The update provided by the Infantile Spasms Working Group (ISWG) in the United States (Pellock et al., 2010) has sought to improve understanding and treatment of infantile spasms (IS). These goals are certainly worthwhile, but it should be appreciated that treatment approaches differ in Europe from the protocols described in this U.S. perspective.

Adrenocorticotropic hormone (ACTH) and vigabatrin are the first-line treatments for IS. There is insufficient evidence to recommend the optimal drug dosage and duration for treatment of ACTH or vigabatrin therapy. Synthetic, long-acting ACTH is used in Europe, but it is not available in United States; natural ACTH is used in the United States, but it is not available in Europe. There are no data comparing the effects of these two drugs. Natural ACTH is much more expensive than synthetic ACTH. The relatively serious side effects of the synthetic drug, which is given on alternate days, are probably due to its prolonged action. The doses of ACTH used in Europe are smaller than those often used in United States. Baram et al. (1996), in a small prospective study, showed high initial response rate (89%) using ACTH 150 U/m2/day. However, no data were given describing the long-term effects. In other studies (Hrachovy et al., 1994; Riikonen, 2001), no significant differences were seen in either response or relapse rates between the patients assigned to high-dose versus low-dose ACTH therapy. The side effects are less and the long-term intellectual outcome is better in patients given low doses (Riikonen, 2001). In a prospective study from the United Kingdom (Lux et al., 2004), 107 patients were randomized to synthetic ACTH, 0.5 mg/day, on alternate days or prednisolone, 40 mg/day; the response rates were 76% and 70%, respectively (not significantly different) at day 14 of treatment.

In Europe, opinions are divided with regard to the first-line drug for IS. Vigabatrin has gained popularity because of its ease of use and effectiveness (Parisi et al., 2007; Willmore et al., 2009), but compared to vigabatrin, ACTH has a response in a higher proportion of patients (Vigevano & Cilio, 1997; Lux et al., 2004, tuberous sclerosis excluded in the latter study). Depending on the study, after 2 weeks of therapy patients treated with vigabatrin were seizure-free in 26% (Granström et al., 1999), 23% (Elterman et al., 2001), and 54% (Lux et al., 2004) of cases. However, at 3 months, the number of seizure-free patients increased to 60–65% in the two former studies. These data suggest that the response with vigabatrin comes later than with ACTH. After 14 months of treatment there was no difference in seizure frequency between patients treated with vigabatrin and those treated with oral hormones (Lux et al., 2004).

The most important goal of therapy is the achievement of good cognitive outcome.The molecular mechanisms that lead to the long-term consequences of IS are poorly understood. In children with IS, insults or stress in early life may affect the synthesis of insulin-like growth factor-1 (IGF-1), which might play a role in the reduction of certain cognitive functions (Riikonen et al., 2010). Early cessation of the spasms appears to be important in achieving optimal cognitive outcome. Better initial control of the spasms in patients allocated to hormonal treatment was associated with significant better cognitive outcome at 14 months and 4 years of age in infants with no identified etiology (Lux et al., 2005, Darke et al., 2010).

Both ACTH and vigabatrin may have severe side effects. The side effects of ACTH are well known, treatable, and reversible. The visual field defects caused by vigabatrin are permanent. Visual field defects occur in one-third of children aged 9 to 19 years, but it is not known how frequent they are in infants. In 2009, the U.S. Food and Drug Administration (FDA) in the approved vigabatrin “if the patients have periodic ophthalmologic evaluations beginning with a baseline evaluation at initiation of therapy as well as 3–6 months after cessation of treatment.” However, to date there is no way to investigate young children younger than 8 to 9 years of age because they are not cooperative at such a young age.

Recent reports have revealed new alarming side effects of vigabatrin. Drugs such as vigabatrin that increase synaptic concentrations of γ-aminobutyric acid (GABA) in the brain can also cause apoptotic degeneration in the developing animal brain (Bittigau et al., 2003). Furthermore, hyperintensities in the basal ganglia, thalamus, brainstem, and dentate nucleus seen on magnetic resonance imaging (MRI) have been shown (Wheless et al., 2009). These MRI abnormalities may occur after 3 months of therapy, and are reversible when the therapy has been discontinued, but may remain unnoticed in patients with psychomotor retardation and dyskinetic movements. The clinical significance of these MRI abnormalities is unknown.

The ISWS report indicates that outcome measures of IS should be “all-or none” [presence or absence of IS, hypsarrhythmia, or epileptiform electroencephalography (EEG) discharges]. However, serial video-EEG recordings show that during vigabatrin treatment there is a transition of motor spasms to subtle spasms (Gaily et al., 2001). Parental reporting is absolutely not sufficient to determine the effectiveness of treatment, particularly since continuing hypsarrhythmia may be associated with unrecognized spasms. A careful clinical and EEG assessment of such infants is required.

Can relapses be avoided with prolonged steroid or vigabatrin treatment, or will we induce more side effects with prolonged treatment (e.g., glucocorticoid-induced cognitive decline (Yeh et al., 2004), or vigabatrin-induced visual field defects and apoptosis in the brain)? The latter possibility would favor the use of short-lasting treatment, 2–3 weeks of ACTH (as recommend by the ISWG) and <3 months of vigabatrin (Willmore et al., 2009).

In Finland, the following guidelines are given (Guidelines of Childhood Epilepsy, 2007): After a short trial of pyridoxine, ACTH or vigabatrin is the first-line drug. ACTH will bring more rapid cessation of the spasms in larger numbers of patients, and might be connected with better cognitive outcomes in the group of IS with unidentified etiology. Vigabatrin should be used a first-line drug for tuberous sclerosis. Because of severe side effects of ACTH and vigabatrin, the smallest effective dose and shortest duration of therapy are used. The dose of ACTH may be 0.03 mg/kg or 0.5 mg, i.m., on alternate days for 2 weeks and then a tapering of the dose during the next 2 weeks, or alternatively doubling the dose to 0.06 mg/kg for 2 weeks and then tapering (Riikonen, 2009). Both drugs may be second-line drugs for children who do not respond. In therapy-resistant cases, valproate, topiramate, lamotrigine, or nitrazepam may be used. Early surgical intervention may also be necessary.


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