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Ann Neurol. 2018 Sep;84(3):347-360. doi: 10.1002/ana.25300. Epub 2018 Aug 31.

Sporadic Fatal Insomnia in Europe: Phenotypic Features and Diagnostic Challenges.

Author information

1
Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy.
2
Neurology and Neuropathology Unit, IRCCS Foundation Carlo Besta Neurological Institute, Milan, Italy.
3
National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, University of Edinburgh, Western General Hospital, Edinburgh, Scotland, United Kingdom.
4
Center for Neuropathology and Prion Research, Ludwig Maximilian University, Munich, Germany.
5
Clinical and Experimental Epileptology, IRCCS Foundation Carlo Besta Neurological Institute, Milan, Italy.
6
Neurology Service, Vall D'Hebron University Hospital, Barcelona, Spain.
7
IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy.
8
Neurology Unit, Maria Vittoria Hospital, Turin, Italy.
9
Rita Levi Montalcini Department of Neuroscience, University of Turin, Turin, Italy.
10
Department of Pathology, Milan University, Milan, Italy.
11
Department of Neuroscience, Psychology, Drug Research, and Child Health, University of Florence, Florence, Italy.
12
IRCCS Don Gnocchi, Florence, Italy.
13
Department of Pathology, University Medical Center, Utrecht, the Netherlands.
14
Neurological Tissue Bank of the Biobanc, - Hospital Clínic - Institut d'Investigacions Biomédiques, August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain.
15
Institute of Neurology, Medical University of Vienna, Vienna, Austria.
16
Department of Neurology, University Medical School, Göttingen, Germany.
17
Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.

Abstract

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 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 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.

PMID:
30048013
DOI:
10.1002/ana.25300

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