Hormonal treatment and vigabatrin
As in all epilepsies, also in EEs the most appropriate treatment is based on the accurate diagnosis of the epilepsy syndromes. Following what has been suggested in a recent publication by McTague and Cross (2013), it is possible to summarize treatment of EEs using the recommendations of the expert consensus of the National Institute for Clinical Excellence (NICE) (http://www.nice.org.uk/cg137).
Table 1 shows treatments suggested for different epileptic syndromes with EEs.
Table 1. AED option by epilepsy syndrome
| ||First-line AED||Adjunctive AEDs||AEDs that may be considered on referral to tertiary care||AEDs that may worsen the EE|
|EIEE|| || || || |
|MPSI|| || || || |
|Infantile spams/West syndrome not due to tuberous sclerosis||ACTH||Vigabatrin|| || |
|Infantile spams/West syndrome due to tuberous sclerosis||Vigabatrin||ACTH, prednisolone|| || |
|Dravet syndrome|| || || || |
|CSWS|| || ||Ketogenic diet|| |
|LGS||Sodium valproate|| || || |
Multiple subpial transection
|MAE|| || ||Ketogenic diet|| |
Efficacy of conventional AEDs is poor in EEs; in Table 1 medications are listed that we might consider “specific” for EEs, as they are used exclusively used in some syndromes; these medications include adrenocorticotropic hormone (ACTH) and corticosteroids, or stiripentol.
ACTH has been used for the treatment of infantile spasms (IS) worldwide since the work of Sorel and Dusaucy-Bauloye (1958).
Even if corticosteroids and vigabatrin (VGB) demonstrated efficacy in the treatment of IS, ACTH still should be considered as a first-line option for this condition (MacKay et al., 2004). After ACTH treatment about 60% of patients with spasms become seizure free; this is a higher percentage than in cases treated with corticosteroids and VGB. Relapse rate after treatment with ACTH is about 30% (Hrachovy et al., 1983).
Although has been gain experience for >50 years, there is no consensus on which agent should be used preferentially and, particularly in the case of ACTH, on the optimal dosing schedule. The only finding through a Cochrane review aimed to determine the efficacy of corticosteroids in terms of seizure control, improvements in cognition, and quality of life is one crossover trial with a small number of patients (Gayatri et al., 2007).
In 2004, MacKay et al. performed an exhaustive meta-analysis of the literature on the medical treatment of IS. Their work confirmed that, despite the widespread use of ACTH and steroids, there are few prospective studies and only five randomized trials showing the efficacy of this drug. Moreover, treatment protocols differ significantly as concerns the dosage, ranging between 0.2 IU/kg and 150 IU/m2, the duration of highest dose, ranging from 7 to 40 days, and the duration of treatment, ranging from 3 to 12 weeks.
Recently Pelloch et al. published the consensus of the U.S. Infantile Spasms Working Group (ISWG) (Pellock et al., 2010) confirming that ACTH should be considered as a first-line treatment for IS, and a low dose treatment with short duration (approximately 2 weeks followed by taper), was suggested.
Oral corticosteroids seem to be less effective than ACTH: the more used drug is prednisolone, even if hydrocortisone is preferred in France.
After broad use in several types of epilepsies, and following the discovery of a peripheral visual field defect as a specific adverse effect, VGB is now exclusively used in the treatment of IS. Some studies confirmed the efficacy of VGB in around 50% of nonselected cases; this percentage increases to 100% in cases with IS that are symptomatic of tuberous sclerosis (Chiron et al., 1997).
The United Kingdom Infantile Spasms Study (UKISS) (Lux et al., 2005; Darke et al., 2010) compared the use of ACTH or oral prednisolone with VGB in a prospective study and found that after 2 weeks of treatment, spasm cessation was achieved in 40 (73%) of 55 patients randomized to hormonal treatment, compared to only 28 (54%) of 52 patients randomized to VGB, even though long-term seizure outcome did not differ between the two treatments. Hormonal treatment was also associated with a better developmental outcome. In a randomized study by Vigevano and Cilio (1997), evidence for a superior efficacy of ACTH over VGB in IS not due to tuberous sclerosis, at least in the short-term, has also been provided.
VGB could be considered as an alternative option to hormonal treatment, even if the duration of treatment should be the shortest the possible, considering the risk of visual field defect.
The hormonal treatment is considered as a first-line treatment also in CSWS, and in Landau-Kleffner syndrome (LKS) (Veggiotti et al., 2012). Both entities are characterized by an extreme activation of EEG abnormalities that are continuous during sleep. The increase of EEG epileptiform abnormalities is associated with a severe cognitive and behavioral impairment. Van Bogaert et al. (2006) in a multicenter study clearly demonstrated that the efficacy of conventional AED, mainly valproate (VPA), ethosuximide (ETS), and sulthiame, is often incomplete and transitory. Carbamazepine (CBZ), phenobarbital (PB), and phenytoin (PHT) are ineffective and may even increase EEG epileptiform abnormalities and the clinical conditions.
The hormonal treatment with prednisolone or hydrocortisone, short and prolonged ACTH, or corticosteroid therapy, or intravenous methylprednisolone pulses followed by oral prednisolone, result in an improvement of language, cognition, and behavior in almost all patients, and is usually accompanied by an improvement on the EEG. Some patients might relapse during steroid withdrawal, requiring second hormonal treatment. The risk of relapse seems to be related to a brief duration of treatment. The relapse is not the rule, and in several patients a unique treatment may arrest the disease.
The positive response to hormonal treatment is highly significantly associated with reversal of cognitive impairment in long-term evaluation (Buzatu et al., 2009).
The hormonal treatment is also used in early infantile epileptic encephalopathy (EIEE) and in Lennox-Gastaut syndrome (LGS) without significant success.
Stiripentol is a drug that is used exclusively for the treatment of Dravet syndrome (DS) (Chiron & Dulac, 2011). The efficacy of DS in combination with clobazam and VPA has been demonstrated in a randomized placebo-controlled trial (Chiron et al., 2000).
Stiripentol acts both through cytochrome P450 (CYP) inhibition and increasing the action and the plasmatic levels of clobazam and VPA, sometimes requiring a reduction of dosage. Likely stiripentol also has a direct anticonvulsant activity owing to enhancement of inhibitory γ-aminobutyric acid (GABA)ergic neurotransmission (Quilichini et al., 2006; Grosenbaugh & Mott, 2013).
Stiripentol seems to be active in the reduction of the number of prolonged seizures that are the hallmark of DS. In addition, stiripentol has been used recently to treat other conditions. Few anecdotical case have been reported showing its efficacy, though data should be confirmed.
The ketogenic diet (KD) is an alternative treatment used in association with conventional AEDs to treat drug-resistant epilepsies in children, and frequently to treat EEs (Freeman et al., 2006).
It has been found to be particularly effective in myoclonic astatic epilepsy (MAE) with positive results in >50% of patients, almost 30% of them becoming seizure free (Caraballo et al., 2006). Caraballo (2011) also reported very good results with KD in DS, with 10 of 16 patients having a 75–99% decrease in seizure frequency and the remaining having a 50–74% decrease in seizures.
Similar results to that reported with other conventional AEDs have been documented in the treatment of LGS (Lemmon et al., 2012).
Following McTague and Cross (2013), KD seems to be particularly effective in EEs with generalized seizures, especially in cases with a prominent myoclonic component.
It is noteworthy that KD is a first-line treatment for patients with GLUT-1 defects and with pyruvate dehydrogenase deficiency, as it provides an alternative cerebral energy source.