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Dextromethorphan (DM) ameliorates effects of neonatal hypoxia on brain morphology and seizures threshold in rats
Society Proceedings 4.
Avolition and pseudo-hypersomnia with bilateral anterior striato.capsular infarcts. -- G.M. REmillard, J. Montplaisir, F. Dubeau, P. Lesp~rance Oltpital Sacr~-Coeur de Montreal and Montreal Neurological Hespital, Quebec, Canada)
Our objective was to further clarify the syndrome associated with bilateral striato-capsular lesions. These lesions typically produce lack of initiative, diminished motivation, striking inactivity and hypersomnia which is not due to depression or psychosis. A 41 year old woman developed a mild right hemiparesis at age 19. A CT-scan then showed atrophy of the head of the left caadate nucleus. From age 25, she developed chronic lack of interest, inactivity unless strongly stimulated, social withdrawal and severe hypersomnia. A brain MRI demonstrated discrete bilateral anterior stfiato..eapsular lesions of probable ischemic origin. A recent night polysomnography recording failed to demonstrate objective sleep abnormalities other than delayed sleep latency. Moreover, mean sleep latency 1115.54 min) at the Multiple Sleep Latency Test during the day showed normal vigilance, although she appeared to be sleeping during the test. The lesions did not result in true objective hypersomnia. Severe apathy, inertia and withdrawal were mistaken for sleep behavior in our patient. In similar situations, it may be difficult to differentiate on a clinical basis severe withdrawal from true sleep. Objective measures may then be useful for better characterization and management of this syndrome.
EEG background predicts electrical seizures in high risk neonates. - N. Laroia, M. McBride, R. Guillet, J. Burchfiel (Depts. of Pediatrics (Neenatology) and Neurology, Children's Hospital at Strong, Rochester, NY) Neonates have electrical seizures (ES) that are clinically undetected. To identify such infants, 31 infants were monitored with continuous EEG because they were considered to be at high risk: 19 with perinatal asphyxia (5 min Apgar score <5 and/or cord pH <7.2 and continuing lethargy at 2 h), of which 11 had suspected clinical seizures (szs); 9 with suspected clinical szs without asphyxia; 1 with unexplained apnea at term; 1 with meningitis; 1 with cerebral anomalies. Monitoring continued for 6-24 h (mean 20 h) if no ES or 13-26 h (mean 21 h) after the last ES. ES were treated initially with phenobarbital (up to 40 mg/kg) or lorazepam (0.1 mg/kg, up to 21doses/8 h); the second drug was added if ES continued. Eighteen of the 31 infants had no ES. Thirteen infants with ES were monitored for a total of 21-97 h (mean 45 h) during which 4-226 (mean 54) ES were recorded. Clinical correlates were seen for fewer than 10% of their ES and 4 of the 13 had no clinical szs noted during monitoring. Seven had >10 ES/h. The initial EEG background was graded as follows: 1, normal; 2, immature for gestation age; 3, mildly abnormal (excessive sharp waves, long and fiat low voltage periods, indistinct sleep states), 4, moderately abnormal (unilateral voltage suppression, asynchron)); 5, severely abnormal (low voltage or isoelectric, burst suppression). Only one of the 15 infants with grade 1 and 2 backgrounds had ES during monitoring; 12 of 16 infants with grades 3-5 background activity had ES (P < 0.001, chi square). Continuous EEG monitoring in higla risk neonates detects ES that are not apparent clinically. Background activity on the initial 1/2 h of recording is highly predictive of which infants will have ES, and hence of which infants should have continued monitoring. A practical system for digital EEG laboratory information
management. - B. Litt a'b, D. Ryan a, S. Hertz a'b, C. Beanland a'c, D. Hepner a, L. Van Sant a, P. Jones a, K. Lincoln a, P. McGuire a, E. Artemova a, P. Azizia, R. Wityk a'b (aSinai Hospital of Baltimore, Baltimore, MD. bJohns Hopkins University School of Medicine, Baltimore, MD. CNow at Egleston Children's Hospital, Atlanta, GA) We describe a digital EEG information management system connecting all areas of a 400 bed hospital, inpatient and remote outpatient
11P
EEG laboratories, with electroencephalographers, central data storage and a simple, useful database. Digital EEG data are acquired anywhere in the system, and transfenv,d over an Etbemet® network to the laboratory server (Micron Pentium 133 MHz PC, 2 gigabyte hard disk drive). During background file transfer, technologists enter patient demographic data into a Microsoft Access® database table, indexed by history number. Information about each EEG is entered into another table indexed by laboratory number and linked to the demographics table by history number. EEG files ate copied from the server to reading stations (486 IBM PC, 350 MB hard disk drives) where reports are generated and distributed over the hospital network. EEGs are transferred to permanent storage (optical or 'writeable' compact discs) and deleted from the server. Physicians log results in the 'record table.' This system allows for rapid acquisition, reading, storage and databasing of EEG laboratory data in a form useful for clinical, quality assurance and research purposes. Automatic report generation from the database, access to physicians at home and transfer/storage of digital video are features under development. 7.
Severity of illness, not EEG pattern or treatment, determine outcome in noneonvulsive status epilepticus (NCSE). - P. Mullinb, B. Litt a'b, S. Hertz a'b, D. Ryan a, IL Wityk a,b (aSinai Hospital of Baltimore, Baltimore, MD. bJohns Hopkins University Department of Neurology, Baltimore, MD.)
We report 31 adults with NCSE identified from EEG laboratory records. Patients were classified by presenting EEG as: generalized (G, 5 patients), complex partial (CP, 9 patients) or atypical (A, 17 patients) NCSE. No cases of absence status epilepticus were identified. Anoxicischemic and primary metabolic encephalopathies were excluded. Mean age was 68.7 years, 32% had a history of seizures, 68% were admitted to ICU. Individuals with advanced directives were managed outside the ICU. Patients were treated with an average of 2.48 antiepileptic drugs, 48% were intubated, 42% experienced significant treatment complications, 42% had PLEDs on EEG sometime during their course. Mean hospital stay was 30.87 days. Outcome (death or survival to discharge) correlated only with the number of organ systems acutely failing (1.4 in survivors vs. 2.9 in fatalities, P = 0.001), intravenous benzodiazepines treatment (P = 0.03) and GNCSE (P = 0.017), though GNCSE patients were sicker than others (3.6 systems failed vs. 1.8; P = 0.001). PLEDs correlated with CNS injury but not poor outcome. CPNCSE and ANCSE had similar outcomes. We propose that severity of underlying illness and not aggressiveness of or ICIS treatment determines outcome in patients with NCSE. EEG pattern and IV benzodiazepine treatment may correlate with outcome, but their significance is unclear.
Dextromethorphan (DM) ameliorates effects of neonatal hypoxia on brain morphology and seizure threshold in rats. - N. Laroia, R. Guillet (Dept. of Pediatrics (Neonatology), Children's Hospital at Strong, Rochester, NY, USA) Hypoxic injury to the brain is mediated in part by NMDA receptors. To test the hypothesis that NMDA receptor blockade with DM, a noncompetitive receptor blocker, would ameliorate injury even when given after the hypoxic insult, 7 day old rats were exposed to 8% 02 for 3 h. Following exposure, animals received 30 mg/kg, i.p. DM, or normal saline, within 30 min of the hypoxia exposure. Control rats (room air (RA) for 3 h) also received DM or saline. Effects investigated were brain histology 7 days after hypoxia (14 days) and seizure threshold using pentylenetetrazol (PTZ) and passive avoidance testing in young adulthood (70-90 days). Neonatally-hypoxic rats had decreased cortical thickness at 14 days compared to RA controls (1.62 ± 0.02 vs. 1.72 ± 0.02mm, P<0.05). This effect was prevented by DM (1.72± 0.08 mm, N.S.). PTZ seizure threshold in adulthood was decreased by 20% in neonatally hypoxic rats compared with controls (10.2 ± 1.0 vs. 12.8 ± 1.0 mg/kg, P < 0.05). Hypoxic animals that received DM had seizure thresholds similar to controls (13.3 ± 0.9 mg/kg, N.S.), suggest-
12P
Society Proceedings
ing amelioration or prevention of the effect of hypoxia. There was no change in seizure threshold in RA controls treated with DM (13.6 + 1.1 mg/kg, N.S.), suggesting that the drag itself did not change the seizure threshold. No significant changes due to hypoxia were observed in learning or memory tested using a passive avoidance paradigm. Mild to moderate hypoxia, previously thought not to produce any histologic changes, causes significant short-term loss of cortical thickness and long-term decrease in seizure threshold. DM appears to ameliorate these effects even when given after the hypoxic insult. 9.
Alpha frequency: a computerized model based on photoperiod data. - M.A. Cortez, X.A. Castro, K.E. Zmigrodzka, P.A. Hwang (The Hospital for Sick Children, Bloorview Epilepsy Program, U.C. of Ecuador. U. of T., Toronto, Ontario, Canada)
Alpha rhythm frequency evolves from 4 to 8 Hz during infancy, from 9 to 13 Hz in adolescence, and is absent in congenital blindness. Photoperiodicity has not been previously reported as a contributing factor to its development. A retrospective study of published environmental light-dark oscillation (LDO) data (McKay D.), and the alpha rhythm frequency data (Kellaway P.), was used to determine the photoperiod/occipital frequency ratio (r). Photoperiod data produced a computerized oscillation by itself: 121.66 LDOs preceded 4 Hz (1 Hz: 30.42 LDOs) (0.032); 243.28 LDOs lead the 5th and 6th Hz (1 Hz: 121.64 LDOs) (0.008); 729.84 LDOs head the 7th and the 8th Hz (1 Hz: 364.92 LDOs) (0.002); 1094.76 LDOs to the 9th Hz (1 Hz: 1094.76 LDOs) (0.0009); 2919.36 LDOs prior to the 10th Hz (I Hz: 2919.36 LDOs) (0.0003); 5108.88 LDOs= 14years (mean_+SD, 510.89 _+ 907.41; Chi 2, 451.88; df, 9; P < 0.00002). The photoperiod
data produced an analogous oscillation and was an objective parameter to determine the LDO/alpha frequency ratio. The oscillatory character of the photoperiod and the evolving alpha rhythm frequency suggests the possibility of photoperiodic oscillation imprinting on alpha generators, coinciding with ontogeny of melatonin secretion. 10. Long-term effects of excitatory amino acid antagonists NBQX and MK-801 on the developing brain. - P. Tandon, Z. Liu, C.E. Stafstrom, M. Sarkisian, S.J. Werner, Y. Yang, G.L. Holmes (Harvard Medical School, Children's Hospital, Boston, MA, USA) Because of the role of excitatory amino acids (EAAs) in epileptogenesis and seizure-induced brain damage, EAA antagonists are now being considered as possible therapy for seizures. However, during development EAAs play a pivotal role in learning, memory and brain plasticity. To evaluate the long-term effects of a short course of EAA antagonists on the developing brain, a non-NMDA antagonist, NBQX, or NMDA antagonist, MK-801, were administered over 7 days by osmotic pumps stereotaxically implanted into the lateral ventricles of normal 20 days old rats. Alternatively, 10 and 20 days old rats received a 7 day course of intraperitoneal (ip) NBQX. One month later, the NBQX, MK-801-treated rats, and controls underwent a series of behavioral studies: handling test, open field, and Morris water maze. Flurothyl inhalation was used to test seizure susceptibility in all groups. Although all of the rats ffeated with NBQX via osmotic pumps had spontaneous seizures, rats surviving infusion of EAAs had no deficits in learning, memory, or behavior and did not differ from controls in seizure susceptibility with flurothyl. In the developing animal, a short term course of EAA antagonists leads to no long-term adverse effects.
Avolition and pseudo-hypersomnia with bilateral anterior striato.capsular infarcts. -- G.M. REmillard, J. Montplaisir, F. Dubeau, P. Lesp~rance Oltpital Sacr~-Coeur de Montreal and Montreal Neurological Hespital, Quebec, Canada)
Our objective was to further clarify the syndrome associated with bilateral striato-capsular lesions. These lesions typically produce lack of initiative, diminished motivation, striking inactivity and hypersomnia which is not due to depression or psychosis. A 41 year old woman developed a mild right hemiparesis at age 19. A CT-scan then showed atrophy of the head of the left caadate nucleus. From age 25, she developed chronic lack of interest, inactivity unless strongly stimulated, social withdrawal and severe hypersomnia. A brain MRI demonstrated discrete bilateral anterior stfiato..eapsular lesions of probable ischemic origin. A recent night polysomnography recording failed to demonstrate objective sleep abnormalities other than delayed sleep latency. Moreover, mean sleep latency 1115.54 min) at the Multiple Sleep Latency Test during the day showed normal vigilance, although she appeared to be sleeping during the test. The lesions did not result in true objective hypersomnia. Severe apathy, inertia and withdrawal were mistaken for sleep behavior in our patient. In similar situations, it may be difficult to differentiate on a clinical basis severe withdrawal from true sleep. Objective measures may then be useful for better characterization and management of this syndrome.
EEG background predicts electrical seizures in high risk neonates. - N. Laroia, M. McBride, R. Guillet, J. Burchfiel (Depts. of Pediatrics (Neenatology) and Neurology, Children's Hospital at Strong, Rochester, NY) Neonates have electrical seizures (ES) that are clinically undetected. To identify such infants, 31 infants were monitored with continuous EEG because they were considered to be at high risk: 19 with perinatal asphyxia (5 min Apgar score <5 and/or cord pH <7.2 and continuing lethargy at 2 h), of which 11 had suspected clinical seizures (szs); 9 with suspected clinical szs without asphyxia; 1 with unexplained apnea at term; 1 with meningitis; 1 with cerebral anomalies. Monitoring continued for 6-24 h (mean 20 h) if no ES or 13-26 h (mean 21 h) after the last ES. ES were treated initially with phenobarbital (up to 40 mg/kg) or lorazepam (0.1 mg/kg, up to 21doses/8 h); the second drug was added if ES continued. Eighteen of the 31 infants had no ES. Thirteen infants with ES were monitored for a total of 21-97 h (mean 45 h) during which 4-226 (mean 54) ES were recorded. Clinical correlates were seen for fewer than 10% of their ES and 4 of the 13 had no clinical szs noted during monitoring. Seven had >10 ES/h. The initial EEG background was graded as follows: 1, normal; 2, immature for gestation age; 3, mildly abnormal (excessive sharp waves, long and fiat low voltage periods, indistinct sleep states), 4, moderately abnormal (unilateral voltage suppression, asynchron)); 5, severely abnormal (low voltage or isoelectric, burst suppression). Only one of the 15 infants with grade 1 and 2 backgrounds had ES during monitoring; 12 of 16 infants with grades 3-5 background activity had ES (P < 0.001, chi square). Continuous EEG monitoring in higla risk neonates detects ES that are not apparent clinically. Background activity on the initial 1/2 h of recording is highly predictive of which infants will have ES, and hence of which infants should have continued monitoring. A practical system for digital EEG laboratory information
management. - B. Litt a'b, D. Ryan a, S. Hertz a'b, C. Beanland a'c, D. Hepner a, L. Van Sant a, P. Jones a, K. Lincoln a, P. McGuire a, E. Artemova a, P. Azizia, R. Wityk a'b (aSinai Hospital of Baltimore, Baltimore, MD. bJohns Hopkins University School of Medicine, Baltimore, MD. CNow at Egleston Children's Hospital, Atlanta, GA) We describe a digital EEG information management system connecting all areas of a 400 bed hospital, inpatient and remote outpatient
11P
EEG laboratories, with electroencephalographers, central data storage and a simple, useful database. Digital EEG data are acquired anywhere in the system, and transfenv,d over an Etbemet® network to the laboratory server (Micron Pentium 133 MHz PC, 2 gigabyte hard disk drive). During background file transfer, technologists enter patient demographic data into a Microsoft Access® database table, indexed by history number. Information about each EEG is entered into another table indexed by laboratory number and linked to the demographics table by history number. EEG files ate copied from the server to reading stations (486 IBM PC, 350 MB hard disk drives) where reports are generated and distributed over the hospital network. EEGs are transferred to permanent storage (optical or 'writeable' compact discs) and deleted from the server. Physicians log results in the 'record table.' This system allows for rapid acquisition, reading, storage and databasing of EEG laboratory data in a form useful for clinical, quality assurance and research purposes. Automatic report generation from the database, access to physicians at home and transfer/storage of digital video are features under development. 7.
Severity of illness, not EEG pattern or treatment, determine outcome in noneonvulsive status epilepticus (NCSE). - P. Mullinb, B. Litt a'b, S. Hertz a'b, D. Ryan a, IL Wityk a,b (aSinai Hospital of Baltimore, Baltimore, MD. bJohns Hopkins University Department of Neurology, Baltimore, MD.)
We report 31 adults with NCSE identified from EEG laboratory records. Patients were classified by presenting EEG as: generalized (G, 5 patients), complex partial (CP, 9 patients) or atypical (A, 17 patients) NCSE. No cases of absence status epilepticus were identified. Anoxicischemic and primary metabolic encephalopathies were excluded. Mean age was 68.7 years, 32% had a history of seizures, 68% were admitted to ICU. Individuals with advanced directives were managed outside the ICU. Patients were treated with an average of 2.48 antiepileptic drugs, 48% were intubated, 42% experienced significant treatment complications, 42% had PLEDs on EEG sometime during their course. Mean hospital stay was 30.87 days. Outcome (death or survival to discharge) correlated only with the number of organ systems acutely failing (1.4 in survivors vs. 2.9 in fatalities, P = 0.001), intravenous benzodiazepines treatment (P = 0.03) and GNCSE (P = 0.017), though GNCSE patients were sicker than others (3.6 systems failed vs. 1.8; P = 0.001). PLEDs correlated with CNS injury but not poor outcome. CPNCSE and ANCSE had similar outcomes. We propose that severity of underlying illness and not aggressiveness of or ICIS treatment determines outcome in patients with NCSE. EEG pattern and IV benzodiazepine treatment may correlate with outcome, but their significance is unclear.
Dextromethorphan (DM) ameliorates effects of neonatal hypoxia on brain morphology and seizure threshold in rats. - N. Laroia, R. Guillet (Dept. of Pediatrics (Neonatology), Children's Hospital at Strong, Rochester, NY, USA) Hypoxic injury to the brain is mediated in part by NMDA receptors. To test the hypothesis that NMDA receptor blockade with DM, a noncompetitive receptor blocker, would ameliorate injury even when given after the hypoxic insult, 7 day old rats were exposed to 8% 02 for 3 h. Following exposure, animals received 30 mg/kg, i.p. DM, or normal saline, within 30 min of the hypoxia exposure. Control rats (room air (RA) for 3 h) also received DM or saline. Effects investigated were brain histology 7 days after hypoxia (14 days) and seizure threshold using pentylenetetrazol (PTZ) and passive avoidance testing in young adulthood (70-90 days). Neonatally-hypoxic rats had decreased cortical thickness at 14 days compared to RA controls (1.62 ± 0.02 vs. 1.72 ± 0.02mm, P<0.05). This effect was prevented by DM (1.72± 0.08 mm, N.S.). PTZ seizure threshold in adulthood was decreased by 20% in neonatally hypoxic rats compared with controls (10.2 ± 1.0 vs. 12.8 ± 1.0 mg/kg, P < 0.05). Hypoxic animals that received DM had seizure thresholds similar to controls (13.3 ± 0.9 mg/kg, N.S.), suggest-
12P
Society Proceedings
ing amelioration or prevention of the effect of hypoxia. There was no change in seizure threshold in RA controls treated with DM (13.6 + 1.1 mg/kg, N.S.), suggesting that the drag itself did not change the seizure threshold. No significant changes due to hypoxia were observed in learning or memory tested using a passive avoidance paradigm. Mild to moderate hypoxia, previously thought not to produce any histologic changes, causes significant short-term loss of cortical thickness and long-term decrease in seizure threshold. DM appears to ameliorate these effects even when given after the hypoxic insult. 9.
Alpha frequency: a computerized model based on photoperiod data. - M.A. Cortez, X.A. Castro, K.E. Zmigrodzka, P.A. Hwang (The Hospital for Sick Children, Bloorview Epilepsy Program, U.C. of Ecuador. U. of T., Toronto, Ontario, Canada)
Alpha rhythm frequency evolves from 4 to 8 Hz during infancy, from 9 to 13 Hz in adolescence, and is absent in congenital blindness. Photoperiodicity has not been previously reported as a contributing factor to its development. A retrospective study of published environmental light-dark oscillation (LDO) data (McKay D.), and the alpha rhythm frequency data (Kellaway P.), was used to determine the photoperiod/occipital frequency ratio (r). Photoperiod data produced a computerized oscillation by itself: 121.66 LDOs preceded 4 Hz (1 Hz: 30.42 LDOs) (0.032); 243.28 LDOs lead the 5th and 6th Hz (1 Hz: 121.64 LDOs) (0.008); 729.84 LDOs head the 7th and the 8th Hz (1 Hz: 364.92 LDOs) (0.002); 1094.76 LDOs to the 9th Hz (1 Hz: 1094.76 LDOs) (0.0009); 2919.36 LDOs prior to the 10th Hz (I Hz: 2919.36 LDOs) (0.0003); 5108.88 LDOs= 14years (mean_+SD, 510.89 _+ 907.41; Chi 2, 451.88; df, 9; P < 0.00002). The photoperiod
data produced an analogous oscillation and was an objective parameter to determine the LDO/alpha frequency ratio. The oscillatory character of the photoperiod and the evolving alpha rhythm frequency suggests the possibility of photoperiodic oscillation imprinting on alpha generators, coinciding with ontogeny of melatonin secretion. 10. Long-term effects of excitatory amino acid antagonists NBQX and MK-801 on the developing brain. - P. Tandon, Z. Liu, C.E. Stafstrom, M. Sarkisian, S.J. Werner, Y. Yang, G.L. Holmes (Harvard Medical School, Children's Hospital, Boston, MA, USA) Because of the role of excitatory amino acids (EAAs) in epileptogenesis and seizure-induced brain damage, EAA antagonists are now being considered as possible therapy for seizures. However, during development EAAs play a pivotal role in learning, memory and brain plasticity. To evaluate the long-term effects of a short course of EAA antagonists on the developing brain, a non-NMDA antagonist, NBQX, or NMDA antagonist, MK-801, were administered over 7 days by osmotic pumps stereotaxically implanted into the lateral ventricles of normal 20 days old rats. Alternatively, 10 and 20 days old rats received a 7 day course of intraperitoneal (ip) NBQX. One month later, the NBQX, MK-801-treated rats, and controls underwent a series of behavioral studies: handling test, open field, and Morris water maze. Flurothyl inhalation was used to test seizure susceptibility in all groups. Although all of the rats ffeated with NBQX via osmotic pumps had spontaneous seizures, rats surviving infusion of EAAs had no deficits in learning, memory, or behavior and did not differ from controls in seizure susceptibility with flurothyl. In the developing animal, a short term course of EAA antagonists leads to no long-term adverse effects.