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Characteristics of Established and Proposed Sporadic Creutzfeldt-Jakob Disease Variants

Posted Aug 11 2009 11:57am
Characteristics of Established and Proposed Sporadic Creutzfeldt-Jakob Disease Variants

Brian S. Appleby, MD; Kristin K. Appleby, MD; Barbara J. Crain, MD, PhD; Chiadi U. Onyike, MD, MHS; Mitchell T. Wallin, MD, MPH; Peter V. Rabins, MD, MPH

Background: The classic Creutzfeldt-Jakob disease (CJD), Heidenhain, and Oppenheimer-Brownell variants are sporadic CJD (sCJD) phenotypes frequently described in the literature, but many cases present with neuropsychiatric symptoms, suggesting that there may be additional sCJD phenotypes.

Objective: To characterize clinical, diagnostic, and molecular features of 5 sCJD variants.

Design: Retrospective analysis.

Setting: The Johns Hopkins and Veterans Administration health care systems.

Participants: Eighty-eight patients with definite or probable sCJD.

Main Outcome Measures: Differences in age at onset, illness progression, diagnostic test results, and molecular subtype.

Results: The age at onset differed among sCJD variants (P=.03); the affective variant had the youngest mean age at onset (59.7 years). Survival time (P.001) and the time to clinical presentation (P=.003) differed among groups. Patients with the classic CJD phenotype had the shortest median survival time from symptom onset (66 days) and those who met criteria for the affective sCJD variant had the longest (421 days) and presented to clinicians significantly later (median time from onset to presentation, 92 days; P=.004). Cerebrospinal fluid analyses were positive for 14-3-3 protein in all of the affective variants, regardless of illness duration. Periodic sharp-wave complexes were not detected on any of the electroencephalography tracings in the Oppenheimer-Brownell group; basal ganglia hyperintensity was not detected on brain magnetic resonance imaging in this group either. All of the Heidenhain variants were of the methionine/ methionine type 1 molecular subtype.

Conclusions: The classic CJD phenotype and the Heidenhain, Oppenheimer-Brownell, cognitive, and affective sCJD variants differ by age at disease onset, survival time, and diagnostic test results. Characteristics of these 5 phenotypes are provided to facilitate further clinicopathologic investigation that may lead to more reliable and timely diagnoses of sCJD.

Arch Neurol. 2009;66(2):208-215

snip...

COMMENT

The findings of this study provide support for the existence of 5 sCJD variants that differ by clinical presentation, disease course, and diagnostic test results. We have confirmed the existence of 3 previously reported clinical subtypes (classic CJD, Heidenhain, and Oppenheimer- Brownell variants) and offer support for the existence of 2 neuropsychiatric variants that are characterized by cognitive impairment and disturbances in mood.

Although sCJD is known to have a range of clinical symptoms, our findings indicate that clinical clusters of cases may be delineated by differences in initial symptoms. It is also significant that the sCJD variants differ with respect to age at symptom onset and survival time, indicating a difference in disease pathology and/or expression. Differences in survival time not only imply differences in the natural history of the illness but also suggest the possibility of differences in the underlying pathologic process of the illness. Clinical sCJD variants may be a reflection of PrPSc type and PRNP codon 129 genotype as previously reported.13,15,16 Individuals who display features of an sCJD variant may also have unique genetic or other disease-altering variables (eg, age) that modulate illness characteristics. Our data may help to provide a basis for developing clinicopathologic associations to facilitate the clinical identification of sCJD variants, which would aid in clinical detection and diagnosis.

The formalization of sCJD phenotypes is valuable for a number of reasons. The heterogeneity of clinical presentations observed in sCJD frequently results in the delayed diagnosis or misdiagnosis of prion diseases.9,17-19 Thus, it is reasonable to conclude that the delineation of various sCJD subtypes can be used to educate clinicians about the variability of clinical symptoms that are commonly observed in sCJD in addition to the disease’s propensity to be misdiagnosed. An example of this would be considering prion disease in the differential diagnosis of a patient with suspected posterior cortical atrophy (ie, owing to knowledge of the Heidenhain variant). Furthermore, patients with neuropsychiatric variants presented to clinicians later in the course of their illness, which is pertinent, as disease duration has been found to affect EEG findings.20 Likewise, prior reports have suggested that 14-3-3 protein is most likely detected in CSF shortly after the onset of symptoms.21 However, our results suggest that clinical subtypes themselves may also be associated with diagnostic test results, as demonstrated by assays positive for the 14-3-3 protein in all of the affective phenotypes despite CSF samples being obtained significantly later in the illness. The lack of classic periodic sharp-wave complexes and hyperintensity in the basal ganglia on brain magnetic resonance imaging in the Oppenheimer-Brownell variant may also reflect an independent phenotype-related feature. Knowledge of this diagnostic test pattern can influence the physician’s clinical judgment and hence contribute to the continued consideration of prion disease despite negative findings of these tests in a patient who presents with pure ataxia of unknown etiology. As a result, the predictive value and utility of diagnostic tests may vary by clinical phenotype as well as by illness duration. Additional studies are needed to clarify the proper interpretation of these diagnostic test results in relation to sCJD variants and the stage of illness.

The association between molecular subtypes and phenotypes confirms prior findings by Parchi and colleagues. 13 Classic CJD and the Heidenhain variant were associated with the Met/Met type 1 and Met/Val type 1 subtypes described in their article. In our study, the longest survival time was observed in the affective group, of whom 2 cases had the only Met/Val type 2 molecular subtypes; this subtype is associated with a prolonged survival time (2 years). On the other hand, patients with the Oppenheimer-Brownell phenotype initially presented with ataxia and did not have periodic sharpwave complexes on EEG tracings. In our sample, the Oppenheimer-Brownell phenotype was not associated with the Val/Val type 2 molecular subtype, as described by Parchi and colleagues.22

There are several limitations to this study. Because retrospective analysis only captures the reported findings of a case, it is possible that symptoms were overlooked or inaccurately recorded. It is difficult to ascertain what the impact or direction of such information biases may be, but it is reasonable to conclude that predominant symptoms are unlikely overlooked. Thus, we argue that information bias unlikely results in the delineation of sCJD variants that do not exist but may result in uncommon phenotypes being overlooked or unclassified. It may be argued that initial neuropsychiatric symptoms of sCJD are prodromal; however, differences in age at onset, survival times, diagnostic test results, and possibly molecular subtypes among these 5 sCJD phenotypes make this possibility unlikely. Not all patients with definite sCJD underwent PRNP genotyping, which raises the possibility that some cases may have been of genetic etiology, which would influence the age at onset, survival time, clinical presentation, and diagnostic test results. We also note that the size of the sample is limited, especially given its stratification across 5 sCJD phenotypes and an indeterminate group. It is also possible that additional phenotypes exist and that indeterminate cases within this analysis represent other phenotypes.

The sample in this study is difficult to classify according to Parchi and colleagues’ system.13 The inclusion of a newly reported prionopathy12 with a novel codon 129 polymorphism and recent findings by Notari and colleagues23 make our molecular data particularly difficult to categorize and interpret. Although PrPSc types 1 and 2 differ in size and glycosylation,22 both are proteaseresistant. In contrast, PSPr is characterized by a predominance of protease-sensitive prion proteins.12 All of the 11 cases reported to date have been homozygous for Val at codon 129 of the PRNP gene,12 but we now report 2 PSPr cases that were heterozygous (Met/Val) at codon 129, implying that Val/Val homozygosity is not required for protease- sensitive prion disease. The report of PSPr heterozygotes in this study is significant, as these 2 cases had longer survival times (7.7 years and 2.8 years) than the Val/Val homozygous PSPr cases described by Gambetti and colleagues (mean, 1.7 years).12 This is consistent with the study by Pocchiari and colleagues,24 which demonstrated longer survival times in heterozygous cases (Met/ Val) compared with homozygous cases (Met/Met and Val/ Val) in typical sCJD. This strengthens the position that prion protein isoforms (eg, types 1, 2, and PSPr) and codon 129 polymorphisms (ie, Met/Met, Val/Val, and Met/ Val) demonstrate clinical variability that may be used for clinicopathologic association studies. As such, findings from this study and Gambetti and colleagues’ article12 suggest that ascertainment rates of PSPr cases may be low owing to their atypical presentation in terms of survival time and nonclassic CJD phenotype. The 2 heterozygous PSPr cases in our article were classified as cognitive and Oppenheimer-Brownell variants, whereas Gambetti and colleagues’ cohort contained 6 cases that presented with mood and/or sleep disturbances and 4 cases that presented with cognitive decline in the absence of mood, sleep, and motor disturbances. Further investigation is necessary to characterize PSPr disease and to develop further clinicopathologic associations. Our findings suggest that neuropsychiatric symptoms should not be overlooked in these investigations, as they are prominent in prion diseases and also require phenomenological distinction (eg, cognitive symptoms, mood symptoms, psychosis) owing to clinical, neuropathologic, and molecular differences.

In conclusion, results from this study suggest that there are 2 neuropsychiatric sCJD variants that present with cognitive impairment and disturbances in mood and affect. These proposed variants, in addition to the 3 previously established sCJD phenotypes, vary in important illness characteristics and diagnostic investigations, indicating that the detection of distinct clinical syndromes may be profitably used for the clinical evaluation and possibly clinicopathologic correlation studies of prion diseases. Findings from this study provide support for a topdown approach in the investigation of genotypephenotype relationships, especially given the complexity of molecular and neuropathologic factors inherent within the spectrum of prion diseases. Based on the findings of this and prior studies, we propose preliminary characteristics for the classification of the 5 sCJD phenotypes listed in Table 4, with the intent to facilitate additional studies focused on early diagnosis, treatment, and clinicopathologic correlations. Additional studies are needed to replicate these findings and to identify whether there are other characteristics of these proposed subtypes or additional sCJD variants.

Accepted for Publication: September 4, 2008. Correspondence: Brian S. Appleby, MD, Johns Hopkins Hospital, 600 N Wolfe St, Meyer Bldg, Room 279, Baltimore, MD 21287 ( mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000602/!x-usc:mailto:bap ).

Author Contributions: Study concept and design: B. S. Appleby, Onyike, and Rabins. Acquisition of data: B. S. Appleby, K. K. Appleby, and Wallin. Analysis and interpretation of data: B. S. Appleby, Crain, Onyike, Wallin, and Rabins. Drafting of the manuscript: B. S. Appleby and Rabins. Critical revision of the manuscript for important intellectual content: B. S. Appleby, K. K. Appleby, Crain, Onyike, Wallin, and Rabins. Statistical analysis: B. S. Appleby and Onyike. Obtained funding: Rabins. Administrative, technical, and material support: K. K. Appleby, Onyike, Wallin, and Rabins. Study supervision: Wallin and Rabins.

Financial Disclosure: None reported. Funding/Support: This research was supported in part by the Stempler Fund for Dementia Research. Additional Contributions: We gratefully acknowledge the work and assistance of the National Prion Disease Pathology Surveillance Center and their generous staff.

================================end...tss




http://archneur.ama-assn.org/






COMMENTS AND OPINIONS

Identification of Creutzfeldt-Jakob Disease Variants

The recent article by Appleby et al1 demonstrated an interesting phenotypic classification of sporadic Creutzfeldt-Jakob disease (sCJD). Of particular note were the characteristics of patients with the affective variant, who reported psychiatric symptoms in the first week of illness. These individuals also experienced the longest median survival time of all phenotypes (421 days). Interestingly, the early psychiatric presentation and prolonged survival of affective cases are reminiscent of variant CJD (vCJD), an entity associated with an exposure to the agent carrying bovine spongiform encephalopathy.2 Although nearly all vCJD cases have emerged in Europe and demonstrate distinct clinical features (including a mean age at onset in the third decade of life), these similarities and additional data presented by Appleby and colleagues do raise concern about our ability to promptly diagnose vCJD in the United States. In particular, the patients with the affective variant experienced the longest median duration of illness until clinical presentation (92 days) and subsequently underwent diagnostic testing far later from the time at onset than those with other phenotypes. The median intervals from disease onset to lumbar puncture for 14-3-3 protein analysis and brain magnetic resonance imaging were 222 and 232 days, respectively.1 Therefore, the duration until clinical diagnosis of CJD was presumably longer.

Even in the United Kingdom, where nearly 80% of vCJD cases have been identified since the condition was first recognized in 1996 (and where the mean interval between the onset of symptoms and diagnosis decreased by an average of 4% annually), the delay to diagnosis was still an estimated 9 months in 2005.3 Since all three American vCJD cases to date have demonstrated a history consistent with an exposure abroad,4 I wonder how long it might take to diagnose a vCJD case less likely to arouse our suspicion but with potentially far greater consequences for the public health: an American citizen with a native exposure and no history of foreign travel. Given the relatively recent identification of cattle with bovine spongiform encephalopathy on American soil,5 such a scenario is not unimaginable. However, further emphasis on the phenotypic features of CJD proposed by Appleby and colleagues may also lead to a more timely diagnosis in this circumstance, potentially minimizing public exposure. An active effort to both educate clinicians about CJD phenotypes and involve them in improving the diagnostic process can make this goal more attainable.

Correspondence: Dr Barash, Department of Neurology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215 ( mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000602/!x-usc:mailto:jba ). Financial Disclosure: None reported.

1. Appleby BS, Appleby KK, Crain BJ, Onyike CU, Wallin MT, Rabins PV. Characteristics of established and proposed sporadic Creutzfeldt-Jakob disease variants. Arch Neurol. 2009;66(2):208-215.

2. Johnson RT. Prion diseases. Lancet Neurol. 2005;4(10):635-642.

3. National CJD Surveillance Unit. Creutzfeldt-Jakob Disease Surveillance in the UK: 14th Annual Report, 2006. Edinburgh, Scotland: National CJD Surveillance Unit; 2006.

4. Centers for Disease Control and Prevention. Fact sheet: variant Creutzfeldt- Jakob disease: vCJD cases reported in the US. http://www.cdc.gov/ncidod/dvrd/vcjd/factsheet_nvcjd.htm. Accessed February 28, 2009.

5. Centers for Disease Control and Prevention. BSE (bovine spongiform encephalopathy, or mad cow disease): BSE cases identified in the United States. http://www.cdc.gov/ncidod/dvrd/bse/. Accessed February 28, 2009.

In reply

We thank Dr Barash for his comments regarding the data presented in our article.1 While we are in strong agreement with Dr Barash, we want to ensure that readers are aware that the affective cases in our study are not cases of vCJD. Nine of the 13 cases (69.2%) underwent postmortem examination and did not have neuropathological or prion protein strain characteristics typical of vCJD.2 Thus, all neuropathologically confirmed cases in our article were of the sCJD type.

In regard to Dr Barash’s comments, expanding our knowledge of the various clinical presentations of prion diseases will improve surveillance of prion diseases in general. Information regarding the typical features of vCJD, including young age at onset (second to third decade of life), atypical disease duration (>1 year), and initial psychiatric and sensory symptoms, has been well documented in the medical literature3 to ensure its proper surveillance. However, the clinically similar affective sCJD variants in our sample underwent diagnostic workup much later than the other cases,1 suggesting that there is a continued need for education regarding the clinical presentations of prion diseases in general. In addition to improving surveillance efforts, education regarding clinical phenotypes will likely lead to earlier diagnoses and allow for more opportune uses of investigational treatments that may preserve a better quality of life compared with treating patients in the later stages of the illness when quality of life is greatly diminished.

Much progress has been made in the neuropathological and molecular characterization of human prion diseases within the last several years, allowing us to distinguish disease etiology in cases of vCJD,2 fatal familial insomnia,4 and Gerstmann-Sträussler-Scheinker disease.5 Prion diseases that share neuropathological and molecular features also share similar clinical phenotypes in the form of symptom presentation, diagnostic study results, and illness duration. As was the case with vCJD,2 the etiologies of nonsporadic cases of prion disease have been discovered by pairing atypical clinical characteristics with neuropathological findings. Further information about sCJD can also be gleaned in this fashion as recently demonstrated by Gambetti et al,6 and similar methods will likely continue to extend our knowledge of prion diseases as a whole.

Correspondence: Dr B. S. Appleby, Department of Psychiatry and Behavioral Sciences, Johns Hopkins Hospital, Meyer Bldg, Room 279, 600 N Wolfe St, Baltimore, MD 21287 ( bappleb1@jhmi.edu ).

Financial Disclosure: None reported.

Funding/Support: This research was supported in part by the Stempler Fund for Dementia Research and the Richman Family Fund for Alzheimer’s and Related Diseases.

1. Appleby BS, Appleby KK, Crain BJ, Onyike CU, Wallin MT, Rabins PV. Characteristics of established and proposed sporadic Creutzfeldt-Jakob disease variants. Arch Neurol. 2009;66(2):208-215.

2. Will RG, Ironside JW, Zeidler M, et al. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet. 1996;347(9006):921-925.

3. Appleby BS, Appleby KK, Rabins PV. Does the presentation of Creutzfeldt- Jakob disease vary by age or presumed etiology? a meta-analysis of the past 10 years. J Neuropsychiatry Clin Neurosci. 2007;19(4):428-435.

4. Gambetti P, Petersen R, Monari L, et al. Fatal familial insomnia and the widening spectrum of prion diseases. Br Med Bull. 1993;49(4):980-994.

5. Parchi P, Chen SG, Brown P, et al. Different patterns of truncated prion protein fragments correlate with distinct phenotypes in P102L Gerstmann- Sträussler-Scheinker disease. Proc Natl Acad Sci U S A. 1998;95(14):8322- 8327.

6. Gambetti P, Dong Z, Yuan J, et al. A novel human disease with abnormal prion protein sensitive to protease. Ann Neurol. 2008;63(6):697-708.

Announcement Trial Registration Required. In concert with the International Committee of Medical Journal Editors (ICMJE), Archives of Neurology will require, as a condition of consideration for publication, registration of all trials in a public trials registry (such as http://ClinicalTrials.gov ). Trials must be registered at or before the onset of patient enrollment. This policy applies to any clinical trial starting enrollment after July 1, 2005. For trials that began enrollment before this date, registration will be required by September 13, 2005, before considering the trial for publication. The trial registration number should be supplied at the time of submission. For details about this new policy, and for information on how the ICMJE defines a clinical trial, see the editorial by DeAngelis et al in the January issue of Archives of Dermatology (2005;141:76-77). Also see the Instructions to Authors on our Web site: www.archneurol.com. Brian S. Appleby, MD Kristin K. Appleby, MD Barbara J. Crain, MD, PhD Peter V. Rabins, MD, MPH Chiadi U. Onyike, MD, MHS Mitchell T. Wallin, MD, MPH


(REPRINTED) ARCH NEUROL/VOL 66 (NO. 8), AUG 2009 WWW.ARCHNEUROL.COM 1046 ©2009


On Mon, Aug 10, 2009 at 4:53 PM,


Terry S. Singeltary Sr. < mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000602/!x-usc:mailto:flo > wrote:


re-Identification of Creutzfeldt-Jakob Disease Variants


http://archneur.ama-assn.org/cgi/content/full/66/8/1045-a



Thank you for your reply We value your contribution. The Archives of Neurology Readers Reply editor will review your submission, which if accepted, should be viewable within a few days.

If you have a problem with this process or other comments that do not pertain to the submission of electronic responses, then please contact us.

Here is your reply as we received it: sporadic cjd

Terry S. Singeltary Sr., none Send reply to journal: Re: sporadic cjd

E-mail Terry S. Singeltary Sr.


Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States 2003 revisited 2009

August 10, 2009

Greetings,

I would like to submit a review of past CJD surveillance in the USA, and the urgent need to make all human TSE in the USA a reportable disease, in every state, of every age group, and to make this mandatory immediately without further delay. The ramifications of not doing so will only allow this agent to spread further in the medical, dental, surgical arena’s. North America seems to have the most species with documented Transmissible Spongiform Encephalopathy's, most all of which have been rendered and fed back to food producing animals and to humans for years. If you look at the statistics, sporadic CJD seems to be rising in the USA, and has been, with atypical cases of the sCJD. I find deeply disturbing in the year of 2009, that Human Transmissible Spongiform Encephalopathy of any strain and or phenotype, of all age groups, and I stress all age groups, because human TSE's do not know age, and they do not know borders. someone 56 years old, that has a human TSE, that has surgery, can pass this TSE agent on i.e. friendly fire, and or passing it forward, and there have been documented nvCJD in a 74 year old. Remembering also that only sporadic CJD has been documented to transmit via iatrogenic routes, until recently with the 4 cases of blood related transmission, of which the origin is thought to be nvCJD donors. However most Iatrogenic CJD cases are nothing more than sporadic CJD, until the source is proven, then it becomes Iatrogenic. An oxymoron of sorts, because all sporadic CJD is, are multiple forms, or strains, or phenotypes of Creutzfeldt Jakob Disease, that the route and source and species have not been confirmed and or documented. When will the myth of the UKBSEnvCJD only theory be put to bed for good. This theory in my opinion, and the following there from, as the GOLD STANDARD, has done nothing more than help spread this agent around the globe. Politics and money have caused the terrible consequences to date, and the fact that TSEs are a slow incubating death, but a death that is 100% certain for those that are exposed and live long enough to go clinical. once clinical, there is no recourse, to date. But, while sub-clinical, how many can one exposed human infect? Can humans exposed to CWD and scrapie strains pass it forward as some form of sporadic CJD in the surgical and medical arenas? why must we wait decades and decades to prove this point, only to expose millions needlessly, only for the sake of the industries involved? would it not have been prudent from the beginning to just include all TSE's, and rule them out from there with transmission studies and change policies there from, as opposed to doing just the opposite? The science of TSE's have been nothing more than a political circus since the beginning, and for anyone to still believe in this one strain, one group of bovines, in one geographical location, with only one age group of human TSE i.e. nvCJD myth, for anyone to believe this today only enhances to spreading of these human and animal TSE's. This is exactly why we have been in this quagmire.

The ones that believe that there is a spontaneous CJD in 85%+ of all cases of human TSE, and the ones that do not believe that cattle can have this same phenomenon, are two of the same, the industry, and so goes the political science aspect of this tobacco and or asbestos scenario i.e. follow the money. I could go into all angles of this man made nightmare, the real facts and science, for instance, the continuing rendering technology and slow cooking with low temps that brewed this stew up, and the fact that THE USA HAD THIS TECHNOLOGY FIRST AND SHIPPED IT TO THE U.K. SOME 5 YEARS BEFORE THE U.S. STARTED USING THE SAME TECHNOLOGY, to save on fuel cost. This is what supposedly amplified the TSE agent via sheep scrapie, and spread via feed in the U.K. bovine, and other countries exporting the tainted product. BUT most everyone ignores this fact, and the fact that the U.S. has been recycling more TSE, from more species with TSEs, than any other country documented, but yet, it's all spontaneous, and the rise in sporadic CJD in the U.S. is a happenstance of bad luck ??? I respectfully disagree. To top that all off, the infamous BSE-FIREWALL that the USDA always brags about was nothing more than ink on paper, and I can prove this. YOU can ignore it, but this is FACT (see source, as late as 2007, in one recall alone, some 10,000,000 MILLION POUNDS OF BANNED MAD COW FEED WENT OUT INTO COMMERCE TO BE FED OUT, and most was never recovered. This was banned blood laced, meat and bone meal. 2006 was a banner year for banned mad cow protein going into commerce in the U.S. (see source of FDA feed ban warning letter below). I stress that the August 4, 1997 USA mad cow feed ban and this infamous BSE firewall, was nothing more than ink on paper, it was never enforceable.

I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2009. With all the science to date refuting it, to continue to validate this old myth, will only spread this TSE agent through a multitude of potential routes and sources i.e. consumption, medical i.e., surgical, blood, dental, endoscopy, optical, nutritional supplements, cosmetics etc. I propose as with Aguzzi, Asante, Collinge, Caughey, Deslys, Dormont, Gibbs, Gajdusek, Ironside, Manuelidis, Marsh, et al and many more, that the world of TSE Transmissible Spongiform Encephalopathy is far from an exact science, but there is enough proven science to date that this myth should be put to rest once and for all, and that we move forward with a new classification for human and animal TSE that would properly identify the infected species, the source species, and then the route. This would further have to be broken down to strain of species and then the route of transmission would further have to be broken down. Accumulation and Transmission are key to the threshold from sub- clinical to clinical disease, and key to all this, is to stop the amplification and transmission of this agent, the spreading of, no matter what strain. In my opinion, to continue with this myth that the U.K. strain of BSE one strain TSE in cows, and the nv/v CJD one strain TSE humans, and the one geographical location source i.e. U.K., and that all the rest of human TSE are just one single strain i.e. sporadic CJD, a happenstance of bad luck that just happens due to a twisted protein that just twisted the wrong way, IN 85%+ OF ALL HUMAN TSEs, when to date there are 6 different phenotypes of sCJD, and growing per Gambetti et al, and that no other animal TSE transmits to humans ??? With all due respect to all Scientist that believe this, I beg to differ. To continue with this masquerade will only continue to spread, expose, and kill, who knows how many more in the years and decades to come. ONE was enough for me, My Mom, hvCJD i.e. Heidenhain Variant CJD, DOD 12/14/97 confirmed, which is nothing more than another mans name added to CJD, like CJD itself, Jakob and Creutzfeldt, or Gerstmann-Straussler-Scheinker syndrome, just another CJD or human TSE, named after another human. WE are only kidding ourselves with the current diagnostic criteria for human and animal TSE, especially differentiating between the nvCJD vs the sporadic CJD strains and then the GSS strains and also the FFI fatal familial insomnia strains or the ones that mimics one or the other of those TSE? Tissue infectivity and strain typing of the many variants of the human and animal TSEs are paramount in all variants of all TSE. There must be a proper classification that will differentiate between all these human TSE in order to do this. With the CDI and other more sensitive testing coming about, I only hope that my proposal will some day be taken seriously. ...

please see history, and the ever evolving TSE science to date ;

Saturday, June 13, 2009

Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States 2003 revisited 2009



http://cjdusa.blogspot.com/2009/06/monitoring-occurrence-of-emerging-forms.html





SEE THE DAMNING VIDEO NOW AT THE BOTTOM OF THE BLOG BELOW ;



http://creutzfeldt-jakob-disease.blogspot.com/2009/07/usa-hiding-mad-cow-disease





Tuesday, July 14, 2009

U.S. Emergency Bovine Spongiform Encephalopathy Response Plan Summary and BSE Red Book Date: February 14, 2000 at 8:56 am PST

WHERE did we go wrong $$$



http://madcowtesting.blogspot.com/2009/07/us-emergency-bovine-spongiform.html





Transgenic mice expressing porcine prion protein resistant to classical scrapie but susceptible to sheep bovine spongiform encephalopathy and atypical scrapie. Emerg Infect Dis. 2009 Aug; [Epub ahead of print]



http://nor-98.blogspot.com/2009/07/transgenic-mice-expressing-porcine.html





Transmissible mink encephalopathy - review of the etiology



http://transmissible-mink-encephalopathy.blogspot.com/2009/07/transmissible-mink





Wednesday, July 1, 2009

Nor98 scrapie identified in the United States J Vet Diagn Invest 21:454-463 (2009)



http://nor-98.blogspot.com/2009/07/nor98-scrapie-identified-in-united.html





Monday, June 01, 2009 Biochemical typing of pathological prion protein in aging cattle with BSE

SOMETHING TO PONDER ???

O.K. confusious asks, IF all these new atypical BSEs i.e. new strains of mad cow disease is just an 'OLD COW PRION DISEASE', why then can not the 'old human prion disease' such as the sporadic CJD, be from an 'old cow prion disease', same as the nvCJD 'young people mad cow disease' (which also happens in 74 year old), but why cannot the 'old cow prion diseases', i.e. l-BSE, h-BSE, and ibncBSE, cause the 'old people prion disease', which looks like sporadic CJD. seems that is what some of the pathology is showing ???

OH, that probably makes too much sense, and that the only answer could be that it's all just a happenstance of bad luck and or a spontaneous event, that just happens out of the clear blue sky $$$

IF this is the case, then where are all the SPONTANEOUS BSE CASES OF MAD COW DISEASE IN THE U.S.A., AND WHERE HAVE THEY BEEN BURIED IN THE USA OVER THE LAST 25 YEARS ???



http://bse-atypical.blogspot.com/2009/06/biochemical-typing-of-pathological.html





Sunday, August 09, 2009

CJD...Straight talk with...James Ironside...and...Terry Singeltary... 2009



http://creutzfeldt-jakob-disease.blogspot.com/2009/08/cjdstraight-talk-withjames





Tuesday, August 04, 2009

Susceptibilities of Nonhuman Primates to Chronic Wasting Disease



http://chronic-wasting-disease.blogspot.com/2009/08/susceptibilities-of-nonhuman





Thursday, July 23, 2009

UW Hospital warning 53 patients about possible exposure to rare brain disease



http://creutzfeldt-jakob-disease.blogspot.com/2009/07/uw-hospital-warning-53-pat





Wednesday, August 05, 2009


Rate of CWD infection increases in core area WISCONSIN



http://chronic-wasting-disease.blogspot.com/2009/08/rate-of-cwd-infection-increa





Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518

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Sunday, August 09, 2009

NATIONAL CREUTZFELDT-JAKOB DISEASE SURVEILLANCE UNIT SCIENTIFIC REPORT 2007/08




http://creutzfeldt-jakob-disease.blogspot.com/2009/08/national-creutzfeldt-jakob





Tuesday, July 29, 2008

Heidenhain Variant Creutzfeldt Jakob Disease Case Report




http://creutzfeldt-jakob-disease.blogspot.com/2008/07/heidenhain-variant-creutzf




JOURNAL OF NEUROLOGY

MARCH 26, 2003

Send Post-Publication Peer Review to journal:

Re: RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob

disease in the United States

Email Terry S. Singeltary:

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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?


http://www.neurology.org/cgi/eletters/60/2/176#535




LANCET INFECTIOUS DISEASE JOURNAL

Volume 3, Number 8 01 August 2003

Newsdesk

Tracking spongiform encephalopathies in North America

Xavier Bosch

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.

49-year-old Singeltary is one of a number of people who have remained largely unsatisfied after being told that a close relative died from a rapidly progressive dementia compatible with spontaneous Creutzfeldt-Jakob disease (CJD). So he decided to gather hundreds of documents on transmissible spongiform encephalopathies (TSE) and realised that if Britons could get variant CJD from bovine spongiform encephalopathy (BSE), Americans might get a similar disorder from chronic wasting disease (CWD)the relative of mad cow disease seen among deer and elk in the USA. Although his feverish search did not lead him to the smoking gun linking CWD to a similar disease in North American people, it did uncover a largely disappointing situation.

Singeltary was greatly demoralised at the few attempts to monitor the occurrence of CJD and CWD in the USA. Only a few states have made CJD reportable. Human and animal TSEs should be reportable nationwide and internationally, he complained in a letter to the Journal of the American Medical Association (JAMA 2003; 285: 733). I hope that the CDC does not continue to expect us to still believe that the 85% plus of all CJD cases which are sporadic are all spontaneous, without route or source.

Until recently, CWD was thought to be confined to the wild in a small region in Colorado. But since early 2002, it has been reported in other areas, including Wisconsin, South Dakota, and the Canadian province of Saskatchewan. Indeed, the occurrence of CWD in states that were not endemic previously increased concern about a widespread outbreak and possible transmission to people and cattle.

To date, experimental studies have proven that the CWD agent can be transmitted to cattle by intracerebral inoculation and that it can cross the mucous membranes of the digestive tract to initiate infection in lymphoid tissue before invasion of the central nervous system. Yet the plausibility of CWD spreading to people has remained elusive.

Part of the problem seems to stem from the US surveillance system. CJD is only reported in those areas known to be endemic foci of CWD. Moreover, US authorities have been criticised for not having performed enough prionic tests in farm deer and elk.

Although in November last year the US Food and Drug Administration issued a directive to state public-health and agriculture officials prohibiting material from CWD-positive animals from being used as an ingredient in feed for any animal species, epidemiological control and research in the USA has been quite different from the situation in the

UK and Europe regarding BSE.

Getting data on TSEs in the USA from the government is like pulling teeth, Singeltary argues. You get it when they want you to have it and only what they want you to have.Norman Foster, director of the Cognitive Disorders Clinic at the University of Michigan (Ann Arbor, MI, USA), says that current surveillance of prion disease in people in the USA is inadequate to detect whether CWD is occurring in human beings; adding that, the cases that we know about are reassuring, because they do not suggest the appearance of a new variant of CJD in the USA or atypical features in patients that might be exposed to CWD. However, until we establish a system that identifies and analyses a high proportion of suspected prion disease cases we will not know for sure. The USA should develop a system modelled on that established in the UK, he points out.

Ali Samii, a neurologist at Seattle VA Medical Center who recently reported the cases of three hunterstwo of whom were friendswho died from pathologically confirmed CJD, says that at present there are insufficient data to claim transmission of CWD into humans; adding that [only] by asking [the questions of venison consumption and deer/elk hunting] in every case can we collect suspect cases and look into the plausibility of transmission further. Samii argues that by making both doctors and hunters more aware of the possibility of prions spreading through eating venison, doctors treating hunters with dementia can consider a possible prion disease, and doctors treating CJD patients will know to ask whether they ate venison. CDC spokesman Ermias Belay says that the CDC will not be investigating the [Samii] cases because there is no evidence that the men ate CWD-infected meat. He notes that although the likelihood of CWD jumping the species barrier to infect humans cannot be ruled out 100% and that [we] cannot be 100% sure that CWD does not exist in humans & the data seeking evidence of CWD transmission to humans have been very limited.



http://www.thelancet.com/journals/laninf/article/PIIS1473309903007151/%20fulltex




he complained in a letter to the Journal of the American Medical Association (JAMA 2003; 285: 733).


>>> I hope that the CDC does not continue to expect us to still believe that the 85% plus of all CJD cases which are sporadic are all spontaneous, without route or source. < < <


actually, that quote was from a more recent article in the Journal of Neurology (see below), not the JAMA article...


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.

FREE FULL TEXT



http://jama.ama-assn.org/cgi/content/extract/285/6/733?maxtoshow=&HITS=10&hits=1



http://jama.ama-assn.org/cgi/content/full/285/6/733?maxtoshow=&HITS=10&hits=10&R




2 January 2000

British Medical Journal

U.S. Scientist should be concerned with a CJD epidemic in the U.S., as well



http://www.bmj.com/cgi/eletters/320/7226/8/b#6117





15 November 1999

British Medical Journal

vCJD in the USA * BSE in U.S.



http://www.bmj.com/cgi/eletters/319/7220/1312/b#5406





THE PATHOLOGICAL PROTEIN

BY Philip Yam

Yam Philip Yam News Editor Scientific American http://www.sciam.com/



http://www.thepathologicalprotein.com/





SEE REVISITING SPORADIC CJD BY PHILIP YAM THE PATHOLOGICAL PROTEIN


Answering critics like Terry Singeltary, who feels that the U.S. undercounts CJD, Schonberger conceded that the current surveillance system has errors but stated that most of the errors will be confined to the older population. ...




http://books.google.com/books?id=ePbrQNFrHtoC&pg=PA224&lpg=PA224&dq=pathological




2008


The statistical incidence of CJD cases in the United States has been revised to reflect that there is one case per 9000 in adults age 55 and older. Eighty-five percent of the cases are sporadic, meaning there is no known cause at present.


http://www.cjdfoundation.org/fact.html




Friday, November 30, 2007

CJD QUESTIONNAIRE USA CWRU AND CJD FOUNDATION



http://cjdquestionnaire.blogspot.com/






Saturday, June 13, 2009


Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States 2003 revisited 2009



http://cjdusa.blogspot.com/2009/06/monitoring-occurrence-of-emerging-forms.html






Terry S. Singeltary Sr.
P.O. Box 42
Bacliff, Texas USA 77518
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