Infantile spasms: Toward a selective diagnostic and therapeutic approach (2010)

To the Editors: In this issue of Epilepsia, Pellock et al. (2010) provide an excellent overview of infantile spasms (IS) in the form of a consensus report by a reliable panel of experts. The recent marketing of vigabatrin in the United States, more than 10 years later than in “Old Europe,” justifies this renewed interest. However, given the cultural and historical differences between the United States and the rest of the world, a few additional remarks are required. The last word of the consensus report is “disease.” IS is all but a disease. Rather, it is a final common pathway of various diseases that share similar features within a specific age range and that express transient—although eventually prolonged—hyperexcitability of the brain. IS is the prototype of epileptic encephalopathy, in which epilepsy plays a major or exclusive role in psychomotor delay or deterioration. Although usually the revealing symptom, spasms may be so mild that several months may pass before the clinician finally pays close attention to the parents’ report of mere behavioral abnormality. The parents may have noticed lack of visual contact, and when no ophthalmologic cause can account for this behavior, investigating brain function with an electroencephalography (EEG) should be the next—but early—step. Onset of IS may be delayed after the age of 1 year when the child has acquired the ability to walk, and spasms cause him to fall; these drop attacks may be erroneously interpreted as myoclonic seizures or negative myoclonus. Although IS should be addressed as an expression of various diseases, the specific clinical manifestation should also be included in the description of specific diseases. Indeed, there is growing evidence that given etiologies determine specific IS clinical/neurophysiological/imaging patterns, permitting the diagnosing physician to include IS into the whole story of the patients’ disease. Therefore, although hypoxic–ischemic encephalopathy is an underlying basis of IS, whether IS occurs following preterm or full-term delivery will partly determine the course. Spasms following preterm delivery usually respond well to medication, and no chronic treatment is required, whereas the course of spasms following full-term delivery tends to be more severe (possibly due to cortical, not white matter, damage). Previous psychomotor delay and/or dysmorphia are clues to identifying IS associated with Down syndrome, 1p36 del, or other chromosomal aberrations. The combination of dystonia with spasms in a boy suggests a mutation in the ARX gene. Delayed onset of spasms (second year of life) combined with diplegia may suggest leukomalacia or a temporal lobe lesion or duplication of the MECP2 gene if it is a boy, or a cryptogenic condition in which tonic and absence seizures are combined with the clusters of spasms (Eisermann et al., 2006). Although not specific, the sequence of early onset of tonic seizures in a girl with no interictal EEG abnormality, followed by spasms and hypsarrhythmia, suggests CDKL5 mutation (Bahi-Buisson et al., 2008). Diffuse high-amplitude fast EEG rhythms before the administration of any drug indicate lissencephaly/pachygyria. Focal interictal slow waves suggest some focal brain lesion. Asymmetric spasms or focal seizures preceding or combined with the spasms, with or without hypsarrhythmia, suggest some focal or multifocal malformation, including Aicardi syndrome, hemimegalencephaly, tuberous sclerosis complex (TSC), or cortical dysplasia [that may require positron emission tomography (PET) scan for diagnosis]. Magnetic resonance imaging (MRI) T2 hypersignal in the basal ganglia suggests some inborn error of metabolism involving the respiratory chain or other energy supply defect. Clinical phenomenology (for example, no loss of visual contact) and EEG features in a child with negative history may make it possible to exclude brain lesion and predict favorable outcome: the rare “idiopathic” cases that require several hours video-EEG monitoring to be identified. Spasms without hypsarrhythmia, but only focal or multifocal spikes and ongoing psychomotor progress, may alternatively suggest focal cortical dysplasia or TSC. Once the spasms have been replaced in their etiologic context, it is possible to treat the disease itself not merely a transient phenomenon. An important part of this treatment is to explain to parents that the lack of interaction often associated with IS is a consequence of the EEG anomalies; distorted sensorial perceptions explain the infant’s poor interaction with the surrounding. The impact on psychomotor development that characterizes epileptic encephalopathy justifies vigorous treatment, not a progressive build-up as is often done to treat epilepsy. Delay to success with vigabatrin is overestimated by studies in which vigabatrin was introduced as the second or third compound. Vigabatrin at 100 mg/kg/day, as first drug, controls the spasms within less than a week in most instances (Granström et al., 1999). For causes of IS other than TSC, although hormonal treatment controls IS better at onset, the incidence of early relapse explains the fact that long-term results are similar to those with vigabatrin. Nevertheless, patients may respond to one treatment only, and replacing a first compound that failed by the alternate medication may be helpful. There is no evidence that, following failure of hormone and vigabatrin treatments, the ketogenic diet is better than pyridoxine or conventional compounds—lamotrigine, valproate, topiramate, sulthiame, or zonisamide. However, a specific indication may be identified in the future. The duration of treatment is another issue. Cortical malformations tend to produce chronic epilepsy in which IS is only transient. Given the risk of relapse with refractory spasms resulting in cognitive deterioration, vigabatrin should be maintained for several years, ideally until the age-related hyperexcitability in the rest of the brain has disappeared (perhaps to the end of the first decade in some patients). Determining how long this therapy should be maintained is one of the greatest current challenges, to be balanced with retinal toxicity of vigabatrin. However, patients with no cortical lesion—for example, those with Down syndrome, leukodystrophy, or cryptogenic cases—usually require no chronic treatment following the control of spasms; hormonal treatment may be stopped after only 1 month and vigabatrin after 6 months. IS should be considered in an etiologic context, both for diagnostic and therapeutic strategies. This concept likely applies also to the development of experimental models. Because IS is not a disease in itself (except for the “idiopathic form”), any search for a model of IS can only be disappointing. However, transgenic approaches may offer opportunities to develop models of specific diseases that include spasms. None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.