Idiopathic Brainstem Neuronal Chromatolysis (IBNC) TSE Prion disease
Idiopathic Brainstem Neuronal Chromatolysis (IBNC) TSE Prion disease
Identification of Idiopathic Brainstem Neuronal Chromatolysis (IBNC) in group 5 samples One of the 21 samples identified in group 5 was shown to have IBNC following histological investigation (03/00002) (figure 8).
Concurrently, we investigated the PrP distribution in known cases of IBNC (Jeffrey et al 2008; “Idiopathic Brainstem Neuronal Chromatolysis (IBNC): a novel prion protein related disorder of cattle?” BMC Vet Res. 2008 Sep 30;4:38. The IHC and histology profile of this case was very similar to that of the known IBNC cases.
Investigation of the distribution and molecular characteristics of PrP from known IBNC
See also: Idiopathic Brainstem Neuronal Chromatolysis (IBNC): a novel prion protein related disorder of cattle? Jeffrey M, Perez BB, Martin S, Terry L, González L. BMC Vet Res. 2008 Sep 30;4:38
Further investigations demonstrated that 57% the assays performed on the confirmed IBNC samples, using the 0.3 Bio-Rad TeSeE assay (n=42), gave values above those of the test kit control and also the BSE negative brain pool control.
Half brains from six IBNC affected animals were retrieved from the TSE archive alongside the brainstem from a seventh animal.
The cortex, brainstem, cerebellum and midbrain from these brains were sub-sampled and the adapted Bio-Rad TeSeE EIA, IDEXX Herdchek and Western Blot protocols applied to these tissues, in order to determine whether they could represent a form of atypical BSE.
These samples had previously been found to be negative using the commercial Bio-Rad EIA and re-testing using this assay and the IDEXX Herdchek assay confirmed their negative status.
When assayed using the adapted Bio-Rad protocol at 0.3µl/ml PK, 24/42 (57%) of the sample assays performed gave values above those of the test kit control and also the BSE negative brain pool control.
Values above twice that of the calculated cut-off levels were found for each case but not for each brain site No PrPres was detected when Western blotting these samples at either 20 or 4µl/ml PK but a signal was detected on the gels when blotted at the 0.12 and 0.3µl/ml PK levels.
At 0.12µl/ml PK the IBNC samples were indistinguishable from the negative controls but at the 0.3µl/ml level more PrPres was detected in the IBNC cases than in the controls with each of the antibodies tested (SHA31, F99, SAF84 and P4). Illustrations of the F99 blot are shown in the paper. Other data not shown.
These data suggest that IBNC affected cattle abnormally express or accumulate PrP in brain and that the abnormal PrP is not strongly resistant to protease digestion. The results suggest that either the range of prion diseases is still wider than previously thought or that abnormalities of prion protein expression may be associated with brain lesions unconnected with prion disorders.
Biochemical and transmission studies are planned in order to investigate further (under SE2014).
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IBNC is likely to represent a subset of this group of cattle. Based on these data, our overall conclusion is that a second type of BSE is unlikely to have co-existed at a high prevalence with the classical form in the cattle population during the UK epidemic.
Final Report - Annex : Atypical prion proteins in cattle (10064k)
Final Report - SID5 : Atypical prion proteins in cattle (201k)
SEAC 102/2
NEW RESULTS ON IDIOPATHIC BRAINSTEM NEURONAL CHROMATOLYSIS FROM THE VETERINARY LABORATORIES AGENCY
ISSUE
1. The Department for Environment, Food and Rural Affairs (Defra) has asked SEAC to consider a research article (Annex A) entitled “Idiopathic Brainstem Neuronal Chromatolysis (IBNC): a novel prion protein related disorder of cattle?” produced by the Veterinary Laboratories Agency.
2. Martin Jeffrey, the lead author of the article, will be present at the meeting to present an overview and answer questions.
BACKGROUND
3. IBNC is a rare1 neurodegenerative disease of adult cattle. This disorder has some clinical similarity to BSE and was initially recognised from histological examination of cattle brains submitted as part of the UK surveillance for BSE diagnosis in 1989. However, the brains of IBNC-affected cattle have pathological features which are clearly different from those seen in BSE. Most cases have been detected in Scotland, but it is not known if this is a true distribution or primarily because Scottish scientists have examined BSE negative cases in more detail. The last reported case of IBNC in an animal presented as a BSE suspect was in 2005, in an animal born in 1992.
PREVIOUS CONSIDERATION BY SEAC
4. SEAC first considered IBNC at its 14th meeting (April 1993) and emphasised the importance of defining the new condition in detail with
1 Between the years 1988 and 1991 IBNC occurred in Scotland with an incidence of 7 cases per 100,000 beef suckler cattle over the age of 6 years (from Annex A).
transmission studies and PrP examination. The next discussion was at the 19th meeting (June 1995), when the committee reflected on results of transmission studies in mice (VM, RIII, C57 and C57xVM mice) from brains of two cattle with IBNC. Some mice had shown signs of TSE disease, but it was suggested this could have been due to low level BSE contamination of the samples. The committee recommended that further investigations should be carried out on isolates from brains of IBNC cases with removal of the brain and subsequent handling under conditions that would prevent contamination.
5. At the 49th meeting (March 1998) the committee considered a further IBNC transmission study in which the brain from an IBNC case was removed under aseptic conditions. The mouse strains challenged were RIII, VM, C57BL, C57BL x VM and IM. These experiments ran for between 577 and 631 days and no clinical signs of transmission were evident. The Committee stated2 it was content that, although little was known about IBNC, it did not constitute a health risk to man because suspect IBNC cases would be taken as BSE suspects or caught by the Over Thirty Months (OTM) Scheme.
6. Annex B contains the minutes of the discussions on IBNC at previous SEAC meetings.
NEW RESULTS
7. The research article “Idiopathic Brainstem Neuronal Chromatolysis (IBNC): a novel prion protein related disorder of cattle?” was published in September 2008. The cases studied concerned brains from cattle killed between 1993 and 2005 when they were between 5 and 15 years of age. All of the 15 cattle tested showed that the brains had abnormally accumulated prion protein.
8. Defra has asked that SEAC considers the VLA paper in order to confirm or revise its previous views on this disorder as:
• This is the first time IBNC has been shown to be associated with abnormal expression or accumulation of the prion protein.
• The previous transmission studies conducted in the 1990s were inconclusive and repeat studies are planned.
• IBNC is thought to be rare but the exact prevalence of the disorder is unknown, as IBNC would not be picked up through the
2 At 49th SEAC meeting (9th March 1998), paragraph 52, see Annex B.
active surveillance programme for BSE which uses rapid post-mortem tests to detect proteinase-K resistant PrPSc.
9. Additionally, TSE controls on older cattle have changed since the previous SEAC advice in 1998. For example the OTM Scheme, which was in operation then, has now been replaced with testing of cattle slaughtered for human consumption aged over 48 months. Other controls remain, such as compulsory notification of suspected BSE, ante-mortem inspection, specified risk for cattle slaughtered for human consumption and a ban on cattle born or reared in UK before 1st August 1996 entering the food chain.
FUTURE RESEARCH
10. VLA are hoping to carry out further mouse transmission studies of IBNC cases as part of a larger project, on TSE molecular sciences, about which Defra is currently in advanced negotiations with VLA. If new cases of IBNC occur, it is planned that the brains from 2 cases of IBNC will be obtained and bioassayed in transgenic mouse lines, expressing bovine PrP or ovine PrP (PrP genotype AHQ), developed by the VLA.
ADVICE SOUGHT
11. The committee is asked to consider:
• if the paper changes the previous opinion of SEAC in 1998?
• if members have any comments on the further research planned?
SEAC SECRETARIAT
FEBRUARY 2009
ANNEX A
A copy of the paper “Idiopathic Brainstem Neuronal
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full text ;
SEAC SPONGIFORM ENCEPHALOPATHY ADVISORY COMMITTEE
SEAC 102/2
NEW RESULTS ON IDIOPATHIC BRAINSTEM NEURONAL CHROMATOLYSIS FROM THE VETERINARY LABORATORIES AGENCY ISSUE
1. The Department for Environment, Food and Rural Affairs (Defra) has asked SEAC to consider a research article (Annex A) entitled “Idiopathic Brainstem Neuronal Chromatolysis (IBNC): a novel prion protein related disorder of cattle?” produced by the Veterinary Laboratories Agency.
2. Martin Jeffrey, the lead author of the article, will be present at the meeting to present an overview and answer questions.
BACKGROUND
3. IBNC is a rare1 neurodegenerative disease of adult cattle. This disorder has some clinical similarity to BSE and was initially recognised from histological examination of cattle brains submitted as part of the UK surveillance for BSE diagnosis in 1989. However, the brains of IBNC-affected cattle have pathological features which are clearly different from those seen in BSE. Most cases have been detected in Scotland, but it is not known if this is a true distribution or primarily because Scottish scientists have examined BSE negative cases in more detail. The last reported case of IBNC in an animal presented as a BSE suspect was in 2005, in an animal born in 1992.
PREVIOUS CONSIDERATION BY SEAC
4. SEAC first considered IBNC at its 14th meeting (April 1993) and emphasised the importance of defining the new condition in detail with
1 Between the years 1988 and 1991 IBNC occurred in Scotland with an incidence of 7 cases per 100,000 beef suckler cattle over the age of 6 years (from Annex A). transmission studies and PrP examination. The next discussion was at the 19th meeting (June 1995), when the committee reflected on results of transmission studies in mice (VM, RIII, C57 and C57xVM mice) from brains of two cattle with IBNC. Some mice had shown signs of TSE disease, but it was suggested this could have been due to low level BSE contamination of the samples. The committee recommended that further investigations should be carried out on isolates from brains of IBNC cases with removal of the brain and subsequent handling under conditions that would prevent contamination.
5. At the 49th meeting (March 1998) the committee considered a further IBNC transmission study in which the brain from an IBNC case was removed under aseptic conditions. The mouse strains challenged were RIII, VM, C57BL, C57BL x VM and IM. These experiments ran for between 577 and 631 days and no clinical signs of transmission were evident. The Committee stated2 it was content that, although little was known about IBNC, it did not constitute a health risk to man because suspect IBNC cases would be taken as BSE suspects or caught by the Over Thirty Months (OTM) Scheme.
6. Annex B contains the minutes of the discussions on IBNC at previous SEAC meetings.
NEW RESULTS
7. The research article “Idiopathic Brainstem Neuronal Chromatolysis (IBNC): a novel prion protein related disorder of cattle?” was published in September 2008. The cases studied concerned brains from cattle killed between 1993 and 2005 when they were between 5 and 15 years of age. All of the 15 cattle tested showed that the brains had abnormally accumulated prion protein.
8. Defra has asked that SEAC considers the VLA paper in order to confirm or revise its previous views on this disorder as:
• This is the first time IBNC has been shown to be associated with abnormal expression or accumulation of the prion protein.
• The previous transmission studies conducted in the 1990s were inconclusive and repeat studies are planned.
• IBNC is thought to be rare but the exact prevalence of the disorder is unknown, as IBNC would not be picked up through the
2 At 49th SEAC meeting (9th March 1998), paragraph 52, see Annex B. active surveillance programme for BSE which uses rapid postmortem tests to detect proteinase-K resistant PrPSc.
9. Additionally, TSE controls on older cattle have changed since the previous SEAC advice in 1998. For example the OTM Scheme, which was in operation then, has now been replaced with testing of cattle slaughtered for human consumption aged over 48 months. Other controls remain, such as compulsory notification of suspected BSE, ante-mortem inspection, specified risk for cattle slaughtered for human consumption and a ban on cattle born or reared in UK before 1st August 1996 entering the food chain.
FUTURE RESEARCH
10. VLA are hoping to carry out further mouse transmission studies of IBNC cases as part of a larger project, on TSE molecular sciences, about which Defra is currently in advanced negotiations with VLA. If new cases of IBNC occur, it is planned that the brains from 2 cases of IBNC will be obtained and bioassayed in transgenic mouse lines, expressing bovine PrP or ovine PrP (PrP genotype AHQ), developed by the VLA.
ADVICE SOUGHT
11. The committee is asked to consider:
• if the paper changes the previous opinion of SEAC in 1998?
• if members have any comments on the further research planned?
SEAC SECRETARIAT
FEBRUARY 2009
ANNEX A
A copy of the paper “Idiopathic Brainstem Neuronal Chromatolysis (IBNC): a novel prion protein related disorder of cattle?”
ANNEX B
FROM MINUTES OF 14TH SEAC MEETING – 22 APRIL 1993
12. The Committee emphasised the importance of defining this new condition in detail with transmission studies and PrP examination (3 had already been examined for PrP, all negative). The total number of cases was now 50 with still only one in England.
FROM MINUTES OF 18TH SEAC MEETING – 10 FEBRUARY 1995
16. A Member told the Committee that no infectivity (by bioassay in mice) nor PrP had been found in the brains of idiopathic brainstem chromatolysis and hippocampal sclerosis cases. It is thought that the condition might be caused by a dietary deficiency, or some other metabolic disease.
FROM MINUTES OF 19TH SEAC MEETING – 21 JUNE 1995
29. A Member described the results of transmission studies in mice from brains of two cows with IBNC (paper SEAC 19/8). At the previous meeting of SEAC, and at the review of R&D, it had been announced that there was no clinical observation of a scrapie-like disease in mice: this information had proved to be incorrect for a number of reasons. Of the mice inoculated with brain tissue from the first cow, there had been mild transient clinical signs, one had shown equivocal lesions of SE but PrP studies had proved negative. From the second cow there were two definite cases of SE though the lesion distribution and incubation period were not the same as seen in mice inoculated with brain from BSE cases or any characterised strain of scrapie. The lesions in these two mice were PrP positive. There was no obvious evidence of any mix up though one possible area of cross-contamination was during the necropsy in the Perth VIC. More evidence would be needed and further transmission studies to validate the results and proposals were put forward for further study.
30. The Committee noted that the results were unusual. They questioned whether there could be coincidental BSE infection or contamination with scrapie. The Chair noted that the feeling of the Committee was that this did not represent a new agent but it was important to be prepared to say something publicly about these findings. A suggested line to take was that these were scientifically unpublishable results but in line with the policy of openness they would be made publicly available and further work done to test their validity. Since the BSE precautions were applied to IBNC cases, human health was protected. Further investigations should be carried out on isolations from brains of IBNC cases with removal of the brain and subsequent handling under strict conditions to avoid the risk of any contamination. 31. A Member informed the Committee that the CVO had informed the CMO about the IBNC results and the transmission from retina and he, like the Committee was satisfied that the controls already in place or proposed were adequate.
FROM MINUTES OF 42ND SEAC MEETING – 23 MAY 1997
62. The Committee were advised that the paper had been circulated for information, and that no further action was proposed until further results were available unless the Committee felt otherwise. The Committee noted the paper.
FROM MINUTES OF 49TH SEAC MEETING – 9 MARCH 1998
52. The Committee had expressed concern last year that IBNC could be a transmissible disease. Mouse assays from cases had been undertaken and SEAC 49/8 was an update on information given to the Committee last year. The positive results obtained from the earlier transmission experiments were now thought probably to have been due to BSE strain 301V contamination in the laboratory. Consequently no firm conclusion could be drawn from them on whether IBNC is transmissible. The latest transmission study, had been running for between 577 and 631 days with no evidence of transmission to date. The Committee were informed that the IBNC cases had tested negative by immunohistochemistry. The Committee were content that, although little was known about IBNC, it did not constitute a health risk to man. Suspect IBNC cases would be taken as BSE suspects or caught by the Over Thirty Months Scheme.
1. Dr. Jeffrey has informed me that Gerald Wells is aware of the research results as a result of discussion with him before he knew of the political implications. I have discussed the issue with Gerald and informed him of the importance of confidentiality at this state.
2. In order to obtain data requested by the CVO and to get an epidemiological viewpoint on how to proceed I considered it necessary to disclose the information to John Wilesmith on the same confidential basis. Before doing so I discussed this with Dr. Little and he agreed. Accordingly John is full infomred and my minuted dated 4 April has been sent to him, Gerald and Martin Jeffrey - the last mentioned to check that there are no significant errors.
3. Please note that a large number of the professional staff at NPU probably know about the transmission data. I have asked David Taylor to maximise the security of this information which is important with BSEP meetings coming up.
4. I have spoken to Prof Mark Vandevelde in Berne and he confirms he has seen cases of IBNC in Switzerland. He has not been informed of our transmission results.
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IBNC IN OTHER COUNTRIES
Two or Three cases of IBNC have been identified during the BSE era, in Switzerland. Two were checked for SAF and PrPSc, both with negative result.
TRANSMISSION STUDIES
Brain tissue from one 9 1/2y Limousin and one 5y Herford cross cow, both with IBNC, has been inoculated into RIII, C57 Black and SV congenic mice.
Transmission of SE and a prion disease (shown by positive ICC, detection of PrPSc in brain sections) has occurred in two of 24 RIII mice inoculated with with brain material from the Hereford cross cow. Two further brains from mice inoculated with the Hereford cross brain are equivocal, as is one inoculated with Limousin brain (ICC not yet done). No disease has occurred in mice other than RIIIs and some remain alive. The incubation period in four RIII mice inoculated with Hereford brain material ranges from 398 - 427 days.
SOURCES OF INFECTION IN RIII MICE
A thorough internal audit has revealed no laboratory origin for infection, or error. The possibility of cross contamination of the cow brains in the VIC in which they were removed cannot be excluded.
HUMAN HEALTH PROTECTION
The public is protected from any possible risk from infection with IBNC agent (if one exists) by the same measures as for BSE, incineration of suspect cases and the SBO ban.
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mad cow wrangling starts with IBNC $$$
SAMPLES RECEIVED
2. A total of 35 cases have been identified out of 196 cattle identified as potential candidates under this project. Diagnosis for the 196 cattle are provided in the appended table, where NSL stands for no significant lesions.
The project has thus identified 36 percent of all the confirmed cases of IBNC in Scotland, with the total now standing at 97.
EPIDEMIOLOGY
3. The epidemiological summary is based on 84 confirmed IBNC cases, and therefore includes cases identified before project started.
>>>All of the 15 cattle tested showed that the brains had abnormally accumulated prion protein. <<<
Broadening spectrum of bovine spongiform encephalopathies
M Füzi 1, P Horváth
Until recently the etiology of bovine spongiform encephalopathy (BSE) was considered uniform. The infectious agent was thought to be a single strain of prion (posttranslationally altered form of normal prion protein: PrPSc) retaining its biochemical and biological characteristics during interspecies transmission. However, alternate PrPSc signatures through large-scale screening have recently been detected. In addition, genetic alterations governing susceptibility to prion infection and a mutation (E211K) capable of eliciting spontaneous BSE have been demonstrated. Thus, the spectrum of BSEs have broadened and three PrPSc variants (BSE-C, BSE-H and BSE-L) are now defined. Moreover, a new condition resembling BSE, idiopathic brainstem neuronal chromatolysis (IBNC), has been described that may also turn out to be a prion disease. Since one of the new BSE variants, L-type BSE, proved highly pathogenic detection and further characterization of the new conditions are essential.
Research article Open Access
Idiopathic Brainstem Neuronal Chromatolysis (IBNC): a novel prion protein related disorder of cattle?
Martin Jeffrey*1, Belinda Baquero Perez2, Stuart Martin1, Linda Terry2 and Lorenzo González1
Address: 1Veterinary Laboratories Agency (VLA-Lasswade), Pentlands Science Park, Bush Loan, Midlothian EH26 0PZ, UK and 2VLA-Weybridge, Addlestone, Surrey, KT15 3NB, UK
Email: Martin Jeffrey* - m.jeffrey@vla.defra.gsi.gov.uk; Belinda Baquero Perez - b.baquero-perez@vla.defra.gsi.gov.uk; Stuart Martin - s.f.martin@vla.defra.gsi.gov.uk; Linda Terry - l.terry@vla.defra.gsi.gov.uk; Lorenzo González - l.gonzalez@vla.defra.gsi.gov.uk * Corresponding author
Abstract
Background: The epidemic form of Bovine Spongiform Encephalopathy (BSE) is generally considered to have been caused by a single prion strain but at least two strain variants of cattle prion disorders have recently been recognized. An additional neurodegenerative condition, idiopathic brainstem neuronal chromatolysis and hippocampal sclerosis (IBNC), a rare neurological disease of adult cattle, was also recognised in a sub-set of cattle submitted under the BSE Orders in which lesions of BSE were absent. Between the years of 1988 and 1991 IBNC occurred in Scotland with an incidence of 7 cases per 100,000 beef suckler cows over the age of 6 years.
Results: When the brains of 15 IBNC cases were each tested by immunohistochemistry, all showed abnormal labelling for prion protein (PrP). Immunohistological labelling for PrP was also present in the retina of a single case available for examination. The pattern of PrP labelling in brain is distinct from that seen in other ruminant prion diseases and is absent from brains with other inflammatory conditions and from normal control brains. Brains of IBNC cattle do not reveal abnormal PrP isoforms when tested by the commercial BioRad or Idexx test kits and do not reveal PrPres when tested by Western blotting using stringent proteinase digestion methods. However, some weakly protease resistant isoforms of PrP may be detected when tissues are examined using mild proteinase digestion techniques.
Conclusion: The study shows that a distinctive neurological disorder of cattle, which has some clinical similarities to BSE, is associated with abnormal PrP labelling in brain but the pathology and biochemistry of IBNC are distinct from BSE. The study is important either because it raises the possibility of a significant increase in the scope of prion disease or because it demonstrates that widespread and consistent PrP alterations may not be confined to prion diseases. Further studies, including transmission experiments, are needed to establish whether IBNC is a condition in which prion protein is abnormally regulated or it is yet a further example of an infectious cattle prion disease.
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Conclusion
The present results indicate that there are changes in PrP expression or accumulation in the neurodegenerative cattle disorder known as IBNC. The pathology and biochemistry of IBNC are quite distinct from that of other prion diseases of cattle and other species but the pathology does include grey matter spongiform changes. The transmissibility of this disorder is undetermined. These results are interesting as they show that either the range of prion diseases and associated pathology is still wider than previously thought or that substantial abnormalities of prion protein expression may be associated with brain lesions unconnected with classical prion diseases. Further biochemical and transmission studies are needed to determine which of these possibilities is correct.
IBNC Tauopathy or TSE Prion disease, it appears, no one is sure
Posted by flounder on 03 Jul 2015 at 16:53 GMT
journals.plos.org/plosone/article/comment?id=10.1371/annotation/5adef4ac-a7e4-46a4-8806-c8533d5c862c
Saturday, February 28, 2009
NEW RESULTS ON IDIOPATHIC BRAINSTEM NEURONAL CHROMATOLYSIS "All of the 15 cattle tested showed that the brains had abnormally accumulated PrP" 2009
SEAC 102/2
Idiopathic brainstem neuronal chromatolysis and hippocampal sclerosis: a novel encephalopathy in clinically suspect cases of bovine spongiform encephalopathy
Oct 17, 1992 · Veterinary Record
2.69
#1M Jeffrey (United Kingdom Ministry of Agriculture, Fisheries and Food)H-Index: 1
#2JW Wilesmith H-Index: 1
Some of the brains submitted for neurohistopathological examination under the Bovine Spongiform Encephalopathy (BSE) Orders did not show lesions of BSE. They showed neuronal chromatolysis and necrosis of the brainstem, perivascular cuffs and meningeal infiltrates of mononuclear cells and large irregularly shaped vacuoles in the neuropil. About half of them also showed loss of pyramidal neurons in the hippocampus, with astrocytic gliosis. The topography of the brainstem neuronal degeneration and vacuolation was the same in all the cattle, suggesting that neuronal necrosis and chromatolysis, vacuolation and hippocampal sclerosis are part of a spectrum of changes common to a single disease. The cows affected with such changes came from most parts of Scotland with the largest number from the north east. They were of various breeds, mostly suckler cows, and were aged from six to 16 years. Some cows had had no reported access to feed supplements. Clinically, the cows showed a range of neurological signs: tremor, ataxia, apprehension and weight loss were described in more than 80 per cent of the cases. The cause of the disorder was not determined.
terry
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