Some lessons from reflex seizures

It is a signal distinction and a pleasure to be asked to contribute to this Festschrift in honor of Frederick and Eva Andermann, one of the most distinguished and memorable couples in biomedical science. I owe my introduction to reflex seizures to Frederick Andermann. The beginning was unsuspected and quite innocent when as a first year resident I asked a clinic patient if anything made his seizures worse. He replied that mental arithmetic triggered seizures. Although this was in his record and the electroencephalography (EEG) studies had been suggestive, it had not been pursued. I had him return for an EEG with a protocol from the one previous report (Ingvar & Nyman, 1962) and thought that with these positive results, I had made my case. Fred, as always, sees more and saw more in this. He had explored pattern-sensitive epilepsy with the distinguished British neuropsychologist Arnold Wilkins using EEG technology developed by Gotman and Ives (Wilkins et al., 1975), and arranged for Arnold to come from Cambridge for a 2-week visit. We then recorded our subject nearly every day, weekends included, generating piles of EEG paper: we had decided not to stop the paper drive during a session so that intervals could be measured by counting pages and using a ruler. After several drafts, the results were published as Seizures Induced by Thinking (Wilkins et al., 1982). Fred saw in this case what was not immediately apparent; anyone who knows him is aware of his ability to link one observation to some previous and occasionally obscure finding and to wonder if there is commonality between them, perhaps even a syndrome. In this case, one might expect that the relatively specific nature of the tasks would have triggered focal epileptiform EEG abnormalities and possibly focal seizures. Instead they triggered unremarkable bilateral spike and wave activity and brief absence attacks—generalized seizures. Similarly, although Binnie, Wilkins, and coworkers showed the relatively localized occipital cortical trigger in pattern-sensitive epilepsy (Binnie et al., 1985), sensitivity to intermittent photic stimulation, to which nearly all pattern-sensitive subjects also react, and to striped patterns, also triggered bilateral or generalized EEG epileptiform activity and apparently generalized seizures. Japanese studies of seizures precipitated by combined thought and action began to appear in Japanese journals at about this time. These were described in English-language book chapters under the unfamiliar term "praxis-induced seizures" (Inoue et al., 1994), and it was at times difficult to grasp the meaning and import of these. A large and important study by Matsuoka et al. (2000) clarified many of these questions, and seemed to confirm and expand the ideas that had been broached in our initial paper and a subsequent Montreal series collected by Frederick Andermann and reported by Goossens et al. (1990). Praxis-induction and seizures induced by thinking appear almost exclusively in idiopathic generalized epilepsies as they are now understood, and particularly in juvenile myoclonic epilepsy, although seizures induced by thinking can occur with no motor component in the stimulus or the response (Inoue & Zifkin, 2004). The model of human pattern-sensitive epilepsy is of special interest in such seizures because it shows that generalized clinical events and generalized or bilateral EEG abnormalities can be activated by a specific functional stimulation with a known localization, in the case of pattern-sensitive epilepsy involving hyperexcitability of primary visual cortex. This electroclinical pattern is found in many subjects with several types of reflex seizure triggers and idiopathic generalized epilepsy, without neurologic deficit or evident lesions on imaging, and who are, therefore, presumed to have diffuse cortical hyperexcitability with a genetic component (Ferlazzo et al., 2005). Seizures induced by thinking and by "praxis" (action programming) and some cases of reading epilepsy appear to follow this model. Similarly, the dissociation between drawing- and writing-induced seizures discussed by Kho et al. (2006) suggests the existence of verbal and nonverbal hyperexcitable networks. Reading epilepsy is characterized by orofacial reflex myoclonus triggered by reading, which the patients may report as jaw jerks, partial seizures which may become generalized convulsions, and in some patients, jerks of the arms and head with bilateral EEG discharges similar to those seen in juvenile myoclonic epilepsy. Functional magnetic resonance imaging (fMRI) shows (Salek-Haddadi et al., 2009) activations in most subjects in areas overlapping or adjacent to those physiologically activated during language and facial motor tasks, including subcortical structures without significant lesions. Reading epilepsy seems to be a further example of activation of a hyperexcitable functional network, which can produce seizures when sufficient critical mass is incorporated by adequate stimuli to produce a seizure, at times a seizure of apparently generalized epilepsy. It may rely on both existing and reorganized functional links between brain regions and need not be confined to physically contiguous brain sites or established neuronal links. Photosensitive occipital partial seizures also occur in patients with idiopathic generalized epilepsy (Guerrini et al., 1995), and motor activity can elicit seizures in nearly 50% of patients with juvenile myoclonic epilepsy (Matsuoka et al., 2000). The pattern of praxis-induction fits well with juvenile myoclonic epilepsy, in which there is apparent regional hyperexcitability of sensorimotor cortex within an apparently generalized epileptic disorder (Wolf, 1994). The importance of coexisting juvenile myoclonic epilepsy has been mentioned in conferring sensitivity to a variety of cortical triggers: whether or not it is a truly generalized epilepsy or something like a regional or network hyperexcitability involving sensorimotor cortex is not clear. Evidence is accumulating that it is a model of a "system" epilepsy (see for example Inoue & Zifkin, 2004; Lin et al., 2009). These and other observations in both reflex and spontaneous epileptogenesis (Binnie, 2004) suggest that the postulated diffuse cortical hyperexcitability in idiopathic generalized epilepsy is not necessarily uniform; specific activities can activate specific cortical systems or functional networks spread over several cortical regions in one or both hemispheres and produce focal or regional discharges, or partial seizures, which may generalize. At least some understanding of how the brain works in the useful yet somewhat artificial construct of generalized epilepsy has come from the study of reflex seizures. The author has no conflicts of interest to disclose.

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