Epilepsy in the Developing Brain: Lessons from the Laboratory and Clinic

Abstract

Summary:Children with epilepsy present unique challenges to the clinician. In addition to having differences in clinical and EEG phenomena, children differ from adults in regard to etiological factors, response to antiepileptic drugs (AEDs), and outcome. It is now recognized that the immature brain also differs from the mature brain in the basic mechanisms of epileptogenesis and propagation of seizures. The immature brain is more prone to seizures due to an imbalance between excitation and inhibition. y-Aminobutyric acid (GABA), the major CNS inhibitory neurotransmitter in the mature brain, can lead to depolarization in the hippocampal CA3 region in very young rats. There are also age-related differences in response to GABA agonists and antagonists in the substantia nigra, a structure important in the propagation of seizures. These age-related Epilepsy is a common disorder, leading to staggering costs, both in regard to human suffering and to economics. Because epilepsy frequently begins during childhood and has a higher incidence during the first decade of life than at any other time (l), issues of morbidity and mortality represent a major concern in pediatrics.Clinicians caring for children with epilepsy and developmental neuroscientists have long been aware that the immature brain differs considerably from the mature brain in the development and propagation of seizures, the behavioral and EEG features of the seizures, and their consequences. It is becoming increasingly clear that lessons learned about the mature brain in regard to the pathophysiology and treatment of seizures can not always be applied to the developing brain. An understanding of the unique features of epileptogenesis during development is essential before progress can be made in improving treatment. Despite the significance of the health care problem, it is surprising that relatively little differences in response to GABAergic agents provide further evidence that the pathophysiology of seizures in the immature brain differs from that in the mature brain. Although prolonged seizures can cause brain damage at any age, the extent of brain damage after prolonged seizures is highly age dependent. Far less histological damage and fewer disturbances in cognition result from prolonged seizures in the immature brain than from seizures of similar duration and intensity in mature animals. However, detrimental effects of AEDs may be greater in the immature brain, than in the mature brain. These lessons from the animal laboratory raise questions about the appropriateness of current therapeutic approaches to childhood seizure disorders. Key Words: Epilepsy-Developing brain-Electroencephalography-Epileptogenesis-Pathophysiology . attention has been directed toward developing treatment strategies that specifically address these age-related factors.In this article, features of epileptogenesis during brain development are reviewed and age-related differences in response to seizures and antiepileptic drugs (AEDs) are discussed. Table 1 shows some of the major p...

Excitatory Actions of Endogenously Released GABA Contribute to Initiation of Ictal Epileptiform Activity in the Developing Hippocampus

“…Despite dramatically lower synaptic connectivity (Bayer, 1980;Gomez-Di Cesare et al, 1997), the immature brain is much more susceptible to seizures than the adult brain (DeLorenzo et al, 1992;Holmes, 1997). Modeling studies clearly indicate that synchronous activity is not easily maintained when synaptic connectivity is low (Traub and Miles, 1991).…”

Neuropeptide-mediated excitability: a key triggering mechanism for seizure generation in the developing brain

“…8 for a recent review). This concept is supported in the human by the much greater incidence of seizures in the infant and young child, as compared with the adult 1,2,9 .…”

“…Enhanced excitability and a higher sensitivity to proconvulsant agents have also been demonstrated in immature experimental animals, including rats, cats and monkeys 10,11 . Several characteristics of developing neuronal circuitry might account for this enhanced excitability 8,12 . For example, GABA, the principal inhibitory neurotransmitter in the mature CNS, has depolarizing, and thus excitatory, properties during the first postnatal week in the rat 12,13 .…”

“…In addition, excitatory amino acid receptors are both more abundant in the immature brain 14 and possess a subunit makeup that promotes neuronal depolarization 15 . These factors are thought to contribute to an altered excitation-inhibition balance during development 8 . At the circuit level, increased neuronal excitability is evident, leading, for example, to the robust long-term potentiation observed during the second postnatal week ('infancy' in the rat) in both hippocampal and cortical synapses 16,17 .…”

“…In addition, the number of cortical and hippocampal excitatory synapses is highest during this period and decreases after the third post-natal week 18 . All of these factors favor enhanced excitation and a propensity to generation and propagation of seizures 8 .…”