Modeling epileptic spasms during infancy: Are we heading for the treatment yet?

Abstract

Infantile spasms (IS or epileptic spasms during infancy) were first described by Dr. William James West (aka West syndrome) in his own son in 1841. While rare by definition (occurring in 1 per 3200-3400 live births), IS represent a major social and treatment burden. The etiology of IS varies - there are many (>200) different known pathologies resulting in IS and still in about one third of cases there is no obvious reason. With the advancement of genetic analysis, role of certain genes (such as ARX or CDKL5 and others) in IS appears to be important. Current treatment strategies with incomplete efficacy and serious potential adverse effects include adrenocorticotropin (ACTH), corticosteroids (prednisone, prednisolone) and vigabatrin, more recently also a combination of hormones and vigabatrin. Second line treatments include pyridoxine (vitamin B6) and ketogenic diet. Additional treatment approaches use rapamycin, cannabidiol, valproic acid and other anti-seizure medications. Efficacy of these second line medications is variable but usually inferior to hormonal treatments and vigabatrin. Thus, new and effective models of this devastating condition are required for the search of additional treatment options as well as for better understanding the mechanisms of IS. Currently, eight models of IS are reviewed along with the ideas and mechanisms behind these models, drugs tested using the models and their efficacy and usefulness. Etiological variety of IS is somewhat reflected in the variety of the models. However, it seems that for finding precise personalized approaches, this variety is necessary as there is no "one-size-fits-all" approach possible for both IS in particular and epilepsy in general.

Keywords: ACTH; Animal models; Epileptic spasms; Genetics; Vigabatrin.

Figure 1 –. Time line of the two-hit (prenatal betamethasone & postnatal NMDA) model of IS

Priming: Pregnant Sprague-Dawley rats are injected IP with two doses of betamethasone (0.4 mg/kg of phosphate salt in saline) on gestational day 15 (G15) at 08:00 and 18:00 hours. Controls (if needed) receive equivalent volume (1 ml/kg) normal saline IP. Offspring are consistently delivered at G23. Note that different strains of rats may have different durations of pregnancy and thus, the timing of prenatal priming needs to be adjusted [see (Kábová, et al., 2000) for comparison]. Prolonged stress delivered to pregnant dams with similar timing as betamethasone on G15 has comparable priming effects (two episodes of 45 min restraint stress each) as injected betamethasone. Day of delivery (G23) in these experiments is considered as postnatal day 0 (P0). Postnatal induction of spasms: Primed offspring are used for induction of spasms between P10-P15. Spasms are triggered by graded doses of N-methyl-D-aspartic acid (NMDA) dissolved in normal saline. For the randomized studies, spasms are triggered on P12 (7.5 mg/kg IP), P13 (12 mg/kg IP) and P15 (15 mg/kg IP) (Chern, et al., 2019). For drug treatment studies, the treatment drug vs. vehicle is started after the first bout of spasms at P12 diminishes to simulate the human condition of treatment initiation after the IS occur. Spasms can be reliably induced before P12, in primed model we used also P10 rats (Chachua, et al., 2011), previously in non-primed rats also P7 rats (Mareš and Velíšek, 1992). Note that the phenotype of NMDA-triggered spasms is fading between P25-P30 and the pattern of NMDA-induced seizures changes to the “adult” type with tonic-clonic seizures predominating (Mareš and Velíšek, 1992) so the spasms are age-specific, similar to human condition.

Figure 2 –. Time course of prenatal development of the CRF, melanocortin (ACTH), and corticosteroid system in the rat

Based on the rat strain, the duration of pregnancy varies between 21–23 days. In the rat, all organ systems with available information are developing from the mid-pregnancy on. Interestingly, development of CRF receptors precedes slightly occurrence of CRF itself (Bugnon, et al., 1982; Insel, et al., 1988; Lovenberg, et al., 1995). ACTH appears early, already present at the mid pregnancy, followed by its effectors, melanocortin receptor isoforms (MCR) (Kistler-Heer, et al., 1998). Appearance of corticosterone also precedes detection of glucocorticoid and mineralocorticoid receptors (GR and MR, respectively) (Noorlander, et al., 2006). Aldosterone, by contrast, is detected around birth (Bohn, et al., 1994).

Figure 3 –. Time course of prenatal development of the CRF, melanocortin (ACTH), and corticosteroid system in humans

In contrast to rodents, in humans, elements of both melanocortin and corticosteroid systems appear early during embryonic life (Taylor, et al., 1953; Thomas, et al., 2018). The melanocortin system appears to be functional by the first trimester of intrauterine development. Later, the CRF system appears as do glucocorticoid and mineralocorticoid receptors (Ackland, et al., 1986; Bresson, et al., 1987; Goto, et al., 2006; Kempna and Fluck, 2008).