Acta Pædiatrica ISSN 0803-5253
EDITORIAL DOI:10.1111/apa.12912
Potentials with potential The complexity of the nervous system as it develops, both phylogenetically and ontogenetically, is beyond our grasp. It could be said that it is more surprising how often it works out well than the fact that sometimes it does not. The main objective of the system is to handle information. It is able to do this because one of its central features is its fantastic capacity to adapt, to be plastic. This means that it reacts to, and is changed by, all the influences by which it is reached. € mTwo studies in this issue – Lloyd et al. (1) and Hellstro Westas et al. (2) – contribute reviews of the practicalities of neonatal electroencephalography (EEG), respectively, focusing on a detailed description of recording techniques for preterm infants and the management of seizures in neonates. The rationale for these practices is well described. However, the handling of neonatal seizures has been a long-standing and controversial issue in neonatology. Views have been put forth advocating all standpoints from that there is no need to treat these events (unusual), via advocating treatment of only so called clinical (i.e. somehow observable) seizures (common) to actively monitoring brain function, aiming for abolishment of seizures detectable with continuous EEG monitoring (unusual). With regard to the situation of hypoxia in the adult brain, Haldane (3) stated that: ‘When the anoxaemia is more severe, the evidence of severe damage becomes more and more marked, so that even when the cause is completely removed, grave symptoms may remain.’ In parallel with that statement, and extending it further, it could be said that seizures in the developing brain not only overactivate the system, often to point of tissue loss; they may also change the system permanently. An adult with disturbed consciousness in an intensive care unit is not left to the mercy of busy staff in the hope that they will recognise the clinical signs that could potentially indicate uncontrolled epileptic activity. [Such signs are so insignificant in neonates that it would be better to toss a coin to decide their presence (4).] Instead, measures are taken to continuously monitor brain function and recent recommendations state that EEG signs, previously regarded as unclear indicators of whether epileptic hyperactivity threatens the brain, should be acted on (5). These EEG signs are considered to be even more established in neonates (6). So why should newborns receive inferior treatment to adults? On the contrary, the brains of these vulnerable individuals are hopefully going to be active for a long time to come. This makes it even more important, if that is conceivable, to counteract harmful influences to their development as much as possible. A large amount of data supporting the notion that seizures in the developing brain are harmful has been available for a considerable amount of time. Experimentally,
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plain tissue damage can be seen, especially when seizures (as often is the case in the clinical setting) are combined with other afflictions such as hypoxia (7). Maybe the change in development that is induced is at least as important for long-term function. The normal patterns of growth and expansion are changed. Other connections are formed than the ones that the undisturbed interaction of internal and external factors would have produced. The activity of some of these will have a negative impact on the functional outcome. For instance, overproduction of mossy fibres to the dentate gyrus is associated with an increased tendency to have a seizure and decreased capacity for localisation (8). Indeed, a single early fever-induced seizure can permanently change the function of the motor system, even more so in predisposed individuals (9). Also, other parts of the system, such as vascular development, may be permanently hampered (10). Clinical studies have demonstrated similar findings. There is an acute and severe derangement of cerebral energy metabolism in seizing neonates, which is remedied by treating the seizures (11). The amount of seizure activity is independently and positively correlated to short-term neurological decline (12). Febrile seizures produce increased connectivity, which is related to defects of working memory and possibly increased risk of epilepsy (13,14). Status epilepticus induces immunological processes that alter the system and are part of the epileptogenic process (15). Even during childhood, the mere presence of epileptiform activity, (i.e. not actual seizures), will lead to worsened neurocognitive outcome if it produces changes in network function (16). Thus, vast amounts of data strongly indicate the necessity of early detection and treatment of seizures, to prevent tissue damage and unfavourable alterations of developmental patterns, including epileptogenesis. What argument could there be against actively treating seizures in newborns? Doubt has been cast on whether this uncontrolled activity really causes damage to the immature brain. Indeed, given that these infants are usually suffering from complex derangements, the influence of seizure activity is difficult to separate out. Moreover, as the affected system is under intense development, traditional lesions may be hard to detect. So, the enormous plastic capacity may counteract the negative effects. However, it must be remembered that this counteractive effect will be acting on a changed substrate, as the original template has gone, the completed puzzle will show a different picture than the one initially intended. Thus, these views must now be seen as outdated given the great amount of data, outlined above, that demonstrates a large number of harmful influences. Another line of argument has been that the actual treatment could pose a threat to the development of the nervous
ª2015 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2015 104, pp. 112–113
Editorial
system (17,18). Naturally, as the brain’s main task is to deal with information, all changes will influence its function, including those of a time-limited blocking of receptors leading to alterations in the conductivity of certain ion channels. However, to claim that this kind of influence should hinder effective treatment to prevent the wellrecognised and devastating effects of uncontrolled seizures, when negative long-term consequences of treatments used have yet to be demonstrated, impose a heavy burden on those advocating this standpoint. It could be said that this reasoning is similar to the arguments put forward by illadvised groups who are against immunisations because they believe they cause damage. In the case of infectious diseases, the human costs are obvious and seen in the short term, in that of neonatal seizures; we have to examine the consequences in long term. To believe is not enough. It may lead to unethical behaviour, as demonstrated by political and religious believers throughout history up to the current day. The verdict of history, if such an entity exists, will be hard on those pursuing a tradition of passivity towards the treatment of neonatal seizures. Giordano Bruno is remembered and honoured as an individual who stuck to the scientific truth as he saw it. The pope who declared him a heretic – Clement VIII – is unknown to most, if not infamous. For the sake of sick newborns, their families and society, we must capture and act on the potential of the potentials generated by the brains of these children trusted to our care!
Magnus Thordstein ([email protected]) Ass. Prof., Senior lecturer, Clinical Neurophysiology, Sahlgrenska University Hospital, Gothenburg, Sweden
References 1. Lloyd RO, Goulding RM, Filan PM, Boylan GB. Overcoming the practical challenges of electroencephalography of very preterm infants in the neonatal intensive care unit. Acta Paediatr 2015; 104: 152–157. € m-Westas L, Boylan G, 2. Hellstro Agren J. Results from multiple surveys on seizure management can guide future development of neonatal anti-epileptic treatment strategies. Acta Paediatr 2015; 104. 3. Haldane JS. A lecture on the symptoms, causes, and prevention of anoxaemia (insufficient supply of oxygen to the tissues), and the value of oxygen in its treatment. Br Med J 1919; 2: 65–71.
Editorial
4. Murray DM, Boylan GB, Ali I, Ryan CA, Murphy BP, Connolly S. Defining the gap between electrographic seizure burden, clinical expression and staff recognition of neonatal seizures. Arch Dis Child Fetal Neonatal Ed 2008; 93: F187–91. 5. Hirsch LJ, LaRoche SM, Gaspard N, Gerard E, Svoronos A, Herman ST, et al. American Clinical Neurophysiology Society’s Standardized Critical Care EEG Terminology: 2012 version. J Clin Neurophysiol 2013; 30: 1–27. 6. Nagarajan L, Palumbo L, Ghosh S. Brief electroencephalography rhythmic discharges (BERDs) in the neonate with seizures: their significance and prognostic implications. J Child Neurol 2011; 26: 1529–33. 7. Wirrell EC, Armstrong EA, Osman LD, Yager JY. Prolonged seizures exacerbate perinatal hypoxic-ischemic brain damage. Pediatr Res 2001; 50: 445–54. 8. Rogalski LI, Minokoshi M, Silveira DC, Cha BH, Holmes GL. Recurrent neonatal seizures: relationship of pathology to the electroencephalogram and cognition. Dev Brain Res 2001; 129: 27–38. 9. Reid AY, Pittman QJ, Teskey GC. A prolonged experimental febrile seizure results in motor map reorganization in adulthood. Neurobiol Dis 2012; 45: 692–700. 10. Whiteus C, Freitas C, Grutzendler J. Perturbed neural activity disrupts cerebral angiogenesis during a postnatal critical period. Nature 2014; 505: 47–412. 11. Younkin DP, Delivoria-Papadopoulos M, Maris J, Donlon E, Clancy R, Chance B. Cerebral metabolic effects of neonatal seizures measured with in vivo ‘P NMR spectroscopy. Ann Neurol 1986; 20: 513–9. 12. Payne ET, Zhao XY, Frndova H, McBain K, Sharma R, Hutchison JS, et al. Seizure burden is independently associated with short term outcome in critically ill children. Brain 2014; 137: 1429–38. 13. Birca A, Lassonde M, Lippe S, Lortie A, Vannasing P, Carmant L. Enhanced EEG connectivity in children with febrile seizures. Epil Res 2014. http://dx.doi.org/10.1016/ j.eplepsyres.2014.11.008. 14. Chang YC, Guo NW, Wang ST, Huang CC, Tsai JJ. Working memory of school-aged children with a history of febrile convulsions. A population study. Neurology 2001; 57: 37–42. 15. Miskin C, Hasbani DM. Status Epilepticus: immunologic and inflammatory mechanisms. Semin Pediatr Neurol 2014; 21: 221–5. 16. Ibrahim GM, Cassel D, Morgan BR, Smith ML, Otsubo H, Ochi A, et al. Resilience of developing brain networks to interictal epileptiform discharges is associated with cognitive outcome. Brain 2014; 137: 2690–702. 17. Bittigau P, Sifringer M, Genz K, Reith E, Pospischil D, Govindarajalu S, et al. Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. Proc Natl Acad Sci USA 2002; 99: 15089–94. 18. Vanhatalo S, Kaila K. Development of neonatal EEG activity: from phenomenology to physiology. Semin Fet Neonat Med 2006; 11: 471–8.
ª2015 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2015 104, pp. 112–113
113
EDITORIAL DOI:10.1111/apa.12912
Potentials with potential The complexity of the nervous system as it develops, both phylogenetically and ontogenetically, is beyond our grasp. It could be said that it is more surprising how often it works out well than the fact that sometimes it does not. The main objective of the system is to handle information. It is able to do this because one of its central features is its fantastic capacity to adapt, to be plastic. This means that it reacts to, and is changed by, all the influences by which it is reached. € mTwo studies in this issue – Lloyd et al. (1) and Hellstro Westas et al. (2) – contribute reviews of the practicalities of neonatal electroencephalography (EEG), respectively, focusing on a detailed description of recording techniques for preterm infants and the management of seizures in neonates. The rationale for these practices is well described. However, the handling of neonatal seizures has been a long-standing and controversial issue in neonatology. Views have been put forth advocating all standpoints from that there is no need to treat these events (unusual), via advocating treatment of only so called clinical (i.e. somehow observable) seizures (common) to actively monitoring brain function, aiming for abolishment of seizures detectable with continuous EEG monitoring (unusual). With regard to the situation of hypoxia in the adult brain, Haldane (3) stated that: ‘When the anoxaemia is more severe, the evidence of severe damage becomes more and more marked, so that even when the cause is completely removed, grave symptoms may remain.’ In parallel with that statement, and extending it further, it could be said that seizures in the developing brain not only overactivate the system, often to point of tissue loss; they may also change the system permanently. An adult with disturbed consciousness in an intensive care unit is not left to the mercy of busy staff in the hope that they will recognise the clinical signs that could potentially indicate uncontrolled epileptic activity. [Such signs are so insignificant in neonates that it would be better to toss a coin to decide their presence (4).] Instead, measures are taken to continuously monitor brain function and recent recommendations state that EEG signs, previously regarded as unclear indicators of whether epileptic hyperactivity threatens the brain, should be acted on (5). These EEG signs are considered to be even more established in neonates (6). So why should newborns receive inferior treatment to adults? On the contrary, the brains of these vulnerable individuals are hopefully going to be active for a long time to come. This makes it even more important, if that is conceivable, to counteract harmful influences to their development as much as possible. A large amount of data supporting the notion that seizures in the developing brain are harmful has been available for a considerable amount of time. Experimentally,
112
plain tissue damage can be seen, especially when seizures (as often is the case in the clinical setting) are combined with other afflictions such as hypoxia (7). Maybe the change in development that is induced is at least as important for long-term function. The normal patterns of growth and expansion are changed. Other connections are formed than the ones that the undisturbed interaction of internal and external factors would have produced. The activity of some of these will have a negative impact on the functional outcome. For instance, overproduction of mossy fibres to the dentate gyrus is associated with an increased tendency to have a seizure and decreased capacity for localisation (8). Indeed, a single early fever-induced seizure can permanently change the function of the motor system, even more so in predisposed individuals (9). Also, other parts of the system, such as vascular development, may be permanently hampered (10). Clinical studies have demonstrated similar findings. There is an acute and severe derangement of cerebral energy metabolism in seizing neonates, which is remedied by treating the seizures (11). The amount of seizure activity is independently and positively correlated to short-term neurological decline (12). Febrile seizures produce increased connectivity, which is related to defects of working memory and possibly increased risk of epilepsy (13,14). Status epilepticus induces immunological processes that alter the system and are part of the epileptogenic process (15). Even during childhood, the mere presence of epileptiform activity, (i.e. not actual seizures), will lead to worsened neurocognitive outcome if it produces changes in network function (16). Thus, vast amounts of data strongly indicate the necessity of early detection and treatment of seizures, to prevent tissue damage and unfavourable alterations of developmental patterns, including epileptogenesis. What argument could there be against actively treating seizures in newborns? Doubt has been cast on whether this uncontrolled activity really causes damage to the immature brain. Indeed, given that these infants are usually suffering from complex derangements, the influence of seizure activity is difficult to separate out. Moreover, as the affected system is under intense development, traditional lesions may be hard to detect. So, the enormous plastic capacity may counteract the negative effects. However, it must be remembered that this counteractive effect will be acting on a changed substrate, as the original template has gone, the completed puzzle will show a different picture than the one initially intended. Thus, these views must now be seen as outdated given the great amount of data, outlined above, that demonstrates a large number of harmful influences. Another line of argument has been that the actual treatment could pose a threat to the development of the nervous
ª2015 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2015 104, pp. 112–113
Editorial
system (17,18). Naturally, as the brain’s main task is to deal with information, all changes will influence its function, including those of a time-limited blocking of receptors leading to alterations in the conductivity of certain ion channels. However, to claim that this kind of influence should hinder effective treatment to prevent the wellrecognised and devastating effects of uncontrolled seizures, when negative long-term consequences of treatments used have yet to be demonstrated, impose a heavy burden on those advocating this standpoint. It could be said that this reasoning is similar to the arguments put forward by illadvised groups who are against immunisations because they believe they cause damage. In the case of infectious diseases, the human costs are obvious and seen in the short term, in that of neonatal seizures; we have to examine the consequences in long term. To believe is not enough. It may lead to unethical behaviour, as demonstrated by political and religious believers throughout history up to the current day. The verdict of history, if such an entity exists, will be hard on those pursuing a tradition of passivity towards the treatment of neonatal seizures. Giordano Bruno is remembered and honoured as an individual who stuck to the scientific truth as he saw it. The pope who declared him a heretic – Clement VIII – is unknown to most, if not infamous. For the sake of sick newborns, their families and society, we must capture and act on the potential of the potentials generated by the brains of these children trusted to our care!
Magnus Thordstein ([email protected]) Ass. Prof., Senior lecturer, Clinical Neurophysiology, Sahlgrenska University Hospital, Gothenburg, Sweden
References 1. Lloyd RO, Goulding RM, Filan PM, Boylan GB. Overcoming the practical challenges of electroencephalography of very preterm infants in the neonatal intensive care unit. Acta Paediatr 2015; 104: 152–157. € m-Westas L, Boylan G, 2. Hellstro Agren J. Results from multiple surveys on seizure management can guide future development of neonatal anti-epileptic treatment strategies. Acta Paediatr 2015; 104. 3. Haldane JS. A lecture on the symptoms, causes, and prevention of anoxaemia (insufficient supply of oxygen to the tissues), and the value of oxygen in its treatment. Br Med J 1919; 2: 65–71.
Editorial
4. Murray DM, Boylan GB, Ali I, Ryan CA, Murphy BP, Connolly S. Defining the gap between electrographic seizure burden, clinical expression and staff recognition of neonatal seizures. Arch Dis Child Fetal Neonatal Ed 2008; 93: F187–91. 5. Hirsch LJ, LaRoche SM, Gaspard N, Gerard E, Svoronos A, Herman ST, et al. American Clinical Neurophysiology Society’s Standardized Critical Care EEG Terminology: 2012 version. J Clin Neurophysiol 2013; 30: 1–27. 6. Nagarajan L, Palumbo L, Ghosh S. Brief electroencephalography rhythmic discharges (BERDs) in the neonate with seizures: their significance and prognostic implications. J Child Neurol 2011; 26: 1529–33. 7. Wirrell EC, Armstrong EA, Osman LD, Yager JY. Prolonged seizures exacerbate perinatal hypoxic-ischemic brain damage. Pediatr Res 2001; 50: 445–54. 8. Rogalski LI, Minokoshi M, Silveira DC, Cha BH, Holmes GL. Recurrent neonatal seizures: relationship of pathology to the electroencephalogram and cognition. Dev Brain Res 2001; 129: 27–38. 9. Reid AY, Pittman QJ, Teskey GC. A prolonged experimental febrile seizure results in motor map reorganization in adulthood. Neurobiol Dis 2012; 45: 692–700. 10. Whiteus C, Freitas C, Grutzendler J. Perturbed neural activity disrupts cerebral angiogenesis during a postnatal critical period. Nature 2014; 505: 47–412. 11. Younkin DP, Delivoria-Papadopoulos M, Maris J, Donlon E, Clancy R, Chance B. Cerebral metabolic effects of neonatal seizures measured with in vivo ‘P NMR spectroscopy. Ann Neurol 1986; 20: 513–9. 12. Payne ET, Zhao XY, Frndova H, McBain K, Sharma R, Hutchison JS, et al. Seizure burden is independently associated with short term outcome in critically ill children. Brain 2014; 137: 1429–38. 13. Birca A, Lassonde M, Lippe S, Lortie A, Vannasing P, Carmant L. Enhanced EEG connectivity in children with febrile seizures. Epil Res 2014. http://dx.doi.org/10.1016/ j.eplepsyres.2014.11.008. 14. Chang YC, Guo NW, Wang ST, Huang CC, Tsai JJ. Working memory of school-aged children with a history of febrile convulsions. A population study. Neurology 2001; 57: 37–42. 15. Miskin C, Hasbani DM. Status Epilepticus: immunologic and inflammatory mechanisms. Semin Pediatr Neurol 2014; 21: 221–5. 16. Ibrahim GM, Cassel D, Morgan BR, Smith ML, Otsubo H, Ochi A, et al. Resilience of developing brain networks to interictal epileptiform discharges is associated with cognitive outcome. Brain 2014; 137: 2690–702. 17. Bittigau P, Sifringer M, Genz K, Reith E, Pospischil D, Govindarajalu S, et al. Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. Proc Natl Acad Sci USA 2002; 99: 15089–94. 18. Vanhatalo S, Kaila K. Development of neonatal EEG activity: from phenomenology to physiology. Semin Fet Neonat Med 2006; 11: 471–8.
ª2015 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd 2015 104, pp. 112–113
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