Keiko Yanagihara

Ictal video-EEG recording of three partial seizures in a patient with the benign infantile convulsions associated with mild gastroenteritis

Summary: Purpose: In infants, benign convulsions can be triggered by febrile illness or mild diarrhea such as Rotavirus gastroenteritis. The triggering mechanism of these convulsions is still unknown. In spite of several reports concerning clinical features, the ictal EEG recordings were rarely analyzed by a video‐EEG monitoring system. To reveal a clue for the triggering mechanism of these convulsions, we analyzed the correlation of clinical manifestations and the EEG discharges during the ictal events and compared with previous reports.

KIF1A mutation in a patient with progressive neurodegeneration

Kinesins are a large superfamily of molecular motors. They move along microtubule filaments and are powered by the hydrolysis of ATP. This transport system is essential for neuronal function and survival. KIF1A belongs to the kinesin 3 family and involves in the anterograde transport of synaptic vesicle precursors along axons. Several studies confirmed that KIF1A mutations cause spastic paraplegia and sensory neuropathy in an autosomal-recessive fashion. A missense mutation in the KIF1A gene (p.Thr99Met) has been reported in a patient with intellectual disability (ID), axial hypotonia and peripheral spasticity. Mild atrophy of the cerebellar vermis was found on magnetic resonance imaging. The mutation was heterozygous and de novo. We identified the second patient with the p.T99M mutation in the KIF1A gene by whole-exome sequencing. He showed severe ID, spasticity, optic atrophy, neurogenic bladder, growth failure and progressive cerebellar atrophy. The p.T99M mutation may be a common recurrent mutation. We suppose that this specific mutation of KIF1A shows a novel neurodegenerative syndrome.

Epilepsy in patients with congenital cytomegalovirus infection

Patients with congenital cytomegalovirus (CMV) infection were at high risk for postnatal seizures, but little is known about epilepsy associated with congenital CMV infection. To define the features of epilepsy, we retrospectively reviewed the clinical, laboratory and neuroradiographic findings in 19 children (male 9) with congenital CMV infection. Seven (37%) patients had developed epilepsy (partial seizure 5 and epileptic spasms 2) at a mean age of 20 months (range 2-37 months). During the clinical course, West syndrome occurred in only three patients. The most common seizure type in our series was partial seizure. At the time of last follow-up (mean 96 months), seizures remained uncontrolled in six patients. Neonatal clinical manifestations (gestational age, gender distribution, birth asphyxia or symptoms at birth) were not predictive of the development of epilepsy. On the contrary, some neuroradiographic findings (ventricular dilatation and migration disorder) were significantly associated with the development of epilepsy.

Diagnostic accuracy of blood and CSF lactate in identifying children with mitochondrial diseases affecting the central nervous system

OBJECTIVE To determine the diagnostic accuracy of blood and cerebrospinal fluid (CSF) lactate and pyruvate concentrations in identifying children with mitochondrial diseases (MD) affecting the central nervous system (CNS). METHODS We studied lactate and pyruvate concentrations in paired samples of blood and CSF collected concurrently from 17 patients with MD (Leigh encephalomyelopathy 10, MELAS 5, Pearson disease 1, PDH deficiency 1) and those from control patients (n=49). RESULTS Although blood and CSF variables (lactate, pyruvate concentrations and lactate/pyruvate ratio) were significantly higher in the mitochondrial group than in the control group, there was considerable overlap of individual values between these two groups. The maximum value of the area under the receiver operating characteristic curve (AUC) was observed for the CSF lactate concentration (0.994, optimal cut-off value 19.9 mg/dl, sensitivity 0.941 and specificity 1.00), followed by the CSF pyruvate level (0.983). There was an inverse relationship between blood lactate and lactate CSF/blood ratio. For blood lactate concentrations between 20 and 40 mg/dl, a significant difference was also noted in the lactate CSF/blood ratio between the two groups (AUC 1.0, optimal cut-off value 0.91, sensitivity 1.0 and specificity 1.0). CONCLUSIONS Our study suggests that that CSF lactate level>19.9 mg/dl is the most reliable variable for identifying patients with MD affecting the CNS. When blood lactate concentrations are marginally elevated (20-40 mg/dl), lactate CSF/blood ratio>0.91 may also provide diagnostic information.

Nationwide survey of glucose transporter-1 deficiency syndrome (GLUT-1DS) in Japan.

OBJECTIVES We conducted a nationwide survey of glucose transporter type-1 deficiency syndrome (GLUT-1DS) in Japan in order to clarify its incidence as well as clinical and laboratory information. SUBJECTS AND METHODS A questionnaire to survey the number of genetically and clinically confirmed cases of GLUT-1DS was sent to 1018 board-certified pediatric neurologists, which resulted in 57 patients being reported. We obtained the clinical and laboratory data of 33 patients through a secondary questionnaire. RESULTS The age of the 33 patients (male: 15, female: 18) at the time of the study ranged between 3 and 35 years (mean: 13.5 years). The age of these patients at the onset of initial neurological symptoms ranged between the neonatal period and 48 months (mean: 9.4 months). GLUT-1DS was diagnosed at a mean age of 8.4 years (range: 1 year to 33 years). The initial symptom was convulsive seizures, which occurred in 15 cases, and was followed by abnormal eye movements in 7 cases and apneic or cyanotic attacks in 4 cases. The latter two symptoms most frequently occurred early in infancy. Thirty-two patients (97%) exhibited some type of epileptic seizure. Neurological findings revealed that most patients had muscle hypotonia, cerebellar ataxia, dystonia, and spastic paralysis. Mild to severe mental retardation was detected in all 33 cases. Furthermore, paroxysmal episodes of ataxia, dystonia/dyskinesia, and motor paralysis were described in approximately 1/3 of all patients. The factors that frequently aggravated these events were hunger, exercise, fever, and fatigue, in that order. The mean CSF/blood glucose ratio was 0.36 (0.28-0.48). Pathological mutations in the SLC2A1 gene were identified in 28 out of 32 cases (87.5%). CONCLUSION The results described herein provided an insight into the early diagnosis of GLUT1-DS, including unexplained paroxysmal abnormal eye movements, apneic/cyanotic attacks, and convulsive seizures in infancy, as well as uncommon paroxysmal events (ataxia, atonia, and motor paralysis) in childhood.

Outcome of ketogenic diets in GLUT1 deficiency syndrome in Japan: A nationwide survey

OBJECTIVES To evaluate the outcome of ketogenic diets (KDs) in patients with glucose transport type 1 deficiency syndrome (GLUT1DS) in Japan. METHODS A nationwide survey for GLUT1DS was conducted by sending questionnaires to board-certified pediatric neurologists nationwide to obtain clinical and laboratory data. RESULTS Among 39 patients whose diagnosis was confirmed molecularly or by the 3-O-methylglucose uptake assay, 31 were treated with KDs for longer than 1month. Seventeen patients (55%) were on the modified Atkins diet, 11 (35%) were on the classic KD, and 3 were on the medium-chain triglyceride (MCT) diet. The median values and ranges of serum β-hydroxybutyrate levels in patients on the modified Atkins diet, classic KD and MCT diet were 2.5mM (0.75-4.1), 1.7mM (0.23-3.5) and 2.6mM (1.5-3.0), respectively. The KDs were effective on seizures (80%), aggravation after fasting (80%) and ataxia (79%). Thus, ataxia was as responsive as seizures. Two patients on the classic KD with a ketogenic ratio as low as 1:1 showed improvement in neurological symptoms. The development or intelligence quotient measured using the same psychological scales before and after the KDs in 9 patients did not show a significant improvement; the median quotients before and after the diets were 40 (12-91) and 46 (12-67). CONCLUSION The KDs were most effective on seizures, transient aggravation after fasting and ataxia. The efficacy on intellectual development was equivocal. The modified Atkins diet was more commonly used for GLUT1DS in this study, and its ketogenicity was equivalent to the classic KD.

Clinical impacts of genomic copy number gains at Xq28.

Duplications of the Xq28 region are the most frequent chromosomal aberrations observed in patients with intellectual disability (ID), especially in males. These duplications occur by variable mechanisms, including interstitial duplications mediated by segmental duplications in this region and terminal duplications (functional disomy) derived from translocation with other chromosomes. The most commonly duplicated region includes methyl CpG-binding protein 2 gene (MECP2), which has a minimal duplicated size of 0.2 Mb. Patients with MECP2 duplications show severe ID, intractable seizures and recurrent infections. Duplications in the telomeric neighboring regions, which include GDP dissociation inhibitor 1 gene (GDI1) and ras-associated protein RAB39B gene (RAB39B), are independently associated with ID, and many segmental duplications located in this region could mediate these frequently observed interstitial duplications. In addition, large duplications, including MECP2 and GDI1, induce hypoplasia of the corpus callosum. Abnormalities observed in the white matter, revealed by brain magnetic resonance imaging, are a common finding in patients with MECP2 duplications. As primary sequence analysis cannot be used to determine the region responsible for chromosomal duplication syndrome, finding this region relies on the collection of genotype–phenotype data from patients.

SLC2A1 gene analysis of Japanese patients with glucose transporter 1 deficiency syndrome

Glucose transporter 1 deficiency syndrome (Glut1-DS) is a congenital metabolic disorder characterized by refractory seizures with early infantile onset, developmental delay, movement disorders and acquired microcephaly. Glut1-DS is caused by heterozygous abnormalities of the SLC2A1 (Glut1) gene, whose product acts to transport glucose into the brain across the blood-brain barrier. We analyzed the SLC2A1 gene in 12 Japanese Glut1-DS patients who were diagnosed by characteristic clinical symptoms and hypoglycorrhachia as follows: all patients had infantile-onset seizures and mild to severe developmental delay, and ataxia was detected in 11 patients. For the 12 patients, we identified seven different mutations (three missense, one nonsense, two frameshift and one splice-site) in exons and exon–intron boundaries of the SLC2A1 gene by direct sequencing, of which six were novel mutations. Of the remaining five patients who had no point mutations and underwent investigation by multiplex ligation-dependent probe amplification, a complex abnormality with deletion and duplication was identified in one patient: this is the first case of such recombination of the SLC2A1 gene. Changes in regulatory sequences in the promoter region or genes other than SLC2A1 might be responsible for onset of Glut1-DS in the other four patients (33%) without SLC2A1 mutation.

Prolonged Elevation of Serum Neuron-Specific Enolase in Children After Clinical Diagnosis of Brain Death

To elucidate the time course of neuronal cell death after the clinical criteria for brain death are met, the authors reviewed serial changes of serum neuron-specific enolase levels in 3 children (age range, 3-15 years) clinically diagnosed as brain dead due to cardiopulmonary arrest. All patients survived for more than 2 months after brain death. Children with brain death had higher peak neuron-specific enolase values (1069-2849 ng/mL) than did 3 control children (256-1800 ng/mL) who did not become brain dead but had poor neurological outcome (1 death, 2 vegetative state) after cardiopulmonary arrest. A major finding is that children with brain death showed persistent elevation of neuron-specific enolase at 4 weeks (>400 ng/mL) and 8 weeks (>50 ng/mL) after cardiopulmonary arrest, in comparison with 2 surviving patients without brain death (<50 ng/mL at 4 weeks). This prolonged elevation of neuron-specific enolase suggests that total brain necrosis might not be present at the time of clinical diagnosis of brain death.

MRI Findings and Steroid Therapy for Neuralgic Amyotrophy in Children

Neuralgic amyotrophy is not uncommon in adults but is relatively rare in children. We recently encountered 2 cases of neuralgic amyotrophy in children. Patient 1 was a 7-year-old girl who developed a right leg paralysis after an epileptic seizure. Lumbar plexus T(2)-weighted magnetic resonance imaging (MRI) revealed a hyperintense and thickened portion extending from the root to the knee region of the right sciatic nerve, and T(1)-weighted conventional spin echo with gadolinium administration revealed enhancement. Patient 2 was a 4-year-old boy who experienced a sudden onset of severe right arm pain and paralysis. T(2)-weighted MRI with a short tau inversion recovery revealed a slightly thickened and high intensity region at the right C(6)-C(8) level. After high-dose methylprednisolone pulse therapy was performed in each case, patient 1 experienced complete recovery, whereas patient 2 experienced only amelioration of pain. A diagnosis of neuralgic amyotrophy in children was facilitated by an MRI study (T(2) weighed with short tau inversion recovery and T(1) weighted with gadolinium enhancement), and early steroid therapy might have improved the condition of these children.