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Sporadic Fatal Insomnia in Europe: Phenotypic Features and Diagnostic Challenges
Author(s) -
AbuRumeileh Samir,
Redaelli Veronica,
Baiardi Simone,
Mackenzie Graeme,
Windl Otto,
Ritchie Diane L.,
Didato Giuseppe,
HernandezVara Jorge,
Rossi Marcello,
Capellari Sabina,
Imperiale Daniele,
Rizzone Mario Giorgio,
Belotti Alessia,
Sorbi Sandro,
Rozemuller Annemieke J. M.,
Cortelli Pietro,
Gelpi Ellen,
Will Robert G.,
Zerr Inga,
Giaccone Giorgio,
Parchi Piero
Publication year - 2018
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.25300
Subject(s) - fatal familial insomnia , polysomnography , medicine , etiology , prnp , magnetic resonance imaging , neurology , disease , insomnia , pediatrics , cerebrospinal fluid , pathology , differential diagnosis , electroencephalography , psychiatry , radiology , prion protein
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 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. 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. Cerebrospinal fluid (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. Electroencephalography and magnetic resonance imaging showed nonspecific findings, whereas fluorodeoxyglucose positron emission tomography (FDG‐PET) demonstrated a profound bilateral thalamic hypometabolism in 71% of cases. Molecular analyses revealed PrP Sc 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 represents an 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. Ann Neurol 2018;84:347–360