Infantile Spasms
IS are a syndrome characterized by the expression of an age-specific seizure manifestation, pathognomonic EEG patterns (hypsarrhythmia and electrodecremental responses) and often associated with a grim prognosis. IS have their onset between 3-7 months of age and 85% start before one year of age. They involve flexion of the body and adduction of the arms or legs (flexion spasms) or contractions of the extensor muscles with sudden extension of the neck and trunk with extension and abduction of the limbs (extension spasms). The ictal EEG pattern consists of an electrodecremental response. The interictal EEG recordings show a disorganized high voltage background with multifocal spikes called hypsarrhythmia32. After the onset of IS, many patients may begin losing developmental milestones and, subsequently, may become mentally retarded, as the epileptic encephalopathy progresses.
Although IS are classified by the Office of Rare Diseases as a rare disease with an incidence of 2.5 per 10,000 live births and a slight (60%) male predominance. However, the IS syndrome is not one actual disease. The causes of IS are diverse and can be multifactorial, often resulting from a combination of genetic predisposition and environmental insults. In one recent review, over 200 etiological and associative factors were linked to IS. For diagnostic purposes, IS can be classified into cryptogenic, idiopathic and symptomatic groups.
In the cryptogenic group, the infants appear neurologically normal; however, a CNS abnormality is suspected but cannot be documented by examination or diagnostic testing The incidence of cryptogenic IS in the cohorts we have assembled is 24% (Figure 1) and this is consistent with the literature (Yoshi verify). In the idiopathic group, the cause is unknown; the infants are normal prior to the onset of IS and remain normal if IS are controlled. A true idiopathic group is extremely rare.
Symptomatic IS are considered the consequence of an identifiable CNS disorder and comprise the largest proportion (76%) of our cases. However, symptomatic IS are manifestation of several rare diseases (Figure 1, smaller pie graph) such as TSC, post severe HIE, cerebral dysgenesis other than TSC, and various other such as cerebral dysgenesis other than TSC; known genetic disorders (ie Trisomy 21, inborn errors of metabolism associated etc); Miscellaneous causes (ie post traumatic, post-infectious, post neonatal stroke); and symptomatic NOS (not otherwise specified which include infants with abnormal development or neurological examination or brain atrophy on imaging but without a specific diagnosis).
The common manifestation in these rare diseases is the presence of IS and, indeed, it is not clear why some and not all patients with these diseases will develop IS. A major overall goal of the consortium is to identify factors that may underlie the development of IS and to develop specific biomarkers predicting their appearance and their progression. Indeed, the emergence of the IS is often associated with developmental regression that infants with a similar burden of disease but without spasms do not undergo. Without the knowledge of natural history, especially the frequency of spontaneous remission of IS, transition to different epileptic syndrome and cognitive impairments including autism spectrum disorders, correct outcome assessments of treatment trials is impossible.
Early recognition of IS and institution of early treatment is required to improve outcome. One of the goals of the consortium will be to assess the efficacy of treatments based on controlled studies of patients with IS secondary to the same underlying cause and similar intervals from onset of IS to the initiation of current treatments that leave a lot to be desired. Indeed, new treatments may be needed that can either be rare disease specific or even better work across the various rare disorders we are investigating. Such treatments can be identified from basic science studies performed in newly developed animal models of IS.