- Email: [email protected]
Postnatal development of click evoked auditory cortical potentials
induced by 1L-1 and opioids were partly or completely blocked by IL-lra, antiserum of B-end, nalaoxone, MK-801 and nifedipine, respectively. (3) IL-1, opioids, and their antagonists induced different levels of c-fos/c-jun mRNA expression. (4) Proenkephalin mRNA expression of neurons was induced 4 hours after treatment with IL-1 and still higher at 6 hours. Radioimmunoassay also revealed a marked increase of LE and B-end in cultured supematant fluid 20 hours after treatment with IL- 1; 1L- Ira partly blocked this action. (5) The activity of IL- 1 in cultured supernatant fluid was not significantly increased 20 hours after treatment with LE and B-end. The IL-1 mRNA expression of neurons was also not increased at 2, 4, 6, 12, and 24 hours after treatment with LE. (6) Antisense oligonucleotides (15 nM) for c-fos and c-jun partly abolished the secretion of LE and 13-end of neurons treated by 1L-l, in contrast with controls and groups treated by sense oligos. The inhibitory effect of antisense appeared to be on a dose-response curve. The effect of IL-I on the synthesis and secretion of opioids in neurons is partly mediated via c-fos and c-jun. According to the above results, we suggest that IL-1, opioids, and lEGs are interrelated and interacted on each other via different manners and mechanisms. Exogenous IL- 1 and opioids play roles in excitation of neurons, but IECs have biphasic regulation in target genes relevant to excitation or suppression of neurons depending on different stimulation factors. This project is supported by the National Science Foundation of China and the Chinese Medical Board.
71. EFFECT OF IBOTENATE ON BRAIN DEVELOPMENT: EXCITOTOXIC MOUSE MODEL OF MICROGYRIA AND POSTHYPOXICLIKE LESIONS S. Marret, R. Mukendi, J-F. Gadisseux, P. Gressens, and Ph. Evrard, Brussels, Belgium Ibotenate (Ibo), a glutamatergic agonist, was injected in developing mouse neopallium. When injected at the time of completion of supragranular neuronal migration (P0), Ibo induces complete neuronal depopulation of layer V and an abnormal sulcation of the overlying supragranular layers. Injected after completion of migration (P5-PI0), Ibo produces severe neuronal loss in layers, I1, III, IV, V, and VI. After being exposed to Ibo between P0 and P5, surviving neurons have the ability to resume migration inducing an abnormal neocortical pattern. Porencephalic cysts and other periventricular white matter lesions are observed after Ibo injection at P2-P10 with a peak of occurrence at P5. Both gray and white matter damages are prevented by DL-2amino-7-phosphonoheptanoic acid (AP 7), an N-methyl-oaspartate receptor antagonist, but not by L(+)-2-amino-3phosphonopropionic acid (AP 3), a metabotropic glutamate receptor antagonist. The microtubule associated protein type 2 (MAP 2), a dendritic marker, is absent in all Ibo lesions, reflecting the developmental impairment of the dendritic phase. These staged lesions of the gray and white matter disclose a developmental sequence of excitotoxin-affected events starting with the selective and layered sensitivity of postmigratory neocortical neurons and continuing in the white matter with astroglial maturation and axonal growth. They mimic faithfully microgyrias, porencephalic cysts, and focal corticosubcortical and white matter damages observed in human perinatal neuropathology of potential hypoxic-ischemic etiology. This mouse model provides tools to differentiate the hypoxic versus nonhypoxic excitotoxic lesions and to investigate protective substances.
104 PEDIATRICNEUROLOGY Vol. 11 No. 2
72. B L O C K A D E OF VIP F U N C T I O N IN E A R L Y MOUSE EMBRYO INDUCES SEVERE MICROCEPHALY P. Gressens, J.M. Hill, B. Paindaveine, I. Gozes, M. Fridkin, and D.E. Brenneman, Bethesda, Maryland, Brussels, Belgium, and Tel Aviv and Rehovot, Israel Understanding the pathophysiology of microcephaly is not only important for the development of preventive and therapeutic strategies, but also for the identification of the essential elements regulating CNS ontogenesis. Vasoactive intestinal peptide (VIP) has potent growth-related actions that influence cell mitosis, neuronal survival, and neurodifferentiation in cell culture. VIP can also produce a dramatic growth in postimplantation mouse embryos in vitro, characterized by large increases in cell division. Based on these data, the goal of our studies was to assess the role of this peptide on early nervous system development in vivo. Pregnant mice were treated with a specific antagonist to VIP. Prenatal administration of the antagonist early in development (E9-E11, premigratory period) produced a severe microcephaly characterized by decreased embryonic brain weight with reduced DNA and protein content. The retardation of growth was disproportionately manifested in brain compared with the body and was prevented by cotreatment with the agonist. Identical treatment with the antagonist later in gestation had no detectable effect on embryonic growth. VIP receptors were increased in the neuroepithelium of antagonist-treated embryos while the number of cells in S-phase was significantly decreased. Thus, VIP regulates brain growth in vivo and inhibition of its action provides insight into a molecular mechanism for microcephaly. These data imply that any interference, whether pharmacologic, viral, or nutritional, with VIP action at this critical period in development may result in reduced head size.
73. P O S T N A T A L D E V E L O P M E N T OF C L I C K EVOKED AUDITORY CORTICAL POTENTIALS Jan J. Rotteveel, Jaco Pasman, and Yvonne Visco, Nijmegen, The Netherlands Previously we studied longitudinally in preterm and term infants the ontogenesis of cortical auditory evoked potentials (CAEPs) until the age of 3 months after birth. The complex changes in waveform morphology have been determined and described. It was postulated that the major components were present at 3 months of age. We report a subsequent study of CAEP maturation in children between newborn and 16 years of age. CAEP were recorded in 97 children. This population was referred for brainstem auditory evoked potentials for a variety of indications. They did not represent a "normal selection." However, the developmental changes were very consistent and remarkable. Composite group averages were constructed for 9 age levels between newborn and 16 years: 0-1, 1-2, 2-4, 4-6, 6-8, 8-10, 10-12, 12-14, and 14-16 years of age. In the group averages the adult waveform was clearly present in the 14-16-year age group. Fast, early CAEP components during the first 50 ms did not change in the temporal course. The slow components, however, demonstrated remarkable changes. The infantile P2N2 components exhibited increasing complexity, suggesting contribution of an increasing number of sources until the age of 6-8 years. From 8-16 years, the adult morphology is present and completed at 14-16 years. It has been concluded that clinical application of the CAEP only holds promise if the developmental changes are de-
fined precisely. Further investigation for the sources of the components of the waveform complex is necessary.
74. TREATMENT OF RECURRENT CRANIOPHARYNGIOMA WITH ADRIAMYCIN Jan J. Rotteveel and Rob J.J. Lippens, Nijmegen, The Netherlands Three children suffered recurrent craniopharyngiomas at 8 months, 4.2 years and 4.5 years, respectively, after the initial subtotal surgical and subsequent radiotherapeutic treatment. A second neurosurgical attempt and course of radiotherapy did not result in stabilization of the disease. Outpatient chemotherapy was administered and consisted of 5 courses adriamycin intravenously (100 mg/m2/72 hours) and CCNU 80 mg/m 2 orally at 6-week intervals. No signs of tumor recurrence were noted at 9, 6, and 3 years respectively. Adriamycin was used in view of observations in animal studies performed previously. We found a selective deposition of adriamycin in the pituitary circulation, but not elsewhere in the brain. The observation in these 3 patients holds promise for the treatment of craniopharyngioma with adriamycin in the case of tumor recurrence or in young infants and subtotal tumor removal, as radiation is associated with great morbidity in the very young. Side effects of chemotherapy consist of alopecia and bone marrow depression. Cardiomyopathy, reported to occur in adriamycin treatment, was not seen in our patients. 75. M I T O C H O N D R I A L E N C E P H A L O M Y O P A T H Y PRESENTING AS COCKAYNE SYNDROME Benjamin Glick, Yaron Degany, Rami Amit, and Yehuda Shapira, Stony Brook, New York and Jerusalem, Israel Cockayne syndrome (CS) is a rare progressive disorder characterized by unusual facies, postnatal growth failure, and intellectual deterioration. Autosomal-recessive transmission was suggested. Etiology is unknown, but DNA repair abnormalities have been documented. We present a 14-year-old girl with clinical features of CS in whom both biochemical and histologic abnormalities suggesting mitochondriopathy were found (i.e., lactic acidosis, muscle biopsy revealing ragged-red fibers, subsarcolemmal depositions, structurally abnormal mitochondria with paracrystalline bodies on EM, and cytochrome c oxidase deficiency). EMG disclosed a myopathic pattern and slow nerve conduction consistent with a demyelinating process. Brain CT and MRI showed ventriculomegaly, basal ganglia calcifications, subthalamic infarcts, and cerebellar atrophy. Association between CS and Kearn-Sayre syndrome has been reported. Our findings support this mitochondrial etiology. 76. INFANTILE MASTURBATION M I M I C K I N G SEIZURES: A VIDEO DEMONSTRATION Raj D. Sheth and John B. Bodensteiner, Morgantown, West Virginia The accurate diagnosis of paroxysmal stereotypic behavior is difficult even after the observation of attacks. A 2-year-old boy was evaluated for stereotypic paroxysmal events which his parents had recorded with a video camera. The events occurred only while the boy was alert and playful. He would lie face down on
the floor and have rhythmic pelvic thrusting movements associated with a rocking movement of his flexed legs lasting 5 to 15 minutes. The entire episode was accompanied by a trancelike pleasurable state, with frequent smiling. Attempts to pick him up were vigorously resisted and he would break away and return to his activity. Electroencephalography and neuroimaging studies were normal. However, because the movements viewed on video tape were felt to be strongly suggestive of seizures, phenobarbital was initiated. After 6 weeks of therapy and despite therapeutic levels the episodes continued unabated. A second opinion identified the movements as infantile masturbation and phenobarbital was discontinued. With the increased ability of parents to supplement the history of paroxysmal events with home video recordings it is important that the algorithm that clinicians utilize in the evaluations of such events by history be applied to video recordings. In the prepubertal child paroxysmal physiologic events, such as masturbation, represent normal behavior and may mimic seizures. 77. F E L B A M A T E AS F I R S T C H O I C E D R U G IN TREATMENT OF NEWLY DIAGNOSED PARTIAL EPILEPSIES M. Carignani, D. Rosso, and M. Taboada, Rosario, Argentina We present 8 previously untreated patients with a mean age of 8.66 years. All had normal neurologic examinations and normal mental states, but suffered partial seizures (simple, complex, secondary generalized), which were treated after diagnosis with felbamate on a low-dose schedule. Cases were selected following the ILAE classification, in the cryptogenic-symptomatic group, in a range of age between 3-15 years. The period of clinical trial was at an average of 9.5 months and results were evaluated in terms of efficiency and tolerance and were good. In spite of the fact that it is impossible to determine the spontaneous progress of symptocryptopartial epilepsies when there is correct nosologic placement, one can expect (but not predict) an always high frequency of events, often daily. Our results were as follows: 5 cases (66%) were seizure free, 2 patients (25%) had 1-5 seizures and the remainder had >5 seizures. We believe it is important to check potential efficacy of new drugs outside of their main indication, not to replace the others, but to search for better results. 78. FACIAL HEMANGIOMA AND ASSOCIATED VASCULAR AND NONVASCULAR MALFORMATIONS Ignacio Pascua1-Castroviejo, Samuel I. Pascual, Juan Via.rio, and Vicente Martinez, Madrid, Spain Pascual-Castroviejo described [Neuroradiology 1978;16:82-4] a new syndrome consisting of the association of facial hemangioma with several types of vascular and nonvascular malformations. All 7 patients were females. Vascular studies were performed by conventional arteriography. During the subsequent years, 5 new patients, also females, were studied by MRI and MR arteriography using a General Electric 1.5 Tesla. Three of the patients have both conventional and MR arteriography. Persistence of the trigeminal artery was found in 3 patients, agenesis of internal carotid artery in 2, agenesis of vertebral artery in 1, agenesis or severe hypoplasia of the middle sized arteries (i.e., anterior cerebral, posterior cerebral, or superior cerebellar) in 2 patients. Cortical heterotopia occurred in 1 patient with cerebral
PEDIATRIC NEUROLOGY Vol. 11 No. 2 105
71. EFFECT OF IBOTENATE ON BRAIN DEVELOPMENT: EXCITOTOXIC MOUSE MODEL OF MICROGYRIA AND POSTHYPOXICLIKE LESIONS S. Marret, R. Mukendi, J-F. Gadisseux, P. Gressens, and Ph. Evrard, Brussels, Belgium Ibotenate (Ibo), a glutamatergic agonist, was injected in developing mouse neopallium. When injected at the time of completion of supragranular neuronal migration (P0), Ibo induces complete neuronal depopulation of layer V and an abnormal sulcation of the overlying supragranular layers. Injected after completion of migration (P5-PI0), Ibo produces severe neuronal loss in layers, I1, III, IV, V, and VI. After being exposed to Ibo between P0 and P5, surviving neurons have the ability to resume migration inducing an abnormal neocortical pattern. Porencephalic cysts and other periventricular white matter lesions are observed after Ibo injection at P2-P10 with a peak of occurrence at P5. Both gray and white matter damages are prevented by DL-2amino-7-phosphonoheptanoic acid (AP 7), an N-methyl-oaspartate receptor antagonist, but not by L(+)-2-amino-3phosphonopropionic acid (AP 3), a metabotropic glutamate receptor antagonist. The microtubule associated protein type 2 (MAP 2), a dendritic marker, is absent in all Ibo lesions, reflecting the developmental impairment of the dendritic phase. These staged lesions of the gray and white matter disclose a developmental sequence of excitotoxin-affected events starting with the selective and layered sensitivity of postmigratory neocortical neurons and continuing in the white matter with astroglial maturation and axonal growth. They mimic faithfully microgyrias, porencephalic cysts, and focal corticosubcortical and white matter damages observed in human perinatal neuropathology of potential hypoxic-ischemic etiology. This mouse model provides tools to differentiate the hypoxic versus nonhypoxic excitotoxic lesions and to investigate protective substances.
104 PEDIATRICNEUROLOGY Vol. 11 No. 2
72. B L O C K A D E OF VIP F U N C T I O N IN E A R L Y MOUSE EMBRYO INDUCES SEVERE MICROCEPHALY P. Gressens, J.M. Hill, B. Paindaveine, I. Gozes, M. Fridkin, and D.E. Brenneman, Bethesda, Maryland, Brussels, Belgium, and Tel Aviv and Rehovot, Israel Understanding the pathophysiology of microcephaly is not only important for the development of preventive and therapeutic strategies, but also for the identification of the essential elements regulating CNS ontogenesis. Vasoactive intestinal peptide (VIP) has potent growth-related actions that influence cell mitosis, neuronal survival, and neurodifferentiation in cell culture. VIP can also produce a dramatic growth in postimplantation mouse embryos in vitro, characterized by large increases in cell division. Based on these data, the goal of our studies was to assess the role of this peptide on early nervous system development in vivo. Pregnant mice were treated with a specific antagonist to VIP. Prenatal administration of the antagonist early in development (E9-E11, premigratory period) produced a severe microcephaly characterized by decreased embryonic brain weight with reduced DNA and protein content. The retardation of growth was disproportionately manifested in brain compared with the body and was prevented by cotreatment with the agonist. Identical treatment with the antagonist later in gestation had no detectable effect on embryonic growth. VIP receptors were increased in the neuroepithelium of antagonist-treated embryos while the number of cells in S-phase was significantly decreased. Thus, VIP regulates brain growth in vivo and inhibition of its action provides insight into a molecular mechanism for microcephaly. These data imply that any interference, whether pharmacologic, viral, or nutritional, with VIP action at this critical period in development may result in reduced head size.
73. P O S T N A T A L D E V E L O P M E N T OF C L I C K EVOKED AUDITORY CORTICAL POTENTIALS Jan J. Rotteveel, Jaco Pasman, and Yvonne Visco, Nijmegen, The Netherlands Previously we studied longitudinally in preterm and term infants the ontogenesis of cortical auditory evoked potentials (CAEPs) until the age of 3 months after birth. The complex changes in waveform morphology have been determined and described. It was postulated that the major components were present at 3 months of age. We report a subsequent study of CAEP maturation in children between newborn and 16 years of age. CAEP were recorded in 97 children. This population was referred for brainstem auditory evoked potentials for a variety of indications. They did not represent a "normal selection." However, the developmental changes were very consistent and remarkable. Composite group averages were constructed for 9 age levels between newborn and 16 years: 0-1, 1-2, 2-4, 4-6, 6-8, 8-10, 10-12, 12-14, and 14-16 years of age. In the group averages the adult waveform was clearly present in the 14-16-year age group. Fast, early CAEP components during the first 50 ms did not change in the temporal course. The slow components, however, demonstrated remarkable changes. The infantile P2N2 components exhibited increasing complexity, suggesting contribution of an increasing number of sources until the age of 6-8 years. From 8-16 years, the adult morphology is present and completed at 14-16 years. It has been concluded that clinical application of the CAEP only holds promise if the developmental changes are de-
fined precisely. Further investigation for the sources of the components of the waveform complex is necessary.
74. TREATMENT OF RECURRENT CRANIOPHARYNGIOMA WITH ADRIAMYCIN Jan J. Rotteveel and Rob J.J. Lippens, Nijmegen, The Netherlands Three children suffered recurrent craniopharyngiomas at 8 months, 4.2 years and 4.5 years, respectively, after the initial subtotal surgical and subsequent radiotherapeutic treatment. A second neurosurgical attempt and course of radiotherapy did not result in stabilization of the disease. Outpatient chemotherapy was administered and consisted of 5 courses adriamycin intravenously (100 mg/m2/72 hours) and CCNU 80 mg/m 2 orally at 6-week intervals. No signs of tumor recurrence were noted at 9, 6, and 3 years respectively. Adriamycin was used in view of observations in animal studies performed previously. We found a selective deposition of adriamycin in the pituitary circulation, but not elsewhere in the brain. The observation in these 3 patients holds promise for the treatment of craniopharyngioma with adriamycin in the case of tumor recurrence or in young infants and subtotal tumor removal, as radiation is associated with great morbidity in the very young. Side effects of chemotherapy consist of alopecia and bone marrow depression. Cardiomyopathy, reported to occur in adriamycin treatment, was not seen in our patients. 75. M I T O C H O N D R I A L E N C E P H A L O M Y O P A T H Y PRESENTING AS COCKAYNE SYNDROME Benjamin Glick, Yaron Degany, Rami Amit, and Yehuda Shapira, Stony Brook, New York and Jerusalem, Israel Cockayne syndrome (CS) is a rare progressive disorder characterized by unusual facies, postnatal growth failure, and intellectual deterioration. Autosomal-recessive transmission was suggested. Etiology is unknown, but DNA repair abnormalities have been documented. We present a 14-year-old girl with clinical features of CS in whom both biochemical and histologic abnormalities suggesting mitochondriopathy were found (i.e., lactic acidosis, muscle biopsy revealing ragged-red fibers, subsarcolemmal depositions, structurally abnormal mitochondria with paracrystalline bodies on EM, and cytochrome c oxidase deficiency). EMG disclosed a myopathic pattern and slow nerve conduction consistent with a demyelinating process. Brain CT and MRI showed ventriculomegaly, basal ganglia calcifications, subthalamic infarcts, and cerebellar atrophy. Association between CS and Kearn-Sayre syndrome has been reported. Our findings support this mitochondrial etiology. 76. INFANTILE MASTURBATION M I M I C K I N G SEIZURES: A VIDEO DEMONSTRATION Raj D. Sheth and John B. Bodensteiner, Morgantown, West Virginia The accurate diagnosis of paroxysmal stereotypic behavior is difficult even after the observation of attacks. A 2-year-old boy was evaluated for stereotypic paroxysmal events which his parents had recorded with a video camera. The events occurred only while the boy was alert and playful. He would lie face down on
the floor and have rhythmic pelvic thrusting movements associated with a rocking movement of his flexed legs lasting 5 to 15 minutes. The entire episode was accompanied by a trancelike pleasurable state, with frequent smiling. Attempts to pick him up were vigorously resisted and he would break away and return to his activity. Electroencephalography and neuroimaging studies were normal. However, because the movements viewed on video tape were felt to be strongly suggestive of seizures, phenobarbital was initiated. After 6 weeks of therapy and despite therapeutic levels the episodes continued unabated. A second opinion identified the movements as infantile masturbation and phenobarbital was discontinued. With the increased ability of parents to supplement the history of paroxysmal events with home video recordings it is important that the algorithm that clinicians utilize in the evaluations of such events by history be applied to video recordings. In the prepubertal child paroxysmal physiologic events, such as masturbation, represent normal behavior and may mimic seizures. 77. F E L B A M A T E AS F I R S T C H O I C E D R U G IN TREATMENT OF NEWLY DIAGNOSED PARTIAL EPILEPSIES M. Carignani, D. Rosso, and M. Taboada, Rosario, Argentina We present 8 previously untreated patients with a mean age of 8.66 years. All had normal neurologic examinations and normal mental states, but suffered partial seizures (simple, complex, secondary generalized), which were treated after diagnosis with felbamate on a low-dose schedule. Cases were selected following the ILAE classification, in the cryptogenic-symptomatic group, in a range of age between 3-15 years. The period of clinical trial was at an average of 9.5 months and results were evaluated in terms of efficiency and tolerance and were good. In spite of the fact that it is impossible to determine the spontaneous progress of symptocryptopartial epilepsies when there is correct nosologic placement, one can expect (but not predict) an always high frequency of events, often daily. Our results were as follows: 5 cases (66%) were seizure free, 2 patients (25%) had 1-5 seizures and the remainder had >5 seizures. We believe it is important to check potential efficacy of new drugs outside of their main indication, not to replace the others, but to search for better results. 78. FACIAL HEMANGIOMA AND ASSOCIATED VASCULAR AND NONVASCULAR MALFORMATIONS Ignacio Pascua1-Castroviejo, Samuel I. Pascual, Juan Via.rio, and Vicente Martinez, Madrid, Spain Pascual-Castroviejo described [Neuroradiology 1978;16:82-4] a new syndrome consisting of the association of facial hemangioma with several types of vascular and nonvascular malformations. All 7 patients were females. Vascular studies were performed by conventional arteriography. During the subsequent years, 5 new patients, also females, were studied by MRI and MR arteriography using a General Electric 1.5 Tesla. Three of the patients have both conventional and MR arteriography. Persistence of the trigeminal artery was found in 3 patients, agenesis of internal carotid artery in 2, agenesis of vertebral artery in 1, agenesis or severe hypoplasia of the middle sized arteries (i.e., anterior cerebral, posterior cerebral, or superior cerebellar) in 2 patients. Cortical heterotopia occurred in 1 patient with cerebral
PEDIATRIC NEUROLOGY Vol. 11 No. 2 105