Enfermedad de Creutzfeldt Jakob - Actualización clínica. Dr. Ignacio Rueda Medina. Unidad de Demencias HGMC. Sesión del Servicio de Neurología del Hospital Mancha Centro del 12-12-2017.

1. ENFERMEDAD DE CREUTZFELDT
JAKOB actualización clínica
IGNACIO RUEDA MEDINA
SERVICIO DE NEUROLOGÍA - HG MANCHA CENTRO
12-12-2017

2. INTRODUCCIÓN
prion
on th
clinica
PRNP
stand
C
Typic
cours
mont
tion
classifi
senta
(Tabl
Table 1 Classification of prion diseases in humans
(1) Sporadic (idiopathic) prion disease
Sporadic Creutzfeldt-Jakob disease (sCJD)
Sporadic fatal insomnia (sFI)
Variably protease-sensitive prionopathy (VPSPr)
(2) Acquired (infected) prion disease
Human origin
Iatrogenic CJD (due to medical procedures)
Kuru
Bovine origin
Variant CJD (vCJD)
(3) Familial (inherited or genetic) prion disease
Genetic CJD
Gerstmann- Sträussler-Scheinker syndrome (GSS)
Fatal familial insomnia (FFI)
Modified from previous reports.1–3
2
Table2ClinicopathologicalcharacteristicsofeachtypeofsporadicCreutzfeldt-Jakobdisease
MM1MV1MM2-corticalMM2-thalamic
Polymorphic
codon129of
thePrPgene
Met/MetMet/
Val
Met/MetMet/Met
PrPtypeType1Type1Type2Type2
Previous
classification
Classic-type,
myoclonic-type,
Heidenhainvariant
NotestablishedThalamicvariant,thalamic
degeneration,sporadicfatal
insomnia
Kuru-
Frequency
Caucasian
(%)
67.62.722
Japanese
(%)
85.3
(includes
6.7%
MM1+2
type)
2.76.74.0(includes1.3%MM2-
cortical+thalamictype)
Clinicalfindings
Ageatonset65.562.164.3(49–77)52.3(36–71)5
© 2016 Japanese Society of Neuropathology
ECJ
esporádica
90%

3. INTRODUCCIÓN
pati
sam
and
the s
of th
not
M
inclu
on t
sCJD
obta
olfa
diag
PrP
try i
met
muc
use,
diag
A
sis o
PrP
stain
lecte
brai
that
part
influence a variety of cellular functions and to result in altered host phenotypes,
including impairments in metal homeostasis, development, synaptic plasticity, circadian
rhythm, and stress responses68–71
. However, some of the reported PrPC
knockout
phenotypes might be attributed to flanking genes72
. In prion diseases, most, if not all, of
the α-helical structure PrPC
is refolded to β sheets and loops concurrent with assembly
into disease-associated PrP multimers, such as amyloid fibrils, with as yet unresolved
tertiary and quaternary structures. Besides its involvement in prion diseases, one the
more renowned pathophysiological roles of PrPC
is mediation of some of the neurotoxic
effects of amyloid–β oligomers in Alzheimer disease models71
.
NMDA, N-methyl-d‑aspartate.
GlycophosphatidylinositolCell surface
Lumen
NH3
+
Cu2+
Glycans
Nature Reviews | Neurology
Functions of PrPC
• Cu2+
and Zn2+
binding/homeostasis
• Cellular signalling and regulation of ion
channels and neuronal excitability
-NMDA receptor modulation
• Cell adhesion (neurite outgrowth)
• Maintenance of peripheral nerve myelin
• Neuronal survival and differentiation
• Neuroprotection
-N-terminal region protects from reactive
oxygen species
-Central region binds to stress-inducible
protein 1
• Receptor for amyloid-β oligomers in
Alzheimer disease, and possibly for other
β-rich protein aggregates
Advanced tests for early and accurate
diagnosis of Creutzfeldt–Jakob
disease
Gianluigi Zanusso1
, Salvatore Monaco1
, Maurizio Pocchiari2
and Byron Caughey3
Abstract | Early and accurate diagnosis of Creutzfeldt–Jakob disease (CJD) is a necessary to
REVIEWS
ECJ
Paso a isoforma PrPsc
43 MM1-type sCJD cases.15
Average age at disease onset of
the series was 69.7 Æ 7.7 years (range, 57–89 years), with an
neocortex, striatum, thalamus and cerebellar cortex.9,15
Spongiform change was of the fine vacuole type (numerous
round vacuoles with clear boundaries and without the ten-
dency for adhesion within the neuropil) (Fig. 3A).9,15
The le-
sion distribution shows apparent system degeneration.9
The
developmentally more recent parts of the brain, such as the
cerebral neocortex and striatum, were found to be consider-
ably involved, whereas older regions such as the hippocam-
pus, brainstem and spinal cord tended to exhibit
degradation to a lesser extent.9,18,19
PrP immunostaining showed diffuse granular synaptic-
type PrP deposition (Fig. 4A).9
PrP deposition has been
particularly observed in the cerebral neocortex, subiculum,
striatum, thalamus, cerebellar cortex (particularly the mo-
lecular layer and granule cell layer), quadrigeminal body,
substantia nigra, pontine nucleus, inferior olivary nucleus
and spinal posterior horn, particularly in the substantia gela-
tinosa.9,18,19
In severe lesions, such as those in the cerebral
neocortex in status spongiosus, PrP deposition was
decreased.9
Staging of cerebral cortical pathology
Fig. 1 A: Diffusion-weighted MRI of a
patient with sporadic CJD (sCJD) shows
extensive hyperintensity regions in the
cerebral cortex and striatum. B: Typical
periodic sharp-wave complexes (PSWCs)
on EEG of a patient with sCJD. R:
right side.
Fig. 2 Coronal section of the cerebrum of a patient with sporadic
CJD (sCJD) after formalin fixation. Severe cerebral atrophy is ob-
served in the cortex, basal ganglia, thalamus and white matter. Bilat-
eral lateral ventricular dilatation is noticeable, but the hippocampus
is relatively preserved from atrophy.
Creutzfeldt-Jakob disease 5

4. INTRODUCCIÓN Table 5 Clinicopathological characteristic of each type of sporadic Creutzfeldt-Jakob disease
Cortical
pathologic
staging
Characteristic
pathology
Simple staging
classification
Pathological findings
Stage 0 No abnormality None No pathologic abnormality can be detected by HE staining. No gliosis,
spongiform change, neuropil rarefaction or neuron loss is observed.At the Stage
0.5, only PrP deposition is observed by immunostaining.
Stage 0.5 PrP deposition
Stage I Spongiform
change(Fig. 5A)
Mild Mild spongiform change is observed in the neuropil. Small round vacuoles with
clear boundaries are recognized in the neuropil. Vacuoles show no tendency to
confluent growth. Gliosis is not apparent or is mildly observed, but hypertrophic
astrocytosis has not yet appeared. No neuropil rarefaction or neuron loss can be
detected. This is the earliest pathologic observation that can be detected by HE
staining in the cerebral neocortex.
Stage II Hypertrophic
astrocytosis(Fig. 5B)
The important difference from Stage I is the presence of hypertrophic
astrocytosis. Gliosis with hypertrophic astrocytosis is apparent in the neuropil.
Numerous vacuoles are observed in the neuropil, but the neuropil shows no or
very mild rarefaction. No tendency to adhesion of vacuoles or further
enlargement of vacuole size is recognized. The shape of the vacuole remains
round. Neuron loss is not apparent, and cortical laminar structure is preserved.
Stage III Neuropil
rarefaction(Fig. 5C)
Moderate Tissue rarefaction of the neuropil is apparent. Neurons are mildly decreased in
number and hypertrophic astrocytosis has become remarkable. The boundary of
the vacuole becomes unclear because of progression of neuropil rarefaction,
whereas coarse vacuolation without clear boundaries becomes apparent. Some
residual neurons, particularly in the deeper cortical layer, show achromatic
neurons with pale cytoplasm and eccentric nucleus, so-called inflated neurons.
The cortical laminar structure is still identifiable.
Stage IV Neuron
loss(Fig. 5D)
Neurons are moderately decreased in number and severe hypertrophic
astrocytosis is observed. Tissue rarefaction of the neuropil becomes remarkable
and vacuoles with a clear boundary that are observed in an earlier stage are no
longer apparent. Many inflated neurons are observed. The cortical laminar
structure becomes ambiguous.
Stage V Status
spongiosus(Fig. 5E)
Severe The neuropil shows severe rarefaction and severe neuron loss with fibrous
gliosis is recognized. Hypertrophic astrocytes are apparent but are decreased in
degree compared with Stage IV. In contrast, many macrophages are recognized.
These lesions correspond to “status spongiosus”. Cortical laminar structures are
unidentifiable.
Stage VI Large cavity
formation(Fig. 5F)
Characteristic large-sized cystic cavitations are observed. Macrophages are
recognized in the cavities. The cavities tend to be formed from the deeper
cortical layer, and the molecular layer tends to be preserved from the cavity
formation. Hypertrophic astrocytosis is no longer remarkable. Neurons are
almost completely missing.
Modified from our previous report.15
© 2016 Japanese Society of Neuropathology
c of each type of sporadic Creutzfeldt-Jakob disease
Simple staging
classification
Pathological findings
7

5. EPIDEMIOLOGIA
Sporadic CJD is rare, with mortality rates of
approximately 1.5 cases per million per annum
in systematic national surveys (Fig. 1) (Lado-
gana et al. 2005). Lower rates in some countries
tors for the development of disease, which have
been largelynegative,withpositivefindingslike-
ly reflecting methodological biases rather than
truebiologicalriskfactors(dePedroCuestaetal.
1.22
1.5
1.3
1.66 1.38
0.96
1.24 0.34
0.22
0.17
1.41
0.93
0.53
0.94
1.23
1.4
0.67
1.02
0.62
0.71
1.27
1.021.09
1.3
0.7
Figure 1. Mean annual mortality rates for sporadic Creutzfeldt–Jakob disease (sCJD) in Europe (periods of
surveillance, 8–21 years).
2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a024364
www.perspectivesinmedicine.org
Sporadic and Infectious Human Prion Diseases
Robert G. Will and James W. Ironside
National Creutzfeldt–Jakob Disease Research and Surveillance Unit, Centre for Clinical Brain Sciences,
Laboratory Press
at MELBOURNE on October 30, 2016 - Published by Cold Spring Harborhttp://perspectivesinmedicine.cshlp.org/rom
MORTALIDAD MEDIA ECJs
1.5 casos / millón / año
1.22

6. FENOTIPOS
CLÍNICOS
Table 2 Clinicopathological characteristics of each type of sporadic Creutzfeldt-Jakob disease
MM1 MV1 MM2-cortical MM2-thalamic MV2 VV1 VV2
Polymorphic
codon 129 of
the PrP gene
Met / Met Met /
Val
Met / Met Met / Met Met / Val Val / Val Val / Val
PrP type Type 1 Type 1 Type 2 Type 2 Type 2 Type 1 Type 2
Previous
classification
Classic-type,
myoclonic-type,
Heidenhain variant
Not established Thalamic variant, thalamic
degeneration, sporadic fatal
insomnia
Kuru-plaques variant Not established Ataxic variant,
Brownell-Oppenheimer
type
Frequency
Caucasian
(%)
67.6 2.7 2 2 9 1 15.7
Japanese
(%)
85.3
(includes
6.7%
MM1 + 2
type)
2.7 6.7 4.0 (includes 1.3% MM2-
cortical + thalamic type)
1.3 0 0
Clinical findings
Age at onset 65.5
(42–91)
62.1
(51–72)
64.3 (49–77) 52.3 (36–71) 59.4 (40–81) 39.3 (24–49) 61.3 (41–80)
Total disease
duration
(months)
3.9 (1–18) 4.9
(2.5–9)
15.7 (9–36) 15.6 (8–24) 17.1 (5–72) 15.3 (14–16) 6.5 (3–18)
Clinical
features
Rapidly progressive
dementia, early and
prominent
myoclonus, typical
EEG, visual
impairment,
unilateral signs
Progressive
dementia, no
typical PSWCs
on EEG
Insomnia, psychomotor
hyperactivity, ataxia, cognitive
impairment, no typical EEG
Ataxia, progressive
dementia, no typical
EEG, long duration
Younger onset,
progressive dementia,
no typical EEG
Ataxia at onset, late
dementia, no typical EEG
Frequency of
myoclonus
(%)
97 100 67 50 77 67 66
Frequency of
PSWCs on
EEG (%)
80 71.4 0 0 7.7 0 7.1
14–3-3
protein in
CSF
Positive Positive Positive Negative Positive in some cases Positive Positive
Neuropathological features
Pathological
findings
Typical fine vacuole Large confluent
vacuole,
cerebellum is
relatively spared
Severe atrophy of the medial
thalamus and inferior olivary
nucleus with little pathology in
other areas; spongiform change
may be absent or focal
Similar to VV2 but
with presence of
amyloid-kuru plaques
in the cerebellum
Severe pathology in the
cerebral cortex and striatum
with sparing of brainstem
and cerebellum
Prominent involvement of
subcortical, including
brainstem, nuclei; in the
neocortex, spongiosis is often
limited to deep layers
PrP
deposition
Synaptic type Perivacuolar
type
Lesser deposition than in the
other variants
Plaque-like or focal
deposits
Synaptic type (very faint) Plaque-like, focal deposits,
as well as prominent
perineuronal staining
Modified from previous reports.1–4
Met, methionine; PSWCs: periodic sharp-wave complexes; sCJD, sporadic Creutzfeldt-Jakob disease; Val, valine.
Creutzfeldt-Jakobdisease3
©2016JapaneseSocietyofNeuropathology
1 3 4 5 62
POLIMORFISMO
GEN PrP CODÓN 129
MM MV VV

7. FENOTIPO CLÍNICO
MM1 - MV1
lecular layer, particularly in the PRNP codon
129 VV genotype (Fig. 7) (Zou et al. 2010).
Microplaques may also occur in the thalamus,
positive. These neuropathological featur
quite distinct from those of the sCJD VV
VV2 subtypes (Fig. 5) (Parchi et al. 1999
A
E F
B
C D
Figure 4. Neuropathology of sporadic Creutzfeldt–Jakob disease (sCJD) subtypes: (A,B) MM1/MV1;
MM2; and (E,F) sporadic fatal insomnia. (A) The frontal cortex in the MM1 and MV1 subtypes shows
vacuolar spongiform change. Hematoxylin and eosin, Â40. (B) PrP accumulates in the cerebral cortex
MM1/MV1 subtypes in a diffuse granular/synaptic pattern. 12F10 antibody, Â40. (C) The frontal cortex
MM2 cortical subtype shows confluent spongiform change. Hematoxylin and eosin, Â20. (D) PrPaccum
in the cerebral cortex in the MM2 cortical subtype in a dense perivacuolar pattern. 12F10 antibody, Â20. (
thalamus in sporadic fatal insomnia (MM2 thalamic subtype) exhibits severe neuronal loss without sign
vacuolation. Hematoxylin and eosin, Â40. (F) Marked thalamic gliosis in sporadic fatal insomnia is d
strated with an antibody to glial fibrillary acidic protein, Â40.
www.perspectivesinmedicine.org
Sporadic and Infectious Human Prion Diseases
Robert G. Will and James W. Ironside
National Creutzfeldt–Jakob Disease Research and Surveillance Unit, Centre for Clinical Brain Sciences,
University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom
Correspondence: r.g.will@ed.ac.uk; james.ironside@ed.ac.uk
Human prion diseases are rare neurodegenerative diseases that have become the subject of
public and scientific interest because of concerns about interspecies transmission and the
unusual biological properties of the causal agents: prions. These diseases are unique in that
theyoccur in sporadic, hereditary, and infectious forms that are characterized byan extended
incubation period between exposure to infection and the development of clinical illness.
Silent infection can be present in peripheral tissues during the incubation period, which
poses a challenge to public health, especially because prions are relatively resistant to
standard decontamination procedures. Despite intense research efforts, no effective treat-
ment has been developed for human prion diseases, which remain uniformly fatal.
Human prion diseases are clinically and
epidemiologically diverse, but are linked
by shared neuropathological features, includ-
ing spongiform degeneration, astrocytic gliosis,
and neuronal loss, sometimes associated with
amyloid plaques. These histological changes
are caused by the deposition of a posttransla-
tionally modified form of a normal host pro-
tein, prion protein (PrPC
). This modified pro-
tein, PrPSc
, is disease-specific and is the major
(if not the sole) component of the transmissible
agent in human and animal prion diseases. The
identification of PrPSc
by immunohistochemi-
cal and biochemical techniques is a key com-
ponent of the tissue-based diagnosis of prion
diseases.
The archetypal human prion disease is
sporadic Creutzfeldt–Jakob disease (sCJD),
which was first identified in 1920 (Creutzfeldt
1920; Jakob 1921), and was regarded as a rare,
atypical form of dementia until it was shown in
1968 (Gibbs et al. 1968) to be experimentally
transmissible to primates by intracerebral inoc-
ulation. This finding followed the earlier trans-
mission of kuru to primates in 1966 (Gajdusek
et al. 1966), which was the first demonstration
that degenerative disorders might be caused
by infectious agents. This seminal discovery
prompted a search for the source of infection
in sCJD through epidemiological studies, but
these analyses have not identified any consistent
risk factor for the development of this disease
(de Pedro Cuesta et al. 2012).
The occurrence of acquired cases of CJD
caused by previous medical or surgical treat-
ments, such as with human pituitary hormones
(Brown et al. 2000), led to awareness of the po-
tential public health implications of diseases
with extended incubation periods and a fatal
outcome. Public and regulatory concern about
these disorders has increased with the identifi-
cation of variant CJD (vCJD) as a zoonosis
Editor: Stanley B. Prusiner
Additional Perspectives on Prion Diseases available at www.perspectivesinmedicine.org
Copyright # 2016 Cold Spring Harbor Laboratory Press; all rights reserved
Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a024364
1
www.perspectivesinmedicine.org
POLIMORFISMO
Met/Met – Met/Val
FRECUENCIA
Met/Met 67.2%
Met/Val 2.7%
EDAD COMIENZO
Met/Met 65.2 años
Met/Val 62.1 años
DURACIÓN MEDIA
Met/Met 3.9 meses
Met/Val 4.9 meses
CLÍNICA
Demencia rápidamente progresiva
Mioclonías comienzo precoz – generalizadas
Alteraciones visuales
Unilateralidad síntomas
EEG típico
HALLAZGOS ESPECÍFICOS
Mioclonías
Met/Met 97% - Met-Val 100%
Complejos periódicos EEG
Met/Met 80 % - Met/Val: 71.4%
14-3-3 LCR
Met/Met – Met/Val: Positiva
ANATOMÍA PATOLÓGICA
Vacuolas pequeñas típicas DEPÓSITO PrP
Fundamentalmente sináptico

8. FENOTIPO CLÍNICO
MM2 - CORTICAL
Sporadic and Infectious Human Prion Diseases
Robert G. Will and James W. Ironside
National Creutzfeldt–Jakob Disease Research and Surveillance Unit, Centre for Clinical Brain Sciences,
University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom
Correspondence: r.g.will@ed.ac.uk; james.ironside@ed.ac.uk
Human prion diseases are rare neurodegenerative diseases that have become the subject of
public and scientific interest because of concerns about interspecies transmission and the
unusual biological properties of the causal agents: prions. These diseases are unique in that
theyoccur in sporadic, hereditary, and infectious forms that are characterized byan extended
incubation period between exposure to infection and the development of clinical illness.
Silent infection can be present in peripheral tissues during the incubation period, which
poses a challenge to public health, especially because prions are relatively resistant to
standard decontamination procedures. Despite intense research efforts, no effective treat-
ment has been developed for human prion diseases, which remain uniformly fatal.
Human prion diseases are clinically and
epidemiologically diverse, but are linked
by shared neuropathological features, includ-
ing spongiform degeneration, astrocytic gliosis,
and neuronal loss, sometimes associated with
amyloid plaques. These histological changes
are caused by the deposition of a posttransla-
tionally modified form of a normal host pro-
tein, prion protein (PrPC
). This modified pro-
tein, PrPSc
, is disease-specific and is the major
(if not the sole) component of the transmissible
agent in human and animal prion diseases. The
identification of PrPSc
by immunohistochemi-
cal and biochemical techniques is a key com-
ponent of the tissue-based diagnosis of prion
diseases.
The archetypal human prion disease is
sporadic Creutzfeldt–Jakob disease (sCJD),
which was first identified in 1920 (Creutzfeldt
1920; Jakob 1921), and was regarded as a rare,
atypical form of dementia until it was shown in
1968 (Gibbs et al. 1968) to be experimentally
transmissible to primates by intracerebral inoc-
ulation. This finding followed the earlier trans-
mission of kuru to primates in 1966 (Gajdusek
et al. 1966), which was the first demonstration
that degenerative disorders might be caused
by infectious agents. This seminal discovery
prompted a search for the source of infection
in sCJD through epidemiological studies, but
these analyses have not identified any consistent
risk factor for the development of this disease
(de Pedro Cuesta et al. 2012).
The occurrence of acquired cases of CJD
caused by previous medical or surgical treat-
ments, such as with human pituitary hormones
(Brown et al. 2000), led to awareness of the po-
tential public health implications of diseases
with extended incubation periods and a fatal
outcome. Public and regulatory concern about
these disorders has increased with the identifi-
cation of variant CJD (vCJD) as a zoonosis
Editor: Stanley B. Prusiner
Additional Perspectives on Prion Diseases available at www.perspectivesinmedicine.org
Copyright # 2016 Cold Spring Harbor Laboratory Press; all rights reserved
Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a024364
1
www.perspectivesinmedicine.org
lecular layer, particularly in the PRNP codon
129 VV genotype (Fig. 7) (Zou et al. 2010).
Microplaques may also occur in the thalamus,
basal ganglia, hippocampus, and cerebral cor-
tex. Immunohistochemistry for PrP shows
patchy diffuse labeling in the cerebral cortex,
whereas the microplaques show more intense
labeling and are periodic acid–Schiff (PAS)
positive. These neuropathological featur
quite distinct from those of the sCJD VV
VV2 subtypes (Fig. 5) (Parchi et al. 1999)
presence of the M129 allele modifies the n
pathologyof VPSPr, with larger plaques ap
ing in the MM genotype (Zou et al. 2010
The defining feature of VPSPr that giv
disorder its name is the presence of PrPSc
E F
C D
Figure 4. Neuropathology of sporadic Creutzfeldt–Jakob disease (sCJD) subtypes: (A,B) MM1/MV1;
MM2; and (E,F) sporadic fatal insomnia. (A) The frontal cortex in the MM1 and MV1 subtypes shows m
vacuolar spongiform change. Hematoxylin and eosin, Â40. (B) PrP accumulates in the cerebral cortex
MM1/MV1 subtypes in a diffuse granular/synaptic pattern. 12F10 antibody, Â40. (C) The frontal cortex
MM2 cortical subtype shows confluent spongiform change. Hematoxylin and eosin, Â20. (D) PrPaccum
in the cerebral cortex in the MM2 cortical subtype in a dense perivacuolar pattern. 12F10 antibody, Â20. (E
thalamus in sporadic fatal insomnia (MM2 thalamic subtype) exhibits severe neuronal loss without sign
vacuolation. Hematoxylin and eosin, Â40. (F) Marked thalamic gliosis in sporadic fatal insomnia is d
strated with an antibody to glial fibrillary acidic protein, Â40.
Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a024364
www.perspectivesinmedicine.org
POLIMORFISMO
Met/Met
FRECUENCIA
2%
EDAD COMIENZO
64.3 años
DURACIÓN MEDIA
15.7 meses
CLÍNICA
Demencia progresiva
Sin hallazgos típicos EEG
HALLAZGOS ESPECÍFICOS
Mioclonías 67%
Complejos periódicos EEG 0%
14-3-3 LCR Positiva
ANATOMÍA PATOLÓGICA
Vacuolas grandes confluentes DEPÓSITO PrP
Perivacuolar

9. FENOTIPO CLÍNICO
MM2 – TALÁMICO
Sporadic and Infectious Human Prion Diseases
Robert G. Will and James W. Ironside
National Creutzfeldt–Jakob Disease Research and Surveillance Unit, Centre for Clinical Brain Sciences,
University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom
Correspondence: r.g.will@ed.ac.uk; james.ironside@ed.ac.uk
Human prion diseases are rare neurodegenerative diseases that have become the subject of
public and scientific interest because of concerns about interspecies transmission and the
unusual biological properties of the causal agents: prions. These diseases are unique in that
theyoccur in sporadic, hereditary, and infectious forms that are characterized byan extended
incubation period between exposure to infection and the development of clinical illness.
Silent infection can be present in peripheral tissues during the incubation period, which
poses a challenge to public health, especially because prions are relatively resistant to
standard decontamination procedures. Despite intense research efforts, no effective treat-
ment has been developed for human prion diseases, which remain uniformly fatal.
Human prion diseases are clinically and
epidemiologically diverse, but are linked
by shared neuropathological features, includ-
ing spongiform degeneration, astrocytic gliosis,
and neuronal loss, sometimes associated with
amyloid plaques. These histological changes
are caused by the deposition of a posttransla-
tionally modified form of a normal host pro-
tein, prion protein (PrPC
). This modified pro-
tein, PrPSc
, is disease-specific and is the major
(if not the sole) component of the transmissible
agent in human and animal prion diseases. The
identification of PrPSc
by immunohistochemi-
cal and biochemical techniques is a key com-
ponent of the tissue-based diagnosis of prion
diseases.
The archetypal human prion disease is
sporadic Creutzfeldt–Jakob disease (sCJD),
which was first identified in 1920 (Creutzfeldt
1920; Jakob 1921), and was regarded as a rare,
atypical form of dementia until it was shown in
1968 (Gibbs et al. 1968) to be experimentally
transmissible to primates by intracerebral inoc-
ulation. This finding followed the earlier trans-
mission of kuru to primates in 1966 (Gajdusek
et al. 1966), which was the first demonstration
that degenerative disorders might be caused
by infectious agents. This seminal discovery
prompted a search for the source of infection
in sCJD through epidemiological studies, but
these analyses have not identified any consistent
risk factor for the development of this disease
(de Pedro Cuesta et al. 2012).
The occurrence of acquired cases of CJD
caused by previous medical or surgical treat-
ments, such as with human pituitary hormones
(Brown et al. 2000), led to awareness of the po-
tential public health implications of diseases
with extended incubation periods and a fatal
outcome. Public and regulatory concern about
these disorders has increased with the identifi-
cation of variant CJD (vCJD) as a zoonosis
Editor: Stanley B. Prusiner
Additional Perspectives on Prion Diseases available at www.perspectivesinmedicine.org
Copyright # 2016 Cold Spring Harbor Laboratory Press; all rights reserved
Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a024364
1
www.perspectivesinmedicine.org
lecular layer, particularly in the PRNP codon
129 VV genotype (Fig. 7) (Zou et al. 2010).
Microplaques may also occur in the thalamus,
basal ganglia, hippocampus, and cerebral cor-
tex. Immunohistochemistry for PrP shows
patchy diffuse labeling in the cerebral cortex,
whereas the microplaques show more intense
labeling and are periodic acid–Schiff (PAS)
posit
quite
VV2
prese
patho
ing in
T
disor
E F
Figure 4. Neuropathology of sporadic Creutzfeldt–Jakob disea
MM2; and (E,F) sporadic fatal insomnia. (A) The frontal cortex
vacuolar spongiform change. Hematoxylin and eosin, Â40. (B
MM1/MV1 subtypes in a diffuse granular/synaptic pattern. 12F
MM2 cortical subtype shows confluent spongiform change. Hem
in the cerebral cortex in the MM2 cortical subtype in a dense peri
thalamus in sporadic fatal insomnia (MM2 thalamic subtype) e
vacuolation. Hematoxylin and eosin, Â40. (F) Marked thalam
strated with an antibody to glial fibrillary acidic protein, Â40.
Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med
www.perspectivesinmedicine.org
POLIMORFISMO
Met/Met
FRECUENCIA
2%
EDAD COMIENZO
52.3 años
DURACIÓN MEDIA
15.6 meses
CLÍNICA
Insomnio
Inquietud motora
Ataxia
Deterioro cognitivo
EEG no típico
HALLAZGOS ESPECÍFICOS
Mioclonías 50%
Complejos periódicos EEG 0%
14-3-3 LCR negativa
ANATOMÍA PATOLÓGICA
Atrofia severa de tálamo medial – nucleo olivar
inferior
Cambios espongiformes ausentes o focales
DEPÓSITO PrP
Menor que en otras variantes

10. FENOTIPO CLÍNICO
MV2
Sporadic and Infectious Human Prion Diseases
Robert G. Will and James W. Ironside
National Creutzfeldt–Jakob Disease Research and Surveillance Unit, Centre for Clinical Brain Sciences,
University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom
Correspondence: r.g.will@ed.ac.uk; james.ironside@ed.ac.uk
Human prion diseases are rare neurodegenerative diseases that have become the subject of
public and scientific interest because of concerns about interspecies transmission and the
unusual biological properties of the causal agents: prions. These diseases are unique in that
theyoccur in sporadic, hereditary, and infectious forms that are characterized byan extended
incubation period between exposure to infection and the development of clinical illness.
Silent infection can be present in peripheral tissues during the incubation period, which
poses a challenge to public health, especially because prions are relatively resistant to
standard decontamination procedures. Despite intense research efforts, no effective treat-
ment has been developed for human prion diseases, which remain uniformly fatal.
Human prion diseases are clinically and
epidemiologically diverse, but are linked
by shared neuropathological features, includ-
ing spongiform degeneration, astrocytic gliosis,
and neuronal loss, sometimes associated with
amyloid plaques. These histological changes
are caused by the deposition of a posttransla-
tionally modified form of a normal host pro-
tein, prion protein (PrPC
). This modified pro-
tein, PrPSc
, is disease-specific and is the major
(if not the sole) component of the transmissible
agent in human and animal prion diseases. The
identification of PrPSc
by immunohistochemi-
cal and biochemical techniques is a key com-
ponent of the tissue-based diagnosis of prion
diseases.
The archetypal human prion disease is
sporadic Creutzfeldt–Jakob disease (sCJD),
which was first identified in 1920 (Creutzfeldt
1920; Jakob 1921), and was regarded as a rare,
atypical form of dementia until it was shown in
1968 (Gibbs et al. 1968) to be experimentally
transmissible to primates by intracerebral inoc-
ulation. This finding followed the earlier trans-
mission of kuru to primates in 1966 (Gajdusek
et al. 1966), which was the first demonstration
that degenerative disorders might be caused
by infectious agents. This seminal discovery
prompted a search for the source of infection
in sCJD through epidemiological studies, but
these analyses have not identified any consistent
risk factor for the development of this disease
(de Pedro Cuesta et al. 2012).
The occurrence of acquired cases of CJD
caused by previous medical or surgical treat-
ments, such as with human pituitary hormones
(Brown et al. 2000), led to awareness of the po-
tential public health implications of diseases
with extended incubation periods and a fatal
outcome. Public and regulatory concern about
these disorders has increased with the identifi-
cation of variant CJD (vCJD) as a zoonosis
Editor: Stanley B. Prusiner
Additional Perspectives on Prion Diseases available at www.perspectivesinmedicine.org
Copyright # 2016 Cold Spring Harbor Laboratory Press; all rights reserved
Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a024364
1
www.perspectivesinmedicine.org
brain that is poorly resistant to PK digestion,
yielding a characteristic 8-kDa amino- and car-
boxy-terminally truncated band in Western
blots, which is often accompanied by a faint
“ladder” of bands extending into the 18–
30 kDa range (Fig. 6) (Gambetti et al. 2008).
Some cases of VPSPr also show an sCJD-like
type 2A pattern in the cerebellum, sugg
molecular overlap with sCJD (Head
2013). Recent studies have indicated that V
is poorly transmissible to transgenic mice
transmission characteristics that are mar
different from those of sCJD (Diack
2014; Notari et al. 2014).
E F
Figure 5. Neuropathologyof sporadic Creutzfeldt–Jakob disease (sCJD) subtypes: (A,B) VV1; (C,D) VV2
MV2.(A)SpongiformchangeinthetemporalcortexintheVV1subtypehasvacuolesintermediateinsizebe
theMM1andMM2subtypes.Hematoxylinandeosin, Â40.(B)Prionprotein (PrP)accumulatesinthetem
cortexinapatchycoarsegranularpatternintheVV1subtype.12F10antibody, Â40.(C)Spongiformchange
VV2 subtype is most marked in the molecular layer of the cerebellum. Hematoxylin and eosin, Â20. (D
accumulates in the frontal cortex in a perineuronal/granular pattern in the VV2 subtype. 12F10 antibody
(E).ThepathologicalhallmarkoftheMV2subtypeisthekuru-typeplaqueinthecerebellum,composedofa
amyloid core with paler peripheral fibrils. Hematoxylin and eosin, Â40. (F) PrP accumulates in the kur
plaques and in a granular/synaptic pattern in the cerebellum of the MV2 subtype. 12F10 antibody, Â40.
8 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a
www.perspectivesinmedicine.org
POLIMORFISMO
Met/Val
FRECUENCIA
9%
EDAD COMIENZO
59.4 años
DURACIÓN MEDIA
17.1 meses
CLÍNICA
Ataxia
Demencia progresiva
EEG no típico
Duración media larga
HALLAZGOS ESPECÍFICOS
Mioclonías 77%
Complejos períodicos EEG 7.7%
14-3-3 LCR Positiva en algunos casos
ANATOMÍA PATOLÓGICA
Igual a VV2 + presencia placas amiloide-kuru en
cerebelo
DEPÓSITO PrP
“Placas-like” o depósitos focales

11. FENOTIPO CLÍNICO
VV1
Sporadic and Infectious Human Prion Diseases
Robert G. Will and James W. Ironside
National Creutzfeldt–Jakob Disease Research and Surveillance Unit, Centre for Clinical Brain Sciences,
University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom
Correspondence: r.g.will@ed.ac.uk; james.ironside@ed.ac.uk
Human prion diseases are rare neurodegenerative diseases that have become the subject of
public and scientific interest because of concerns about interspecies transmission and the
unusual biological properties of the causal agents: prions. These diseases are unique in that
theyoccur in sporadic, hereditary, and infectious forms that are characterized byan extended
incubation period between exposure to infection and the development of clinical illness.
Silent infection can be present in peripheral tissues during the incubation period, which
poses a challenge to public health, especially because prions are relatively resistant to
standard decontamination procedures. Despite intense research efforts, no effective treat-
ment has been developed for human prion diseases, which remain uniformly fatal.
Human prion diseases are clinically and
epidemiologically diverse, but are linked
by shared neuropathological features, includ-
ing spongiform degeneration, astrocytic gliosis,
and neuronal loss, sometimes associated with
amyloid plaques. These histological changes
are caused by the deposition of a posttransla-
tionally modified form of a normal host pro-
tein, prion protein (PrPC
). This modified pro-
tein, PrPSc
, is disease-specific and is the major
(if not the sole) component of the transmissible
agent in human and animal prion diseases. The
identification of PrPSc
by immunohistochemi-
cal and biochemical techniques is a key com-
ponent of the tissue-based diagnosis of prion
diseases.
The archetypal human prion disease is
sporadic Creutzfeldt–Jakob disease (sCJD),
which was first identified in 1920 (Creutzfeldt
1920; Jakob 1921), and was regarded as a rare,
atypical form of dementia until it was shown in
1968 (Gibbs et al. 1968) to be experimentally
transmissible to primates by intracerebral inoc-
ulation. This finding followed the earlier trans-
mission of kuru to primates in 1966 (Gajdusek
et al. 1966), which was the first demonstration
that degenerative disorders might be caused
by infectious agents. This seminal discovery
prompted a search for the source of infection
in sCJD through epidemiological studies, but
these analyses have not identified any consistent
risk factor for the development of this disease
(de Pedro Cuesta et al. 2012).
The occurrence of acquired cases of CJD
caused by previous medical or surgical treat-
ments, such as with human pituitary hormones
(Brown et al. 2000), led to awareness of the po-
tential public health implications of diseases
with extended incubation periods and a fatal
outcome. Public and regulatory concern about
these disorders has increased with the identifi-
cation of variant CJD (vCJD) as a zoonosis
Editor: Stanley B. Prusiner
Additional Perspectives on Prion Diseases available at www.perspectivesinmedicine.org
Copyright # 2016 Cold Spring Harbor Laboratory Press; all rights reserved
Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a024364
1
www.perspectivesinmedicine.org
brain that is poorly resistant to PK digestion,
yielding a characteristic 8-kDa amino- and car-
type 2A pattern in the cerebellum, sugg
molecular overlap with sCJD (Head
A B
C
E F
D
Figure 5. Neuropathologyof sporadic Creutzfeldt–Jakob disease (sCJD) subtypes: (A,B) VV1; (C,D) VV2
MV2.(A)SpongiformchangeinthetemporalcortexintheVV1subtypehasvacuolesintermediateinsizebe
theMM1andMM2subtypes.Hematoxylinandeosin, Â40.(B)Prionprotein (PrP)accumulatesinthetem
cortexinapatchycoarsegranularpatternintheVV1subtype.12F10antibody, Â40.(C)Spongiformchange
VV2 subtype is most marked in the molecular layer of the cerebellum. Hematoxylin and eosin, Â20. (D
accumulates in the frontal cortex in a perineuronal/granular pattern in the VV2 subtype. 12F10 antibody
(E).ThepathologicalhallmarkoftheMV2subtypeisthekuru-typeplaqueinthecerebellum,composedofa
amyloid core with paler peripheral fibrils. Hematoxylin and eosin, Â40. (F) PrP accumulates in the kur
plaques and in a granular/synaptic pattern in the cerebellum of the MV2 subtype. 12F10 antibody, Â40.
www.perspectivesinmedicine.org
POLIMORFISMO
Val/Val
FRECUENCIA
1%
EDAD COMIENZO
39.3 años
DURACIÓN MEDIA
15.3 meses
CLÍNICA
Comienzo edad temprana
Demencia progresiva
EEG no típico
HALLAZGOS ESPECÍFICOS
Mioclonías 67%
Complejos periódicos EEG 0%
Proteína 14-3-3 LCR Positiva
ANATOMÍA PATOLÓGICA
Afectación severa corteza y estriado
Cerebelo y troncoencéfalo preservados
DEPÓSITO PrP
Tipo sináptico muy débil

12. FENOTIPO CLÍNICO
VV2
Sporadic and Infectious Human Prion Diseases
Robert G. Will and James W. Ironside
National Creutzfeldt–Jakob Disease Research and Surveillance Unit, Centre for Clinical Brain Sciences,
University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom
Correspondence: r.g.will@ed.ac.uk; james.ironside@ed.ac.uk
Human prion diseases are rare neurodegenerative diseases that have become the subject of
public and scientific interest because of concerns about interspecies transmission and the
unusual biological properties of the causal agents: prions. These diseases are unique in that
theyoccur in sporadic, hereditary, and infectious forms that are characterized byan extended
incubation period between exposure to infection and the development of clinical illness.
Silent infection can be present in peripheral tissues during the incubation period, which
poses a challenge to public health, especially because prions are relatively resistant to
standard decontamination procedures. Despite intense research efforts, no effective treat-
ment has been developed for human prion diseases, which remain uniformly fatal.
Human prion diseases are clinically and
epidemiologically diverse, but are linked
by shared neuropathological features, includ-
ing spongiform degeneration, astrocytic gliosis,
and neuronal loss, sometimes associated with
amyloid plaques. These histological changes
are caused by the deposition of a posttransla-
tionally modified form of a normal host pro-
tein, prion protein (PrPC
). This modified pro-
tein, PrPSc
, is disease-specific and is the major
(if not the sole) component of the transmissible
agent in human and animal prion diseases. The
identification of PrPSc
by immunohistochemi-
cal and biochemical techniques is a key com-
ponent of the tissue-based diagnosis of prion
diseases.
The archetypal human prion disease is
sporadic Creutzfeldt–Jakob disease (sCJD),
which was first identified in 1920 (Creutzfeldt
1920; Jakob 1921), and was regarded as a rare,
atypical form of dementia until it was shown in
1968 (Gibbs et al. 1968) to be experimentally
transmissible to primates by intracerebral inoc-
ulation. This finding followed the earlier trans-
mission of kuru to primates in 1966 (Gajdusek
et al. 1966), which was the first demonstration
that degenerative disorders might be caused
by infectious agents. This seminal discovery
prompted a search for the source of infection
in sCJD through epidemiological studies, but
these analyses have not identified any consistent
risk factor for the development of this disease
(de Pedro Cuesta et al. 2012).
The occurrence of acquired cases of CJD
caused by previous medical or surgical treat-
ments, such as with human pituitary hormones
(Brown et al. 2000), led to awareness of the po-
tential public health implications of diseases
with extended incubation periods and a fatal
outcome. Public and regulatory concern about
these disorders has increased with the identifi-
cation of variant CJD (vCJD) as a zoonosis
Editor: Stanley B. Prusiner
Additional Perspectives on Prion Diseases available at www.perspectivesinmedicine.org
Copyright # 2016 Cold Spring Harbor Laboratory Press; all rights reserved
Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a024364
1
www.perspectivesinmedicine.org
brain that is poorly resistant to PK digestion,
yielding a characteristic 8-kDa amino- and car-
boxy-terminally truncated band in Western
blots, which is often accompanied by a faint
“ladder” of bands extending into the 18–
30 kDa range (Fig. 6) (Gambetti et al. 2008).
Some cases of VPSPr also show an sCJD-like
type 2A pattern in the cerebellum, sugg
molecular overlap with sCJD (Head
2013). Recent studies have indicated that V
is poorly transmissible to transgenic mice
transmission characteristics that are mar
different from those of sCJD (Diack
2014; Notari et al. 2014).
C
E F
D
Figure 5. Neuropathologyof sporadic Creutzfeldt–Jakob disease (sCJD) subtypes: (A,B) VV1; (C,D) VV2
MV2.(A)SpongiformchangeinthetemporalcortexintheVV1subtypehasvacuolesintermediateinsizebe
theMM1andMM2subtypes.Hematoxylinandeosin, Â40.(B)Prionprotein (PrP)accumulatesinthetem
cortexinapatchycoarsegranularpatternintheVV1subtype.12F10antibody, Â40.(C)Spongiformchang
VV2 subtype is most marked in the molecular layer of the cerebellum. Hematoxylin and eosin, Â20. (D
accumulates in the frontal cortex in a perineuronal/granular pattern in the VV2 subtype. 12F10 antibody
(E).ThepathologicalhallmarkoftheMV2subtypeisthekuru-typeplaqueinthecerebellum,composedofa
amyloid core with paler peripheral fibrils. Hematoxylin and eosin, Â40. (F) PrP accumulates in the kur
plaques and in a granular/synaptic pattern in the cerebellum of the MV2 subtype. 12F10 antibody, Â40.
8 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a
www.perspectivesinmedicine.org
POLIMORFISMO
Val/Val
FRECUENCIA
15.7%
EDAD COMIENZO
61.3 años
DURACIÓN MEDIA
6.5 meses
CLÍNICA
Ataxia al comienzo
Demencia tardía
EEG no típico
HALLAZGOS CLÍNICOS
Mioclonías 66%
Complejos periódicos EEG 7.1%
Proteína 14-3-3 LCR Positiva
ANATOMÍA PATOLÓGICA
Afectación subcortical incluido troncoencéfalo
Espongiosis limitada capas profundas
DEPÓSITO PrP
“Placas-like”
Depósitos focales
Tinción predominante perineuronal

13. FENOTIPO CLÍNICO
Variante VPSPr
Variably protease-sensitive Prionopathy
Sporadic and Infectious Human Prion Diseases
Robert G. Will and James W. Ironside
National Creutzfeldt–Jakob Disease Research and Surveillance Unit, Centre for Clinical Brain Sciences,
University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom
Correspondence: r.g.will@ed.ac.uk; james.ironside@ed.ac.uk
Human prion diseases are rare neurodegenerative diseases that have become the subject of
public and scientific interest because of concerns about interspecies transmission and the
unusual biological properties of the causal agents: prions. These diseases are unique in that
theyoccur in sporadic, hereditary, and infectious forms that are characterized byan extended
incubation period between exposure to infection and the development of clinical illness.
Silent infection can be present in peripheral tissues during the incubation period, which
poses a challenge to public health, especially because prions are relatively resistant to
standard decontamination procedures. Despite intense research efforts, no effective treat-
ment has been developed for human prion diseases, which remain uniformly fatal.
Human prion diseases are clinically and
epidemiologically diverse, but are linked
by shared neuropathological features, includ-
ing spongiform degeneration, astrocytic gliosis,
and neuronal loss, sometimes associated with
amyloid plaques. These histological changes
are caused by the deposition of a posttransla-
tionally modified form of a normal host pro-
tein, prion protein (PrPC
). This modified pro-
tein, PrPSc
, is disease-specific and is the major
(if not the sole) component of the transmissible
agent in human and animal prion diseases. The
identification of PrPSc
by immunohistochemi-
cal and biochemical techniques is a key com-
ponent of the tissue-based diagnosis of prion
diseases.
The archetypal human prion disease is
sporadic Creutzfeldt–Jakob disease (sCJD),
which was first identified in 1920 (Creutzfeldt
1920; Jakob 1921), and was regarded as a rare,
atypical form of dementia until it was shown in
1968 (Gibbs et al. 1968) to be experimentally
transmissible to primates by intracerebral inoc-
ulation. This finding followed the earlier trans-
mission of kuru to primates in 1966 (Gajdusek
et al. 1966), which was the first demonstration
that degenerative disorders might be caused
by infectious agents. This seminal discovery
prompted a search for the source of infection
in sCJD through epidemiological studies, but
these analyses have not identified any consistent
risk factor for the development of this disease
(de Pedro Cuesta et al. 2012).
The occurrence of acquired cases of CJD
caused by previous medical or surgical treat-
ments, such as with human pituitary hormones
(Brown et al. 2000), led to awareness of the po-
tential public health implications of diseases
with extended incubation periods and a fatal
outcome. Public and regulatory concern about
these disorders has increased with the identifi-
cation of variant CJD (vCJD) as a zoonosis
Editor: Stanley B. Prusiner
Additional Perspectives on Prion Diseases available at www.perspectivesinmedicine.org
Copyright # 2016 Cold Spring Harbor Laboratory Press; all rights reserved
Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a024364
1
www.perspectivesinmedicine.org
many cases was the presence of amyloid plaques
with a solid core and radiating fibrils in the cer-
ebellar cortex, subsequently termed “kuru
white matter degeneration. The neuropath
ical features appear to have been influenc
the PRNP codon 129 genotype, with kuru
A B
C D
E F
Figure 7. Neuropathology: (A,B) variably protease-sensitive prionopathy (VPSPr) (C,D) kuru; and (E,F)
genic Creutzfeldt–Jakob disease (iCJD). (A) The cerebellar molecular layer in VPSPr shows patchy spong
change. Hematoxylin and eosin, Â20. (B) Prion protein (PrP) accumulates in the cerebellar cortex in num
microplaques, one of the pathological hallmarks of VPSPr. 12F10 antibody, Â20. (C) The granular layer
cerebellum in kuru often contains characteristic plaques, with a dense amyloid core and pale peripheral
Hematoxylin and eosin, Â40. (D) PrPaccumulates in the cerebellar plaques in kuru and in a patchy distrib
in the granular layer. KG9 antibody, Â20. (E) The cerebellum in iCJD in hGH recipients is atrophic, with m
neuronal loss and gliosis. Hematoxylin and eosin, Â20. (F) PrP accumulates in the frontal cortex in iCJD
hGH recipient in a plaque-like pattern with widespread granular/synaptic positivity. 12F10 antibody, Â4
www.perspectivesinmedicine.org
EPIDEMIOLOGÍA
Descripción EEUU 2008
Etiología idiopática
Portadores de genotipo VV > MV > MM
CLÍNICA
Lentamente progresiva
Trastornos movimiento
Signos extrapiramidales
Ataxia cerebelosa
Deterioro cognitivo
SIN CRITERIOS CLÍNICOS DEFINIDOS
EDAD COMIENZO
> 70 años
DURACIÓN MEDIA
> 24 meses
ANATOMÍA PATOLÓGICA
Vacuolas tamaño intermedio
Sustancia gris corteza, gánglios de la base,
tálamo y cortex cerebeloso

14. DIAGNÓSTICO
Criterios diagnósticos
radiographics.rsna.org
Table 4: Diagnostic Criteria for sCJD
Diagnosis Pathologic Analysis Clinical Features Paraclinical Tests
Definite PrP or scrapie-associated fibrils
demonstrated with standard
neuropathologic techniques,
immunocytochemistry, or
Western blot
... ...
Probable Unavailable Rapidly progressive de-
mentia and at least two
of the following:
Myoclonus
Visual or cerebellar signs
Pyramidal or extrapyrami-
dal signs
Akinetic mutism
Positive result with at least one of
the following:
Typical EEG*
CSF assay for 14-3-3 protein†
MR imaging‡
Without routine investigations indi-
cating an alternative diagnosis
Possible Unavailable Same as “probable” and
duration of illness <2
years
Negative result with any of the three
laboratory tests that allow classifi-
cation of a case as “probable”
Without routine investigations indi-
cating an alternative diagnosis
*Periodic sharp wave complexes during an illness of any duration.
†
In a patient with disease duration less than 2 years.
‡
High signal intensity in the caudate nucleus or putamen at DWI or FLAIR imaging.NEUROLOGIC/HEADANDNECKIMAGING
234
Imaging of Creutzfeld
Disease: Imaging Pat
Their Differential Dia
Diagnosis of sporadic Creutz
a challenge because of the lar
especially in its early stages, w
treatable disorders.The mole
as its brain propagation and t
become better understood in
listed recognizable clinical fea
ment the replicable diagnostic
lack specific data about the d
ing, mainly regarding those d
features (mimicking disorders
the neuroimaging patterns of
magnetic resonance (MR) im
nario and molecular basis of t
genetic, and imaging correlat
eases. A long list of differentia
pictorial review, with the aim
Diego Cardoso Fragoso, MD
Augusto Lio da Mota Gonçalves Filho,
MD
FelipeTorres Pacheco, MD, PhD
Bernardo Rodi Barros, MD
Ingrid Aguiar Littig, MD
Renato Hoffmann Nunes, MD
Antônio Carlos Martins Maia Júnior,
MD, PhD
Antonio J. da Rocha, MD, PhD
Abbreviations: ADC = apparent diffusion co-
efficient, CJD = Creutzfeldt-Jakob disease,
CSF = cerebrospinal fluid, DWI = diffusion-
weighted imaging, EEG = electroencephalog-
raphy, FLAIR = fluid-attenuated inversion-
recovery, PrPSc
= scrapie prion protein, sCJD =
sporadic CJD
RadioGraphics 2017; 37:234–257
Published online 10.1148/rg.2017160075
Thiscopy isfor personal use only. To order printed copies, c
neocortex, striatum, th
Spongiform change was
round vacuoles with clea
dency for adhesion withi
sion distribution shows a
developmentally more re
cerebral neocortex and s
ably involved, whereas o
pus, brainstem and
Fig. 1 A: Diffusion-weighted MRI of a
patient with sporadic CJD (sCJD) shows
extensive hyperintensity regions in the
cerebral cortex and striatum. B: Typical
periodic sharp-wave complexes (PSWCs)
on EEG of a patient with sCJD. R:
right side.
Creutzfeldt-Jakob disease
43 MM1-type sCJD cases.15
Average age at disease onset of
the series was 69.7 Æ 7.7 years (range, 57–89 years), with an
neocortex, striatum, thalamus and cerebellar cortex.9,15
Spongiform change was of the fine vacuole type (numerous
round vacuoles with clear boundaries and without the ten-
dency for adhesion within the neuropil) (Fig. 3A).9,15
The le-
sion distribution shows apparent system degeneration.9
The
developmentally more recent parts of the brain, such as the
cerebral neocortex and striatum, were found to be consider-
ably involved, whereas older regions such as the hippocam-
pus, brainstem and spinal cord tended to exhibit
degradation to a lesser extent.9,18,19
PrP immunostaining showed diffuse granular synaptic-
type PrP deposition (Fig. 4A).9
PrP deposition has been
particularly observed in the cerebral neocortex, subiculum,
striatum, thalamus, cerebellar cortex (particularly the mo-
lecular layer and granule cell layer), quadrigeminal body,
substantia nigra, pontine nucleus, inferior olivary nucleus
and spinal posterior horn, particularly in the substantia gela-
tinosa.9,18,19
In severe lesions, such as those in the cerebral
neocortex in status spongiosus, PrP deposition was
decreased.9
Staging of cerebral cortical pathology
Fig. 1 A: Diffusion-weighted MRI of a
patient with sporadic CJD (sCJD) shows
extensive hyperintensity regions in the
cerebral cortex and striatum. B: Typical
periodic sharp-wave complexes (PSWCs)
on EEG of a patient with sCJD. R:
right side.
Fig. 2 Coronal section of the cerebrum of a patient with sporadic
CJD (sCJD) after formalin fixation. Severe cerebral atrophy is ob-
served in the cortex, basal ganglia, thalamus and white matter. Bilat-
eral lateral ventricular dilatation is noticeable, but the hippocampus
is relatively preserved from atrophy.
Creutzfeldt-Jakob disease 5

15. DIAGNÓSTICO
128 Á. Annus et al. / Clinical Neurology and Neurosurgery 150 (2016) 125–132
Table 4
Steps in the diagnosis of Creutzfeldt-Jakob disease.
Type Sensitivity Specificity References
Present practice
1. Clinical symptoms [66]
2. EEG sCJD 64% 91% [67,68]
3. MRI sCJD 96% 93% [69,64]
4. CSF 14-3-3 protein measurement probable sCJDgCJD 43–100% 47–97% [72,71]
5. PRNP analysis gCJD [4,65]
Novel findings
6. CSF PrPsc
detection by RT-QuIC sCJD 96% 100% [76]
7. Nasal brushing—PrPsc
detection in the olfactory epithelium by RT-QuIC sCJD gCJD 97% 100% [77]
8. Urinary PrPsc
detection by PMCA and Western blotting vCJD 93% 100% [78]
Abbreviations: CSF: cerebrospinal fluid; EEG: electroencephalogram; gCJD: genetic Creutzfeldt-Jakob disease; MRI: magnetic resonance imaging; PMCA: protein misfolding
cyclic amplification; PRNP: prion protein gene; PrPsc
: pathological prion protein (scrapie); RT-QuIC: real-time quaking-induced conversion; sCJD: sporadic Creutzfeldt-Jakob
disease; vCJD: variant Creutzfeldt-Jakob disease.
Table 5
Transmission of prion diseases.
128 Á. Annus et al. / Clinical Neurology and Neurosurgery 150 (2016) 125–132
Table 4
Steps in the diagnosis of Creutzfeldt-Jakob disease.

16. DIAGNÓSTICO
RMN cerebral
NEUROLOGIC/HEADANDNECKIMAGING
234
Imaging of
Disease: Im
Their Differ
D
a
e
t
a
b
l
m
l
i
f
t
m
n
g
e
p
t
g
i
Diego Cardoso Fragoso, MD
Augusto Lio da Mota Gonçalves Filho,
MD
FelipeTorres Pacheco, MD, PhD
Bernardo Rodi Barros, MD
Ingrid Aguiar Littig, MD
Renato Hoffmann Nunes, MD
Antônio Carlos Martins Maia Júnior,
MD, PhD
Antonio J. da Rocha, MD, PhD
Abbreviations: ADC = apparent diffusion co-
efficient, CJD = Creutzfeldt-Jakob disease,
CSF = cerebrospinal fluid, DWI = diffusion-
weighted imaging, EEG = electroencephalog-
raphy, FLAIR = fluid-attenuated inversion-
recovery, PrPSc
= scrapie prion protein, sCJD =
sporadic CJD
RadioGraphics 2017; 37:234–257
Published online 10.1148/rg.2017160075
Content Codes:
1
From the Division of Neuroradiology, Serviço
Thiscopy isfor personal u
Topography Characteristic Appearance Most Usual Sequences Key References
Cerebral cortex Focal or diffuse, symmetric or
asymmetric involvement
Perirolandic area usually spared
FLAIR and mainly DWI/ADC
Signal intensity abnormality
may fluctuate
Ukisu et al (35)
Tschampa et al (40)
Vitali et al (41)
Eisenmenger et al (42)
Basal ganglia Symmetric or asymmetric
involvement, particularly of
caudate and putamen
Anterior-posterior gradient
FLAIR and mainly DWI/ADC
Increase in both extent and de-
gree of signal intensity abnor-
mality as disease progresses
Meissner et al (18)
Vitali et al (41)
Eisenmenger et al (42)
Cerebellum Atrophy Typically negative at imaging
Only a few reports show clear
DWI hyperintensity
Young et al (43)
Cohen et al (45)
Poon et al (46)
Note.—There are three major patterns of FLAIR/DWI hyperintensities in sCJD: cortical and subcortical
(45%–68%), predominantly neocortical (24%–41%), and predominantly subcortical (5%–12.5%) (38,44).

17. DIAGNÓSTICO
RMN cerebral
Axial diffusion-weighted images at three levels show the usual findings on the right side of the
brain and the unusual findings on the left side. BG = basal ganglia.
NEUROLOGIC/HEADANDNECKIMAGING
234
Imaging of
Disease: Im
Their Differ
D
a
e
t
a
b
li
m
la
in
f
t
m
n
g
e
p
t
Diego Cardoso Fragoso, MD
Augusto Lio da Mota Gonçalves Filho,
MD
FelipeTorres Pacheco, MD, PhD
Bernardo Rodi Barros, MD
Ingrid Aguiar Littig, MD
Renato Hoffmann Nunes, MD
Antônio Carlos Martins Maia Júnior,
MD, PhD
Antonio J. da Rocha, MD, PhD
Abbreviations: ADC = apparent diffusion co-
efficient, CJD = Creutzfeldt-Jakob disease,
CSF = cerebrospinal fluid, DWI = diffusion-
weighted imaging, EEG = electroencephalog-
raphy, FLAIR = fluid-attenuated inversion-
recovery, PrPSc
= scrapie prion protein, sCJD =
sporadic CJD
RadioGraphics 2017; 37:234–257
Published online 10.1148/rg.2017160075
Thiscopy isfor personal us

18. NEUROIMAGEN
DIAGNÓSTICO DIFERENCIAL – AFECTACIÓN PREDOMINANTE CORTEZA CEREBRAL
ENCEFALOPATÍA HIPÓXICO
ISQUÉMICA SEVERA
ENCEFALITIS AUTOINMUNE
PARANEOPLÁSICA
ENCEFALITIS INFECCIOSA
Severe hypoxic ischemic encephalopathy in a 36-year-old woman who experienced recent
cardiorespiratory arrest. (a) Axial FLAIR image shows bilateral selective hyperintensity in the striatum
(arrows) associated with faint parieto-occipital abnormality (arrowheads). (b) Axial diffusion-weighted
image clearly shows cortical restricted areas attributed to brain anoxia.
Autoimmune-mediated Encephalopathy.—Cor-
tical involvement can occur in paraneoplastic
striatal encephalitis, brainstem encephalitis, and
leukoencephalopathy (67).
Severe hypoglycemia
and coma in a young man with
type 1 diabetes after self-admin-
istration of insulin. (a) Axial FLAIR
image shows bilateral and sym-
metric abnormal signal intensity
in the vulnerable areas, mainly in
the cortical and deep gray matter
areas. (b) Axial diffusion-weighted
image shows reduced diffusion in
the striatum (arrows) and parieto-
occipital cortex (arrowheads).
radiographics.rsna.org
Infectious Disease (Encephalitis).—Herpes sim-
plex virus is the most common agent of acute fatal
sporadic encephalitis in humans and has been
listed as a trigger for anti-NMDA (N-methyl-D-
aspartate) encephalitis (69).This disease manifests
as an acutely decreased level of consciousness and
a broad range of nonspecific signs and symptoms
of focal encephalopathy, including headache, fever,
nuchal rigidity, and changes in personality. In
adults, it typically involves the anterior and medial
addition to the classic hippocampal involvement,
postictal lesions may involve the neocortex with
variable extension to the subcortical white matter,
splenium of the corpus callosum, basal ganglia,
thalami, and cerebellum. Follow-up brain MR im-
aging may confirm a transient lesion, reinforcing
the postictal signal intensity changes in a specific
clinical and EEG scenario (71).
Hyperammonemia.—Prolonged hyperammo-
Paraneoplastic auto-
immune encephalitis in a 63-year-
old woman with breast cancer.
(a) Axial FLAIR image shows pre-
dominant subcortical hyperinten-
sity involving the left hemisphere,
mainly the insula and temporal
lobe (arrowheads), with mass ef-
fect characterized by effaced sulci
and a compressed ipsilateral ven-
tricle (arrows). (b) Axial diffusion-
weighted image shows reduced
diffusion in the same areas (ar-
rowheads). Note the left thalamus
involvement, which mimics the
hockey stick sign on the FLAIR im-
age and the pulvinar sign on the
diffusion-weighted image.
Herpes simplex virus encephalitis. (a) Coronal T2-weighted image shows asymmetric bilateral in-
volvement of the temporal lobes with high signal intensity and swelling (arrowheads), which extends to the
right lower frontal lobe (not shown) and the bilateral insular areas (arrows). (b) Corresponding follow-up image
7 months later shows marked atrophy of the involved areas, mainly in the temporal lobes (arrowheads).
Postictal state with MR imaging abnor-
234
Imaging of Creutzfeldt-Jakob
Disease: Imaging Patterns and
Their Differential Diagnosis1
Diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) remains
a challenge because of the large variability of the clinical scenario,
especially in its early stages, which may mimic several reversible or
treatable disorders.The molecular basis of prion disease, as well
as its brain propagation and the pathogenesis of the illness, have
become better understood in recent decades. Several reports have
listed recognizable clinical features and paraclinical tests to supple-
ment the replicable diagnostic criteria in vivo. Nevertheless, we
lack specific data about the differential diagnosis of CJD at imag-
ing, mainly regarding those disorders evolving with similar clinical
features (mimicking disorders).This review provides an update on
the neuroimaging patterns of sCJD, emphasizing the relevance of
magnetic resonance (MR) imaging, summarizing the clinical sce-
nario and molecular basis of the disease, and highlighting clinical,
genetic, and imaging correlations in different subtypes of prion dis-
eases. A long list of differential diagnoses produces a comprehensive
pictorial review, with the aim of enabling radiologists to identify
Diego Cardoso Fragoso, MD
Augusto Lio da Mota Gonçalves Filho,
MD
FelipeTorres Pacheco, MD, PhD
Bernardo Rodi Barros, MD
Ingrid Aguiar Littig, MD
Renato Hoffmann Nunes, MD
Antônio Carlos Martins Maia Júnior,
MD, PhD
Antonio J. da Rocha, MD, PhD
Abbreviations: ADC = apparent diffusion co-
efficient, CJD = Creutzfeldt-Jakob disease,
CSF = cerebrospinal fluid, DWI = diffusion-
weighted imaging, EEG = electroencephalog-
raphy, FLAIR = fluid-attenuated inversion-
recovery, PrPSc
= scrapie prion protein, sCJD =
sporadic CJD
RadioGraphics 2017; 37:234–257
Published online 10.1148/rg.2017160075
Thiscopy isfor personal use only. To order printed copies, contact reprints@rsna.org
Axial diffusion-weighted images at three leve
brain and the unusual findings on the left side. BG = ba
The physicochemical basis for DWI abnormali-
ties remains unclear. Histopathologic studies have
revealed vacuolization of the neurophil, astrogliosis,
and—in certain subgroups of prion diseases—for-
mation and deposition of amyloid plaques within
the brain (47).Thus, abnormalities at DWI are at-
tributed to
partmental
may reflect
somehow r
As the d
tent increa

19. NEUROIMAGEN
DIAGNÓSTICO DIFERENCIAL – AFECTACIÓN PREDOMINANTE CORTEZA CEREBRAL
HIPOGLUCEMIA
POSTCRISIS
HIPERAMONIEMIA
Severe hypoxic ischemic encephalopathy in a 36-year-old woman who experienced recent
cardiorespiratory arrest. (a) Axial FLAIR image shows bilateral selective hyperintensity in the striatum
(arrows) associated with faint parieto-occipital abnormality (arrowheads). (b) Axial diffusion-weighted
image clearly shows cortical restricted areas attributed to brain anoxia.
Autoimmune-mediated Encephalopathy.—Cor-
tical involvement can occur in paraneoplastic
or nonparaneoplastic disorders associated with
a heterogeneous spectrum of clinical presenta-
tions, including those triggered by infectious
agents (66). Patients usually present with
subacute encephalopathy that leads to cognitive
impairment, behavioral or personality changes,
ataxia, seizures, or a variety of other neuro-
logic syndromes in a different scenario than
that expected for sCJD. Autoimmune-mediated
encephalopathy can be recognized by its associa-
tion with autoantibodies and by certain recog-
nizable features at MR imaging, which include
limbic encephalitis, cerebellar degeneration,
striatal encephalitis, brainstem encephalitis, and
leukoencephalopathy (67).
Limbic encephalitis is the most common pat-
tern of autoimmune encephalopathy and is char-
acterized by usually isolated FLAIR/T2-weighted
imaging hyperintensity in the mesial temporal
lobes (Fig 11), typically involving the amygdala and
hippocampus, areas not often affected in sCJD.
Conversely, a particular concern is the common
involvement of the insular cortex and anterior cin-
gulate areas in autoimmune disorders, as these are
also commonly affected areas in sCJD. A compre-
hensive search for autoantibodies and an underlying
systemic malignancy should be considered when an
autoimmune process is suspected (68).
Severe hypoglycemia
and coma in a young man with
type 1 diabetes after self-admin-
istration of insulin. (a) Axial FLAIR
image shows bilateral and sym-
metric abnormal signal intensity
in the vulnerable areas, mainly in
the cortical and deep gray matter
areas. (b) Axial diffusion-weighted
image shows reduced diffusion in
the striatum (arrows) and parieto-
occipital cortex (arrowheads).
radiographics.rsna.org
Hyperammonemia. FLAIR
image shows extensive symmetric ab-
normalities with high signal intensity,
mainly involving both the cortex and
subcortical white matter in the insula
and frontal lobes. Both thalami are also
involved (hyperintense). The plasma
ammonium level was 244 mmol/L.
Mitochondrial Disorders.—This group of diseases
has variable findings, but as a general rule, bilat-
eral deep gray matter involvement and peripheral
white matter abnormalities, especially if associated
with elevated lactate at MR spectroscopy, should
suggest the diagnosis of a mitochondrial disor-
der. Mitochondrial encephalopathy with lactate
acidosis and stroke-like episodes, known by the
acronym MELAS, manifests as multifocal stroke-
like cortical lesions in different stages of evolution,
which cross the cerebral vascular territories and
show a predilection for the posterior parietal and
occipital lobes (Fig 15). MR imaging findings can
overlap with those of sCJD, but the clinical presen-
tations will be mostly distinguishable.
Posterior Cortical Atrophy.—This uncommon
neurodegenerative disease is clinically dominated
by disruption of the visual processes, frequently
including visual hallucinations with early and
pronounced apraxia and visual agnosia, which can
Herpes simplex virus encephalitis. (a) Coronal T2-weighted image shows asymmetric bilateral in-
volvement of the temporal lobes with high signal intensity and swelling (arrowheads), which extends to the
right lower frontal lobe (not shown) and the bilateral insular areas (arrows). (b) Corresponding follow-up image
7 months later shows marked atrophy of the involved areas, mainly in the temporal lobes (arrowheads).
Postictal state with MR imaging abnor-
mality. (a) Axial diffusion-weighted image shows
selective hyperintensity involving the left temporal
and insular cortex. (b) Coronal T2-weighted im-
age shows striking hyperintensity with additional
swelling in these areas. These T2-weighted imaging
features are not usual in sCJD. FLAIR images 1 week
later demonstrated reversibility of these findings.
Mitoc
has va
eral d
white
with e
sugge
der. M
acido
acron
like c
which
show
occip
overla
tation
Poste
neuro
by dis
includ
prono
resem
imagi
heavi
occip
the af
volvement of the temporal lobes with high signal intensity and swelling (a
right lower frontal lobe (not shown) and the bilateral insular areas (arrows). (
7 months later shows marked atrophy of the involved areas, mainly in the te
Post
mality. (a) Axia
selective hyperin
and insular cort
age shows striki
swelling in these
features are not u
later demonstrate
Herpes simplex virus encephalitis. (a) Coronal T2-weighted image shows asymmetric bilateral in-
volvement of the temporal lobes with high signal intensity and swelling (arrowheads), which extends to the
right lower frontal lobe (not shown) and the bilateral insular areas (arrows). (b) Corresponding follow-up image
7 months later shows marked atrophy of the involved areas, mainly in the temporal lobes (arrowheads).
Postictal state with MR imaging abnor-
mality. (a) Axial diffusion-weighted image shows
selective hyperintensity involving the left temporal
and insular cortex. (b) Coronal T2-weighted im-
age shows striking hyperintensity with additional
swelling in these areas. These T2-weighted imaging
features are not usual in sCJD. FLAIR images 1 week
later demonstrated reversibility of these findings.
234
Imaging of Creutzfeldt-Jakob
Disease: Imaging Patterns and
Their Differential Diagnosis1
Diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) remains
a challenge because of the large variability of the clinical scenario,
especially in its early stages, which may mimic several reversible or
treatable disorders.The molecular basis of prion disease, as well
as its brain propagation and the pathogenesis of the illness, have
become better understood in recent decades. Several reports have
listed recognizable clinical features and paraclinical tests to supple-
ment the replicable diagnostic criteria in vivo. Nevertheless, we
lack specific data about the differential diagnosis of CJD at imag-
ing, mainly regarding those disorders evolving with similar clinical
features (mimicking disorders).This review provides an update on
the neuroimaging patterns of sCJD, emphasizing the relevance of
magnetic resonance (MR) imaging, summarizing the clinical sce-
nario and molecular basis of the disease, and highlighting clinical,
genetic, and imaging correlations in different subtypes of prion dis-
eases. A long list of differential diagnoses produces a comprehensive
pictorial review, with the aim of enabling radiologists to identify
Diego Cardoso Fragoso, MD
Augusto Lio da Mota Gonçalves Filho,
MD
FelipeTorres Pacheco, MD, PhD
Bernardo Rodi Barros, MD
Ingrid Aguiar Littig, MD
Renato Hoffmann Nunes, MD
Antônio Carlos Martins Maia Júnior,
MD, PhD
Antonio J. da Rocha, MD, PhD
Abbreviations: ADC = apparent diffusion co-
efficient, CJD = Creutzfeldt-Jakob disease,
CSF = cerebrospinal fluid, DWI = diffusion-
weighted imaging, EEG = electroencephalog-
raphy, FLAIR = fluid-attenuated inversion-
recovery, PrPSc
= scrapie prion protein, sCJD =
sporadic CJD
RadioGraphics 2017; 37:234–257
Published online 10.1148/rg.2017160075
Thiscopy isfor personal use only. To order printed copies, contact reprints@rsna.org
Axial diffusion-weighted images at three leve
brain and the unusual findings on the left side. BG = ba
The physicochemical basis for DWI abnormali-
ties remains unclear. Histopathologic studies have
revealed vacuolization of the neurophil, astrogliosis,
and—in certain subgroups of prion diseases—for-
mation and deposition of amyloid plaques within
the brain (47).Thus, abnormalities at DWI are at-
tributed to
partmental
may reflect
somehow r
As the d
tent increa

20. NEUROIMAGEN
DIAGNÓSTICO DIFERENCIAL – AFECTACIÓN PREDOMINANTE CORTEZA CEREBRAL
ATROFIA CORTICAL
POSTERIOR
ENF. MITOCONDRIAL
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). (a, b) Axial FLAIR (a) and diffusion-
weighted (b) images show hyperintensity in the right cortical lobe (arrows in a) with restricted diffusion. Note the bilateral striated
nuclei sequelae. (c–f) Axial FLAIR (c, e) and and diffusion-weighted (d, f) images show atrophic changes in the frontal lobes (arrow
in c), with restricted diffusion resolution in these areas and emergence of new hyperintensities and DWI-positive areas in the left
thalamus and cingulate isthmus, as well as in the bilateral frontoparietal cortex, mainly on the left (arrowheads in c). MR spectroscopy
demonstrated a high lactate peak, supporting the diagnosis.
Hyperammonemia. FLAIR
image shows extensive symmetric ab-
normalities with high signal intensity,
mainly involving both the cortex and
subcortical white matter in the insula
and frontal lobes. Both thalami are also
involved (hyperintense). The plasma
ammonium level was 244 mmol/L.
Posterior cortical atrophy in a 68-year-old man with visuospatial dysfunction.
(a) Axial PET/CT image shows selectively reduced metabolism in the bilateral parietal, poste-
rior temporal, and lateral occipital cortex (arrowheads), mimicking the Heidenhain subtype
of CJD. (b) Axial diffusion-weighted image is unremarkable, as opposed to what is expected
in a prion disease.
NEUROLOGIC/HEADANDNECKIMAGING
234
Imaging of
Disease: Im
Their Differ
D
a
e
tr
a
b
li
m
la
in
fe
th
m
n
g
e
p
ty
Diego Cardoso Fragoso, MD
Augusto Lio da Mota Gonçalves Filho,
MD
FelipeTorres Pacheco, MD, PhD
Bernardo Rodi Barros, MD
Ingrid Aguiar Littig, MD
Renato Hoffmann Nunes, MD
Antônio Carlos Martins Maia Júnior,
MD, PhD
Antonio J. da Rocha, MD, PhD
Abbreviations: ADC = apparent diffusion co-
efficient, CJD = Creutzfeldt-Jakob disease,
CSF = cerebrospinal fluid, DWI = diffusion-
weighted imaging, EEG = electroencephalog-
raphy, FLAIR = fluid-attenuated inversion-
recovery, PrPSc
= scrapie prion protein, sCJD =
sporadic CJD
RadioGraphics 2017; 37:234–257
Published online 10.1148/rg.2017160075
Thiscopy isfor personal us
Axial diffusion-weighted images at three leve
brain and the unusual findings on the left side. BG = ba
The physicochemical basis for DWI abnormali-
ties remains unclear. Histopathologic studies have
revealed vacuolization of the neurophil, astrogliosis,
and—in certain subgroups of prion diseases—for-
mation and deposition of amyloid plaques within
the brain (47).Thus, abnormalities at DWI are at-
tributed to
partmental
may reflect
somehow r
As the d
tent increa

21. NEUROIMAGEN
DIAGNÓSTICO DIFERENCIAL – AFECTACIÓN PREDOMINANTE EN GANGLIOS DE LA BASE
MIELINOLISIS OSMÓTICA
EXTRAPONTINA
ENCEFALITIS VEB
ENCEFALITIS AUTOINMUNE
PARANEOPLÁSICA
hyperintensity on FLAIR/T2-weighted images
(Fig 16).The clinically more rapid time course
and DWI abnormalities in sCJD support the dif-
ferential diagnosis.
Predominant Basal Ganglia Involvement
Extrapontine Osmotic Demyelination.—Often
associated with electrolyte imbalances, this severe
acute spastic hemiparesis, pseudobulbar palsy,
decreased level of consciousness, and coma.The
distribution of findings at MR imaging parallels
the distribution of the oligodendroglial cells that
are more susceptible to osmotic stresses. Extra-
pontine myelinolysis manifests predominantly as
areas of bilateral FLAIR/T2-weighted imaging
hyperintensity in the globus pallidus, putamen,
and thalamus, which are often symmetric (Fig
Posterior cortical atrophy in a 68-year-old man with visuospatial dysfunction.
(a) Axial PET/CT image shows selectively reduced metabolism in the bilateral parietal, poste-
rior temporal, and lateral occipital cortex (arrowheads), mimicking the Heidenhain subtype
of CJD. (b) Axial diffusion-weighted image is unremarkable, as opposed to what is expected
in a prion disease.
Extrapontine osmotic demyelination in a 21-year-old man after rapid correction
of hyponatremia. Axial FLAIR (a) and diffusion-weighted (b) images show symmetric bilateral
involvement of the caudate nucleus (small arrows) and lenticular nucleus (large arrows). Both
thalami were less involved.
radiographics.rsna.org
EBV encephalitis in a 10-year-old girl with fever, ataxia, nystagmus, and confu-
sion. (a) Axial FLAIR image shows selective bilaterally symmetric swelling and hyperintensity
in the basal ganglia (arrows). (b) Corresponding FLAIR image 6 months later shows faint
residual hyperintensity with discrete atrophy, attributed to sequelae.
radiographics.rsna.org
EBV encephalitis in a 10-year-old girl with fever, ataxia, nystagmus, and confu-
sion. (a) Axial FLAIR image shows selective bilaterally symmetric swelling and hyperintensity
in the basal ganglia (arrows). (b) Corresponding FLAIR image 6 months later shows faint
residual hyperintensity with discrete atrophy, attributed to sequelae.
Paraneoplastic striatal encephalitis associated with anti-CV2 autoantibodies in a
57-year-old man. (a) Axial FLAIR image shows selective hyperintensity of the bilateral striatum
(arrowheads). (b) Axial diffusion-weighted image is unremarkable. Paraneoplastic encephalitis
was considered, and a testicular tumor was confirmed.
234
Imaging of Creutzfeldt-Jakob
Disease: Imaging Patterns and
Their Differential Diagnosis1
Diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) remains
a challenge because of the large variability of the clinical scenario,
especially in its early stages, which may mimic several reversible or
treatable disorders.The molecular basis of prion disease, as well
as its brain propagation and the pathogenesis of the illness, have
become better understood in recent decades. Several reports have
listed recognizable clinical features and paraclinical tests to supple-
ment the replicable diagnostic criteria in vivo. Nevertheless, we
lack specific data about the differential diagnosis of CJD at imag-
ing, mainly regarding those disorders evolving with similar clinical
features (mimicking disorders).This review provides an update on
the neuroimaging patterns of sCJD, emphasizing the relevance of
magnetic resonance (MR) imaging, summarizing the clinical sce-
nario and molecular basis of the disease, and highlighting clinical,
genetic, and imaging correlations in different subtypes of prion dis-
eases. A long list of differential diagnoses produces a comprehensive
pictorial review, with the aim of enabling radiologists to identify
Diego Cardoso Fragoso, MD
Augusto Lio da Mota Gonçalves Filho,
MD
FelipeTorres Pacheco, MD, PhD
Bernardo Rodi Barros, MD
Ingrid Aguiar Littig, MD
Renato Hoffmann Nunes, MD
Antônio Carlos Martins Maia Júnior,
MD, PhD
Antonio J. da Rocha, MD, PhD
Abbreviations: ADC = apparent diffusion co-
efficient, CJD = Creutzfeldt-Jakob disease,
CSF = cerebrospinal fluid, DWI = diffusion-
weighted imaging, EEG = electroencephalog-
raphy, FLAIR = fluid-attenuated inversion-
recovery, PrPSc
= scrapie prion protein, sCJD =
sporadic CJD
RadioGraphics 2017; 37:234–257
Published online 10.1148/rg.2017160075
Thiscopy isfor personal use only. To order printed copies, contact reprints@rsna.org
Axial diffusion-weighted images at three level
brain and the unusual findings on the left side. BG = basa
The physicochemical basis for DWI abnormali-
ties remains unclear. Histopathologic studies have
revealed vacuolization of the neurophil, astrogliosis,
and—in certain subgroups of prion diseases—for-
mation and deposition of amyloid plaques within
the brain (47).Thus, abnormalities at DWI are at-
tributed to r
partmentaliz
may reflect d
somehow re
As the di
tent increas

22. NEUROIMAGEN
DIAGNÓSTICO DIFERENCIAL – AFECTACIÓN PREDOMINANTE EN GANGLIOS DE LA BASE
DEGENERACIÓN ESTRIATAL
AUTOSÓMICA DOMINANTE
with autoimmune-mediated encephalopathy to
findings (19). However, one should keep in mind
that thalamic signal intensity abnormalities are not
pathognomonic for this particular form of prion
disease (56).Thalamic involvement is also present
and more commonly observed in sCJD (17).
Wilson Disease.—The acquired hepatolenticular
degeneration caused by accumulation of cop-
per resulting from a deficiency of ceruloplasmin
affects the brain, liver, and other tissues, more
commonly in young individuals. Symptoms
include ataxia, tremors, dystonia, dysarthria, par-
kinsonian symptoms, and psychiatric problems.
Kayser-Fleischer rings in the cornea are charac-
teristically associated (76).
Typical MR imaging findings include areas
of high signal intensity on FLAIR/T2-weighted
images in the putamen, globus pallidus, caudate
nucleus, and thalamus (Fig 21).Thalamic involve-
ment is typically confined to the ventrolateral
aspect.The cortical and subcortical regions, mid-
brain, pons, vermis, and dentate nucleus may also
be involved. Diffusion restriction is often observed
in the early stages of the disease (77). Differentia-
tion from sCJD is based on age, laboratory tests,
Autosomal-dominant striatal degen-
eration. Axial diffusion-weighted image shows
typical bilateral symmetric abnormalities in the
posterior two-thirds of the putamen (large ar-
rows), tail of the caudate nucleus (small arrows),
and nucleus accumbens (arrowheads).
EDAD
40-50 años
CURSO
Lentamente progresivo
CLÍNICA
Disartria, bradicinesia, trastorno de la marcha,
rigidez muscular y disdiacocincesia
NEUROLOGIC/HEADANDNECKIMAGING
234
Imaging of Creutzfeldt-Jakob
Disease: Imaging Patterns and
Their Differential Diagnosis1
Diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) remains
a challenge because of the large variability of the clinical scenario,
especially in its early stages, which may mimic several reversible or
treatable disorders.The molecular basis of prion disease, as well
as its brain propagation and the pathogenesis of the illness, have
become better understood in recent decades. Several reports have
listed recognizable clinical features and paraclinical tests to supple-
ment the replicable diagnostic criteria in vivo. Nevertheless, we
lack specific data about the differential diagnosis of CJD at imag-
ing, mainly regarding those disorders evolving with similar clinical
features (mimicking disorders).This review provides an update on
the neuroimaging patterns of sCJD, emphasizing the relevance of
magnetic resonance (MR) imaging, summarizing the clinical sce-
nario and molecular basis of the disease, and highlighting clinical,
genetic, and imaging correlations in different subtypes of prion dis-
eases. A long list of differential diagnoses produces a comprehensive
pictorial review, with the aim of enabling radiologists to identify
Diego Cardoso Fragoso, MD
Augusto Lio da Mota Gonçalves Filho,
MD
FelipeTorres Pacheco, MD, PhD
Bernardo Rodi Barros, MD
Ingrid Aguiar Littig, MD
Renato Hoffmann Nunes, MD
Antônio Carlos Martins Maia Júnior,
MD, PhD
Antonio J. da Rocha, MD, PhD
Abbreviations: ADC = apparent diffusion co-
efficient, CJD = Creutzfeldt-Jakob disease,
CSF = cerebrospinal fluid, DWI = diffusion-
weighted imaging, EEG = electroencephalog-
raphy, FLAIR = fluid-attenuated inversion-
recovery, PrPSc
= scrapie prion protein, sCJD =
sporadic CJD
RadioGraphics 2017; 37:234–257
Thiscopy isfor personal use only. To order printed copies, contact reprints@rsna.org
Axial diffusion-weighted images at three level
brain and the unusual findings on the left side. BG = basa
The physicochemical basis for DWI abnormali-
ties remains unclear. Histopathologic studies have
revealed vacuolization of the neurophil, astrogliosis,
and—in certain subgroups of prion diseases—for-
mation and deposition of amyloid plaques within
the brain (47).Thus, abnormalities at DWI are at-
tributed to r
partmentaliz
may reflect d
somehow re
As the di
tent increas

23. NEUROIMAGEN
DIAGNÓSTICO DIFERENCIAL – AFECTACIÓN PREDOMINANTE TALÁMICA
ECJ - VARIANTE
ENFERMEDAD DE WILSON
ENCEFALOPATÍA WERNICKE
234
Imaging of Creutzfeldt-Jakob
Disease: Imaging Patterns and
Their Differential Diagnosis1
Diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) remains
a challenge because of the large variability of the clinical scenario,
especially in its early stages, which may mimic several reversible or
treatable disorders.The molecular basis of prion disease, as well
as its brain propagation and the pathogenesis of the illness, have
become better understood in recent decades. Several reports have
listed recognizable clinical features and paraclinical tests to supple-
ment the replicable diagnostic criteria in vivo. Nevertheless, we
lack specific data about the differential diagnosis of CJD at imag-
ing, mainly regarding those disorders evolving with similar clinical
features (mimicking disorders).This review provides an update on
the neuroimaging patterns of sCJD, emphasizing the relevance of
magnetic resonance (MR) imaging, summarizing the clinical sce-
nario and molecular basis of the disease, and highlighting clinical,
genetic, and imaging correlations in different subtypes of prion dis-
eases. A long list of differential diagnoses produces a comprehensive
pictorial review, with the aim of enabling radiologists to identify
Diego Cardoso Fragoso, MD
Augusto Lio da Mota Gonçalves Filho,
MD
FelipeTorres Pacheco, MD, PhD
Bernardo Rodi Barros, MD
Ingrid Aguiar Littig, MD
Renato Hoffmann Nunes, MD
Antônio Carlos Martins Maia Júnior,
MD, PhD
Antonio J. da Rocha, MD, PhD
Abbreviations: ADC = apparent diffusion co-
efficient, CJD = Creutzfeldt-Jakob disease,
CSF = cerebrospinal fluid, DWI = diffusion-
weighted imaging, EEG = electroencephalog-
raphy, FLAIR = fluid-attenuated inversion-
recovery, PrPSc
= scrapie prion protein, sCJD =
sporadic CJD
RadioGraphics 2017; 37:234–257
Published online 10.1148/rg.2017160075
Thiscopy isfor personal use only. To order printed copies, contact reprints@rsna.org
radiographics.rsna.org
Unusual recognizable MR imaging patterns in sCJD. (a) Axial diffusion-weighted image
shows restricted diffusion limited to the pulvinar (arrowheads) and dorsomedial (arrows) thalamic
nucleus, producing the characteristic “double hockey stick” sign. (b) Axial diffusion-weighted image in
another patient shows symmetric restricted diffusion in the pulvinar thalamic nuclei (arrowheads) with
additional hyperintensity in the striatum (arrows), which is an important key to distinguish sCJD from
variant CJD on MR images.
radiographics.rsna.org
Wilson disease in a 13-year-old girl with pro-
gressive gait and speech incoordination. (a) Axial ADC map
shows restricted diffusion in the bilateral frontal cortex,
mainly on the left (arrows). (b) Coronal T2-weighted image
shows hyperintensities in the frontal lobes (arrows) and in
both thalami and corticospinal tracts (arrowheads). (c) Pho-
tograph shows a Kayser-Fleischer ring (copper accumulation
along the circumference of the iris) (arrowheads), an impor-
tant marker of neurologic impairment in Wilson disease.
Recognizing the thrombus in a deep vein on
MR venograms or structural images (clot sign),
particularly in the subacute stage (hyperintense
on T1-weighted images), is crucial for diagnosis
Wernicke encephalopathy in a non-
alcoholic patient. Axial FLAIR image shows a se-
lective hyperintensity along the medial surface of
the thalami (arrowheads), mimicking the double
hockey stick sign. The diagnosis was based on
clinical and laboratory features.
Wilson disease in a 13-year-old girl with pro-
gressive gait and speech incoordination. (a) Axial ADC map
shows restricted diffusion in the bilateral frontal cortex,
mainly on the left (arrows). (b) Coronal T2-weighted image
shows hyperintensities in the frontal lobes (arrows) and in
both thalami and corticospinal tracts (arrowheads). (c) Pho-
tograph shows a Kayser-Fleischer ring (copper accumulation
along the circumference of the iris) (arrowheads), an impor-
tant marker of neurologic impairment in Wilson disease.
Recognizing the thrombus in a deep vein on
MR venograms or structural images (clot sign),
particularly in the subacute stage (hyperintense
on T1-weighted images), is crucial for diagnosis
and therapeutic approach (Fig 23). Ischemic
infarction involving the artery of Percheron can
also cause partial bilateral thalamic lesions, in a
particular identifiable setting (62).
Infectious Diseases (Encephalitis).—Some Flavivi-
ruses have been reported as agents of acute enceph-
alitis, including dengue virus andWest Nile virus
to illustrate this particular setting. Although a wide
clinical picture is possible, MR imaging findings
may vary from unremarkable to selective or diffuse
hyperintensity on FLAIR/T2-weighted and diffu-
sion-weighted images involving both thalami and
the brainstem, basal ganglia, and deep white matter
(Fig 24). Similarly, influenza virus A, MurrayValley
encephalitis, and other members of the Japanese
encephalitis serocomplex have been described
with bilateral thalamic or basal ganglia abnormali-
ties. Epidemiology and specific serologic reactions
are discriminative from sCJD. Additionally, some
other infectious agents and postinfectious disorders
can affect children, in different scenarios that are
beyond the scope of this review (62).
Globi Pallidi T1 Hyperintensity
Spectacular Shrinking Deficit.—This refers to a
sudden major hemispheric stroke syndrome fol-
Axial diffusion-weighted images at three level
brain and the unusual findings on the left side. BG = basa
The physicochemical basis for DWI abnormali-
ties remains unclear. Histopathologic studies have
revealed vacuolization of the neurophil, astrogliosis,
and—in certain subgroups of prion diseases—for-
mation and deposition of amyloid plaques within
the brain (47).Thus, abnormalities at DWI are at-
tributed to r
partmentaliz
may reflect d
somehow re
As the di
tent increas

24. NEUROIMAGEN
DIAGNÓSTICO DIFERENCIAL – AFECTACIÓN PREDOMINANTE TALÁMICA
INFARTO VENOSO PROFUNDO
NEUROLOGIC/HEADANDNECKIMAGING
234
Imaging
Disease:
Their Di
Diego Cardoso Fragoso, MD
Augusto Lio da Mota Gonçalves Filh
MD
FelipeTorres Pacheco, MD, PhD
Bernardo Rodi Barros, MD
Ingrid Aguiar Littig, MD
Renato Hoffmann Nunes, MD
Antônio Carlos Martins Maia Júnio
MD, PhD
Antonio J. da Rocha, MD, PhD
Abbreviations: ADC = apparent diffusion
efficient, CJD = Creutzfeldt-Jakob dis
CSF = cerebrospinal fluid, DWI = diffu
weighted imaging, EEG = electroenceph
raphy, FLAIR = fluid-attenuated inver
recovery, PrPSc
= scrapie prion protein, sCJ
sporadic CJD
RadioGraphics 2017; 37:234–257
Published online 10.1148/rg.2017160075
Thiscopy isfor p
Venous thrombosis in a young woman with acute impairment of consciousness. (a) Sagittal T1-weighted image shows
heterogeneous material with some hyperintense foci consistent with clot in the vein of Galen (arrow), extending to the straight sinus
and confluence of sinuses (arrowheads). (b) Axial FLAIR image shows hyperintensity of the thalami (arrows), representing discrete
expansive local effect. (c) Axial susceptibility-weighted image shows enlargement of the internal cerebral veins (arrowheads) with
hemorrhagic foci in both thalami (arrows), mainly on the left. (d) Axial diffusion-weighted image shows heterogeneous high signal
intensity in both thalami (arrows), but without true restriction on the ADC map (not shown). The patient experienced clinical im-
provement after thrombolytic therapy, with almost total reversibility of signal intensity abnormalities.
ENCEFALITIS INFECCIOSA
radiographics.rsna.org
Dengue encephalitis in a 27-year-old man. (a) Axial FLAIR image shows hyperin-
tensity and expansion of both lenticular nuclei (arrows) and thalami (arrowheads). (b) Axial
diffusion-weighted image shows signal intensity abnormalities in the same areas, but without
true restriction on the ADC map (not shown). The patient recovered clinically, and a control
study demonstrated resolution of the signal intensity abnormalities in these areas.
Manganese deposition
in a patient with cirrhosis. (a) Axial
T1-weighted image shows sym-
metric hyperintense signal in the
globi pallidi (arrows). (b) Diffu-
sion-weighted image is unremark-
Axial diffusion-weighted images at three level
brain and the unusual findings on the left side. BG = basa
The physicochemical basis for DWI abnormali-
ties remains unclear. Histopathologic studies have
revealed vacuolization of the neurophil, astrogliosis,
and—in certain subgroups of prion diseases—for-
mation and deposition of amyloid plaques within
the brain (47).Thus, abnormalities at DWI are at-
tributed to r
partmentaliz
may reflect d
somehow re
As the di
tent increas

25. NEUROIMAGEN
DIAGNÓSTICO DIFERENCIAL – AFECTACIÓN PREDOMINANTE GLOBO PÁLIDO HIPERINTENSIDAD T1
NEUROLOGIC/HEADANDNECKIMAGING
234
Imaging of Cre
Disease: Imagin
Their Different
Diagnosis o
a challenge
especially in
treatable di
as its brain
become bet
listed recog
ment the re
lack specific
ing, mainly
features (m
the neuroim
magnetic re
nario and m
genetic, and
eases. A lon
pictorial rev
typical and
Diego Cardoso Fragoso, MD
Augusto Lio da Mota Gonçalves Filho,
MD
FelipeTorres Pacheco, MD, PhD
Bernardo Rodi Barros, MD
Ingrid Aguiar Littig, MD
Renato Hoffmann Nunes, MD
Antônio Carlos Martins Maia Júnior,
MD, PhD
Antonio J. da Rocha, MD, PhD
Abbreviations: ADC = apparent diffusion co-
efficient, CJD = Creutzfeldt-Jakob disease,
CSF = cerebrospinal fluid, DWI = diffusion-
weighted imaging, EEG = electroencephalog-
raphy, FLAIR = fluid-attenuated inversion-
recovery, PrPSc
= scrapie prion protein, sCJD =
sporadic CJD
RadioGraphics 2017; 37:234–257
Published online 10.1148/rg.2017160075
Thiscopy isfor personal use only. To or
INTOXICACIÓN POR
MANGANESO
helps in recognition of manganese deposition. In
addition to the typical distribution of manganese
deposition in the brain and possible manifesta-
neurons, particularly granule cell neurons of the
granular layer of the cerebellum. Progressive
atrophy and abnormal cerebellar cortical signal
Dengue encephalitis in a 27-year-old man. (a) Axial FLAIR image shows hyperin-
tensity and expansion of both lenticular nuclei (arrows) and thalami (arrowheads). (b) Axial
diffusion-weighted image shows signal intensity abnormalities in the same areas, but without
true restriction on the ADC map (not shown). The patient recovered clinically, and a control
study demonstrated resolution of the signal intensity abnormalities in these areas.
Manganese deposition
in a patient with cirrhosis. (a) Axial
T1-weighted image shows sym-
metric hyperintense signal in the
globi pallidi (arrows). (b) Diffu-
sion-weighted image is unremark-
able, in contrast to the expected
pattern in sCJD.

26. NEUROIMAGEN
DIAGNÓSTICO DIFERENCIAL – AFECTACIÓN PREDOMINANTE CEREBELOSA
INFECCIÓN VJC
NEURONOPATÍA GRANULAR
DEGENERACIÓN CEREBELOSA
SUBAGUDA PARANEOPLÁSICA
JC virus granule cell neuronopathy
in a patient with AIDS. (a) Axial FLAIR image
shows faint hyperintensity involving the left
middle peduncle (arrowheads) and atrophy of
the cerebellar hemispheres. (b) Corresponding
FLAIR image 2 months later shows more severe
atrophy and widespread signal intensity abnor-
malities bilaterally.
headache, and altered mental status. It may be
caused by various infectious agents but may also
manifest as postinfectious immune-mediated
cerebellitis, which more frequently occurs in chil-
nent cerebellar symptoms, usually in the absenc
of imaging abnormalities. Autoimmune cerebel
has been reported in adults with atrophy and is
rarely accompanied by hyperintensities on FLA
JC virus granule cell neuronop
in a patient with AIDS. (a) Axial FLAIR im
shows faint hyperintensity involving the
middle peduncle (arrowheads) and atroph
the cerebellar hemispheres. (b) Correspon
FLAIR image 2 months later shows more se
atrophy and widespread signal intensity ab
malities bilaterally.
Paraneoplastic cerebellar degeneration in an adult patient with subacute ataxia. (a) Axial FLAIR
image shows bilateral cerebellar cortical hyperintensities (arrowheads). (b) Axial CT image of the chest after
intravenous administration of contrast material shows an asymptomatic tumor mass in the right hilum (arrow),
which was confirmed to be an oat cell carcinoma.
Axial diffusion-weighted images at three lev
brain and the unusual findings on the left side. BG = ba
The physicochemical basis for DWI abnormali-
ties remains unclear. Histopathologic studies have
revealed vacuolization of the neurophil, astrogliosis,
and—in certain subgroups of prion diseases—for-
mation and deposition of amyloid plaques within
the brain (47).Thus, abnormalities at DWI are at-
tributed to
partmental
may reflect
somehow r
As the d
tent increa

27. DIAGNÓSTICO
128 Á. Annus et al. / Clinical Neurology and Neurosurgery 150 (2016) 125–132
Table 4
Steps in the diagnosis of Creutzfeldt-Jakob disease.
Type Sensitivity Specificity References
Present practice
1. Clinical symptoms [66]
2. EEG sCJD 64% 91% [67,68]
3. MRI sCJD 96% 93% [69,64]
4. CSF 14-3-3 protein measurement probable sCJDgCJD 43–100% 47–97% [72,71]
5. PRNP analysis gCJD [4,65]
Novel findings
6. CSF PrPsc
detection by RT-QuIC sCJD 96% 100% [76]
7. Nasal brushing—PrPsc
detection in the olfactory epithelium by RT-QuIC sCJD gCJD 97% 100% [77]
8. Urinary PrPsc
detection by PMCA and Western blotting vCJD 93% 100% [78]
Abbreviations: CSF: cerebrospinal fluid; EEG: electroencephalogram; gCJD: genetic Creutzfeldt-Jakob disease; MRI: magnetic resonance imaging; PMCA: protein misfolding
cyclic amplification; PRNP: prion protein gene; PrPsc
: pathological prion protein (scrapie); RT-QuIC: real-time quaking-induced conversion; sCJD: sporadic Creutzfeldt-Jakob
disease; vCJD: variant Creutzfeldt-Jakob disease.
Table 5
Transmission of prion diseases.
128 Á. Annus et al. / Clinical Neurology and Neurosurgery 150 (2016) 125–132
Table 4
Steps in the diagnosis of Creutzfeldt-Jakob disease.

28. DIAGNÓSTICO
Detección PrP en tejidos y fluidos biológicos
Sporadic CJD Variant CJD
Tonsil biopsy
PrPCJD
detection by
immunoblotting
Blood
ELISA (PrPCJD
enriched using
stainless steel
powder)
Urine
PMCA
Olfactory mucosa
brushing
RT-QuIC assay
Cerebrospinal fluid
RT-QuIC
Genetic CJD
Blood
PRNP
sequencing
Brain biopsy
PrPCJD
detection by
immunohistochemistry
and immunoblotting
Muscle and
lymphoreticular
tissues*
Muscle and
lymphoreticular tissues*
will be needed t
brushing appro
gression in the
(Bongianni, M.
The results ob
testing of nasal
native or a conf
mortem diagno
to its potential
brushing approa
analyses to con
the need for au
from autopsies,
would not prov
the distribution
or associated p
replace neuropa
Finally, alth
human prion di
studies have sho
very sensitively
homogenized b
REVIEWS
Advanced tests for early and accurate
diagnosis of Creutzfeldt–Jakob
disease
Gianluigi Zanusso1
, Salvatore Monaco1
, Maurizio Pocchiari2
and Byron Caughey3
Abstract | Early and accurate diagnosis of Creutzfeldt–Jakob disease (CJD) is a necessary to
distinguish this untreatable disease from treatable rapidly progressive dementias, and to prevent
REVIEWS
1
A
B
C
D
E
F
G
H
2 3 4 5 6 7 8 9 101112
uri ed
re o inant
PrPC
su strate
io avin
io avin
PrPC
su strate
ro
E. coli
luores en e late reader
260,000
225,000
190,000
155,000
120,000
85,000
50,000
0 5 10 15 20 25 30 3540
oni ator
Sonication–rest
cycles
Serial rounds of
reseeding and sonication
ilution into res rain o o enate
roteinase
di estion
st
round
est sa le rion
rain dilutions
estern lot
nd
round
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round
t
round
10–3
10–4
10–5
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10–8
10–9
10–10M
W
NBH
PMCA
Test sample
rion in e ted
tissue
PrPCJD
seed
Shake–rest cycles
E. coli
ultures
RT- QulC
PrP su strate
in rain
o o enate
l os lation
sites
an or
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rain dilutions
uoresene
i e
10–3
10
est sa le
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dilutions
A
B
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D
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1 2 3 4 5 6 7 8 9 101112
Nature Reviews | NeurologyFigure 2 | Diagnostic testing for Creutzfeldt–Jakob disease: PMCA versus RT-QuIC. The principles of protein
misfolding cyclic amplification (PMCA) and real-time quaking-induced conversion (RT-QuIC) are illustrated. In PMCA,
the test sample is mixed with a suitable source of normal prion protein (PrPC
), usually uninfected brain homogenate,
and subjected to cycles of sonication and rest, typically for 48h. Additional rounds of PMCA are performed by diluting
products of the previous round into fresh brain homogenate, followed again by sonication cycles. The typical readout
is the detection of any prion-seeded, protease-resistant PrP reaction products by digestion with proteinase K (to
eliminate any remaining PrPC
substrate in the uninfected brain homogenate) and western blotting. The western blot
shows that the number of rounds required to generate a detectable band correlates inversely with the prion
concentration in the test sample. In the example shown, reactions were seeded with serial 10-fold dilutions of brain
homogenate from an individual with prion disease. In RT-QuIC, the test sample is mixed with recombinant PrPC
in
multiwell plates and subjected to cycles of shaking and rest. As the reaction progresses, prion-seeded recombinant
PrP amyloid fibrils are detected by the enhanced fluorescence of thioflavin T (ThT), an amyloid-sensitive dye. The
graph provided shows the cumulative ThT fluorescence from eight replicate wells seeded with serial 10-fold dilutions
of prion brain homogenate. The stepwise increases in fluorescence are due to rapid growth of prion-seeded amyloid
fibrils in individual wells after different lag phases, which is often more evident in reactions seeded with extreme
dilutions of prion-containing samples. Permission obtained from Macmillan Publishers Ltd © Morales, R. et al.
Nat. Protoc. 7, 1397–1409 (2012). GPI, glycophosphatidylinositol; PrPSc
, scrapie prion protein.
REVIEWS
RT-QuIC
”REAL TIME QUAKING INDUCED
CONVERSION”