Aetiology
More than half of those with infantile spasms have an identifiable underlying disorder such as periventricular leukomalacia, hypoxic-ischaemic encephalopathy, neuronal migration disorders, metabolic defects, and genetic disorders such as Down syndrome. The most recent classification of the aetiology of infantile spasms groups the causes as structural-metabolic, genetic, infectious-immune, and unknown groups.[2][3] See Classification.
Many children who would previously have been classified as idiopathic or cryptogenic are now being diagnosed with variants in genes associated with developmental and epileptic encephalopathy (DEE). Over 100 DEE genes have now been identified.[12] One third of children with tuberous sclerosis will develop infantile spasms, and these children comprise 10% of those with infantile spasms.[13]
Pathophysiology
Despite infantile spasms first being reported in 1841, there has been slow progress in understanding the pathophysiology and biological basis of the condition. The diverse aetiologies may converge on a final common pathway, culminating in the shared manifestation of this unique and specific seizure type. Indeed, it is known that many aetiologies of infantile spasms activate the stress response, including corticotropin-releasing hormone.[14] Exogenous corticosteroids have formed the empirical mainstay of treatment for over 60 years, and interruption of the stress response by adrenocorticotrophic hormone (ACTH)/prednisolone therapy may provide insight into the pathophysiology. Those with an unknown aetiology have lower excitatory parameters, such as nitric oxide, and lower inhibitory parameters, such as beta-nerve growth factor, ACTH, and gamma-aminobutyric acid in cerebrospinal fluid.[14] An immature, developing central nervous system may also be important in pathogenesis.
It is likely that, in the future, various animal models will provide further insight into the mechanisms of increased excitability and loss of inhibition that culminate in this age-specific seizure type, hypsarrhythmic electroencephalogram, and the accompanying significant cognitive impairment.[15]
Classification
International League Against Epilepsy (ILAE)[1][2][3]
Epileptic spasms, including infantile spasms, cannot be classified easily. According to the 2017 ILAE operational classification of seizure types, infantile spasms can have either a focal or a generalised onset, or onset may be unknown.[3]
Aetiological classification of infantile spasms should no longer include the terms 'idiopathic', 'symptomatic', and 'cryptogenic'. The 2017 ILAE report recommends that all seizures should be classified into one or more of the following six aetiological groups (of which structural, genetic, metabolic, and unknown are the most applicable to infantile spasms):
Structural: examples include cortical malformations and ischaemic brain injury
Genetic: examples include trisomy 21, and ARX and CDKL5 mutations
Metabolic: such as non-ketotic hyperglycinaemia and mitochondrial disorders
Infectious
Immune
Unknown.
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