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To the Editors:

I have read with great interest the article by Pellock et al. (2010) titled “Infantile spasms: A U.S. consensus report” (Pellock et al., 2010) and commend the effort to summarize the current state of affairs in the clinical and experimental studies on infantile spasms (IS), which will be an invaluable reference for future studies. Because recent progress on the animal models of infantile spasms (IS) has been significant, I would like to offer my comments and amend some recent information pertaining to the animal models of IS, as this probably anteceded the finalization of this article.

The biologic relevance of the triple-hit model (originally described as “multiple-hit” model) (Scantlebury et al., 2010) is that it recreates the cortical and subcortical pathologies that have been described in brain pathology studies of patients with IS (Lado & Moshe, 2002). The triple-hit is one of the four current models of IS that exhibit spontaneous spasms: triple-hit model (Scantlebury et al., 2010), tetrodotoxin (TTX) model (Lee et al., 2008), aristaless-related homeobox gene (ARX) conditional knockout (Lee et al., 2008), and ARX knockin mouse with expansion of the first polyalanine repeat (Price et al., 2009). Among those chronic models, only the triple-hit and ARX knockin mouse models exhibit age-specific expression of spontaneous spasms early in life, whereas both the TTX model and ARX knockout models manifest them in older ages, including adulthood. Among the four chronic models, cognitive and sociability deficits have been described only in the triple-hit and ARX knockin models (Price et al., 2009; Scantlebury et al., 2010), whereas the other two chronic models have not yet been characterized in that respect.

Although most of the existing models exhibit epileptiform interictal electroencephalography (EEG) studies, I agree with the authors that the best hypsarrhythmia-like patterns have so far been described in the TTX model, in adults. However, as also acknowledged by Price et al. (Price et al., 2009), documentation of hypsarrhythmia is technically difficult in developing rodents, due to the small size and fragility of the skull bones that prevent the placement of many electrodes on the head. An additional factor that needs to be considered is that the onset of hypsarrhythmia and appearance of IS may not necessarily temporally coincide, especially in rodents in which brain development is much accelerated compared to humans (Avishai-Eliner et al., 2002). In support, several models of IS describe an early phase of low-voltage interictal EEG [N-methyl-d-aspartate (NMDA), TTX, triple-hit, and ARX knockout models], despite the presence of spasms, with subsequent increase in the background amplitude that, in the TTX model, reaches a hypsarrhythmic-like pattern in adulthood. This evolution may reflect the acute–subacute impact of the underlying brain lesion or dysfunction that may generate the initial low-amplitude phase, whereas the hypsarrhythmia may be a relatively delayed interictal manifestation of the syndrome. If this is confirmed, it may suggest that hypsarrhythmia, although important for the wider functional deficits, may not be necessary for the expression of spasms, which are more closely linked with electrodecremental ictal responses, in both animal models and human patients. Future longitudinal studies in humans are warranted to document the temporal evolution of ictal and interictal abnormalities, starting as early as the preclinical stage.

Pharmacosensitivity profiles already exist for three of the acute models of IS (NMDA, NMDA/GC, and Ts65Dn/γ-butyrolactone models) and only one of the chronic models (triple-hit model) (Chudomelova et al., 2010).

In addition, I would like to comment on the reference as to the investigative use of rapamycin as a novel candidate therapy for IS. The work published by Michael Wong’s group in a model of tuberous sclerosis (Zeng et al., 2008) was seminal in suggesting a potential role for rapamycin as an antiepileptogenic (or possibly epileptostatic) compound. However, none of the existing animal models, where the antiepileptic effects of rapamycin have been tested so far, exhibits IS, which are known for their distinct pharmacosensitivity profile. Our group has offered the first evidence that in the triple-hit model of symptomatic IS rapamycin can suppress spasms. These results have been previously announced at the American Epilepsy Society and American Neurological Association meetings (2008, 2009) (Raffo et al., 2009; Chudomelova et al., 2010).

I share with the authors the feeling that the availability of animal models of IS can provide an essential tool to study the pathophysiology of and identify new therapies for IS. At present, we have in our armamentarium three acute and four chronic models of IS with or without hypsarrhythmia, with sufficient differences in their etiologies and underlying pathologies. Recognizing their common features as well as their differences, will be essential in identifying new therapies with broad spectrum of efficacy across IS of different etiologies as well as therapies that aim to abolish hypsarrhythmia. However, I agree that it is important to have a consensus as to the treatment protocols tested in these models so as to better translate these findings into a clinically relevant therapeutic intervention (Chudomelova et al., 2010; Pellock et al., 2010).

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I confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this letter is consistent with these guidelines. I have no conflicts of interest to disclose in respect to this letter.

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