Ataxia telangiectasia (AT) is a primary immunodeficiency syndrome characteri zed by cerebellar ataxia, extrapyramidal signs, oculocutaneous telangiectasia, recurrent respiratory infections and development of malignancies. AT is a complex autosomal recessive disorder involving several systems other than lymphoid cells or the central nervous system. Such a diversity of abnormalities includes hypersensitivity of fibroblasts and lymphocytes to ionizing radiation (anomaly of DNA repair), non-random chromosomal rearrangements in lymphocytes, elevated serum level of α-fetoprotein, premature aging and endocrine disorders. A DNA processing or repair protein is the suspected common denominator in this pathology. Whatever the putative common underlying mechanism, AT patients have profound alterations of the humoral and cellular immune system whose mechanisms should be discussed in terms similar to those for other immunodeficiency diseases.
The usual immunological abnormalities in this disease include decreased levels of CD 3 and CD 4 positive T lymphocytes, impaired delayed hypersensitivity, hypoplasia of thymus, decreased blast transformation in vitro in response to mitogen or antigenic stimulation, and decreased levels of serum IgA, IgE, and IgG 2 subclass.
In this paper, the results of our recent studies on the defects of B cells in patients with AT were presented. (1) We found that the geometric means of IgA production in the supernatants of the lymphoblastoid cell lines established by EB virus, from all patients with AT, were significantly lower than those from healthy controls (P<0.01). (2) IgG subclasses of the patients' sera were also measured by ELISA, and IgG 4 was defective in four cases among six patients with AT. Both results that indicate a defect of humoral immunity in patients with AT is attributable in part to an intrinsic abnormality of B cells. (3) Eleven patients with AT were studied concerning the status of specific EBV serology. All the AT patients had high EBV antibody titers of IgG to viral capsid antigen (VCA) and early antigen (EA), and low titers of IgG to EBV- associated nuclear antigen (EBNA) compared with healthy controls. It is considered to be related with the deficiency of EBV specific T cell killer function. (4) In the study of reactivity of peripheral lymphocytes to EB virus in the patients with AT, lymphoblastoid cell lines from the patients easily expressed EA and VCA by P 3 HR-1 strain EBV infection. These results suggest that a defect in immune surveillance and target cell defectiveness with genetic predisposition are the major factors of virus induced carcinogenesis.

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The purpose of this symposium is to review recent advances in child epileptology. Seven symposiasts discussed various aspects of clinical and basic epileptology ranging from classification, diagnosis, pathophysiology to drug therapy and comprehensive treatment.

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The development of a rational approach and prognostication of epilepsy is based on a special profile of seizure events or the suggested diagnosis of a specific disorder. Although classifications based on neurobiological knowledge would be highly desirable, the present state of inadequate information makes such task difficult. Current classification schemes are, therefore, based on clinical signs and symptoms which are readily identifiable. The significant progress of epileptology has brought us to the stage where one can delineate a number of epileptic syndromes, provide a precise definition, and orient individual syndromes. With further accumulation of both clinical experience and new knowledge in neurosciences, the proposed classification will develop to more appropriate schemes.

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Clinical applications of experimental models of complex partial seizure were studied using kainic acidinduced limbic seizures and amygdaloid kindling models.
The following experiments were done aiming to study the basic approach for the treatment of the intractable complex partial seizures.
1) Degenerative focal lesions were made in bilateral substantia nigra and substantia innominata by a local microinjection of the ibotenic acid and influences upon limbic seizures were studied. Substantia innominata has a facilitatory effect upon secondary generalization of the limbic seizure while substantia nigra has an inhibitory influence. Degenerative lesions of the bilateral hippocampus inhibited development process as well as establishment of the kindling.
2) Resection of the primary epileptic focus in a limbic seizure status resulted in seizure control in cats with a single focus but not in another with multiple foci.
3) An autoradiography was done during limbic seizure status induced by kainic acid microinjection, and local cerebral glucose utilization (LCGU) and local cerebral blood flow were studied in order to study the relationship between cerebral metabolism and cerebral blood flow during limbic seizures. In the pyramidal cell of the hippocampus, an increased ratio of LCGU (x 4.1) is larger than that of LCBF (x 1.6). This uncoupling may be one reason of the neuronal cell damage during the limbic seizure status.
4) Autoradiography of the calcium suggested that one of the causes of hippocampal degeneration in intractable complex partial seizures should be a consequence of calcium influx into pyramidal cells during repeated limbic seizures.

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The patients whose EEG demonstrates spikes in the midline-parietal, left and/or right centro-parietal areas can be belonged to a category of benign epilepsy in childhood. In these patients, an extremely high voltage somatosensory evoked potential (SEP) mimicking a spike is elicited by electric stimulation to both upper and lower extremities. The peaks of this giant SEP show extraordinarily high amplitude at N32 and at N50 by stimulation to median and posterior tibial nerves, respectively. It is thought that these spikes originate from the somatosensory cortex in the light of the latencies of the giant SEP.
It is not uncommon that the infants with perinatal problems show insufficient staring and tracking. Among these infants, those who have occipital irregular polyspikes and slow waves later develop infantile spasms. This unique combination may be important as the high risk signs of infantile spasms. The visual outcome of these patients relates to persistence of seizures and discharges rather than the pattern of visual evoked potential.

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We designed a new cassette EEG recording system which consists of a recording block (an ambulatorytype data recorder and a newly developed pre-amplifier) and a reproduction block (a fixed-type data recorder, a personal computer equipped with A/D converting board and an intervening EEG device for a bandpass filter).
This system was applied to 36 epileptic children, and 33 ictal records were obtained. The seizure type could be precisely classified by a comparative analysis of the data computed from this system and from the ictal symptoms.
Three representative cases were presented with actual analysis procedures.

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There are numerous important problems concerning relationship between epilepsy and sleep. To clarify the clinical significance and pathophysiology of the nonconvulsive status epilepticus with continuous diffuse spike-waves during slow-wave sleep (CSWS) in EEG, this study was carried out on seven cases each of epilepsies with electrical status epilepticus during slow sleep (ESES) and with peculiar type of nonconvulsive status epilepticus in childhood (PNSE) and four cases of atypical benign partial epilepsy (ABPE).
Mental deterioration was most frequently observed in ESES, less in PNSE but none in ABPE. In both ESES and PNSE, mentally deteriorated cases showed suppression of CSWS at significantly later ages than those without deterioration. And spike-wave indices durig slow-wave sleep, which were the highest in ESES and lower in PNSE and ABPE, also had a strong relation to mental deterioration.
In these three disorders, both clinical seizures and CSWS were suppressed at or before 16 years of age, although they were intractable before adolescence. This finding indicated age dependent evolutions of the three disorders.
Coherence and phase analysis of CSWS was undertaken to differentiate primary and secondary bilateral synchrony in seven cases of these three disorders, which have both features of generalized and partial epilepsies. This analysis disclosed secondary bilateral synchrony as the nature of CSWS in six cases. And this analysis method was considered to provide a clue to their pathophysiology.
Thus, in these disorders, importance of early diagnosis by EEG including deep sleep and early treatment was recognized.

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In the treatment of epileptic children, it is important to give considerations to the child's psychological aspects. One of considerations should be given to the neuropsychological disorders, since it is sometimes observed that learning disabilities coincide with epilepsy. Another consideration should be given to psychiatric disorders. Mental retardation occurs about 20% of epileptic children. Among personality and behavioral problems, hyperactivity is observed in younger children, while a viscous tendency is seen after puberty. The incidence of these two problems is related to the severity of mental retardation. In the course of the treatment of epileptic children, puberty is an important period. It is necessary to assist epileptic children to cope with the disease they have. Although the incidence is small, an acute or chronic epileptic psychosis is observed after puberty. An existence of pseudoseizures should not be forgotten. Cognitive or behavioral problems may occur as a result of anti-epileptic drugs.

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Clinical and electroencephalographic studies were performed to elucidate the characteristics of epilepsy in severely handicapped children. The subjects were 56 severely mentally and physically handicapped children whose ictal seizures were documented by simultaneous EEG-VTR monitoring. Seizure types were infantile spasms in 17 (30.4%), atypical absence in 5 (8.9%), myoclonic seizures in 3 (5.4%), generalized tonicclonic seizures in 2 (3.6%), secondary generalized partial seizures in 11 (19.6%), and undetermined in 4 (7.1%). Epilepsy types were also classified by the ictal seizure types and clinical courses: West syndrome in 27 (48.1%), Lennox-Gastaut syndrome (LGS) (at onset) in 5 (8.9%), partial epilepsy in 13 (23.2%) and others (at onset) in 11 (19.8%). Among 29 cases with West syndrome, 22 (81%) developed LGS, and among 11 cases with others group, 64% developed LGS. After all, LGS appeared in 60.7% of all 56 severe epileptic children associated with severe physical and mental handicaps.

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During the past 10 years, better results in the treatment of epilepsy have been obtained through the application of pharmacokinetic data to drug therapy of epilepsy. However, pediatric drug therapy is complicated by the continuous change in body weight and body composition with the growth and development, especially during infancy. Younger children require a higher dose per kilogram of body weight than older children in order to achieve comparable plasma concentrations.
Plasma levels and seizure control were investigated in a prospective randomized study when phenytoin, carbamazepine (CBZ) or sodium valproate (VPA) was given as a single drug to pediatric patients with several types of epileptic seizures. Studies on newly referred, previously untreated children suggest that both partial and generalized tonic-clonic seizures can be prevented by each of the three drugs. No significant differences in clinical efficacy were found among the three drugs, when optimum plasma concentration ranges were maintained with blood level monitoring.
Clonazepam (CZP) may be effective in partial seizures. However, as a wide range of plasma levels was associated with complete freedom from seizures, it was not possible to define a therapeutic range for CZP.
Any patient who receives multiple-drug therapy is at risk to develop a drug-drug interaction. Simultaneous administration of VPA was associated with a raised plasma level of carbamazepine-10, 11-epoxide (CBZ-E), a major metabolite of CBZ, relative to the CBZ dose, whereas the plasma CBZ level remained unaltered. High plasma concentration of CBZ-E may be responsible for side effects in some patients.
Drug-protein binding interactions are another source of side effects. The unbound or protein-free levels of both CBZ and CBZ-E in patients treated with CBZ and VPA were significantly higher than those in patients treated with CBZ alone.
A working knowledge of the pharmacokinetic principles is an important basis for treating children with antiepileptic drugs.

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Agarose gel electrophoresis and immunofixation of CSF and serum from 16 patients aged from 1 day to 13 years with CNS infectious diseases (5 with purulent meningitis, 5 with aseptic meningitis, 4 with acute encephalitis, 1 with subdural empyema and 1 with SSPE) revealed oligoclonal IgG bands in 10 cases. In 4 cases, a high CSF/serum albumin ratio was recognized without an increase of IgG-index, probably representing a systemic immune response. Neither IgA nor IgM bands were recognized. IgG light chain was examined in 7 cases and IgG kappa bands predominated in 6 cases. IgG lambda bands predominance presented in only one case. Free IgG kappa or lambda chain was not found. These results suggested that the measurement of not only IgG-index but oligoclonal bands may have a diagnostic usefulness to know about local production of immunoglobulins in CSF.

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The brain metabolites were studied in the neonatal hypothyroid rat brain using ³¹P and ¹H nuclear magnetic resonance (NMR) spectroscopy. In vivo ³¹P spectroscopy of the brains in hypothyroid rats showed the tendency of decrease in phosphocreatine/Pi and phosphocreatine/ATP ratio, suggesting suppressed brain energy status. On proton analysis using perchloric acid extracts of the brain, 10 metabolites were easily recognized. Quantitative analysis of individual metabolites revealed decreased contents of GABA, NAA (N-acety laspartate) and phosphocreatine and increased contents of taurine in hypothyroid rat. It was concluded that NMR is a useful and promising tool to evaluate brain metabolites.

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We studied the 3rd lumbar vertebral trabecular bone mineral density in 59 cross-sectional pictures of quantitative computed tomography (QCT) with CaCO₃ phantom for 28 hospital control children and 30 cases of suspected bone metabolic disorders. The QCT value of bone mineral density of control children showed neither age dependency nor sexual difference before puberty; for males was 221.8±30.2 mg CaCO₃/cm₃ (Mean±SD) under 4 years, 218.1±39.7 at 5-9 years and 217.2±30.9 at 10-15 years; and for females 220.9±18.3 under 4 years and 240.0±29.4 at 5-9 years.
The QCT values of bone mineral density in bed-ridden patients, children receiving glucocorticoids and children receiving anticonvulsants were significantly lower than that in control children (p<0.005). The QCT value of bone mineral density of bed-ridden patients was significantly lower than that of children receiving glucocorticoids and of children receiving anticonvulsants (p<0.05, p<0.005 respectively). Our study confirmed that single energy quantitative CT was very useful in pediatric clinical application.

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A male infant developed left-sided myoclonus associated with low grade fever at 21 days of age. The course of pregnancy and delivery had been uneventful. Birth weight was 2, 240g at 38 weeks of gestation. Physical examination at 26 days of age revealed hyperirritability and incomplete Moro reflex. EEG showed periodic discharges originating in the right central region. Initial brain CT at 26 days of age showed no apparent abnormality. In lumbar CSF protein was 173 mg/dl, and nucleated cells 328/mm³ (polynuclear cells 6 and mononuclear cells 322). Cultures of CSF for bacteria and viruses were negative. Although, the serum titers of CF antibody to herpes simplex virus (HSV) were 1: 4 to 1: 8 during hospitalization and those in CSF were not increased significantly, ELISA titers for IgG and IgM in serum and CSF rose significantly. The diagnosis of HSV encephalitis was made at 41 days of age. His myoclonus was well controlled with phenobarbital and clonazepam. He was treated with acyclovir and CSF findings returned to normal. On 2nd brain CT (39 days of age), calcification at thalamus, basal ganglia and right frontal lobe, which is extremely rare CT findings for HSV encephalitis, was noticed. His DQ at discharge was about 90. It is emphasized that the early diagnosis of HSV encephalitis can be made by ELISA and serial brain CT examinations, and that HSV encephalitis should be considered when calcification of thalamus and basal ganglia are detected on brain CT.

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[in Japanese]

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[in Japanese]

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[in Japanese]

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