Excitatory amino acid neurotoxicity--a broader horizon for cerebral protection?
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Brain↗
Biomedical subjects
R C Tasker
Publications and source records attributed to R C Tasker.
The regional vulnerability to hypoglycemia-induced neurotoxicity in organotypic hippocampal culture: protection by early tetrodotoxin or delayed MK-801.
Profound hypoglycemia selectively damages CA1 and the dentate gyrus of the hippocampus. We have examined the time course of hippocampal neuronal injury in organotypic cultures following in vitro "hypoglycemia," using the fluorescent vital dye propidium iodide to observe directly the regional distribution of early neuronal membrane injury in living cultures. The in vivo hippocampal pattern of hypoglycemic injury was reproduced by a 2 hr exposure to glucose-free media, which resulted in simultaneous, selective propidium staining of CA1 and the dentate gyrus starting by 4 hr after exposure. After 24 hr of recovery, CA3 remained spared. A similar pattern of propidium staining was produced by incubation of cultures for briefer periods in glucose-free medium containing 5 mM 2-deoxyglucose (2-DG) to inhibit glycolysis. This "hypoglycemic" pattern and time course of neuronal injury was mimicked by 300 microM aspartate but not by glutamate. The NMDA receptor antagonists MK-801 and CPP, but not the relatively selective non-NMDA receptor antagonist 6-cyano-7-dinitroquinoxaline-2,3-dione, prevented the development of propidium staining. MK-801 protected against injury even if added to the recovery media 30 min after the insult, while TTX (10 microM) protected only if added by the end of the exposure. The appearance of propidium staining after 4-6 hr of recovery was well correlated with histological observation of pyknotic neuronal nuclei in the injured regions. The characteristic hippocampal regional vulnerability of CA1 and the dentate gyrus to injury following profound hypoglycemia can be reproduced in organotypic hippocampal culture and appears to be mediated both by an early TTX-sensitive component and by a more prolonged period of toxic NMDA receptor activation, extending for at least 30 min into the recovery period.
Animals↗
Direct observation of the agonist-specific regional vulnerability to glutamate, NMDA, and kainate neurotoxicity in organotypic hippocampal cultures.
Excessive activation of excitatory amino acid receptors has been implicated in the neuronal degeneration caused by ischemia, hypoglycemia, and prolonged seizures. We have observed directly the time course and regional vulnerability of hippocampal neurons to glutamate receptor-mediated injury in organotypic hippocampal cultures, a preparation which combines accessibility and long-term survival with preservation of regional differentiation and neuroanatomic organization. Cultures were incubated with the fluorescent dye propidium iodide which selectively enters and stains cells only after membrane damage. After 5 to 10 min of a 30-min exposure to kainate (100 microM), large neurons in the hilus of the dentate were first to become brightly fluorescent. Propidium staining subsequently appeared in the other regions of the hippocampus and increased to a maximum over the first 6 h of recovery. NMDA (10 microM) caused propidium staining that was limited to CA1 and the dentate gyrus of the cultures, sparing CA3, consistent with the regions of highest NMDA receptor density in vivo. Glutamate (1 mM) caused a delayed, progressive pattern of staining that began in CA1 (2 to 4 h after exposure), then extended to include CA3 and finally the dentate gyrus over the next 24 h. Release of LDH activity into the media was slower and less sensitive than propidium staining. Histologic degeneration was limited to neurons 24 h after agonist exposure and was consistent with the propidium staining. NMDA, kainate, and glutamate each produced a unique pattern of neuronal injury. Most notably, glutamate had low potency as a toxin and its pattern of neuronal injury was not reproduced by NMDA.
Animals↗
Cerebral intraparenchymal pressure monitoring in non-traumatic coma: clinical evaluation of a new fibreoptic device.
Initial reporting and validation of the Camino miniaturised fibreoptic cerebral intraparenchymal pressure monitoring device has indicated that this tip transducing system (a) allows direct measurement of brain tissue pressure, (b) has a rapid response rate to intracranial changes and (c) correlates well with intraventricular pressure. However, there are no specific reports of this form of monitoring during non-traumatic coma in children, or any evaluation of change in clinical practice when compared with experience of other forms of invasive intracranial pressure monitoring. Over a 5-year-period (1985-1989) on the General Paediatric Intensive Care Unit, 74 children with presumed raised intracranial pressure complicating non-traumatic coma have had invasive intracranial pressure monitoring with a variety of devices. An intraventricular catheter was used in 16 patients, a subdural catheter in 6 patients, a subarachnoid screw in 35 patients and a fibreoptic intraparenchymal catheter in 17 patients. In 1985 to 1986 our preferred technique was the subarachnoid screw (33/49 patients monitored). Between 1987 and 1989 we have mainly used the Camino fibreoptic intraparenchymal monitoring system (17/25 patients monitored). In the whole series there were no cases of acute haemorrhage related to monitoring and only one patient developed infection and in this child an intraventricular catheter was used. The experience with the fibreoptic system has been favourable and the technique for insertion does not require additional expertise in comparison with standard subarachnoid screw pressure monitoring. Therefore in young children with raised intracranial pressure complicating non-traumatic coma, cerebral fibreoptic intraparenchymal pressure monitoring should be used in preference to standard subarachnoid screw pressure monitoring.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
The clinical significance of seizures in critically ill young infants requiring intensive care.
The aetiology, severity of systemic and biochemical abnormalities, seizure duration, EEGs and CT scans have been reviewed in previously normal young infants with an acute critical illness occurring after the first week of life; none of whom had birth asphyxia. Findings were related to outcome in an attempt to evaluate the significance of seizures during the acute phase of severe illness. In three years seizures occurred in 54/251 (22%) young infants requiring ventilatory support. In these patients the acute illness was most commonly infection and encephalitis/encephalopathy. Twenty-one died, 24 had good or moderate outcome and 9 poor outcome (follow-up 6-27 months). The outcome was not directly related to diagnosis, but to systemic and biochemical changes, the most important being severe hypotension (40/54). After correction of these factors, in survivors, increasing number of days over which seizures occurred during the acute phase of illness was related to worsening outcome (tau(c) = 0.66, p less than 0.0001). In many of these patients one of three abnormal low density changes (generalized, boundary zone and focal) were seen on CT scan and were not uncommonly associated with focal/multifocal clonic seizures and characteristic type, distribution and evolution of EEG discharge. In the 45 patients with EEGs from presentation, severity of encephalopathy assessed by predominant background EEG activity was most closely related to outcome, irrespective of aetiology and seizures. There was a significant relationship between graded severity of background EEG activities and outcome both in the initial and serial recordings (tauB = 0.70, p less than 0.0001 and 0.75, p less than 0.0001 respectively). Seizures are a common occurrence in the previously well young infant with an acute critical illness necessitating intensive care. Prompt recognition and treatment may influence outcome in patients with a potentially reversible encephalopathy. However, in many patients seizures reflect severe, often multifactorial cerebral insult with variable morphological changes, EEG patterns and clinical outcome.
Anticonvulsants↗
The cerebral function analysing monitor in paediatric medical intensive care: applications and limitations.
Practical guidelines for continuous single channel EEG monitoring using the Cerebral Function Analysing Monitor (CFAM) have been outlined based on experience of 54 critically ill comatose and/or paralysed sedated children monitored for up to 9 days during the acute phase of illness. Fall in amplitude and slowing of frequency following either a cerebral insult or barbiturate administration as well as paroxysmal events were readily recognisable in the CFAM traces. Such changes could be used to (1) identify effects of cerebral insults (acute or cumulative), (2) recognise unstable patients exquisitely sensitive to aspects of standard care and (3) evaluate seizure control. Despite these useful contributions to clinical care, significant limitations were apparent. It is recommended that CFAM monitoring should be combined with serial conventional EEG recording in order to check the appropriateness of the cortical areas being monitored, the quality and type of signal being processed as well as the significance of the 1 or 2 channel CFAM findings in relation to global cerebral function.
Adolescent↗
Computed tomography in the assessment of raised intracranial pressure in non-traumatic coma.
Cranial computed tomography (CT) scans and invasive intracranial pressure (ICP) measurements were reviewed for 34 children with non-traumatic coma from various causes. CT scan features including focal or generalised changes in density were noted and changes in cerebrospinal fluid (CSF) spaces were graded and correlated with the level of maximum ICP in the first 12 hours of treatment and monitoring. Seven patients had normal findings and 27 had abnormal scans. Nineteen of the 27 patients with abnormal scans had generalised abnormalities with varying degrees of loss of CSF space. Seventeen of these 19 patients had pressures greater than 15 mmHg. The highest pressures being found in those with the greatest degree of CSF space obliteration. In the remaining 8 patients, who had focal abnormalities either within the basal ganglia or cerebral hemisphere, there was no relationship between local CSF space obliteration and the level of ICP. In the 7 patients with normal scans three had ICPs of 20 mmHg or greater in the first 12 hours of monitoring and a further two also developed an ICP of this level 13-36 hours after the initiation of monitoring. In non-traumatic coma of various causes there is an association between loss of CSF space and increased ICP. However, there were two important exceptions to this; firstly in patients with focal abnormalities either within the basal ganglia or cerebral hemisphere, in whom the loss of adjacent CSF spaces was not a good indicator of generalised raised ICP; secondly some patients with normal scans, in whom this finding did not indicate normal ICP nor ensure that it remained at this level.
Adolescent↗
Intracranial pressure monitoring following hypoxic-ischaemic cerebral insults.
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Child↗
EEG monitoring of prolonged thiopentone administration for intractable seizures and status epilepticus in infants and young children.
Thiopentone anaesthesia was used in the treatment of seizures in 19 infants and young children. Nine had a pre-existing seizure disorder without acute cerebral injury and 10 had status epilepticus secondary to an acute cerebral illness. Clinical details, drug levels and findings from serial multichannel electroencephalograms (EEG) and continuous 1 to 2 channel signal processed EEGs using a Cerebral Function Analysing Monitor (CFAM) were reviewed to evaluate the contribution of these techniques to clinical management. Initial EEGs showed discharges that were not generalised in 16/19 patients. This necessitated the use of 7 different montages for continuous monitoring. Three different CFAM patterns representing particular EEG paroxysmal findings were seen. Acute seizure control was achieved in all 19 patients. All patients with a pre-existing seizure disorder survived, although 4/10 with an acute cerebral illness died. During treatment, patterns of burst-suppression to electrocerebral silence (ECS) were eventually seen in 16/19 patients and repeat EEGs demonstrated concordant multi-channel findings in 8/8. Although increasing thiopentone levels (13 patients) correlated with deeper suppression of cortical electrical activity, there was marked inter-patient variability. Inotropic support was not required during the period of treatment even when ECS was induced. In young children a combination of multi-channel EEG and continuous 1 to 2 channel monitoring has advantages over either method used alone. In individual patients on-line monitoring can be easily incorporated in a protocol of controlled cortical suppression and drug titration for seizure control.
Child, Preschool↗
Monitoring in non-traumatic coma. Part I: Invasive intracranial measurements.
The arterial blood pressure, intracranial pressure, and organ system failure scores were reviewed for 49 infants and children with non-traumatic coma from various causes. The neurological outcome was good in 21 patients, moderate in five, and poor in 23. There was no significant difference in maximum intracranial pressures between patients with a good outcome and those with a poor one, but patients with a poor outcome had significantly lower minimum cerebral perfusion pressures. During the period of admission 18 patients had cardiovascular failure, none had renal failure, and two developed severe coagulopathy. Seventeen of the 19 patients in whom at least one of these systems failed died. Our findings emphasise the diversity of illnesses associated with raised intracranial pressure in children and the number who develop multiple organ failure, and the values and limitations of using minimum cerebral perfusion pressure and the organ system failure scores as guides to severity of illness and prognosis.
Acute Disease↗
Monitoring in non-traumatic coma. Part II: Electroencephalography.
Forty eight comatose children had electroencephalograms (EEG) recorded during the acute phase of their illnesses. These were classified according to a simple grading system and the findings correlated with the presence of seizures, deep coma, minimum cerebral perfusion pressure, and eventual neurological outcome. Serial EEGs proved important, particularly when slow activity was seen initially. None of the 20 patients who showed low amplitude EEG activity or electrocerebral silence at any stage of the acute illness did well. Discharges were seen in only 13 of the 29 patients with seizures and their presence did not correlate with outcome except in five patients with a distinctive pattern of discharges, none of whom had a good outcome. EEG findings associated with poor outcome did not always correlate with the clinical assessment of deep coma, emphasising the difficulties of neurological evaluation in these patients. Five of the patients with cerebral perfusion pressures greater than 42 mm Hg had a poor outcome that was predicted by serial EEGs. In nine patients with a minimum cerebral perfusion pressure in the borderline range 38-42 mm Hg the EEG was useful as an indication of the outcome. The EEG reflects changes in cerebral function which may be due to multifactorial or repeated insults. An EEG is therefore important in both the initial assessment and as an indicator of the neurological outcome, particularly in those patients in whom the cerebral perfusion pressure has apparently been adequate or within the borderline range.
Acute Disease↗
Absent aortic valve leaflets.
A newborn with difficulty in feeding and with tachypnoea was admitted to the hospital. During the following days his condition deteriorated and he died at the age of 8 days. At autopsy we found an unusual association of hypoplastic left heart syndrome and absence of the aortic leaflets.
Aortic Valve↗