Infantile sPAsMs AND west sYNDRoME

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Natural or synthetic adrenocorticotropic hormone (ACTH), glucocorticosteroids and vigabatrin (VGB) are the main pharmacological agents currently suggested for the treatment of infantile spasms (IS). In addition, conventional and newer anti-epileptic drugs, as well as vitamin B6, are used. There is no agreement which agent should be commenced first line. Protocols differ in dosing regimes as well as duration of treatment courses, depending on geographical area and availability of these agents. VGB is not licensed in the US, natural ACTH has been replaced by synthetic ACTH in some European countries and Japan, and different types of oral steroids are in use. Despite a large number of published trials investigating efficacy and tolerability of VGB, glucocorticosteroids, ACTH and other anti-epileptic drugs for the treatment of ISs, only limited conclusions can be drawn due to differences in design and treatment protocols as well as poor overall quality of most randomized studies [38, 39]. Two systematic literature reviews have been published recently: (i) the practice parameter for the medical treatment of infantile spasms of the American Academy of Neurology (AAN) and the Child Neurology Society based on a review that included 159 articles (published between 1966 and May 2002) classified into four levels of evidence (Class I: prospective randomized controlled trial with masked outcome assessment; Class II: prospective matched group cohort study in representative population with masked outcome assessment; Class III: all other controlled trials, including natural history controls or patients serving as own controls; Class IV: uncontrolled studies, case series, case reports or expert opinion) [39] and (ii) a Cochrane review in the UK that included 11 randomized controlled trials [38].

ACTH and oral steroids

Hormonal therapy in the form of ACTH has been used for the treatment of infantile spasms for more than 40 years. It is thought to reduce corticotropin-releasing hormone (CRH) through its action on cerebral melanocortin receptors [40]. There is evidence from animal rodent models that CRH has epileptogenic properties in the immature brain. CRH is also increased in patients with infantile spasms [41]. Another suggested mode of action is the modulation of neurocorticosteroids that act on GABAa receptors [42].

The AAN practice parameter concluded that ACTH is probably effective for the short treatment of IS and resolution of hypsarrhythmia [39]. The proportion of patients experiencing cessation of spasms, usually within 2 weeks of treatment, varied between 42% and 87% in five randomized trials (one class II and four class III trials). The total duration of treatment ranged from 4 to 12 weeks (highest dose 2 to 6 weeks) and relapses occurred in 15-33%. There was insufficient evidence to recommend an optimum dose. One class I [43] and one class III trial [44] comparing low-dose against high-dose regimes revealed no significant differences: Hrachovy et al. 1994 compared 150 IU/m2/day with 20-30 IU/m2/day (natural ACTH) and Yanagaki et al. 1999, 1 IU/kg/day with 0.2 IU/kg/day (synthetic ACTH). Dosing regimes for ACTH vary according to country, with starting doses of 10-20 IU/day (synthetic ACTH) used in Japan to 150 IU/m2/day, more commonly 40 IU/day for 1-2 months in the US [45].

With respect to oral glucocorticosteroids the AAN review concludes that there is insufficient evidence for efficacy of oral steroids in the treatment of IS. One class II and several class III trials showed cessation of spasms in < 42% of patients at doses of 2 mg/kg/day. Two studies (Baram et al., 1996; Hrachovy et al., 1983) compared ACTH with prednisolone (2 mg/kg/day). Whilst Baram et al. showed superiority of ACTH vs. prednisolone using a high-dose regime (150 units/m2/day), Hrachovy et al. failed to show a difference with lower doses of ACTH (2030 units/day). In the Cochrane review, results from the two studies were combined showing a responder rate of 67% for ACTH compared with 31% for prednisolone (Peto odds ratio 4.2, 95% confidence interval [CI] 1.4-12.4). The authors concluded that treatment with ACTH was superior to low-dose prednisolone (2 mg/kg/day).

The common reported adverse effects associated with ACTH treatment and oral steroids are hypertension, irritability, infection and cerebral atrophy. Hypertension and cerebral atrophy were more common with higher doses of ACTH [39]. In addition, longer duration of ACTH treatment was associated with cardiomyopathy [46]. A number of retrospective studies, as well as an open-label prospective comparative study from Japan, suggest that lower doses of synthetic ACTH (doses ranging from 0.2 to 1.28 IU/kg/day) are better tolerated than and as effective as higher doses [44, 47]. A total of 51 out of 106 patients were seizure free at follow-up (98 patients were followed > 2 years) in one retrospective series [48]. Cessation of spasms and resolution of hypsarrhythmia was reported in 17 out of 27 (55%) patients treated with 0.2 IU/kg/day for 2-3 weeks [49]. Of the 27 patients that were followed up for > 12 months, 13 (48%) remained in remission, including one patient who received a second 2-week treatment course of synthetic ACTH at higher dose (1 IU/kg/day). Cryptogenic ISs show better responses compared with symptomatic cases that may require higher doses [48, 50].

Vigabatrin

Vigabatrin (VGB) increases availability of the inhibitory neurotransmitter y-aminobutyric acid (GABA) by binding irreversibly to its degrading enzyme, GABA transaminase. Because it is only minimally metabolized and almost entirely eliminated by renal secretion, there is no induction of hepatic enzymes and interaction with other anti-epileptic drugs. Efficacy of VGB for the treatment in IS has been shown in a number of studies. The AAN review identified three controlled trials (one class I, two class III), including one randomized placebo-controlled trial, and 11 class IV studies. In the three controlled studies, 22-44% of symptomatic IS and 27-55% of idiopathic IS responded with relapse rates ranging from 8% to 20%. Higher doses of VGB (100-150 mg/kg/day) appear to be more effective for seizure cessation and resolution of hypsarrhythmia. However, Mackay et al. were unable to determine dose dependency from nine prospective trials with various dosing regimes because the number of patients was too small [39]. Patients with IS associated with tuberous sclerosis (TS) show particularly good responses to VGB. In their systematic review, Mackay et al. pooled data from seven studies (two class III and five class IV) showing remission of spasms in 41 (91%) out of 45 patients [39]. Another small trial comparing VGB with hydrocortisone, which included only patients with TS, found 100% responder in the VGB group (n = 11) vs. 4 out of 11 (45%) in the hydrocortisone group [51].

Adverse effects include sedation, irritability, insomnia and hypotonia leading to withdrawal in 0-6% [39]. Of more concern are irreversible concentric visual field defects that occur in up to 43% of patients [52-54]. Whether these effects are dose dependent and cumulative over time or are the result of an idiosyncratic drug reaction is a controversial topic [52, 55, 56]. The evaluation of visual fields is difficult in infants. Although alternative assessment methods that are tolerated by young children have been developed, at present no recommendations can be made with respect to frequency and methods used for evaluation [57, 58, 39].

Vigabatrin vs. ACTH or Prednisolone

A recently published multicentre randomized controlled trial compared effectiveness of tetracosactide (synthetic ACTH: 0.5 mg [40 IU] on alternate days for 2 weeks, increased to 0.75 mg [60 IU] on alternate days if seizure control had not been achieved after 1 week), prednisolone (10 mg four times per day for 2 weeks, increasing to 20 mg three times per day if seizures were not controlled after 1 week) and VGB (maximum dose 150 mg/kg/day) for the short-term treatment of cryptogenic and symptomatic IS. After 2 weeks, patients allocated to prednisolone or tetracosactide received a reducing dose of prednisolone (reduction by 10 mg every 5 days or, if on a higher dose of prednisolone, reduction to 40 mg, 20 mg and 10 mg every 5 days). Patients with TS were excluded, presuming VGB to be more effective in TS [59].

Cessation of spasms on days 13 and 14 was more likely with hormonal treatments - 78% of patients enrolled to prednisolone and tetracosactide vs. 54% in the VGB group were spasm free (difference 19%, 95% CI 1-36, P = 0.045). The early superior effect of corticosteroids was not maintained in the long term. The study was under-powered to establish difference or equivalency between prednisolone and tetracosactide. At follow-up after 12 or 13 months, there was no difference between the treatment groups with respect to proportion of patients with absence of spasms (80 out of 106, 75%) and patients seizure free (60 out of 106, 57%) [60]. The neurodevelopmental outcome was assessed using the Vineland Adaptive Behaviour Scale (VABS), a survey questionnaire that is completed through an interview with carers. The VABS composite score in the subgroup of patients with no aetiology was higher in the hormone-treatment group (difference 9.3, 95% CI 1.3-17.3; P = 0.025) at 14 months' follow-up compared with the VGB group. Five children had died during the follow-up: one child with Staphylococcus aureus septicaemia on day 15 of prednisolone treatment and four children died later from other causes (Leigh's disease, aspiration pneumonia and epileptic encephalopathy).

other Agents

Sodium valproate (VPA), benzodiazepines (nitrazepam, clonazepam), topiramate (TPM), zonisamide (ZNS) and high-dose pyridoxal-phosphate have been used for the treatment of IS. The majority of studies are uncontrolled retrospective or prospective case series providing insufficient evidence for their efficacy [39]. One controlled study compared nitrazepam with ACTH [61]. The reported outcome measure, however, was reduction rather than cessation of spasms. The proportion of subjects showing > 50 % reduction of spasms in the short term was higher in the nitrazepam group. However, relapse rates, effects on EEG and long-term outcome are not reported [38]. Although suppression of spasms and improvement of EEG abnormalities can be achieved with benzodiazepines such as nitrazepam and clonazepam, unwanted effects such as hypotonia and increase of secretions with risk of aspirations limits their use in clinical practice [46]. Sodium VPA, often used in higher doses (27 mg/kg/day to 100 mg/kg/day or 100-200 mg/kg/day), suppressed spasms in 70-90% of patients with relapses in 23% of cases. Thrombocytopenia has been observed in several studies [39].

A small pilot study showed that TPM (doses 8-25 mg/kg/day) suppressed spasms in 5 of 11 (45%) young children, who did not respond to other anti-epileptic drugs. One child relapsed (20%) and after 18 months, four (36%) remained seizure free. Adverse effects were irritability, sleep disturbance, rapid breathing and unsteadiness. Data from recent case series are more disappointing, showing cessation of spasms in 0-20% in the short term [62, 63], in 16% (9 out of 54) after long-term follow-up [64] and around one-third of patients showed > 50% seizure reduction [62, 63]. The mean doses of TPM were lower in two of these studies (4.7 mg/kg/day and 5.2 mg/kg/day) [63, 64]. The most common reported side-effects included irritability, weight loss and anorexia. In addition, clinically symptomatic metabolic acidosis has been reported recently in case series of infants and toddlers [65].

A number of Japanese case series report cessation of spasms after treatment with ZNS in 20-38% (doses 4-13 mg/kg/day) [66]. The proportion of responders was higher amongst cryptogenic IS. Over one-third of patients relapsed as documented in two studies with long-term follow-up [67, 68]. A recent study reported cessation of spasms and resolution of hypsarrhythmia in 6 of 23 (26%) children with symptomatic IS. Children who were refractory to ZNS failed also to respond to VBT and ACTH [69].

Around 30 of 216 (15%) of patients with IS went into remission following treatment with high-dose PLP (30-50 mg/kg/day). This was more likely to occur with cryptogenic cases. Twenty per cent relapsed (all symptomatic IS) within 10 months after initial suppression of spasms [70]. The efficacy of sulthiam ([STM], doses 5-10 mg/kg/day) has also been investigated in a multicentre randomized placebo-controlled trial that included 30 symptomatic and seven cryptogenic IS patients. All patients were started on pyridoxine 3 days prior to and continued treatment during the 6-day double-blind period. Six of 20 (30%) patients in the treatment group responded (cessation of spasms and resolution of hypsarrhythmia) and none in the placebo group (n = 17). The three TS patients in the treatment group failed to respond. Somnolence was more commonly observed in the treatment group (4 out of 20 [20%] vs. 1 out of 17 [6%]). None of the responders relapsed during the follow-up period (6-32 months, mean 16 months) [71]. The ketogenic diet is a further option in resistant cases and will be discussed later in this chapter.

Further data are required to make evidence-based recommendations on the treatment of infantile spasms. The choice remains between steroids and vigabatrin as first-line therapy and this may be influenced by the aetiology, and preference of the caring physician with the parents. Synthetic ACTH and oral steroids appear to be most efficacious in short-term control only of infantile spasms without TS but are associated with significant side-effects. Data from retrospective series suggest that a greater time lag between appropriate treatment and remission of spasms [72-74] or more recently longer duration of hysparrhythmia [75], is associated with a more unfavourable developmental/cognitive outcome. However, there is a lack of data from prospective longitudinal studies that use appropriate standardized methods for the neurodevelopmental evaluation, to support the view that early aggressive treatment would achieve a better cognitive outcome independently from the underlying aetiology. The choice of the most appropriate treatment has to be made for each patient in discussion with the parents under consideration of the individual clinical circumstances and adverse effects.

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