Sporadic Fatal Insomnia in Europe: Phenotypic features and diagnostic challenges

Samir Abu-Rumeileh; Veronica Redaelli; Simone Baiardi; Graeme Mackenzie; Otto Windl; Diane L Ritchie; Giuseppe Didato; Jorge Hernandez-Vara; Marcello Rossi; Sabina Capellari; Daniele Imperiale; Mario Giorgio Rizzone; Alessia Belotti; Sandro Sorbi; Annemieke J M Rozemuller; Pietro Cortelli; Ellen Gelpi; Robert G Will; Inga Zerr; Giorgio Giaccone; Piero Parchi

doi:10.1002/ana.25300

Sporadic Fatal Insomnia in Europe: Phenotypic features and diagnostic challenges

Samir Abu-Rumeileh, Veronica Redaelli, Simone Baiardi, Graeme Mackenzie, Otto Windl, Diane L Ritchie, Giuseppe Didato, Jorge Hernandez-Vara, Marcello Rossi, Sabina Capellari, Daniele Imperiale, Mario Giorgio Rizzone, Alessia Belotti, Sandro Sorbi, Annemieke J M Rozemuller, Pietro Cortelli, Ellen Gelpi, Robert G Will, Inga Zerr, Giorgio GiacconePiero Parchi

Research output: Contribution to journal › Article › peer-review

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 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.

Original language	English
Journal	Annals of Neurology
Early online date	26 Jul 2018
DOIs	https://doi.org/10.1002/ana.25300
Publication status	E-pub ahead of print - 26 Jul 2018

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Abu-Rumeileh, S., Redaelli, V., Baiardi, S., Mackenzie, G., Windl, O., Ritchie, D. L., Didato, G., Hernandez-Vara, J., Rossi, M., Capellari, S., Imperiale, D., Rizzone, M. G., Belotti, A., Sorbi, S., Rozemuller, A. J. M., Cortelli, P., Gelpi, E., Will, R. G., Zerr, I., ... Parchi, P. (2018). Sporadic Fatal Insomnia in Europe: Phenotypic features and diagnostic challenges. Annals of Neurology. Advance online publication. https://doi.org/10.1002/ana.25300

@article{62ca6b85d1194164ae960bb0f050f645,

title = "Sporadic Fatal Insomnia in Europe: Phenotypic features and diagnostic challenges",

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 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.",

author = "Samir Abu-Rumeileh and Veronica Redaelli and Simone Baiardi and Graeme Mackenzie and Otto Windl and Ritchie, \{Diane L\} and Giuseppe Didato and Jorge Hernandez-Vara and Marcello Rossi and Sabina Capellari and Daniele Imperiale and Rizzone, \{Mario Giorgio\} and Alessia Belotti and Sandro Sorbi and Rozemuller, \{Annemieke J M\} and Pietro Cortelli and Ellen Gelpi and Will, \{Robert G\} and Inga Zerr and Giorgio Giaccone and Piero Parchi",

year = "2018",

month = jul,

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doi = "10.1002/ana.25300",

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journal = "Annals of Neurology",

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Abu-Rumeileh, S, Redaelli, V, Baiardi, S, Mackenzie, G, Windl, O, Ritchie, DL, Didato, G, Hernandez-Vara, J, Rossi, M, Capellari, S, Imperiale, D, Rizzone, MG, Belotti, A, Sorbi, S, Rozemuller, AJM, Cortelli, P, Gelpi, E, Will, RG, Zerr, I, Giaccone, G & Parchi, P 2018, 'Sporadic Fatal Insomnia in Europe: Phenotypic features and diagnostic challenges', Annals of Neurology. https://doi.org/10.1002/ana.25300

TY - JOUR

T1 - Sporadic Fatal Insomnia in Europe

T2 - Phenotypic features and diagnostic challenges

AU - Abu-Rumeileh, Samir

AU - Redaelli, Veronica

AU - Baiardi, Simone

AU - Mackenzie, Graeme

AU - Windl, Otto

AU - Ritchie, Diane L

AU - Didato, Giuseppe

AU - Hernandez-Vara, Jorge

AU - Rossi, Marcello

AU - Capellari, Sabina

AU - Imperiale, Daniele

AU - Rizzone, Mario Giorgio

AU - Belotti, Alessia

AU - Sorbi, Sandro

AU - Rozemuller, Annemieke J M

AU - Cortelli, Pietro

AU - Gelpi, Ellen

AU - Will, Robert G

AU - Zerr, Inga

AU - Giaccone, Giorgio

AU - Parchi, Piero

PY - 2018/7/26

Y1 - 2018/7/26

N2 - 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.

AB - 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.

U2 - 10.1002/ana.25300

DO - 10.1002/ana.25300

M3 - Article

C2 - 30048013

SN - 0364-5134

JO - Annals of Neurology

JF - Annals of Neurology

ER -

Sporadic Fatal Insomnia in Europe: Phenotypic features and diagnostic challenges

Abstract

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