Energy metabolism in the discharge pathway is massively increased during seizures

During seizure activity, there is a greater increase in cerebral metabolic rate (CMR) than under any other circumstance (see Chaps. 31 and 54). This is seen in measurements of oxygen consumption (CMRO₂) and glucose uptake and metabolism (reviewed in [25]). It is also reflected in a marked increase in cerebral blood flow (CBF). The metabolic activation is confined to the brain regions involved in the seizure propagation; for example, during limbic seizures, such as those induced by kainic acid, the increases in CBF and CMRO₂ and the metabolic changes described in Table 37-4 are confined to the limbic system. In contrast, generalized, global seizures cause metabolic activation to a varying degree in all brain regions. During seizures, there is commonly both an increase in arterial blood pressure and a marked local vasodilation, the latter partly due to local formation of nitric oxide and adenosine. The increase in CBF often exceeds the increase in CMRO₂ so that the oxygen content of the venous blood is increased. Provided that arterial blood pressure, arterial oxygenation and blood glucose concentration are maintained, this enhanced metabolism can also be maintained in excess of an hour of seizure activity.

Energy metabolites decrease rapidly

Despite the sharp increase in oxygen and glucose supply to the brain, the massive increase in energy demand associated with the onset of seizure activity causes a rapid fall in brain energy metabolites. Tissue stores of glycogen and glucose are rapidly depleted, and concentrations of phosphocreatine and, to a lesser extent, ATP fall rapidly and transiently. Associated with the fall in nucleotide is a concomitant sharp rise in nucleosides, including adenosine and free bases, for example, hypoxanthine.

Concentrations of lactate and certain amino acids change rapidly

Seizure activity is associated with a doubling or more of brain lactate, ammonia and alanine contents within 1 min [25]. There is a modest fall in the intracellular pH at the same time. The lactate increase occurs in the absence of hypoxia and reflects the relatively greater increase in the glycolytic rate than in CMRO₂, the maximally activated pyruvic acid dehydrogenase being the rate-limiting step. Glutamate, aspartate and GABA concentrations initially remain constant, but if seizure activity is prolonged, glutamate and aspartate usually fall and glutamine and GABA rise [26].

Second messengers change rapidly

There are dramatic changes in all of the second messengers that reflect increased release of neurotransmitters acting on metabotropic receptors within the first minute of seizure activity (see Chaps. 10, 15 and 20–22). Increases in cAMP are partly due to activation of α-adrenergic receptors (see Chap. 12). Increases in cGMP are partly due to formation of nitric oxide, following ionotropic glutamate receptor (NMDA) activation. Activation of glutamate, α₁-adrenergic or muscarinic metabotropic receptors causes phospholipase C (PLC) activation and phosphoinositide breakdown (see Chaps. 21 and 35). The lipase activity results in the formation of diacylglycerol, which activates protein kinase C, and of inositolphosphate, which causes release of Ca²⁺ from nonmitochondrial stores (see Chap. 23). There is also a marked increase in intracellular Ca²⁺ concentration, [Ca²⁺]_i, due to enhanced Ca²⁺ entry, through receptor and voltage-operated calcium ion channels (see Chap. 23).

The effects of these changes are to phosphorylate many enzymes, ion channels and cell membrane receptors and to directly activate calcium-dependent enzymes (see Chap. 24). Among the latter is phospholipase A₂, leading to the formation of free fatty acids, in particular arachidonic acid (see below and Chap. 35).

Free fatty acids and prostaglandins increase

Primarily due to activation of phospholipases, free fatty acids are liberated during seizure activity. The greatest increase during seizures induced by electroshock or bicuculline is in the unsaturated fatty acid arachidonic acid, 20:4, which acts as a precursor for various prostaglandins (Table 37-4) (see Chaps. 34 and 35).

Release of neurotransmitter amino acids is rapidly increased at the beginning of a seizure

The synaptic release of amino acid neurotransmitters was studied by in vivo microdialysis. In patients with epileptic foci in the temporal lobe, the extracellular hippocampal concentrations of glutamate and aspartate increase directly prior to or at the moment of seizure onset; the extracellular concentration of GABA rises with a slight delay in both the epileptic focus and the contralateral temporal lobe [27]. A similar enhanced release of aspartate, glutamate and GABA is seen associated with the onset of seizures in chronically seizure-prone rodents, kindled rats or rats with spontaneous, recurrent seizures. It is more difficult to demonstrate an enhanced release of excitatory amino acids or GABA at the onset of acute, evoked seizures in rats, perhaps due to an optimally functioning amino acid-transporter system during these conditions.

Seizures produce changes in gene expression and protein synthesis

Seizure activity has a dramatic effect on gene transcription. This has been studied in rats by in situ hybridization with mRNA probes (see Chap. 26). There are increases in expression of the immediate early genes c-fos, c-jun, junB and tissue plasminogen activator (tPA) in many structures involved in seizure activity, notably in the granule cells of the dentate gyrus (Table 37-4). Immunocytochemistry with specific antisera reveals that synthesis of the proteins encoded by the immediate early genes is also enhanced [28].

There are also selective increases in the mRNAs for various trophic factors, such as nerve growth factor and neurotrophin 3. These factors are detailed in Chapter 19. These changes have a longer latency of approximately 1 hr and a longer duration than the changes in the immediate early genes. With a longer latency still, there are increases in the expression of the genes encoding various peptide neurotransmitters and their precursors (Table 37-4) (see also Chap. 18).

Although the synthesis of some proteins, such as those mentioned above and the enzyme ornithine decarboxylase, is increased by seizures, the synthesis of most proteins is impaired during or after prolonged seizures in rats or newborn marmosets. When studied with labeled amino acid precursors and autoradiography, protein synthesis is impaired in those regions showing the greatest metabolic activation. The rate of protein synthesis depends on the cellular GDP:GTP ratio, with GDP increases being inhibitory.

Positron emission tomography studies show ictal hypermetabolism and interictal hypometabolism

PET (see Chap. 54) can be used to study the regional metabolism of the human brain during seizures and in the interictal period (Figs. 37-1 and 37-2). Regional glucose uptake can be studied with [¹⁸F]fluorodeoxyglucose and oxygen extraction with [¹⁵O]oxygen (see Chap. 31). In partial epilepsy, enhanced metabolism is usually seen in the zone of seizure initiation during a seizure. Interictal studies in partial epilepsy commonly show a large zone of hypometabolism, which may be more extensive than the presumed focal zone. Children with absence attacks show a marked diffuse increase in cerebral metabolism during the attack and normal interictal metabolism [2].

Figure 37-1

Ictal PET scan images with [¹⁸F]2-fluoro-2-deoxy-d-glucose. The scan, performed during continuous partial seizures originating in the left frontal and temporal cortices, shows asymmetrical hypermetabolism of the left frontal motor cortex, orbitofrontal (more...)

Figure 37-2

Interictal PET scan images with [¹⁸F]2-fluoro-2-deoxy-d-glucose. The images depict typical reduction in metabolic rate in both the mesial and lateral temporal cortex on the side of the seizure focus (right side of images). Note also the bilateral reduction (more...)