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Neuropathology 2016; ••, ••–•• doi:10.1111/neup.12355

Symposium: Fundamentals learned from diversity among

typical and atypical appearances

Creutzfeldt-Jakob disease
Yasushi Iwasaki
1
Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan

This review will explore the clinical and pathological find- such as the MM1-type. However, even in atypical cases it
ings of the various forms of Creutzfeldt-Jakob disease seems that clinical findings can be used for an accurate
(CJD). Clinical findings of CJD are characterized by rapidly diagnosis.
progressive cognitive dysfunction, diffusion-weighted mag-
netic resonance imaging (DWI) hyperintensity, myoclonus, Key words: akinetic mutism state, diffusion-weighted mag-
periodic sharp-wave complexes on electroencephalogram netic resonance imaging, myoclonus, panencephalopathic-
and akinetic mutism state. Neuropathologic findings of type, pyramidal sign.
CJD are characterized by spongiform changes in gray mat-
ter, gliosis—particularly hypertrophic astrocytosis—neuropil INTRODUCTION
rarefaction, neuron loss and prion protein (PrP) deposition.
The earliest pathological symptom observed by HE staining Prion diseases, previously known as transmissible
in the cerebral cortex is spongiform change. This spongiform spongiform encephalopathy, are fatal neurodegenerative
change begins several months before clinical onset, and is diseases affecting both human and non-human mammals.1
followed by gliosis. Subsequently, neuropil rarefaction ap- The word “prion”, coined by Stanley B. Prusiner in 1982,
pears, followed by neuron loss. Regions showing fine is derived from “proteinaceous infectious particle”.1 In
vacuole-type spongiform change reflect synaptic-type PrP humans, prion diseases are extremely rare with an annual
deposition and type 1 PrPSc deposition, whereas regions mortality rate of approximately one to two per million, and
showing large confluent vacuole-type spongiform changes can be classified as sporadic, acquired by infection, or
reflect perivacuolar-type PrP deposition and type 2 PrPSc familial (Table 1).1–3 Creutzfeldt-Jakob disease (CJD) is
deposition. Hyperintensities of the cerebral gray matter ob- the most common human prion disease worldwide, and
served in DWI indicate the pathology of the spongiform can also be classified as sporadic, acquired or familial.1–4
change in CJD. The cerebral cortical lesions with large con- CJD was first described by German neurologist Hans
fluent vacuoles and type 2 PrPSc show higher brightness and Gerhard Creutzfeldt in 1920 and shortly afterwards by
more continuous hyperintensity on DWI than those with Alfons Maria Jakob.1
fine vacuoles and type 1 PrPSc. CJD cases showing diffuse The diverse clinicopathological phenotypic characteris-
myelin pallor of cerebral white matter have been described tics of CJD have earned it the role of an “outstanding joker”
as panencephalopathic-type, and this white matter in the fields of both neurology and neuropathology. Detailed
pathology is mainly due to secondary degeneration caused investigations into the relationship between clinical neuro-
by cerebral cortical involvement, particularly in regard to logical findings and neuropathological observations, in not
neuron loss. In conclusion, clinical and neuroimaging only typical cases but also atypical cases, are thus required
findings and neuropathologic observations are well matched so that CJD pathogenesis can be determined. This article de-
in both typical and atypical cases in CJD. The clinical scribes the general investigation of our previous observa-
diagnosis of CJD is relatively easy for typical CJD cases tions with a review of the literature on sporadic CJD
(sCJD), particularly the MM1-type, MM2-cortical type and
MM2-thalamic-type, and familial CJD (notably V180I
genetic CJD).
Correspondence: Yasushi Iwasaki M.D., Ph.D., Department of
Neuropathology, Institute for Medical Science of Aging, Aichi Medical CLASSIFICATION OF CJD
University; 1-1 Yazakokarimata, Nagakute, Aichi 480-1195, Japan.
Email: iwasaki@sc4.so-net.ne.jp Human prion protein (PrP), expressed most predominantly
Received 10 September 2016; revised 18 October 2016 and accepted in the nervous system but also in many other tissues through-
19 October 2016. out the body, is encoded by the PrP gene, PRNP.1 PRNP is
© 2016 Japanese Society of Neuropathology
2 Y Iwasaki

Table 1 Classification of prion diseases in humans on the mutant allele.1,3 Comprehensive analyses of these
(1) Sporadic (idiopathic) prion disease clinical and neuropathologic findings as well as analyses of
Sporadic Creutzfeldt-Jakob disease (sCJD) PRNP and prion strain should be applied to better under-
Sporadic fatal insomnia (sFI) stand these atypical CJD cases.
Variably protease-sensitive prionopathy (VPSPr)
(2) Acquired (infected) prion disease
Human origin CLINICAL CHARACTERISTICS OF CJD
Iatrogenic CJD (due to medical procedures)
Kuru Typical sCJD cases show a rapidly progressive clinical
Bovine origin
course and patients reach the akinetic mutism state several
Variant CJD (vCJD)
(3) Familial (inherited or genetic) prion disease months after disease onset.1,3–5 Before the recent introduc-
Genetic CJD tion of the molecular and phenotypic analysis-based
Gerstmann- Sträussler-Scheinker syndrome (GSS) classifications, CJD was classified according to clinical pre-
Fatal familial insomnia (FFI)
sentation, with several distinct clinical phenotypes known
Modified from previous reports.1–3 (Table 3).10,11 Clinically, typical CJD cases with rapidly pro-
gressive cognitive dysfunction, myoclonus and PSWCs on
located on the short arm of chromosome 20 and the primary EEG—the so-called “classic triad”—have been traditionally
sequence is 253 amino acids long before post-translational called “Classic-type” or “Myoclonic-type.”
modification.1 PrP can exist in multiple isoforms, the normal The clinical course of typical CJD cases is divided into
PrP described as “PrPC,” and the disease-causing PrP de- three stages (Table 4).4,10,11 In the first stage, nonspecific
scribed as “PrPSc”; the C refers to ‘cellular’, while the Sc re- symptoms such as psychiatric symptoms, visual disorder
fers to ‘scrapie’. PRNP genotype and the PrPSc type have a and memory disturbance are observed. Diffusion-weighted
major influence on the disease phenotype in both sporadic MRI (DWI) shows hyperintensity in the cerebral cortex
and familial human prion diseases.1–3 The clinicopathologic and striatum (Fig. 1A). This DWI hyperintensity is very use-
manifestations of CJD, particularly in sCJD, are influenced ful for the diagnosis of the CJD.8 In the second stage, pa-
by several factors, particularly by PRNP polymorphism at tients show rapidly progressive cognitive impairment.
codon 129 and prion strain (type 1 PrPSc or type 2 PrPSc, Myoclonus and PSWCs on EEG (Fig. 1B) are observed.
classified according to the size of protease-resistant PrPSc The appearance of myoclonus or DWI hyperintensity has
fragments by Western blot analysis). Based on the combina- sometimes led to an initial suspicion of sCJD.8 In the third
tions of the codon 129 polymorphism involving methionine stage, the disease progresses to the akinetic mutism state.
(Met) or valine (Val) (Met/Met, Met/Val, or Val/Val) and The patient generally dies of infection, aspiration pneumo-
physicochemical properties of type 1 PrPSc or type 2 PrPSc, nia, respiratory failure or general prostration.
sCJD has been classified into six subtypes: MM1, MM2, Among Caucasians, about 90% of patients with sCJD die
MV1, MV2, VV1 and VV2.5 MM2-type sCJD is further di- within 1 year of disease onset; however, Japanese patients
vided into two types on the basis of the clinicopathological have a considerably longer survival because of the manage-
phenotype: MM2-cortical-type and MM2-thalamic-type.5 ment procedures followed in Japan.12–14 The crucial factor
The clinical and pathological features are summarized for resulting in longer survival is thought to be the introduction
each sCJD subtype in Table 2. of tube feeding.12–14
Because the frequency of polymorphic codon 129 differs
greatly between Caucasian and Japanese people, the fre-
quency of each sCJD subtype is also very different.6,7 The
NEUROPATHOLOGICAL
normal Japanese population shows 91.6% Met homozygos-
CHARACTERISTICS OF CJD
ity, 8.4% Val heterozygosity and 0% Val homozygosity.6 Neuropathologic findings of CJD are characterized by
By contrast, the normal Caucasian population shows 37% spongiform changes in gray matter, gliosis—particularly in
Met homozygosity, 51% Val heterozygosity and 12% Val hypertrophic astrocytosis—neuropil rarefaction, neuron loss
homozygosity.5 Therefore, MM-type sCJD is more common and PrP deposition.1,9,15,16 Macroscopic cerebral atrophy is
in Japanese compared to Caucasian patients; many of these not conspicuous in the short disease duration cases, but the
are MM1-types, but there are relatively more MM2-types.7–9 atrophy progresses with clinical course and cases with
MM1-type represents the typical clinical features of sCJD, prolonged disease duration present with severe atrophy
namely, myoclonus and periodic sharp-wave complexes (Fig. 2).9,15,16 The hippocampus is largely spared, regardless
(PSWCs) on electroencephalogram (EEG) and rapidly pro- of the cerebral pathology or disease duration.1,5,9
gressive cognitive impairment, referred to as “classic-type In general, the cerebral neocortex is the most severely af-
CJD.”5 Familial CJD is also classified into many haplotypes fected region in sCJD pathology, and the severity of damage
based on the PRNP mutation and polymorphic codon 129 is associated with total disease duration.9,15 The earliest
© 2016 Japanese Society of Neuropathology
 Table 2 Clinicopathological characteristics of each type of sporadic Creutzfeldt-Jakob disease

MM1 MV1 MM2-cortical MM2-thalamic MV2 VV1 VV2

Polymorphic Met / Met Met / Met / Met Met / Met Met / Val Val / Val Val / Val
codon 129 of Val
the PrP gene
PrP type Type 1 Type 1 Type 2 Type 2 Type 2 Type 1 Type 2
Previous Classic-type, Not established Thalamic variant, thalamic Kuru-plaques variant Not established Ataxic variant,
classification myoclonic-type, degeneration, sporadic fatal Brownell-Oppenheimer
Creutzfeldt-Jakob disease

Heidenhain variant insomnia type

Frequency
Caucasian 67.6 2.7 2 2 9 1 15.7
(%)
Japanese 85.3 2.7 6.7 4.0 (includes 1.3% MM2- 1.3 0 0
(%) (includes cortical + thalamic type)
6.7%
MM1 + 2

© 2016 Japanese Society of Neuropathology

type)
Clinical findings
Age at onset 65.5 62.1 64.3 (49–77) 52.3 (36–71) 59.4 (40–81) 39.3 (24–49) 61.3 (41–80)
(42–91) (51–72)
Total disease 3.9 (1–18) 4.9 15.7 (9–36) 15.6 (8–24) 17.1 (5–72) 15.3 (14–16) 6.5 (3–18)
duration (2.5–9)
(months)
Clinical Rapidly progressive Progressive Insomnia, psychomotor Ataxia, progressive Younger onset, Ataxia at onset, late
features dementia, early and dementia, no hyperactivity, ataxia, cognitive dementia, no typical progressive dementia, dementia, no typical EEG
prominent typical PSWCs impairment, no typical EEG EEG, long duration no typical EEG
myoclonus, typical on EEG
EEG, visual
impairment,
unilateral signs
Frequency of 97 100 67 50 77 67 66
myoclonus
(%)
Frequency of 80 71.4 0 0 7.7 0 7.1
PSWCs on
EEG (%)
14–3-3 Positive Positive Positive Negative Positive in some cases Positive Positive
protein in
CSF
Neuropathological features
Pathological Typical fine vacuole Large confluent Severe atrophy of the medial Similar to VV2 but Severe pathology in the Prominent involvement of
findings vacuole, thalamus and inferior olivary with presence of cerebral cortex and striatum subcortical, including
cerebellum is nucleus with little pathology in amyloid-kuru plaques with sparing of brainstem brainstem, nuclei; in the
relatively spared other areas; spongiform change in the cerebellum and cerebellum neocortex, spongiosis is often
may be absent or focal limited to deep layers
PrP Synaptic type Perivacuolar Lesser deposition than in the Plaque-like or focal Synaptic type (very faint) Plaque-like, focal deposits,
deposition type other variants 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.
3
4 Y Iwasaki

Table 3 Clinical subtypes of Creutzfeldt-Jakob disease

(1) Classic type / myoclonic type

This type shows acute progressive cognitive dysfunction.
The patient reaches the akinetic mutism state within several months after onset of symptoms.
Myoclonus and PSWCs on EEG are observed in the early disease stages.
(2) Heidenhain variant
This type is characterized by visual symptoms, such as visus defigurata, defective color vision, cortical blindness and Anton’s syndrome.
Acute cognitive dysfunction and other neuropsychiatric symptoms with myoclonus subsequently progress.
PSWCs on EEG may be more evident at the occipital lobe.
(3) Brownwell-Oppenheimer variant / ataxic variant
This type is characterized by the onset of cerebellar symptoms and dementia progresses subsequently.
In many cases, no PSWCs on EEG are observed.
(4) Thalamic degeneration / sporadic fatal insomnia
This type is characterized by psychiatric symptoms, autonomic dysfunction and sleep disorders.
EEG shows slowing of basic rhythm and PSWCs are not present. Myoclonus is not remarkable.
(5) Amyotrophic form
This type is extremely rare and characterized by a remarkable muscle atrophy.
Modified from references.4,10,11 PSWCs, periodic sharp-wave complexes.

Table 4 Typical clinical course and findings of Creutzfeldt-Jakob disease

(1) First stage

The disease onset is more common in patients in their 50s and 60s, although the incidence of cases with a later onset has been on the rise
recently. The patient initially presents with nonspecific symptoms such as fatigue, unsteadiness, dizziness, decrease in activity, anxiety,
depression, visual disorder and memory disturbance. Diffusion-weighted MRI (DWI) shows hyperintensity regions in the cerebral cortex and
striatum at this stage or several months before the clinical onset.
(2) Second stage
Cognitive dysfunction worsens rapidly. Communication becomes difficult and myoclonus appears. Gait disturbance progresses and difficulty
in walking makes the patient bedridden. Neurological examinations show various neuropsychiatric signs, such as motor paralysis, aphasia,
apraxia, sensory disturbance, brisk deep tendon reflex, appearance of pathological reflex, cerebellar ataxia, muscle rigidity, dystonia,
gegenhalten and startle reaction. Periodic sharp-wave complexes (PSWCs) on EEG are observed.
(3) Third stage
The disease progresses to the akinetic mutism state† and the patient subsequently presents with decorticate rigidity or tetraplegia in flexion
with contracture. Myoclonus, PSWCs on EEG, and hyperintensity regions on DWI gradually diminish and finally disappear.
The patient generally dies of infection, aspiration pneumonia, respiratory failure or general prostration.
†
Modified from references.4,10,11 The state in which patients lack voluntary movement and the ability to produce meaningful words. In this state,
involuntary movements such as myoclonus, startle reaction, dystonia and convulsion might be present, and the patients might be able to produce unin-
telligible and nonsensical sounds such as groans.

pathologic finding in the cerebral cortex, observed by HE loss with fibrous gliosis should be called “status spongiosus”
staining, is spongiform change, and this is followed by in CJD pathology.9,15 In CJD pathology, the terms
gliosis.15 Subsequently, neuropil rarefaction appears, “spongiform change” and “status spongiosus” are applied
followed by neuron loss.15 to the cerebral cortical stages from I to III and from IV to
The term “status spongiosus” is often confused with V, respectively.
“spongiform change” or “large confluent vacuole” in the
pathologic description of CJD, yet it should be appropriately
pathologically distinguished.15 Status spongiosus defines a INVESTIGATION ABOUT THE RELATION
“burnt-out lesion” showing severe neuron loss with gliosis BETWEEN CLINICAL FINDINGS AND
and neuropil rarefaction, and is observed in various neuro- NEUROPATHOLOGICAL FINDINGS
degenerative conditions as well as CJD.9,15,17 According to
the pathologic observations of CJD, when cerebral cortical MM1-type sCJD
pathology progresses, particularly to neuropil rarefaction,
Clinical findings
spongiform change with clear boundaries, as seen in the
early stage, becomes unclear.9,15 Thus, the pathologic condi- We previously reported the relationship between clinical
tion showing severe neuropil rarefaction and severe neuron findings and progression of cerebral cortical pathology in
© 2016 Japanese Society of Neuropathology
Creutzfeldt-Jakob disease 5

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.

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,
Fig. 2 Coronal section of the cerebrum of a patient with sporadic
substantia nigra, pontine nucleus, inferior olivary nucleus
CJD (sCJD) after formalin fixation. Severe cerebral atrophy is ob-
served in the cortex, basal ganglia, thalamus and white matter. Bilat- and spinal posterior horn, particularly in the substantia gela-
eral lateral ventricular dilatation is noticeable, but the hippocampus tinosa.9,18,19 In severe lesions, such as those in the cerebral
is relatively preserved from atrophy. neocortex in status spongiosus, PrP deposition was
decreased.9
43 MM1-type sCJD cases.15 Average age at disease onset of
the series was 69.7  7.7 years (range, 57–89 years), with an Staging of cerebral cortical pathology
average total disease duration of 13.5  9.7 months (range,
We proposed staging of cerebral cortical pathology based on
2–32 months).15 All DWI-examined cases showed cerebral
the detailed examination of MM1-type sCJD series; Stage I,
cortical hyperintensity at the time of first imaging; average
spongiform change; Stage II, hypertrophic astrocytosis;
duration between disease onset and first observation of cere-
Stage III, neuropil rarefaction; Stage IV, neuron loss; Stage
bral cortical hyperintensity on DWI was 1.6  1.3 months
V, status spongiosus; and Stage VI, large cavity formation
(range, 0.5–7 months).15 Average durations between disease
(Fig. 5, Table 5).15 This cortical pathologic staging is useful
onset and first observation of myoclonus and PSWCs on
because this can be judged only by HE staining from the
EEG were 2.1  1.1 months (range, 0.5–6 months) and
early disease stage to the prolonged disease stage.15 A more
2.2  1.3 months (range, 0.75–7 months), respectively.12
simple staging classification has also been suggested: Stage I
Average duration between disease onset and reaching the
and II, mild; Stage III and IV, moderate; and Stage Vand VI,
akinetic mutism state was 3.2  1.4 months (range,
severe.15
1–8 months).15 Average brain weight was 971.2  211.5 g
(range, 590–1520 g).15
Statistical analysis between total disease duration and brain
weight, and cortical pathologic stage
Pathological fi ndings
In our 43 cases with MM1-type sCJD, we obtained strong
Various degrees of spongiform change, gliosis, tissue rarefac- statistically significant positive correlation coefficients be-
tion and neuronal loss have been observed in the cerebral tween the total disease duration and the cortical pathologic
© 2016 Japanese Society of Neuropathology
6 Y Iwasaki

Fig. 3 A: Fine vacuole-type spongiform change

observed in a patient with MM1-type sporadic
CJD (sCJD). Numerous round vacuoles with
clear boundaries and without the tendency for ad-
hesion are observed within the neuropil. B: Large
confluent vacuole-type spongiform change ob-
served in a patient with MM2-cortical type sCJD.
Large vacuoles in small coalescing groups can be
seen. C: Non-confluent various-sized vacuole-type
spongiform change observed in a patient with
V180I genetic CJD. HE staining. Scale bars:
200 μm.

Fig. 4 A: Synaptic-type PrP deposition observed

in a patient with MM1-type sporadic CJD (sCJD).
Granular PrP deposits are diffusely observed in
the neuropil. B: Perivacuolar-type PrP deposition
observed in a patient with MM2-cortical type
sCJD. Intense PrP deposits around areas of con-
fluent spongiform change are observed. C:
Coarse-type PrP deposition observed in a patient
with MM2-cortical type sCJD. Anti-PrP (3F4) im-
munostaining. Scale bars: 100 μm.

stage of each neocortical region (Fig. 6).15 Strong statistically 1.3 months, 14.6 months and 27.9 months after disease onset,
significant negative correlation coefficients were also ob- respectively.15 Furthermore, according to this linear equa-
tained between brain weight and the cortical pathologic tion, Stage 0, which is the virtual pathological onset, was
stage of each neocortical region (Fig. 7).15 According to 12.0 months before the clinical disease onset.15 Similarly, ac-
these correlation coefficient results, we were able to estimate cording to the occipital neocortical stage, which showed the
the total disease duration or brain weight from only one area highest correlation coefficient between pathologic stage and
of the cerebral neocortex. For example, according to the pa- brain weight (pathologic stage = 0.0063 × brain weight
rietal neocortical stage, which showed the highest correla- (grams)  10.273), Stages II, IV and VI correspond to
tion coefficient between pathologic stage and total disease 1313.2 g, 995.7 g and 678.3 g, respectively.15 Conversely, a
duration (pathologic stage = 0.1501 × total disease duration brain weight of 1000 g approximately corresponds to the
(months)  1.8051), Stages II, IV and VI correspond to early phase of Stage IV of the occipital neocortical stage.15
© 2016 Japanese Society of Neuropathology
Creutzfeldt-Jakob disease 7

Fig. 5 Neuropathologic findings of the

cerebral cortex at each stage. Cited from
Ref. #15. Scale bars: A–E, 100 μm; F,
500 μm. HE staining.

Table 5 Clinicopathological characteristic of each type of sporadic Creutzfeldt-Jakob disease

Cortical Characteristic Simple staging Pathological findings

pathologic pathology classification
staging
Stage 0 No abnormality None No pathologic abnormality can be detected by HE staining. No gliosis,
Stage 0.5 PrP deposition spongiform change, neuropil rarefaction or neuron loss is observed.At the Stage
0.5, only PrP deposition is observed by immunostaining.
Stage I Spongiform Mild Mild spongiform change is observed in the neuropil. Small round vacuoles with
change(Fig. 5A) 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 The important difference from Stage I is the presence of hypertrophic
astrocytosis(Fig. 5B) 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 Moderate Tissue rarefaction of the neuropil is apparent. Neurons are mildly decreased in
rarefaction(Fig. 5C) 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 Neurons are moderately decreased in number and severe hypertrophic
loss(Fig. 5D) 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 Severe The neuropil shows severe rarefaction and severe neuron loss with fibrous
spongiosus(Fig. 5E) 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 Characteristic large-sized cystic cavitations are observed. Macrophages are
formation(Fig. 5F) 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

8 Y Iwasaki

DWI at 1.6 months after disease onset approximately

corresponded to the early phase of Stage II of the neocortex.
The average first observation of both myoclonus at
2.1 months and PSWCs on EEG at 2.2 months after disease
onset also approximately corresponded to the early phase of
Stage II of the neocortex. The average time of 3.2 months af-
ter disease onset to reach the akinetic mutism state approx-
imately corresponded to the middle phase of Stage II, which
progresses toward Stage III of the neocortex.

MM2-cortical-type sCJD
MM2-cortical-type sCJD is relatively frequent in Japan,4,7
and shows atypical but characteristic clinicopathologic fea-
tures.4,5,20,21 Spongiform change is observed in the cerebral
Fig. 6 Results of statistical analysis of the relationship between the cortex and striatum, and shows a characteristic “large conflu-
stage of cerebral cortical pathology and total disease duration. A
ent vacuole” appearance (large vacuoles in small coalescing
strong statistically significant positive correlation coefficient was ob-
tained between the mean value of each cerebral neocortical patho- groups) (Fig. 3B).5,20,21 Hypertrophic astrocytosis and neu-
logic stage and total disease duration (rs = 0.95, P < 0.0001, ron loss are relatively mild compared with that observed
Spearman’s rank correlation coefficient). Linear equation by simple for MM1-type sCJD.20,21 The cerebellum and brainstem
regression analysis (x indicates total disease duration (months), y in-
are preserved from pathological involvement.5,20,21 These
dicates mean value of each cerebral neocortical pathologic stage).
pathological findings correspond well to clinical findings,
such as a slow progression, apparent cerebral cortical symp-
toms such as dementia and aphasia, mild or absent myoclo-
nus, and the absence of PSWCs on EEG.20,21
PrP immunostaining shows perivacuolar-type PrP deposi-
tion (intense PrP deposits around areas of confluent
spongiform change) (Fig. 4B) and coarse-type PrP deposi-
tion (irregular plaque-like PrP deposition) (Fig. 4C).5,20,21

MM1 + 2-type sCJD

There may be mixed pathology in single sCJD cases that
present both fine vacuole-type spongiform change, as well
as large confluent vacuole-type spongiform change.5,20–22
These pathological findings suggest that there is a combined
MM1 + MM2-cortical-type sCJD.5,20–22 In general, regions
showing fine vacuole-type spongiform change reflect
synaptic-type PrP deposition and type 1 PrPSc deposition,
Fig. 7 Results of statistical analysis of the relationship between the whereas regions showing large confluent vacuole-type
stage of cerebral cortical pathology and brain weight. A statistically
significant negative correlation coefficient was obtained between spongiform change reflect perivacuolar-type PrP deposition
the mean value of each cerebral neocortical pathologic stage and and type 2 PrPSc deposition.5,20–22 Because the neuropatho-
brain weight (rs = 0.77, P < 0.0001, Spearman’s rank correlation logical examination best identified features of the mixed
coefficient). Linear equation by simple regression analysis (x indi- types 1 PrPSc and 2 PrPSc,21,22 Western blot analysis is unnec-
cates brain weight (grams), y indicates mean value of each cerebral
neocortical pathologic stage). essary in the analysis of the PrP type, at least in sCJD cases
with Met/Met polymorphism at codon 129. Also, it is appro-
priate to determine the MM1 + 2 type sCJD based on a sig-
nificant increase of type 2 sCJD pathology, as seen by
Relationship between clinical findings and neuropathological
neuropathological observation rather than Western blot
findings
analysis.21,22 In terms of the pathogenesis of type 1 + 2 PrPSc
According to the observations of our MM1-type sCJD cases, combined sCJD cases, it has been speculated that one prion
we estimated the approximate relationship between clinical strain occurs first, and different strains are produced later
findings and the neocortical pathologic stage (Table 6).15 on.20,21 However, the mechanism underlying this is as yet un-
The average first observation of cortical hyperintensity on known. In the pathological description of the MM1 + 2-type
© 2016 Japanese Society of Neuropathology
Creutzfeldt-Jakob disease 9
Approximate
brain weight sCJD, we suggest that the diagnosis of “MM1 + 2C

1000–1200
1100–1300

900–1100

< 1000
1200 <

< 800
combined-type”, “MM1 with MM2C-type”, or “MM2C with
(g)

Modified from our previous report.15 DWI, diffusion-weighted MRI; PSWCs, periodic sharp-wave complexes; PE-type, panencephalopathic type; SSE, subacute spongiform encephalopathy.
MM1-type” must be essentially made based on the early
clinical features and major pathological findings.20,21 To
total duration
Approximate

our knowledge, there is no case report of

of disease
(months)

10–16

12 <

20 <
5–12
2–5
MM1 + MM2-thalamic-type sCJD.
<2

MM2-thalamic-type sCJD
Akinetic
mutism
state

- or+

The cerebral neocortex usually shows no apparent involve-

-or+
Correspondence of clinical findings

+
ment in MM2-thalamic-type sCJD, but, depending on the
case, may exhibit spongiform change and PrP deposition to
clonus
Myo-

- or +

+ or -

varying degrees.5,23 Severe neuron loss, tissue rarefaction

+

and hypertrophic astrocytosis are observed in the medial

PSWCs

EEG

thalamus and inferior olivary nucleus (Fig. 8).5,23 No appar-

- or +

+ or -
on

ent PrP deposition is observed in the medial thalamus or in-

+

ferior olivary nucleus.5,23

hyperintensity

These pathological findings are compatible with clinical

on MRI
DWI

characteristics of conspicuous insomnia and autonomic dis-

+ or -

turbance, and also compatible with the absences of PSWCs

+

on EEG, myoclonus and DWI hyperintensity.5,23

classification
Approximate degree of pathologic findings and correspondence of the clinical findings for each stage

Pathologic

SSE or PE-

SSE or PE-

PE-type

PE-type

MM2-cortical + thalamic-type sCJD

type

type
SSE

SSE

Because thalamic lesions can be observed in MM2-cortical-

type sCJD, and cerebral cortical lesions can be observed in
Disappearance
Disappearance
Cortical layer
architecture

MM2-thalamic-type, and there is no clear definition for a

Ambiguous
Preserved

Preserved

Preserved

combined-type (MM2-cortical + thalamic) sCJD, problems

in the use of this terminology are inevitable.20,21 In the path-
ological description of the MM2-type sCJD, a diagnosis of
“MM2-cortical + thalamic combined-type”, “MM2-thalamic
Disappearance

with cortical-type” or “MM2-cortical with thalamic-type”

neurons
Inflated

Decrease

must be essentially based on the early clinical features and

Many
Some
None

None

major pathologic findings, and not on later widespread in-

volvement of the lesions due to a prolonged duration of
the disease.20,21
Moderate
Pathologic findings

complete
Neuron

Almost
loss

Severe
None

None

Mild

loss

V180I genetic CJD

rarefaction
Neuropil

CJD with a point mutation of Val to isoleucine (Ile) at codon

Moderate
very mild

or severe
None or

Severe
Severe

180 in the PrP gene is extremely rare in Caucasian patients

None

Mild

with CJD,24 but it is the most frequent type of genetic CJD

in Japan.7 The clinical features are relatively uniform, but
None or mild

hypertrophic

hypertrophic

remarkable)
astrocytosis

astrocytosis

considerably different from those of typical CJD: (i) older

(no longer
Gliosis

Moderate
Mild with
without

age of onset; (ii) prolonged disease duration with a slower

Severe

Severe

Severe

progression course; (iii) frequent cortical dysfunction such

as dementia, aphasia and apraxia, whereas cortical visual
(large cavity
Spongiform

spongiosus)

symptoms or cerebellar signs are not recognized; (iv) lower

formation)
Moderate
change

moderate

positive rate of brain-specific proteins such as neuron-

Mild or

Severe

Severe

Severe
(status
Mild

specific enolase, total tau protein and 14–3-3 protein in the

cerebrospinal fluid; (v) no PSWCs on EEG throughout the
pathologic

course of the disease; (vi) less prominent myoclonus, the ap-

Table 6
Cortical

staging

pearance of which is later; (vii) noticeable pathological

IV

VI
III

laughing (Fig. 9A) and startle reactions; and (viii) a lack of

V
II
I

© 2016 Japanese Society of Neuropathology

10 Y Iwasaki

Fig. 8 MM2-thalamic-type sporadic CJD

(sCJD). A: Macroscopic appearance of coronal
section of the cerebral hemisphere shows severe
involvement of the medial thalamus. The cerebral
cortex and white matter, basal ganglia and hippo-
campus are preserved. B: The medial thalamus
shows severe tissue rarefaction and neuron loss
with hypertrophic astrocytosis. C: The inferior
olivary nucleus shows severe neuron loss with hy-
pertrophic astrocytosis. Cited from Ref. #23. A:
KB staining; B, C: HE staining. Scale bars, A:
10 mm; B, C: 100 μm.

Fig. 9 A: Pathological laughing observed

in V180I genetic CJD (permission to
publish this photograph was obtained
from the patient’s family). B: MRI shows
regions with extensive hyperintensity
on diffusion-weighted MRI (B1) and
edematous cortical hyperintensity on
fluid-attenuated inversion recovery image
(B2) in the cerebral cortex, except for the
medial occipital region. R, right side.

similarly affected family members and appearance as a spo- protective factor against the rapid progression of the clinical
radic neurodegenerative disorder.25,26 Extensive DWI course and development of pathological involvement is as-
hyperintensities are observed in the cerebral cortex, except sociated with V180I genetic CJD.25,26
for the medial occipital region, for a longer duration and These pathological findings well correspond to clinical
with higher brightness than that noted in cases of typical findings, particularly in the slowly progressing, cerebral
CJD (Fig. 9B1).25 Characteristic edematous cortical cortical symptoms, MRI findings, as well as mild or absent
hyperintensity is also characteristic in fluid-attenuation in- myoclonus and no typical PSWCs on EEG.25,26
version recovery and T2-weighted MRI (Fig. 9B2).25
Pathologically, extensive spongiform change is observed
in the cerebral cortex and striatum, but gliosis and neuron THE RELATIONSHIP BETWEEN CLINICAL
loss are generally mild.26 The vacuole size varies, but vacu- FINDINGS AND NEUROPATHOLOGICAL
oles do not tend to be confluent and are thus termed non- FINDINGS
confluent various-sized vacuoles (Fig. 3C).26 The brainstem
and cerebellum are preserved from pathological involve-
Hyperintensities of DWI
ment.26 Although these pathologic findings partly resemble As described earlier, all DWI-examined MM1-type sCJD
those of MM2-cortical-type sCJD, the appearance of the cases showed cerebral cortical hyperintensity at the time of
spongiform change is highly characteristic of V180I genetic first imaging.15 We previously reported an autopsied case
CJD; and we could speculate the V180I diagnosis only with of MM1 + 2-type sCJD presenting with hyperintensities on
the appearance. PrP deposition is very mild and shows weak DWI 8 months before the clinical onset.21 Because DWI
synaptic-type.26 On the basis of these neuropathological hyperintensities in the cerebral cortices of patients with
findings, it has been hypothesized that an unknown CJD reflect the pathology of the spongiform change,15 the
© 2016 Japanese Society of Neuropathology
Creutzfeldt-Jakob disease 11

Fig. 10 Relationship between the diffusion-weighted MRI findings and the pathological findings. The left medial occipital cortex shows
hyperintensity and is accompanied with more high-brightness region (A1). The cortical region of hyperintensity with less high-brightness
(B1) shows fine vacuoles (B1a) and synaptic-type PrP deposition (B1b). The cortical region with more high-brightness (B2; surrounded by
a rectangle) shows large confluent vacuoles (B2a) and perivacuolar-type PrP deposition (B2b). In macroscopic loupe images, the vacuoles
are easily recognized in regions with large confluent vacuoles but difficult to see in regions with fine vacuoles (A2). The transitional region
of both sites (B3) shows a mixture of both types of spongiform change (B3a) and PrP deposition (B3b). Cited from Ref. #21. A2, B1a, B2a,
B3a: HE staining. B1b, B2b, B3b: anti-PrP (3F4) immunostaining. Scale bars: 200 μm.

spongiform changes associated with CJD must begin several is thought to originate from the involvement of the cerebral
months before the clinical onset.21 Furthermore, long-term cortex, basal ganglia and/or thalamus, but the detailed path-
hyperintensities of DWI were observed for this patient, ological origins are not well understood.
and the brightness of the hyperintensities was greater in re- As described earlier, the first appearance of myoclonus in
gions that showed large confluent vacuole-type spongiform MM1-type sCJD can be said to approximately correspond to
change than in regions that showed fine vacuole-type the early phase of Stage II of the cerebral cortical stage.15 In
spongiform change (Fig. 10).21 We may therefore be able this stage, spongiform changes with hypertrophic
to speculate about which types of PrPSc are deposited in astrocytosis are extensively observed and ballooned neurons
the cerebral cortex according to the brightness and duration in the cerebral neocortex begin to appear.15 Interestingly,
of the DWI hyperintensities alone, before relying on au- spongiform change is also observed in AD, CBD (Fig. 11A)
topsy or Western blot analysis. and DLB. However, spongiform change in CJD is observed
in all layers of the cerebral cortex,9 whereas in AD, CBD
and DLB, spongiform change is predominantly observed
Myoclonus in the superficial layer of the cerebral cortex. Ballooned neu-
Myoclonus refers to the sudden and involuntary jerking of rons are also observed in CBD (Fig. 11B1) and these are
groups of muscles. It is observed not only in CJD, but also larger than those observed in CJD (Fig. 11B2).
several other diseases such as infection, head injury, stroke,
brain tumors, kidney or liver failure, lipid storage disease,
chemical and drug poisoning, as well as neurodegenerative
Akinetic mutism state
disorders such as Alzheimer’s disease (AD), corticobasal de- In CJD, use of the term “akinetic mutism state” differs from
generation (CBD) and dementia with Lewy bodies (DLB). its use in other neurodegenerative diseases.4,12,15 In CJD, it
In neurodegenerative diseases, including CJD, myoclonus refers to the state in which patients lack voluntary

Fig. 11 A: Spongiform change of the cerebral

cortex observed in a patient with corticobasal de-
generation (CBD). The appearance could not be
distinguished from that of CJD. B: Ballooned neu-
ron of the cerebral cortex observed in patients
with CBD (B1) and CJD (B2). The size of
ballooned neurons observed in CJD is smaller
than that in CBD. HE staining. Scale bars, A:
100 μm; B1, B2: 50 μm.

© 2016 Japanese Society of Neuropathology

12 Y Iwasaki

Fig. 12 A: A patient with CJD who has

just reached the akinetic mutism state.
The extremities present an extension po-
sition and the spasticity is not conspicu-
ous. B: A patient with CJD several
months after reaching the akinetic mutism
state. The extremities present dystonic
posture and spasticity is apparent. Disuse
muscle atrophy is observed. C: A patient
with CJD with prolonged disease dura-
tion. The extremities show tetraplegia in
flexion with contracture. D: Pyramidal
tract degeneration observed in the cervi-
cal spinal cord of the patient with CJD
with prolonged disease duration. Degen-
eration is observed not only in the lateral
funiculus but also in the anterior funicu-
lus. Cited from Ref. #19. A-C: Permission
to publish the photographs was obtained
from the respective patients’ families. D:
KB staining. Scale bar: 5 mm.

movement and the ability to produce meaningful extremities (not including disuse muscle atrophy), do not oc-
words.4,12,15 In other words, this state of CJD might be asso- cur in typical CJD.
ciated with the presence of involuntary movements such as
myoclonus, startle reaction, dystonia and convulsion, and SUBACUTE SPONGIFORM
with the production of unintelligible and nonsensical sounds ENCEPHALOPATHY AND
such as groans.4,12,15 PANENCEPHALOPATHIC-TYPE CJD
As described above, it can be estimated that progression The pathological classification of panencephalopathic-type
to the akinetic mutism state in MM1-type sCJD approxi- (PE-type) CJD and its pathogenesis still seem compli-
mately corresponds to the middle phase of Stage II, which cated.9,16,28 PE-type pathology is characterized by extensive
progresses toward Stage III of the cerebral cortical stage.15 involvement of not only the cerebral neocortex, but also the
In this stage, the cerebral neocortex begins to show tissue cerebral white matter, and includes extensive myelin pallor
rarefaction and neuron loss.15 with tissue rarefaction, numerous foamy macrophages, axon
loss and hypertrophic astrocytosis (Fig. 13A2).9,15,16 While
approximately half of Japanese CJD cases show PE-type pa-
Pyramidal signs thology, PE-type CJD is very rare in Europe and North
Pyramidal signs such as spasticity, brisk deep tendon reflex America.9,16 Indeed, the majority of European and North
and the Babinski sign, can become apparent over the clinical American CJD cases show subacute spongiform encepha-
course of CJD (Fig. 12A-C).8 With prolonged disease dura- lopathy (SSE) pathology, in which damage is predominantly
tion, pyramidal tract degeneration is observed in the seen in the cerebral and cerebellar cortices without apparent
brainstem and spinal cord of patients with CJD cerebral white matter pathology (Fig. 13A1).9,16 The total
(Fig. 12D).18,19,27 In the cerebral neocortex, the precentral disease duration of PE-type sCJD is said to be significantly
gyrus, including Betz cells, tend to be relatively preserved longer than that of SSE.9,16 This prolonged disease duration
but present with neuron loss associated with prolonged dis- may explain why the Japanese sCJD series includes so many
ease duration.9,21,27 On the other hand, the number of neu- PE-type sCJD cases.9,16 PE-type is a pathological classifica-
rons in the spinal cord, including large motor neurons, is tion and occurs not only in sCJD but also in genetic CJD
well preserved regardless of disease duration.19,27 These with the V180I mutation26 or M232R mutation,29 and
pathological findings are thought to coincide with the ap- Gerstmann-Sträussler-Scheinker disease.30
pearance of pyramidal signs, and suggest that lower motor PE-type pathology has been found to appear approxi-
neuron signs, such as flaccid paralysis, diminished deep ten- mately 12 months after disease onset in patients with
don reflex, fasciculation and muscle atrophy of the MM1-type sCJD,15,16 and it is presumed that PE-type
© 2016 Japanese Society of Neuropathology
Creutzfeldt-Jakob disease 13

Fig. 13 A: Macroscopic appearance of the two

subtypes of sporadic CJD (sCJD) according to
the cerebral pathology findings. In subacute
spongiform encephalopathy, damage is observed
predominantly in the cerebral cortices with pre-
served cerebral white matter without apparent
myelin pallor (A1). In panencephalopathic-type
(PE-type), severe damage is observed in the cere-
bral cortex and white matter with myelin pallor
(A2). The basal ganglia and thalamus also show
severe atrophy. Cited from Ref. #15. B:
Circumscribed spongy foci in the subcortical white
matter (B1, arrows). Extensive PrP deposition is
observed in the cerebral cortex, but not in the foci
(B2). A1, A2, B1: KB staining; B2: anti-PrP (3F4)
immunostaining. Scale bars, A: 10 mm; B: 500 μm.

pathology appears in the period during which the cerebral Japan, and Grants-in-Aid for Scientific Research
neocortical pathology shifts from cerebral cortical pathology <KAKENHI > Grant Number H27-15 K08369.
stage III to IV, which pathologically corresponds to the pro-
gressive state of neuron loss.15 This observation supports the DISCLOSURE
idea that the pathologic difference between SSE and
There are no conflicts of interest to declare.
PE-type sCJD is mainly due to secondary white matter de-
generation caused by severe cerebral cortical involvement,
particularly with regard to neuronal loss.9,15,16 COMPETING INTERESTS
Although the circumscribed spongy foci in cerebral white The authors have declared that no competing interests exist.
matter has been suggested to be the pathologic hallmark by
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© 2016 Japanese Society of Neuropathology