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The major catastrophic epileptic syndromes of childhood include infantile spasms, Lennox-Gastaut syndrome, and the progressive myoclonus epilepsies (PMEs). Although each of these syndromes manifests in an age-specific manner and is defined by distinct electroclinical features, they are all refractory to medical therapy and are invariably associated with psychomotor deficits, and in the most severe cases, either epileptic encephalopathy or progressive neurodegeneration. While much has been written about the clinical features and natural history of the catastrophic epilepsies, very little is known about the underlying pathophysiology. Progress in our understanding and treatment of these conditions has been hampered by the lack of suitable animal models in which putative mechanisms and novel targets for intervention could be rigorously studied. Nevertheless, recent clinical and basic investigations have identified certain mechanisms that may be relevant to their pathogenesis. In this review, three major hypotheses regarding the pathophysiology of infantile spasms are highlighted: the corticotropin-releasing hormone (CRH) hypothesis, the N-methyl-D-aspartate (NMDA) hypothesis, and the serotonin-kynurenine hypothesis. One or more of these mechanisms may be relevant in part to later-onset catastrophic epilepsies since infantile spasms can persist into later childhood and, like Lennox-Gastaut syndrome, well into adulthood. There is a profound need to develop more relevant animal models of the developmental encephalopathic epilepsies to truly develop better therapeutic strategies for these catastrophic disorders.

The role of the endogenous convulsant kynurenine (K) in the mechanisms of the development of epileptic seizures in alcoholic persons was studied on a clinical material of 63 patients suffering from alcoholism with the presence on the EEG of paroxysmal alterations without epileptic fits (n = 28) and alcoholic epilepsy (n = 35), epileptic patients not abusing alcohol (n = 20), and practically healthy subjects (n = 10). There was a significant increase of the K concentration in alcoholic patients with paroxysmal disturbances on the EEG or convulsive seizures. That increase directly correlated with the rate of convulsive epileptic fits. The rise of K in patients with alcoholic epilepsy was lower than in epileptic patients, being, however, significantly higher than in practically healthy subjects abusing alcohol and having but paroxysmal alterations on the EEG (without seizures).

Seizure disorders are believed to be frequently linked to an imbalance between excitatory and inhibitory processes in the hippocampal formation. Thus, epileptic phenomena can probably be caused by a net hyperexcitation of hippocampal "pacemaker" neurons, which in turn leads to more generalized excitation and is often accompanied by selective neuronal loss. Several transmitter systems have been implicated in the etiology of seizures. However, the close mimicry of some forms of epilepsy by the actions of neuroexcitatory amino acids (EAA) and the anticonvulsant activity of EAA antagonists acting at the N-methyl-D-aspartate (NMDA) receptor have focussed recent attention on EAA as trigger factors in epilepsy. The heterocyclic metabolite quinolinic acid (QUIN), a NMDA agonist present in the brain, has attracted particular interest in this regard because of its potent convulsant and neurodegenerative properties, which are especially pronounced in the hippocampus. QUIN's metabolic enzymes have been identified in the brain and localized by immunohistochemical techniques to glial cells. Notably, QUIN biosynthesis seems to take place in cellular entities which are distinct from those responsible for QUIN degradation, implying that QUIN can gain access to the extracellular space (where it can interact with neuronal NMDA receptors) and can subsequently enter different cells to meet its catabolic fate. An endogenous compound metabolically related to QUIN, kynurenic acid (KYNA) is a potent antagonist of the convulsant and neurodegenerative effects of QUIN. The pathogenesis of seizure disorders can therefore now be hypothesized to be a problem of KYNA-deficiency as well as (or in addition to) QUIN-hyperfunction. It thus seems prudent to carefully examine the relationship between the function of QUIN and KYNA in the brain in view of possible implications for the precipitation of seizure phenomena.