Saturday, March 10, 2018

Dura Mater Graft–Associated Creutzfeldt-Jakob Disease — Japan, 1975–2017 Update

Dura Mater Graft–Associated Creutzfeldt-Jakob Disease — Japan, 1975–2017 Update

Weekly / March 9, 2018 / 67(9);274–278

Ryusuke Ae, MD, PhD1; Tsuyoshi Hamaguchi, MD, PhD2; Yosikazu Nakamura, MD1; Masahito Yamada, MD, PhD2; Tadashi Tsukamoto, MD, PhD3; Hidehiro Mizusawa, MD, PhD3; Ermias D. Belay, MD4; Lawrence B. Schonberger, MD4 (View author affiliations)

Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disorder that, according to the most well accepted hypothesis (1), is caused by replicating, transmissible, abnormal forms of a host-encoded prion protein (prions). Most CJD cases occur spontaneously (sporadic CJD) or are inherited (genetic CJD). Iatrogenic CJD can occur after exposure to prion-contaminated instruments or products in medical/surgical settings. Cadaveric dura mater graft–associated CJD (dCJD) accounts for a common form of iatrogenic CJD. This report summarizes the epidemiologic features of 154 cases of dCJD identified in Japan during 1975–2017; these cases account for >60% of dCJD cases reported worldwide (1,2). The unusually high prevalence of dCJD in Japan was first reported in 1997 (3). In 2008, a single brand of graft (Lyodura [B. Braun Melsungen AG, Melsungen, Germany]), frequently used as a patch in neurosurgical procedures, was identified as the probable vehicle of transmission (4). No international recall of the implicated Lyodura occurred, the product had a relatively long shelf life, and the grafts were used frequently in Japanese patients with non–life-threatening conditions (4,5). Since 2008, additional cases have been ascertained, reflecting the identification of previously missed cases and the occurrence of new cases with longer latency periods (interval from exposure to symptom onset) for dCJD (up to 30 years), underscoring the importance of maintaining surveillance for dCJD.

In 1996, after the first report of variant CJD (the human prion disease caused by the agent of bovine spongiform encepathalopathy [“mad cow disease”]) in the United Kingdom (6), the nongovernmental Japanese CJD Surveillance Committee (J-CJDSC), with support from the Japanese Ministry of Health, Labour, and Welfare, conducted a preliminary nationwide mail survey to identify cases of human prion disease in Japan; since 1999, J-CJDSC has maintained a national CJD registry (7). J-CJDSC members investigate each reported suspected CJD case in cooperation with CJD specialists in each prefecture. The methods for identifying dCJD cases in Japan have been described previously (5,7,8). All identified CJD cases, including cases of dCJD, are entered into the J-CJDSC database, which contains demographic and clinical information, including a detailed history of any surgical procedures and international travel and CJD laboratory test results (including cerebrospinal fluid analyses and genetic testing) (7).

Among 829 identified physician-diagnosed cases of CJD during 1979–May 1996, a total of 43 (5%) patients had received a dura mater graft as part of a surgical procedure (typically a patch during neurosurgery); 41 (95%) of these dCJD patients had received a Lyodura graft (3). A 1987 U.S. investigation of a dCJD case found that Lyodura produced before May 1987 carried an unusually high risk for dCJD because of the contamination-prone method of production (9,10); after that report, the manufacturer reported revising its collection and processing procedures to reduce the CJD transmission risk.

By 2008, a total of 132 dCJD cases had been reported in Japan, and among 120 (91%), Lyodura was identified as the probable vehicle of transmission; the graft brand for the other 12 dCJD patients was unknown (4). By the end of 2017, the J-CJDSC database included 154 patients with dCJD, including an additional 22 patients identified since the last report (4).

Among 154 dCJD patients, receipt of a Lyodura graft was documented in 140 (91%); the brand of dural graft received by 14 patients was not identified. The most common medical conditions for which patients received the cadaveric dura mater grafts were brain tumors (including meningioma) (69; 45%), facial palsy or trigeminal neuralgia (26; 17%), and brain hemorrhage (25; 16%). Less common conditions included intracranial aneurysm (10; 6%), unspecified anomalies (eight; 5%), intracranial hematoma (seven; 5%), trauma (seven; 5%), and other (two; 1%). The median age at symptom onset among dCJD patients was 58 years (range = 15–81 years; mean = 56 years); 89 (58%) patients were female. All patients had received their dura mater graft during 1975–1993 (Figure 1) (Figure 2), and dates of illness onset ranged from 1985 to 2016.

Although the shelf life of Lyodura established by the manufacturer was 5 years, three dCJD patients had surgical procedures in 1993, at least 6 years after the company had changed their collection and processing procedures. J-CJDSC determined that all three patients had received a Lyodura graft, and that at least one of the grafts was processed before 1987, and had therefore expired (the processing date of the second and third patients’ grafts are unknown). Eleven (7%) dCJD patients identified by J-CJDSC received grafts during 1988–1993 (Figure 2), including eight during 1988–1991, indicating that they might have received unexpired Lyodura produced before the company changed its processing procedures in 1987. In 1997, a case occurred in a patient with a history of two neurosurgical procedures in 1991. Investigation by J-CJDSC revealed that the patient had received a graft produced before 1987 during the first procedure. None of the dCJD cases identified to date received a dural graft after 1993.

In Japan, it is estimated that 20,000 persons received a Lyodura graft each year during 1983–1987, approximately 50 times more than the estimated number of U.S. recipients (4). During this period, 123 Japanese patients who subsequently developed dCJD had surgical procedures, including 114 (93%) who had documentation of receipt of a Lyodura graft (the graft brand of the other nine patients was unknown), indicating that the risk for developing dCJD within 30 years of receiving a Lyodura graft in Japan was at least one per 877 (i.e., 114 dCJD cases per 100,000 Lyodura graft recipients). In this analysis, both the median and mean intervals from receipt of dural graft to illness onset (latency period) were 13 years (range = 1–30 years) (Figure 3). Since the update in 2008, 11 of the 22 newly reported dCJD cases have had latency periods exceeding 24 years, the longest interval reported in 2008 (4) (Figure 3). In three of these 11 cases, the latency period was 30 years, the longest reported to date.


A comprehensive 2012 global summary of dCJD cases by country (2) reported that 142 (62%) of 228 cases of dCJD described worldwide occurred in Japan, and that at least one dCJD case was reported from 20 other countries. In the United States, four cases attributed to dura mater grafts have been identified; three were linked to a Lyodura graft produced before 1987, and one to a different commercially produced cadaveric dura mater graft. Lyodura grafts produced before 1987 were widely distributed to many countries, but most frequently to Japan.

During the U.S. investigation of the first Lyodura-associated CJD case in 1987 (9,10), investigators learned that the company mixed dura from multiple donors during batch processing of single lots and sterilized the grafts with gamma irradiation, a procedure that does not inactivate prions (10). A Lyodura representative also reported that the company did not maintain records identifying donors, so they could not be traced. Lyodura was only available to U.S. hospitals by mail if ordered from a non-U.S. distributor because the manufacturer did not produce the product for distribution in the United States.

Owing to Lyodura’s 5-year shelf life, it is likely that the eight dCJD patients in Japan who received Lyodura during 1988–1991 received grafts produced before the company changed its processing procedures in 1987. In addition, the three patients who received a graft in 1993 all received Lyodura grafts, one of which was documented to be an expired graft processed before 1987.

Age at onset of dCJD depends on the patient’s age at receipt of a dural graft and the latency period. Although the latency period varies among patients, currently available data indicate that the upper limit is at least 30 years, which is longer than has been reported previously (4). The most recently diagnosed case, for example, occurred in a patient who received Lyodura during surgery for a craniopharyngioma in 1985 at age 27 years and developed dCJD 30 years later in 2015.

The findings in this report are subject to at least four limitations related to ascertainment of dCJD cases. First, because it is possible that dCJD patients with an unknown brand of dural graft did, in fact, receive Lyodura, it is likely that one dCJD case per 877 Lyodura recipients is an underestimate of the proportion of dCJD patients with Lyodura-related CJD. Second, the risk for a Lyodura-related CJD infection among dural graft recipients is unknown because many infected patients likely died from other causes before developing CJD. Third, additional dCJD cases related to receipt of Lyodura might still occur. The increased use of Lyodura in Japan is the most likely reason for the unusually high number of dCJD cases in Japan (4), although only estimates of the numbers of recipients in Japan and other countries, including the United States, are available. Finally, the medical conditions for which dura mater grafts were used in Japan differed from those in other countries (5): patients with dCJD in Japan more frequently received dura mater grafts for non–life-threatening conditions than did patients in other countries (5).

The cases described in this report indicate that recipients of prion-contaminated grafts could remain at risk for CJD for at least 30 years after receiving grafts. Given the known potential for even longer latency periods for prion diseases, this outbreak is expected to continue. The dCJD cases underscore the importance of establishing measures to eliminate or greatly reduce the possibility of CJD transmissions (e.g., strict donor screening, appropriate record keeping, prevention of cross-contaminations, and ideally, the use of validated sterilization methods) whenever human tissues, particularly of cadaveric origin, might be used to treat other patients. In addition, a system of human disease surveillance to detect the possible emergence of new sources of prion disease transmissions is needed. Furthermore, physicians maintaining a high index of suspicion for unusual prion disease cases, as well as a system of human disease surveillance to detect the emergence of new sources of prion disease transmissions, is needed to enable the prevention of infections Finally, maintaining surveillance for CJD in Japan is important to better assess the impact of the outbreak of dCJD and to identify additional cases.

Ministry of Health, Labour and Welfare, Japan.

P81 Iatrogenic Creutzfeldt-Jakob disease related to dura mater grafts

Professor Masahito Yamada1, Dr. Tsuyoshi Hamaguchi1, Dr. Kenji Sakai1, Dr. Moeko Noguchi-Shinohara1, Dr. Ichiro Nozaki1, Yu Taniguchi1, Dr. Atushi Kobayashi2, Dr. Atsuko Takeuchi3, Prof. Tetsuyuki Kitamoto3, Prof. Yosikazu Nakamura4, Prof. Nobuo Sanjo5, Dr. Tadashi Tsukamoto6, Prof. Masaki Takao7, Dr. Shigeo Murayama8, Dr. Yasushi Iwasaki9, Prof. Mari Yoshida9, Dr. Hiroshi Shimizu10, Prof. Akiyoshi Kakita10, Prof. Hitoshi Takahashi10, Dr. Hiroyoshi Suzuki11, Prof. Hironobu Naiki12, Prof. Hidehiro MIzusawa6

1Kanazawa University, Kanazawa, Japan, 2Hokkaido University, Sapporo, Japan, 3Tohoku University, Sendai, Japan, 4Jichi Medical University, Shimotsuke, Japan, 5Tokyo Medical and Dental University, Tokyo, Japan, 6National Center of Neurology and Psychiatry, Tokyo, Japan, 7Saitama Medical University International Medical Center, Hidaka, Japan, 8Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan, 9Aichi Medical University, Nagakute, Japan, 10University of Niigata,, Niigata, Japan, 11National Hospital Organization Sendai Medical Center, Sendai, Japan, 12University of Fukui, Fukui, Japan

Aims: To elucidate epidemiological, clinicopathological, and molecular features of dura mater graft-associated Creutzfeldt-Jakob disease (dCJD), and deposition of pathogenic proteins of neurodegenerative diseases in dCJD.

Methods: We investigated dCJD patients identified in Japan, including epidemiological and clinicopathological features, genetic and molecular characteristics of prion protein (PrP), and transmission properties to mice expressing human PrP (Ki-HuPrP). Deposition of amyloid β protein (Aβ) and other pathogenic proteins in dCJD patients were analysed in comparison with age-matched patients with sporadic CJD (sCJD).

Results: Until September 2016, 152 patients with dCJD have been identified in Japan, comprising about two-thirds of the world cases. They received dura mater grafts between 1975 and 1993 at the ages of 1-70 (av. 43) years for the surgery of brain tumor, hemorrhage, hemifacial spasm, etc. After the incubation periods of 1-30 (av. 13) years, they had dCJD onset at the ages of 15-80 (av. 56) years in 1985-2015. The higher incidence of dCJD in Japan may be related to more frequent use of cadaveric dura mater for non-life-threatening conditions than in other countries. dCJD was classified to plaque and non-plaque types. Non-plaque type had clinicopathological features of classical CJD, while, plaque type was characterized by relatively slow progression, lack or late occurrence of periodic encephalogram, unique MRI findings, methionine homozygosity (M/M) at codon 129 of the PrP gene, intermediate type PrPres (type i), and kuru plaques in the brain (MMiK). Transmission studies with the plaque type dCJD to Ki-HuPrP mice showed properties identical to sCJD-VV2 and MV2, indicating that the origin of the plaque type would be VV2 or MV2 sCJD (V2 prion strain). Furthermore, we identified two atypical cases of MMiK type among patients with “sCJD”; the two MMiK cases showed same properties as sCJD-VV2 or MV2 in transmission and protein misfolding cyclic amplification (PMCA) studies, indicating transmission of the V2 prion prion to these cases in the absence of dura mater or other grafts. Compared with sCJD, dCJD showed significantly severe cerebrovascular Aβ deposition (CAA), especially meningeal CAA, and subpial Aβ deposition; the severity was correlated with incubation period from dura mater grafting to death.

Conclusions: We revealed epidemiological, clinicopathological, and molecular features of dCJD. Plaque type dCJD was characterized by MMiK, indicating cross-sequence transmission of the V2 prion strain to methionine homozygotes. MMiK could be a marker to identify acquired prion diseases. Cerebral β-amyloidosis could be transmitted from humans to humans via cadaveric dura mater grafting. 

P119 Type-dependant diverse extension patterns of hyperintensity on diffusion-weighted MR images in dura mater graft-associated Creutzfeldt-Jakob disease

Dr Kenji Sakai1, Dr Tsuyoshi Hamaguchi1, Dr Nobuo Sanjo2, Dr Hiroyuki Murai3, Dr Yasushi Iwasaki4, Dr Tadanori Hamano5, Dr Mari Honma6, Dr Moeko Noguchi-Shinohara1, Dr Ichiro Nozaki1, Prof Yosikazu Nakamura7, Prof Tetsuyuki Kitamoto8, Dr Hidehiro Mizusawa9, Prof Masahito Yamada1 1Kanazawa University, Kanazawa, Japan, 2Tokyo Medical and Dental University, Tokyo, Japan, 3Kyushu University, Fukuoka, Japan, 4Aichi Medical University, Nagakute, Japan, 5University of Fukui, Fukui, Japan, 6Masu Memorial Hospital, Nihonmatsu, Japan, 7Jichi Medical University, Shimtsuke, Japan, 8Tohoku University, Sendai, Japan, 9National Center of Neurology and Psychiatry, Kodaira, Japan

Aims: Studies of dura mater graft-associated Creutzfeldt-Jakob disease (dCJD) cases have proposed that abnormal prion protein may propagate directly from the contaminated dura mater graft to the adjacent brain regions and spread to other brain areas. We aimed to elucidate extension patterns of the hyperintense areas on diffusion-weighted images (DWI) in patients with dCJD.

Methods: We collected the MR images and the medical records of dCJD cases identified by CJD Surveillance Committee in Japan between April 1999 and September 2016. The dCJD cases were classified into two clinicopathological subtypes (non-plaque type and plaque type). We analyzed a relationship among the abnormal signals on DWI, the pathological classification, and the sites of grafting. Sequential images were also assessed.

Results: We collected MR images of 11 patients with dCJD. Lyodura® was transplanted in all proven cases. Four cases were female. The median with range of the age at onset, the age at dural grafting, and the incubation period were 41 (26–76) years, 19 (10–53) years, and 22 (16–29) years, respectively. The dCJD cases were classified into 8 cases of the non-plaque type and 3 cases of the plaque type. Four of the 8 non-plaque-type cases and all the plaque-type cases were pathologically confirmed. Brain MRI was performed 3 (1–22) months, reported as median (range), after the onset. Initial brain MRI was taken significantly earlier in cases with non-plaque type (non-plaque 2.5 months vs plaque 10 months; P = 0.012). Regarding non-plaque type, hyperintense cerebral cortex and basal ganglia (BG) were obvious in all cases. Abnormal signals were much brighter on the side of dural grafting. Subsequent MRI performed in 5 cases showed widespread hyperintense lesions in the brain. In contrast, the plaque type cases showed diverse patterns of hyperintensity on DWI. In one case, initial hyperintense areas were shown in the BG, frontal cortex, and thalamus. The other case demonstrated the lesion confined to the BG and thalamus. Sequential images presented with frontal lesions in addition to BG and thalamus. The third case showed no apparent abnormalities in the cerebral cortex or BG on DWI 7 months after the onset; however, serial images showed hyperintensity in the cerebral cortex, thalamus, and cerebellum.

Conclusions: In cases with non-plaque type dCJD, there could be a close relationship between the hyperintense signals on DWI and the sites of dural grafting. Plaque-type prions could have different patterns of propagation in human CNS.


P126 Clinical and pathological characterization of “sporadic Creutzfeldt-Jakob disease” with histories of neurosurgery to identify iatrogenic cases

Dr. Tsuyoshi Hamaguchi1, Dr. Kenji Sakai1, Dr. Atsushi Kobayashi2, Professor Tetsuyuki Kitamoto3, Dr. Ryusuke Ae4, Professor Yosikazu Nakamura4, Professor Nobuo Sanjo5, Dr. Tadashi Tsukamoto6, Professor Hidehiro Mizusawa6, Professor Masahito Yamada1 1Department Of Neurology, Kanazawa University Hospital, Kanazawa, Japan, 2Laboratory of Comparative Pathology, Hokkaido University, Sapporo, Japan, 3Department of Neurological Science, Tohoku University, Sendai, Japan, 4Division of Public Health, Center for Community Medicine, Jichi Medical University, Shimotsuke, Japan, 5Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Tokyo, Japan, 6Department of Neurology, National Center of Neurology and Psychiatry, Kodaira, Japan

Aims: Recently, we revealed that patients with plaque-type dura mater graft-associated Creutzfeldt-Jakob disease (dCJD) showed atypical molecular features characterized by methionine homozygote at codon 129 of the prion protein gene (PrP), intermediate type PrPSc, and Kuru plaques, called MMiK. Surprisingly, we discovered that 2 patients who had been diagnosed as having sporadic Creutzfeldt-Jakob disease (sCJD) showed clinical, pathological, and molecular features identical to MMiK type, suggesting possible iatrogenic transmission. In this study, the objective is to investigate the possibility of iatrogenic transmission of prion disease in patients who have been diagnosed as having sCJD.

Methods: We investigated 1836 patients who were diagnosed as having sCJD and 5 patients who were diagnosed as having unclassified type CJD because of insufficient information of dura mater grafting in the nationwide surveillance of CJD in Japan, and compared between those with and without histories of neurosurgeries.

Results: Among 1841 patients with sCJD, 51 had histories of neurosurgery, but 13 patients were excluded from the study because they underwent neurosurgeries within 1 year before or after the onset of CJD. Between the patients with and without histories of neurosurgery, positive rate (84.2%, 32/38 patients) of periodic sharp-wave complexes (PSWCs) on electroencephalogram (EEG) in the patients with histories of neurosurgery were significantly less than that (94.4%, 1677/1776 patients) in the patients without histories of neurosurgery, although age at onset of CJD, sex distribution, distribution of polymorphism at codon 129 of PrP, disease duration of CJD (duration between the onset of CJD and the appearance of the akinetic mutism or death in the patients who died without akintic mutism), and positive rate of 14-3-3 protein and total tau (cut off 1200 pg/ml) in cerebrospinal fluid were not significantly different. Among 38 sCJD patients with histories of neurosurgery, 9 (23.7%) had atypical CJD features that showed no PSWCs on EEG or had disease duration longer than 1 year. Three of the 9 atypical patients with histories of neurosurgery were autopsied, and one patient was MM2-thalamic form, one patient was MM2-cortical form, and another one patient was MMiK.

Conclusions: Among the patients who were diagnosed as sCJD or unclassified type CJD, some patients with histories of neurosurgery, but without dura mater grafting, had atypical clinical and neuropathological features similar to plaque type dCJD. Neuropathological study with PrP typing is essential to identify iatrogenic cases in patients with prion disease and history of neurosurgery.


Iatrogenic CJD after human cadaver-sourced growth hormone treatment in France: identifying risk factors associated with susceptibility

Ms Laurene Peckeu1, PhD Dominique Costagliola4, MD Jean-Philippe Brandel1,2, MD, PhD Stephane Haïk1,2,3 1Institut Du Cerveau Et De La Moelle Épinière (ICM) - Team "alzheimer's And Prion Diseases "inserm Umr-1127/cnrs Umr 7225, Paris, France, 2AP-HP, Cellule Nationale de Référence des maladies de Creutzfeldt-Jakob, Groupe Hospitalier Pitié-Salpêtrière, Paris, France, 3AP-HP, Laboratoire de Neuropathologie R Escourolle, Groupe Hospitalier Pitié-Salpêtrière, Paris, France, 4Institut Pierre Louis d’Epidémiologie et de Santé Publique, Sorbonne Universités, Inserm et UPMC Univ Paris 06 (UMR_S 1136), Paris, France

Background: Human growth hormone (hGH) treatment is the main cause of iatrogenic CJD (iCJD-hGH) in France. Among the 1443 patients who received cadaver-sourced hGH during the high-risk period from December 1983 to July 1985, 119 patients developed Creutzfeldt-Jakob disease. In this study, risk factors associated with the susceptibility of developing iCJD-hGH were analysed.

Methods: Two multivariate cox analyses were performed on the 1443 subjects. The first one (Bonferroni correction, level of significance for univariate analysis at 0.0008) aimed to determine, among all the 63 batches dispensed during this period, those significantly associated with the risk of developing CJD. The second model aimed to assess the association of sex, age at beginning of treatment, treatment duration and number of doses received from each batch with susceptibility. In this model all variables individually associated with susceptibility at a significant level of p<0 .1="" analysis="" in="" included="" level="" multivariate="" of="" p="" significance:="" span="" the="" then="" were="">

Results: Nineteen batches were identified after univariate analysis. Five of them were significantly associated with susceptibility after multivariate analysis. The number of doses delivered from batches identified at risk was statistically different (mean=55.3 for hGH-CJD group and 16.1 for non hGH-CJD group). iCJD-hGH was significantly more frequent in males (10%) compared to females (5%). Median age at the beginning of treatment was 12.0 years in non hGH-CJD group, and 12.1 in hGH-CJD group. Treatment duration was significantly higher in hGH-CJD group. Risk factors associated with the susceptibility identified by the second model were gender (HR, 1.70; 95%CI, 1.08-2.67) and the number of doses from the batches identified at risk by the first analysis (HR, 2.90; 95%CI, 2.22-3.79).

Discussion: In the final model, among the five batches that were significantly associated with susceptibility, four were previously reported as at risk (Huillard d’Aignaux et al., 1998). Of the 1443 patients, 550 were exposed to at least one of these five batches and only 18% (n=100) of them developed iCJD-hGH suggesting that additional risk factors were involved. The second model showed a significant association between sex, doses and susceptibility of developing iCJD-hGH. While the relationship between infectious dosis and attack rate is a well known phenomenon in experimental infectious models of prion diseases, this is the first evidence, to our knowledge, that it also applies in humans. Surprinsingly, we observed an effect of gender with a two-fold higher proportion in male that could not been explained by a difference in exposure. 

THURSDAY, MAY 17, 2012 

Iatrogenic Creutzfeldt-Jakob Disease, Final Assessment 

Volume 18, Number 6—June 2012

Paul Brown , Jean-Philippe Brandel, Takeshi Sato, Yosikazu Nakamura, Jan MacKenzie, Robert G. Will, Anna Ladogana, Maurizio Pocchiari, Ellen W. Leschek, and Lawrence B. Schonberger Author affiliations: Centre à l’Energie Atomique, Fontenay-aux-Roses, France (P. Brown); Institut National de la Santé et de la Recherche Médicale, Paris, France (J.-P. Brandel); Nanohana Clinic, Tokyo, Japan (T. Sato); Jichi Medical University, Yakushiji, Japan (Y. Nakamura); Western General Hospital, Edinburgh, Scotland, UK (J. MacKenzie, R.G. Will); Istituto Superiore de Sanità, Rome, Italy (A. Ladogana, M. Pocchiari); National Institutes of Health, Bethesda, Maryland, USA (E.W. Leschek); Centers for Disease Control and Prevention, Atlanta, Georgia, USA (L.B. Schonberger)


The era of iatrogenic Creutzfeldt-Jakob disease (CJD) has nearly closed; only occasional cases with exceptionally long incubation periods are still appearing. The principal sources of these outbreaks are contaminated growth hormone (226 cases) and dura mater grafts (228 cases) derived from human cadavers with undiagnosed CJD infections; a small number of additional cases are caused by neurosurgical instrument contamination, corneal grafts, gonadotrophic hormone, and secondary infection with variant CJD transmitted by transfusion of blood products. No new sources of disease have been identified, and current practices, which combine improved recognition of potentially infected persons with new disinfection methods for fragile surgical instruments and biological products, should continue to minimize the risk for iatrogenic disease until a blood screening test for the detection of preclinical infection is validated for human use.

I hope and pray that Paul Brown et al rosey outlook is correct, and the end of iatrogenic Creutzfeldt Jakob Disease is truly over, bbut, I have my doubts. ...TSS

5.3.3 The greatest risk, in theory, would be from parenteral injection of material derived from bovine brain or lymphoid tissue. Medicinal products for injection or surgical implantation which are prepared from bovine tissues, or which utilise bovine serum albumin or similar agents in their manufacture, might also be capable of transmitting infectious agents. All medicinal products are licensed under the Medicines Act by the Licensing Authority following guidance, for example from the Committee on Safety of Medicines (CSM), the Committee on Dental and Surgical Materials (CDSM) and their subcommittees. The Licensing Authority have been alerted to potential concern about BSE in medicinal products and will ensure that scrutiny of source materials and manufacturing processes now takes account of BSE agent.


No papers were presented by our American guests and none covered the subject of pharmaceuticals. ...

The documents below were provided by Terry S. Singeltary Sr on 8 May 2000. They are optically character read (scanned into computer) and so may contain typos and unreadable parts.


Mr Cunningham CMP3 From: D O Hagger MBI Dr Salisbury MED/IMCD3 Mr Burton PD/STB/PG1B B/17/2 Date: 15.02.1989 Mr Dudley PD/AD4


89/06.19/8.1 BSE3/1 0191 Hr J Maslin (MAFF) Ref: Maslin3g

From: Dr H Pickles Med SEB/B Date: 3 July 1989


I was interested to see the list of by-products sent to the HSE. Those of particular concern included:

* small intestines: sutures (I thought the source was ovine but you are checking this)

* spinal cord: pharmaceuticals

* thymus: pharmaceuticals

Are you able to give me more information on which UK manufacturers use these materials? Our proposed ban on bovine offal for human consumption would not affect these uses, I assume.

snip...see full text ;

Thursday, October 23, 2008

Creutzfeldt-Jakob Disease Associated with Cadaveric Dura Mater Grafts – Japan, 1979-2008 : UPDATE 


A case of Iatrogenic Creutzfeldt Jakob Disease (iCJD) in a patient who had received a German-manufactured human dura mater graft 23 years ago

Monday, February 01, 2010

Import Alert 57-20 and 84-03 Human Dura Mater and risk factors there from due to Creutzfeldt Jakob Disease (CJD) 

Wednesday, June 29, 2011 

TSEAC Meeting August 1, 2011 donor deferral ... 

Thursday, March 8, 2018

Familial human prion diseases associated with prion protein mutations Y226X and G131V are transmissible to transgenic mice expressing human prion protein


 CJD * Lyodura-B.Braun Melsungen AG, Germany


 "Terry S. Singeltary Sr."


 Bovine Spongiform Encephalopathy


 Mon, 27 Sep 1999 10:35:09 -0500




 Parts/Attachments text/plain (10 lines)

Reply Reply

Terry S. Singeltary Sr., Bacliff, Texas USA -- Greetings, I was hoping Roland or someone, could tell me if this Company (Lyodura-B.Braun Melsungen AG, Germany) is still paying out settlements for the medical deaths from CJD and their product? How far back, has their product been found to be infected and or, was it found to be deadly in 1982? Was the material in 1982 taken from cows or humans or both?

Many Thanks, Terry


 Re: CJD * Lyodura-B.Braun Melsungen AG, Germany


 Jennifer Cooke


 Bovine Spongiform Encephalopathy


 Wed, 29 Sep 1999 00:24:32 +1000




 Parts/Attachments text/plain (55 lines)

Reply Reply

Cear Terry,

I devoted most of one chapter in my book, Cannibals Cows & the CJD Catastrophe (Random House Australia) to CJD deaths from dura mater including Lyodura, that have been reported in the literature since the initial FDA warning about Lyodura in 1987.

Several cases related to 1982 - either because the Lyodura was manufactured in that year, or the operation of the victim took place in that year. One confidential settlement I know of was to the family of a British man who died of CJD in 1989 following a Lyodura graft in 1985.

There have now been four deaths in Australia from CJD after Lyodura grafts - all of which related to operations carried out in 1982. The latest death occurred in June this year - which means that the incubation period has now blown out to more than 17 years for this type of peripheral infection. Quite horrifying. I believe the family intends to sue ...


Jennifer Cooke



 Japan releases bad Lyodura lot numbers




 Bovine Spongiform Encephalopathy


 Wed, 20 Sep 2000 14:53:39 -0800




 Parts/Attachments text/plain (62 lines)

Reply Reply

######### Bovine Spongiform Encephalopathy #########

This is hot, they actually published the bad lot numbers on the Lyodura in the newspaper. NIH has fought off US residents for years. on the growth hormone lot numbers, to protect their crazy man in North Carolina who insisted on injecting crude pituitary extracts. Some recipients do want to know whether they got an injection from a bad lot; some don't -- but I never heard from anyone who wanted Big Brother making the decision for them.

There is a staggering amount of this Lyodura implanted in people: Japan alone imported "12,545 boxes of the dura mater, manufactured in 1982 by B. Braun Melsungen AG." It doesn't say how many uses per box or how many boxes comprise a serial number, or how many individuals were pooled per serial number.

It would be so cool if some serial number 2105 or so is still around -- then we could test it to see what species it came from (I say sheep, given that is what their contract surgeon, who died of CJD a few years thereafter, was removing as dura mater source).


 CJD-linked product banned in U.S. was imported to ... Kyodo World Service Wed, Sep 20, 2000

 TOKYO, Sept. 21 (Kyodo) -- The government on Wednesday admitted to the likelihood that Japan imported German medical products which reportedly caused Creutzfeldt-Jakob Disease (CJD) even after the United States had warned of the danger in 1987, contradicting its previous claims.

 Kazuo Maruta, a senior official at the Health and Welfare Ministry, said the German-made dried dura mater used for brain surgery produced in 1982 was likely to have been imported before 1997.

 The U.S. Food and Drug Administration (FDA) in 1987 issued a domestic advisory not to use such dura mater made in that year, after learning about a report that it could cause CJD.

 Symptoms of the disease include rapidly progressive dementia, loss of cerebral functions, and paralysis of limbs, with parts of the brain becoming sponge-like.

 Maruta, chief of the ministry's Pharmaceutical and Medical Safety Bureau, told members of the Health and Welfare Committee at the House of Representatives that it is "likely" that the product, Lyodura with serial numbers 2000 to 2999, was imported into Japan.

 He cited a report by Tokyo importer Nihon B.S.S. which said 12,545 boxes of the dura mater, manufactured in 1982 by B. Braun Melsungen AG, were imported that year.

 Health and Welfare Minister Yuji Tsushima also told the committee, "It was impossible (for the government) to foresee the dangers of the product."

 Previously, the ministry has denied the possibility of any imports, insisting that Lyodura with the serial number 2105, which the U.S. government said caused the first-discovered case of CJD, was not imported into Japan.

 The German firm recalled the 2105 Lyodura in early 1987 and the FDA advised domestic medical facilities to abandon the product with serial numbers from 2000 to 2999.

 It was only 10 years later that the Japanese ministry prohibited use of the product.

 More than 40 people, including CJD victims and their relatives, have filed two damages suits with the Tokyo District Court and the Otsu District Court, Shiga Prefecture, accusing the Japanese companies involved and the German firm of negligence, as well as the Japanese government.

############ ############


 Re: Japan releases bad Lyodura lot numbers


 "Bossers, A."


 Bovine Spongiform Encephalopathy


 Thu, 21 Sep 2000 08:44:59 +0200




 Parts/Attachments text/plain (23 lines)

Reply Reply

######### Bovine Spongiform Encephalopathy #########


Sorry but I don't get it.

> It would be so cool if some serial number 2105 or so is still > around -- > then we could test it to see what species it came from (I say > sheep, given > that is what their contract surgeon, who died of CJD a few years > thereafter, was removing as dura mater source). > > tom >

You think that Lyodura grafts were made of other origin than human? Do you have references to that? Thought they were of human origin solely and that only animal products were used for ie. catgut / sutures?


############ ############


 Re: Japan releases bad Lyodura lot numbers




 Bovine Spongiform Encephalopathy


 Thu, 21 Sep 2000 06:36:13 -0800




 Parts/Attachments text/plain (54 lines)

Reply Reply

######### Bovine Spongiform Encephalopathy #########

>> It would be so cool if some serial number 2105 or so is still >> around -- >> then we could test it to see what species it came from (I say >> sheep, given >> that is what their contract surgeon, who died of CJD a few years >> thereafter, was removing as dura mater source).

>You think that Lyodura grafts were made of other origin than human? Do you >have references to that? Thought they were of human origin solely and that >only animal products were used for ie. catgut / sutures? >

I was surprised to find that xenotransplants have been going on for decades on a truly massive scale in many countries. It is not just cowgut surgical sutures, but anything and everything that doesn't set off too bad an immune response. One of the more insiduous aspects of the BSE epidemic is the large number of bovinebiologicals that came onto the international comodity markets. We saw just one British company selling 40,000 bovine pericardium patches at year for use in human heart valve replacements.

I posted many months back all the species used previously for dura mater transplants in human, as seen in simple Medline searches. I also posted some ideas on how to experimentally determine the species of origin for a given piece of dura mater, be it still in the box or removed from a iatrogenic CJD cadaver (there are a couple of intrinsic proteins that could be seen with IgG).

I also posted a newspaper account of the German orthopedic surgeon employed by this dura mater company to remove dura mater from sheep brain. The cause of his CJD was never determined (though the diagnosis was not in doubt); it could have been anything from handling sheep scrapie dura mater to inherited. I don't know if he also handled human dura mater for the company. Scrapie is only uncommonly reported in German sheep.

The idea here is not to make assumptions about the species origin of Lyodura, but rather to test the species origin experimentally. The purpose here is not to investigate the company.

Rather, Japan may have inadvertently done the scrapie-to-human intra-cerebral injection experiment that medical ethics prevents us from doing directly today. This would complement the successful in vitro conversion experiments that you and your colleagues have published.

Given the scale of dura mater use in Japan, there may still be boxes left of dura mater in the 2000-2999 serial number range. Or there may be material recoverable from 2105 recipients. Given the low incidence of CJD compared to scrapie, I would say that if any of the dura mater is sheep, the whole episode can be probably be attributed to scrapie.


############ ############


 Re: Japan releases bad Lyodura lot numbers




 Bovine Spongiform Encephalopathy


 Thu, 21 Sep 2000 08:48:32 -0800




 Parts/Attachments text/plain (169 lines)

Reply Reply

######### Bovine Spongiform Encephalopathy #########


Mon, 19 Jul 1999 was when this came up. Here is the relevent Lancet article. 

 Transmission of Creutzfeldt-Jakob disease by handling of dura mater.

The Lancet Volume 341(8837) January 9, 1993 pp 123-124 Weber, Thomas; Tumani, Hayrettin; Holdorff, Bernd; Collinge, John; Palmer, Mark; Kretzschmar, Hans A.; Felgenhauer, Klaus

Sir,- Creutzfeldt-Jakob disease (CJD) can be transmitted iatrogenically by human pituitary growth hormone, corneal transplants, and dura mater grafts (1). Possible accidental transmission has been reported in only four people-a neurosurgeon (2), a pathologist (3), and two laboratory technicians (4,5) . We have encountered an unusually rapid case of CJD probably acquired through handling of sheep and human dura mater.

In May, 1992, a 55-year-old orthopaedic surgeon developed paraesthesia of the left arm. A few days later he had spatial disorientation, apraxia, and gait ataxia. In June he was admitted and a neurologist suspected CJD on the basis of the clinical signs, typical electroencephalogram (EEG) pattern, and history. An EEG in June revealed a typical pattern of periodic biphasic and triphasic sharp wave complexes.

We saw the patient in July, 1992. He was awake and oriented, with dyscalculia, dysgraphia, disturbed vision, apraxia mainly of the left side, rigidity of wrists, spasticity of all muscles, myoclonus of the left arm, increased tendon reflexes, ataxia of limbs and trunk, and incoordination of left arm. Within 3 weeks he had impaired consciousness and attention, mildly impaired memory, and threatening visual hallucinations with restless turning. He had periodic states with movements of his head and eye-bulbs resembling tonic adversive seizures. During sleep these motor disturbances stopped. 2 1/2 months later the patient died.

This patient had worked with sheep and human dura mater from 1968 to 1972. He handled about 150 specimens of ovine origin and at least a dozen human preparations for research. Handling involved opening skulls with a band saw, removing dura, and testing them either fresh (usually), preserved, or lyophilised for mechanical qualities.

These specimens were sent to a company that has sold dura mater preparations by which CJD was transmitted in six instances. No information was available from the company about a possible connection with this patient's disease and the earlier cases of transmitted CJD.

Brain biopsy was consistent with diagnosis of CJD. Cerebrospinal fluid obtained in July showed neuron-specific enolase (NSE) at 82.0 ng/mL, compared with 16.7 ng/mL in serum of other cases (6). Proton magnetic resonance spectroscopy of parieto-occipital and temporal grey matter, parietal white matter, and thalamus revealed a 20-30% reduction of N-acetylaspartate, as described (7). DNA was genotyped with allele-specific oligonucleotides (8) and was homozygous for methionine at the polymorphic codon 129. Subsequent direct DNA sequencing for the PrP gene open-reading frame demonstrated normal sequence on both alleles, excluding known or novel pathogenic PrP mutations.

It is tempting to speculate that prions were transmitted to this patient from sheep or human dura mater through small lacerations of his skin, but the patient and his wife did not remember any significant injury during his four years of working with these samples. It cannot be excluded that this was a case of sporadic CJD although this assumption is unlikely in view of the clinical course which was similar to iatrogenic CJD transmitted by peripheral inoculation, such as with human pituitary growth hormone or gonadotropin or to kuru (1). Iatrogenic cases resulting from intracerebral inoculation with the transmissible agent, for instance following dura mater grafts (2-5), present with a dementing picture, as is usual in sporadic CJD, rather than with ataxia as in this case.

=-==-=-=- Iatrogenic scrapie from sheep dura mater?

Mon, 19 Jul 1999 Listserve and Lancet January 9, 1993 pp 123-124

An orthopaedic surgeon employed by the Lyodura company [Braun Melsungen] extracted dura mater from sheep and human cadavers and came down with fast CJD 22 years later. The ratio of sheep to human dura mater he collected was150 sheep to 12 humans. Apparently the surgeon and the sheep were German. Scrapie has long been present in Germany but reported levels are very low, about a flock a year has to be destroyed. I am not aware of any high sensitivity tests or random screening every being used in Germany to assess the levels of preclinical animals.

This raises the question, what did the lyodura company do with so much dura mater from sheep? The market for specialty surgical products was overwelmingly in humans in 1968. Are there companies today that sell sheep dura mater for research? The Lancet article only says it was for research -- but in what species? Perhaps dura mater gives an immune response across species after processing, ruling out its use in humans. But blood type or other genetic differences do not matter within humans, ie, there is no tissue matching with dura mater.

How CJD could show up from a handful of human dura mater donations with sporadic CJD supposedly so rare -- this would be extraordinary bad luck that any of 150 sheep + 12 humans could have carried the disease. On the other hand, there would be no surprise at all if a case of subclinical scrapie showed up in 150 sheep. [While Germany only reports one case a year of scrapie and destroys the flock, the disease nonetheless persists, indicating under-reporting.]

This raises the question, have dura mater recipients or the surgeon subsequently been strain-typed? This might give a very different outcome than other forms of iatrogenic CJD or simply co-classify with pituitary growth hormone if route of infection (injected, oral, hereditary, etc.) is more important than strain source.

Otherwise, iatrogenic scrapie (like cwdCJD) is somwhat unpredictable in its gel pattern (though strains of scrapie in other primate species might be re-examined). The original scrapie strain is not be identifiable directly because material was not likely retained. Strain-typing was not available at the time of the article -- but Collinge was one of the authors.

There is little doubt that scrapie could be transfered to humans by intracerebral injection (based on lack of species barrier in primates) and that processed pooled (human?) dura mater can carry sufficient infectivity to cause CJD. Animal experiments have not commonly used sheep dura mater as experimental dose source.

If any humans received sheep dura mater, it is doubtful that this will be disclosed or that specific recipients will be identified to their doctors. It is probably better to trace backwards from affected recipients -- see if they strain-type out to be sheep.

Japan has been particularly hard hit by dura mater CJD (curious in itself) and researchers there might be motivated to find out what happened. I am not aware of agricultural agencies that would impede research over there.

############ ############



While this clearly is a cause for concern we should not jump to the conclusion that this means that pigs will necessarily be infected by bone and meat meal fed by the oral route as is the case with cattle. ...

we cannot rule out the possibility that unrecognised subclinical spongiform encephalopathy could be present in British pigs though there is no evidence for this: only with parenteral/implantable pharmaceuticals/devices is the theoretical risk to humans of sufficient concern to consider any action.

Our records show that while some use is made of porcine materials in medicinal products, the only products which would appear to be in a hypothetically ''higher risk'' area are the adrenocorticotrophic hormone for which the source material comes from outside the United Kingdom, namely America China Sweden France and Germany. The products are manufactured by Ferring and Armour. A further product, ''Zenoderm Corium implant'' manufactured by Ethicon, makes use of porcine skin - which is not considered to be a ''high risk'' tissue, but one of its uses is described in the data sheet as ''in dural replacement''. This product is sourced from the United Kingdom.....



Location: Virus and Prion Research

Title: Disease-associated prion protein detected in lymphoid tissues from pigs challenged with the agent of chronic wasting disease

Author item Moore, Sarah item Kunkle, Robert item Kondru, Naveen item Manne, Sireesha item Smith, Jodi item Kanthasamy, Anumantha item West Greenlee, M item Greenlee, Justin

Submitted to: Prion Publication Type: Abstract Only Publication Acceptance Date: 3/15/2017 Publication Date: N/A Citation: N/A Interpretive Summary:

Technical Abstract: Aims: Chronic wasting disease (CWD) is a naturally-occurring, fatal neurodegenerative disease of cervids. We previously demonstrated that disease-associated prion protein (PrPSc) can be detected in the brain and retina from pigs challenged intracranially or orally with the CWD agent. In that study, neurological signs consistent with prion disease were observed only in one pig: an intracranially challenged pig that was euthanized at 64 months post-challenge. The purpose of this study was to use an antigen-capture immunoassay (EIA) and real-time quaking-induced conversion (QuIC) to determine whether PrPSc is present in lymphoid tissues from pigs challenged with the CWD agent.

Methods: At two months of age, crossbred pigs were challenged by the intracranial route (n=20), oral route (n=19), or were left unchallenged (n=9). At approximately 6 months of age, the time at which commercial pigs reach market weight, half of the pigs in each group were culled (<6 challenge="" groups="" month="" pigs="" remaining="" the="">6 month challenge groups) were allowed to incubate for up to 73 months post challenge (mpc). The retropharyngeal lymph node (RPLN) was screened for the presence of PrPSc by EIA and immunohistochemistry (IHC). The RPLN, palatine tonsil, and mesenteric lymph node (MLN) from 6-7 pigs per challenge group were also tested using EIA and QuIC.

Results: PrPSc was not detected by EIA and IHC in any RPLNs. All tonsils and MLNs were negative by IHC, though the MLN from one pig in the oral <6 5="" 6="" at="" by="" detected="" eia.="" examined="" group="" in="" intracranial="" least="" lymphoid="" month="" months="" of="" one="" pigs="" positive="" prpsc="" quic="" the="" tissues="" was="">6 months group, 5/6 pigs in the oral <6 4="" and="" group="" months="" oral="">6 months group. Overall, the MLN was positive in 14/19 (74%) of samples examined, the RPLN in 8/18 (44%), and the tonsil in 10/25 (40%). Conclusions:

This study demonstrates that PrPSc accumulates in lymphoid tissues from pigs challenged intracranially or orally with the CWD agent, and can be detected as early as 4 months after challenge.

CWD-infected pigs rarely develop clinical disease and if they do, they do so after a long incubation period. This raises the possibility that CWD-infected pigs could shed prions into their environment long before they develop clinical disease.

Furthermore, lymphoid tissues from CWD-infected pigs could present a potential source of CWD infectivity in the animal and human food chains.


Disease-associated prion protein detected in lymphoid tissues from pigs challenged with the agent of chronic wasting disease


*** Disease-associated prion protein detected in lymphoid tissues from pigs challenged with the agent of chronic wasting disease ***


----- Original Message -----

From: Terry S. Singeltary Sr.


Sent: Wednesday, November 29, 2006 1:24 PM

Subject: TSE advisory committee for the meeting December 15, 2006 [TSSSUBMISSION] November 29, 2006

Greetings FDA, DHH, Dr. Freas, and Dr. Harvey et al,

a kind and warm Holiday Greetings to you all. i kindly wish to submit the following to the TSE advisory committee for the meeting December 15, 2006, about the assessment for potential exposure to vCJD in human plasma-derived antihemophilic factor (FVIII) products manufactured from U.S. plasma donors and related communication material ; 

i see the media picked up on this as a 'low risk', from what the gov. agency perceived to be to them;,0,7955259.story?coll=ny-leadhealthnews-headlines 

however, i seem to disagree. from my primitive ciphering, i see it anotherway. this is a huge catastrophic risk. 3 in 160 is 1.9%. so call that 2% which is 1 in 50 or twenty per thousand or 20,000 per million. also, what about the mixed genotypes/mixed susceptibility? what about the silent carriers that donated tainted blood? what about the sporadic CJDs of UNKNOWN strain or phenotype? this risk assessment is just more BSe to me. just another in a long line of ...

Greetings again Dr. Freas et al at FDA,

THIS was like closing the barn door after the mad cows got loose. not only the red cross, but the FDA has failed the public in protecting them from the TSE aka madcow agent. TSE agent i.e. bse, base, cwd, scrapie, tme, and any sub strains thereof. we do not know if these strains will or have transmitted to humans as subclinical TSE or clinical disease, and we do not know if they have or will transmit second, third, forth passage via friendly fire i.e. multiple potential routes via medical, surgical, pharmaceutical etc. IF you remember correctly Dr. Freas et al, i called this long ago, almost 6 years ago ;


Terry S. Singeltary Sr. [] Monday, January 08, 200l 3:03 PM freas ...Freas, William From: Terry S. Singeltary Sr. [] Sent: Monday, January 08,200l 3:03 PM

To: freas@CBS5055530.CBER.FDA.GOV

Subject: CJD/BSE (aka madcow) Human/Animal TSE?s--U.S.--Submission

To Scientific Advisors and Consultants Staff January 2001 Meeting (short version)

Greetings again Dr. Freas and Committee Members,

I wish to submit the following information to the Scientific Advisors and Consultants Staff 2001 Advisory Committee (short version). I understand the reason of having to shorten my submission, but only hope that you add it to a copy of the long version, for members to take and read at their pleasure, (if cost is problem, bill me, address below). So when they realize some time in the near future of the 'real' risks i speak of from human/animal TSEs and blood/surgical products.


I am beginning to think that the endless attempt to track down and ban, potential victims from known BSE Countries from giving blood will be futile. You would have to ban everyone on the Globe eventually? AS well, I think we MUST ACT SWIFTLY to find blood test for TSE's, whether it be blood test, urine test, eyelid test, anything at whatever cost, we need a test FAST. DO NOT let the incubation time period of these TSEs fool you. To think of Scrapie as the prime agent to compare CJD, but yet overlook the Louping-ill vaccine event in 1930's of which 1000's of sheep where infected by scrapie from a vaccine made of scrapie infected sheep brains, would be foolish. I acquired this full text version of the event which was recorded in the Annual Congress of 1946 National Vet. Med. Ass. of Great Britain and Ireland. From the BVA and the URL is posted in my (long version). ...

see full text ;



Transmissible Spongiform Encephalopathies Advisory Committee; Termination




Norway 30,000 deer animals have so far been tested for Skrantesyke chronic wasting disease CWD TSE PRION DISEASE

TUESDAY, MARCH 06, 2018 


Sunday, February 25, 2018 


MONDAY, MARCH 05, 2018 

Chronic Wasting Disease: Status, Science, and Management EXPLANATION U.S. Department of the Interior U.S. Geological Survey Open-File Report 2017–1138 March 2018


Transmissible Spongiform Encephalopathy TSE Prion Chronic Wasting Disease CWD Cervids Zoonosis Update


Michigan DNR CWD National Perspective: Voluntary Captive Herd Certification Program - Dr. Tracy Nichols

MONDAY, MARCH 05, 2018 



Cervid, Wild Hogs, Coyotes, Wolves, Cats, Rodents, Gut Piles and Scavengers, A Potential Risk as Regards Disease Transmission CWD TSE Prion


Northern Ireland Industry to be landed with £143,000 BSE testing bill under TSE changes Industry to be landed with £143,000 BSE testing bill under TSE changes


Creutzfeldt Jakob Disease CJD National Prion Disease Pathology Surveillance Center Cases Examined to December 14, 2017

Discussion: The C, L and H type BSE cases in Canada exhibit molecular characteristics similar to those described for classical and atypical BSE cases from Europe and Japan.
*** This supports the theory that the importation of BSE contaminated feedstuff is the source of C-type BSE in Canada.
*** It also suggests a similar cause or source for atypical BSE in these countries. ***
see page 176 of 201 pages...tss
*** Singeltary reply ; Molecular, Biochemical and Genetic Characteristics of BSE in Canada Singeltary reply;
Wednesday, July 15, 2015
Additional BSE TSE prion testing detects pathologic lesion in unusual brain location and PrPsc by PMCA only, how many cases have we missed?
***however in 1 C-type challenged animal, Prion 2015 Poster Abstracts S67 PrPsc was not detected using rapid tests for BSE.
***Subsequent testing resulted in the detection of pathologic lesion in unusual brain location and PrPsc detection by PMCA only.
*** IBNC Tauopathy or TSE Prion disease, it appears, no one is sure ***
Posted by Terry S. Singeltary Sr. on 03 Jul 2015 at 16:53 GMT

Alzheimer's disease or TSE Prion ???

Re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy 

>>> 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 




[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.]

snip...see full Singeltary Nature comment here at bottom ; 

re-Evidence for human transmission of amyloid-? 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)

I would kindly like to comment on the Nature Paper, the Lancet reply, and the newspaper articles.

First, I applaud Nature, the Scientist and Authors of the Nature paper, for bringing this important finding to the attention of the public domain, and the media for printing said findings.

Secondly, it seems once again, politics is getting in the way possibly of more important Transmissible Spongiform Encephalopathy TSE Prion scientific findings. findings that could have great implications for human health, and great implications for the medical surgical arena. but apparently, the government peer review process, of the peer review science, tries to intervene again to water down said disturbing findings.

where have we all heard this before? it?s been well documented via the BSE Inquiry. have they not learned a lesson from the last time?

we have seen this time and time again in England (and other Country?s) with the BSE mad cow TSE Prion debacle.

That ?anonymous' Lancet editorial was disgraceful. The editor, Dick Horton is not a scientist.

The pituitary cadavers were very likely elderly and among them some were on their way to CJD or Alzheimer's. Not a bit unusual. Then the recipients ? who got pooled extracts injected from thousands of cadavers ? were 100% certain to have been injected with both seeds. No surprise that they got both diseases going after thirty year incubations.

That the UK has a "system in place to assist science journalists" to squash embargoed science reports they find ?alarming? is pathetic.

Sounds like the journalists had it right in the first place: ?Alzheimer?s may be a transmissible infection? in The Independent to ?You can catch Alzheimer?s? in The Daily Mirror or ?Alzheimer?s bombshell" in The Daily Express

if not for the journalist, the layperson would not know about these important findings.

where would we be today with sound science, from where we were 30 years ago, if not for the cloak of secrecy and save the industry at all cost mentality?

when you have a peer review system for science, from which a government constantly circumvents, then you have a problem with science, and humans die.

to date, as far as documented body bag count, with all TSE prion named to date, that count is still relatively low (one was too many in my case, Mom hvCJD), however that changes drastically once the TSE Prion link is made with Alzheimer?s, the price of poker goes up drastically.

so, who makes that final decision, and how many more decades do we have to wait?

the iatrogenic mode of transmission of TSE prion, the many routes there from, load factor, threshold from said load factor to sub-clinical disease, to clinical disease, to death, much time is there to spread a TSE Prion to anywhere, but whom, by whom, and when, do we make that final decision to do something about it globally? how many documented body bags does it take? how many more decades do we wait? how many names can we make up for one disease, TSE prion?

Professor Collinge et al, and others, have had troubles in the past with the Government meddling in scientific findings, that might in some way involve industry, never mind human and or animal health.

FOR any government to continue to circumvent science for monetary gain, fear factor, or any reason, shame, shame on you.

in my opinion, it?s one of the reasons we are at where we are at to date, with regards to the TSE Prion disease science i.e. money, industry, politics, then comes science, in that order.

greed, corporate, lobbyist there from, and government, must be removed from the peer review process of sound science, it?s bad enough having them in the pharmaceutical aspect of healthcare policy making, in my opinion.

my mother died from confirmed hvCJD, and her brother (my uncle) Alzheimer?s of some type (no autopsy?). just made a promise, never forget, and never let them forget, before I do.

I kindly wish to remind the public of the past, and a possible future we all hopes never happens again. ...


Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?


Alzheimer’s disease and Transmissible Spongiform Encephalopathy disease have both been around a long time, and was discovered in or around the same time frame, early 1900’s. Both diseases are incurable and debilitating brain disease, that are in the end, 100% fatal, with the incubation/clinical period of the Alzheimer’s disease being longer (most of the time) than the TSE prion disease. Symptoms are very similar, and pathology is very similar.


Through years of research, as a layperson, of peer review journals, transmission studies, and observations of loved ones and friends that have died from both Alzheimer’s and the TSE prion disease i.e. Heidenhain Variant Creutzfelt Jakob Disease CJD.


I propose that Alzheimer’s is a TSE disease of low dose, slow, and long incubation disease, and that Alzheimer’s is Transmissible, and is a threat to the public via the many Iatrogenic routes and sources. It was said long ago that the only thing that disputes this, is Alzheimer’s disease transmissibility, or the lack of. The likelihood of many victims of Alzheimer’s disease from the many different Iatrogenic routes and modes of transmission as with the TSE prion disease.


There should be a Global Congressional Science round table event set up immediately to address these concerns from the many potential routes and sources of the TSE prion disease, including Alzheimer’s disease, and a emergency global doctrine put into effect to help combat the spread of Alzheimer’s disease via the medical, surgical, dental, tissue, and blood arena’s. All human and animal TSE prion disease, including Alzheimer’s should be made reportable in every state, and Internationally, WITH NO age restrictions. Until a proven method of decontamination and autoclaving is proven, and put forth in use universally, in all hospitals and medical, surgical arena’s, or the TSE prion agent will continue to spread. IF we wait until science and corporate politicians wait until politics lets science _prove_ this once and for all, and set forth regulations there from, we will all be exposed to the TSE Prion agents, if that has not happened already.


Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?

source references ...end...tss 

Hello Nicole,

by all means, please do use my poster. but I thought this was already taken care of, and I could not attend for my poster presentation, therefore, it was not going to be presented. I have some health issues and could not make the trip.

please see old correspondence below...

From: Nicole Sanders Sent: Tuesday, April 10, 2012 5:37 PM To: Terry S. Singeltary Sr. Subject: RE: re-submission

Dear Terry,

The decline of proposal number 30756 is registered in the system. Thank you for your consideration.

Best Regards,


Nicole Sanders

Senior Specialist, Membership & Conference Programming


From: xxxx 

To: Terry Singeltary 

Sent: Saturday, December 05, 2009 9:09 AM 

Subject: 14th ICID - abstract accepted for 'International Scientific Exchange'

Your preliminary abstract number: 670

Dear Mr. Singeltary,

On behalf of the Scientific Committee, I am pleased to inform you that your abstract

'Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America update October 2009'

WAS accepted for inclusion in the INTERNATIONAL SCIENTIFIC EXCHANGE (ISE) section of the 14th International Congress on Infectious Diseases. Accordingly, your abstract will be included in the "Intl. Scientific Exchange abstract CD-rom" of the Congress which will be distributed to all participants.

Abstracts accepted for INTERNATIONAL SCIENTIFIC EXCHANGE are NOT PRESENTED in the oral OR poster sessions.

Your abstract below was accepted for: INTERNATIONAL SCIENTIFIC EXCHANGE

#0670: Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America update October 2009

Author: T. Singeltary; Bacliff, TX/US

Topic: Emerging Infectious Diseases Preferred type of presentation: International Scientific Exchange

This abstract has been ACCEPTED.

#0670: Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America update October 2009

Authors: T. Singeltary; Bacliff, TX/US

Title: Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America update October 2009

Body: Background

An update on atypical BSE and other TSE in North America. Please remember, the typical U.K. c-BSE, the atypical l-BSE (BASE), and h-BSE have all been documented in North America, along with the typical scrapie's, and atypical Nor-98 Scrapie, and to date, 2 different strains of CWD, and also TME. All these TSE in different species have been rendered and fed to food producing animals for humans and animals in North America (TSE in cats and dogs ?), and that the trading of these TSEs via animals and products via the USA and Canada has been immense over the years, decades.


12 years independent research of available data


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 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. Restricting the reporting of CJD and or any human TSE is NOT scientific. Iatrogenic CJD knows NO age group, TSE knows no boundaries.

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.

Keywords: Transmissible Spongiform Encephalopathy Creutzfeldt Jakob Disease Prion

page 114 ;

Tuesday, December 12, 2017 

Neuropathology of iatrogenic Creutzfeldt–Jakob disease and immunoassay of French cadaver-sourced growth hormone batches suggest possible transmission of tauopathy and long incubation periods for the transmission of Abeta pathology


Blood-derived amyloid-β protein induces Alzheimer’s disease pathologies

Tuesday, December 12, 2017 

Neuropathology of iatrogenic Creutzfeldt–Jakob disease and immunoassay of French cadaver-sourced growth hormone batches suggest possible transmission of tauopathy and long incubation periods for the transmission of Abeta pathology

SUNDAY, MARCH 4, 2018 

Can Aβ Seeds Be Transferred During Neurosurgery?

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. 

Tracking spongiform encephalopathies in North America

Xavier Bosch

Published: August 2003


“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 hunters "two of whom were friends" who 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". 

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? 

2001 FDA CJD TSE Prion Singeltary Submission 


2 January 2000 British Medical Journal U.S. 

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

15 November 1999 British Medical Journal hvCJD in the USA * BSE in U.S. 

Tuesday, December 12, 2017 

Neuropathology of iatrogenic Creutzfeldt–Jakob disease and immunoassay of French cadaver-sourced growth hormone batches suggest possible transmission of tauopathy and long incubation periods for the transmission of Abeta pathology

SUNDAY, MARCH 4, 2018 

Can Aβ Seeds Be Transferred During Neurosurgery?

Thursday, March 8, 2018 

Familial human prion diseases associated with prion protein mutations Y226X and G131V are transmissible to transgenic mice expressing human prion protein

*** Transmission of Creutzfeldt-Jakob disease to a chimpanzee by electrodes contaminated during neurosurgery *** 

Gibbs CJ Jr, Asher DM, Kobrine A, Amyx HL, Sulima MP, Gajdusek DC. 

Laboratory of Central Nervous System Studies, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892. Stereotactic multicontact electrodes used to probe the cerebral cortex of a middle aged woman with progressive dementia were previously implicated in the accidental transmission of Creutzfeldt-Jakob disease (CJD) to two younger patients. The diagnoses of CJD have been confirmed for all three cases. More than two years after their last use in humans, after three cleanings and repeated sterilisation in ethanol and formaldehyde vapour, the electrodes were implanted in the cortex of a chimpanzee. Eighteen months later the animal became ill with CJD. This finding serves to re-emphasise the potential danger posed by reuse of instruments contaminated with the agents of spongiform encephalopathies, even after scrupulous attempts to clean them. 

Sunday, February 25, 2018 


Terry S. Singeltary Sr.