Infantile spasms is a severe developmental epilepsy with several unique clinical features (1
). The syndrome begins during a specific window in the first year of life, commonly between 3 and 10 months of age, and has numerous etiologies, with more than 200 already described (3
). These etiologies span a wide range of acquired and congenital causes and can be categorized as symptomatic (cause known) or cryptogenic (no obvious brain disorder; cause unknown). Importantly, infantile spasms typically begins weeks to months following an initiating injury; during this latent period, neural circuits become epileptogenic. It is not known how or why the infant brain develops infantile spasms. Infantile spasms is associated with specific and unique EEG findings, consisting of interictal hypsarrhythmia (chaotic, high-voltage slow waves intermixed with multifocal spikes) and an ictal generalized slow waves, followed by generalized voltage attenuation. Unfortunately, most conventional anticonvulsants are ineffective for infantile spasms; rather, the spasms may respond to treatments such as glucocorticoids, adrenocorticotropic hormone (ACTH), and vigabatrin. The outcome of infantile spasms is usually poor, evolving into other seizure types after the first year of life; neurological development is often abnormal, especially when delay is noted prior to the onset of spasms and the spasms do not disappear with therapy.
The lack of a detailed pathophysiological explanation for many aspects of infantile spasms has been related to the frustrating absence of an animal model to investigate mechanisms (4
). In fact, such a model has been considered to be a “holy grail” of epilepsy research (5
). A valid animal model would not only enhance the understanding of disease pathophysiology but also encourage the development of new diagnostic approaches, permit testing of novel treatments, and help to devise strategies to reduce the cognitive and epileptic consequences. Ideal, sufficient, and minimal criteria for an animal model of infantile spasms have been proposed (6
). Optimally, the model would mimic the human disorder, including features of: 1) the occurrence of spasm-type spontaneous seizures (flexor, extensor, or mixed flexor/extensor) in response to various etiologies and brain insults, 2) a specific developmental window during which spasm-type seizures begin, 3) a timing of spasms in relation to the sleep–wake cycle (especially during sleep–wake transitions), and 4) the presence of spasms in clusters. The validity of an experimental model would be strengthened if the interictal and ictal EEG findings resemble those in the human syndrome.
An ideal model would include an anticonvulsant response, with a pattern of efficacy that could be replicated in babies. For example, the therapeutic effect of ACTH for infantile spasms is not immediate, typically taking 1 to 3 days to occur (8
). This outcome suggests that ACTH may not act directly as an anticonvulsant, but instead may act via a mechanism that obviously requires a longer time course. Furthermore, the ACTH effect on spasms and associated EEG abnormalities is usually all or none. Therefore, ACTH functions differently than conventional anticonvulsant drugs, by both suppressing the seizures and modifying the natural history of the disorder (9
). Finally, a demonstration of cognitive stagnation or regression would strengthen a model's correlation with the human disorder.
Although no animal model can be expected to reproduce every aspect of the human syndrome faithfully, relevant and testable hypotheses, nonetheless, can be generated from experimental models. A model without ideal face validity may nevertheless provide valuable information about disease mechanism. For example, an animal model with mutation of a specific gene causative of infantile spasms in human infants or an animal model with cortical dysplpasia, such as tubers, but without spasm-type seizures, still could be informative (7
The challenges to the development of an animal model include the interspecies differences in brain development; these differences are confounded by the lack of a developmental biomarker that can conclusively compare brains of humans and animals and by the differential expression of seizure phenotype and EEG in different species. Rather than try to mimic the human syndrome in every detail, a more productive approach is to use animal models to understand the neurobiological principles of infantile spasms, by asking specific questions on each model. This article reviews several new infantile spasms models (see ) that are injecting excitement into a field that has long been stagnant.
Animal Models of Infantile Spasms