medications infantile spasms west syndrome epilepsy seizures hypsarrhythmia eeg childhood epilepsy infant seizures developmental delay information myclonic baby acth

Medications

Adrenocorticotropic Hormone  (ACTH)

In 1958, Sorel reported administering ACTH to seven patients, four of whom responded within a few days and only one of whom had no response at all (21). Despite nearly a half century of use, there is no agreement about dose or duration of treatment. Dosing ranges from 0.2 IU/kg/day (22) to 150 IU/m2 (23). However, the very low doses are not really comparable with the higher ones, as most of the very low-dose studies were performed in Japan where they used synthetic ACTH, which requires a much lower dose (~1:40) compared with the natural product available in the United States. A commonly used ACTH dose is 40 IU/day. Riikonen reviewed seven studies and could not verify a better response using 150 IU/day compared with 40 IU/day (24). The overall long-term response rate is 53 to 91 percent. A frequently used approach is to begin with 40 IU/day for 1 to 2 weeks. If there is an incomplete response, the ACTH may be increased to 60 IU/day or even to 80 U/day. If ACTH is successful in completely controlling the spasms and the hypsarrhythmia disappears from the EEG, then the ACTH is tapered over 1 to 4 months. If ACTH has not been successful, it should be rapidly tapered, discontinued, and another medication should be tried.

ACTH side effects are significant. The majority of children will develop cushingoid obesity and become very irritable. More serious side effects may develop, including arterial hypertension, electrolyte imbalance, gastric ulcer, growth retardation, cardiomyopathy, and immunosuppression. In one study, the risk of serious side effects with ACTH was 43% in the children treated with 160 IU/day (25) but lower in children treated with lower doses. By keeping the dose as low as efficacy allows and the duration as short as possible, morbidity and mortality can be minimized. Patients receiving ACTH should be comedicated with a proton pump inhibitor to prevent gastrointestinal bleeding and should have follow-up visits, with regular blood pressure measurements and blood workup for electrolytes.

Vigabatrin

In 1991, Chiron et al. reported that vigabatrin showed remarkable efficacy with infantile spasms (26). Sixty-eight medically refractory patients were treated with vigabatrin as add-on therapy, and 29 of them (43%) showed complete resolution of the spasms. The authors also noted that 12 of 14 patients who had tuberous sclerosis responded with complete control. Numerous other studies confirm the observations of Chiron and colleagues (27, 28). Vigabatrin also may improve developmental outcome in patients with tuberous sclerosis (29). However, an important issue is how vigabatrin compares with ACTH. Vigevano et al. performed a randomized study of children with newly diagnosed infantile spasms. The patients were given either ACTH 10 IU/day or vigabatrin 100 to 150 mg/kg/day. Eleven of 23 vigabatrin patients responded (1 later relapsed) compared with 14 of 19 patients treated with ACTH (6 later relapsed). After relapses were taken into account, the long-term response rate was similar for the two groups (i.e., 10 of 23 with vigabatrin; 8 of 19 with ACTH) (30). ACTH was more effective for patients with perinatal hypoxic ischemic encephalopathy. There was no difference in the cryptogenic cases.

Vigabatrin generally is well tolerated in young children. There are reports of hypotonia, somnolence, or insomnia (26)—all of which would be expected from a drug that enhances GABA activity. Visual field constriction is the one serious side effect that substantially limits the use of vigabatrin. The visual loss is usually very subtle, so it took more than a decade to recognize the side effect (31). Since 1997, there have been numerous reports indicating that peripheral visual fields are constricted in 15 to 50 percent of adult patients. No one knows if visual field constriction occurs in very young children because there is no effective method of testing for it. However, given the catastrophic nature of infantile spasms, even if it is proven to occur in infants, visual field constriction may be an acceptable side effect to trade for seizure control and an improved opportunity for normal development (32). Thus, the visual field issue notwithstanding, many pediatric epileptologists consider vigabatrin to be the drug of choice for children with infantile spasms that are due to tuberous sclerosis and for other conditions as well.

Valproic acid

This is one of the most widely prescribed anti-epileptic drugs for children. It is sometimes effective in children with infantile spasms. Side effects which are common include increased appetite and stomach upset. Very occasionally more severe and unpredictable side effects occur, including sudden liver failure (which may begin as a vomiting illness with unexpected drowsiness).

Valproic acid probably has the best anecdotal evidence of efficacy, but there have been no prospective randomized studies of efficacy for infantile spasms. Doses range from 20 mg/kg/day to 100 mg/kg/day (37–39). Although none of the reported patients developed liver failure, it nevertheless is a risk in children less than 2 years of age (40) and should be used with caution for children with infantile spasms—virtually all of whom are less than 2 years of age. Thus, the risk/benefit ratio should be determined.

Benzodiazepenes

Of these drugs nitrazepam (Mogadon) has been most widely used in children with infantile spasms. Clonazepam (Rivotril) and clobazam (Frisium) are sometimes prescribed. These are drugs with an anti-epileptic effect. They may cause excessive sleepiness, altered behaviour and excessive salivation. Many doctors now believe that very long-term use of these drugs is not desirable, as there may be psychological dependence. Although benzodiazepenes may be useful in stopping seizures, it is not uncommon for seizures to restart at a later stage whilst on treatment. 

One of the earliest nonsteroid treatments for infantile spasms were the benzodiazepines (41) but are only occasionally successful. Clonazepam and nitrazepam both have anecdotal evidence of efficacy (42, 43). However, nitrazepam is associated with an increase in oral secretions and a higher incidence of aspiration and pneumonia, with several deaths reported in one series (44). Rintahaka et al. reported that the incidence of mortality with nitrazepam was 3.98 deaths per 100 patient years compared with 0.26 deaths per 100 patient years if the medication was discontinued (45). Thus, nitrazepam and possibly other benzodiazepines carry a significant risk of aspiration pneumonia and mortality and should be used with caution.

Zonisamide

Has shown some promise as an effective therapy for infantile spasms, but there have been no controlled or comparison trials to date. The Japanese experience suggests that zonisamide may be effective in about a third of patients (46). A recent report indicated that 5 of 25 patients with infantile spasms had a complete clinical and electrographic response to zonisamide within 1 to 2 weeks, with doses ranging from 8 to 32 mg/kg/day (47). Zonisamide is generally well tolerated. If the 30% or greater efficacy rates hold up in controlled studies, zonisamide could become a first-line therapy.

Topiramate

 was shown to be effective in 4 of 11 intractable infantile spasms patients in doses up to 25 mg/kg/day in a study by Glauser et al. (48). Mikaeloff et al. reported that topiramate reduced seizures in 43% of 14 infantile spasms patients, but 29% were made worse and none became seizure free (49).

Felbamate

 was considered promising as a therapy for infantile spasms—with three of four medically intractable patients, in one study, responding to it as an add-on therapy (50)—until aplastic anemia was identified as a serious side effect of the drug. Now that it is clear that the aplastic anemia does not affect prepubertal patients, felbamate actually may be as safe as some of the more commonly used drugs and could be recommended if other medications have failed.

Lamotrigine

 is another of the newer antiepileptic drugs with some anecdotal evidence of efficacy for infantile spasms, although there are no prospective controlled trials. One report of 3 patients who had failed vigabatrin and ACTH responded to lamotrigine in 1 dosage (51). The usual dose of lamotrigine is 6 to 10 mg/kg/day (52). The major side effect is rash, which is dependent to some extent on how rapidly the dose is increased. The usual recommendation is to increase the dose slowly over 2 months to the minimum expected therapeutic dose. Given the severe nature of infantile spasms and the need to achieve control as soon as possible, taking 2 months to get to a therapeutic level obviously decreases the value of lamotrigine as a therapeutic option. However, if the lowest dose is effective, then lamotrigine becomes a drug to try when standard therapies have failed.

Medications

medications infantile spasms west syndrome epilepsy seizures hypsarrhythmia eeg childhood epilepsy infant seizures developmental delay information myclonic baby acth

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