Magnetic resonance imaging volumetry and clinical analysis of epilepsy patients with unilateral hippocampal abnormality.

BACKGROUND: In order to clarify the correlation between morphological characteristics and clinical features in epilepsy patients with unilateral hippocampal abnormality, morphological and morphometric magnetic resonance imaging studies were performed. METHODS: We selected a series of childhood-onset epilepsy patients with unilateral hippocampal abnormality. The volume of hippocampal formation and anterior temporal lobe were measured, and the hippocampal morphology was compared with their clinical features. The morphological characteristics of the hippocampal formation were classified into three groups: group I, diffuse and severe volume reduction of the hippocampal formation and anterior temporal lobe with abnormal signal; group II, focal atrophy or focal abnormal signal in the hippocampal formation; and group III, no significant volume reduction but an enlargement of the temporal horn. RESULTS: All of the patients in group I had a history of status epilepticus in infancy. Temporal lobe epilepsy (TLE) was found in three of four patients. Group II contained TLE in three and frontal lobe epilepsy in one. One patient with intractable TLE had a history of status epilepticus in infancy. Group III contained miscellaneous epilepsies, including benign partial epilepsy with centro-temporal spikes in three of seven patients. Five patients in group III showed some characteristic features of hippocampal malrotation, which refers to incomplete hippocampal infolding. CONCLUSIONS: Diffuse and severe volume reduction of the hippocampal formation and anterior temporal lobe with unilateral hippocampal sclerosis was strongly associated with status epilepticus in infancy. Both hippocampal sclerosis and hippocampal malrotation suggest significant roles in the pathogenesis of epilepsy.

Diagnosing nocturnal frontal lobe epilepsy: a case study of two children.

We describe two children of nocturnal frontal lobe epilepsy (NFLE) diagnosed using carefully observed nocturnal sleep EEGs and detailed patient histories. Case #1, a 14-year-old boy, showed repeated generalized tonic convulsions and frequent eyes opening seizures during sleep. Conventional EEGs - done with the patient awake or in sleep stage I - showed no abnormalities, while a nocturnal sleep EEG - done during in sleep stage II - revealed the repeated, sharp wave bursts predominantly in the right frontal lobe characteristic of NFLE. During these wave bursts, we noticed the boy's eyes opening, although his parents had not been aware this NFLE symptom. Case #2, a 12-year-old boy, showed one daytime generalized convulsion. He had also been suffering from repeated paroxysmal episodes similar to parasomnia - waking up, sitting, walking, screaming, and speaking - which always followed the same patterns lasting several minutes. During the nocturnal sleep EEG, episodes occurred twice, showing abnormal epileptic discharges predominantly in the frontal lobe. His parents did not mention the episodes to us until questioned, as they had recognized them as parasomnia. The previous conventional EEG showed abnormal slow waves in the frontal lobe, which led us to suspect frontal lobe epilepsy and to take a detailed patient history. The frequency and stereotypy of their symptoms during sleep caused us to perform nocturnal sleep EEGs and led us NFLE diagnosis. Detailed patient histories including sleep habits and carefully observed nocturnal sleep EEGs enabled us to recognize these NFLE clinical features.

Clinical study of childhood acute disseminated encephalomyelitis, multiple sclerosis, and acute transverse myelitis in Fukuoka Prefecture, Japan.

Acute disseminated encephalomyelitis (ADEM) has recently been studied in several countries owing to the development and wide spread use of imaging technology, but few epidemiological studies of childhood ADEM have been undertaken in Asian countries. To perform a comprehensive survey of ADEM and related diseases in Japanese children, we conducted a multicenter, population-based study on childhood ADEM, multiple sclerosis, and acute isolated transverse myelitis in Fukuoka Prefecture, Japan. We identified 26 children with ADEM, 8 with multiple sclerosis, and 4 with acute transverse myelitis during 5 years between September 1998 and August 2003. The incidence of childhood ADEM under the age of 15 years was 0.64 per 100,000 person-years, mean age at onset was 5.7 years, and male-female ratio was 2.3:1. The prevalence of childhood multiple sclerosis was 1.3 per 100,000 persons. The mean age at onset of multiple sclerosis, 9.3 years, was significantly higher than that of ADEM. Nineteen (73%) and four (15%) patients with ADEM experienced antecedent infectious illnesses and vaccinations, respectively, within 1 month before the onset. Clinical and radiological findings of ADEM revealed that the frequency of seizures, mean white blood cell counts in cerebrospinal fluid, and the frequency of subcortical lesions in Fukuoka study, seemed to be higher than those in previous non-Asian studies. These findings suggest that there are ethnic or geographical differences in the incidence and clinical features of ADEM, and that there might be potent genetic or environmental risk factors for ADEM distinct from those for multiple sclerosis.

A de novo KCNQ2 mutation detected in non-familial benign neonatal convulsions.

BACKGROUND: The underlying genetic abnormalities of rare familial idiopathic epilepsy have been identified, such as mutation in KCNQ2, a K(+) channel gene. Yet, few genetic abnormalities have been reported for commoner epilepsy, i.e., sporadic idiopathic epilepsy, which share a phenotype similar to those of familial epilepsy. OBJECTIVE: To search for the genetic cause of seizures in a girl with the diagnosis of non-familial benign neonatal convulsions, and define the consequence of the genetic abnormality identified. METHODS: Genetic abnormality was explored within candidate genes for benign familial neonatal and infantile convulsions, such as KCNQ2, 3, 5, KCNE2, SCN1A and SCN2A. The electrophysiological properties of the channels harboring the identified mutation were examined. Western blotting and immunostaining were employed to characterize the expression and intracellular localization of the mutant channel molecules. RESULTS: A novel heterozygous mutation (c.910-2delTTC or TTT, Phe304del) of KCNQ2 was identified in the patient. The mutation was de novo verified by parentage analysis. The mutation was associated with impaired functions of KCNQ K(+) channel. The mutant channels were expressed on the cell surface. CONCLUSION: The mutant Phe304del of KCNQ2 leads to null function of the KCNQ K(+) channel but the mutation does not alter proper channel sorting onto the cell membrane. Our findings indicate that the genes responsible for rare inherited forms of idiopathic epilepsy could be also involved in sporadic forms of idiopathic epilepsy and expand our notion of the involvement of molecular mechanisms in the more common forms of idiopathic epilepsy.

Rats harboring S284L Chrna4 mutation show attenuation of synaptic and extrasynaptic GABAergic transmission and exhibit the nocturnal frontal lobe epilepsy phenotype.

Mutations of genes encoding alpha4, beta2, or alpha2 subunits (CHRNA4, CHRNB2, or CHRNA2, respectively) of nAChR [neuronal nicotinic ACh (acetylcholine) receptor] cause nocturnal frontal lobe epilepsy (NFLE) in human. NFLE-related seizures are seen exclusively during sleep and are characterized by three distinct seizure phenotypes: "paroxysmal arousals," "paroxysmal dystonia," and "episodic wandering." We generated transgenic rat strains that harbor a missense mutation S284L, which had been identified in CHRNA4 in NFLE. The transgenic rats were free of biological abnormalities, such as dysmorphology in the CNS, and behavioral abnormalities. The mRNA level of the transgene (mutant Chrna4) was similar to the wild type, and no distorted expression was detected in the brain. However, the transgenic rats showed epileptic seizure phenotypes during slow-wave sleep (SWS) similar to those in NFLE exhibiting three characteristic seizure phenotypes and thus fulfilled the diagnostic criteria of human NFLE. The therapeutic response of these rats to conventional antiepileptic drugs also resembled that of NFLE patients with the S284L mutation. The rats exhibited two major abnormalities in neurotransmission: (1) attenuation of synaptic and extrasynaptic GABAergic transmission and (2) abnormal glutamate release during SWS. The currently available genetically engineered animal models of epilepsy are limited to mice; thus, our transgenic rats offer another dimension to the epilepsy research field.

Developmental changes in KCNQ2 and KCNQ3 expression in human brain: possible contribution to the age-dependent etiology of benign familial neonatal convulsions.

Several mutations of KCNQ2 and KCNQ3 are considered to be associated with benign familial neonatal convulsions (BFNC). BFNC is characterized by seizures starting within several days of life and spontaneous remission within weeks to months. KCNQ channel is a heteromeric voltage-dependent potassium channel consisting of KCNQ2 and KCNQ3 subunits. To clarify the age-dependent etiology of BFNC, we examined the developmental changes in KCNQ2 and KCNQ3 expression in human hippocampus, temporal lobe, cerebellum and medulla oblongata obtained from 23 subjects who died at 22 gestation weeks to adulthood. Formalin-fixed and paraffin-embedded specimens were used for immunohistochemistry. Unique developmental changes in KCNQ2 and KCNQ3 were found in each region. A high expression of KCNQ2 was identified in the hippocampus, temporal cortex, cerebellar cortex and medulla oblongata in fetal life, but such expression decreased after birth. The expression of KCNQ3 increased in late fetal life to infancy. Simultaneous and high expressions of KCNQ2 and KCNQ3 were observed in each region from late fetal life to early infancy, coinciding with the time when BFNC occurs. Such coexpression may contribute to the pathogenesis of BFNC.

Different perceptual sensitivities for Chernoff's face between children and adults.

The aim of this study was to investigate the differences between children and adults in recognizing facial expressions of simple line drawings of "Chernoff's face". First, the angles of the eyebrows and mouth of Chernoff's face were changed in a stepwise way with a personal computer, and the emotional response of the subjects was evaluated by a questionnaire. Second, three drawings of non-target stimuli (neutral face, angry face, and wheelchair) and target stimuli were used to elicit event-related potentials (ERPs). Children had higher scores for the facial expressions than adults, and relied much more on the angles of the eyebrows and mouth. The major ERP findings were (1) the latencies of P100 and N170 were significantly longer in children than adults, (2) the amplitudes of P100 were significantly larger in children than adults, but the N170 amplitudes were not significantly different, and (3) a slow negative shift was recorded with a latency of 240-460ms at the posterior-temporal site for angry face compared with neutral face in adults but not in children. These results suggest that the differences in the electrophysiological recognition of facial expressions can be set at 240ms after appearance of the Chernoff's face in adults but not in children.

[Sympathetic skin response in patients with severe motor and intellectual disabilities].

To elucidate autonomic function in individuals with severe motor and intellectual disabilities, we evaluated sympathetic skin response in 14 patients with severe motor and intellectual disabilities. The results of sympathetic skin response were compared with those of patients with mild or moderate motor and intellectual disabilities who could walk and had an intelligence quotient > or = 35 (7 cases) and neuromuscular diseases (3 cases). No sympathetic skin response was recorded in patients with severe motor and intellectual disabilities, whereas all patients with mild or moderate motor and intellectual disabilities defined above and neuromuscular diseases showed sympathetic skin response. The results suggested that all patients with severe motor and intellectual disabilities had autonomic dysfunction, and sympathetic skin response can be a useful test that can evaluate autonomic function in patients with severe motor and intellectual disabilities.

Molecular characterization of water-selective AQP (EbAQP4) in hagfish: insight into ancestral origin of AQP4.

Hagfish (Eptatretus burgeri) are agnathous and are the earliest vertebrates still in existence. Pavement cells adjacent to the mitochondria-rich cells show orthogonal arrays of particles (OAPs) in the gill of hagfish, a known ultrastructural morphology of aquaporin (AQP) in mammalian freeze-replica studies, suggesting that an AQP homolog exists in pavement cells. We therefore cloned water channels from hagfish gill and examined their molecular characteristics. The cloned AQP [E. burgeri AQP4 (EbAQP4)] encodes 288 amino acids, including two NPA motifs and six transmembrane regions. The deduced amino acid sequence of EbAQP4 showed high homology to mammalian and avian AQP4 (rat, 44%; quail, 43%) and clustered with AQP4 subsets by the molecular phylogenetic tree. The osmotic water permeability of Xenopus oocytes injected with EbAQP4 cRNA increased eightfold compared with water-injected controls and was not reversibly inhibited by 0.3 mM HgCl(2). EbAQP4 mRNA expression in the gill was demonstrated by the RNase protection assay; antibody raised against the COOH terminus of EbAQP4 also detected (by Western blot analysis) a major approximately 31-kDa band in the gill. Immunohistochemistry and immunoelectron microscopy showed EbAQP4 localized along the basolateral membranes of gill pavement cells. In freeze-replica studies, OAPs were detected on the protoplasmic face of the split membrane comprising particles 5-6 nm long on the basolateral side of the pavement cells. These observations suggest that EbAQP4 is an ancestral water channel of mammalian AQP4 and plays a role in basolateral water transport in the gill pavement cells.

Developmental changes in the expression of GABAA receptor alpha 1 and gamma 2 subunits in human temporal lobe, hippocampus and basal ganglia: an implication for consideration on age-related epilepsy.

Mutations of genes encoding GABA(A) receptor alpha 1 (GABARA1) and gamma 2 subunit (GABARG2) are associated with age-dependent epilepsy. The development of the subunits expression may be related to the age-dependency of epilepsy. Nevertheless, developmental and spatial changes in expression of GABA(A) receptors have not been examined in the human brain. Using immunohistochemistry, we examined the development of GABARA1 and GABARG2 in the human temporal lobe, hippocampus and basal ganglia in specimens obtained from 21 fetuses/subjects who died aged 22 gestation weeks (GW) to 75 years. Unique developmental changes of GABARA1 and GABARG2 were recorded in each region. In hippocampal pyramidal cells, GABARA1 was already found from 22 GW mainly on CA2-3, whereas GABARG2 was expressed later than GABARA1 predominantly in CA3. In the temporal cortex, both subunits appeared in the pyramidal cells layer from 22 GW, while GABARA1 and GABARG2 expression was increased from 29 to 38 GW, respectively. Furthermore, transient increase of GABARA1 was detected in the granular cell layer of the hippocampus from 29 GW to 4 months, in the cortical pyramidal cell layer from 29 to 40 GW, and in the putamen from birth to 5 years of age. Thus gradual or transient increase of GABARA1 and GABARG2 was found in every region at different age. These developmental changes in the expression of these subunits may contribute to the age dependency in some epilepsy syndromes where deficiency of GABARA1 and GABARG2 is involved.

An infant with a mitochondrial A3243G mutation demonstrating the MELAS phenotype.

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a syndrome associated with mitochondrial DNA mutations such as A3243G, the most common mutation. Ragged-red fibers and strongly succinate dehydrogenase-reactive blood vessels in the muscle are diagnostic pathologic features of MELAS. In general, the first typical attack of MELAS occurs in children at school age; it is rare for stroke-like episodes to occur in early infancy. This report describes a 4-month-old male harboring A3243G, whose phenotype at onset was consistent with that of MELAS in infancy. The patient was admitted because of disturbances of consciousness and ventilatory insufficiency. Remarkable lactic acidosis was observed. MRI revealed several bilateral lesions. Periodic lateralized epileptic discharges on the EEG suggested regional lesions. Biopsied muscle displayed scattered ragged-red fibers and succinate dehydrogenase-reactive blood vessels; over 90% of muscle mitochondrial DNA had A3243G. This case suggests that MELAS can develop in early infancy with its typical clinical presentation. The high percentage of A3243G may contribute to the early onset of the MELAS phenotype in this patient.

Clinicopathologic correlation of C1q nephropathy in children.

BACKGROUND: Clinicopathologic correlation of C1q nephropathy is clarified poorly. The aim of our study is to clarify clinicopathologic correlation in childhood C1q nephropathy. METHODS: Thirty children aged 3 to 15 years who met criteria proposed by Jennette and Hipp were enrolled in this study. RESULTS: According to their presentation at onset, children were divided into 2 groups: the asymptomatic urinary abnormalities (asymptomatic) group (n = 18) and the nephrotic syndrome (NS) group (n = 12). Light microscopy showed minimal change disease (MCD) in 22 children (73%), mesangial proliferative glomerulonephritis in 6 children (20%), and focal segmental glomerulosclerosis (FSGS) in 2 children (7%). Four children in the asymptomatic group and all children in the NS group were administered prednisolone and/or cyclosporine. Normal urinalysis results were found in 8 children in the asymptomatic group and 3 children in the NS group during the follow-up period of 3 to 15 years. Eight children in the NS group were frequent relapsers at the latest follow-up. Two children with FSGS (1 child, asymptomatic group; 1 child, NS group) received dialysis 10 and 15 years after the diagnosis. There were no differences in histological findings and clinical outcomes between the 2 groups. Four children with MCD in the NS group underwent a second biopsy. C1q deposits disappeared in 2 children, and 1 of these 2 children showed FSGS. CONCLUSION: Childhood C1q nephropathy is found in a wide clinical spectrum. Some children showed disappearance of C1q deposits through the follow-up period. A large number of children with C1q nephropathy showed MCD. However, FSGS may develop in some children on repeated biopsy. Therefore, long-term follow-up is needed in children with C1q nephropathy.

Genetics of idiopathic epilepsies.

PURPOSE: To search for clues to molecular genetics of common idiopathic epilepsy syndromes. Genetic defects have been identified recently in certain inherited epilepsy syndromes in which the phenotypes are similar to those of common idiopathic epilepsies. METHODS: Mutations identified as the causes of inherited idiopathic epilepsies were reviewed. RESULTS: Mutations of the genes encoding two subunits of the neuronal nicotinic acetylcholine receptor were found in autosomal dominant nocturnal frontal lobe epilepsy. Mutations of two K(+)-channel genes were identified in benign familial neonatal convulsions. Mutations of the genes encoding several subunits of the voltage-gated Na(+)-channel and gamma-aminobutyric acid (GABA)(A) receptor also were identified as the underlying causes of various epilepsy syndromes, such as autosomal dominant epilepsy with febrile seizures plus, benign familial neonatal infantile seizures, and autosomal dominant juvenile myoclonic epilepsy. Mutations within the same gene may result in different epilepsy phenotypes. Thus, the Na(+) channel, GABA(A) receptor, and their auxiliaries may be involved in the pathogenesis of various types of epilepsy. Some forms of juvenile myoclonic epilepsy, idiopathic generalized epilepsy, and absence epilepsy may result from mutations of Ca(2+) channels. Mutations of the Cl(-) channel have been recently found to be associated with a certain type of epilepsy. The recent discovery that mutations of LGI1, a gene encoding a nonchannel molecule, are associated with autosomal partial epilepsy with auditory features may provide a new insight into our understanding of the genetics of idiopathic epilepsy. CONCLUSIONS: These findings suggest the involvement of brain channelopathies in the pathogenesis of certain types of idiopathic epilepsy.

Biliary atresia associated with jejunal atresia and a review of the literature in Japan.

An unusual case of biliary atresia with jejunal atresia is herein described. Only 12 cases demonstrating biliary atresia associated with a jejunal atresia have been previously reported in Japan. The pathogenesis of biliary atresia is thought to be secondary to the influence of jejunal atresia.

[A case of parietal lobe epilepsy with ictal laughter].

We report here about an 8-year-old boy with parietal lobe epilepsy (PLE) and ictal laughter. At the age of 6, he began to experience drop seizures, followed by sensory fits. Interictal EEG showed frequent spikes at C3, C4, P3 and Cz. Despite treatment with antiepileptic drugs, he often fell down in seizures after feeling abnormal sensations in the right shoulder. On ictal video EEG at the age of 7 years, (1) he became motionless and complained of fear and pain in the right hand, (2) he had clonic seizures of the right upper limb and fell down to his left, (3) he laughed though he did not feel funny. Ictal EEG showed spikes which originated in Pz and then were generalized. In many of the previously reported cases, ictal laughter is associated with hypothalamic hamartomas, infantile spasms,. complex partial seizures of frontal, temporal, or parietal origin. We diagnosed the present case as having PLE. However, other localization could not be roled out because the spikes were generalized quickly. To date, there are two reported cases of ictal laughter with PLE, but ictal EEG is lacking in these patients. Ictal laughter is rare in non-lesional cryptogenic PLE, but it may imply PLE's pathogenesis.

[Rolandic epilepsy: neurophysiological aspects].

Rolandic epilepsy (RE) is a common epileptic syndrome, which child neurologists often see. However, many problems concerning RE remains unsolved despite previous extensive studies. This paper discusses the current status of knowledge and our own observation especially on neurophysiological aspects of RE, such as the morphology of rolandic discharge (RD), effectiveness of clonazepam on RD, rhythmic slow activity, extreme somatosensory evoked potentials, and generator of RD. RD is characteristic of RE, and sometimes appears to be enigmatic to child neurologists. RE is a representative epileptic syndrome in childhood, and should be investigated further to address its underlying mechanism.

Mutations of neuronal voltage-gated Na+ channel alpha 1 subunit gene SCN1A in core severe myoclonic epilepsy in infancy (SMEI) and in borderline SMEI (SMEB).

PURPOSE: Severe myoclonic epilepsy in infancy (SMEI) is a distinct epilepsy syndrome. Patients with borderline SMEI (SMEB) are a subgroup with clinical features similar to those of core SMEI but are not necessarily consistent with the accepted diagnostic criteria for core SMEI. The aim of this study was to delineate the genetic correlation between core SMEI and SMEB and to estimate the frequency of mutations in both phenotypes. METHODS: We examined 96 healthy volunteers and 58 unrelated individuals whose clinical features were consistent with either core SMEI (n = 31) or SMEB (n = 27). We screened for genetic abnormalities within exons and their flanking introns of the genes encoding major subunits of the Na+ channels (SCN1A, SCN2A, SCN1B, and SCN2B) by using a direct sequencing method. RESULTS: In both core SMEI and SMEB, various mutations of SCN1A including nonsense and missense mutations were identified, whereas no mutations of SCN2A, SCN1B, and SCN2B were found within the regions examined. All mutations were heterozygous and not found in 192 control chromosomes. Mutations were identified in 26 (44.8%) of the 58 individuals and were more frequent (p < 0.05) in core SMEI (19 of 31) than in SMEB (seven of 27), as assessed by the continuity-adjusted chi2 test. Mutations resulting in a molecular truncation were found only in core SMEI. Among the mutations, two missense mutations were found in both core SMEI and SMEB. CONCLUSIONS: Our findings confirm that SMEB is part of the SMEI spectrum and may expand the recognition of SMEI and suggest other responsible or modifying genes.

F-waves in neonates: increased spinal anterior horn motor neuron excitability.

We analyzed characteristics of F-waves in neonates to establish normal parameters for this age. F-waves recorded from the median nerve in 26 normal neonates were analyzed and compared to those in 10 adults. F-wave parameters measured included occurrence rate (Fpersistence), latency (Flatency), latency corrected for subject height (normalized Flatency), duration (Fduration), amplitude (Famplitude) and its ratio to M-wave amplitude (F/M ratio), F-wave conduction velocity (FCV), and Fchronodispersion. Mean Fpersistence in neonates was 100%. Famplitude and the F/M ratio were higher in neonates than in adults. Similar F-wave waveforms were observed repeatedly in neonates, while waveforms varied in adults. These results in neonates suggest increased excitability of motor neurons in the spinal anterior horn reflecting immaturity of inhibition by the central nervous system.