Chitose Sugiura

Genomic copy number variations at 17p13.3 and epileptogenesis

Deletion of the terminal end of 17p is responsible for Miller-Dieker syndrome (MDS), which is characterized by lissencephaly, distinctive facial features, growth deficiency, and intractable seizures. Using microarray-based comparative genomic hybridization, 3 patients with epilepsy were revealed to have genomic copy number aberrations at 17p13.3: a partial LIS1 deletion in a patient with isolated lissencephaly and epilepsy, a triplication of LIS1 in a patient with symptomatic West syndrome, and a terminal deletion of 17p including YWHAE and CRK but not LIS1 in a patient with intractable epilepsy associated with distinctive facial features and growth retardation. In this study, it was suggested that the identified gain or loss of genomic copy numbers within 17p13.3 result in epileptogenesis and that triplication of LIS1 can cause symptomatic West syndrome.

A Japanese girl with leukoencephalopathy with vanishing white matter

A Japanese girl with peculiar leukoencephalopathy was reported. Following normal development until 1 year of age, she showed progressive neurological deterioration with ataxia, epilepsy, pyramidal tract signs and choreic movement. Serial brain computed tomographies (CTs) revealed markedly low density and progressive volume loss in whole white matter. In extensive laboratory investigations, the level of glycine in the urine was elevated. She died at the age of 4 years, and the neuropathological findings were comprised of severe extensive changes in cerebral and cerebellar white matter, such as marked rarefaction or cystic degeneration with axonal loss. The pontine central tegmental tracts were also affected. Neuronal loss was seen in the cerebellar cortex. These features were compatible with leukoencephalopathy with vanishing white matter, which was recently established as a clinical entity. To our knowledge, this is the first report of a non-Caucasian patient with this new type of leukoencephalopathy.

Early predictors of status epilepticus-associated mortality and morbidity in children

BACKGROUND Early predictors of status epilepticus (SE)-associated mortality and morbidity have not been systematically studied in children, considerably impeding the identification of patients at risk. OBJECTIVES To determine reliable early predictors of SE-associated mortality and morbidity and identify the etiology of SE-associated sequelae in Japanese children. METHODS We conducted a prospective multicenter study of clinical findings and initial laboratory data acquired at SE onset, and assessed outcomes at the last follow-up examination. In-hospital death during the acute period and neurological sequelae were classified as poor outcomes. RESULTS Of the 201 children who experienced their first SE episode, 16 exhibited poor outcome that was most commonly associated with acute encephalopathy. Univariate analysis revealed that the following were associated with poor outcomes: young age (⩽24 months); seizure duration >90 min; seizure intractability (failure of the second anticonvulsive drug); biphasic seizures; abnormal blood glucose levels (<61 or >250 mg/dL); serum aspartate aminotransferase (AST) ⩾56 U/L; and C-reactive protein (CRP) levels >2.00 mg/dL. Multivariate analysis revealed that young age, seizure intractability, abnormal blood glucose levels, and elevated AST and CRP levels were statistically significant. CONCLUSIONS Young age and seizure intractability were highly predictive of poor outcomes in pediatric SE. Moreover, abnormal blood glucose levels and elevated AST and CRP levels were predictors that might be closely associated with the etiology, especially acute encephalopathy and severe bacterial infection (sepsis and meningitis) in Japanese children.

Delayed neuropsychiatric syndrome in a child following carbon monoxide poisoning.

Here, we report the case of a five-year-old boy with carbonic monoxide (CO) poisoning. The patient initially recovered after the initiation of hyperbaric oxygen (HBO) therapy, but lethargy as well as visual and gait disturbances appeared two days later. Left hemiparesis and mood lability also subsequently appeared. Slow frontal activity was noted on electroencephalography, while fluid-attenuation inversion recovery and diffusion-weighted magnetic resonance imaging (MRI) revealed high signal-intensity lesions in the hippocampus and deeper layers of the occipital and frontal cerebral cortex. The neurological symptoms subsided gradually during the 10-day course of HBO therapy, but the left-hand paresis and quadrantic hemianopsia persisted, in association with impaired attention, slow mental processing, and incontinence. Lesions in the globus pallidum were noted on follow-up MRI at 14 days, and cortical lesions became evident as linear, low signal-intensity areas on T1-weighted imaging 4 months after presentation. Delayed neuropsychiatric syndrome in CO poisoning is rare in childhood, although children should be carefully monitored after CO exposure. The finding of cortical laminar necrosis in this patient is quite atypical in CO poisoning, and suggests a broader and previously nonpredicted pathomechanism in this condition.

Immunohistochemical expression of fibroblast growth factor‐2 in developing human cerebrum and epilepsy‐associated malformations of cortical development

To elucidate the biological significance of fibroblast growth factor‐2 (FGF‐2) expression in epilepsy‐associated malformations of cortical development, immunohistochemical expression of FGF‐2 was investigated in the developing human cerebral mantles obtained from 30 autopsy cases of fetuses, stillborn infants and children ranging from 12 weeks gestation to 15 years old, and 70 surgically‐resected corticectomy specimens from patients with medically intractable epilepsy, including: group I, 12 tubers of tuberous sclerosis; group II, 24 cases of focal cortical dysplasia (FCD) with balloon cells (BC); group III, 11 FCD without BC; group IV, 23 histologically normal‐appearing neocortices from patients with Rasmussen encephalitis, cystic‐gliotic encephalopathy, temporal lobe epilepsy; and group V, 14 normal‐appearing neocortices adjacent to dysplastic lesions from groups I and II. FGF‐2 expression was detected in a population of matrix cells and/or neuroblasts within the ventricular zone in fetuses younger than 19 weeks gestation. Nuclei of glioblasts and immature astrocytes were also positive for FGF‐2 in cases older than 18 weeks gestation. FGF‐2 expression was not detected in immature cortical plate neurons. Astrocytes and ependymal cells were positive for FGF‐2 in the postnatal brains. Choroid plexus epithelium was strongly positive for FGF‐2 in all cases examined. Among the corticectomy specimens, the cytoplasms and/or nuclei of dysmorphic neurons (DNs) and BCs in groups I and II were variably positive for FGF‐2. The proportions of FGF‐2 immunoreactive cells (FGF‐2‐IR%) was significantly higher in groups I (36.9 ± 9.6) and II (45.1 ± 7.0) than in groups III (21.0 ± 5.7), IV (14.4 ± 4.7) and V (24.3 ± 10.3), and that in group V was higher than in group IV (P < 0.01). These results indicate that FGF‐2 upregulation in DNs and BCs is an important feature common to groups I and II, and suggest that BCs and DNs in these groups represent disturbed gliogenesis from matrix cells and disturbed maturation of cortical neurons from migrating neuroblasts, respectively.

Long-Term Weekly ACTH Therapy for Relapsed West Syndrome

Adrenocorticotrophic hormone (ACTH) therapy is an established treatment for West syndrome. However, some patients may relapse after this therapy, for whom there is no established treatment. We describe 3 patients with symptomatic West syndrome and multiple, poor prognostic factors who relapsed after initial ACTH therapy. They were treated with a second round of ACTH therapy, i.e., daily intramuscular injection for 2-3 weeks and subsequent withdrawal, alternative days for 1 or 2 weeks, every 3 days for 1 or 2 weeks, followed by weekly or biweekly for >/=1 year. Clinical seizures and hypsarrhythmia resolved in all 3 patients within 4 weeks, and these clinical improvements continued through a second round of ACTH therapy. Two patients developed other types of seizures and aggravation of paroxysms on electroencephalography, but no hypsarrhythmia, soon after termination of ACTH therapy. In the other patient, although electroencephalographic findings remained normal during weekly ACTH therapy, focal sharp waves with irregular slow waves appeared after the injection interval became biweekly. After a second round of ACTH therapy, all patients exhibited developmental progress, particularly in gross motor development and visual functions. No serious adverse events occurred during treatment. Long-term weekly ACTH therapy is a potentially effective treatment option for relapsed West syndrome.

Myocerebrohepatopathy spectrum disorder due to POLG mutations: A clinicopathological report.

We report on the clinical, neuropathological, and genetic findings of a Japanese case with myocerebrohepatopathy spectrum (MCHS) disorder due to polymerase gamma (POLG) mutations. A girl manifested poor sucking and failure to thrive since 4 months of age and had frequent vomiting and developmental regression at 5 months of age. She showed significant hypotonia and hepatomegaly. Laboratory tests showed hepatocellular dysfunction and elevated protein and lactate levels in the cerebrospinal fluid. Her liver function and neurologic condition exacerbated, and she died at 8 months of age. At autopsy, fatty degeneration and fibrosis were observed in the liver. Neuropathological examination revealed white matter-predominant spongy changes with Alzheimer type II glia and loss of myelin. Enzyme activities of the respiratory chain complex I, III, and IV relative to citrate synthase in the muscle were normal in the biopsied muscle tissue, but they were reduced in the liver to 0%, 10%, and 14% of normal values, respectively. In the liver, the copy number of mitochondrial DNA compared to nuclear DNA was reduced to 3.3% of normal values as evaluated by quantitative polymerase chain reaction. Genetic analysis revealed compound heterozygous mutations for POLG (I1185T/A957V). This case represents the differential involvement of multiple organs and phenotype-specific distribution of brain lesions in mitochondrial DNA depletion disorders.

Spontaneous remission of infantile spasms and hypsarrhythmia following acute infection with high-grade fever.

To elucidate the pathogenesis of spontaneous remission of infantile spasms (ISs) and hypsarrhythmia following infection, we reviewed 58 patients with ISs from 1986 through 2006 in our hospital. Five patients showed spontaneous remission of spasms or hypsarrhythmia following infections with high-grade fever (SR group). In control, we analyzed five patients with complete improvement of ISs for ACTH therapy (ACTH group). In the SR group, ISs stopped in an average of 4.0 days after the onset of infection. In three patients performing EEG during the infection, hypsarrhythmia disappeared within an average of 8 days after the onset of infection. In the ACTH group, ISs stopped an average of 4.6 days and hypsarrhythmia disappeared within an average of 10 days after ACTH therapy. During the remission course of ISs, low-voltage background activity (BGA) on EEG showed in one patient of the SR group and in all patients of the ACTH group. ACTH is known to the efficacy for ISs and suppression of cortical activity on human EEG. This similar remission course between in the SR group and in the ACTH group suggest neuroendocrinal products in response to infection, which is resembled ACTH-related cascade, may play a role for spontaneous remission following infection.