Journal of Alzheimer’s Disease 50 (2016) 465–476 465

DOI 10.3233/JAD-150668
IOS Press

Revisiting the Heidenhain Variant of

Creutzfeldt-Jakob Disease: Evidence for
Prion Type Variability Influencing Clinical
Course and Laboratory Findings
Simone Baiardia , Sabina Capellaria,b , Anna Ladoganac , Silvia Strumiad , Mario Santangeloe ,
Maurizio Pocchiaric and Piero Parchia,b,∗
a Dipartimento di Scienze Biomediche e Neuromotorie (DiBiNeM), Università di Bologna, Bologna, Italy
b IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy
c Dipartimento di Biologica Cellulare e Neuroscienze, Istituto Superiore di Sanità, Roma, Italy
d UOC di Neurologia, Ospedale Morgagni-Pierantoni, Forlı̀, Italy
e UOC di Neurologia, Ospedale Ramazzini, Carpi, Italy

Handling Associate Editor: Brian Appleby

Accepted 21 October 2015

Abstract. The Heidenhain variant defines a peculiar clinical presentation of sporadic Creutzfeldt-Jakob disease (sCJD) char-
acterized by isolated visual disturbances at disease onset and reflecting the early targeting of prions to the occipital cortex.
Molecular and histopathological typing, thus far performed in 23 cases, has linked the Heidenhain variant to the MM1 sCJD
type. To contribute a comprehensive characterization of cases with the Heidenhain variant, we reviewed a series of 370 defi-
nite sCJD cases. Eighteen patients (4.9%) fulfilled the selection criteria. Fourteen of them belonging to sCJD types MM1 or
MM1+2C had a short duration of isolated visual symptoms and overall clinical disease, a high prevalence of periodic sharp-wave
complexes in EEG, and a marked increase of cerebrospinal fluid proteins t-tau and 14-3-3 levels. In contrast, three cases of the
MM 2C or MM 2+1C types showed a longer duration of isolated visual symptoms and overall clinical disease, non-specific EEG
findings, and cerebrospinal fluid concentration below threshold for the diagnosis of “probable” CJD of both 14-3-3 and t-tau.
However, a brain DWI-MRI disclosed an occipital cortical hyperintensity in the majority of examined cases of both groups.
While confirming the strong linkage with the methionine genotype at the polymorphic codon 129 of the prion protein gene,
our results definitely establish that the Heidenhain variant can also be associated with the MM 2C sCJD type in addition to the
more common MM1 type. Likewise, our results highlight the significant differences in clinical evolution and laboratory findings
between cases according to the dominant PrPSc type (type 1 versus type 2).

Keywords: Dementia, molecular typing, neurodegenerative diseases, occipital cortex, prion diseases, prion protein

INTRODUCTION

∗ Correspondence
Creutzfeldt-Jakob disease (CJD) belongs to the
to: Prof. Piero Parchi, MD, PhD, IRCCS Isti-
tuto delle Scienze Neurologiche, Via Altura 3, 40139 Bologna,
human transmissible spongiform encephalopathies or
Italy. Tel.: +39 051 4966740; Fax: +39 051 4966208; E-mail: prion diseases, a group of neurodegenerative disorders
piero.parchi@unibo.it. characterized by tissue deposition of a misfolded form

ISSN 1387-2877/16/$35.00 © 2016 – IOS Press and the authors. All rights reserved
This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License.
466 S. Baiardi et al. / Prion Type Heterogeneity in CJD Heidenhain Variant

of the cellular prion protein (PrPSc ). Despite their rel- described, most often as small case series [11, 13–18]
ative rarity, prion diseases show a wide spectrum of or individual case reports [19–37] and referred to as
clinical and pathological phenotypes. Accordingly, the the Heidenhain variant of CJD [38]. To date, molecular
clinical presentation of sporadic CJD (sCJD) includes and histopathological analyses have been performed in
a wide range of neurological signs of cortical, sub- 23 cases with this clinical presentation, and the large
cortical, or cerebellar origin, either isolated or in majority (22 out of 23) belonged to the MM-MV1 sCJD
various combinations [1–4]. Different strains of pri- type [11, 13, 16, 34, 35]. In a single case, however, the
ons, likely enciphered by alternative conformations Heidenhain variant has also been linked to the MM
of PrPSc , are considered the main cause of this phe- 2C type, which has widened the molecular basis and
notypic diversity [5]. In addition, the host variability histotype classification of this peculiar clinical phe-
in the gene encoding PrP (PRNP), as determined in notype [29]. To contribute a comprehensive clinical,
humans by polymorphisms or mutations, also mod- histopathological, and molecular characterization of
ulates the disease phenotype [6, 7]. Current sCJD cases presenting with the Heidenhain variant, we here
classification [3, 8] recognizes six major variants with provide the results of a review of a series of 370 definite
distinctive clinic-pathological features largely corre- sCJD cases, including the detailed description of three
lating at the molecular level with the genotype at the peculiar cases of the Heidenhain variant belonging to
polymorphic codon 129 (methionine, M or valine, V) the rare MM 2C and MM 2C+1 sCJD types.
in the prion protein gene and two PrPSc profiles (type
1 and type 2) distinguishable by the size of the pro- MATERIAL AND METHODS
teinase K-resistant core of the protein (21 and 19 kDa,
respectively). More precisely, with only minor excep- This study has been conducted with the highest
tions, each phenotypic variant or “type” of sCJD results respect for each participant according to the Decla-
from a specific codon 129 genotype/PrPSc type com- ration of Helsinki [39].
bination (e.g., MM1, VV1, MM2, VV2, etc.). Most
significantly, two types with distinctive histopatholog- Patients
ical features in the cerebral cortex and in the thalamus
have been linked to the rare MM2 molecular com- Three hundred and seventy cases with a definite
bination and designated accordingly (MM2-cortical diagnosis of sCJD were selected based on available
or MM 2C and MM2-thalamic or MM 2T). Finally, medical records including a detailed description of the
mixed types, comprising clinical-pathological features clinical evolution of symptoms and signs from onset.
of two pure types, especially involving the co-existence The case series included all sCJD phenotypic vari-
of MM1 and MM 2C, have also been recognized [9, ants described to date in a relative proportion fairly
10]. One of the most peculiar clinical presentations representing their current reported incidence in the
of CJD occurs in the so-called Heidenhain variant, Caucasian population [3, 9, 40]. Three hundred and
which is characterized by isolated visual symptoms fifteen subjects were Italian patients referred to our
including poor vision, disturbed perception of colors laboratory for diagnosis from 2003 to 2013, while the
or structures, and optical distortions as well as halluci- remaining 55 were part of a previously published case
nations without any ocular disease. The fact that visual series [9]. All the Italian cases were also part of the
symptoms may persist in isolation for weeks with- National CJD Registry in Rome, which collects data
out cognitive decline or motor signs and sometimes of all suspected CJD patients aiming to ascertain all
causing diagnostic difficulty makes the Heidenhain cases with definite or probable disease in Italy. The
variant of particular clinical interest. Indeed, affected presence of clinically suspected patients is notified
patients sometimes present to ophthalmologists and to the reference center by their treating physicians,
are subjected to needless ocular interventions with mainly neurologists. Most suspected patients are also
risks of onward transmission [11]. Originally, Hei- examined by a neurologist of the surveillance unit at
denhain ascribed to CJD the severe histopathological the reporting hospital, and copies of patients’ medical
changes to include severe neuronal loss with glial records are collected. For case selection, we combined
reaction or status spongiosus found in the occipi- the information recorded in the two available databases
tal cortex of two patients with a pre-senile form of (Bologna and Rome) to search for cases presenting
rapidly progressive dementia presenting with promi- visual symptoms at onset. Subsequently, only patients
nent visual disturbances despite normal disc and fundi suffering from isolated, non-transient, visual symp-
examination [12]. Since 1954, similar cases have been toms of cortical/subcortical origin at disease onset were
 S. Baiardi et al. / Prion Type Heterogeneity in CJD Heidenhain Variant 467

diagnosed with the Heidenhain variant. Visual symp- methodology and consensus criteria [8, 43]. Specifi-
toms included at least one of the following: blurred cally, we analyzed at least four brain regions (middle
vision, visual field restriction, vision loss up to cortical temporal gyrus, parietal cortex, occipital cortex, and
blindness, disturbed perception of colors or structures, thalamus) for PrPSc typing and at least eight (middle
optical hallucinations, and visual agnosia. Duration of frontal gyrus, middle temporal gyrus, parietal cortex,
visual symptoms was calculated based on the timing occipital cortex, basal ganglia, hippocampus, thala-
of appearance of associated neurological symptoms, mus, and cerebellum) for histotyping.
as reported in the available medical records. Results
of electroencephalographic (EEG) recordings were RESULTS
classified into three categories: periodic sharp-wave
complexes (PSWCs), paroxysmal discharges (PDs), Among the 370 cases examined, 70 (18.9%) had
and diffuse non-specific slowing. When available, visual symptoms at onset, but in many case, they were
cerebrospinal fluid (CSF) biomarker assays included not isolated. Therefore, only 18 (4.9%) cases fulfilled
the measurement of total tau (t-tau) protein concen- the criteria for the Heidenhain variant (Tables 1 and
tration by quantitative Elisa (INNOTEST® hTAU Ag, 2). Molecular and histopathological analyses demon-
Innogenetics) and the semiquantitative detection of strated that the cases belonged to four sCJD types:
protein 14-3-3 by western blotting, performed as pre- MM1 (10 cases), MM 1+2C (5 cases), MM 2+1C (2
viously described [41]. In particular, two CSF controls cases), and MM 2C (1 case).
(with a weak or a strong 14-3-3 signal, respectively)
were loaded in duplicate in every gel together with the MM1
CSF samples to be analyzed. The immunoreactivity
signals were rated as negative, ambiguous, or positive Mean age at the onset was 70.7 ± 7.8 years (range
on the basis of optical densitometric (OD) compari- 57–80), mean duration of isolated visual symptoms
son with the weakly positive control as follows: the was 1.6 ± 0.5 months (range 1-2), and mean total dis-
14-3-3 signal was classified as negative when the 14- ease duration was 4.2 ± 2.1 months (range 2.5–10).
3-3 band OD was lower than the control; ambiguous According to frequency, visual symptoms included the
(i.e., weakly positive) when the 14-3-3 OD was up following: disturbed perception of structures and/or
to two times higher than the control, and positive colors (i.e., metamorphopsia, micropsia, dyschro-
when it was at least two times higher than the con- matopsia) (80%), visual field restriction (60%), loss
trol. The latter decision point was chosen as optimal of vision (40%), blurred vision (30%), optical hal-
after an analysis of the test predictive value at different lucinations, and optical anosognosia (20%). EEG
densitometry value ranges in a large series (>1000) examination revealed PSWCs in eight patients (80%),
of CSF samples from subjects with suspected CJD whereas PDs or a diffuse non-specific slowing were
(unpublished data). Finally, cerebral magnetic reso- observed in one case each (10%). Fluid attenu-
nance imaging (MRI) studies were reviewed when ated inversion recovery (FLAIR) and DWI brain
available. According to currently accepted clinical MRI sequences were performed in four patients.
diagnostic criteria for sCJD [42], high signal abnor- They showed a typical (parietal and occipital, and/or
malities in caudate nucleus and putamen or at least two basal ganglia) hyperintensity on FLAIR and/or DWI
cortical regions (temporal-parietal-occipital) either in sequences in three (50%), a hyperintensity con-
diffusion-weighted imaging (DWI) or fluid attenuated fined to the left parietal lobe in one, and were
inversion recovery (FLAIR) sequences was consid- unremarkable in the other one. CSF 14-3-3 pro-
ered “typical,” while non-specific findings included tein was positive, and t-tau markedly elevated (range
signal abnormalities suggesting gliosis, microvascular 2335–2522 pg/ml) in all patients analyzed (five and
changes, or atrophy. two, respectively). Histopathological examination and
PrPSc typing revealed the typical features of sCJD
Molecular studies and CJD histotype classification MM1 in all cases [44].

To exclude cases carrying mutations and to deter- MM1+2C

mine the genotype of PRNP polymorphic codon 129,
we conducted a molecular analysis in all cases as previ- Mean age at the onset of symptoms was 66.6 ± 9.4
ously described [40]. We performed PrPSc typing and years (range 54–80), mean duration of isolated visual
sCJD histotype classification according to established symptoms was 1.5 ± 0.5 months (range 1–2.5), and
 468
Table 1
Clinical features of patients with the Heidenhain variant of sCJD
N◦ Gender Age Visual symptoms (VS) VS duration (mo) Other symptoms Disease duration (mo)
1 F 54 Visual field restriction, loss of vision, disturbed 2.5 Delirium, confusion, disorientation, dystonia, pyramidal 5
perception of colors or objects, hallucinations signs, akinetic mutism
2 M 63 Blurred vision, visual field restriction, 2 Aphasia, attentive deficit, cerebellar signs, myoclonus 4
3 M 67 Blurred vision, visual field restriction, vision loss up to 1.5 Cognitive disturbances, abnormal behavior, myoclonus, 5
cortical blindness tremor, pyramidal signs, akinetic mutism
4 M 80 Blurred vision, disturbed perception of colors or 1 Ataxia, disorientation 4
structures, hallucinations
5 M 69 Blurred vision, vision loss 1 Dysarthria, myoclonus, cognitive and gait disturbances 2.5
6 F 70 Blurred vision, vision loss up to cortical blindness, 2 Ataxia, cognitive decline, myoclonus, akinetic mutism 10
disturbed perception of colors or structures (several months with parenteral nutrition in vegetative
state)
7 F 80 Disturbed perception of colors or objects, optical 1 Cognitive decline, cerebellar and pyramidal signs, 5
anosognosia seizures, myoclonus, akinetic mutism
8 M 78 Disturbed perception of structures, optical 1.5 Alien arm syndrome, apraxia, involuntary movements, 3.5
hallucinations ataxia
9 M 69 Visual field restriction, vision loss, optical hallucination 2 Pyramidal signs, myoclonus, abrupt stupor, coma 4
(palinopsia)
10 F 64 Blurred vision, disturbed perception of objects 1.5 Myoclonus, memory loss, disorientation, ataxic gait, 2.5
(simultanagnosia) akinetic mutism
11 F 77 Visual field restriction, vision loss up to cortical 1 Myoclonus, ideomotor apraxia, disorientation 3.5
blindness, optical anosognosia
12 F 63 Visual field restriction, vision loss up to cortical 2 Memory loss, aphasia, weakness, myoclonus 3.5
blindness, disturbed perception of objects (distortion)
13 M 57 Visual field restriction, blurred vision, disturbed 2 Dementia, myoclonus, rigidity, seizures, coma 3
perception of objects
14 F 79 Disturbed perception of colors and objects, visual field 2 Ataxia, myoclonus, dementia, aphasia, coma 4
restriction
S. Baiardi et al. / Prion Type Heterogeneity in CJD Heidenhain Variant

15 F 70 Disturbed perception of colors or objects, visual field 1 Ataxic gait, ideomotor apraxia, dystonia, memory loss, 3
restriction myoclonus, rigidity, apallic state
16 F 70 Vision loss, disturbed perception of colors or structures, 6 Ataxia, dysphonia, dysphagia, cognitive disturbances, 26
optical anosognosia pyramidal signs
17 M 54 Optical hallucination, environmental agnosia 12 Discalculia, pyramidal signs, disorientation, psychosis 44
18 M 48 Blurred vision, visual field restriction, vision loss up to 2.5 Dysarthria, dysphagia, disorientation, myoclonus 6
cortical blindness
 S. Baiardi et al. / Prion Type Heterogeneity in CJD Heidenhain Variant 469

Table 2
Histotype classification and results of neurophysiologic, neuroimaging, and CSF studies of sCJD patients with the Heidenhain clinical variant
N◦ sCJD Type Brain MRI EEG CSF
(timing)b 14-3-3 (test result) t-tau (pg/ml) Timingb
1 MM 1+2C Parietal and occipital PSWCs (3)c Ambiguous 5600 2
hyperintensity on DWI
2 MM 1+2C Normal (routine MRIa ) PSWCs (2.5)c Positive 6459 2.5
3 MM 1+2C Bilateral frontal atrophy PSWCs (2) Positive NA 2
(routine MRIa )
4 MM 1+2C Parietal and temporal+BG PSWCs (2) Positive 3990 2
hyperintensity on DWI
5 MM 1+2C White matter signal PSWCs (1.5) Positive 7579 1.5
alterations
6 MM1 Parieto-occipital and basal PSWCs (1.5)c Positive 2522 0.5
ganglia hyperintensity on
DWI
7 MM1 Non-specific (routine MRIa ) PSWCs (3)c Positive NA 1.5
8 MM1 Non-specific PDs (0.5) Positive 2335 0.5
9 MM1 Non-specific (routine MRIa ) PSWCs (1.5) NA NA
10 MM1 Parietal and occipital PSWCs (1.5) Positive NA 2
hyperintensity on FLAIR
and DWI
11 MM1 Normal (routine MRIa ) PSWCs (2) Positive NA 2
12 MM1 NA PSWCs (2) NA NA
13 MM1 Right parietal atrophy PSWCs (2)c NA NA
(routine MRIa )
14 MM1 Left parietal hyperintensity Generalized slowing (3) Positive NA 3
on FLAIR and DWI
15 MM1 Non-specific vascular signs PSWCs (2.5)c NA NA
(routine MRIa )
16 MM 2C+1 Normal (routine MRIa ) Generalized slowing (9,13) Ambiguous NA 9, 13
17 MM 2C+1 Parietal and occipital Generalized slowing Ambiguous 1070 6
hyperintensity on FLAIR (6,8,11,13,20)
and DWI
18 MM 2C Parietal and occipital Generalized slowing (3,5,6) Ambiguous 1140 3
hyperintensity on FLAIR
and DWI
a routineMRI not including DWI and FLAIR sequences; b months after onset of symptoms; c EEG recording/s performed earlier in the clinical
course did not show PSWCs; NA, not available; see text for other abbreviations.

mean disease duration was 4.1 ± 1 months (range bral cortex and/or in the thalamus as a relatively minor
2.5–5). Cortical visual symptoms included blurred co-occurring type.
vision (80%), visual field restriction (60%), vision loss
(60%), image distortion (40%), and optical hallucina- MM2C+1
tions (40%). EEG recording revealed PSWCs in all
patients (100%). Brain MRI with FLAIR and DWI Patient #16, a 70-year-old female, presented with a
sequences was positive in two subjects (66%) and non- subacute loss of visual acuity associated with visuo-
specific in one (33%). CSF analysis of protein 14-3-3 spatial distortion and a mild campimetric deficit.
was positive in four patients (80%) and ambiguous After three months of isolated visual disturbances, she
in one (20%), while t-tau was markedly elevated in developed gait difficulties and a rapidly progressive
all four patients (range 3990–7579 pg/ml) that were cognitive impairment. Six months later, her difficulties
tested. Histopathological examination and PrPSc typ- were followed by cerebellar signs (ataxia, dysmetria),
ing revealed the typical features of sCJD MM1 except myoclonus, dysphagia, and dysphonia. EEG record-
for the presence of clusters of large vacuoles associated ing showed a non-specific generalized slowing, routine
with perivacuolar and coarse PrP deposits mainly in the brain MRI was normal, while the 14-3-3 protein test
cerebral cortex or thalamus. Consistently, PrPSc type 1 was ambiguous. The patient progressed to akinetic
was detected by western blotting in all areas analyzed, mutism after 21 months of clinical course and died
whereas PrPSc type 2 was only seen focally in the cere- five months later. Histopathological examination and
470 S. Baiardi et al. / Prion Type Heterogeneity in CJD Heidenhain Variant

Fig. 1. Distinctive histopathology and regional distribution of PrPSc in patient #16 (MM 2C+1). (A) Spongiform change characterized by large,
confluent vacuoles (H&E stain) and (B) perivacuolar and coarse PrP deposits (PrP immunohistochemistry) in the occipital cortex; (C) mixed
type of spongiform change with large, confluent vacuoles intermixed with smaller vacuoles in the striatum (H&E stain); (D) spongiform change
characterized by small, fine, microvacuoles (H&E stain) and (E) synaptic pattern of PrP deposition in the cerebellum (PrP immunohistochemistry).
All pictures (A-E) have the same magnification (×100); F) PrPSc typing by western blot showing the co-occurrence of protein types 1 and 2 in
all regions but the cerebellum, where only a relatively low amount of type 1 is seen. While the amount of PrPSc type 2 is higher than that of type
1 in most samples from the cerebral cortex, subcortical gray matter structures show either a similar amount of the two proteins or a predominant
accumulation of type 1.

PrPSc typing revealed all the distinctive features of of both parietal lobes and left temporal lobe in DWI
sCJD MM 2C+1. In particular, spongiform change (Fig. 2A–C) and FLAIR sequences. EEG was desyn-
comprised either large, confluent vacuoles correlating chronized and slow. Neuropsychological evaluation
with perivacuolar and coarse PrP deposits or relatively revealed a mild encoding memory deficit, while frontal
small interspersed vacuoles associated with a synap- lobe functions were normal. CSF examination dis-
tic pattern of PrP staining (Fig. 1A–E). As typically closed 1070 pg/ml of t-tau, while the 14-3-3 protein
seen in sCJD MM 2C+1, the cerebral cortex was pre- test was ambiguous. The clinical course was slowly
dominantly affected by the former type of spongiosis, progressive; after two years, the patient became dis-
whereas the cerebellum only showed the latter type oriented and developed a psychosis with paranoid
(Fig. 1A,D). PrPSc typing revealed the co-occurrence delusions as well as pyramidal signs. He died after
of types 1 and 2 in all regions analyzed but the cere- a prolonged lethargic state lasting approximately 15
bellum (Fig. 1F). Consistent with histopathological months. At the neuropathologic examination, status
findings, the amount of PrPSc type 2 was higher than spongiosus associated with severe gliosis and neuronal
that of type 1 in most samples from the cerebral cor- loss was the predominant finding in the cerebral cor-
tex, whereas only type 1 was detected in the cerebellum tex (Fig. 2D) and striatum. Typical spongiform change
(Fig. 1F). with vacuoles of intermediate or large size was only
Patient #17, a 54 year-old male, presented with six seen focally in relatively preserved areas of the cerebral
month history of visual hallucinations (he saw ladders, cortex (Fig. 2F) and striatum as well as in the molecular
houses, or bikes while driving a digger), environmen- layer of cerebellum (Fig. 2H). In the latter, however,
tal agnosia (he failed to recognize the gate entrance of PAS positive, unicentric, amyloid plaques were also
his house while driving), and dyscalculia. At this time, noticed (Fig. 2I). PrP immunohistochemistry predom-
campimetry disclosed left homonymous hemianopsia. inantly revealed a coarse granular pattern of staining in
A brain MRI showed a diffused and bilateral hyperin- the cerebral cortex, striatum, thalamus, and cerebellum
tensity in the occipital cortex with partial involvement (Fig. 2E,G,L). In the latter, however, the coarse pattern
 S. Baiardi et al. / Prion Type Heterogeneity in CJD Heidenhain Variant 471

Fig. 2. Results of neuroimaging, histopatological, and PrPSc studies in patient #17 (MM 2C+1). Brain DWI-MRIs at 12 (A), 16 (B), and 19
months (C) from clinical onset showing a prominent occipital hyperintensity extending to the parietal cortices during the clinical course. (D)
Status spongiosus associated with severe gliosis and neuronal loss in the occipital cortex (H&E stain); (E) coarse granular pattern of PrP staining
in the occipital cortex (PrP immunohistochemistry); (F) focal spongiform change with vacuoles of intermediate to large size in the temporal
cortex (H&E stain); (G) coarse and perivacuolar PrP deposits in the frontal cortex (PrP immunohistochemistry); (H) focal mild spongiform
change in the cerebellum (H&E stain); (I) PAS positive, unicentric, amyloid plaque in the molecular layer of cerebellum (PAS stain); (L)
plaque-like type of PrP deposition predominantly involving the molecular layer in the cerebellum. All pictures (D-L) in the panel have the same
magnification (×100) except for L (×40). (M) PrPSc typing by western blot showing PrPSc 2 in all areas analyzed co-occurring with relatively
low amount of PrPSc type 1 in the cerebral cortex, brainstem, and cerebellum. Overall, the PrPSc amount is highest in the cerebral cortex;
intermediate in the striatum, thalamus, and cerebellum; and lowest in the hippocampus, hypothalamus, and brainstem.

was associated with a plaque-like type of PrP deposi- MM 2C

tion predominantly involving the molecular layer and
correlating with the anatomic distribution of amyloid Patient #18, a 48-year-old obese and heavy smoker,
plaques (Fig. 2L). In addition, foci of synaptic PrP presented with subacute visual complaints charac-
deposits were visible (Fig. 2L). PrPSc typing revealed terized by dazzling from lampposts at night. An
the presence of PrPSc type 2 in all areas analyzed. The ophthalmologic examination revealed an irregular
relative amount of the protein was highest in the cere- campimetric deficit in the right eye, while visual acu-
bral cortex of all lobes; lowest in the hippocampus, ity was normal. After two and a half months, he
hypothalamus, and brainstem; and intermediate in the became disinhibited, sometimes unsettled, and the
striatum, thalamus, and cerebellum (Fig. 2M). In addi- visual campimetric disturbance progressed to a right
tion, traces or a relatively low amount of PrPSc type homonymous hemianopsia. Neurological examination
1 were detected in some samples from the cerebral disclosed optic apraxia and simultanagnosia, psy-
cortex, brainstem, and cerebellum. chomotor slowing, and executive function impairment.
472 S. Baiardi et al. / Prion Type Heterogeneity in CJD Heidenhain Variant

Fig. 3. Results of neuroimaging, histopatological, and PrPSc studies in patient #18 (MM 2C). Hyperintensity of occipital cortex in DW- (A and
B) and FLAIR- (C) sequences. (D) Spongiform change characterized by large, confluent vacuoles diffusely involving the gray matter (H&E
stain, occipital cortex); (E) sparse foci of spongiform change especially involving the middle layers (H&E stain, frontal cortex); (F) perivacuolar
pattern of PrP deposition in the occipital cortex; (G) sparse foci of coarse PrP deposits in the frontal cortex; (H) mild spongiform changes
characterized by small vacuoles in the cerebellum (H&E stain); (I) lack of significant spongiform change in the putamen (H&E stain). Pictures
(D-I) in the panel have the same magnification (×100). (L) PrPSc typing by western blotting revealing a type 2 pattern of electrophoretic mobility
in all regions; PrPSc is overall more abundant in the cerebral cortex (especially in occipital cortex) than in subcortical areas where only traces
or a relatively low amount of the abnormal protein are detected.

A brain MRI revealed a hyperintense signal involv- striking difference in the degree of spongiform and
ing the occipital and parietal cortices in both DWI neurodegenerative changes between the posterior and
(Fig. 3A,B) and FLAIR (Fig. 3C) sequences. EEG anterior cortices. While the occipital gray matter was
showed a diffuse slowing of background activity. CSF entirely occupied by large confluent vacuoles, the
assays revealed 1,140 pg/ml of t-tau, while protein fronto-temporal cortices only showed sparse foci of
14-3-3 analyses yielded an ambiguous result. Dur- spongiform change (Fig. 3D,E), especially involving
ing the following two months, the patient developed the middle layers. Outside the cerebral cortex, spongi-
cortical blindness, complete spatial and temporal dis- form changes were mild and limited to small foci
orientation, amnesia, severe dysarthria and dysphagia, in the thalamus and molecular layer of cerebellum
paratonic rigidity, and recurring myoclonic jerks. The (Fig. 3H), while the striatum was spared (Fig. 3I). PrP
patient died of septic shock six months after the onset of immunohistochemistry revealed a perivacuolar pattern
visual symptoms. Histopathological examination and of protein deposition in all cortical areas (Fig. 3F,G).
PrPSc typing were consistent with sCJD type MM 2C. In addition, sparse foci of coarse PrP deposits were
Specifically, histopathologic examination revealed a present in the thalamus, whereas no immunodeposition
 S. Baiardi et al. / Prion Type Heterogeneity in CJD Heidenhain Variant 473

was seen in the cerebellum (data not shown). PrPSc t-tau levels (well above the 1200 pg/ml threshold) and
typing revealed a type 2 pattern (Fig. 3L). PrPSc was above threshold levels of protein 14-3-3 (i.e., positive
more abundant in the occipital cortex than in the test) in virtually all cases. Interestingly, analyses of
other cortical or subcortical areas where only traces the timing of appearance of PSWCs in the EEG and
or relatively low amounts of the protein were detected of a “positive” CSF assay suggest that the latter might
(Fig. 3L). be more sensitive than the EEG early in the clinical
course (i.e., when patients suffer from isolated visual
symptoms). Indeed, while the time of appearance of
DISCUSSION PSWCs in our series ranged from one and a half to
three months after onset, in two cases 14-3-3 and t-
Heidenhain variant defines a peculiar clinical pre- tau assays were already positive two weeks after onset
sentation of CJD characterized by isolated visual (Table 2).
disturbances, reflecting the early and prevalent involve- At variance with previous studies, three cases (17%)
ment of the occipital cortex by the degenerative in our series demonstrated distinctive clinical fea-
changes. tures and an exclusive or predominant deposition of
In our large series of sCJD, the prevalence of PrPsc type 2. Indeed, in these patients, the duration
Heidenhain variant was 4.9%. This number is quite of isolated visual symptoms was significantly longer,
consistent with that (3.7%) reported by Cooper et al. and the clinical course was more slowly progres-
[11]. However, it is significantly lower than that sive than in MM1 or MM1+2C sCJD types. Two of
reported by Kropp et al. (20%) [13] who applied them had a disease duration longer than two years,
less stringent clinical criteria for the definition of while in the third, the relatively mild histopathological
Heidenhain variant (e.g., visual symptoms at onset changes were observed in all areas, but the occipi-
notwithstanding their being isolated for some time). tal cortex also indicated a relatively slow progression.
sCJD is a highly heterogeneous disease caused by EEG findings, showing a diffuse slowing of back-
prion strains showing distinctive neuronal targeting ground activity without PSWCs, were not distinctive in
[45]. Detailed studies of the regional distribution of these patients. Similarly, both 14-3-3 and t-tau analy-
lesions (the so-called lesion profile) across the spec- ses revealed pathological values that were below the
trum of CJD types have shown that sCJD MM-MV1 required threshold for the diagnosis of “probable”
(e.g., M1 strain) is associated with significant corti- CJD [42]. In contrast, typical occipito-parietal hyper-
cal pathology, and that this is often predominant in the intensity on FLAIR and DWI sequences were clearly
occipital lobe [3, 46]. Accordingly, early molecular and seen on brain MRI in both patients who underwent
histotype analyses performed in cases with the Hei- these analyses. Thus, the results of laboratory inves-
denhain clinical presentation indicated that all these tigations significantly differ between the two sCJD
cases belonged to the MM-MV1 type [3, 11, 13]. More types, which is in agreement with the known dif-
recently, however, a clinical onset with isolated visual ferent pathophysiology of the disease process (e.g.,
symptoms has also been described in a case affected earlier and more rapidly evolving neuronal dysfunction
by MM 2C [29], a rarer sCJD type also characterized in MM1) and the significantly different transmis-
by prominent cortical targeting [3, 47]. In the present sion properties (e.g., significantly shorter incubation
study, we definitely establish that the Heidenhain vari- time and higher transmission rate of MM1 prions)
ant can be also associated with the MM 2C sCJD type, [47, 48, 49] between the two sCJD types. Accord-
either isolated or co-occurring with the MM1 type, and ingly, CSF biomarkers (i.e., t-tau >1200 pg/ml and
highlight the significant differences in clinical evolu- 14-3-3) and EEG abnormalities (i.e., PSWCs), reflect-
tion as well as laboratory findings between the two ing either a subacute neurodegeneration or a rapidly
sCJD types. As expected, the majority of patients in our evolving cortical and subcortical dysfunction, show
series (83%) were affected either by the MM1 (55.5%) a higher sensitivity in sCJD MM1. In contrast, the
or MM1+2C sCJD type (27.5%). In both instances, brain DWI-MRI increased signal, which instead cor-
patients were clinically characterized by a short dura- relates with the degree of spongiform change in the
tion of isolated visual symptoms and overall disease cerebral gray matter [50], has also a good sensitivity
course. EEG disclosed PSWCs in the majority of them, (or even higher according to our results) in MM2C,
while 80% had a typical occipito-parietal hyperinten- which shows a very distinctive type of spongiform
sity on DWI or FLAIR MRI sequences. Finally, CSF change characterized by numerous large and conflu-
assays, when performed, showed markedly increased ent vacuoles. Although the present study focused on
474 S. Baiardi et al. / Prion Type Heterogeneity in CJD Heidenhain Variant

sCJD, it is worth mentioning that a CJD type with ACKNOWLEDGMENTS

identical or very similar clinical-pathological features
and transmission properties of sCJDMM1 has also This work was financially supported by the Ital-
been described in genetic CJD cases carrying the ian Ministry of Health, grant RF2011-02351092, and
V210I-129M or the E200K-129 PRNP haplotype [7, by the Gino Galletti Foundation. We wish to thank
48, 51]. Thus, it is expected that cases with the Barbara Polischi and Sabrina Boninsegna for their
Heidenhain variant may also occur in genetic CJD. valuable technical assistance.
Consistently, isolated visual symptoms at onset have Authors’ disclosures available online (http://j-alz.
been recently reported in two subjects carrying the com/manuscript-disclosures/15-0668r2).
V210I-129M PRNP haplotype, which further under-
lines the importance of genetic testing in all cases REFERENCES
of possible and probable CJD, including those pre-
senting with visual signs [54]. Despite its rarity, the [1] Will RG, Matthews WB (1984) A retrospective study of
Heidenhain variant of CJD remains of clinical rele- Creutzfeldt-Jakob disease in England and Wales 1970-79. I:
vance. A significant number of patients are initially Clinical features. J Neurol Neurosurg Psychiatry 47, 134-140.
[2] Brown P, Cathala F, Castaigne P, Gajdusek DC (1986)
referred to the ophthalmologist, and misdiagnoses Creutzfeldt-Jakob disease: Clinical analysis of a consecutive
are not uncommon, especially in the early clinical series of 230 neuropathologically verified cases. Ann Neurol
stages as well as in the clinical neurological setting. In 20, 597-602.
addition to ocular diseases, differential diagnosis may [3] Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer
W, Windl O, Zerr I, Budka H, Kopp N, Piccardo P, Poser S,
include occipital stroke and other neurodegenerative Rojiani A, Streichemberger N, Julien J, Vital C, Ghetti B,
conditions causing a posterior cortical atrophy (PCA) Gambetti P, Kretzschmar H (1999) Classification of sporadic
syndrome, including Alzheimer’s disease, demen- Creutzfeldt-Jakob disease based on molecular and phenotypic
tia with Lewy bodies, and corticobasal degeneration analysis of 300 subjects. Ann Neurol 46, 224-233.
[4] Krasnianski A, Kaune J, Jung K, Kretzschmar HA, Zerr I
[53, 54]. In agreement with the recent literature, (2014) First symptom and initial diagnosis in sporadic CJD
which suggests that phenotypic differences (i.e., dif- patients in Germany. J Neurol 261, 1811-1817.
ferent visual symptoms) within PCA cases might [5] Aguzzi A, Heikenwalder M, Polymenidou M (2007) Insights
most appropriately be judged to represent points on into prion strains and neurotoxicity. Nat Rev Mol Cell Biol 8,
552-561.
a continuum of variation, we failed to recognize a [6] Gambetti P, Kong Q, Zou W, Parchi P, Chen SG (2003) Spo-
unitary clinical posterior cortical syndrome among radic and familial CJD: Classification and characterisation.
sCJD cases that would justify the proposal of a Br Med Bull 66, 213-239.
[7] Capellari S, Strammiello R, Saverioni D, Kretzschmar H,
distinct syndromic subtype of PCA. Since physical
Parchi P (2011) Genetic Creutzfeldt-Jakob disease and fatal
examination is unremarkable in most PCA cases, familial insomnia: Insights into phenotypic variability and
it is also unhelpful for the differential diagnosis. disease pathogenesis. Acta Neuropathol 121, 21-37.
Nonetheless, the presence of symmetrical parkinson- [8] Parchi P, de Boni L, Saverioni D, Cohen ML, Ferrer I,
Gambetti P, Gelpi E, Giaccone G, Hauw JJ, Höftberger R,
ism or rapid eye movement sleep behavior disorder Ironside JW, Jansen C, Kovacs GG, Rozemuller A, Seilhean
(suggestive of Lewy body pathology) as well as asym- D, Tagliavini F, Giese A, Kretzschmar HA (2012) Consen-
metric myoclonus/dystonia (suggestive of corticobasal sus classification of human prion disease histotypes allows
degeneration) can give clues to the underlying cause of reliable identification of molecular subtypes: An inter-rater
study among surveillance centres in Europe and USA. Acta
PCA [52]. When PCA is suspected, the clinical course, Neuropathol 124, 517-529.
CSF biomarker analysis, brain DWI- or FLAIR-MRI, [9] Parchi P, Strammiello R, Notari S, Giese A, Langeveld JP,
and, to a lesser extent, EEG recordings, remain the Ladogana A, Zerr I, Roncaroli F, Cras P, Ghetti B, Poc-
most important tools in the differential diagnosis. In chiari M, Kretzschmar H, Capellari S (2009) Incidence and
spectrum of sporadic Creutzfeldt-Jakob disease variants with
this respect, the findings of the present study high- mixed phenotype and co-occurrence of PrPSc types: An
light the fact that, despite their relative rarity, CJD updated classification. Acta Neuropathol 118, 659-671.
cases presenting with isolated visual symptoms may [10] Cali I, Castellani R, Yuan J, Al-Shekhlee A, Cohen ML, Xiao
belong to different disease variants that are charac- X, Moleres FJ, Parchi P, Zou WQ, Gambetti P (2006) Classifi-
cation of sporadic Creutzfeldt-Jakob disease revisited. Brain
terized by a distinct profile of laboratory findings. In 129, 2266-2277.
particular, clinicians should be aware that the Heidein- [11] Cooper SA, Murray KL, Heath CA, Will RG, Knight
hain variant may also occur in atypical cases showing RS (2005) Isolated visual symptoms at onset in sporadic
Creutzfeldt-Jakob disease: The clinical phenotype of the
a relatively slow progression, negative or ambiguous
“Heidenhain variant”. Br J Ophthalmol 89, 1341-1342.
CSF biomarkers results, and lack of specific EEG [12] Heidenhain A (1929) Klinische und anatomische Unter-
abnormalities. suchungen uber eine eigenartige organische Erkrankung des
 S. Baiardi et al. / Prion Type Heterogeneity in CJD Heidenhain Variant 475

Zentralnervensystems im Praesenium. Zeitschrift für die [30] Keyrouz SG, Labib BT, Sethi R (2006) MRI and EEG findings
gesamte Neurologie und Psychiatrie 118, 49-114. in Heidenhain variant of Creutzfeldt-Jakob disease. Neurol-
[13] Kropp S, Schulz-Schaeffer WJ, Finkenstaedt M, Riedemann ogy 67, 333.
C, Windl O, Steinhoff BJ, Zerr I, Kretzschmar HA, Poser S [31] Foundas M, Donaldson MD, McAllister IL, Bridges LR
(1999) The Heidenhain variant of Creutzfeldt-Jakob disease. (2008) Vision loss due to coincident ocular and central causes
Arch Neurol 56, 55-61. in a patient with Heidenhain variant Creutzfeldt-Jakob dis-
[14] Jacobs DA, Lesser RL, Mourelatos Z, Galetta SL, Balcer LJ ease. Age Ageing 37, 231-232.
(2001) The Heidenhain variant of Creutzfeldt-Jakob disease: [32] Cornelius JR, Boes CJ, Ghearing G, Leavitt JA, Kumar
Clinical, pathologic, and neuroimaging findings. J Neurooph- N (2009) Visual symptoms in the Heidenhain variant of
thalmol 21, 99-102. Creutzfeldt-Jakob Disease. J Neuroimaging 19, 283-287.
[15] Proulx AA, Strong MJ, Nicolle DA (2008) Creutzfeldt-Jakob [33] Kher M, Rao MY, Acharya PT, Mahadevan A, Shankar SK
disease presenting with visual manifestations. Can J Ophthal- (2009) Heidenhain variant of Creutzfeldt-Jakob disease: An
mol 43, 591-595. autopsy study from India. Ann Indian Acad Neurol 12, 48-51.
[16] Appleby BS, Appleby KK, Crain BJ, Onyike CU, Wallin MT, [34] del Barrio-Manso I, Toribio-Garcı́a A, Cordero-Coma M,
Rabins PV (2009) Characteristics of established and proposed Tuñón L, Baragaño E (2010) Creutzfeldt - Jakob presenting
sporadic Creutzfeldt-Jakob disease variants. Arch Neurol 66, with isolated visual symptoms: The Heidenhain variant. Arch
208-215. Soc Esp Oftalmol 85, 341-344.
[17] Cartier LR, Quiroz G, Leiva MH, Vergara CR (2012) Clinical [35] Prasad S, Lee EB, Woo JH, Alavi A, Galetta SL, Photo essay
and pathologic identification of different forms of Creutzfeldt (2010) MRI and positron emission tomography findings in
Jakob disease in Chile. Rev Med Chil 140, 161-168. Heidenhain variant Creutzfeldt-Jakob disease. J Neurooph-
[18] Parker SE, Gujrati M, Pula JH, Zallek SN, Kattah JC (2014) thalmol 30, 260-262.
The Heidenhain variant of Creutzfeldt-Jakob disease–a case [36] Verma R, Junewar V, Sahu R (2013) Creutzfeldt-Jakob disease
series. J Neuroophthalmol 34, 4-9. presenting with visual symptoms: A case of the ‘Heidenhain
[19] Grünwald F, Pohl C, Bender H, Hartmann A, Menzel variant’. BMJ Case Rep 2013, pii: bcr2012008006.
C, Ruhlmann J, Keller E, Biersack HJ (1996) 18F- [37] Vachalová I, Gindl V, Heckmann JG (2014) Acute inferior
fluorodeoxyglucose-PET and 99mTc-bicisate-SPECT in homonymous quandrantanopia in a 71-year-old woman. J
Creutzfeldt-Jakob disease. Ann Nucl Med 10, 131-134. Clin Neurosci 21, 683-685.
[20] Staffen W, Trinka E, Iglseder B, Pilz P, Homann N, Ladurner [38] Meyer A, Leigh D, Bagg CE (1954) A rare presenile dementia
G (1997) Clinical and diagnostic findings in a patient with associated with cortical blindness (Heidenhain’s syndrome).
Creutzfeldt-Jakob disease (type Heidenhain). J Neuroimaging J Neurol Neurosurg Psychiatry 17, 129-133.
7, 50-54. [39] World Medical Association (2013) World Medical Associa-
[21] Finsterer J, Bancher C, Mamoli B (1999) Giant visually- tion Declaration of Helsinki: Ethical principles for medical
evoked potentials without myoclonus in the Heidenhain type research involving human subjects (2013) JAMA 310, 2191-
of Creutzfeld-Jakob disease. J Neurol Sci 167, 73-75. 2194.
[22] Deschauer M, Stephan M, Stuhlträger U, Holzhausen HJ, [40] Jansen C, Parchi P, Capellari S, Ibrahim-Verbaas CA, Schuur
Duncker G, Zierz S (2000) Bilateral inferior hemianopsia M, Strammiello R, Corrado P, Bishop MT, van Gool WA, Ver-
as an early symptom of Heidenhain type Creutzfeldt-Jakob beek MM, Baas F, van Saane W, Spliet WG, Jansen GH, van
disease. Klin Monbl Augenheilkd 216, 227-231. Duijn CM, Rozemuller AJ (2012) Human prion diseases in
[23] Mathews D, Unwin DH (2001) Quantitative cerebral blood the Netherlands (1998-2009): Clinical, genetic and molecular
flow imaging in a patient with the Heidenhain variant of aspects. PLoS One 7, e36333.
Creutzfeldt-Jakob disease. Clin Nucl Med 26, 770-773. [41] Castellani RJ, Colucci M, Xie Z, Zou W, Li C, Parchi P, Capel-
[24] Pachalska M, Kurzbauer H, MacQueen BD, Formińska- lari S, Pastore M, Rahbar MH, Chen SG, Gambetti P (2004)
Kapuścik M, Herman-Sucharska I (2001) Neuropsycholog- Sensitivity of 14-3-3 protein test varies in subtypes of sporadic
ical features of rapidly progressive dementia in a patient with Creutzfeldt-Jakob disease. Neurology 63, 436-442.
an atypical presentation of Creutzfeldt-Jakob Disease. Med [42] Zerr I, Kallenberg K, Summers DM, Romero C, Taratuto A,
Sci Monit 7, 1307-1315. Heinemann U, Breithaupt M, Varges D, Meissner B, Lado-
[25] Arruda WO, Bordignon KC, Milano JB, Ramina R (2004) gana A, Schuur M, Haik S, Collins SJ, Jansen GH, Stokin GB,
Creutzfeldt-Jakob disease, Heidenhain variant: Case report Pimentel J, Hewer E, Collie D, Smith P, Roberts H, Brandel JP,
with MRI (DWI) findings. Arq Neuropsiquiatr 62, 347-352. van Duijn C, Pocchiari M, Begue C, Cras P, Will RG, Sanchez-
[26] Tsuji Y, Kanamori H, Murakami G, Yokode M, Mezaki T, Juan P (2009) Updated clinical diagnostic criteria for sporadic
Doh-ura K, Taniguchi K, Matsubayashi K, Fukuyama H, Kita Creutzfeldt-Jakob disease. Brain 132, 2659-2668.
T, Tanaka M (2004) Heidenhain variant of Creutzfeldt-Jakob [43] Parchi P, Notari S, Weber P, Schimmel H, Budka H, Fer-
disease: Diffusion-weighted MRI and PET characteristics. rer I, Haik S, Hauw JJ, Head MW, Ironside JW, Limido L,
J Neuroimaging 14, 63-66. Rodriguez A, Ströbel T, Tagliavini F, Kretzschmar HA (2009)
[27] Rizzo M, Bruni A, Barberio C, Magro G, Foncin JF (2004) Inter-laboratory assessment of PrPSc typing in creutzfeldt-
A Heidenhain variant of reutzfeldt-Jakob disease: Forensic jakob disease: A Western blot study within the NeuroPrion
implication. Forensic Sci Int 146, 51-54. Consortium. Brain Pathol 19, 384-391.
[28] Fauquembergue M, Tilikete C, Perret-Liaudet A, Kopp N, [44] Parchi P, Strammiello R, Giese A, Kretzschmar H (2011) Phe-
Krolak-Salmon P, Vighetto A (2005) Heidenhain’s variant of notypic variability of sporadic human prion disease and its
Creutzfeldt-Jakob’s disease. Rev Neurol (Paris) 161, 578-581. molecular basis: Past, present, and future. Acta Neuropathol
[29] Nozaki I, Hamaguchi T, Noguchi-Shinohara M, Ono K, Shi- 121, 91-112.
rasaki H, Komai K, Kitamoto T, Yamada M (2006) The [45] Parchi P, Saverioni D (2012) Molecular pathology, classifica-
MM2-cortical form of sporadic Creutzfeldt-Jakob disease tion, and diagnosis of sporadic human prion disease variants.
presenting with visual disturbance. Neurology 67, 531-533. Folia Neuropathol 50, 20-45.
476 S. Baiardi et al. / Prion Type Heterogeneity in CJD Heidenhain Variant

[46] Parchi P, Capellari S, Gambetti P (2000) Intracerebral distri- Montagna P, Lodi R, Barbiroli B (2009) Pathologic corre-
bution of the abnormal isoform of the prion protein in sporadic lates of diffusion MRI changes in Creutzfeldt-Jakob disease.
Creutzfeldt-Jakob disease and fatal insomnia. Microsc Res Neurology 72, 1425-1431.
Tech 50, 16-25. [51] Nonno R, Bari MAD, Cardone F, Vaccari G, Fazzi P,
[47] Bishop MT, Will RG, Manson JC (2010) Defining sporadic Dell’Omo G, Cartoni C, Ingrosso L, Boyle A, Galeno
Creutzfeldt-Jakob disease strains and their transmission prop- R, Sbriccoli M, Lipp HP, Bruce M, Pocchiari M, Agrimi
erties. Proc Natl Acad Sci U S A 107, 12005-12010. U (2006) Efficient Transmission and Characterization of
[48] Parchi P, Cescatti M, Notari S, Schulz-Schaeffer WJ, Capel- Creutzfeldt–Jakob Disease Strains in Bank Voles. PLoS
lari S, Giese A, Zou WQ, Kretzschmar H, Ghetti B, Brown P Pathog 2, e12.
(2010) Agent strain variation in human prion disease: Insights [52] Imbriani P, Marfia GA, Marciani MG, Poleggi A, Pocchiari M,
from a molecular and pathological review of the National Puoti G, Caltagirone C, Pisani A (2015) Heidenhain variant in
Institutes of Health series of experimentally transmitted dis- two patients with inherited V210I Creutzfeldt-Jakob disease.
ease. Brain 133, 3030-3042. Int J Neurosci, doi: 10.3109/00207454.2015.1047017
[49] Kobayashi A, Teruya K, Matsuura Y, Shirai T, Nakamura Y, [53] Victoroff J, Ross GW, Benson DF, Verity MA, Vinters HV
Yamada M, Mizusawa H, Mohri S, Kitamoto T (2015) The (1994) Posterior cortical atrophy. Neuropathologic correla-
influence of PRNP polymorphisms on human prion disease tions. Arch Neurol 51, 269-274.
susceptibility: An update. Acta Neuropathol 130, 159-170. [54] Crutch SJ, Lehmann M, Schott JM, Rabinovici GD, Rossor
[50] Manners DN, Parchi P, Tonon C, Capellari S, Strammiello MN, Fox NC (2012) Posterior cortical atrophy. Lancet Neurol
R, Testa C, Tani G, Malucelli E, Spagnolo C, Cortelli P, 11, 170-178.