://dx.doi.org/10.1016/j.braindev.2018.08.004DOI Listing
February 2019

Clinical characteristics of acute encephalopathy with acute brain swelling: A peculiar type of acute encephalopathy.

Brain Dev 2018 Oct 7;40(9):792-798. Epub 2018 Jun 7.

Department of Pediatrics, Aizenbashi Hospital, Osaka, Japan.

Objectives: Acute encephalopathy has been observed with acute brain swelling (ABS) that is characterized by rapid progression to whole-brain swelling. The objective of this study was to describe the clinical characteristics of ABS.

Methods: We encountered four patients with ABS and retrospectively investigated their clinical data with a medical chart review.

Results: Three patients had seizure clustering or status epilepticus in the clinical course. Signs of elevated intracranial pressure (ICP) appeared 3-9 h after the first convulsive attack in three patients. In all patients, signs of brainstem involvement appeared 1-8 h after signs of elevated ICP. Mild hyponatremia that progressed after signs of elevated ICP appeared was noted in three patients. Brain CT revealed mild brain swelling in the initial phase, which rapidly progressed to whole-brain swelling. No focal abnormalities were detected on brain MRI in one patient. Continuous electroencephalography was initially normal, but in two patients, high-amplitude slow waves appeared with rapid changes before signs of brainstem involvement. Although recovery was achieved without sequelae in two patients, outcome was fatal for the other two.

Conclusions: The pathogenesis of ABS has yet to be clarified, but clinical features in our patients are not consistent with any established subtypes of acute encephalopathy. Therefore, we believe that ABS should be recognized as a new type of acute encephalopathy.
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http://dx.doi.org/10.1016/j.braindev.2018.05.004DOI Listing
October 2018

variants in and cause neurodevelopmental disorders.

Ann Clin Transl Neurol 2018 03 29;5(3):280-296. Epub 2018 Jan 29.

Department of Biochemistry Hamamatsu University School of Medicine 1-20-1 Handayama, Higashi-ku Hamamatsu 431-3192 Japan.

Objective: () and () isoforms of Calcium/calmodulin-dependent protein kinase II (CaMKII) play a pivotal role in neuronal plasticity and in learning and memory processes in the brain. Here, we explore the possible involvement of - and -CaMKII variants in neurodevelopmental disorders.

Methods: Whole-exome sequencing was performed for 976 individuals with intellectual disability, developmental delay, and epilepsy. The effect of and variants on CaMKII structure and firing of neurons was evaluated by computational structural analysis, immunoblotting, and electrophysiological analysis.

Results: We identified a total of five de novo and variants in three and two individuals, respectively. Seizures were common to three individuals with variants. Using a minigene splicing assay, we demonstrated that a splice site variant caused skipping of exon 11 leading to an in-frame deletion of the regulatory segment of CaMKII . By structural analysis, four missense variants are predicted to impair the interaction between the kinase domain and the regulatory segment responsible for the autoinhibition of its kinase activity. The Thr286/Thr287 phosphorylation as a result of release from autoinhibition was increased in three mutants when the mutants were stably expressed in Neuro-2a neuroblastoma cells. Expression of a CaMKII mutant in primary hippocampal neurons significantly increased A-type K currents, which facilitated spike repolarization of single action potentials.

Interpretation: Our data highlight the importance of CaMKII and CaMKII and their autoinhibitory regulation in human brain function, and suggest the enhancement of A-type K currents as a possible pathophysiological basis.
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http://dx.doi.org/10.1002/acn3.528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846454PMC
March 2018

Efficacy and safety of everolimus in patients younger than 12 months with congenital subependymal giant cell astrocytoma.

Brain Dev 2018 May 2;40(5):415-420. Epub 2018 Feb 2.

Department of Pediatric Neurosurgery, Osaka City General Hospital, Osaka, Japan.

Tuberous sclerosis complex (TSC) is a multisystem genetic disorder that activates mammalian target of rapamycin and produces tumor growth in several organs. We present five patients younger than 12 months who were diagnosed with TSC and treated with everolimus (EVL), after which congenital subependymal giant astrocytoma (cSEGA) promptly regressed in all patients. All patients achieved at least 50% reduction in the volume of cSEGA within 6 months. The most rapid reduction of cSEGA volume (79.1%) was found during the initial 3 months of EVL treatment. Patients underwent EVL treatment for an average of 27 months (range: 4-55 months). Mean EVL maintenance dose was 1.35 mg per day. EVL blood trough concentrations ranged from 2.0 to 11.7 ng/ml. The cSEGA became larger after discontinuing EVL in two patients. In all four patients who had multiple cardiac rhabdomyomas (CRMs), the CRMs showed accelerated regression after receiving EVL. Adverse events were noted in four patients: infection, stomatitis, and increased triglycerides. Four patients had febrile status epilepticus, which occurred during acute encephalopathy in a patient, and after discontinuing EVL in another. Three patients were still receiving EVL at their latest evaluations. Maintenance therapy with EVL is an effective therapeutic option for patients with cSEGA, and moreover may have additional favorable effects on other complications, even in early infancy; however, adverse effects should be carefully monitored.
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http://dx.doi.org/10.1016/j.braindev.2018.01.001DOI Listing
May 2018

Functional neuroimaging in Rasmussen syndrome.

Epilepsy Res 2018 02 5;140:120-127. Epub 2018 Jan 5.

Department of Pediatrics, Osaka City University Graduate School of Medicine.

Purpose: For a diagnosis of Rasmussen syndrome (RS), clinical course together with electroencephalography (EEG) and magnetic resonance imaging (MRI) findings are considered important, but there are few reports on functional neuroimaging. This study investigated cerebral blood flow (CBF)-single photon emission computed tomography (SPECT), central benzodiazepine receptor (BZR)-SPECT, and fluorine-18 fluorodeoxy glucose-positron emission tomography (FDG-PET) in RS patients, and correlated neuroimaging results with MRI and pathological findings.

Methods: Twenty-three patients diagnosed with RS according to Bien's (2005) diagnostic criteria (including 12 patients with a histological diagnosis) were studied. CBF-SPECT, BZR-SPECT and FDG-PET images were visually evaluated, and the findings correlated with MRI and histological findings.

Results: Hypoperfusion areas were observed in 16 of 22 patients by interictal CBF-SPECT. Hyperperfusion areas were observed in 10 of 12 patients by ictal CBF-SPECT, which correlated with ictal onset area by ictal EEG (IOAE). In the limited data of BZR-SPECT in nine patients, lowered uptake was detected in all nine patients, including two with no MRI abnormalities. Lowered glucose metabolism was observed in affected areas in all five patients by FDG-PET. Histological examination revealed findings of chronic encephalitis in all 12 patients examined, concomitant with focal cortical dysplasia in five patients.

Conclusion: In RS patients, functional neuroimaging reveals clear abnormal findings, even before the appearance of MRI abnormalities. BZR-SPECT and FDG-PET could detect the IOAE efficiently even in the absence of MRI abnormalities, while interictal CBF-SPECT occasionally failed to detect IOAE if MRI was normal. Based on BZR-SPECT, refractory epileptic seizures in RS may suggest possible impairment of inhibitory neurons.
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http://dx.doi.org/10.1016/j.eplepsyres.2018.01.001DOI Listing
February 2018

Three Cases of KCNT1 Mutations: Malignant Migrating Partial Seizures in Infancy with Massive Systemic to Pulmonary Collateral Arteries.

J Pediatr 2017 12 5;191:270-274. Epub 2017 Oct 5.

Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.

KCNT1 mutations are gain-of-function mutations in potassium channels resulting in severe infantile epilepsy. Herein we describe 3 infants with malignant migrating partial seizures with KCNT1 mutations accompanied by massive systemic to pulmonary collateral arteries with life-threatening hemoptysis and heart failure.
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http://dx.doi.org/10.1016/j.jpeds.2017.08.057DOI Listing
December 2017

Clinicopathological features of neuroblastic tumors with opsoclonus-myoclonus-ataxia syndrome: Follicular structure predicts a better neurological outcome.

Pathol Int 2017 Oct;67(10):503-509

Department of Pediatric Hematology and Oncology, Osaka City General Hospital, Miyakojima-ku, Osaka, Japan.

Neuroblastic tumors (NT) with opsoclonus-myoclonus syndrome (OMS) display characteristic histological features, such as lymphocytic infiltration with lymphoid follicles, indicating an underlying immune response. We retrospectively assessed NT patients from 2001 to 2016. Five cases of NT with OMS and 76 cases of NT without OMS were histopathologically reviewed in this study. The grade of lymphocytic infiltration was evaluated. The number of follicles was counted and the presence or absence of lymphoid follicles was recorded for each case. We also confirmed the presence or absence of follicular dendritic cells (FDCs). We investigated the relationship between the histopathological and clinical findings of NT with OMS. Lymphocytic infiltration was observed in all cases; however, the precise follicular structure was occasionally unclear. Patients with clear follicular structures displayed germinal centers including tingible body macrophages and FDCs. All patients without neurological sequelae demonstrated a clear follicular structure with a FDC meshwork pattern. The interval between OMS onset and the detection and initial treatment of NT was typically longer in patients with neurological sequelae compared to those without neurological sequelae. Early detection and treatment of NT with OMS at the phase of a clear follicular formation with multiple FDC may provide favorable neurological outcomes.
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http://dx.doi.org/10.1111/pin.12591DOI Listing
October 2017

Disturbed chromosome segregation and multipolar spindle formation in a patient with mutation.

Mol Genet Genomic Med 2017 Sep 12;5(5):585-591. Epub 2017 Jul 12.

Department of Human GeneticsYokohama City University Graduate School of MedicineYokohamaJapan.

Background: Patients with intellectual disability (ID) typically exhibit significant defects in both intelligence and adaptive behavior. Aberration of several genes involved in proper progression of mitosis has been reported to underlie ID. Here, we report a new patient with a novel mutation of .

Methods: Whole exome sequencing (WES) analysis was performed. We isolated lymphoblast cells from the patient and observed chromosome segregation.

Results: We identified a de novo frameshift mutation in . We find that these cells exhibit an increase in centrosome number and resulting multipolar spindle formation. The phenotypes observed in the patient's lymphoblastoid cells were presumably because of cytokinesis failure. We also confirm the identical phenotypes in human culture cells depleted of CHAMP1.

Conclusion: encodes a protein regulating kinetochore-microtubule attachment and chromosome segregation. These data strongly support that mutations cause ID, and suggest that CHAMP1 is critical for progression of cytokinesis and maintenance of centrosome number.
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http://dx.doi.org/10.1002/mgg3.303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5606869PMC
September 2017

Congenital fiber-type disproportion presenting as ventricular fibrillation.

Pediatr Int 2017 Sep 7;59(9):1025-1027. Epub 2017 Aug 7.

Department of Pediatric Neurology, Osaka City General Hospital, Osaka, Japan.

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http://dx.doi.org/10.1111/ped.13339DOI Listing
September 2017

A child with acute transverse myelitis requiring permanent pacemaker implantation.

Brain Dev 2017 Oct 24;39(9):811-814. Epub 2017 May 24.

Department of Emergency Medicine, Osaka City General Hospital, Osaka, Japan.

We diagnosed a 3-year-old girl with acute transverse myelitis (ATM). She presented with weakness of the limbs and developed urination difficulty and respiratory disturbance. Magnetic resonance imaging revealed a symmetric area of high signal intensity on T2-weighted images involving the lower end of the medulla oblongata to the level of the fourth thoracic vertebra. Anti-aquaporin-4 antibody was negative. She was treated with intravenous methylprednisolone pulse therapy, immunoglobulin therapy, and plasmapheresis; however, her clinical symptoms did not change. At 10 and 20days after symptom onset, cardiac arrest occurred on postural change, requiring cardiopulmonary resuscitation. A permanent pacemaker was implanted 23days after onset. In the presence of sympathetic nerve hypofunction, relative hyperactivity of the parasympathetic nerves may have led to severe bradycardia and cardiac arrest in the presence of an inducer, such as a postural change. This is the first reported case of pacemaker implantation for management of ATM.
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http://dx.doi.org/10.1016/j.braindev.2017.05.002DOI Listing
October 2017