{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T02:20:38Z","timestamp":1789870838180,"version":"4.0.1"},"reference-count":50,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2018,8,31]],"date-time":"2018-08-31T00:00:00Z","timestamp":1535673600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2018,9]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Comprehensively describe the phenotypic spectrum of sporadic fatal insomnia (sFI) to facilitate diagnosis and management of this rare and peculiar prion disorder.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A survey among major prion disease reference centers 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>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\u2010polysomnography demonstrated a severe reduction of total sleep time and\/or a disorganized sleep. Cerebrospinal fluid (CSF) levels of proteins 14\u20103\u20103 and t\u2010tau were unrevealing, the concentration of neurofilament light protein (NfL) was more consistently increased, and the real\u2010time quaking\u2010induced conversion assay (RT\u2010QuIC) revealed a positive prion seeding activity in 60% of cases. Electroencephalography and magnetic resonance imaging showed nonspecific findings, whereas fluorodeoxyglucose positron emission tomography (FDG\u2010PET) demonstrated a profound bilateral thalamic hypometabolism in 71% of cases. Molecular analyses revealed PrP<jats:sup>Sc<\/jats:sup> type 2 and methionine homozygosity at <jats:italic>PRNP<\/jats:italic> codon 129 in all cases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>sFI is a disease of young or middle\u2010aged adults, which is difficult to reconcile with the hypothesis of a spontaneous etiology related to stochastic, age\u2010related PrP misfolding. The combination of psychiatric and\/or sleep\u2010related symptoms with oculomotor abnormalities represents an early peculiar clinical feature of sFI to be valued in the differential diagnosis. Video\u2010polysomnography, FDG\u2010PET, and especially CSF prion RT\u2010QuIC and NfL constitute the most promising supportive diagnostic tests in vivo. 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