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Brain maturational aspects relevant to pathophysiology of infantile spasms
G Avanzini1, F Panzica, S Franceschetti
1Department of Experimental Research and Diagnostics, Istituto Nazionale Neurologico Carlo Besta, 21033 Milan, Italy.
Insights
Infantile spasms (IS), a severe epilepsy, may stem from cortical discharges influencing brain stem circuits during a specific developmental window. This is linked to heightened N-methyl-D-aspartate (NMDA) transmission, offering new therapeutic targets.
Area of Science:
- Neuroscience
- Developmental Biology
- Epilepsy Research
Background:
- Infantile spasms (IS) are often equated with West syndrome, a severe infantile epilepsy.
- Current hypotheses on IS pathophysiology (cortical or brain stem generators) do not fully explain clinical features.
- The age-related expression of IS suggests critical maturational factors are involved.
Purpose of the Study:
- To review clinical and experimental data on infantile spasms (IS) pathophysiology.
- To explore maturational aspects contributing to the age-specific occurrence of IS.
- To propose a unifying hypothesis for IS generation.
Main Methods:
- Review of clinical observations and experimental findings related to IS.
- Analysis of developmental changes in neurotransmission, particularly NMDA receptor function.
- Examination of experimental induction of spasms in immature models.
Main Results:
- Neither solely cortical nor brain stem generator models fully explain IS.
- A proposed mechanism involves cortical discharges influencing archaic brain stem circuits.
- Facilitated N-methyl-D-aspartate (NMDA) transmission during a specific developmental window (0-18 postnatal days in rats) increases IS probability.
- Experimental administration of NMDA can elicit spasms in this age range.
Conclusions:
- Infantile spasms may arise from a specific interaction between cortical activity and brain stem circuits during a critical developmental period.
- Enhanced NMDA receptor function during early development is a key factor in IS pathophysiology.
- Understanding this mechanism provides a basis for developing novel therapeutic strategies against infantile epilepsy.
Abstract:
Infantile spasms (IS) are so typically associated with West syndrome that the term IS, properly referred to as a seizure type, is currently used synonymously with this severe infantile epilepsy. This chapter reviews some clinical and experimental observations relevant to IS pathophysiology with particular regard to maturational aspects that may account for IS age-related expression. Neither the cortical nor the brain stem generator hypotheses account for all the clinical features of IS. It is suggested that IS are generated whenever a cortical discharge is able to influence some archaic circuit located putatively in the brain stem through either an excitatory or a disinhibitory mechanism. This may occur with the highest probability during a developmental window in which IS typically occur, when N-methyl-D-aspartate (NMDA) transmission is particularly facilitated due a reduced sensitivity of NMDA receptors to the Mg2+ block. Interestingly, in this age range (0-18 postnatal day in rat), flexion spasms can be elicited experimentally by NMDA administration. These data provide an important key to further investigating IS pathophysiology, thus allowing us to design more effective strategies aimed at counteracting this harmful infantile epilepsy.