Is the Cure Worse 1 than the Disease? Caveats in the Move from Laboratow to Clinic I
THE explosion of knowledge of the mechanisms of hypoxic-ischaemic neuronal death to a large extent has been based on the use of pharmacological probes to dissect pathways initiated by the insult. Because in many experimental approaches significant neuronal protection has been obtained, clinicians naturally have wished to apply this knowledge rapidly, particularly in the neonatal period. However, caveats that must be placed on the interpretation of many of these experiments. Many of the models used d o not replicate pathophysiological situations encountered clinically, and often the potential side-effects and/or interactions have been inadequately considered. Because knowledge is expanding rapidly and because practical approaches to neuronal rescue are on the horizon, it is useful to consider these caveats in some depth. The design of clinical trials and the selection of rescue approaches must be based on a detailed understanding of the issues. This discussion will focus on the potential use of neural rescue therapies in the neonate after presumed hypoxic encephalopathy. The majority of mechanistic studies of neuronal asphyxia have been performed either in vitro using, for example, hippocampal slices, or in vivo in rats or gerbils using either global asphyxial or focal ischaemic preparations. Relatively few studies have been performed on the immature brain. The most common method has been to administer the putative protective agent immediately before the insult. In contrast, neural rescue therapies will be applied after the insult and generally there will be a delay of some hours before their use can be considered. This in itself is not unrealistic for, as
discussed elsewhere, it is now clear that many neurons die well after the insult' and the cascades of events initiated by asphyxia can be blocked* However, the issue of timing is critical. A number of therapies which have been shown to be effective when given before the insult are not effective when given after the insult, and vice versa. It is unfortunate that few experimental studies actually address this critical issue of timing. For example flunarazine, a calcium channel blocker with neuroprotective properties, is effective in reducing neuronal loss when given before a hypoxicischaemic insult in infant rat^^,^, but is totally ineffective when given after the insult'. Further, as will be discussed below, postasphyxial use of a calcium channel blocker following a global insult is likely to lead to cardiovascular compromise'. We have found that central insulin-like growth factor 1 (IGF-I) is neuroprotective when given after an insult during the depressive phase4, but not before'. Conversely, the N-methyl Dasparate (NMDA) channel blocker MKSOI can adversely affect outcome when given before a global asphyxial insult, but can reduce seizure-related damage when given in low doses during the hyperexcitability phase2. It is essential, therefore, that the clinician assesses what is known about the effectiveness of a potential therapy in temporal relationship to the insult. It follows that the initial evaluation of the therapy must be of infants in whom the phasing is definable-is the infant in the postasphyxial depressive phase, the secondary hyperexcitability phase, etc. A range of hypoxic-ischaemic encephalopathies are seen in the developing brain: these different patterns of damage are influenced by the nature of the insult. Similarly, the predominant mechanisms of damage-and thus the efficacy of specific therapies-depend on the severity and nature of the primary injury, and clinical trials must be appropriately designed. After ischaemic episodes of up to 30 minutes, many neurons recover membrane function but some subsequently degenerate hours later: in contrast, after 40 or more minutes of total ischaemia, many neurons fail to recover membrane function". Rescue therapies are unlikely
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to benefit these acutely damaged cells. During prolonged focal stroke-like injuries, there is a volume of marginally perfused cells around the dense ischaemic core. Treatments that maintain viability of this population of cells do not. necessarily protect or prevent the degeneration of cells during or after brief global injuries that are likely to occur during asphyxial episodes. For example while NMDA receptor antagonists such as MK801 are neuroprotective during prolonged focal stroke-like injuries, they fail to show consistent benefits when given before transient global injuries". Similarly, hyperglycaemia is beneficial during focal stroke-like insultsI2, but can exacerbate the damage resulting from global insult^'^. In contrast, gangliosides can protect neurons when give before or soon after a global i n s ~ l t ' ~or , during stroke-like injuries". The subgroups of infants selected for trials of neuroprotective therapies will need to be carefully and rapidly identified to ensure that they are likely to benefit from treatment. Of particular concern is that many potential agents have been tested only in adult animals or in focal ischaemic models and the potential role of sensitising factors such as growth retardation has not been considered. Failure to consider these issues can lead to unfortunate clinical decisions. For example while kainic acid (KA) receptor blockade is neuroprotective in the mature brain, there are few KA receptors in the immature brain16. Intrauterine growth retardation (IUGR) is associated with a high risk of perinatal asphyxial encephal~pathy''-'~.Such infants have altered metabolic and endocrine profiles and a disordered cardiovascular system. Further, most insults in the perinatal period produce global asphyxiai.e. the heart as well as the brain is asphyxiated. These issues are directly relevant to the use of neural rescue therapies. For example calcium channel blockers are cardiac depressant and the developing heart is especially susceptible. While we found a low dose of flunarazine therapy given before an insult to be protective against asphyxial injury in the fetal lamb, at higher doses it was not protective because the associated hypotension
aggravated the severity of the insult. Further, when given to growth-retarded fetal lambs it was universally fatal because of severe cardiac depression'. It is reasonable to deduce that a calcium channel antagonist given after a global asphyxial insult will cause cardiac depression, and indeed the limited clinical experience confirms this2'. Any systematic therapy to be given after an insult must be tested experimentally in situations that test these considerations, and in particular consider cardiovascular effects. It is widely known that hypothermia is neuroprotective, and cooling the brain by as little as 2"c can improve outcome2'. Since the brain tends to cool after hypoxic-ischaemic injury, it is conceivable that some efforts to maintain body temperature may interfere with this response and worsen outcome. Similarly, although many consider that acidosis is detrimental, some have shown that mild acidosis can protect neurons against hypoxic-ischaemic injury, at least in vitro '2. Many putative rescue agents have potent neurophysiological effects, yet most outcomes reported have been based on short-term recovery (in some cases only for minutes!) and not in terms of long-term neural outcome. For example there is evidence that electrical activity, or perhaps even seizures, is desirable for functional recovery2', so excessive use of some anti-excitatory agents may interfere with CNS developmentz4 or the plasticity or reorganisation that occurs after injury". Long-term recovery experiments are essential before potent neuroactive substances are used. Several studies have suggested a cocktail approach to neural rescue. For example the combined use in animals of an antioedema agent, a calcium-channel blocker and a free radical scavenger has been reported26. If neural loss is indeed the consequence of several coincident processes, such an approach may be logical. However, it is essential to investigate fully the potential for interaction across the pathophysiological spectrum. We recently evaluated the potential of combining calcium channel blockade with NMDA receptor antagonism in hypoxic-ischaemic rats: this proved to be a toxic interaction, with rapid presumed cardiovascular collapse.
The above selected examples serve to demonstrate a number of principles that are not always obvious in extrapolating from animal to human study. It is crucial to be able to identify rapidly the subgroups of infants in terms of both nature and severity of injury who are most likely to benefit from treatment. The dimension of time is a key factor: it is inappropriate to enter clinical trials with treatments that have not been evaluated with respect to this dimension. The importance of considering effects on the heart after global asphyxia! episodes is apparent, as is the need to consider studies of preparations in which the basal state may be compromised, for example by IUGR. Potential interactions with other drugs must not be ignored. It is understandable that clinicians feel a considerable sense of urgency to commence clinical trials with putative neuroprotective agents. However, the animal experience t o date suggests that any such agent must meet rigorous criteria before clinical trials are considered.
PETERD. GLUCKMAN, M.B., Ch.B., D.Sc., F.R.S.(NZ)
CHRISTOPHER E. WILLIAMS, Ph.D.
Department of Paediatrics, University of Auckland, Private Bag, Auckland, New Zealand. References 1. Massarweh, W., Vinters, H., Schwartz, P., Dwyer, B. E., Fujikawa, D., Wasterlain, C. G. (1987) ‘Delayed neuronal necrosis in neonatal hypoxia-ischaemia.’ Society for Neuroscience Abstracts. 13, 10. 2. Tan, K. M. W., Williams, C. E., Gunn, A. J., Mallard, E. C., Gluckman, P. D. (1992) ‘Suppression of post-ischemic epileptiform activity with MK-801 improves neural outcome in fetal sheep.’ Annals of Neurology (in press). 3. Andine, P., Lehmann, A., Ellren, K., Wennberg, E., Kjellmer, I., Nielsen, T., Hagberg, H . (1988) ‘The excitatory amino acid antagonist kyneurenic acid administered after hypoxic-ischemia in neonatal rats offers neuroprotection.’ Neuroscience Letters, 90, 208-zit. 4. Gluckrnan, P. D., Klempt, N . D., Guan, J.,
Mallard, E. C., Sirmanne, E., Dragunow, M., Sinah. K.. KlemDt. M.. Williams. C. E.. NiLolics, K. (199i) “A role for IGF-I in the rescue of CNS neurons following hypoxicischemic injury.’ Biochemical and Biophysical Research Communications, 182, 593-599. 5. Silverstein, F. S., Buchanan, K., Hudson, C., Johnston, M. V. (1986) ‘Flunarizine limits
hypoxia-ischemia induced morphologic injury in immature rat brain.’ Stroke, 17, 477-482. Gunn, A. J . , Mydlar, T., Bennet, L., Faull, R., Gorter, S., Cook, C. J., Johnston, B. M., Gluckman, P. D. (1989) ‘The neuroprotective actions of a calcium channel antagonist, flunarizine, in the infant rat.’ Pediatric Research, 25, 573-576. Gunn, A. J . , Gluckman, P. D. (1991) ‘Flunarizine, a calcium channel antagonist, is not neuroprotective when given after hypoxiaischemia in the infant rat.’ Developmental Pharmacology and Therapeutics, 17,205-209. Gunn. A. J., Mallard, E. C., Williams, C. E., Gluckman, P. D. (1992) ‘Effects of flunarizine therapy in cerebral ischemia in the fetal sheep.’ Pediatric Research (in press). Guan, J., Williams, C. E., Mallard, C., G u m , A., Gluckman, P. D. (1992) ‘Effect of intraventricular (IVC) administration of IGF-I on secondary neuronal loss following transient hypoxic-ischemic (IH) brain injury in adult rats.’ Annual Meeting of the New Zealand Endocrinological Society. (Abstract.) 10. Williams, C. E., Gunn, A. J., Gluckman, P. D. (1991) ‘Time course of intracellular edema and epileptiform activity following prenatal cerebral ischemia in sheep.’ Stroke, 22, 516-521. 1 1 . Choi, D. W . (1990) ‘Cerebral hypoxia: some new approaches and unanswered questions.’ Journal of Neuroscience, 10, 2493-2501. 12. Kraft, S. A., Larson, C. P., Shuer, L. M., Steinberg, G. K., Benson, G. V., Pearl, R. G. (1990) ‘Effect of hyperglycemia on neuronal changes in a rabbit model of focal cerebral ischemia.’ Stroke, 21, 447-450. 13. Warner, D. S., Smith, M. L., Siesjo, B. K. (1987) ‘Ischemia in normo- and hyperglycemic rats: effects on brain water and electrolytes.’ Stroke, 18, 464-471. 14. Serens, M. S., Rubini, R., Lauaro, A., Zanoni, R., Fiori, M. G., Leon, A. (1991) ‘Protective effects of a monosialoganglioside derivative following transitory forebrain ischemia in rats.’ Stroke, 21, 1607-1612. 15. Rotondo, G., Maniero, G., Toffano, G. (1990) ‘New perspectives in the treatment of hypoxic and ischemic brain damage: effect of gangliosides.’ Aviation, Space and Environmental Medicine, 61, 162-164. 16. McDonald, J . W., Johnston, M. (1990) ‘Physiological and pathophysiological roles of excitatory amino acids during central nervous system development.’ Brain Research Reviews, ’ 15,41-70. 17. Bauer, R., Zwiener, U.,Buchenau, W., Hoyer, D., Witte, H., Lampe, V., Burgold, K., Zeiger, M. (1989) ‘Restricted cardiovascular and cerebral performance in intra-uterine growth retarded newborn piglets during severe hypoxia.’ Biomedica et Biochimica Acta, 48, 697-705. 18. Soothill, P. W., Nicolaides, K. H., Campbell, S. (1987) ‘Prenatal asphyxia, hyperlactemia, hypoglycemia and erythroblastosis in growth retarded fetuses.’ British Medical Journal,
294, 1051-1053. 19. Thordstein, M., Kjellmer, 1. (1988) ‘Cerebral tolerance of hypoxia in growth-retarded and approximately grown newborn guinea pigs.’ ‘ Pediatric Research, 24, 633-638. 20. Levene, M. I., Gibson, N. A., Fenton, A. C., Papathoma, E., Barnett, D. (1990) ‘The use of calcium channel blocker, nicardipine, for severely asphyxiated newborn infants.’
-s
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Developmental Medicine and Child Neurology, 32, 567-574. 21. Busto, R., Dietrich, W. D., Globus, M. Y., Valdes, I . , Schejuberg, P., Gunsberg, M. D. (1987) 'Small differences in intraischemic brain temperature critically determine the extent o f ischemic neuronal injury.' Journal of Cerebral Blood Flow and Metabolism, 7, 729-738. 22. Giffard, R. G . , Monyer, H., Christine, C. W., Choi, D. W. (1990) 'Acidosis reduces NMDA receptor activation, glutamate neurotoxicity, and oxwen-ducose demivation neuronal injury in corfical cultures.' Brain Research, 506, 339-342. 23. Schallert. T . , Hernandez, T., Bath, T. M. (1986) 'Recovery of function after brain damage: severe and chronic disruption by
h
Mahagement of Epilepsy THEabolition of seizures without adverse
1018
effects is the most important goal in the treatment of epilepsy. Recognition of seizure types' and epileptic syndromes' is an essential component of both the choice of the appropriate anti-epileptic drug(s) (AED) and the calculation of the risk of recurrence should plans be made for the AED to be withdrawn after a period of freedom from seizure^^.^. After the initial seizure, the risk of recurrence of absence, atonic, atypical absence and myoclonic seizures, and of infantile spasms, is virtually 100 per cent, so it is simple to make a positive decision to introduce an AED at the time of diagnosis. For other seizure types, however, deciding when to start treatment may be more difficult. Persistent seizures are associated with loss of intellectual activity'. Delay in the institution of AEDs can be associated with greater difficulties in subsequent c ~ n t r o l ~ . ~ *but ' , introducing an AED after a first seizure does not necessarily prevent a recurrence'. The cumulative risks of recurrence have been variously computed to be 69 per cent if a non-febrile seizure occurs before the age of seven years'; 42 per cent over-all, but 60 per cent by three years if there is a 'remote symptomatic' aetiology''; and 52
diazepam.' Brain Research, 379, 104-1 I I . 24. Gorier, J . A., Veerman, M., Mirmiran, M., Bos, N. P., Corner, M. A. (1991) 'Spectral analysis of the electroencephalogram in neonatal rats chronically treated with the NMDA antagonist MK-801.' Developmental Brain Research, 64, 37-41. 25. Barth, T., Grant, M. L., Schallert, T. (1990) 'Effects of MK-801 on recovery from sensorimotor cortex lesions.' Stroke, 21 (Suppl. 3). 153-157.
26. Thiringer, K . , Hrbek, A . , Karlsson, K . , Rosen, K . , Kjellmer, I . (1987) 'Postasphyxial cerebral survival in newborn sheep after treatment with oxygen free radical scavengers and a calcium antagonist.' Pedialric Researcfi, 221, 62-66.
per cent if absence, akinetic and atonic seizures and infantile spasms are excluded'. 79 per cent of children having one recurrence will have further episodes'. There might be some justification for starting an AED after an initial seizure if there are abnormal neurological signs and/or epileptiform discharges on the EEG*>'O, but with few exceptions an AED is definitely indicated after the second unprovoked seizure. The exceptions are benign partial epijepsy with centrotemporal spikes, for which an AED is not essential"; and purely photosensitive seizures, where treatment by actual or functional occlusion of the vision to one eye during provocation can abolish the tendency to attacksI2. Drugs can be given continuously or intermittently during exacerbations of seizures. Intermittent diazepam (DZM) can be used as the sole drug for prophylaxis of febrile seizures, but only if there is apparent inefficacy of all drugs used for chronic therapy would intermittent DZM be considered as the sole AED for recurrent unprovoked seizures. Home-use of DZM has been established in the treatment of break-through serial and prolonged seizures in children on maintenance AEDS, resulting in very significant reductions in the use of emergency-room services and improvements in social a d j ~ s t m e n t ' ~Intermittent . DZM can also be very effective in the treatment of nonconvulsive status epilepticu~'~. Approximately 80 per cent of patients placed on chronic therapy will respond to a single AED, if used to maximum benefit',
THE explosion of knowledge of the mechanisms of hypoxic-ischaemic neuronal death to a large extent has been based on the use of pharmacological probes to dissect pathways initiated by the insult. Because in many experimental approaches significant neuronal protection has been obtained, clinicians naturally have wished to apply this knowledge rapidly, particularly in the neonatal period. However, caveats that must be placed on the interpretation of many of these experiments. Many of the models used d o not replicate pathophysiological situations encountered clinically, and often the potential side-effects and/or interactions have been inadequately considered. Because knowledge is expanding rapidly and because practical approaches to neuronal rescue are on the horizon, it is useful to consider these caveats in some depth. The design of clinical trials and the selection of rescue approaches must be based on a detailed understanding of the issues. This discussion will focus on the potential use of neural rescue therapies in the neonate after presumed hypoxic encephalopathy. The majority of mechanistic studies of neuronal asphyxia have been performed either in vitro using, for example, hippocampal slices, or in vivo in rats or gerbils using either global asphyxial or focal ischaemic preparations. Relatively few studies have been performed on the immature brain. The most common method has been to administer the putative protective agent immediately before the insult. In contrast, neural rescue therapies will be applied after the insult and generally there will be a delay of some hours before their use can be considered. This in itself is not unrealistic for, as
discussed elsewhere, it is now clear that many neurons die well after the insult' and the cascades of events initiated by asphyxia can be blocked* However, the issue of timing is critical. A number of therapies which have been shown to be effective when given before the insult are not effective when given after the insult, and vice versa. It is unfortunate that few experimental studies actually address this critical issue of timing. For example flunarazine, a calcium channel blocker with neuroprotective properties, is effective in reducing neuronal loss when given before a hypoxicischaemic insult in infant rat^^,^, but is totally ineffective when given after the insult'. Further, as will be discussed below, postasphyxial use of a calcium channel blocker following a global insult is likely to lead to cardiovascular compromise'. We have found that central insulin-like growth factor 1 (IGF-I) is neuroprotective when given after an insult during the depressive phase4, but not before'. Conversely, the N-methyl Dasparate (NMDA) channel blocker MKSOI can adversely affect outcome when given before a global asphyxial insult, but can reduce seizure-related damage when given in low doses during the hyperexcitability phase2. It is essential, therefore, that the clinician assesses what is known about the effectiveness of a potential therapy in temporal relationship to the insult. It follows that the initial evaluation of the therapy must be of infants in whom the phasing is definable-is the infant in the postasphyxial depressive phase, the secondary hyperexcitability phase, etc. A range of hypoxic-ischaemic encephalopathies are seen in the developing brain: these different patterns of damage are influenced by the nature of the insult. Similarly, the predominant mechanisms of damage-and thus the efficacy of specific therapies-depend on the severity and nature of the primary injury, and clinical trials must be appropriately designed. After ischaemic episodes of up to 30 minutes, many neurons recover membrane function but some subsequently degenerate hours later: in contrast, after 40 or more minutes of total ischaemia, many neurons fail to recover membrane function". Rescue therapies are unlikely
i
m
N-
ot
Q'
h
B
1015
v)
C
.-0 .d
m
.d
C
4
1016
to benefit these acutely damaged cells. During prolonged focal stroke-like injuries, there is a volume of marginally perfused cells around the dense ischaemic core. Treatments that maintain viability of this population of cells do not. necessarily protect or prevent the degeneration of cells during or after brief global injuries that are likely to occur during asphyxial episodes. For example while NMDA receptor antagonists such as MK801 are neuroprotective during prolonged focal stroke-like injuries, they fail to show consistent benefits when given before transient global injuries". Similarly, hyperglycaemia is beneficial during focal stroke-like insultsI2, but can exacerbate the damage resulting from global insult^'^. In contrast, gangliosides can protect neurons when give before or soon after a global i n s ~ l t ' ~or , during stroke-like injuries". The subgroups of infants selected for trials of neuroprotective therapies will need to be carefully and rapidly identified to ensure that they are likely to benefit from treatment. Of particular concern is that many potential agents have been tested only in adult animals or in focal ischaemic models and the potential role of sensitising factors such as growth retardation has not been considered. Failure to consider these issues can lead to unfortunate clinical decisions. For example while kainic acid (KA) receptor blockade is neuroprotective in the mature brain, there are few KA receptors in the immature brain16. Intrauterine growth retardation (IUGR) is associated with a high risk of perinatal asphyxial encephal~pathy''-'~.Such infants have altered metabolic and endocrine profiles and a disordered cardiovascular system. Further, most insults in the perinatal period produce global asphyxiai.e. the heart as well as the brain is asphyxiated. These issues are directly relevant to the use of neural rescue therapies. For example calcium channel blockers are cardiac depressant and the developing heart is especially susceptible. While we found a low dose of flunarazine therapy given before an insult to be protective against asphyxial injury in the fetal lamb, at higher doses it was not protective because the associated hypotension
aggravated the severity of the insult. Further, when given to growth-retarded fetal lambs it was universally fatal because of severe cardiac depression'. It is reasonable to deduce that a calcium channel antagonist given after a global asphyxial insult will cause cardiac depression, and indeed the limited clinical experience confirms this2'. Any systematic therapy to be given after an insult must be tested experimentally in situations that test these considerations, and in particular consider cardiovascular effects. It is widely known that hypothermia is neuroprotective, and cooling the brain by as little as 2"c can improve outcome2'. Since the brain tends to cool after hypoxic-ischaemic injury, it is conceivable that some efforts to maintain body temperature may interfere with this response and worsen outcome. Similarly, although many consider that acidosis is detrimental, some have shown that mild acidosis can protect neurons against hypoxic-ischaemic injury, at least in vitro '2. Many putative rescue agents have potent neurophysiological effects, yet most outcomes reported have been based on short-term recovery (in some cases only for minutes!) and not in terms of long-term neural outcome. For example there is evidence that electrical activity, or perhaps even seizures, is desirable for functional recovery2', so excessive use of some anti-excitatory agents may interfere with CNS developmentz4 or the plasticity or reorganisation that occurs after injury". Long-term recovery experiments are essential before potent neuroactive substances are used. Several studies have suggested a cocktail approach to neural rescue. For example the combined use in animals of an antioedema agent, a calcium-channel blocker and a free radical scavenger has been reported26. If neural loss is indeed the consequence of several coincident processes, such an approach may be logical. However, it is essential to investigate fully the potential for interaction across the pathophysiological spectrum. We recently evaluated the potential of combining calcium channel blockade with NMDA receptor antagonism in hypoxic-ischaemic rats: this proved to be a toxic interaction, with rapid presumed cardiovascular collapse.
The above selected examples serve to demonstrate a number of principles that are not always obvious in extrapolating from animal to human study. It is crucial to be able to identify rapidly the subgroups of infants in terms of both nature and severity of injury who are most likely to benefit from treatment. The dimension of time is a key factor: it is inappropriate to enter clinical trials with treatments that have not been evaluated with respect to this dimension. The importance of considering effects on the heart after global asphyxia! episodes is apparent, as is the need to consider studies of preparations in which the basal state may be compromised, for example by IUGR. Potential interactions with other drugs must not be ignored. It is understandable that clinicians feel a considerable sense of urgency to commence clinical trials with putative neuroprotective agents. However, the animal experience t o date suggests that any such agent must meet rigorous criteria before clinical trials are considered.
PETERD. GLUCKMAN, M.B., Ch.B., D.Sc., F.R.S.(NZ)
CHRISTOPHER E. WILLIAMS, Ph.D.
Department of Paediatrics, University of Auckland, Private Bag, Auckland, New Zealand. References 1. Massarweh, W., Vinters, H., Schwartz, P., Dwyer, B. E., Fujikawa, D., Wasterlain, C. G. (1987) ‘Delayed neuronal necrosis in neonatal hypoxia-ischaemia.’ Society for Neuroscience Abstracts. 13, 10. 2. Tan, K. M. W., Williams, C. E., Gunn, A. J., Mallard, E. C., Gluckman, P. D. (1992) ‘Suppression of post-ischemic epileptiform activity with MK-801 improves neural outcome in fetal sheep.’ Annals of Neurology (in press). 3. Andine, P., Lehmann, A., Ellren, K., Wennberg, E., Kjellmer, I., Nielsen, T., Hagberg, H . (1988) ‘The excitatory amino acid antagonist kyneurenic acid administered after hypoxic-ischemia in neonatal rats offers neuroprotection.’ Neuroscience Letters, 90, 208-zit. 4. Gluckrnan, P. D., Klempt, N . D., Guan, J.,
Mallard, E. C., Sirmanne, E., Dragunow, M., Sinah. K.. KlemDt. M.. Williams. C. E.. NiLolics, K. (199i) “A role for IGF-I in the rescue of CNS neurons following hypoxicischemic injury.’ Biochemical and Biophysical Research Communications, 182, 593-599. 5. Silverstein, F. S., Buchanan, K., Hudson, C., Johnston, M. V. (1986) ‘Flunarizine limits
hypoxia-ischemia induced morphologic injury in immature rat brain.’ Stroke, 17, 477-482. Gunn, A. J . , Mydlar, T., Bennet, L., Faull, R., Gorter, S., Cook, C. J., Johnston, B. M., Gluckman, P. D. (1989) ‘The neuroprotective actions of a calcium channel antagonist, flunarizine, in the infant rat.’ Pediatric Research, 25, 573-576. Gunn, A. J . , Gluckman, P. D. (1991) ‘Flunarizine, a calcium channel antagonist, is not neuroprotective when given after hypoxiaischemia in the infant rat.’ Developmental Pharmacology and Therapeutics, 17,205-209. Gunn. A. J., Mallard, E. C., Williams, C. E., Gluckman, P. D. (1992) ‘Effects of flunarizine therapy in cerebral ischemia in the fetal sheep.’ Pediatric Research (in press). Guan, J., Williams, C. E., Mallard, C., G u m , A., Gluckman, P. D. (1992) ‘Effect of intraventricular (IVC) administration of IGF-I on secondary neuronal loss following transient hypoxic-ischemic (IH) brain injury in adult rats.’ Annual Meeting of the New Zealand Endocrinological Society. (Abstract.) 10. Williams, C. E., Gunn, A. J., Gluckman, P. D. (1991) ‘Time course of intracellular edema and epileptiform activity following prenatal cerebral ischemia in sheep.’ Stroke, 22, 516-521. 1 1 . Choi, D. W . (1990) ‘Cerebral hypoxia: some new approaches and unanswered questions.’ Journal of Neuroscience, 10, 2493-2501. 12. Kraft, S. A., Larson, C. P., Shuer, L. M., Steinberg, G. K., Benson, G. V., Pearl, R. G. (1990) ‘Effect of hyperglycemia on neuronal changes in a rabbit model of focal cerebral ischemia.’ Stroke, 21, 447-450. 13. Warner, D. S., Smith, M. L., Siesjo, B. K. (1987) ‘Ischemia in normo- and hyperglycemic rats: effects on brain water and electrolytes.’ Stroke, 18, 464-471. 14. Serens, M. S., Rubini, R., Lauaro, A., Zanoni, R., Fiori, M. G., Leon, A. (1991) ‘Protective effects of a monosialoganglioside derivative following transitory forebrain ischemia in rats.’ Stroke, 21, 1607-1612. 15. Rotondo, G., Maniero, G., Toffano, G. (1990) ‘New perspectives in the treatment of hypoxic and ischemic brain damage: effect of gangliosides.’ Aviation, Space and Environmental Medicine, 61, 162-164. 16. McDonald, J . W., Johnston, M. (1990) ‘Physiological and pathophysiological roles of excitatory amino acids during central nervous system development.’ Brain Research Reviews, ’ 15,41-70. 17. Bauer, R., Zwiener, U.,Buchenau, W., Hoyer, D., Witte, H., Lampe, V., Burgold, K., Zeiger, M. (1989) ‘Restricted cardiovascular and cerebral performance in intra-uterine growth retarded newborn piglets during severe hypoxia.’ Biomedica et Biochimica Acta, 48, 697-705. 18. Soothill, P. W., Nicolaides, K. H., Campbell, S. (1987) ‘Prenatal asphyxia, hyperlactemia, hypoglycemia and erythroblastosis in growth retarded fetuses.’ British Medical Journal,
294, 1051-1053. 19. Thordstein, M., Kjellmer, 1. (1988) ‘Cerebral tolerance of hypoxia in growth-retarded and approximately grown newborn guinea pigs.’ ‘ Pediatric Research, 24, 633-638. 20. Levene, M. I., Gibson, N. A., Fenton, A. C., Papathoma, E., Barnett, D. (1990) ‘The use of calcium channel blocker, nicardipine, for severely asphyxiated newborn infants.’
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Developmental Medicine and Child Neurology, 32, 567-574. 21. Busto, R., Dietrich, W. D., Globus, M. Y., Valdes, I . , Schejuberg, P., Gunsberg, M. D. (1987) 'Small differences in intraischemic brain temperature critically determine the extent o f ischemic neuronal injury.' Journal of Cerebral Blood Flow and Metabolism, 7, 729-738. 22. Giffard, R. G . , Monyer, H., Christine, C. W., Choi, D. W. (1990) 'Acidosis reduces NMDA receptor activation, glutamate neurotoxicity, and oxwen-ducose demivation neuronal injury in corfical cultures.' Brain Research, 506, 339-342. 23. Schallert. T . , Hernandez, T., Bath, T. M. (1986) 'Recovery of function after brain damage: severe and chronic disruption by
h
Mahagement of Epilepsy THEabolition of seizures without adverse
1018
effects is the most important goal in the treatment of epilepsy. Recognition of seizure types' and epileptic syndromes' is an essential component of both the choice of the appropriate anti-epileptic drug(s) (AED) and the calculation of the risk of recurrence should plans be made for the AED to be withdrawn after a period of freedom from seizure^^.^. After the initial seizure, the risk of recurrence of absence, atonic, atypical absence and myoclonic seizures, and of infantile spasms, is virtually 100 per cent, so it is simple to make a positive decision to introduce an AED at the time of diagnosis. For other seizure types, however, deciding when to start treatment may be more difficult. Persistent seizures are associated with loss of intellectual activity'. Delay in the institution of AEDs can be associated with greater difficulties in subsequent c ~ n t r o l ~ . ~ *but ' , introducing an AED after a first seizure does not necessarily prevent a recurrence'. The cumulative risks of recurrence have been variously computed to be 69 per cent if a non-febrile seizure occurs before the age of seven years'; 42 per cent over-all, but 60 per cent by three years if there is a 'remote symptomatic' aetiology''; and 52
diazepam.' Brain Research, 379, 104-1 I I . 24. Gorier, J . A., Veerman, M., Mirmiran, M., Bos, N. P., Corner, M. A. (1991) 'Spectral analysis of the electroencephalogram in neonatal rats chronically treated with the NMDA antagonist MK-801.' Developmental Brain Research, 64, 37-41. 25. Barth, T., Grant, M. L., Schallert, T. (1990) 'Effects of MK-801 on recovery from sensorimotor cortex lesions.' Stroke, 21 (Suppl. 3). 153-157.
26. Thiringer, K . , Hrbek, A . , Karlsson, K . , Rosen, K . , Kjellmer, I . (1987) 'Postasphyxial cerebral survival in newborn sheep after treatment with oxygen free radical scavengers and a calcium antagonist.' Pedialric Researcfi, 221, 62-66.
per cent if absence, akinetic and atonic seizures and infantile spasms are excluded'. 79 per cent of children having one recurrence will have further episodes'. There might be some justification for starting an AED after an initial seizure if there are abnormal neurological signs and/or epileptiform discharges on the EEG*>'O, but with few exceptions an AED is definitely indicated after the second unprovoked seizure. The exceptions are benign partial epijepsy with centrotemporal spikes, for which an AED is not essential"; and purely photosensitive seizures, where treatment by actual or functional occlusion of the vision to one eye during provocation can abolish the tendency to attacksI2. Drugs can be given continuously or intermittently during exacerbations of seizures. Intermittent diazepam (DZM) can be used as the sole drug for prophylaxis of febrile seizures, but only if there is apparent inefficacy of all drugs used for chronic therapy would intermittent DZM be considered as the sole AED for recurrent unprovoked seizures. Home-use of DZM has been established in the treatment of break-through serial and prolonged seizures in children on maintenance AEDS, resulting in very significant reductions in the use of emergency-room services and improvements in social a d j ~ s t m e n t ' ~Intermittent . DZM can also be very effective in the treatment of nonconvulsive status epilepticu~'~. Approximately 80 per cent of patients placed on chronic therapy will respond to a single AED, if used to maximum benefit',
