Transcript Creutzfield * Jacob Disease: What the

Creutzfeldt – Jakob Disease:
What the Neuroradiologist
Needs to Know
By: LP Rachakonda MD, P Watal MD, A Jones MD, T Sato MD, A
Capizzano MD, J Kademian MD, T Moritani MD PhD
Table of Contents
Imaging
Prion Diseases
Introduction
Examples
Kuru
Etiology
Transmission
Pathology
Mechanism of Disease
Histopathology
Gross Pathology
Epidemiology
Subtypes of CJD
Clinical Features
Clinical Subtypes
Clinical Diagnosis
Variant CJD
sCJD Imaging
T2/FLAIR
DWI/ADC
Heidenhain variant
vCJD Imaging
Lumbar Puncture in
Suspected CJD
References
Prion Diseases: Introduction
• Prion diseases are also known as Transient Spongiform
Encephalopathies (TSEs).
• The term “prion”, coined in 1982 by Stanley B. Prusiner, is a
compound word derived from the words “protein” and “infection” 1
• “Prion” is short for “proteinaceous infectious particle”, which refers to
the ability of prions to self-propogate 2
• Prion diseases are caused by these proteinaceous infectious particles
(“prions”), which lack DNA and RNA
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Prion Diseases: Examples
• Examples of human prion diseases include:
•
•
•
•
Kuru
Gerstmann-Straussler Schenker syndrome
Fatal Familial Insomnia
Creutzfeldt – Jakob Disease (CJD)
• Certain prion diseases are found only in animals:
• Scrapie (sheep and goats)
• First identified prion disease
• Feline encephalopathy (cats)
• Chronic wasting disease (deer and elk)
• Bovine spongiform encephalopathy (“Mad Cow Disease”)3
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Prion Diseases: Kuru
• Kuru was the first prion disease discovered in
humans.
• Kuru is an incurable, degenerative, neurologic
disorder endemic to the Fore population of
Papua New Guinea.
• In the Fore language (spoken in Papua New
Guinea), the term “kuru” refers to body
tremors, which are a characteristic feature of
the disease.
• Symptoms progress from unsteady gait and
tremors, to loss of muscle coordination,
severe ataxia, and death, over the course of 3
months to 2 years. 4
Image from: https://kristimitchell.wordpress.com/
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Prion Diseases: Kuru
• Kuru was transmitted among members
of the Fore tribe of Papua New Guinea
via funerary cannibalism. 5
• An epidemic of kuru resulted in 1000
deaths between 1957 and 1960 in
Papua New Guinea. 5
• Kuru has largely disappeared with the
discontinuation of cannibalism, the only
source of human to human transmission
• The agent responsible for kuru was
found to be a proteinaceous particle
lacking DNA and RNA, later termed a
prion.
Image from: https://kristimitchell.wordpress.com/
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Prion Diseases: Etiology
• Prion diseases are caused by self-replicating proteinaceous infectious
particles
• These self replicating proteins induce neurodegenerative disorders
• As prion diseases are transmissible, they are classified as infectious
diseases 6
• There are 3 major forms of prion diseases:
• Sporadic
• Genetic
• Acquired 7
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Prion Diseases: Etiology: PrPC
• The normal host prion protein (PrPC) is predominantly expressed in
brain.
• However, PrPC is a constituent of various other tissues, including
heart, lung, kidney, pancreas, and blood. 8
• The normal PrPC protein is involved in several processes, including
neuronal activities, immunity, and anti-oxidative processes.
• PrPC may play a role in transporting copper into cells. 9
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Prion Diseases: Etiology: PrPSc
• Abnormal prion proteins (PrPSc) are misfolded isoforms of the normal
host prion protein (PrPC).
• The misfolded isoforms (PrPSc) of the normal host protein (PrPC) cause
prion diseases.
Image from:
http://users.sussex.ac.uk/~ctf20/dphil_2005/Thesis/Chapter1/prions.htm
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Prion Diseases: Etiology: PRNP Gene
• PRNP is the gene that encodes the human prion
protein.
• PRNP maps to the short arm of chromosome 20. 10
• There are 6 molecular variants of PRNP, due to
pleomorphism at codon 129 of the PRNP gene. 11
• Different mutations of the PRNP gene code for
different isoforms of the prion protein, and are linked
to different genetic forms of prion disease.
• Sporadic, somatic mutations in the PRNP gene result in
sporadic CJD (sCJD).
• Genetic CJD (gCJD) has been linked to 20 different genetic
mutations. It can be inherited in an autosomal dominant
(AD) fashion. 8
Image from: https://en.wikipedia.org/wiki/PRNP
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How Are Prion Diseases Transmitted?
• Prion diseases can be transmitted by exposure to prion contaminated
tissues, or exposure to biologic materials obtained from hosts with
prion disease.
• The most widely accepted hypothesis for transmission of prion
disease is known as the “protein only hypothesis”. 12
• In the “protein only” hypothesis, the abnormal, misfolded prion
protein (PrPSc) is transmitted when the abnormal protein (PrPSc)
induces a conformational change in the prion protein of its host,
converting the normal host PrPC into PrPSc. 12
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Transmission of Prion Disease
• The conversion of the PrPC protein of the host to the PrPSc
conformation is the fundamental event resulting in transmission of
prion disease. 13
Image from:
http://curtis.wawiki.wikispaces.net/Bradley+Waddell
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Pathology: Mechanism of Disease
• In summary, abnormal prion isoforms can enter cells through:
• expression of inherited mutation in the PRNP gene (e.g., gCJD)
• expression of spontaneous, somatic mutation in the PRNP gene (e.g., sCJD)
• conformational change in the normal host PrPC to the abnormal PrPSc protein
induced by an infectious prion (e.g, iCJD, vCJD).
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Pathology: Mechanism of Disease
• Once PrPSc is within the neuron, it accumulates in intracellular and extracellularspaces, which
is toxic to the endoplasmic reticulum and causes neuronal dysfunction. 10, 14
Image from:
http://www.cell.com/trends/molecular-medicine/fulltext/S1471-4914(10)00129-2
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Pathology: Mechanism of Disease
• Since no antibody is produced against PrPSc, no inflammatory
changes are seen in prion diseases.
• Misfolded PrPSc contains beta-pleated sheets that are resistant to
proteolysis and standard sterilizing techniques. 14
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Pathology: Histopathology
• The characteristic histologic features in CJD are neuronal loss,
spongiform degeneration of the grey matter, and astrogliosis. 14
Image from:
http://www.nature.com/nrn/journal/v2/n10/fig_tab/nrn1001-745a_F1.html
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Pathology: Histopathology
• Amyloid plaques are noted in 10% of cases.
Image from: http://www.federationofscientists.org/pmpanels/tse/visuals.asp
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Pathology: Gross Pathology
• Gross pathology demonstrates cortical volume loss, enlargement of
the ventricular system, and atrophy of the caudate.
• Cortical volume loss can affect the cerebral or cerebellar
hemispheres, and often, the deep nuclei. 10
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Pathologic Diagnosis
• PrPSc immunoreactivity is the gold standard for the pathologic
diagnosis of PrPSc
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Epidemiology: Subtypes of CJD
• CJD is the most common human prion disease
• There are 4 subtypes of CJD:
•
•
•
•
Sporadic CJD (sCJD)
Genetic CJD (gCJD)
Iatrogenic CJD (iCJD)
Variant CJD (vCJD)
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Epidemiology: Subtypes of CJD
• Sporadic CJD is caused by somatic mutations in the PRNP gene
• Genetic CJD is caused by inherited mutations in the PRNP gene
• Iatrogenic CJD is caused by the transmission of CJD to normal host
neurons via objects that are contaminated by prions.
• The infectious PrPSc protein induces a conformational change in the normal
host PrPC protein, converting it to the PrPSc isoform.
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Epidemiology: Subtypes of CJD
• Although there have been epidemics of other prion diseases, such as
kuru, in the past, today, 90% of all prion disease is caused by CJD.
• ~ 85% of cases of CJD are due to sporadic CJD (sCJD).
• ~ 15% of cases of CJD are due to genetic CJD (gCJD).
• Today, fewer than 1% of cases of CJD are due to variant CJD (vCJD)
and iatrogenic CJD (iCJD). 15
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Clinical Features of CJD
• Median age of onset is 65 years
• Median survival is 4 months
• Initial clinical symptoms include confusion and amnesia, followed by
rapidly progressive dementia and ataxia
• Occasionally the clinical symptoms are nonspecific and may include
weakness, extrapyramidal symptoms, and sensory and visual
disturbances. 16
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Clinical Features: Clinical Subtypes
• There are a few less common clinical subtypes of sporadic CJD (sCJD)
• Heidenhain variant: Visual symptoms predominate and precede other clinical
manifestations 17, 18
• Brownell-Oppenheimer variant: Cerebellar symptoms predominate
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Clincal Diagnosis
• In sCJD, EEG may show bilateral
periodic sharp wave complexes
(sensitivity 40–67%) which occur
relatively late in the disease
course. 19, 20
• Identification of 14-3-3 protein in
the CSF supports the clinical
diagnosis of sCJD
• Sensivity is 85%
• Specificity is low, with multiple false
positives 20, 21, 22
Image from:
http://www.epilepsy.com/information/professionals/diagnosis-treatment/epilepsy-clinic%E2%80%93test-your-clinical-knowledge/dementia
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“Mad Cow Disease” and Variant CJD
• Variant CJD is caused by a distinct
prion with an abnormal PrPSc
isoform.
• The prion that causes vCJD is
believed to be the same prion
that causes Bovine Spongiform
Encephalopathy (BSE) in cattle.
• BSE is also known as “Mad Cow
Disease”.
• The consumption of cattle
products infected with the prion
that causes BSE is strongly linked
to vCJD in humans. 23
Image from:
http://www.ibtimes.co.uk/mad-cow-disease-bse-found-dead-cow-welsh-farm-1522008
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Variant CJD
• From October 1996 to March 2011, 175 cases of vCJD were reported
in the UK, with 49 cases reported in other countries.
• Compared to the other forms of CJD, vCJD affects younger patients
(median age at death of 28 years, as opposed to 68 years) and has a
longer duration of illness (median of 14 months as opposed to 4.5
months).
• The clinical features of vCJD differ from other forms, as initially,
patients experience psychiatric or sensory symptoms.
• EEG changes are typically absent 23
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sCJD Imaging
• CT is neither sensitive or specific
• The only CT finding may be brain atrophy, in the advanced stages of the
disease
• MRI is sensitive and specific
• Sensitivity of MRI for sCJD has been reported to be between 83 and
100%, and 92–94% in prospective studies using DWI
• However, there are false negative cases of CJD on MRI 24,25,26, 27,28
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sCJD Imaging: T2/FLAIR MRI
• T2/FLAIR images demonstrate subtle hyperintense lesions in the
cerebral cortex and basal ganglia
• T2/FLAIR changes usually occur 2-5 months after onset of symptoms
• T2/FLAIR hyperintensity in sCJD is pathologically correlated with astrocytosis
and PrPSc deposition rather than spongiform changes. 24,25,26, 27,28
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sCJD Imaging: T2/FLAIR
• Basal ganglia and cortical involvement is common in sCJD
• Basal ganglia are involved in 60-100% of cases and cortex in 54-88%.
• Isolated cortical involvement and isolated basal ganglia involvement have
been reported.
• Basal ganglia involvement is correlated with early onset of dementia and
shorter clinical course
• Isolated cortical involvement is correlated with longer survival.
• White matter can be involved as T2 hyperintensity in the
periventricular area 4-5 months after clinical onset, with extension to
the deep and subcortical white matter during the following several
months. 24,25,26, 27,28
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Case 1: T2/FLAIR
Case 1: A 68 year old woman presented with memory problem and behavioral
changes.
FLAIR image demonstrates diffuse, high signal in
the cortex, more prominent on the right.
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sCJD: DWI
• DWI is the most sensitive MRI technique in detecting early findings in
sCJD with sensitivity ranging from 86 to 94%.
• DWI may be positive in the absence of typical EEG changes.
• DWI lesions may migrate during the course of the disease.
• Hyperintense DWI lesions in sCJD are often associated with decreased
ADC.
• Electron microscopy shows vacuoles that result from focal swelling of neuritic
processes, from cellular edema, which most likely causes reduced diffusivity.
• Another possibility is that PrPSc plaque deposition is responsible for the
decreased water diffusivity. 24,25,26, 27,28
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sCJD: DWI
• Cortical involvement is usually asymmetric, which does not correspond to an
arterial territory
• Basal ganglia or thalamic involvement is often symmetric, but can be
asymmetric in the early stage and become symmetric later on
• Marked selective abnormalities in glutamate receptors may explain the
characteristic distribution of DWI abnormalities in CJD.
• The presence of autoantibodies to the NMDA receptor (a glutamate receptor) has been
reported in sCJD.
• In the late stages of sCJD, abnormal hyperintense signals disappear with
prominent brain atrophy, histologically representing neuronal loss and
marked fibrillary gliosis 24,25,26, 27,28
Case 1: DWI
Diffusion weighted images
and ADC map demonstrate
diffuse, cortically based
“ribbons” of restricted
diffusion.
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Case 2: T2/FLAIR
51 year old male with progressive dementia.
T2-weighted image
demonstrates mild
hyperintensity
bilaterally in the caudate
nuclei, putamina and
pulvinar of the thalami
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Case 2: DWI and ADC
DW image clearly demonstrates
hyperintense lesions in the
bilateral caudate, putamina, and
pulvinar nuclei. ADC is decreased.
This is an example of the basal
ganglia and thalamic involvement
in sCJD. Basal ganglia involvement
is correlated with early onset of
dementia and shorter clinical
course.
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Case 3: Iatrogenic CJD (iCJD)
Creutzfeldt–Jakob disease in a 57-year-old woman with progressive dementia 10 years after surgery
using cadaver dura matter.
T2-weighted image shows
postoperative change in the
left temporo-occipital region
with mild ventricular
dilatation.
DW image reveals bilateral
hyperintensity in the caudate
nuclei (arrows) and mild
increased signal diffusely in
the left hemisphere. Findings
in iCJD are similar to sCJD.
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Case 3: 4 month follow-up of iCJD
• Imaging findings of iCJD are similar to sCJD
• Findings include T2/FLAIR hyperintensity in
the basal ganglia, thalami, and cerebral
cortex
• In the late stages of CJD, abnormal
hyperintense signals disappear with
prominent brain atrophy. Histologically, this
represents neuronal loss and marked
fibrillary gliosis
4 month follow-up FLAIR image demonstrates marked brain
atrophy
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vCJD Imaging
• Thalamic involvement is common and predominant in vCJD, including:
• pulvinar (pulvinar sign)
• dorsomedial and anterolateral thalamus (hockey-stick sign)
• Pulvinar sign has been seen in 90% of vCJD cases with high sensitivity
and specificity for the diagnosis
• However, the pulvinar and hockey-stick signs may also be seen in sCJD
• Periaqueductal gray matter, caudate nuclei and parieto-occipital
white matter can be involved. 29, 30
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Case 4
A 25-year-old man, returning from England, presented with rapid cognitive
decline associated with myoclonus.
• FLAIR images demonstrate
high signal in the
posteromedial thalami
bilaterally. This represents
the “hockey-stick” sign.
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Case 5: sCJD- Heidenhain Variant
58-year-old woman with altered mental status and visual symptoms (Heidenhain clinical variant).
T2-weighted image shows
hyperintensities in the basal
ganglia. DWI demonstrates
hyperintensities
only in the left basal ganglia
(arrows). Hyperintense lesions
are also noted in the right
temporo-occipital cortices,
which does not correspond to a
single vascular territory
(arrows).
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LP in Suspected CJD
• Diagnosis of CJD typically requires lumbar puncture (LP). This may be
performed under fluoroscopy by the neuroradiologist.
• LP in suspected CJD requires some special considerations.
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LP in Suspected CJD
While typical lumbar puncture tray may be used, additional personal
protective equipment (PPE) should be utilized, including:
Fluid resistant gown
Face mask with shield
Shoe protectors
Typical sterile gloves
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LP in Suspected CJD
• The procedure (LP) is carried out in the typical fashion.
However, there should be increased caution and alertness for
CSF spill onto equipment, floor, and personal protective
equipment (PPE).
• After the procedure:
• The spinal needle, other sharps, and connection tubing should be
disposed of in a separate, marked, hard plastic “Biohazard” container.
• PPE, sterile towels, and remaining items on the procedure tray should
be disposed into a separate, red “Biohazard” bag.
• Per protocol established with hazardous waste contractors, this waste is
secured, placed into a Biohazard box and sealed. The waste is then held
in a secure Biohazard room until it is transported to an incinerator for
incineration.
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LP in Suspected CJD
• If there is no spill of CSF the fluoroscopy suite should be sprayed with a one-step,
quaternary-based disinfectant cleaner concentrate providing broad spectrum
disinfection, such as Virex. After 10 minutes, the fluoroscopy suite should again
be sprayed with the disinfectant.
• If there is a spill of CSF during the LP, the surfaces contaminated by TSE agents
can be disinfected by flooding, for one hour, with NaOH or sodium hypochlorite,
followed by water rinses 31.
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References
1. Prusiner, Stanley B.; Woerman, Amanda L.; Mordes, Daniel A.; et al. "Evidence for α-synuclein prions causing multiple system atrophy in
humans with parkinsonism". Proceedings of the National Academy of Sciences 112 (38): E5308–17.
2. "Stanley B. Prusiner — Autobiography". NobelPrize.org. Retrieved 2007-01-02.
3. "Prion Diseases". United States Centers for Disease Control and Prevention.
4. "Kuru: The Dynamics of a Prion Disease". As.ua.edu. Retrieved 2010-02-01
5. Mo Costandi (26 September 2013). "Mad cows, cannibalism and the shaking death". The Guardian. Retrieved 20 January 2016.
6. Johnson RT, Gibbs CJ Jr. Creutzfeldt–Jakob disease and related transmissible spongiform encephalopathies. N Engl J Med. 1998;339:1994–
2004
7. Letourneau-Guillon L, Wada R, Kucharczyk W. Imaging of prion diseases. J Magn Reson Imaging. 2012;35:998-1012
8. Brown K, Mastrianni JA. The prion diseases. J Geriatr Psychiatry Neurol. 2010;23:277–298
9. Brown DR, Qin K, Herms JW, Madlung A, Manson J, Strome R, Fraser PE, Kruck T, von Bohlen A, Schulz-Schaeffer W, Giese A, Westaway D,
Kretzschmar H (1997). "The cellular prion protein binds copper in vivo". Nature 390 (6661): 684–7.
10. du Plessis DG. Prion protein disease and neuropathology of prion disease. Neuroimaging Clin N Am. 2008;18:163–182
Back to Table of Contents
References
11. Parchi P, Giese A, Capellari S, et al. Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300
subjects. Ann Neurol. 1999;46:224–233
12. Puoti G et al: Sporadic human prion diseases: molecular insights and diagnosis. Lancet Neurol. 11(7):618-28, 2012
13. Sikorska B et al: Creutzfeldt-Jakob disease. Adv Exp Med Biol. 724:76-90, 2012
14. Lucassen PJ, Williams A, Chung WCJ, et al. Detection of apoptosis in murine scrapie. Neuroscience Letters. 1995;198:185–188
15. WHO Consultation on Global Surveillance, Diagnosis and Therapy of Human Transmissible Spongiform Encephalopathies
WHO/EMC/ZDI/98.9 Geneva:WHO;1998
16. Will RG, Matthews WB. A retrospective study of Creutzfeldt-Jakob disease in England and Wales 1970-79. I. Clinical features.J Neurol
Neurosurg Psychiatry. 1984;47:134–140
17. Cornelius JR, Boes CJ, Ghearing G, Leavitt JA, Kumar N. Visual symptoms in the Heidenhain variant of Creutzfeldt-Jakob Disease. J
Neuroimaging. 2009;19:283–287
18. Keyrouz SG, Labib BT, Sethi R. MRI and EEG findings in Heidenhain variant of Creutzfeldt-Jakob disease. Neurology. 2006;67:333
19. Steinhoff BJ, Zerr I, Glatting M, Schulz-Schaeffer W, Poser S, Kretzschmar HA. Diagnostic value of periodic complexes in Creutzfeldt-Jakob
disease. Ann Neurol. 2004;56:702–708
20. Zerr I, Pocchiari M, Collins S, et al. Analysis of EEG and CSF 14-3-3 proteins as aids to the diagnosis of Creutzfeldt-Jakob disease. Neurology.
2000;55:811–815
Back to Table of Contents
References
21. Chohan G, Pennington C, Mackenzie JM, et al. The role of cerebrospinal fluid 14-3-3 and other proteins in the diagnosis of sporadic Creutzfeldt-Jakob
disease in the UK: a 10-year review. J Neurol Neurosurg Psychiatry. 2010;81:1243–1248
22. Collins SJ, McGlade A, Boyd A, Masters CL, Klug GM. 14-3-3 protein detection and sporadic CJD: the status quo serves well while awaiting progress. J
Neurol Neurosurg Psychiatry. 2010;81:1181
23. Zeidler M, Stewart GE, Barraclough CR, et al. New variant Creutzfeldt-Jakob disease: neurological features and diagnostic tests. Lancet. 1997;350:903–
907
24. Shiga Y, Miyazawa K, Sato S, et al. Diffusion-weighted MRI abnormalities as an early diagnostic marker for Creutzfeldt-Jakob disease. Neurology.
2004;63:443–449
25. Zerr I, Kallenberg K, Summers DM, et al. Updated clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease. Brain. 2009;132:2659–2668
26. Young GS, Geschwind MD, Fischbein NJ, et al. Diffusion-weighted and fluid-attenuated inversion recovery imaging in Creutzfeldt-Jakob disease: high
sensitivity and specificity for diagnosis. AJNR Am J Neuroradiol. 2005;26:1551–1562
27. Lodi R, Parchi P, Tonon C, et al. Magnetic resonance diagnostic markers in clinically sporadic prion disease: a combined brain magnetic resonance
imaging and spectroscopy study. Brain. 2009;132:2669–2679
28. Tian HJ, Zhang JT, Lang SY, Wang XQ. MRI sequence findings in sporadic Creutzfeldt-Jakob disease. J Clin Neurosci. 2010;17: 1378–1380
29. Collie DA, Summers DM, Sellar RJ, et al. Diagnosing variant Creutzfeldt-Jakob disease with the pulvinar sign: MR imaging findings in 86
neuropathologically confirmed cases. AJNR Am J Neuroradiol. 2003;24:1560–1569
30. Zeidler M, Sellar RJ, Collie DA, et al. The pulvinar sign on magnetic resonance imaging in variant Creutzfeldt-Jakob disease. Lancet. 2000;355:1412–
1418
31. WHO Infection Control Guidelines for Transmissible Spongiform Encephalopathies. Report of a WHO consultation Geneva, Switzerland: 23-26 March
1999.
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