Different anticonvulsants have been used and drug resistant epilepsy described in AS patients. Today there is enough evidence that some drugs act better than others and that often, (as in RTT patients) movement abnormalities, tremors and attention deficit spells can be misinterpreted as seizures given that the EEG anomalies persist also in absence of crises.

From an accurate evaluation of 45 cases, Valente et al[30] reported a good control of crises with Valproate (VPA) alone or in association with benzodiazepines (fenobarbital PB or clonazepam CZP). Recurrent myoclonic SE were best controlled by VPA and ethosuximide. On the contrary, epilepsy was worsened by carbamazepine (CBZ), oxacarbazepine and vigabatrin[31]. Topiramate (Franz et al[32]) and ethosuximide (Sugiura et al[33]) were successful in small samples of AS patients with drug resistant epilepsy.

Dion et al[34] evaluated Lamotrigine(LMT) efficacy in 5 patients with different types of seizures (myoclonic, tonic clonic, atypical absences) unresponsive to other drugs (VPA, Benzodiazepines, phenytoine, carbamazepine and topiramate) obtaining a good control in 3 of them. The potential myoclonic effect of LMT limits its possible use in these patients, and more case controlled studies are needed.

Ketogenic diet was helpful in some children with untreatable epilepsy[4]. Piracetam is said to be effective in controlling distal myoclonus[26].

Non convulsive status epilepticus, which should be early treated according to protocols, demonstrated a variable response to treatment with benzodiazepines, ketamine and corticosteroids[35] in limited number of patients.

Personal experience

Our series of patients with AS showed a seizures type distribution similar to that reported in Literature. All patients had febrile seizures before the onset of a frank epilepsy. Myoclonic seizures were the most frequent in infancy, followed by atypical absences and tonic clonic seizures. None had convulsive SE. Valproate and topiramate were preferentially used anticonvulsants but in the majority of cases epilepsy was hardly controlled. The critical EEG showed parossistic 1-1.5 c/s discharges of spike-waves complexes. The background activity was constituted by a persistent generalized 4-6 hz activity arising from the temporo-parietal regions (Fig. 2a). With time the EEG pattern changed showing a very slow background activity mixed with multifocal spikes (Fig. 2b).

Figure 2 EEG at different ages. (a) Generalized burst of spike and spike waves with high amplitude, prevalent in the anterior regions, (b) Very slow background activity mixed with multifocal spikes. Full size image

Besides these data, our personal experience suggests us the importance of a early diagnosis in view of a possible familial recurrence. Babies with AS, are initially easily unrecognized as the facial and behaviour phenotype become clear later in life. Seizures can occur as early as the first few months and other more common diagnosis are often considered (i.e. perinatal brain hypoxia, febrile seizures, B6 unresponsive seizures). At that age, the observation of fine finger tremors may represent the only clue that should press the clinician to ask for genetic tests.

Later in life, in girls with microcephaly, seizures, stereotyped hand movements and hyperventilation Rett syndrome must be ruled out.

Nevertheless, a number of patient can remain undefined on a molecular basis. We now are aware of another condition, named Pitt-Hopkins syndrome with similar clinical signs and we suggest to verify also this possible diagnosis in AS and RTT cases without a molecular confirmation. Pitt-Hopkins syndrome, initially described in 1978 in two unrelated patients with mental retardation[36], is characterized by severe psychomotor delay, seizures and recurrent episodes of hyperventilation, acquired microcephaly and distinctive facial appearance: large nose with high philtrum, cupid's bow lips, macrostomia and wide-spaced teeth. With time a progressive protrusion of the lower face structures appear. This phenotype can easily suggest the diagnosis of AS being often associated with happy demeanor, sleep disturbances and seizures. EEG shows occipital or central delta waves unusual for the age and, in older patients, pseudoperiodic complexes during wakefulness mixed with spikes and slow spike/waves.

Pitt-Hopkins syndrome is linked to a microdeletion of chromosome 18q21 and mutations of the TCF4 gene[37]. This gene shows a widespread expression in developing human embryos playing a role on cell fate determination and differentiation during development. The impaired development of the noradrenergic neurons pathway might cause abnormal respiratory network inside the brain.