Cognitive neurology

RESEARCH PAPER

A proposal of new diagnostic pathway for fatal

familial insomnia
A Krasnianski,1,2 P Sanchez Juan,3,4 Claudia Ponto,1 M Bartl,1 U Heinemann,1
D Varges,1 W J Schulz-Schaeffer,5 H A Kretzschmar,6 I Zerr1
1
Clinical Dementia Center and ABSTRACT possible on the basis of the criteria established for
National Reference Center for Background In absence of a positive family history, sporadic Creutzfeldt–Jakob disease (sCJD) or famil-
TSE at Department of
Neurology Georg-August
the diagnosis of fatal familial insomnia (FFI) might be ial CJD.10–13 Disease duration in FFI is as rule pro-
University, Göttingen, Germany difficult because of atypical clinical features and low longed and CJD typical signs such as myoclonus
2
Department of Psychiatry, sensitivity of diagnostic tests. FFI patients usually do not are either absent or seen only very late in the
Psychosomatics and fulfil the established classification criteria for Creutzfeldt– disease course. Laboratory tests and technical inves-
Psychotherapy Goethe Jakob disease (CJD); therefore, a prion disease is not tigations which are frequently positive in other
University Frankfurt/M,
Germany always suspected. prion diseases (14-3-3 proteins in cerebrospinal
3
University Hospital Marqués Objective To propose an update of diagnostic pathway fluid (CSF), EEG, MRI) are usually normal or non-
de Valdecilla IFIMAV, for the identification of patients for the analysis of specifically changed and so they do not provide any
Santander, Spain D178-M129 mutation. further clues to the diagnosis.7 14 Clinical criteria
4
Centro de Investigación
Biomédica en Red sobre
Design and methods Data on 41 German FFI of FFI proposed several years ago are helpful in the
Enfermedades patients were analysed. Clinical symptoms and signs, diagnosis of FFI.15 16 However, sensitivity and spe-
Neurodegenerativas, MRI, PET, SPECT, polysomnography, EEG and cificity of these criteria have to be determined in a
Santander, Spain
5
cerebrospinal fluid biomarkers were studied. context of differential diagnosis of rapid progres-
Department of
Results An algorithm was developed which correctly sive dementia. Moreover, some new data have been
Neuropathology, Georg-August
University, Göttingen, Germany identified at least 81% of patients with the FFI diagnosis collected since publication of the criteria, and the
6
Department of during early disease stages. It is based on the detection role of the codon 129 genotype in FFI phenotype
Neuropathology, Ludwig- of organic sleep disturbances, either verified clinically or has been recently demonstrated.9 The aim of the
Maximilian University, Munich, by a polysomnography, and a combination of vegetative present study was to develop a scheme to support
Germany
and focal neurological signs and symptoms. Specificity of the clinical diagnosis of possible FFI and to provide
Correspondence to the approach was tested on three cohorts of patients a basis for the selection of patients who should be
Professor Inga Zerr, National (MM1 sporadic CJD patients, non-selected sporadic CJD subjected to a PRNP analysis in the absence of clear
TSE Reference Center, and other neurodegenerative diseases). family history for FFI. In addition, such a scheme
Department of Neurology,
Conclusions The proposed scheme may help to might be helpful when PRNP analysis is not avail-
Georg-August-University,
Robert-Koch-Str. 40, improve the clinical diagnosis of FFI. As the sensitivity of able for various reasons.
Göttingen D-37075, Germany; all diagnostic tests investigated but polysomnography is
epicjd@med.uni-goettingen.de low in FFI, detailed clinical investigation is of special DESIGN AND METHODS
importance. Study design
Received 9 July 2013
Revised 8 October 2013 Patients with suspected prion disease were reported
Accepted 18 October 2013 to the CJD Surveillance Unit in Göttingen and
Published Online First INTRODUCTION examined at the notifying hospital by the authors;
18 November 2013 the clinical data were collected as described previ-
The most common genetic form of prion disease
worldwide is caused by a point mutation at codon ously.17 Data on sleep disturbances were obtained
200 of the PRNP.1 In contrast, in Germany, the from anamnestical means ( patients, their relatives,
most frequently occurring mutation is located at treating physicians), especially in the absence of
the codon 178 of the PRNP (D178N mutation in polysomnography. CSF, blood samples and copies
coupling with methionine at codon 129: (D178N, of the diagnostic tests (EEG, MRI, [18F]FDG posi-
129M))2 and leads subsequently to fatal familial tron emission tomography (PET), 123I-IMP single-
insomnia (FFI). Clinicopathological features com- photon emission CT (SPECT), polysomnography,
patible with FFI have been described as early as in laboratory tests) were taken. Because genetic testing
1939 and 1963.3 4 Lugaresi et al5 were the first to was not available at the time as patients were
describe FFI in a patient with a family history of enrolled into the study, they were classified accord-
insomnia and autonomous disorders. Postmortem ing to established diagnostic criteria of sCJD.10 11
examination revealed marked atrophy of the anter-
Open Access
Scan to access more ior and dorsomedial thalamic nuclei. Later the dis- MRI and EEG findings
free content
order was classified as a prion disease and its The MRI images were classified as CJD-typical
transmissibility was confirmed in animal experi- according to the established criteria.18 The EEGs
ments.6 So far, a number of FFI patients with het- were analysed according to established criteria.19
To cite: Krasnianski A,
Sanchez Juan P, Ponto C, erogeneous clinical phenotypes have been
et al. J Neurol Neurosurg reported.7 The clinical phenotype in FFI seems also Polysomnography
Psychiatry 2014;85: to depend on the M129V polymorphism.7–9 In Polysomnographic recordings were obtained at the
654–659. most cases, the clinical diagnosis of FFI is hardly notifying hospitals according to standard

654 Krasnianski A, et al. J Neurol Neurosurg Psychiatry 2014;85:654–659. doi:10.1136/jnnp-2013-305978

 Cognitive neurology

procedures;20 however, no specific analysis with respect to FFI onset and a more rapid disease course. However, this association
diagnosis was done since FFI was not specifically suspected in was not statistically significant.
most patients.
Clinical findings
PET and SPECT Data on the clinical findings have been previously published by
PET and SPECT were performed at the notifying hospitals as the authors.9 The clinical features varied by M129V genotype
described previously.14 21 22 Special attention was paid to thal- (figure 1). The time of occurrence of symptoms and signs
amic hypometabolism. during disease course also varied depending on the M129V
genotype (table 2).
Neuropathological and molecular studies
Western blot analysis and immunohistochemistry (in biopsied/ Neuropathological studies
autopsied patients) and the analysis of PRNP were performed Autopsy was performed on 21 of our FFI patients. Overall, 20
using standard methods.23–25 of 21 patients showed FFI typical neuropathological findings
with prominent thalamo-olivaric pathology.27 Severe astrocytic
Biochemical CSF analysis gliosis and nerve cell loss but weak spongiform changes were
The 14-3-3 protein analysis was performed at least twice in observed. Fine reticular PrPSc deposits in the thalamus were
each CSF sample as described previously.26 only detectable with the PET blot method.25 This pattern
resembles PrPSc type 1, although an electrophoretic mobility
Statistical analysis comparable with PrPSc type 2 was described in FFI patients.28
Significances ( p) were tested by the SIGMASTAT 3.1 soft- Only one patient with confluent vacuoles (this without
ware (Systat Software Inc., Point Richmond, USA) using thalamo-olivaric pathology) showed perivacuolar PrPSc deposits,
Student t test/Mann–Whitney rank sum test or χ2 test/Fisher which were detectable with conventional immunohistochemical
exact test. A p value <0.05 was considered as statistically staining methods.
significant.
Diagnostic tests
Detailed data on the diagnostic tests have been published previ-
RESULTS
ously.9 Almost all clinical and paraclinical tests revealed no or
Study collective
only slight non-specific changes. In FFI patients, the 14-3-3 test
From 1 June 1993 to 31 May 2005, 105 patients with a con-
in the CSF, otherwise helpful in diagnosing prion diseases, was
firmed PRNP mutation were detected. Out of these patients, 32
positive in two of 28 cases only. In one of them, inflammatory
were diagnosed with FFI. In addition, we included nine further
CSF changes (slight pleocytosis and oligoclonal bands) were
FFI patients with available clinical data from the same families.
detected.12 29
Since in a few cases some data (eg, on the 14-3-3 test or MRI)
were incomplete, some results were obtained on the basis of
Family history of FFI
lower case numbers. In all, 28 patients were male and 13 were
Data on family history were available in 29 patients. Family
female (ratio 2.2 : 1). The median age at disease onset was 56
history was negative in 10 of these patients (35%) and positive
(range 23–73) years. The median disease duration was 11 (range
in 19 (65%).
6–24) months. There were 20 MM (12 male, eight female) and
eight MV (seven male, one female) patients. In 13 patients, no
Development of the diagnostic pathway for FFI
M129V genotype was available, but the diagnosis had been con-
All possible combinations of symptoms and signs were tried and
firmed by autopsy, and family history for (genetically proven)
that with the highest sensitivity was selected. The weighting was
FFI was positive. The median age at disease onset in MM
performed by dividing the frequency of symptoms by week at
patients was 55 years (range 27–70), and the median disease
appearance. The most common clinical symptoms and signs
duration was 10 months (range 6–21). The median age at
were grouped into three categories (A, B, C) (table 3). The first
disease onset in MV patients was 60 years (range 23–69) and
category comprises organic sleep disturbances (A), which were
the median disease duration was 19 months (range 10–24).
observed in almost all patients (96%). The second category (B)
Disease onset and duration varied by codon M129V genotype
consists of symptoms and signs frequently occurring in sCJD,
(table 1), with a non-significantly earlier onset and significantly
which is the major differential diagnosis of FFI (CJD-like symp-
shorter duration in methionine homozygous (MM) patients
toms).12 30 The third category (C) comprises symptoms and
( p=0.007). Male gender was associated with an earlier age at
signs which are typical for FFI,7 31–34 and are not included in
the diagnostic criteria of sCJD.10 To select the items required
for the diagnosis of FFI, we weighted them in terms of their
Table 1 Patient characteristics stratified by codon 129 genotype chronological occurrence (table 4). Some signs and symptoms
Duration of were not evaluated either because they were observed in few
Codon 129
Age at onset illness (months) cases only or, in most cases, because they could not be linked to
polymorphism Sex n Median Range n Median Range a particular disease stage. In a second step, we divided the items
into major and minor diagnostic parameters. The most import-
MM m 12 53 27–67 10 9 6–21 ant parameter was sleep disturbance, which occurred as the first
f 8 57 50–70 5 13 9–17
symptom of FFI in all patients, except in one case. The minor
∑ 20 55 27–70 15 10 6–21
parameters were selected and weighted according to their fre-
MV m 7 61 23–69 5 15 10–24
f 1 – 48 1 23 – quency and chronological occurrence (category C). Our aims
∑ 8 60 23–69 6 19 10–24 were:
f, female; m, male. 1. High sensitivity
2. High specificity

Krasnianski A, et al. J Neurol Neurosurg Psychiatry 2014;85:654–659. doi:10.1136/jnnp-2013-305978 655

 Cognitive neurology

Figure 1 Frequency of clinical

symptoms and signs stratified by
codon 129 genotype (%).

3. Reliable classification as FFI no later than in the middle of since June 2005 and were not included in the dataset for the
the disease course scheme development. In these patients (n=16), the proposed
4. Easy applicability (analogously to the CJD criteria). scheme correctly identified 13 of 16 (81.3%) of the patients.
Major reasons for failure were lack of autonomic disturbances
In accordance with this scheme, all patients must have organic and no data on weight loss or no weight loss.
sleep disturbances (clinically apparent or by polysomnography). To test specificity of our diagnostic approach for differentiation
In addition, at least one symptom typical for FFI and two of FFI and sCJD, we applied our scheme to 40 randomly selected
CJD-like symptoms are required for diagnosis of suspected FFI MM1 sCJD patients (24 women, 16 men; age range 54–86,
(figure 2). In these patients, a PRNP analysis is required as the median 68 years; median disease duration 4, range 1–19 months)
subsequent diagnostic step. representing classical CJD. For randomisation, 40 subsequent
MM1 patients diagnosed during the time period of the FFI
Verification of accuracy and applicability recruitment for this study were taken. Only seven of these 40
The proposed scheme reached a sensitivity of 91% in our ori- sCJD patients fulfilled the criteria of FFI, so that the specificity
ginal patient group. Based on their use, it was possible to estab- within this group was high (83%). This control group was selected
lish the diagnosis of FFI within a median of 17 weeks because it represents the most frequent classical CJD type.
(4.4 months) after disease onset. While a sensitivity of 100% Loss of weight with a cut-off point of more than 10 kg
was found in our MV FFI patients, it was 88% in MM FFI during the last 6 months was observed in 5% of sCJD patients
patients. The median disease duration was 11 months, so the in comparison with 83% in FFI ( p<0.001). Vegetative signs
diagnosis based on the proposed criteria was established early in were found in only 33% of MM1 patients compared with 83%
the disease course. We tested the applicability in an additional in FFI ( p<0.001). Husky voice was noticed in none of MM1
cohort of FFI patients who were seen in a prospective setting patients, but in 22% of FFI patients ( p=0.005).

Table 2 Time of occurrence of symptoms/signs present both in codon 129 MM and codon 129 MV patients
N patients (%) Mean±SD (weeks) Median (weeks)
Symptom/sign
Genotype MM (n=17) MV (n=6) MM (n=17) MV (n=6) MM (n=17) MV (n=6)

Vegetative 13 (77) 6 (100) 4±0 18.5±3 0 23

Sleeping disturbances 17 (100) 5 (83) 3±0 15±0 0 0
Bulbar 5 (29) 5 (83) 19±0.5 23±16 11 20
Visual 11 (65) 5 (83) 13±1 6±2 12 2
Cognitive/mnestic 14 (82) 6 (100) 13±0 16±0 12 20
Hallucinations 12 (71) 2 (33) 16±0 57.5±19 14 57.5
Spatial disorientation 13 (77) 2 (33) 20±2 38.5±1 16 38.5
Ataxia 13 (77) 6 (100) 21±4 9±2 20 4
Dysarthria 10 (59) 4 (67) 21±0 27±0.5 20 28.5
Myoclonus 13 (77) 3 (50) 16±1 32±3.5 21 32
Pyramidal 8 (47) 2 (33) 29.5±5 28±5 26 28

656 Krasnianski A, et al. J Neurol Neurosurg Psychiatry 2014;85:654–659. doi:10.1136/jnnp-2013-305978

 Cognitive neurology

Table 3 Frequency of clinical symptoms and signs in fatal familial Table 4 Symptoms in fatal familial insomnia patients (n=23)
insomnia patients (n=23) stratified by time of occurrence
Symptoms and signs N % Time of Frequency
Symptom/sign Frequency* occurrence (d) weighted by time
Category A Organic sleep disturbances* 22 96
Category B Cognitive/mnestic deficits 20 87 Loss of weight 19 14 1.357
Spatial disorientation 15 65 (<10 kg)
Psychiatric 20 87 Husky voice 5 14 0.357
Hallucinations† 14 61 Psychiatric 20 84 0.238
Personality change 13 57
Sleeping 22 107 0.206
Depression 5 22
disturbances
Anxiety 4 17
Aggressiveness 2 9 Vegetative 19 124 0.153
Disinhibition 2 9 Visual 16 157 0.102
Listlessness 2 9 Cognitive/mnestic 20 207 0.097
Others‡, each 1 4 Frontal lobe signs 2 22 0.091
Ataxia 19 83
Myoclonus 16 226 0.071
Myoclonus 16 70
Visual 16 70 Ataxia 19 273 0.070
Double vision 12 52 Bulbar 10 145 0.069
Blurred vision 5 22 Extrapyramidal 5 78 0.064
Others§, each 1 4
Spatial 15 260 0.058
Dysarthria¶ 14 61
disorientation
Pyramidal 10 43
Extrapyramidal** 8 35 Dysarthria 14 259 0.054
Category C Loss of weight 19 83 Pyramidal 10 205 0.049
Vegetative signs 19 83 *Number of patients with positive symptom/sign.
Hyperhidrosis 13 57
Newly diagnosed arterial hypertonia 6 26
Tachycardia 4 17
Obstipation 3 13 included 30 patients (14 women, 16 men; age range 26–87,
Hyperthermia 2 9
median 73.5 years; median disease duration 11.5, range 1–
Others††, each 1 4
Bulbar symptoms 10 43 70.5 months). There were 15 patients with Alzheimer’s disease
Husky voice 5 22 (AD), four patients with inflammatory CNS diseases, two with
Dysphagia 3 13 both AD and Levy body disease (DLB), two with DLB, and one
Bulbar speech 3 13 each with AD and congophil amyloidopathy, AD and vascular
Tongue fasciculation 1 4
Pruritus 3 13
dementia, AD and unclear taupathy, congophil amyloidopathy,
vascular dementia, autosomally dominant leukodystrophy, and
*Including polysomnography; insomnia, hypersomnia, restless sleep and sleep attacks.
†Optical in 14 patients, additionally acoustic in two of them.
metabolic CNS disease. In this patient group, only 20% were
‡Paranoia, fearfulness and rage to clean up. identified by the algorithm as potential FFI cases. Loss of weight
§Seeing of flashes, poor vision, sliding field of vision and bad spatial vision. with a cut-off point of more than 10 kg during the last 6 months
¶Pseudobulbar and cerebellar.
**Nearly equally rigour, tremor and dystonia, mostly in combination. was observed in 3% of neuropathologically confirmed non-prion
††Tachypnoea, arterial hypotonia, intolerance of warmth, goose bumps, cardiac disease patients compared with 83% in FFI ( p<0.001).
arrhythmia and abrogated day–night rhythm of blood pressure. Vegetative signs were found in only 30% of non-prion disease
patients in comparison with 83% in FFI ( p<0.001). Husky voice
was absent in non-prion disease patients, but reported in 22% of
FFI patients ( p=0.012).
We also applied our algorithm to 40 randomly selected sCJD
patients (23 MM, nine MV, eight VV genotype). There were 28
women, 12 men; age range was 41–81 years, median age was DISCUSSION
73 years; and median disease duration was 10 months (range 2–28 The aim of the present study was to develop a scheme for the
months). For randomisation, 40 subsequent patients with excluded clinical diagnosis of FFI. In addition, such a scheme might be
PRNP mutation diagnosed during the time period of the FFI recruit- also helpful when PRNP analysis is not available for various
ment for this study were taken. Only seven of these 40 sCJD patients reasons.
fulfilled the criteria of FFI, and so the specificity within this group As discussed previously and shown in table 2, there is a sig-
was high (83%). nificant phenotypic variability between MM and MV geno-
Loss of weight with a cut-off point of more than 10 kg types. Myoclonus, spatial disorientation and hallucinations
during the last 6 months was observed in 10% of these patients were more frequent in the MM patients.7 9 Bulbar disturbances
in comparison with 83% in FFI ( p<0.001). Vegetative signs and vegetative dysfunction were more common in MV FFI
were found in only 30% of non-selected sCJD patients com- patients. Phenotypic differences between MV and MM FFI
pared with 83% in FFI ( p<0.001). Husky voice was noticed in patients may be caused by different rates of PrPc to PrPSc
none of non-selected sCJD patients, but in 22% of FFI patients conversion.35
( p=0.005). Thus, the results in this group were very similar to Differently from our previous study,9 we analysed the clinical
those in MM1 patients. data in FFI patients in order to develop a scheme for early identi-
Moreover, we established a further control group consisting of fication of patients who should be subjected to PRNP analysis.
all German CJD surveillance patients with neuropathologically The rationale for this study is given in the Introduction section.
proved diagnosis other than prion disease referred ante mortem To our knowledge, diagnostic criteria of FFI have been suggested
to the surveillance centre as a potential prion disease, which twice.15 16 They are based on data from 24 FFI patients. No

Krasnianski A, et al. J Neurol Neurosurg Psychiatry 2014;85:654–659. doi:10.1136/jnnp-2013-305978 657

 Cognitive neurology

Figure 2 Diagnostic algorithm

for fatal familial insomnia.

specificity or sensitivity of these criteria has been reported. They CONCLUSIONS

consist of six items and include clinical data, EEG and PET inves- Summarizing, we attempted to establish an easily applicable
tigation. Since the availability of PET is limited, we intended to scheme allowing reliable classification as FFI no later than in the
develop an easy and widely applicable scheme, which consists of middle of the disease course. This facilitates differentiation both
three items and allows raising the suspicion of FFI by clinical from the classical CJD and non-CJD cases initially classified as
means. The specificity of this approach was tested on two control possible CJD as the most frequent classification in FFI patients
groups with relevant differential diagnoses. according to CJD criteria.10 11 Suspicion of FFI and consecutive
We attempted to establish an easily applicable scheme allow- order of appropriate genotyping by clinicians may be more fre-
ing reliable identification as a possible FFI no later than in the quent and could arise earlier, if updated, easily applicable clin-
middle of the disease course. To make the attempt as precise as ical criteria are available. The scheme would also allow the
possible, we stratified the symptoms and signs of FFI by time of clinical diagnosis in cases with no available genetic testing.
occurrence and their frequency. The scheme facilitates differen- A specificity of at least 80% and a sensitivity of 81.3%–91%
tiation from the classical CJD, non-selected sCJD and non-CJD could be reached. Early diagnosis of FFI might be important for
cases according to CJD criteria.10 11 However, differentiation early and sufficient counselling of patients and their relatives,
from atypical sCJD subtypes may sometimes be more difficult. also concerning the risk of inheritance, and potentially also for
A specificity of at least 80% could be reached for each of the treatment studies. We hope that this attempt may improve the
groups. In contrast to FFI criteria (ICSD criteria and criteria pro- early recognition of this peculiar and rare prion disease.
posed in the British Medical Bulletin15) which both require the Acknowledgements We thank Ms Bodemer and Ms Ciesielczyk for technical
presence of an autosomal dominant disease or a familial pattern, assistance. The assistance of Ms Ehrlich and Ms Schneider-Dominco is gratefully
here we can select patients from families in which the FFI diagnosis acknowledged.
is not established, as our studies showed that about a third of our Contributors AK: Conceptualisation of the study, analysis and interpretation of the
patients did not fulfil this criterion.9 This fact might be explained data, drafting the manuscript, final approval. PSJ: Statistical analysis and interpretation of
by missing information about the presence of a neurodegenerative the data, drafting the manuscript, final approval. CP: Analysis and interpretation of the
data, final approval. MB, UH and DV: Analysis and interpretation of the data, drafting the
disorder by the family members or by occurrence of new manuscript, final approval. WJS-S and HAK: Report of neuropathological findings, drafting
mutations. the manuscript, final approval. IZ: Conceptualisation of the study, analysis and
Interestingly, psychiatric symptoms were frequent in our FFI interpretation of the data, final approval. Statistical analysis was performed by PSJ.
patients, and they are also common in sCJD.36 However, they Funding This work was supported by the Federal Ministry of Health (grant number
are not a part of sCJD criteria, while we found them an import- 1369-341) and by European Commission (PRIORITY FP7-KBBE-2007–2A).
ant part of our FFI criteria. Competing interests All authors disclose any actual or potential conflicts of
Although the diagnosis of atypical subtypes of sCJD using the interest. This includes any financial, personal or other relationships with other
established criteria may fail, some diagnostic tests, such as MRI people/organisations within 3 years of beginning the work submitted that could
in the MV2 subtype and detection of the 14-3-3 proteins in inappropriately influence their work.
MM2 and VV1 subtypes, are helpful in the sCJD diagnosis.37–39 Ethics approval Any necessary ethics committee approval was secured for the
The clinical diagnosis of FFI, by contrast, is solely based on the study reported by the local ethic committee of the Medical University of Goettingen.
careful observation of the clinical course, and only polysomno- Provenance and peer review Not commissioned; externally peer reviewed.
graphy and, to some extent, PET may contribute to the FFI diag- Open Access This is an Open Access article distributed in accordance with the
nosis before genetic testing is performed and a PRNP mutation is Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which
detected.14 All reports on FFI have emphasised the diagnostic permits others to distribute, remix, adapt, build upon this work non-commercially,
and license their derivative works on different terms, provided the original work is
importance of polysomnography in FFI, and this is also con- properly cited and the use is non-commercial. See: http://creativecommons.org/
firmed in our study.7 20 34 40 licenses/by-nc/3.0/

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