Tomoyuki Takano

Seizure Susceptibility Due to Antihistamines in Febrile Seizures

The aim of this study was to determine whether seizure susceptibility due to antihistamines is provoked in patients with febrile seizures. The study population comprised 14 patients with simple febrile seizures and 35 patients with complex febrile seizures. Detailed clinical manifestations were compared between patients with and without administration of antihistamine. The time from fever detection to the seizure onset was significantly shorter in the antihistamine group than that in the nonantihistamine group, and the duration of seizures was significantly longer in the antihistamine group than that in nonantihistamine group. Interleukin-1beta is thought to be associated with causing febrile seizures via its dual role as a pyrogen and convulsant substance. Moreover, interleukin-1beta may activate the turnover of hypothalamic neural histamine. These considerations, along with the present results, suggest that the depletion of hypothalamic neuronal histamine induced by antihistamines may increase neuronal excitability, thereby increasing seizure susceptibility in patients with febrile seizures.

Seizure susceptibility in polymicrogyria: Clinical and experimental approaches

Polymicrogyria is a cerebral cortical malformation characterized by an excessively folded cortical ribbon of miniature and individually thin convolutions. Although polymicrogyria is a highly epileptogenic lesion, its epileptogenic mechanism is unclear. The anomalous cortex associated with polymicrogyria includes less excitable neural tissue such as a cell sparse zone, but involves a part of a larger epileptic network extending to adjacent cortical areas. This malformation can be modeled in rats with a transcortical prenatal or neonatal freeze lesion, which mimics the histological characteristics of a human four-layered polymicrogyria. Several hypotheses have so far been presented for seizure susceptibility in polymicrogyria, including alterations of glutamate receptor distribution, abnormalities in ion channels, new excitatory or inhibitory connections, and downregulation of GABA(A) receptor subunits. The cortical hyperexcitability in polymicrogyria may be reduced by the inhibitory neuronal network. Further detailed investigations of a population with aberrantly migrating inhibitory interneurons will provide novel and important insights into the pathogenetic mechanisms of epilepsy in polymicrogyria.

A pediatric case of reversible cerebral vasoconstriction syndrome with cortical subarachnoid hemorrhage

Reversible cerebral vasoconstriction syndrome (RCVS) is a rare disorder characterized by acute onset, severe headache, with reversible vasoconstriction of cerebral arteries often accompanied by additional neurological symptoms. This syndrome is seen mainly in middle-aged adults, predominantly women. Herein, we report on a pediatric case of RCVS with cortical subarachnoid hemorrhage (SAH). A 12-year-old boy developed acute, severe headache with paralysis of lower extremities causing gait disturbance after administration of eletriptan. Brain magnetic resonance angiography (MRA) revealed multifocal narrowing of the cerebral arteries, whereas magnetic resonance imaging (MRI) demonstrated sulcal hyperintensity on fluid-attenuated inversion recovery, consistent with cortical SAH. The patients clinical symptoms resolved spontaneously after a few days and the MRI and MRA findings disappeared 3 months later, suggesting a diagnosis of RCVS. Eletriptan might cause vasoconstriction of cerebral arteries. Although most patients with RCVS are adults and pediatric cases are rare, RCVS should be considered in a child complaining of severe headache.

A Japanese patient with Kabuki syndrome and unilateral perisylvian cortical dysplasia

Kabuki syndrome is a rare multiple anomaly syndrome characterized by a peculiar face, skeletal and dermatoglyphic anomalies, postnatal growth retardation and mental retardation. We report a case of Kabuki syndrome with unilateral perisylvian cortical dysplasia. This two-year old boy was referred to our hospital at 3-months of age for his growth retardation and muscle hypotonia. Because of his peculiar face, brachydactyly V and fingertip pad, we diagnosed him as having Kabuki syndrome. His MRI revealed cortical dysplasia along the left sylvian fissure. However, neither epileptic seizures nor epileptiform discharges on electroencephalogram were observed. Cortical dysplasia is a relatively rare brain malformation among the central nervous system anomalies accompanying with this syndrome. We have to take into consideration the likely onset of epilepsy in this patient because it is one of the most frequent neurological consequences of cortical dysplasia.

Polymicrogyria without epilepsy by aberrantly migrating inhibitory interneurons.

Polymicrogyria is the presence of an excess number of abnormally small gyri that produce an irregular cortical surface. Although polymicrogyria is associated with severe epilepsy in 65% of patients [1], few data concerning the epileptogenic zone and its relationship with the polymicrogyric tissue are available because patients with polymicrogyria are rarely considered suitable candidates for epilepsy surgery [2]. An experimental model in which a single or few microgyri are generated by a freezing insult suggests a widespread area of functional disruption that extends beyond the visualized abnormality [3]. However, the detailed mechanism of epileptogenesis has not yet been well characterized for polymicrogyria [4]. We previously demonstrated that the intracerebral injection of ibotenate produces excitotoxic brain lesions to mimic neuronal migration disorders [5]. We also reported that subventricular zone cells play an important role in the formation of cortical dysplasia [6]. Based on these experimental studies, we conducted a neuronal tracing study for progenitor cells in the ganglionic eminence, and thereby demonstrated that the interneurons are mobilized to the microgyric area out of the ganglionic eminence, which thus leads to the construction of a part of the abnormal neuronal arrangement of this microgyria. All procedures used in the study described here were approved by the Committee on Animal Experimentation and Animal Care of Shiga University of Medical Science, Japan. One microgram (1 μL) of ibotenate (Sigma, St. Louis, MO, USA) was injected intracerebrally into 18 Syrian hamsters within 24 hours of birth (postnatal day 0 [P0]) using stereotaxic methods as described previously [5]. Biotinylated dextran amine (BDA-10000 Neuronal Tracer Kit, N7167; Molecular Probes, Eugene, OR, USA) was used as a neuronal tracer. BDA is a highly sensitive tool in anterograde and retrograde pathway tracing studies of the nervous system. The high-molecularweight BDA employed in this experiment yields sensitive and exquisitely detailed labeling of axons and terminals using preferentially anterograde transport. After the ibotenate injection, 1 μL (0.05 μg) of BDA was injected into the ganglionic eminence of the identical hemisphere with a 5-μl Hamilton syringe at P0, as also described previously [6]. Seven animals injected in the same manner with the same amount of phosphate-buffered saline served as the control group. BDA immunohistochemistry and hematoxylin and eosin staining were performed on P1, P2, and P5. One day after ibotenate injection (P1), the resultant cortical lesion was recognized as a disorganized neuronal arrangement, extending from the marginal zone to the ventricular zone. On P5, the cortical lesions were restricted to the marginal zone and superficial layer of the

Compound Heterozygote of a Novel Missense Mutation (p.K402T) and a Double Missense Mutation (p.[G71R;Y486D]) in Type II Crigler-Najjar Syndrome

362 C rigler-Najjar syndrome type II (CN-II; # Mendelian Inheritance in Man [MIM] 606785) is a moderate type of hereditary unconjugated hyperbilirubinemia caused by mutations of the bilirubin uridine diphosphate-glucuronosyltransferase gene UGT1A1 (1). Diagnosis of this syndrome is important in distinguishing it from the severe phenotype of hereditary unconjugated hyperbilirubinemia, known as Crigler-Najjar syndrome type I (CNI; MIM #218800). The serum bilirubin concentration of CN-I is more than 20 mg/dL (343mmol/L) and can reach 30 to 50 mg/dL (513–855mmol/L). Patients with CN-I are in danger of kernicterus and must receive daily phototherapy right from the neonatal period (2). They should undergo liver transplantation to avoid kernicterus. Hyperbilirubinemia in patients with CN-II is less severe than CN-I (1). The serum bilirubin concentration of CN-II is seldom harmful after the neonatal period. The serum bilirubin concentration of patients with CN-I or CN-II is often intermediate between the values specifying the 2 syndromes. Accurate diagnosis of the 2 syndromes is necessary for appropriate treatment. A phenobarbitalloading test is effective in differential diagnosis (3), but the results are not always clear, in which case genetic diagnosis is necessary. The cDNA of UGT1A1 was first cloned in 1991, and a large number of mutations have been found in patients with CN-I, CN-II, and Gilbert syndrome (GS; MIM #143500) (4,5). Mutations of UGT1A1 differ according to ethnic grouping. East Asians display many unique mutations; in particular, a major polymorphic mutation is c.211G>A: p.G71R in exon 1 of UGT1A1 (6). p.G71R reduces glucuronidation ability to less than 32% of wild type and is an important cause of Gilbert syndrome (7). One of the most important causes of CN-II in Asians is a double missense mutation, p.[G71R;Y486D] (8). This double mutation has hardly ever been detected in white and African populations.

Congenital polymicrogyria including the perisylvian region in early childhood.

Six pediatric cases including four infants with congenital polymicrogyria including the perisylvian region are presented herein. Their clinical features were analyzed and compared with patients suffering from congenital bilateral perisylvian syndrome (CBPS). Two specific abnormalities were diagnosed as accompanying disorders in two cases, namely Kabuki syndrome and Peters anomaly. In the other four cases, the pathogenetic etiology was not elucidated. Subtle symptoms, such as choking and drooling became detectable in one case each, and expressive language development was delayed in two patients. A developmental delay became apparent in five cases during the follow‐up period, and epilepsy was observed in one patient with onset at 12u2003years of age. Our results indicate that the presence of perisylvian polymicrogyria may not always result in the development of oropharyngoglossal dysfunction or dysarthria, although most patients tend to gradually show the onset of developmental disorders. To support cognitive and psychosocial development, an early integrated approach, including not only conventional speech and language therapy, but also various communication methods is essential for patients with congenital polymicrogyria including the perisylvian region.

Group A streptococcal brain abscess: A case report and a review of the literature since 1988

Abstract Brain abscesses caused by group A Streptococcus (GAS) are rare infectious diseases. In this report we present a case of brain abscess due to GAS infection occurring after milk tooth extraction in a healthy child. A literature review of previously reported cases is presented.

Aprosencephaly with rhombencephalosynapsis and hamartomatous midbrain dysplasia.

Aprosencephaly/atelencephaly refers to a rudimentary prosencephalon, while holoprosencephaly is a failure of telencephalon cleavage [1]. Rhombencephalosynapsis is a rare cerebellar malformation characterized by vermal agenesis or hypogenesis, and the fusion of hemispheres and the dentate nuclei [2]. This report presents the case of a neonate with aprosencephaly accompanied by rhombencephalosynapsis. This case also showed hamartomatous midbrain dysplasia. To our knowledge, this is the first report of this combined pathology. This male infant was born after 31-week gestation as the first of dizygotic and diamniotic twins by a Caesarean section, because of remarkable ventricular dilatation that was recognized at the 14th week of gestation. His Apgar scores were 7 and 8 points, at 1 and 5 min after birth, respectively, body weight 1264 g (-1.52 SD), height 39.3 cm (-0.43 SD), and chest and head circumferences 22.5 cm and 29.8 cm (+0.6 SD), respectively. The patient had midline facial abnormalities, including anophthalmia, a nasal defect, and cleft lip and palate (Figure 1C). Brain CT showed an absence of most of the cerebrum including the basal ganglia and thalamus (Figure 1A). The pons and cerebellum were present. The bilateral orbital structures and nasal bones were completely absent (Figure 1B). He died 3 h and 23 min after birth due to progressive respiratory failure. The autopsy showed no cerebral cortex, basal ganglia or thalamus, and the cranial cavity was filled with clear cerebrospinal fluid (Figure 1D).The brain weight was 15 g.The midbrain showed a dysplastic appearance, and it was difficult to detect the basic components such as the tectum mesencephali, tegmentum and cerebral peduncle. The cerebellum appeared to be small. The vermis was absent, accompanied by a complete fusion of hypoplastic cerebellar hemispheres and folia running across the midline suggesting rhombencephalosynapsis (Figure 1E,F). Microscopical examination of the rostral part of the midbrain revealed the markedly distorted lumen of the aqueduct. A nodular well-circumscribed mass emerging from the tectum mesencephali protruded into the dysplastic lumen (Figure 2A). This nodule was composed of densely packed undifferentiated neuroepithelial cells, which partly ruptured the ependymal layer and grew into the aqueduct (Figure 2B). Onion peel-like fibrous elements were observed to highly proliferate in the centre of this nodule (Figure 2C). The inner surface of this distorted lumen was composed of a disorganized ependymal lining, including a large number of small ependymal canals (Figure 2D). This dysplastic lumen was not surrounded by any central gray substance separating the tectum from the tegmentum. No organized mesencephalic nucleus was formed. Minor dysplasias were found in the cerebellum. The dentate nuclei were apposed (not shown) and contained nests or strands of round or spindle-shaped germinal cells in their neuropil or perivascularly (Figure 2E). Abnormal clusters of gray matter were found in the cerebellar white matter, thus suggesting local dysplasia (Figure 2F). They consisted of poorly organized germinal tissue intermingled with disaligned Purkinje cells (Figure 2G). Small heterotopias were also found. Each one contained large neurones and small nests of germinal cells forming a heterotopic island (Figure 2H). No abnormal findings were observed in either the medulla oblongata or spinal cord. Aprosencephaly/atelencephaly refers to a rare forebrain malformation defined by a lack of prosencephalic derivates [3]. In aprosencephaly the prosencephalon is absent, while in atelencephaly it exists as a rudimentary medial vesicle resembling the diencephalon but without the lateral telencephalic vesicles. Craniofacial malformations similar to holoprosencephaly are also found in aprosencephaly/atelencephaly and involve the frontonasal eminence, which ranges from cyclopia/synophtalmia, cebocephaly, and midline cleft to mild hypotelorism or normal face [4]. The question of whether aprosencephaly/ atelencephaly results from a disruptive lesion or is due to growth failure remains controversial [5]. In the present case, the autopsy findings fulfil the criteria for the diagnosis of aprosencephaly, namely, the absence of cerebral cortex, basal ganglia and thalamus and the presence of severe craniofacial midline anomalies. Rhombencephalosynapsis is an uncommon cerebellar malformation of unknown aetiology, defined by vermian

Oral-facial-digital syndrome type 1 with hypothalamic hamartoma and Dandy-Walker malformation.

We report a 1-year-old girl with oral-facial-digital syndrome type 1 with multiple malformations of the oral cavity, face, digits, and central nervous system, including agenesis of the corpus callosum, the presence of intracerebral cysts, and agenesis of the cerebellar vermis, which is associated with the subarachnoid space separating the medial sides of the cerebellar hemispheres. This child also had a hypothalamic hamartoma and a Dandy-Walker malformation, which have not been reported previously. The clinical features, including cerebral malformations, in several types of oral-facial-digital syndrome, overlap with each other. Further accumulation of new case reports and identification of new genetic mutations in oral-facial-digital syndrome may provide novel and important insights into the genetic mechanisms of this syndrome.