Validation and utilization of amended diagnostic criteria in Creutzfeldt-Jakob disease surveillance
Peter Hermann, Mareike Laux, Markus Glatzel, Jakob Matschke, Tobias Knipper, Stefan Goebel, Johannes Treig, Walter Schulz-Schaeffer, Maria Cramm, Matthias Schmitz, Inga Zerr
First published June 22, 2018, DOI: https://doi.org/10.1212/WNL.0000000000005860 FULL PDF CITATION PERMISSIONS COMMENT
Downloads0 Add to Cart ($39) Article Info Abstract Objective To validate an amended protocol for clinical diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) including real-time quaking-induced conversion (RT-QuIC) and to observe its use in CJD surveillance.
Methods In the framework of a prospective epidemiologic study, all neuropathologically confirmed cases with sCJD who received CSF RT-QuIC analysis during diagnostic workup (n = 65) and a control group of individuals without CJD (n = 118) were selected to investigate the accuracy of an amended diagnostic protocol. The patients had been referred to the German National Reference Center for Transmissible Spongiform Encephalopathies. The influence of the amended protocol on incidence figures was evaluated in the context of 3 years of surveillance activity (screened cases using 14-3-3 test n = 18,789, highly suspicious cases of CJD n = 704). Annual incidences were calculated with current criteria and the amended protocol.
Results The amended protocol showed a sensitivity of 97% and a specificity of 99%. When it was applied to all suspected cases who were referred to the reference center, the assessed incidence of CJD increased from 1.7 to 2.2 per million in 2016.
Conclusion CJD surveillance remains challenging because information from external health care institutions can be limited. RT-QuIC shows excellent diagnostic accuracy when applied in the clinical setting to symptomatic patients. Data for RT-QuIC alone when applied as a general screening test are not available yet. We propose an amended research protocol that improves early and accurate clinical diagnosis of sCJD during surveillance activities. The use of this protocol will probably lead to a significant increase of the incidence rate.
Classification of evidence This study provides Class III evidence that for patients with suspected sCJD, criteria for clinical diagnosis plus the CSF RT-QuIC accurately identifies patients with sCJD (sensitivity 97%, specificity 99%).
Received December 13, 2017. Accepted in final form April 16, 2018. © 2018 American Academy of Neurology AAN Members: Sign in with your AAN member credentials (e-mail or 6-digit Member ID number)
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http://n.neurology.org/content/early/2018/06/22/WNL.0000000000005860.long
Chapter 10 - Variably protease-sensitive prionopathy
Author links open overlay panelSilvioNotari1Brian S.Appleby1234PierluigiGambetti1 Show more
Abstract
Variably protease-sensitive prionopathy (VPSPr), originally identified in 2008, was further characterized and renamed in 2010. Thirty-seven cases of VPSPr have been reported to date, consistent with estimated prevalence of 0.7–1.7% of all sporadic prion diseases. The lack of gene mutations establishes VPSPr as a sporadic form of human prion diseases, along with sporadic Creutzfeldt–Jakob disease (sCJD) and sporadic fatal insomnia. Like sCJD, VPSPr affects patients harboring any of the three genotypes, MM, MV, and VV at the prion protein (PrP) gene polymorphic codon 129, with VPSPr VV accounting for 65% of all VPSPr cases. Distinguishing clinical features include a median 2-year duration and presentation with psychiatric signs, speech/language impairment, or cognitive decline. Neuropathology comprises moderate spongiform degeneration, PrP amyloid miniplaques, and a target-like or plaque-like PrP deposition. The abnormal PrP associated with VPSPr typically forms an electrophoretic profile of five to seven bands (according to the antibody) presenting variable protease resistance depending on the 129 genotype. The familial prion disease associated with the V180I PrP gene mutation which harbors an abnormal PrP with similar electrophoretic profile might serve as a model for VPSPr.
***Transmission to animals has definitively established VPSPr as a prion disease. Because of its recent identification, rarity, and the elusiveness of its abnormal PrP, VPSPr remains largely understudied.
Previous chapter in volumeNext chapter in volume Keywords sensitive transmissible sporadic anchorless internal fragment psychiatric abnormalities speech impairment cognitive decline normal-pressure hydrocephalus atypical dementia
SATURDAY, JUNE 23, 2018
Diagnosis of Methionine/Valine Variant Creutzfeldt-Jakob Disease by Protein Misfolding Cyclic Amplification
Volume 24, Number 7—July 2018 Dispatch
MONDAY, JUNE 18, 2018
Ecuador Six Case series of Creutzfeldt-Jakob disease in a third-level hospital in Quito
WEDNESDAY, JUNE 13, 2018
Sporadic Creutzfeldt-Jakob Disease in a Woman Married Into a Gerstmann-Sträussler-Scheinker Family: An Investigation of Prions Transmission via Microchimerism
TUESDAY, JUNE 20, 2017
Prion 2017
Conference Transmissible prions in the skin of Creutzfeldt-Jakob disease patients
Prion 2017 Conference Transmissible prions in the skin of Creutzfeldt-Jakob disease patients
Dr. Wenguan Zou1, Dr. Christina Orru2, Jue Yuan1, Brian Appleby1, Baiya Li1, Dane Winner1, Yian Zhan1,3, Mark Rodgers1, Jason Rarick1, Robert Wyza1, Tripti Joshi1, Gongxian Wang3, Mark Cohen1, Shulin Zhang1, Bradley Groveman2, Robert Petersen1, James Ironside4, Miguel Quinones-Mateu1, Jiri Safar1, Qingzhong Kong1, Byron Caughey2
1Case Western Reserve University, Cleveland, United States, 2Rocky Mountain Laboratories, National Institutes of Health, Hamilton, United States, 3Nanchang University, Nanchang, China, 4Universitv of Edinburgh, Edinburgh, United Kingdom
Aims: Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is transmissible by neuroinvasive iatrogenic routes due to abundant prion infectivity in the central nervous system (CNS). The disease-associated prion protein (PrPSc) and its infectivity have never been detected in skin from sCJD patients; however, some epidemiological studies have associated sCJD risk with skin-involved non-CNS surgeries. The aims of our study were to explore potential prion seeding activity and infectivity of skin and the feasibility of skin-based CJD diagnosis.
Methods: Skin samples were collected at autopsy or biopsy from twenty-one sCJD, two variant CJD, and fifteen non-CJD patients and analysed by Western blotting and real-time quaking-induced conversion (RT- QulC) for PrPSc. Infectivity of skin from two sCJD patients was determined by bioassay using two lines of humanized transgenic (Tg) mice.
Results: Western blotting demonstrated PrPSc in the skin of one of five deceased sCJD patients examined. However, the more sensitive RT-QuIC assay detected prion-seeding activity in skin from all 23 CJD decedents but not in non-CJD controls, indicating preliminary ClD diagnostic sensitivities and specificities of 100% (95% confidence intervals of 85-100%, and 78-100%, respectively). Although sCJD skins contained ~102-105-fold lower RT-QuIC seeding activity than sCJD brains, ten out of twelve mice from two Tg mouse lines inoculated with skin homogenates of two patients with two different subtypes of sCJD succumbed to prion disease within 450 days after inoculation.
Conclusions: O sCJD patients' skin may contain both detectable prion seeding activity and transmissible prions. Our findings not only suggest a new basis for diagnostic sCJD testing, but also raise concerns about the potential for iatrogenic sCJD transmission via skin. (Funded by the CJD Foundation, the National Institute of Neurological Disorders and Stroke, the Centers for Disease Control and Prevention, as well as others)
DISORDERS PRION 2017 DECIPHERING NEURODEGENERATIVE
*sCJD patients' skin may contain both detectable prion seeding activity and transmissible prions.
*Our findings not only suggest a new basis for diagnostic sCJD testing, but also raise concerns about the potential for iatrogenic sCJD transmission via skin.
Oral Session14：45～15：00O-12 Wenquan Zou
*** PrPSc in the skin of CJD patients
Unexpectedly, our latest preliminary study identified two types of PK-resistant PrP molecules [with gel mobility similar to the PrPSc types 1 and 2 from the brain of sporadic CJD (sCJD)] in the fibroblast cells extracted from the skin of clinical sCJD patients and asymptomatic subjects carrying PrP mutations linked to familial CJD (fCJD). We also detected PrPSc in the skin of humanized transgenic (Tg) mice inoculated intracerebrally with a human prion. Moreover, prion infectivity has been observed in the skin of infected greater kudu (Cunningham et al., 2004) and a murine prion inoculated to mice via skin scarification can not only propagate in the skin, but also spread to the brain to cause prion disease (Wathne et al., 2012). We hypothesize that the skin of patients with prion disease harbors prion infectivity and the presence of PK-resistant PrP in the skin is a novel diagnostic marker for preclinical CJD patients.
A Kiss of a Prion: New Implications for Oral Transmissibility
The transmissibility of scrapie among sheep (intraspecies) is well recognized. It must be emphasized that horizontal transfer (from one individual to another) of scrapie is the main route of infection, because vertical transmission of disease from mother to offspring via milk or placental tissue occurs infrequently. Thus, in view of the report by Maddison et al, the oral transmissibility of prions among sheep may serve as a major route for horizontal scrapie transfer. This occurrence is plausible because sheep often lick each other. Maddison et al [10] indicate that, because of the similarities in prion tissue distribution, their implications for the oral transmission of ovine scrapie might be true for other prion diseases, such as cervid chronic wasting disease and human vCJD. If this is true for humans, a kiss of a prion may sometimes have lethal consequences.
PERSON TO PERSON TRANSMISSION OF THE TSE PRION DISEASE, never say never. as the disease mutates, it becomes more virulent in some cases, and cwd is efficiently transmitted from cervid to cervid. there are now multiple strains of CWD in cervids, as with the TSE prion disease in bovine, sheep and goats, and we now have the atypical TSE in these species, that have mutated, and some strains _have_ become more virulent. we now have younger humans dying from the TSE prion disease, with shorter incubation period, and that are much younger. human to human casual transmission of the TSE prion disease...again, never say never. ...TSS
see more here;
The occurrence of the disease in a patient who had contact with cases of familial C.J.D., but was not genetically related, has been described in Chile (Galvez et al., 1980) and in France (Brown et al., 1979b). In Chile the patient was related by marriage, but with no consanguinity, and had social contact with subsequently affected family members for 13 years before developing the disease. The contact case in France also married into a family in which C.J.D. was prevalent and had close contact with an affected member. In neither instance did the spouse of the non-familial case have the disease. The case described in this report was similarly related to affected family members and social contact had occurred for 20 years prior to developing C.J.D. If contact transmission had occurred, the minimum transmission period would be 11 years. Contact between sporadic cases has not been described and it is remarkable that possible contact transmissions have all been with familial cases. No method of transmission by casual social contact has been suggested.
***The occurrence of contact cases raises the possibility that transmission in families may be effected by an unusually virulent strain of the agent.
snip...see full text here;
-----Original Message-----
From: Terry Singeltary
To: Sent: Thu, Nov 23, 2017 10:22 am
Subject: re-NIH scientists and collaborators find infectious prion protein in skin of CJD patients
>>>Although sCJD patient skin contained ~103- to 105-fold lower prion seeding activity than did sCJD patient brain tissue, all 12 mice from two transgenic mouse lines inoculated with sCJD skin homogenates from two sCJD patients succumbed to prion disease within 564 days after inoculation<<<
for something to be 103 to 105 fold lower prion seeding, yet still be 100% fatal in all test subjects, very disturbing...terry
WEDNESDAY, NOVEMBER 22, 2017
NIH scientists and collaborators find infectious prion protein in skin of CJD patients
WEDNESDAY, NOVEMBER 22, 2017
Prion seeding activity and infectivity in skin samples from patients with sporadic Creutzfeldt-Jakob disease
PRION 2018
17:00 Wen-Quan Zou (Case Western Reserve University): Preclinical detection of prions in skin samples of scrapie-infected animals by serial PMCA and RT-QuIC assays.
THURSDAY, MAY 24, 2018
Prion 2018 May, 22-25 2018 Santiago de Compostela
Skin as a Potential Source of Prion Infectivity Mammalian skin is composed of different strata and cell types, which are both innervated and carry blood vessels. There is therefore the potential for skin to harbor prions and facilitate its excretion into the environment. Cunningham and coworkers demonstrated the presence of prion infectivity in the skin of BSE-affected kudu.87 Subsequently, Thomzig et al. used a rodent model to demonstrate that skin-associated prions could be identified from late preclinical stages of disease for both scrapie and BSE,88 estimating that there is likely to be 5,000–10,000 times less prion in the skin of hamsters challenged with scrapie than in the brains of those same animals. This study also demonstrated the presence of prions in the skin of sheep during the late stages of naturally acquired scrapie where PrPSc was generally associated with small nerve fibers within the dermis. More recently, PrPSc was found within the skin of a vCJD patient.89 In addition, cervine CWD prions have been found within antler velvet,90 a vascularized skin layer covering the developing antler of male deer, which is shed after the ossification of antlers.
Skin may therefore represent another route by which prions contaminate the environment. Mechanisms of prion shedding from this organ could include natural sloughing of skin, abrasions of the skin and, in the case of sheep, skin cuts and nicks that are introduced during shearing.
UCSF
Office of Environment, Health and Safety (EH&S)
Prion Exposure Protocol
Organism or Agent: Prions Exposure Risk: Human Prion Disease (Creutzfeldt-Jakob Disease/New variant CDJ, BSE, etc.)
UCSF Occupation Health: 415-885-7580 (work hours, 8am to 5pm) Exposure Hotline Pager: 415-353-7842 (24 hours) Environment, Health & Safety: 415-476-1300 (work hours) UCSF Police Department; 415-476-1414 or 9-911 (In case of emergency, 24 hours) EH&S Public Health Officer: 415-514-3531 (work hours) Campus Bio-Safety Officer 415-514-2824 California Poison Control: 800-222-1222 SFDPH Emergency Number 415-554-2830 CDC Emergency Operation 770-488-7100 Occ Hlth Proto Button
*****************************************************************************************
In the event of an accidental exposure or injury, the protocol is as follows:
1. Modes of Transmission: Skin puncture or injection Ingestion Contact with mucous membranes (eyes, nose, mouth) Contact with non-intact skin Exposure to aerosols
2. First Aid: There is no evidence of occupational transmission of prion disease to healthcare workers.
Perform first aid as self-care according to the type of exposure/ injury.
a. First Aid for an unbroken Skin Exposure: Wash with soap and abundant quantities of warm water (avoid scrubbing), rinse, and dry. Apply for 1 minute, 0.1N Sodium Hydroxide (NaOH) or a 1:10 dilution of bleach (sodiumhypochlorite).
When decontaminating with 0.1N NaOH or sodium hypochlorite, a face shield and eye goggles or eye goggles with mask should be worn for protection.
It is important to decontaminate the wound with the appropriate agent for the appropriate length of time in order to denature the protein as soon as possible.
See the special precautions for NaOH below. After decontamination, rinse well with soap and water to neutralize the base. Bring the 0.1N sodium hydroxide SDS to the ED
b. First Aid for lacerations or needlestick injuries:
Gently encourage bleeding; wash (avoid scrubbing) with warm soapy water, rinse, dry and cover with a waterproof dressing.
Further treatment (e.g. sutures) should be appropriate to the type of injury.
c. First Aid for splashes to the Eye, Nose or Mouth: Immediately flush the area with running water or normal saline. Continue washing for 15 minutes. Do not use sodium hydroxide or sodium hypochlorite in or around your eyes. Do not rub or keep eyes closed.
d. Following the administration of first aid, the employee will:
Inform your supervisor of the exposure.
Remove any garments that may have become soiled/contaminated with prions or NaOH, and place them in a double plastic bag.
Close the bag securely, label it as contaminated, and wash your hands thoroughly.
Identify any equipment involved in the exposure and the mechanism of exposure.
Make sure that the area has been secured and that notification of contamination has been posted to prevent other individuals from entering the area.
If you need immediate care for your injury, proceed to the Emergency Department(ED).
When you injury is stable, Contact the Needlestick Exposure Hotline (415-353-7842) to report the exposure.
The injured employee will need to follow up in the UCSF Occupational Health Clinic.
Be sure to go to the clinic for medical evaluation and complete all necessary workers’ compensation paperwork.
e. Splash Affecting Garments, remove garments that may have become soiled or contaminated and place them in a double biohazard red plastic bag.
Disposable gloves and gowns should dispose of by incineration, according to World Health Organization guidelines.
3. Treatment
snip...end
how many of you have donated your loved ones brains for research of the tse prion disease?
do you think you should be able to have access to any of the research?
apparently, these folks don't...
-----Original Message-----
From: Terry Singeltary <flounder9@verizon.net>
To: xestioneventos <xestioneventos@usc.es>
Sent: Fri, Jun 22, 2018 9:14 am
To: xestioneventos <xestioneventos@usc.es>
Sent: Fri, Jun 22, 2018 9:14 am
Subject: Re: PRION 2018 CONGRESSIONAL ABSTRACTS AND POSTERS
very sad for those that donated their loved ones brains for this research, and very disturbing that you will not share this information with them. this is the first year of ALL PRION CONFERENCE that this information was/is not shared...very sad...thank you, kind regards, terry
-----Original Message-----
From: Oficina de Congresos USC
To: 'Terry Singeltary' <flounder9@verizon.net>
Sent: Fri, Jun 22, 2018 2:20 am
Subject: RE: PRION 2018 CONGRESSIONAL ABSTRACTS AND POSTERS
From: Oficina de Congresos USC
To: 'Terry Singeltary' <flounder9@verizon.net>
Sent: Fri, Jun 22, 2018 2:20 am
Subject: RE: PRION 2018 CONGRESSIONAL ABSTRACTS AND POSTERS
Dear friend,
we are not allowed to share this information. As long as I know, this information is just available for the conference attendants.
best regards,
xxxxxxxxx
Oficina de Congresos da USC
Complexo CEA-CE
Parque Vista Alegre - Rua Salvadas s/n
15705 Santiago de Compostela
tel 881816329 ext 16329
E-mail:@usc.es
De: Terry Singeltary [mailto:flounder9@verizon.net]
Enviado el: jueves, 21 de junio de 2018 18:19
Para: @usc.es
Asunto: PRION 2018 CONGRESSIONAL ABSTRACTS AND POSTERS
Enviado el: jueves, 21 de junio de 2018 18:19
Para: @usc.es
Asunto: PRION 2018 CONGRESSIONAL ABSTRACTS AND POSTERS
Hello Again,
a kind greetings from Bacliff, Texas.
is there any way now that the conference is over, that i can get a copy of the PRION 2018 CONGRESSIONAL ABSTRACTS AND POSTERS. i have followed the tse prion science with great interest following the demise of my mother to the heidenhain variant of creutzfeldt jakob disease hvCJD. i have no access to the full conference pdf files, but it would be most appreciative i you might send them to me...
with kindest regards, terry
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
Singeltary, Sr et al. JAMA.2001; 285: 733-734. Vol. 285 No. 6, February 14, 2001 JAMA Diagnosis and Reporting of Creutzfeldt-Jakob Disease
To the Editor:
In their Research Letter, Dr Gibbons and colleagues1 reported that the annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable since 1985. These estimates, however, are based only on reported cases, and do not include misdiagnosed or preclinical cases. It seems to me that misdiagnosis alone would drastically change these figures. An unknown number of persons with a diagnosis of Alzheimer disease in fact may have CJD, although only a small number of these patients receive the postmortem examination necessary to make this diagnosis. Furthermore, only a few states have made CJD reportable. Human and animal transmissible spongiform encephalopathies should be reportable nationwide and internationally.
Terry S. Singeltary, Sr Bacliff, Tex
1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323.
THURSDAY, MAY 24, 2018
Prion 2018 May, 22-25 2018 Santiago de Compostela
http://transmissiblespongiformencephalopathy.blogspot.com/2018/05/prion-2018-may-22-25-2018-santiago-de.html
Prion 2018 May, 22-25 2018 Santiago de Compostela
http://transmissiblespongiformencephalopathy.blogspot.com/2018/05/prion-2018-may-22-25-2018-santiago-de.html
Terry S. Singeltary Sr.