Fatal familial insomnia and Agrypnia Excitata: Autonomic dysfunctions and pathophysiological implications

Fatal Familial Insomnia (FFI) is a hereditary prion disease caused by a mutation at codon 178 of the prion-protein gene leading to a D178N substitution in the protein determining severe and selective atrophy of mediodorsal and anteroventral thalamic nuclei. FFI is characterized by physiological sleep loss, which polygraphically appears to be a slow wave sleep loss, autonomic and motor hyperactivation with peculiar episodes of oneiric stupor. Alteration of autonomic functions is a great burden for FFI patients consisting in sympathetic overactivation, dysregulation of its physiological responses and disruption of circadian rhythms. The cardiovascular system is the most frequently and severely affected confirming the increased sympathetic drive with preserved parasympathetic responses. Sleep loss, autonomic and motor hyperactivation define Agrypnia Excitata (AE), which is not exclusive to FFI, but it has been canonically described also in Morvan Syndrome and Delirium Tremens. These three conditions present different pathophysiological mechanisms but share the same thalamo-limbic impairment of which AE is one of the possible clinical presentations. FFI, and consequently also AE, is a model for the investigation of the essential role of the thalamus in the organization of body homeostasis, integrating both sleep and autonomic function control.