OBJECTIVE: Comprehensively describe the phenotypic spectrum of sporadic Fatal Insomnia (sFI) to facilitate diagnosis and management of this rare and peculiar prion disorder.
METHODS: A survey among major prion disease reference Centres in Europe identified 13 patients diagnosed with sFI in the past 20 years. We undertook a detailed analysis of clinical and histopathological features, and the results of diagnostic investigations.
RESULTS: Mean age at onset was 43 years and mean disease duration 30 months. Early clinical findings included psychiatric, sleep and oculomotor disturbances, followed by cognitive decline and postural instability. In all tested patients, video-polysomnography demonstrated a severe reduction of total sleep time and/or a disorganized sleep. CSF levels of proteins 14-3-3 and t-tau were unrevealing, the concentration of neurofilament light protein (NfL) was more consistently increased, and the real-time quaking-induced conversion assay (RT-QuIC) revealed a positive prion seeding activity in 60% of cases. EEG and MRI showed non-specific findings, whereas FDG-PET demonstrated a profound bilateral thalamic hypometabolism in 71% of cases. Molecular analyses revealed PrPSc type 2 and methionine homozygosity at PRNP codon 129 in all cases.
INTERPRETATION: sFI is a disease of young or middle-aged adults, which is difficult to reconcile with the hypothesis of a spontaneous etiology related to stochastic, age-related, PrP misfolding. The combination of psychiatric and/or sleep-related symptoms with oculomotor abnormalities represent early peculiar clinical feature of sFI to be valued in the differential diagnosis. Video-polysomnography, FDG-PET, and especially CSF prion RT-QuIC and NfL constitute the most promising supportive diagnostic tests in vivo. This article is protected by copyright. All rights reserved.