NOR-98 ATYPICAL SCRAPIE TSE Prion Disease: March 2008

Agriculture: BSE Lord Vinson asked Her Majesty's Government:

In view of the conclusion of the Spongiform Encephalopathy Advisory Committee in December 2006 that the prevalence of BSE in the United Kingdom sheep population was likely to be zero and that the precautionary measure of splitting sheep to remove the spinal cord was unnecessary, when they will adopt the European Union-approved process of vacuum removal, as practised in France and elsewhere; and how much this alternative method would benefit the United Kingdom sheep and meat industry annually. [HL2116]

The Parliamentary Under-Secretary of State, Department of Health (Lord Darzi of Denham): The Community TSE Regulations ((EC) 999/2001) lays down the rules for prevention, control and eradication of certain transmissible spongiform encephalopathies (TSE). This requires that the spinal cord of sheep and goats over 12 months of age, or which have a permanent incisor erupted, must be removed and stained and disposed of as specified risk material (SRM). The Community regulation does not specify any method of removal and no particular methods of removal are specifically European Union approved.

We have been advised by the Food Standards Agency (FSA) that the latest Spongiform Encephalopathy Advisory Committee (SEAC) advice on the prevalence of bovine spongiform encephalopathy (BSE) in the United Kingdom sheep flock is that it may be zero or in the worst case no more than 10 flocks would be affected. SEAC has also advised of the importance of maintaining current SRM controls in order to minimise public health risk were BSE ever to enter the sheep flock and that a possible human health risk from atypical scrapie (another TSE of sheep) cannot, at present, be ruled out. SEAC has not issued any advice on the method of removal of spinal cord in sheep and goats.

We have also been advised that the FSA will be re-examining the effectiveness of the suction method for removal of sheep spinal cord and the possible methods of verification of complete removal. The agency will remain in close contact with the industry during this re-evaluation of the issue.

http://www.publications.parliament.uk/pa/ld200708/ldhansrd/text/80310w0001.htm#08031025000002

Tissue distribution. For atypical scrapie, what is PrPres and infectivity distribution within sheep of different genotypes, particularly with respect to SRM removal? For classical scrapie and experimental BSE in sheep, tissue distribution of infectivity is widespread. Thus, even with SRM controls in place, an infected sheep poses around 1000 times the risk to human health than does an infected cow22. Does the distribution depend on whether infection is by the oral or intracerebral route? Are some VRQ sheep carriers with no neurological symptoms?

21 Gubbins S. Prevalence of BSE in sheep: interpreting the results of retrospective and prospective testing of sheep TSE cases. SEAC 84 open meeting 22 paper presented to Food Standards Agency board on 9 December 2004. http://www.foodstandards.gov.uk/multimedia/pdfs/fsa041204.pdf Also see paper SEAC/84/2 Annex 2: McLean, A. Page 13 © SEAC 27 February 2006

SEAC SHEEP SUBGROUP POSITION STATEMENT

http://www.seac.gov.uk/pdf/positionstatement-sheep-subgroup.pdf

NOR-98 ATYPICAL SCRAPIE USA UPDATE AS AT OCT 2007 (documented now in 5 different states)

SCRAPIE PROGRAM FY REPORT 2007

Prepared by National Center for Animal Health Programs Ruminant Health Programs Team November 15, 2007

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Infected and Source Flocks

During FY 2007, there were a total of 76 new infected or source flocks identified. Of those new flocks identified, 30 were infected flocks and 46 were source flocks (Figure 2). As of September 30, 2007, there were 38 scrapie infected and source flocks with open statuses (Figure 3). ...

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In FY 2007, 331 scrapie cases have been confirmed and reported by the National Veterinary Services Laboratories (NVSL), including 59* Regulatory Scrapie Slaughter Surveillance (RSSS) cases (Figure 5 and Slide 16). In FY 2007, two field cases, one validation case, and two RSSS cases were consistent with Nor-98 scrapie. The Nor98-like cases originated from flocks in California, Minnesota, Colorado, Wyoming and Indiana respectively. Nineteen cases of scrapie in goats have been reported since 1990 (Figure 6). The last goat case was reported in September 2007.

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see full report here ;

http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/downloads/yearly_report.pps

P03.141

Aspects of the Cerebellar Neuropathology in Nor98

Gavier-Widén, D1; Benestad, SL2; Ottander, L1; Westergren, E1 1National Veterinary Insitute, Sweden; 2National Veterinary Institute, Norway

Nor98 is a prion disease of old sheep and goats. This atypical form of scrapie was first described in Norway in 1998. Several features of Nor98 were shown to be different from classical scrapie including the distribution of disease associated prion protein (PrPd) accumulation in the brain. The cerebellum is generally the most affected brain area in Nor98. The study here presented aimed at adding information on the neuropathology in the cerebellum of Nor98 naturally affected sheep of various genotypes in Sweden and Norway. A panel of histochemical and immunohistochemical (IHC) stainings such as IHC for PrPd, synaptophysin, glial fibrillary acidic protein, amyloid, and cell markers for phagocytic cells were conducted. The type of histological lesions and tissue reactions were evaluated. The types of PrPd deposition were characterized. The cerebellar cortex was regularly affected, even though there was a variation in the severity of the lesions from case to case. Neuropil vacuolation was more marked in the molecular layer, but affected also the granular cell layer. There was a loss of granule cells. Punctate deposition of PrPd was characteristic. It was morphologically and in distribution identical with that of synaptophysin, suggesting that PrPd accumulates in the synaptic structures. PrPd was also observed in the granule cell layer and in the white matter. ***The pathology features of Nor98 in the cerebellum of the affected sheep showed similarities with those of sporadic Creutzfeldt-Jakob disease in humans.

http://www.prion2007.com/pdf/Prion%20Book%20of%20Abstracts.pdf

typical scrapie transmits to primates by there NON-FORCED ORAL CONSUMPTION ;

76/10.12/4.6

http://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf

full text ;

http://nor-98.blogspot.com/

http://scrapie-usa.blogspot.com/

Caprine Scrapie Prevalence Study (CSPS)

CSPS was initiated in May 2007 to estimate the national prevalance of scrapie in adult goats at slaughter. If no scrapie is found we will be able to conclude that the prevalence in goats is greater than zero and less than 0.1 percent. AS of January 31, 2008, 2,942 goats have been sampled for scrapie testing (1,515 in FY 2007 and 1,427 in FY 2008). Collection numbers by quarter in FY 2008 is shown in Chart 8. To date, no goats have tested positive for scrapie as part of this surveillance program. HOWEVER, THREE POSITIVE GOATS have been identified this fiscal year through field investigations. One was a clinical suspect submitted for testing and THE OTHER TWO WERE MEMBERS OF THE OF THE BIRTH HERD OF THE CLINICAL CASE.

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please see full text ;

http://www.aphis.usda.gov/animal_health/animal_diseases/scrapie/downloads/monthly_scrapie_rpt.pps

SPONGIFORM ENCEPHALOPATHY ADVISORY COMMITTEE Draft minutes of the 99th meeting held on 14th December 2007

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• A member explained that a confirmed case of atypical scrapie had been recently identified in a research project at the Institute of Animal Health (IAH). The animal had been born in 1997 in New Zealand, imported into the UK in 1998, spending the first six months at the Arthur Rickwood Sheep Unit (ARSU) before transfer to the IAH site at Compton. Thus, it is possible it may have become infected either in New Zealand, whilst at ARSU, where two other cases have now been confirmed, or at Compton, perhaps as a result of the experiments conducted during the research study involving transfusion of blood between sheep. The case is under further investigation.

• Members considered a report describing a case of Creutzfeldt-Jakob Disease (CJD) of prion protein gene codon 129 VV genotype who had died in 2000 at the age of 39 years old. The case had unusual neuropathological features and abnormal prion protein (PrPSc) western blot banding pattern1. One possible interpretation of these data was that this could represent the first case of vCJD in an individual of VV genotype. However, members noted that the clinical, cerebral Magnetic Resonance Imaging and neuropathological features were within the range previously observed with sporadic CJD (sCJD). Although there were similarities between the molecular features of PrPSc in the case and those of cases of vCJD, they were not identical and only strain typing mouse bioassays could provide conclusive evidence about the causative transmissible spongiform encephalopathy (TSE) agent. The paper stated that transmission studies of this case, in transgenic mice, were being undertaken but there was no information about the current status of these experiments. The Chair asked the Acting Secretary to contact

1 Mead et al. (2007) Creutzfeldt-Jakob disease, prion protein gene codon 129VV, and a novel PrPSc type in a young British women. Arch. Neurol. 64, 1780-1784. 5 © SEAC 2007

the research group to ask about such transmission experiments.

• A member informed SEAC that the Department for Environment, Food and Rural Affairs (Defra) was consulting on cost and responsibility sharing for animal health and welfare2 and that this included specific proposals for TSE controls between government and industry.

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11. Dr Danny Matthews (Veterinary Laboratories Agency [VLA]) noted that all three of the atypical scrapie cases associated with ARSU are of the Cheviot breed and two were homozygous and one was heterozygous for the AFRQ allele. It was possible that the sheep carrying this allele may be susceptible to atypical scrapie that arises spontaneously.

2 Defra consultation on sharing costs and responsibility: animal health and welfare.

http://www.defra.gov.uk/news/latest/2007/animal-1211.htm

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12. Members asked what measures might be taken to minimise the spread of atypical scrapie at the site referred to in paragraph 15 of the report and were informed that manure from the Unit had been spread on adjacent farmland, which provided a source of straw of the Unit. It had been suggested this practice might represent a potential route for recycling of the atypical scrapie agent, and may be inadvisable.

13. In relation to (ii), members noted there were four hypotheses for the interpretation of the findings from passage of two sheep TSE cases in mice: an experimental error had occurred, the features observed may be a normal consequence of passage of classical scrapie isolates in the breed and genotype of sheep, a strain conversion may have occurred or the features observed may reflect a mixed BSE-classical scrapie infection in sheep.

14. Dr Matthews explained that an internal audit had found no evidence of experimental error but an independent audit was planned with Professor Alun Williams as the scientific advisor. Dr Jim Hope (VLA) explained that the suggestion that the features observed on strain typing of two sheep TSE cases may be a normal consequence of passage of classical scrapie isolates from the particular breed and genotype of sheep, had arisen as one of the cases was an ARQ/ARQ Swaledale. Sheep of this genotype and breed rarely succumb to classical scrapie. Only one other case of classical scrapie in an animal of this genotype and breed had been strain typed by mouse bioassay with the features on passage consistent with classical scrapie.

15. The Chair considered that of the four possibilities, the first two appear to be the least likely, the third possibility may be the most likely but is unproven and the fourth possibility cannot be excluded. It is important to note that the features observed on mouse bioassay are not consistent with features observed when BSE is passaged in mice. If the findings did reflect a mixed BSE-classical scrapie infection, the isolates were from historic sheep TSE cases and the probability of mixed infections was low. Thus, there is no indication from these data of a current significant risk to human health from BSE in sheep.

16. A member asked why the report only considered mixed infections of classical scrapie and BSE rather than atypical scrapie as it is known that classical and atypical scrapie can occur together. The Chair explained that as the report described the analysis of two sheep TSE cases that discriminatory testing indicated were cases

7 © SEAC 2007

of classical scrapie, only mixed infections of classical scrapie and BSE had been considered.

17. A member suggested that less certainty should be reflected in the estimate of the probability of mixed infection arising (footnote 8 of the draft report) as the estimates relied on an assumption that BSE and classical scrapie would occur independently. In addition, it was incorrect to state that the most likely prevalence of BSE in sheep was zero (paragraphs 32 and 39 of the draft report); the sample gives an estimate of the maximum prevalence that is consistent with the results of the survey.

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ITEM 5 – SCIENTIFIC BASIS OF CLASSICAL SCRAPIE CONTROLS (SEAC 99/3)

21. Mr Andrew Gresham (Defra) gave an overview of the background and policy context of the issue. The European Court of First Instance had, following an application by the French Government and, pending a full hearing, suspended clauses in new European Commission legislation to allow sheep from classical scrapie affected flocks to enter the human food chain if testing negative for TSE. The UK intended to support the Commission at the full hearing but wished to seek SEAC’s advice in relation to possible links between classical scrapie and human TSEs and the performance characteristics of discriminatory tests for sheep TSEs. SEAC had been provided with the opinions of the French Food Safety Authority (AFSSA), the European Food Safety Authority

(EFSA) and the German TSE advisory committee (KOM AG TSE) 8 © SEAC 2007

that had considered these issues. Advice from SEAC could be incorporated into a UK submission to the Court.

22. A member noted that the AFSSA opinion reflected concerns that as a consequence of the release of animals from classical scrapieaffected sheep flocks into the human chain, cases of undiagnosed BSE may also be inadvertently released into the food chain. Furthermore, a greater number of classical scrapie infected sheep may enter the food chain even though it is not possible to exclude a risk to human health from classical scrapie. Three key uncertainties had been identified by AFSSA, EFSA and KOM AG TSE, although there were some differences in emphasis about the uncertainties in the opinions. The uncertainties related to (i) the capability of tests to detect TSEs in sheep during the stage when PrPSc is accumulating in the periphery only, (ii) the ability of the tests to detect BSE when another TSE is present and (iii) the evidence suggesting a lack of link between human and animal TSEs other than BSE. In relation to (iii), observations that classical scrapie has been an endemic disease in sheep for more than 200 years without any apparent association with human disease, and that sporadic Creutzfeldt-Jakob Disease (sCJD) exists in countries such as Australia and New Zealand with no reported cases of classical scrapie, are incontrovertible. However, it should be noted that it would be very difficult to demonstrate an epidemiological link between such relatively rare diseases in animals and humans. Authors of two epidemiological studies3,4 that had examined risk factors for sporadic Creutzfeldt-Jakob Disease (sCJD) dismissed a link between classical scrapie and sCJD. However, these data could be interpreted differently to suggest a potential link, this could be a chance association arising from biases inherent in the design of these retrospective studies. It was therefore important not to be completely dismissive of a lack of a link as it would be very difficult to prove an epidemiological link between such rare diseases.

23. Members noted that, although there is no evidence for a risk to human health from classical scrapie, a risk could never be ruled out. However, even if there is a risk, the risk must be very small indeed as the observed prevalence of sCJD is very low.

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ITEM 8 – PUBLIC QUESTION AND ANSWER SESSION

40. The Chair explained that the purpose of the question and answer session was to give members of the public an opportunity to ask questions related to the work of SEAC. Mr Terry Singeltary (Texas, USA) had submitted a question prior to the meeting, asking: “With the Nor-98 now documented in five different states so far in the USA in 2007, and with the two atypical BSE H-base

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cases in Texas and Alabama, with both scrapie and chronic wasting disease (CWD) running rampant in the USA, is there any concern from SEAC with the rise of sporadic CJD in the USA from ''unknown phenotype'', and what concerns if any, in relations to blood donations, surgery, optical, and dental treatment, do you have with these unknown atypical phenotypes in both humans and animals in the USA? Does it concern SEAC, or is it of no concern to SEAC? Should it concern USA animal and human health officials?”

41. A member considered that this question appeared to be primarily related to possible links between animal and human TSEs in the USA. There is no evidence that sCJD is increasing in the USA and no evidence of any direct link between TSEs and CJD in the USA. Current evidence does not suggest that CWD is a significant risk to human health. There are unpublished data from a case of human TSE in the USA that are suggestive of an apparently novel form of prion disease with distinct molecular characteristics. However, it is unclear whether the case had been further characterised, if it could be linked to animal TSEs or if other similar cases had been found in the USA or elsewhere. In relation to the possible public health implications of atypical scrapie, H-type BSE and CWD, research was being conducted to investigate possible links and surveillance was in place to detect any changes in human prion diseases. Although possible links between these diseases and human TSEs are of concern and require research, there is no evidence to suggest immediate public health action is warranted. The possible human health risks from classical scrapie had been discussed earlier in the meeting. Members noted that there are effective channels of discussion and collaboration on research between USA and European groups. Members agreed it is important that to keep a watching brief on new developments on TSEs.

ITEM 9 – UPDATE ON vCJD AND sCJD EPIDEMIOLOGY

42. Dr Richard Knight (NCJDSU) presented an update on the epidemiology of cases of sCJD and vCJD in the UK and elsewhere. Between May 1990 and October 2007, 944 cases of sCJD had been identified in the UK with a mean age at onset of 66 (range 15-94) years and mean age of death of 67 (range 20-95) years. There is no significant gender difference in sCJD incidence. There had been a trend towards an increasing number of cases over time to almost 80 cases per year in 2003; this increased trend had also been observed in other countries and was considered to be a result of better surveillance and diagnosis of disease. There has been a decline in number since 2003, but this may not be of

15 © SEAC 2007

significance. The post mortem rate for sCJD referral is about 60%. The genotype distribution of sCJD cases was 64% MM, 18% MV and 18% VV at codon 129 of the prion protein gene. 43. Dr Knight explained that the total number of definite and probable vCJD cases in the UK up to November 2007 was 166, with four cases still alive. Three of out of four vCJD cases treated with pentosan polysulphate (PPS) had appreciably longer survival times, but it is not proven that this is the result of treatment. No statistically significant gender difference had been observed in vCJD cases. The age distribution of vCJD had not altered over the course of the UK epidemic, with the median age of death of 30 (range 14-75) years. Statistical analysis of the UK incidence of deaths from vCJD suggested the epidemic had peaked in 2000 with 28 deaths. There are three cases identified with onset in 2006 and four deaths in 2007. Geographical distribution of vCJD cases in the UK shows higher incidence in the North than South. All 146 vCJD cases tested to date are of the MM genotype. 44. Dr Knight explained that elsewhere in the world up to November 2007, 39 vCJD cases have been reported with 23 in France, four in the Republic of Ireland (RoI), three in the USA, two in the Netherlands, two in Portugal and single cases in Italy, Canada, Japan, Saudi Arabia and Spain. Infection is considered likely to have occurred in the UK in two RoI cases, two USA cases, one French case, the Japanese, and Canadian cases. One of the French cases had a history of possibly significant residence in the UK. One USA case is thought likely to have been exposed to infection in Saudi Arabia, rather than the USA.

45. Dr Knight explained that the Transfusion Medicine Epidemiology Review study had identified four instances of vCJD infection resulting from receipt of non-leucodepleted red blood cells donated by individuals who had subsequently developed vCJD. The donors developed clinical vCJD ranging from 17 months to 3.5 years after blood donation and this indicates that blood can be infective 3.5 years before the development of clinical disease. Clinical vCJD was identified in three recipients (all of MM genotype) between 6.5 and 8.3 years after receipt of blood. The fourth recipient, who died of non-neurological disease, with only lymphoreticular evidence of vCJD infection was of MV genotype.

46. In response to a question about the neuropathology of the vCJD case that died after receiving PPS, Dr Knight explained that no autopsy was undertaken.

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47. A member asked about the reason for the increase in sCJD detection in the year up to 2003. Dr Knight replied that it was probably due to better awareness of the disease and the availability of better diagnostic methods such as cerebrospinal fluid testing and magnetic resonance imaging.

48. Mr Mark Noterman (Department of Health [DH]) asked whether the neuropathological referrals rate had increased after the Chief Medical Officer’s letter to clinicians earlier in the year to remain vigilant about cases of neurological disease that could be related to prion disease. Dr Knight replied that there had been no subsequent significant increase in referral rate.

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ITEM 11 – RE-ASSESSMENT OF THE POTENTIAL RISK OF vCJD TRANSMISSION VIA DENTISTRY (SEAC 99/7)

59. Dr Bennett and Dr Peter Grove (DH) presented findings of an interim assessment examining the risk that vCJD may be transmitted via dental procedures. As there is a lack of substantial

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data with which to accurately quantify many of the key parameters in the risk assessment, plausible ranges for parameters were established to take account of the often large uncertainties in the data. The key areas of uncertainty are infectivity in dental and oral tissues of patients incubating vCJD, the level of protein residues on dental instruments following decontamination, the efficacy of autoclaving, the current prevalence of vCJD infection in the population, and the epidemiology of vCJD. These uncertainties strongly influence the quantification of the risk. 60. It was explained that many plausible scenarios built up using ranges for each of these factors suggest that dental transmission may have no detectable effect on the course of the vCJD epidemic. However, there are some scenarios which include a combination of pessimistic assumptions as regards the infectivity of dental/oral tissues and the effects of instrument decontamination which suggest that there could be some hundreds of vCJD transmissions per annum via dentistry, albeit against a background of many thousand existing subclinical vCJD infections, or where dental transmission could generate a self-sustaining reservoir of vCJD infection within the population. Should a large proportion of secondary transmissions result in subclinical infections, either never developing into clinical disease or doing so over an extended time-scale, and such infections are infectious, the likelihood of a self-sustaining epidemic increases. The proportion of individuals that may be infected from having consumed BSE contaminated food or from human to human transmission of vCJD that may enter such a subclinical carrier state is unknown. Research to address the key uncertainties is on-going and new data would enable some of the assumptions underpinning these scenarios to be revised. 61. The committee welcomed the risk assessment, acknowledging it had been developed in collaboration with a scientific reference group of independent experts. Studies to address the scientific uncertainties were considered important, particularly infectivity studies on human oral and dental tissues from vCJD patients. 62. A member suggested that following secondary transmission, the agent may adapt to become infectious to all prion protein genotypes. Dr Grove noted that since the risk assessment considers four scenarios ranging from one in which no secondary infection develops into clinical disease to one in which everyone who is infected develops clinical disease, this possibility is considered.

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63. Members noted that there were two obvious precautionary measures that could be put in place to dramatically reduce the potential risk of vCJD transmission via dental procedures: making endodontic files and reamers single use, which was implemented in April 2007 and improving instrument decontamination using current technologies. A 0.5 – 1.0 log reduction in infectivity from improved decontamination practice could remove the risk of a self sustaining epidemic. It is very important, therefore, that DH ensures dentists do adopt good practice throughout the profession and that this is audited. Introduction of consistent decontamination practices would also reduce the observed variability of instrument contamination, and thus reduce the risk of local outbreaks of transmission.

64. Mr Barry Cockcroft (Chief Dental Officer, DH) noted that the effect of the guidance on making endodontic files and reamers single use had been included in the risk assessment. There is good evidence that dentists are adhering to the guidance. A survey by DH Regional Directors of Public Health could not find any dentists who are unaware of the Chief Dental Officer’s Professional Letter advising that files and reamers should be treated as single use only, and dental instrument suppliers have reported that sales of files and reamers have increased dramatically since the guidance was issued. A draft Health Technical Memorandum would be issued for consultation in early 2008 designed specifically for dental practitioners and their staff as a comprehensive guide to best practice. An audit tool will be available to help dentists assess their own compliance with the guidance and to enable DH to assess whether new guidance is working in practice. Dental nurses will now also be regulated and registered with the General Dental Council.

snip...end...full text ;

http://www.seac.gov.uk/minutes/99.pdf

SEAC 99th meeting on Friday 14th December 2007

http://seac992007.blogspot.com/

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NOR-98 ATYPICAL SCRAPIE TSE Prion Disease

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Tuesday, March 11, 2008

BSE IN SHEEP Lord Vinson asked Her Majesty's Government

Tuesday, March 4, 2008

Fw: [BSE-L] SCRAPIE DOCUMENTED IN CLINICAL SUSPECT GOAT, WITH TWO MORE DOCUMENTED IN SAME BIRTH HERD OF CLINICAL CASE