Variant Creutzfeldt–Jakob Disease Diagnosed 7.5 Years after Occupational Exposure
Variant Creutzfeldt–Jakob Disease Diagnosed 7.5 Years after Occupational Exposure
Variant Creutzfeldt–Jakob disease was identified in a technician who had cut her thumb while handling brain sections of mice infected with adapted BSE 7.5 years earlier. The long incubation period was similar to that of the transfusion-transmitted form of the disease.
TO THE EDITOR:
We report a case of variant Creutzfeldt–Jakob disease (CJD) that was plausibly related to accidental occupational exposure in a technician who had handled murine samples contaminated with the agent that causes bovine spongiform encephalopathy (BSE) 7.5 years earlier.
In May 2010, when the patient was 24 years of age, she worked in a prion research laboratory, where she handled frozen sections of brain of transgenic mice that overexpressed the human prion protein with methionine at codon 129. The mice had been infected with a sheep-adapted form of BSE. During this process, she stabbed her thumb through a double pair of latex gloves with the sharp ends of a curved forceps used to handle the samples. Bleeding was noted at the puncture site.
In November 2017, she began having burning pain in the right shoulder and neck. The pain worsened and spread to the right half of her body during the following 6 months. In November 2018, an examination of a sample of cerebrospinal fluid (CSF) obtained from the patient was normal. Magnetic resonance imaging (MRI) of the brain showed a slight increase in the fluid-attenuated inversion recovery (FLAIR) signal in the caudates and thalami (Fig. S1A and S1B in the Supplementary Appendix, available with the full text of this letter at NEJM.org). In January 2019, she became depressed and anxious and had memory impairment and visual hallucinations. There was hypertonia on the right side of her body. At that time, an analysis of CSF for 14-3-3 protein was negative. In March 2019, MRI showed an increased FLAIR signal in pulvinar and dorsomedial nuclei of thalami (Fig. S1C through S1E).
The patient was found to be homozygous for methionine at codon 129 of the prion protein gene without mutation. An analysis of a sample of CSF on real-time quaking-induced conversion analysis was negative for a diagnosis of sporadic CJD. However, an analysis of plasma and CSF by means of protein misfolding cyclic amplification was positive for the diagnosis of variant CJD (Figure 1A and 1B). The patient died 19 months after the onset of symptoms. Neuropathological examination confirmed the diagnosis of variant CJD (Figure 1C and 1D). Western blot analysis showed the presence of type 2B protease-resistant prion protein in all sampled brain areas. The clinical characteristics of the patient and the postmortem neuropathological features were similar to those observed in 27 patients with variant CJD who had previously been reported in France.1 (Additional details are provided in the Supplementary Appendix.)
There are two potential explanations for this patient’s condition. Oral transmission from contaminated cattle products cannot be ruled out because the patient was born at the beginning of the French BSE outbreak in cattle. However, the last two patients who had confirmed variant CJD with methionine homozygosity at codon 129 in France and the United Kingdom died in 2014 and 2013, respectively, which makes oral transmission unlikely. In France, the risk of variant CJD in 2019 was negligible or nonexistent in the post-1969 birth cohort.2
Percutaneous exposure to prion-contaminated material is plausible in this patient, since the prion strain that she had handled was consistent with the development of variant CJD.3 The 7.5-year delay between the laboratory accident and her clinical symptoms is congruent with the incubation period in the transfusion-transmitted form of the disease. The ability of this strain to propagate through the peripheral route has been documented, and experimental studies with scrapie strains have shown that scarification and subcutaneous inoculation are effective routes.4,5 The last known Italian patient with variant CJD, who died in 2016, had had occupational contact with BSE-infected brain tissues, although subsequent investigation did not disclose a laboratory accident (Pocchiari M, Italian Registry of CJD: personal communication). Thus, the last two cases of variant CJD outside the United Kingdom have been associated with potential occupational exposure. Such cases highlight the need for improvements in the prevention of transmission of variant CJD and other prions that can affect humans in the laboratory and neurosurgery settings, as outlined in the Supplementary Appendix.
Jean-Philippe Brandel, M.D. Assistance Publique–Hôpitaux de Paris, Paris, France
M. Bustuchina Vlaicu, M.D. Groupe Hospitalier Nord-Essonne, Orsay, France
Audrey Culeux, B.Sc. INSERM Unité 1127, Paris, France
Maxime Belondrade, M.Sc. Daisy Bougard, Ph.D. Etablissement Français du Sang, Montpellier, France
Katarina Grznarova, Ph.D. Angeline Denouel, M.Sc. INSERM Unité 1127, Paris, France
Isabelle Plu, M.D. Elodie Bouaziz-Amar, Pharm.D., Ph.D. Danielle Seilhean, M.D., Ph.D. Assistance Publique–Hôpitaux de Paris, Paris, France
Michèle Levasseur, M.D. Groupe Hospitalier Nord-Essonne, Orsay, France
Stéphane Haïk, M.D., Ph.D. INSERM Unité 1127, Paris, France stephane.haik@upmc.fr
Supported by a grant (ANR-10-IAIHU-06) from Programme d’Investissements d’Avenir and Santé Publique France.
Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.
July 2, 2020 N Engl J Med 2020; 383:83-85 DOI: 10.1056/NEJMc2000687
Supplementary Appendix
This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Brandel J-P, Vlaicu MB, Culeux A, et al. Variant Creutzfeldt–Jakob disease diagnosed 7.5 years after occupational exposure. N Engl J Med 2020;383:83-5. DOI: 10.1056/NEJMc2000687
Full case report
A woman, born in 1986, with only a medical history of dental avulsion and the removal of a nevus started to complain, in November 2017, of burning pain in the right shoulder and the right side of the neck. Over the next 6 months, the pain worsened and spread to the right half-body including the buttocks, the back of the thigh and the foot sole, and the face with ear pain. After several consultations, a first hospital assessment was carried out in November 2018. CSF examination was normal and brain MRI interpreted as normal despite slight high signals in the caudate nucleus and thalami (Supplementary figure 1). The diagnosis of Lyme disease was suspected and treatment with ceftriaxone was initiated. Pain persisted and the patient who was showing signs of depression was referred to a psychiatrist for antidepressant treatment. Memory impairment was noted by relatives in January 2019 and the patient was admitted to a neurology department in February 2019. Right extrapyramidal hypertonia, visual hallucinations and memory problems of recent events were observed. Neurological alterations were associated with severe anxiety. Inflammatory markers, biological and immunological assessments were normal. Serology for conventional agents was negative. Detection of anti-neuronal, anti-thyroid peroxidase, anti-thyroglobulin and anti-thyroidstimulating hormone receptor antibodies yielded negative results. Vitamin B1 and B6 levels were within normal limits. Standard CSF analysis was normal and 14-3-3 protein detection was negative. MRI from mid-March 2019 showed a high signal on the FLAIR sequences in the pulvinar and dorsomedian nuclei of the thalamus, bilaterally, more intense than those observed in the striatum (Supplementary figure 1). A generally slow activity was observed on EEGs. PRNP analysis revealed a homozygous methionine-methionine (MM) genotype at codon 129 without mutation. At this time, the patient fulfilled criteria of probable vCJD. Two different protein misfolding amplification methods were performed. As predicted in a suspected case of vCJD, RT-QuIC detection in the CSF gave a negative result.1 A PMCA test, recently validated for the diagnosis of vCJD in plasma and CSF was performed.2,3 PMCA detection was positive in plasma and CSF. Evolution was marked by the
3
worsening of cognitive impairment, a small step with balance disorders and an extrapyramidal syndrome.
The patient died 19 months after disease onset.
Neuropathological examination confirmed the diagnosis of vCJD by showing typical florid plaques in the cerebral cortex and cerebellum. Spongiform changes, gliosis and neuronal loss were predominantly observed in the subcortical gray matter. In addition, PrP immunohistochemistry showed multicentric plaques, clumpses, peri-cellular and peri-vascular PrP deposition (Supplementary figure 2). Western blot detection of PrPres was positive and type 2B PrPres was consistently detected in all studied brain areas.
The epidemiological survey revealed that the patient had been employed from 2009 to 2012 in a laboratory involved in prion research. In particular, she has worked on transgenic animal models expressing human and bovine PrP and infected with strains of human or bovine prions. The patient had two work accidents. In May 2010, she stabbed her thumb with sharp ends curved forceps used to handle brain frozen sections of humanized transgenic mice infected with a sheep-adapted BSE agent. The mouse brain handled at the time of the accident was from a secondary intra-cerebral subpassage of sheep BSE in transgenic mice overexpressing a methionine 129-human PrP. To note transmission studies indicate a low or absent transmission barrier to sheep BSE in human M129-PrP mice. The neuropathological phenotype is similar to that observed in mice infected with cattle BSE or vCJD suggesting that sheep-BSE could act as a causal vCJD agent especially in codon 129-methionine homozygotes.
4,5 The patient immediately noticed a bleeding wound. After leaving the level 3 biosafety laboratory, the wounded finger was cleaned with water and immersed for more than ten minutes in a freshly diluted 2% sodium hypochlorite solution. The second accident occurred in September 2011 in a conventional laboratory with no contact with infectious prion material. No other risk factors were identified with the exception, as most French people in her age cohort, a dietary exposure from 1986 to 1996 to bovine products with a BSE risk.
4
Methods
Clinical and epidemiological data As with all other cases of French vCJD, a direct interview with the patient’s family was conducted. Clinical data were extracted from the medical records and further information was collected using the European network (EuroCJD) questionnaire. The data collected were gender, age at onset and death, clinical features, results of investigations, and specific medical risk factors. These included history of growth hormone therapy, transplantation, surgery, blood transfusion, blood products therapy (albumin, immunoglobulin, clotting factors), vaccinations, professional activity, and stays in UK. The reports of the two accidents at work were collected. Additional data were obtained from the authorities of the research institute. They explained precisely how the patient had been injured, the biological materials handled and how the wounds had been disinfected and treated. Genetic analysis The prion protein gene (PRNP) was analyzed as described previously to obtain the genotype at codon 129 and to exclude a pathogenic mutation.6 An informed consent for genetic analysis was obtained from the patient's husband.
Neuropathological analysis
Samples were taken from 1cm-thick coronal sections after two months of fixation in 10% formalin as described previously.7 After formic acid treatment, specimens were embedded in paraffin. Threemicrometer-thick sections were stained with hematoxylin and eosin and Periodic Acid–Schiff (PAS) methods. PrP immunohistochemistry was performed using the 12F10 mouse monoclonal antibody.8,9 Biochemical analysis PrPres analysis by Western blot was performed from frozen samples of the brain. Tissue homogenization, digestion with proteinase K, purification, electrophoresis and immunoblotting were
5
done as described previously.10 The biochemical classification according to Parchi and colleagues was used.11
Amplification methods
RT-QuIC analysis in the CSF was performed using hamster full-length (23–231) recombinant PrP as previously described.12 Thirty µl of CSF per well were added and analysis was performed in quadruplicate using a BMG-LABTECH Omega. PMCA amplification in plasma and CSF was performed as described by using brains from transgenic mice overexpressing human M129-PrP as substrate.2,3 For plasma samples, a capture of abnormal PrP using plasminogen-coated magnetic nanobeads was performed before serial amplification. Each round of PMCA comprised 80 cycles of 30 min incubation/20 s sonication. Implications If one considers our patient as a case of a documented accidental transmission of CJD in a research laboratory, several important points should be stressed:
- A single puncture without hollow needle containing infectious material is sufficient to transmit prions in human even with a short contact.
- The incubation period is similar to that seen in MM patients with transfusion-transmitted vCJD, suggesting that the level of accidentally delivered infectious dose is in the same range as that contained in a unit of non-leukodepleted red blood cells.
- Immersing this type of lesion in a freshly diluted 2% sodium hypochlorite solution was not sufficient to prevent contamination. Important consequences in terms of prevention of occupational risks and public health issue associated with prions should be underlined:
6
- Individual protection against accidental wounds should be reinforced in research laboratories, neuropathology department and autopsy rooms. Neurosurgery teams should take the risk into account, especially when a cortical biopsy is performed to explore patients with unexplained encephalopathy. This implies accurate information and training of exposed professionals.
- The efficacy of decontamination procedures to be applied in case of accidental exposure has not been demonstrated using adequate in vivo models of transmission. A more aggressive postexposure management is to be defined and validated experimentally.
- The mechanisms of prion neuro-invasion in this specific scenario are unknown and may involve prion propagation through (1) the peripheral innervation of digital pulp, (2) an up-take by phagocytes driving prion replication in the lymphoid system followed by propagation via the autonomous nervous system or (3) blood transport.
- No preventive treatment is available to date. While a few approaches that may limit peripheral prion propagation and neuro-invasion have been proposed (such as corticoids and pentosan polysulfate), their efficiency in such a transmission pattern and in the use of relevant prion strains has to be confirmed.
7
References
1. Zanusso G, Monaco S, Pocchiari M, Caughey B. Advanced tests for early and accurate diagnosis of Creutzfeldt-Jakob disease. Nat Rev Neurol 2016;12:325-33.
2. Bougard D, Brandel JP, Belondrade M, et al. Detection of prions in the plasma of presymptomatic and symptomatic patients with variant Creutzfeldt-Jakob disease. Science translational medicine 2016;8:370ra182.
3. Bougard D, Belondrade M, Mayran C, et al. Diagnosis of Methionine/Valine Variant Creutzfeldt-Jakob Disease by Protein Misfolding Cyclic Amplification. Emerging infectious diseases 2018;24:1364-6.
4. Plinston C, Hart P, Chong A, et al. Increased susceptibility of human-PrP transgenic mice to bovine spongiform encephalopathy infection following passage in sheep. Journal of virology 2011;85:1174-81.
5. Joiner S, Asante EA, Linehan JM, et al. Experimental sheep BSE prions generate the vCJD phenotype when serially passaged in transgenic mice expressing human prion protein. J Neurol Sci 2018;386:4-11.
6. Laplanche JL, Delasnerie-Lauprêtre N, Brandel JP, et al. Molecular genetics of prion diseases in France. Neurology 1994;44:2347-51.
7. Hauw JJ, Sazdovitch V, Laplanche JL, et al. Neuropathologic variants of sporadic CreutzfeldtJakob disease and codon 129 of PrP gene. Neurology 2000;54:1641-6.
8. Haik S, Faucheux BA, Sazdovitch V, et al. The sympathetic nervous system is involved in variant Creutzfeldt-Jakob disease. Nature medicine 2003;9:1121-3.
9. Privat N, Laffont-Proust I, Faucheux BA, et al. Human prion diseases: from antibody screening to a standardized fast immunodiagnosis using automation. Mod Pathol 2008;21:140-9.
8
10. Levavasseur E, Laffont-Proust I, Morain E, et al. Regulating factors of PrP glycosylation in Creutzfeldt-Jakob disease--implications for the dissemination and the diagnosis of human prion strains. PloS one 2008;3:e2786.
11. Parchi P, Notari S, Weber P, et al. Inter-laboratory assessment of PrPSc typing in creutzfeldtjakob disease: a Western blot study within the NeuroPrion Consortium. Brain pathology 2009;19:384- 91.
12. McGuire LI, Poleggi A, Poggiolini I, et al. Cerebrospinal fluid real-time quaking-induced conversion is a robust and reliable test for sporadic creutzfeldt-jakob disease: An international study. Annals of neurology 2016;80:160-5.
snip...
Variant Creutzfeldt–Jakob Disease Diagnosed 7.5 Years after Occupational Exposure
Variant Creutzfeldt–Jakob disease was identified in a technician who had cut her thumb while handling brain sections of mice infected with adapted BSE 7.5 years earlier. The long incubation period was similar to that of the transfusion-transmitted form of the disease.
TUESDAY, AUGUST 12, 2008
Biosafety in Microbiological and Biomedical Laboratories Fifth Edition 2007 (occupational exposure to prion diseases)
re-Human Prion Diseases in the United States Posted by flounder on 01 Jan 2010 at 18:11 GMT
Research articles Health professions and risk of sporadic Creutzfeldt– Jakob disease, 1965 to 2010
15. Terry S. Singeltary Sr. Doctor Antonio Ruiz Villaespesa, pathologist and CJD researcher deceased because of Creutzfeldt-Jakob Disease SPAIN. 21 Apr 2009. [Accessed 11 Apr 2012]. In: Monitoring the occurrence of emerging forms of CJD [blog]. Available from:
MONDAY, JANUARY 14, 2019
Evaluation of iatrogenic risk of CJD transmission associated with Chronic Wasting Disease TSE Prion in Texas TAHC TPWD
SUNDAY, OCTOBER 27, 2013
A Kiss of a Prion: New Implications for Oral Transmissibility
THURSDAY, MAY 17, 2012
Iatrogenic Creutzfeldt-Jakob Disease, Final Assessment Volume 18, Number 6—June 2012
Thursday, April 12, 2012
Health professions and risk of sporadic Creutzfeldt–Jakob disease, 1965 to 2010
Eurosurveillance, Volume 17, Issue 15, 12 April 2012
Research articles
Saturday, January 16, 2010
*** Evidence For CJD TSE Transmission Via Endoscopes 1-24-3 re-Singeltary to Bramble et al
Evidence For CJD/TSE Transmission Via Endoscopes
From Terry S. Singletary, Sr flounder@wt.net 1-24-3
Terry S. Singeltary Sr., P.O. , Bacliff, Texas 77518 USA
Professor Michael Farthing wrote:
*** Louise Send this to Bramble (author) for a comment before we post. Michael
Wednesday, August 20, 2008
Tonometer disinfection practice in the United Kingdom: A national survey
Tuesday, August 12, 2008
Biosafety in Microbiological and Biomedical Laboratories Fifth Edition 2007 (occupational exposure to prion diseases)
Monday, December 31, 2007
Risk Assessment of Transmission of Sporadic Creutzfeldt-Jakob Disease in Endodontic Practice in Absence of Adequate Prion Inactivation
Subject: CJD: update for dental staff
Date: November 12, 2006 at 3:25 pm PST
1: Dent Update. 2006 Oct;33(8):454-6, 458-60.
CJD: update for dental staff.
FRIDAY, JANUARY 31, 2020
CJD TSE Prion Blood Products, iatrogenic transmission, Confucius is confused again, WHAT IF? Docket Number: FDA-2012-D-0307
Sent: Sun, May 26, 2019 10:21 am Subject: Arguments for Alzheimer’s and Parkinson’s diseases caused by prions Stanley B. Prusiner
''From a large array of bioassays, we conclude that AD, PD, MSA, and the frontotemporal dementias, including PSP and CBD, are all prion diseases'' 11.
Arguments for Alzheimer’s and Parkinson’s diseases caused by prions Stanley B. Prusiner Institute of Neurodegenerative Diseases, and Professor of Neurology and Biochemistry, University of California San Francisco ABSTRACT Arguments for Alzheimer’s (AD) and Parkinson’s diseases (PD) being caused by prions continue to advance with new evidence. Findings in the brains of deceased AD patients argue that both Aβ and tau prions can be demonstrated by bioassays in cultured cells as well as in transgenic (Tg) mice. Likewise, studies of the brains of deceased MSA patients have been found to contain α-synuclein prions by bioassays in cultured cells and Tg mice. Conversely, the brains of AD patients do not contain α-synuclein prions, and the brains of MSA patients do not contain Aβ or tau prions. Additionally, while the brains of patients who died of either progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD) contained tau prions, neither Aβ nor α-synuclein prions were detectable. Merely measuring the levels of Aβ, tau, and α-synuclein appears to give misleading information about the etiology and pathogenesis of neurodegenerative diseases (NDs). From a large array of bioassays, we conclude that AD, PD, MSA, and the frontotemporal dementias, including PSP and CBD, are all prion diseases. Our findings argue that changes in the conformations of Aβ, tau, and α-synuclein underlie the acquisition of prion infectivity in all of these NDs.
''From a large array of bioassays, we conclude that AD, PD, MSA, and the frontotemporal dementias, including PSP and CBD, are all prion diseases''
Published: 09 September 2015
Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
Zane Jaunmuktane, Simon Mead, Matthew Ellis, Jonathan D. F. Wadsworth, Andrew J. Nicoll, Joanna Kenny, Francesca Launchbury, Jacqueline Linehan, Angela Richard-Loendt, A. Sarah Walker, Peter Rudge, John Collinge & Sebastian Brandner
>>> The only tenable public line will be that "more research is required’’ <<<
>>> possibility on a transmissible prion remains open<<<
O.K., so it’s about 23 years later, so somebody please tell me, when is "more research is required’’ enough time for evaluation ?
Re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
Nature 525, 247?250 (10 September 2015) doi:10.1038/nature15369 Received 26 April 2015 Accepted 14 August 2015 Published online 09 September 2015 Updated online 11 September 2015 Erratum (October, 2015)
snip...see full Singeltary Nature comment here;
Alzheimer's disease
let's not forget the elephant in the room. curing Alzheimer's would be a great and wonderful thing, but for starters, why not start with the obvious, lets prove the cause or causes, and then start to stop that. think iatrogenic, friendly fire, or the pass it forward mode of transmission. think medical, surgical, dental, tissue, blood, related transmission. think transmissible spongiform encephalopathy aka tse prion disease aka mad cow type disease...
Commentary: Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
Self-Propagative Replication of Ab Oligomers Suggests Potential Transmissibility in Alzheimer Disease
*** Singeltary comment PLoS ***
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?
Posted by flounder on 05 Nov 2014 at 21:27 GMT
IN CONFIDENCE
5 NOVEMBER 1992
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES
[9. Whilst this matter is not at the moment directly concerned with the iatrogenic CJD cases from hgH, there remains a possibility of litigation here, and this presents an added complication.
There are also results to be made available shortly
(1) concerning a farmer with CJD who had BSE animals,
(2) on the possible transmissibility of Alzheimer’s and
(3) a CMO letter on prevention of iatrogenic CJD transmission in neurosurgery, all of which will serve to increase media interest.]
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.
doi:10.1016/S1473-3099(03)00715-1 Copyright © 2003 Published by Elsevier Ltd. Newsdesk
Tracking spongiform encephalopathies in North America
Xavier Bosch
Available online 29 July 2003.
Volume 3, Issue 8, August 2003, Page 463
“My name is Terry S Singeltary Sr, and I live in Bacliff, Texas. I lost my mom to hvCJD (Heidenhain variant CJD) and have been searching for answers ever since. What I have found is that we have not been told the truth. CWD in deer and elk is a small portion of a much bigger problem..” ............................
January 28, 2003; 60 (2) VIEWS & REVIEWS
Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States
Ermias D. Belay, Ryan A. Maddox, Pierluigi Gambetti, Lawrence B. Schonberger
First published January 28, 2003, DOI: https://doi.org/10.1212/01.WNL.0000036913.87823.D6
Abstract
Transmissible spongiform encephalopathies (TSEs) attracted increased attention in the mid-1980s because of the emergence among UK cattle of bovine spongiform encephalopathy (BSE), which has been shown to be transmitted to humans, causing a variant form of Creutzfeldt-Jakob disease (vCJD). The BSE outbreak has been reported in 19 European countries, Israel, and Japan, and human cases have so far been identified in four European countries, and more recently in a Canadian resident and a US resident who each lived in Britain during the BSE outbreak. To monitor the occurrence of emerging forms of CJD, such as vCJD, in the United States, the Centers for Disease Control and Prevention has been conducting surveillance for human TSEs through several mechanisms, including the establishment of the National Prion Disease Pathology Surveillance Center. Physicians are encouraged to maintain a high index of suspicion for vCJD and use the free services of the pathology center to assess the neuropathology of clinically diagnosed and suspected cases of CJD or other TSEs.
Received May 7, 2002. Accepted August 28, 2002.
RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States
Terry S. Singeltary, retired (medically)
Published March 26, 2003
26 March 2003
Terry S. Singeltary, retired (medically) CJD WATCH
I lost my mother to hvCJD (Heidenhain Variant CJD). I would like to comment on the CDC's attempts to monitor the occurrence of emerging forms of CJD. Asante, Collinge et al [1] have reported that BSE transmission to the 129-methionine genotype can lead to an alternate phenotype that is indistinguishable from type 2 PrPSc, the commonest sporadic CJD. However, CJD and all human TSEs are not reportable nationally. CJD and all human TSEs must be made reportable in every state and internationally. I hope that the CDC does not continue to expect us to still believe that the 85%+ of all CJD cases which are sporadic are all spontaneous, without route/source. We have many TSEs in the USA in both animal and man. CWD in deer/elk is spreading rapidly and CWD does transmit to mink, ferret, cattle, and squirrel monkey by intracerebral inoculation. With the known incubation periods in other TSEs, oral transmission studies of CWD may take much longer. Every victim/family of CJD/TSEs should be asked about route and source of this agent. To prolong this will only spread the agent and needlessly expose others. In light of the findings of Asante and Collinge et al, there should be drastic measures to safeguard the medical and surgical arena from sporadic CJDs and all human TSEs. I only ponder how many sporadic CJDs in the USA are type 2 PrPSc?
Reply to Singletary Ryan A. Maddox, MPH Other Contributors: Published March 26, 2003
Mr. Singletary raises several issues related to current Creutzfeldt- Jakob disease (CJD) surveillance activities. Although CJD is not a notifiable disease in most states, its unique characteristics, particularly its invariably fatal outcome within usually a year of onset, make routine mortality surveillance a useful surrogate for ongoing CJD surveillance.[1] In addition, because CJD is least accurately diagnosed early in the course of illness, notifiable-disease surveillance could be less accurate than, if not duplicative of, current mortality surveillance.[1] However, in states where making CJD officially notifiable would meaningfully facilitate the collection of data to monitor for variant CJD (vCJD) or other emerging prion diseases, CDC encourages the designation of CJD as a notifiable disease.[1] Moreover, CDC encourages physicians to report any diagnosed or suspected CJD cases that may be of special public health importance (e.g...., vCJD, iatrogenic CJD, unusual CJD clusters).
As noted in our article, strong evidence is lacking for a causal link between chronic wasting disease (CWD) of deer and elk and human disease,[2] but only limited data seeking such evidence exist. Overall, the previously published case-control studies that have evaluated environmental sources of infection for sporadic CJD have not consistently identified strong evidence for a common risk factor.[3] However, the power of a case-control study to detect a rare cause of CJD is limited, particularly given the relatively small number of subjects generally involved and its long incubation period, which may last for decades. Because only a very small proportion of the US population has been exposed to CWD, a targeted surveillance and investigation of unusual cases or case clusters of prion diseases among persons at increased risk of exposure to CWD is a more efficient approach to detecting the possible transmission of CWD to humans. In collaboration with appropriate local and state health departments and the National Prion Disease Pathology Surveillance Center, CDC is facilitating or conducting such surveillance and case- investigations, including related laboratory studies to characterize CJD and CWD prions.
Mr. Singletary also expresses concern over a recent publication by Asante and colleagues indicating the possibility that some sporadic CJD cases may be attributable to bovine spongiform encephalopathy (BSE).[4] The authors reported that transgenic mice expressing human prion protein homozygous for methionine at codon 129, when inoculated with BSE prions, developed a molecular phenotype consistent with a subtype of sporadic CJD. Although the authors implied that BSE might cause a sporadic CJD-like illness among persons homozygous for methionine, the results of their research with mice do not necessarily directly apply to the transmission of BSE to humans. If BSE causes a sporadic CJD-like illness in humans, an increase in sporadic CJD cases would be expected to first occur in the United Kingdom, where the vast majority of vCJD cases have been reported. In the United Kingdom during 1997 through 2002, however, the overall average annual mortality rate for sporadic CJD was not elevated; it was about 1 case per million population per year. In addition, during this most recent 6-year period following the first published description of vCJD in 1996, there was no increasing trend in the reported annual number of UK sporadic CJD deaths.[3, 5] Furthermore, surveillance in the UK has shown no increase in the proportion of sporadic CJD cases that are homozygous for methionine (Will RG, National CJD Surveillance Unit, United Kingdom, 2003; personal communication)..
References
1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Diagnosis and reporting of Creutzfeldt-Jakob disease. JAMA 2001;285:733-734.
2. Belay ED, Maddox RA, Gambetti P, Schonberger LB. Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States. Neurology 2003;60:176-181.
3. Belay ED. Transmissible spongiform encephalopathies in humans. Annu Rev Microbiol 1999;53:283-314.
4. Asante EA, Linehan JM, Desbruslais M, et al. BSE prions propagate as either variant CJD-like or sporadic CJD-like prion strains in transgenic mice expressing human prion protein. EMBO J 2002;21:6358-6366.
5. The UK Creutzfeldt-Jakob Disease Surveillance Unit. CJD statistics. Available at: http://www.cjd.ed.ac.uk/figures.htm. Accessed February 18, 2003.
Competing Interests: None declared.
Volume 2: Science
4. The link between BSE and vCJD
Summary 4.29 The evidence discussed above that vCJD is caused by BSE seems overwhelming. Uncertainties exist about the cause of CJD in farmers, their wives and in several abattoir workers. It seems that farmers at least might be at higher risk than others in the general population. 1 Increased ascertainment (ie, increased identification of cases as a result of greater awareness of the condition) seems unlikely, as other groups exposed to risk, such as butchers and veterinarians, do not appear to have been affected. The CJD in farmers seems to be similar to other sporadic CJD in age of onset, in respect to glycosylation patterns, and in strain-typing in experimental mice. Some farmers are heterozygous for the methionine/valine variant at codon 129, and their lymphoreticular system (LRS) does not contain the high levels of PrPSc found in vCJD.
***>It remains a remote possibility that when older people contract CJD from BSE the resulting phenotype is like sporadic CJD and is distinct from the vCJD phenotype in younger people...end
BSE INQUIRY
SATURDAY, JUNE 23, 2018
CDC
***> Diagnosis of Methionine/Valine Variant Creutzfeldt-Jakob Disease by Protein Misfolding Cyclic Amplification
Volume 24, Number 7—July 2018 Dispatch
Terry S. Singeltary Sr.
posted by Terry S. Singeltary Sr. | 3:05 PM
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