- I have researched human/animal TSEs now for over 5 years
due to the death of my Mother from the Heidenhain Variant Creutzfeldt Jakob
disease, one of six - known - variants of the infamous 'sporadic' CJD.
-
- I did a little survey several years ago about CJD and
ENDOSCOPY in 2001, and then went there again when another article was released
recently. However, they seemed to only be concerned with the vCJD strain
and risk from endoscopy equipment.
-
- My concerns are if vCJD can be transmitted by blood,
and there are now 6 variants of the infamous sporadic CJDs that they are
documenting to date, how do they know that none of these 6 variants will
not transmit the agent (prion) via blood?...especially since the sporadic
CJDs are the only ones documented to date to transmit via the surgical
arena and now that the CWD is spreading more and more, who knows about
the cattle?
-
- I would always read this study and it would bring me
back to reality as to how serious/dangerous this agent is in the surgical/medical
arena. You might want to read this short abstract from the late, great
Dr. Gibbs twice, and let it really sink in. And please remember while reading
some of these transmission studies, that most all, if not ALL these agents
transmit freely to primates. Humans, of course, are primates.
-
- Regarding claims that:
-
- 'Well, it has never been documented to transmit to humans."
-
- There are two critical factors to think about:
-
- A. CJD/TSEs in the USA are NOT reportable in most states
and there is NO CJD/TSE questionnaire for most victims and their families,
and the one they are now issuing asks absolutely nothing about route and
source of the (prion) agent, only how the disease was diagnosed. Furthermore,
the elderly are only very rarely autopsied, ie looking for Alzheimer's
or 'FAST Alzheimer's' OR prion disease-related factors and phenomena, such
as heart failure caused by disease.
-
- B. It is unethical and against the law to do transmission
studies of TSEs to humans, they are 100% FATAL.
-
- I suggest you read these case studies about medical arena
CJD transmission very carefully:
-
- 1: J Neurol Neurosurg Psychiatry 1994 Jun;57(6):757-8
-
- 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.
-
- http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8006664&dopt=Abstract
-
- Tissue Infectivity and TSEs (brain = high / rectum =
medium)
-
- [PDF]TSE infectivity distribution in ruminant tissues
-
- ... small intestine Distal small intestine Proximal colon
Distal colon Rectum ... on the basis of the most recent scientific data,
the sheep tissue infectivity ...
-
- http://www.europa.eu.int/comm/food/fs/sc/ssc/out241_en.pdf
-
- ... entire bovine intestine from duodenum to rectum ...
in any other extra neural tissue ... could promote the spread of infectivity
... Abnormal prion protein could also be ...
-
- http://www.europa.eu.int/comm/food/fs/sc/ssc/out215_en.pdf
-
- Transmission of prion diseases by blood transfusion
-
- Nora Hunter,1 James Foster,1 Angela Chong,1 Sandra McCutcheon,2
David Parnham,1 Samantha Eaton,1 Calum MacKenzie1 and Fiona Houston2
-
- 1 Journal of General Virology (2002), 83, 2897-2905.
Printed in Great Britain Published ahead of print (16 July 2000) in JGV
Direct as DOI 10.1099/vir.0.18580-0 Transmission of prion diseases by blood
transfusion Nora Hunter,1 James Foster,1 Angela Chong,1 Sandra McCutcheon,2
David Parnham,1 Samantha Eaton,1 Calum MacKenzie1 and Fiona Houston2 1
Institute for Animal Health, Neuropathogenesis Unit, West Mains Road, Edinburgh
EH9 3JF, UK 2 Institute for Animal Health, Compton, Newbury, Berkshire
RG20 7NN, UK Author for correspondence: Nora Hunter. Fax +44 131 668 3872.
e-mail nora.hunter@bbsrc.ac.uk Received 16 May 2002; Accepted 9 July 2002
This article is now available in the November 2002 print issue of JGV (vol.
83, 2897-2905). The complete issue of the journal may be seen in electronic
form on JGV Online (http://vir.sgmjournals.org). 0001-8580 © 2002
SGM
-
- Abstract
-
- Attempts to detect infectivity in the blood of humans
and animals affected with transmissible spongiform encephalopathies (TSEs
or prion diseases) have often been inconclusive because of the limitations
of cross-species bioassays and the small volumes of blood that can be injected
by the intracerebral route. A model has been developed for the experimental
study of TSE transmission by blood transfusion using sheep experimentally
infected with bovine spongiform encephalopathy (BSE) or natural scrapie
as donors and susceptible scrapie-free sheep as recipients. Donors and
recipients of the same species greatly increase the sensitivity of the
bioassay and in sheep large volumes of blood can be injected by the intravenous
(i.v.) route. Transmission of BSE to a single animal using this approach
was reported recently. This study confirms this result with a second transmission
of BSE and four new cases of transmission of natural scrapie. Positive
transmissions occurred with blood taken2 at pre-clinical and clinical stages
of infection. Initial studies indicate that following such infection by
the i.v. route, deposition of the abnormal prion protein isoform, PrPSc,
in peripheral tissues may be much more limited than is seen following oral
infection. These results confirm the risks of TSE infection via blood products
and suggest that the measures taken to restrict the use of blood in the
UK have been fully justified.
-
- Introduction
-
- Creutzfeldt-Jakob disease (CJD) is one of a group of
related diseases known as prion diseases or transmissible spongiform encephalopathies
(TSEs), a group that also includes scrapie in sheep and bovine spongiform
encephalopathy (BSE) in cattle. A new variant of CJD (vCJD) in human beings
in the UK (Will et al., 1996) is thought to have been the result of infection
with the same agent that causes BSE in cattle (Bruce et al., 1997). The
numbers of vCJDinfected people remain unknown, although, to date, over
100 clinical cases have been recordedin the UK. Amongst many sources of
concern, one major question relates to the safety of blood transfusions
and blood products - especially when inadvertently sourced from individuals
during the long pre-clinical phase of vCJD, a time at which these individuals
may act as asymptomatic carriers of the infectious agent. There is no epidemiological
evidence to indicate that iatrogenic CJD has ever occurred via blood or
blood products but vCJD is a new disease with a different pathogenesis
and may present different risks.
-
- The TSE disease-associated form of the prion protein
(PrPSc) of the neuronal glycoprotein PrPC is often used as a marker for
infectivity. Using a sensitive Western blotting technique, no PrPSc was
detected in the buffy coat from one vCJD patient (Wadsworth et al., 2001).
Although a novel method for detection of PrPSc in scrapie sheep blood has
been described (Schmerr et al., 1997), the study was limited by a low number
of samples and the technique requires further validation. Other investigators
using the more conventional method of immunocytochemistry failed to demonstrate
PrPSc in peripheral blood leucocytes of scrapie-infected sheep (Herrmann
et al., 2002).
-
- An alternative to PrPSc detection is direct bioassay
of infectivity by inoculation of material into hosts of the same or different
species. In laboratory rodents experimentally infected with TSE, a number
of investigators have demonstrated infectivity in blood and blood components
during the pre-clinical and clinical phases of infection (Brown et al.,
1998; Diringer, 1984; Manuelidis et al., 1978). However, infectivity has
not been isolated, so far, from blood components of natural animal hosts
of TSEs (Hadlow et al., 1982; Marsh et al., 1973). Isolated reports of
transmission of CJD to laboratory rodents by whole blood or buffy coat
from human3 patients have been questioned for a variety of reasons (Brown,
1995).
-
- A large-scale study conducted by the National Institutes
of Health failed to demonstrate infectivity in blood from 13 patients with
CJD, using either highly susceptible primates or rodents as bioassay hosts
(Brownet al., 1994). With vCJD, no infectivity was detected in blood from
two patients using mouse bioassays (Bruce et al., 2001). Many of these
studies could have failed to reveal low levels of infectivity in blood
because of the use of rodents as bioassay hosts, thus limiting the sensitivity
by crossing a species barrier. Also, in most cases, the intracerebral (i.c.)
route of inoculation was used, because it is the most efficient, but this
severely limits the volume of blood that can be assayed.
-
- Thus, where transmission from blood has been successful,
infectivity was usually concentrated in some way, for example, by the use
of buffy coat fractions. Transmission by the intravenous (i.v.) route has
been shown to be up to seven times less efficient than following i.c. infection
(Brown et al., 1999), but there have been very few attempts to transmit
TSEs by whole blood transfusion. Units of whole blood from three CJD cases
were transfused into chimpanzees with negative results (Brown et al., 1994)
and pooled blood from three terminally ill TSEinfected mice produced disease
in 1 of 20 transfusion recipients (Brown et al., 1999). Sheep infected
orally with BSE show widespread deposition of PrPSc in the lymphoreticular
system (LRS) (Foster et al., 1996a, 2001b), similar to that seen in human
vCJD patients.
-
- In contrast, in cases of sporadic human CJD and cattle
BSE, peripheral pathogenesis does not appear to involve the LRS (Hill et
al., 1999; Wells et al., 1998). Sheep were chosen as a model in which to
study transmission of TSEs by blood transfusion because of the similarity
of the pathogenesis with vCJD and because large volumes of blood can be
transferred in the absence of a species barrier. We have transfused whole
blood and buffy coat from BSE-infected sheep and natural scrapie-infected
sheep into susceptible but scrapie-free recipient animals. In the first
report on these experiments (Houston et al., 2000), we described a single
case of BSE infection via blood transfusion.
-
- The significance of this finding in a single animal has
been questioned. However, the present report gives details of further successful
transmissions from BSE and natural scrapie cases, the latter being the
first conclusive demonstration of infectivity in blood of naturally infected
individuals. Although still incomplete, our study indicates a frequency
of transmission of TSEs in at least 10 % of the transfusion recipients.
We have decided to provide an update of our results because of the potential
importance of the study for human health. In addition, in the two BSE transfusion
cases examined so far, deposition of PrPSc in peripheral tissues appears
rather limited when compared with sheep infected by the oral route. The
potential implications of this observation for pre-clinical diagnosis and
screening are discussed.
-
- SNIP...
-
- 14 Discussion
-
- With this report we have confirmed and extended our initial
observation of a single case of BSE following transfusion of blood from
a BSE-infected sheep and have provided the first conclusive evidence of
significant levels of infectivity in blood in a naturally occurring TSE
(scrapie). The experiment may take up to 5 years to complete; however,
so far we have clear evidence of disease transmission by the blood transfusion
route in 2 of 24 sheep (8 %) with BSE and 4 of 21 sheep (19 %) with scrapie,
with two additional animals showing clinical signs in the BSE group. If
the clinically suspect BSE-transfused sheep progress as expected, this
would bring the transmission rate for BSE up to 17 %, comparable with the
scrapie rate.
-
- Positive transmissions have occurred not only with samples
taken from sheep at the clinical phase of disease but also with those from
apparently healthy donors as early as halfway through the incubation period
(Fig. 1, lane 9; no PrPSc detection in the brain of donor J2746). Each
TSE is transmitting to its appropriate susceptible genotype (AXQ/AXQ for
BSE and VRQ/VRQ for scrapie) and Western blot/glycoform analyses support
the conclusion that donors and recipients are infected with the same strains
of BSE and scrapie. Our negative controls remain healthy, although still
at relatively early stages post-transfusion and our positive controls are
developing clinical signs at around, or greater than, 600 days post-challenge,
showing incubation periods very similar to the transfusion cases. Whole
blood transfusion (400-450 ml) cases are presenting incubation periods
of around 600 days, which is very similar to those resulting from i.v.
injection of 0.2 g BSE cattle brain homogenate. The transfusions might
be expected to be more efficient because they are a sheepto-sheep transmission
with no species barrier, which contrasts with the i.v. brain infections,
which is a cattle-to-sheep transmission.
-
- A full titration of the inoculum used in the cattle BSE
brain i.v. controls is under way in mice but is incomplete at the time
of writing. Accurate estimation of the levels of infectivity in blood will
require i.v. titration in sheep; however, the results presented here suggest
that they are significantly higher than suspected previously. Another important
consideration is the distribution of infectivity among different blood
components. Perhaps surprisingly, most positive transmissions so far have
followed transfusion of whole blood rather than buffy coat, whereas previous
studies have tended to find infectivity concentrated in the buffy coat
fraction. As we now have a clinical case of scrapie resulting from transfusion
of buffy coat, it is clear that, in our model, infectivity is also carried
by the cells in this fraction. However, these preliminary results suggest
that infectivity is not confined to the buffy coat fraction and that there
may also be significant levels of infectivity in the plasma and/or red
cell fractions. 15
-
- The presence of infectivity in blood suggests that it
should be possible to detect PrPSc or other surrogates of infectivity by
alternative methods, with obvious benefits for development of ante-mortem
diagnostic tests. Early reports of the use of capillary electrophoresis
to detect PrPSc in the blood of scrapie-infected sheep showed some promise
(Schmerr et al., 1997); however, a recent study could not detect PrPSc
in peripheral blood leucocytes of scrapie-infected sheep using immunocytochemistry
(Herrmann et al., 2002). PrPC is known to be expressed only on peripheral
blood mononuclear cells in sheep, in contrast to humans where it is also
found on platelets and, at low levels, on erythrocytes (Barclay et al.,
2002; Herrmann et al., 2001; Holada et al., 1998). Since tissues that express
PrPC do not always equate with areas that accumulate PrPSc and infectivity
during disease, the distribution of infectivity in blood fractions of different
species clearly merits more detailed analysis.
-
- Immunocytochemical detection of PrPSc in peripheral tissues
of two of the BSE transfusion cases has shown a greatly reduced involvement
of lymphoid tissues, including tonsil, in the peripheral pathogenesis compared
with NPU Cheviot sheep orally infected with BSE or natural scrapie (Foster
et al., 2001a). A recent report has shown that a proportion of Romney sheep
in the late pre-clinical stages of infection with BSE following oral dosing
(22 months post-infection) have PrPSc deposits in the CNS in the absence
of any detectable involvement of peripheral lymphoid tissues (Jeffrey et
al., 2001). This study also noted the relatively late and variable onset
of PrPSc accumulation in the lymphoid tissues of BSE-infected sheep.
-
- A more detailed study of BSE and scrapie transfusion
cases, and positive controls, will be undertaken to determine whether lack
of involvement of the LRS is a consistent feature in animals infected by
the i.v. route; the results will be published at a later date. If our preliminary
observations are confirmed, there may be implications for human patients
with the misfortune to have received blood products from vCJD cases, because
a negative tonsil biopsy as a means of reassurance might very well be unreliable.
On the other hand, it also may mean that if a human patient became infected
with vCJD by the i.v. route, then the peripheral tissues and blood of this
secondary case may not themselves be highly infectious. In conclusion,
our results so far indicate that, with more than 10 % of transfusions resulting
in disease in the recipients, blood transfusion represents an appreciable
risk for transmission of TSEs in sheep and, by extension, of vCJD in human
beings. The relatively short and consistent incubation periods seen in
positive cases suggests that levels of infectivity in the blood may be
higher than suspected previously, even in the pre-clinical stages of infection,
and/or that transmission by the i.v. route is highly efficient. From these
preliminary results, it would appear that measures taken to safeguard the
blood supply in the UK are fully justified. 16
-
- However, further work, in particular a thorough investigation
of the distribution of infectivity in different blood fractions, is required
before a reliable estimate of the risks associated with contaminated blood
products can be made.
-
- Acknowledgements The authors are indebted to the UK Department
of Health, European Union and DEFRA for their financial contribution to
this study.
-
- see full text:
-
- http://www.socgenmicrobiol.org.uk/JGVDirect/18580/18580ft.pdf
-
- also, older data pertaining to CJD/TSEs/BLOOD...TSS
-
- Sir, -- Professor Manuelidis and his colleagues (Oct
19, p896) report transmission to animals of Creutzfeldt-Jakob disease (CJD)
from the buffy coat from two patients. We also transmitted the disease
from whole blood samples of a patient (and of mice) infected with CJD.1
Brain, Cornea, and urine from this patient were also infectious, and the
clinicopathological findings2 are summarised as follows.
-
- A 70-year-old man was noted to have a slowing of speech
and writing and some disorientation, all of which progressed rapidly. Decorticate
rigidity, forced grasping, positive snout reflex, and myoclonus appeared
within 2 months. Electroencephalogram revealed typical periodic synchronous
discharge, and he died of pneumonia and upper gastrointestinal haemorrhage,
about 3 months after onset of the symptoms. The Brain weighed 1290g and
showed severe histological changes diagnostic of CJD, including spongiform
change, loss of nerve cells, and diffuse proliferation of astrocytes. There
were no inflammatory cells, microglia, neurofibrillary tangles, and amyloid
plaques, although virus-like particles were detected by electron microscopy.
-
- Results of innoculation in Mice
-
- Inocula NO* Incubation
period (days)+ Brain 7/10 (4) 789 (+ or
- 112) Cornea 1/6 (0) 1037 Blood
2/13 (0) 1080 (+ or - 69) Urine
5/10 (1) 880 (+ or - 55) CSF 0/10
-
- * Number of mice with CJD change/number examined histologically.
Number with amyloid plaques shown in parentheses.
-
- + means + or - SD
-
- Samples were taken aseptically at necropsy. 10% crude
homogenates of brain and cornea in saline, whole blood (after crushing
a clot), and untreated CSF and urine were innoculated intracerebrally into
CF1 strain mice (20 ul per animal). Some mice showed emaciation, bradykinesia,
rigidity of the body and tail, and sometimes tremor after long incubation
periods. Tissues obtained after the animal died (or was killed) were studied
histologically (table). Animals infected by various inocula showed common
pathological changes, consisting of severe spongiform changes, glial proliferation,
and a moderate loss of nerve cells. A few mice inoculated with brain tissue
or urine had the same amyloid plaques found in patients and animals with
CJD.3
-
- In our long-term experiments, inoculating materials taken
from twenty patients with CJD or Gerstmann-Straussler-Scheinker's disease
(GSS) into rodents, positive results were obtained in seventeen cases,
including this patient. Brain tissue transmitted the disease most frequently
within the shortes incubation period, except for one case where the lymph
node was the most infectious. Transmission through the cornea has been
noted in man4 and in guineapigs.5 Whole blood samples taken from three
patients were inoculated and a positive transmission occured only in the
case recorded here. Mouse-to-mouse transmission through blood inoculation
was successful after a mean incubation period of 365 days.1 Transmission
through urine was positive in this patient only, and negative in one other
patient and in many infected animals. Transmission through the CSF from
eight patients was negative, yet transmission via the CSF of infected rats
was positive.1
-
- As viraemia has been proved in guineapigs,6 mice,1,7
and lately in patients with CJD, blood for transfusion or blood products
for medical use must be tested for unconventional pathogens. For this purpose,
we inoculated blood products inot rodents.8 The CJD pathogen was not found
in the products examined. However, this approach takes too long to be of
practical value. More efficient methods must be developed to detect pathogens
and to eliminate them from blood. One proposal9 is to apply membrane filtration
to the pruification protocol of human growth hormone suspected of being
contaminated with CJD. Similar methods are needed for blood contamination.
-
- Department of Neuropathology, Neurological Institute,
Faculty of Medicine, Kyushu University, Fukuoka812, Japan
-
- JUN TATEISHI
-
- 1. Tateishi J, Sato Y, Kaga M. Don H, Ohta M. Experimental
transmission of (bum??cannot read) subacute spongiform encephalopathy to
small rodents I: Clinical and histological observations. Acta Neuropathol
(Berl) 1980; 51: 127.
-
- 2. Shibayama Y, Sakaguchi Y, Nakata K, et al, Creutzfeldt-Jakob
disease with demonstration of virus-like particles. Acta pathol Jpn 1982;32:
695.
-
- 3. Tateishi J, Nagara H, Hikita K, Sato Y. Amyloid plaques
in the brains of mice with Creutzfeldt-Jakob disease. A?? Neurol 1984;
15: 278.
-
- 4. Duffy P, Wolf J, Colings G, DeVoe AG, Streeten B,
Cowen D. Possible person-to-person transmission of Creutzfeldt-Jakob disease.
N Engl J Med 1974; 290?: 692.
-
- 5. Manuelidis EE, Angelo JN, Gorgacz EJ, Kim JH, Manuelidis
L. Experimental Creutzfeldt-Jakob disease transmitted via the eye with
infected cornea. N Engl J Med 1977; 296: 1334.
-
- 6. Manuelidis EE, Gorgacz EJ, Manuelidis L. Viremia in
experimental Creutzfeldt-Jakob disease. Science 1978: 209?: 1069.
-
- 7. Kuroda Y, Gibbs CJ Jr, Amyx HL, Gajdusek DC. Creutzfeldt-Jakob
disease in mice. Persistent viremiam and preferential replication of virus
in low-density lymphocytes. Infect Immun 1983; 41: 154.
-
- 8. Tateishi J, Tsuji S. Unconventional pathogens causing
spongiform encephalopathis absent in blood products. J Med Virol 1985;
15: 11.
-
- 9. Tateishi J, Kitamoto T, Hiratani H. Creutzfeldt-Jakob
disease pathogen in growth hormone preparations is eliminatable. Lancet
(in press).
-
- =================================
-
- Something I submitted to GUT previously;
-
- Subject: Re: gutjnl_el;21 Terry S. Singeltary Sr. (3
Jun 2002) "CJDs (all human TSEs) and Endoscopy Equipment" Date:
Thu, 20 Jun 2002 16:19:51 -0700 From: "Terry S. Singeltary Sr."
<flounder@wt.net> To: Professor Michael Farthing <mjf7p@clinmed.gla.ac.uk>
CC: lcamp@BMJgroup.com References: <001501c21099$5c8bc620$7c58d182@mfacdean1.cent.gla.ac.uk>
-
- Greetings again Professor Farthing and BMJ,
-
- I was curious why my small rebuttal of the article described
below was not listed in this month's journal of GUT? I had thought it was
going to be published, but I do not have full text access. Will it be
published in the future? Regardless, I thought would pass on a more lengthy
rebuttal of mine on this topic, vCJD vs sCJDs and endoscopy equipment.
I don't expect it to be published, but thought you might find it interesting,
i hope you don't mind and hope to hear back from someone on the questions
I posed...
-
- Here is my short submission I speak of, lengthy one to
follow below that:
-
- >> Date submitted: 3 Jun 2002 >> eLetter
ID: gutjnl_el;21 >> >> Gut eLetter for Bramble and Ironside
50 (6): 888 >> >>Name: Terry S. Singeltary Sr. >>Email:
flounder@wt.net >>Title/position: disabled {neck injury}
>>Place of work: CJD WATCH >>IP address: 216.119.162.85
>>Hostname: 216-119-162-85.ipset44.wt.net >>Browser:
Mozilla/5.0 (Windows; U; Win98; en-US; rv:0.9.4) >>Gecko/20011019
Netscape6/6.2 >> >>Parent ID: 50/6/888 >>Citation:
>> Creutzfeldt-Jakob disease: implications for gastroenterology
>> M G Bramble and J W Ironside >> Gut 2002; 50: 888-890
(Occasional viewpoint) >> http://www.gutjnl.com/cgi/content/abstract/50/6/888
>> http://www.gutjnl.com/cgi/content/full/50/6/888 >>-----------------------------------------------------------------
>>"CJDs (all human TSEs) and Endoscopy Equipment" >>-----------------------------------------------------------------
>> >><!-- article ID: 50/6/888 --> >> >><P>
regarding your article; >> >><P> Creutzfeldt-Jakob
disease: implications for gastroenterology >> >><P>
I belong to several support groups for victims and relatives >>of
CJDs. Several years ago, I did a survey regarding >>endoscopy equipment
and how many victims of CJDs have >>had any type of this procedure
done. To my surprise, many >>victims had some kind of endoscopy work
done on them. >>As this may not be a smoking gun, I think it should
>>warrant a 'red flag' of sorts, especially since data now >>suggests
a substantial TSE infectivity in the gut wall >>of species infected
with TSEs. If such transmissions >>occur, the ramifications of spreading
TSEs from >>endoscopy equipment to the general public would be >>horrible,
and could potential amplify the transmission >>of TSEs through other
surgical procedures in that >>persons life, due to long incubation
and sub-clinical >>infection. Science to date, has well established
>>transmission of sporadic CJDs with medical/surgical >>procedures.
-
- >>Terry S. Singeltary Sr. >>CJD WATCH
-
- Again, many thanks, Kindest regards,
-
- Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA
77518 flounder@wt.net CJD WATCH
-
- [scroll down past article for my comments]
-
- Subject: Creutzfeldt-Jakob disease: implications for
gastroenterology & CJD 38 years after _diagnostic_ use of hGH (Iatrogenic
CJDs & sporadic CJDs) Date: Mon, 17 Jun 2002 16:46:46
-0700 From: "Terry S. Singeltary Sr." <flounder@wt.net>
Reply-To: Bovine Spongiform Encephalopathy <BSE-L@uni-karlsruhe.de>
To: BSE-L@uni-karlsruhe.de
-
- Bovine Spongiform Encephalopathy <BSE-L@UNI-KARLSRUHE.DE>
-
-
- OCCASIONAL VIEWPOINTS
-
- Creutzfeldt-Jakob disease' implications for gastroenterology
-
- M G Bramble, J W Ironside
-
- Gut 2002;50:888-890
-
- The current clinical views regarding variant Creutzfeldt-Jakob
disease, and in particular transmission via endoscopy, of those representing
both gastroenterology and the Spongiform Encephalopathy Advisory Committee
are presented in an attempt to guide clinicians as to "best practice"
given the current state of our knowledge.
-
- See end of article for authors' affiliations
-
- Correspondence to: Professor MG Bramble, Endoscopy Centre,
James Cook University Hospital, Marton Rd, Middlesbrough TS4 3BN, UK;
-
- Most gastroenterologists working in the UK have been
aware for some time that endoscopy may be a vector for the transmission
of prions from a patient incubating, but not clinically manifesting, variant
Creutzfeldt-Jakob disease (vCJD) to the next individuals undergoing the
same procedure on the same list. To date there are no recorded cases of
iatrogenic transmission of vCJD via endoscopy but it remains a risk which
will be present for many years to come. Advice to health authorities on
individual cases is through the CJD Incidents Panel. However, we are aware
that advice to health professionals performing endoscopy needs to be as
comprehensive as current evidence will allow, without making it impossible
to perform endoscopic procedures on patients who will clearly derive long
term health benefits from an accurate endoscopic diagnosis and/or treatment.
This article represents the current clinical views of those representing
both gastroenterology and the Spongiform Encephalopathy Advisory Com-mittee
(SEAC). Both authors sit on the CJD Inci-dents Panel and have been advising
the Depart-ment of Health on individual cases during the last year. It
is important to note that the advice given in this article may be superseded
if additional information or evidence becomes available.
-
- CJD is a member of a group of neurological disorders
known as the transmissible spongilorm encephalopathies or prion diseases,
which affect both animals (such as scrapie in sheep or bovine spongiform
encephalopathy (BSE) in cows) and humans. The precise nature of the transmissible
agents responsible for these disorders is unknown but there is increasing
evidence to support the prion hypothesis, which states that the agent is
composed of an abnormally folded form of a host encoded protein, prion
protein. The normal prion protein (PrPc) is expressed in many tissues but
occurs at the highest levels in neurones in the central nervous system
(CNS) where it may act as a copper binding protein, although its precise
physiological role is unknown. The abnormal form of the protein (PrPSc)
accumulates in the CNS in prion diseases; the infectious agent is remarkably
resistant to most forms of degradation. The association between PrPSc and
the gut has been eloquently described in a previous lead-ing article1 and
gastroenterologists need to understand where we are in terms of our present
day knowledge of this entity.
-
- In humans, prion diseases occur in three major categories:
sporadic, acquired, and familial. All are currently untreatable and universally
fatal although recent studies have indicated that a combination of drugs
may be effective in experimental prion diseases2: this approach is under
consideration as a clinical trial. The sporadic form of CJD affects approximately
one person per mil-lion per annum in the population on a worldwide basis.
CJD has also occurred as an acquired iatrogenic disorder, transmitted to
other humans through direct (inadvertent) inoculation of the brain via
contaminated neurosurgical instruments, via corneal and dura mater grafts,
or through administration of human pituitary ex-tracts used to treat growth
hormone or gonadotrophin deficiency. Variant CJD (vCJD) is a new acquired
form of CJD which was first reported in 1996 affecting mainly young adults
and with a unique neuropathological phenotype.3 It is now widely accepted
that bovine prions passed into the human population through consumption
of BSE infected bovine tissues; the transmissible agent responsible for
vCJD is identical to the BSE agent (but different from the agent in sporadic
CJD). The incubation period for vCJD is likely to be lengthy and may have
a mean value of 10-30 years. During this time the affected person has the
potential to transmit the disease to others via surgical procedures which
might result in the transfer of infected tissue into the next person operated
on with the same surgical instruments.
-
- The distribution of PrPSc in the body is different in
sporadic and variant CJD, reflecting the differ-ent pathogenesis of the
two forms. In the case ot sporadic CJD, prion infectivity is largely limited
to the CNS (including the retina) and only opera-tions involving the brain
and eye have resulted in iatrogenic transmission of the disease. Gastro-intestinal
endoscopy is unlikely to be a vector for the transmission of sporadic CJD
as infected tissue is not encountered during the procedure. No special
precautions are necessary during or after the procedure and the endoscope
should be cleaned and disinfected in the normal thorough way.4
-
- "Endoscopy on patients who are incubating vCJD may
result in exposure of the instrument (and particularly the biopsy forceps)
to PrPsc''
-
- In contrast, in vCJD the lymphoreticular system throughout
the body contains PrPSc at the time of death, and experimental evidence
suggests that the lymphoreticular system may contain significant levels
of infectivity for most of the incuba-tion period.5 To support this, in
vCJD abnormal prion protein was found in the germinal centres in the wall
of an appendix from a vCJD patient that was removed eight months before
the onset of neurological disease.6 As lymphoid follicles and germinal
centres are widely distributed in the gastrointestinal tract (and are often
biopsied), it is possible that endoscopy on patients who are incubating
vCJD may result in exposure of the instrument (and particularly the biopsy
forceps) to PrPsc. Consequently, the question now arises, how great is
the risk of secondary (person to person) transmission in endoscoping a
patient incubating vCJD? There are three scenarios which gastroenterologists
are likely to encounter and this editorial will attempt to guide clinicians
as to "best practice" given the current state of our knowledge.
-
- UPPER GASTROINTESTINAL ENDOSCOPY
-
- Scenario No 1
-
- Occasionally gastroenterologists may be requested to
endo-scope a patient with known or probable sporadic CJD (usually to site
a PEG feeding tube). This can be carried out in the rou-tine way provided
vCJD is not suspected. If inadvertently a patient with suspected vCJD is
endoscoped, the instrument used should be quarantined until the postmortem
diagnosis is known. If sporadic CJD is diagnosed, the endoscope can be
returned to use following thorough cleaning and decontami-nation, as is
normal practice. If vCJD is diagnosed the endoscope cannot be used again
and should be quarantined or sent to the National CJD Surveillance Unit
in Edinburgh for research purposes. The previous advice to destroy such
instru-ments represents a lost opportunity to study the risks involved
in more detail. It would also be good practice to inform colleagues locally
that a quarantined instrument was available for use in other endoscopy
units if they too had a patient with suspected vCJD requiring endoscopy.
-
- Scenario No 2
-
- For patients with known or probable vCJD,7 endoscopy
should only be a last resort. Ultrasound guided insertion of a gastrostomy
feeding tube would be preferable to a PEG feeding tube if local expertise
is available. If not, endoscopy should be per-formed using an instrument
already set aside for such patients. If no such instrument is available
locally, one can be loaned to any hospital by the National CJD Surveillance
Unit in Edinburgh (contact telephone number 0131 537 1980). If scenario
No 2 becomes more common, endoscopes may need to be held regionally for
this purpose.
-
- Scenario No 3
-
- This scenario covers patients who have been endoscoped
by an instrument previously used on a patient who was not known to be incubating
vCJD at the time of endoscopy but who sub-sequently went on to develop
the disease. This could become the commonest scenario and it must be assumed
that the patient who went on to develop vCJD was incubating the dis-ease
at the time of the original endoscopy. This also means that infectious
material may not have been removed completely by current methods of decontaminating
endoscopes, and that subsequent patients have been exposed to the prion
agent. The instrument used should therefore be quaran-tined until advice
has been sought from the CJD Incidents Panel (Department of Health, Skipton
House, London; contact telephone 0207 972 1761) as to the management of
the situa-tion. Local infection control teams will need to be involved
with contact tracing and information handling.
-
- LOWER GASTROINTESTINAL ENDOSCOPY
-
- It is unlikely that colonoscopy would be clinically justifiable
in a patient known or strongly suspected as suffering from vCJD. However,
it is quite possible that an asymptomatic patient incubating vCJD may undergo
colonoscopy prior to diagnosis and this situation is essentially the same
as in scenario 3. The risks of transmitting prion protein to the next patient
are much greater however, due to a number of factors which relate to the
amount of lymphatic tissue encountered during endos-copy and the number,
site, and size of mucosal biopsies obtained by this method.
-
- In general the risks of transmitting vCJD from one patient
to another are dependent on the infectivity of the tissues involved, the
amount of tissue contaminating the instrument, the effectiveness of the
decontamination processes, and the susceptibility of subsequently exposed
patients. Experimental studies suggest that levels of infectivity in prion
diseases are highest in the CNS and retina, which are approximately two
logs higher than in the tonsils and other lymphoreticular tis-sue. A recent
study has also detected the abnormal form of the prion protein in rectal
tissue from a patient with vCJD by western blot examination of autopsy
tissues.8 The risk of transmitting vCJD through the endoscopy procedure
itself is likely to be small, but contamination of the endoscope and forceps
as a result of biopsy of lymphoid tissues may represent a larger (but currently
unquantifiable) risk, even though only small amounts of tissue are involved.
-
- "The risks of transmitting vCJD from one patient
to another are dependent on the infectivity of the tissues involved, the
amount of tissue contaminating the instrument, the effectiveness of the
decontamination processes, and the susceptibility of subsequently exposed
patients"
-
- The greatest risk is undoubtedly that which ensues from
biopsy of the terminal ileum where Peyer's patches may con-tain significant
levels of prion protein for a patient incubating vCJD. The biopsy forceps
and the colonoscope become poten-tial vectors for disease transmission
under these circum-stances. Meticulous manual cleaning of the colonoscope
is probably the best defence against person to person transmis-sion. The
same is true of the biopsy forceps, but as disposable forceps are now available
there is a strong argument for mov-ing towards the universal use of disposable
biopsy forceps for mucosal samples taken at colonoscopy. Endoscopy units
should now work towards a policy of using disposable biopsy forceps as
the only practical way of minimising the risk which results from ileal
biopsy. In addition, "random" biopsies should be kept to a minimum
as lymphoid tissue is distributed widely throughout the gastrointestinal
tract. Although thor-ough cleaning of flexible endoscopes ensures patient
safety for "normal" pathogens, the same process may not be adequate
for the PrPsc. The main benefit of the decontamination process under these
circumstances is undoubtedly effective manual cleaning, as glutaraldehyde
may stabilise PrPSc on the metal surface of the endoscope, with potentially
adverse conse-quences. It follows that brushes used to clean the channels
of the endoscope are used only once to ensure maximum efficiency and biopsy
forceps should also be functioning opti-mally and discarded as soon as
they appear to be under performing (tearing tissue rather than cutting
it). The rubber valve protecting the biopsy channel is another item which
is potentially disposable and serious consideration should be given to
single use valves. Again, more research is required to determine "best
practice". For rigid endoscopes, autoclaving at the recommended conditions
for CJD9 is the best way of attempting decontamination.
-
- What should endoscopists do in the short term? The answer
to this question must be to ensure as far as possible that manual cleaning
of endoscopes and reuseable accessories is of the highest standard. Endoscopy
has a major role in patient care, and this should not be compromised unless
it is absolutely unavoidable in the public interest. It is also essen-tial
that endoscopes should be individually identifiable and their use traceable
in any given patient population. Random biopsies should be kept to an absolute
minimum (particularly of the ileum in colonoscopy) and endoscopy itself
should be as atraumatic as possible, especially gastroscopy where the instrument
is in contact with the mucosa covering the tonsils. Biopsy forceps should
be treated as "high risk" and undergo thorough ultrasonic cleaning
followed by autoclaving. As research in the UK progresses, it is likely
that other procedures will be developed to inactivate prion infectivity
and to remove proteins from instrument surfaces. The development of such
techniques (along with more sensitive tests for prion detection) may well
have an impact on future advice concern-ing endoscopy and CJD.
-
- Depending on the final numbers of people infected with
vCJD, we must assume that a significant number may undergo endoscopy before
neurological symptoms appear10. It is there-fore up to every endoscopist
to be aware of the dangers and follow the advice set out here. Further
advice on specific cases and possible exposure incidents can be obtained
from the CJD Incidents Panel (Department of Health, Skipton House, London;
contact telephone 0207 972 1761).
-
- Authors' affiliations M G Bramble, Endoscopy Centre,
James Cook University Hospital, Marton Road, Middlesbrough TS4 3BW, UK
J W Ironside, CJD Surveillance Unit, Western General Hospital, Crewe Road,
Edinburgh EH4 2XU, UK
-
- mike.bramble@stees.nhs.uk
-
- Accepted for publication 19 November 2001
-
- REFERENCES
-
- 1 Shmakov AN, Ghosh S. Prion proteins and the gut: une
liaison dangereuse? Gut 2001;48:443-7.
-
- 2 Korth C, May BCH, Cohen FE, et al. Acridine and phenothiazine
derivatives as pharmacotherapeutics for prion disease. Proc Nail Acad Sci
USA 2001;98:9836-41.
-
- 3 Will RG, Ironside JW, Zeidler M, et al. A new variant
of Creutzfeldt-Jakob disease in the UK. Lancet 1996;347:921-5.
-
- 4 Report of a Working Party of the British Society of
Gastroenterology Endoscopy Committee. Cleaning and disinfection of equipment
for gastrointestinal endoscopy. Gut 1998;42:585-93.
-
- 5 Hill AF, Butterworth R J, Joiner S, et al. Investigation
of variant Creutzfeldt-Jacob disease and other human prion diseases with
tonsil biopsy samples. Lancet 1999;353:183-9.
-
- 6 Hilton DA, Fathers E, Edwards P, et al. Prion immunoreactivity
in the appendix before the clinical onset of new variant Creutzfeldt-Jacob
disease. Lancet 1998;352:703-4.
-
- 7 Will RG, Zeidler M, Stewart GE, et al. Diagnosis of
new variant Creutzfeldt-Jakob disease. Ann Neuro12000;47:575-82.
-
- 8 Wadsworth JD, Joiner S, Hill AF, et al. Tissue distribution
of protease resistant prion protein in variant Creutxfleldt-Jakob disease
using a highly sensitive immunoblotting assay. Lancet 2001 ;358:171-80.
-
- 9 Dangerous Pathogens Spongiform Encephalopathy Advisory
Committee. Transmissible spongiform encephalopathy agents: safe working
and the prevention of infection. London: The Stationary Office, 1998.
-
- 10 Ironside JW, Hilton DA, Ghani A, et al. Retrospective
study of prion protein accumulation in tonsil and appendix tissue. Lancet
2000;355:1693-94.
-
- http://www.gutjnl.com/cgi/content/abstract/50/6/888 ========================================================
-
- Greetings List Members,
-
- This is _very_ disturbing to me:
-
- snip...
-
- The distribution of PrPSc in the body is different in
sporadic and variant CJD, reflecting the different pathogenesis of the
two forms. In the case ot sporadic CJD, prion infectivity is largely limited
to the CNS (including the retina) and only operations involving the brain
and eye have resulted in iatrogenic transmission of the disease. Gastro-intestinal
endoscopy is unlikely to be a vector for the transmission of sporadic CJD
as infected tissue is not encountered during the procedure. No special
precautions are necessary during or after the procedure and the endoscope
should be cleaned and disinfected in the normal thorough way.4
-
- snip...
-
- i personally believe it is irresponsible for anyone to
state in this day and time, that sporadic CJDs (now at 6 variants) will
not transmit the disease by this route. considering infective dose cannot
be quantified, only speculated, such a statement is thus, irresponsible.
to hypothosize that sporadic CJD just happens spontaneously (with no scientific
proof), that the PrPSc distribution in tissues of all sporadic CJDs is
entirely different than that of vCJD, without being able to quantify the
titre of infection, or even confirm all the different variants yet, again
is _not_ based on all scientific data, then it's only a hypothosis. who
is to say that some of these variants of sporadic CJD were not obtained
_orally_?
-
- also stated:
-
- snip...
-
- Although thorough cleaning of flexible endoscopes ensures
patient safety for ''normal'' pathogens, the same process may not be adequate
for the PrPSc.
-
- snip...
-
- The sporadic form of CJD affects approximately one person
per mil-lion per annum in the population on a worldwide basis.
-
- who is to say how much infectivity are in some of these
variants of sporadic CJDs, without confirming this? if we look at the 6
different variants of sporadic CJDs, has the infective dose for all 6 _documented_
variants been quantified, and documented as being 'measurable'?
-
- will there be more variants of sporadic CJDs, and what
of the ramifications from them?
-
- what of other strains/variants of TSE in cattle, BSE
in sheep, CWD in cattle, or any of the 20+ strains of Scrapies in deer/elk?
i get dizzy thinking of the different scenerio's. what would the human
TSEs from these species look like and how can anyone quantify any tissue
infectivity from these potential TSE transmissions to humans, and the risk
scenerio described here from this potential route? could not some of these
sporadic CJDs have derived directly or indirectly from one of these species,
and if so, pose a risk by the route described here?
-
- something else to consider, in the recent finding of
the incubation period of 38 years from a _small_ dose of human growth hormone;
-
- snip...
-
- > We describe the second patient with hGH related
CJD in the Netherlands. The patient developed the disease 38 years after
hGH injections. To our knowledge, this is the longest incubation period
described for any form of iatrogentic CJD. Furthermore, our patient was
_not_ treated with hGH, but only received a _low_ dose as part of a diagnostic
procedure. (see full text below).
-
- snip...
-
- so my quesion is, how low is 'low' in quantifing the
infectious dose in vCJD, comparing to _all_ sporadic CJDs, from the different
potential routes, sources, and infectivity dose?
-
- will the titre of infectivity in every tissue and organ
of all sporadic CJDs stay exact or constant, no matter what the infective
dose, route and species may be? this is considering you don't buy the fact
that sporadic CJDs 85%+ of _all_ CJDs, are a happen stance of bad luck,
happen spontaneously without cause, and are one-in-a-million world wide,
with no substantial surveillance to confirm this.
-
- Diagnosis and Reporting of Creutzfeldt-Jakob Disease
T. S. Singeltary, Sr; D. E. Kraemer; R. V. Gibbons, R. C. Holman, E. D.
Belay, L. B. Schonberger
-
- http://jama.ama-assn.org/issues/v285n6/ffull/jlt0214-2.html
-
- and what of Dr. Prusiner et al recent work about tissue
infectivity;
-
- Prions in skeletal muscle
-
- snip...
-
- Our data demonstrate that factors in addition to the
amount of PrP expressed determine the tropism of prions for certain tissues.
That some muscles are intrinsically capable of accumulating substantial
titers of prions is of particular concern. Because significant dietary
exposure to prions might occur through the consumption of meat, even if
it is largely free of neural and lymphatic tissue, a comprehensive effort
to map the distribution of prions in the muscle of infected livestock is
needed. Furthermore, muscle may provide a readily biopsied tissue from
which to diagnose prion disease in asymptomatic animals and even humans.
-
- snip...
-
- http://www.pnas.org/cgi/content/abstract/99/6/3812?maxtoshow=&HITS=10&hits=
- 10&RESULTFORMAT=&author1=prusiner&author2=prusiner&titleabstract=prions+meat+
- tissue+mice&fulltext=prions+meat+tissue+mice&searchid=1024346978866_6016&stored_
- search=&FIRSTINDEX=0&fdate=1/1/2002
-
- can the science/diagnostic measures used to date, measure
this, and at the same time guarantee that no titre of infectivity exists
from sporadic CJDs (all of the variants), from this potential mode and
route of transmission?
-
- i don't think so, this is just my opinion. this is why
i get paid nothing, and these scientists get the big bucks. i just hope
i am wrong and the big bucks are correct in their _hypothisis_ of this
potential mode/route of transmission with endoscopy equipment, from _all_
human TSEs.
-
- i understand we have to weigh the risks of what we know
to what we don't know, to the disease we _may_ catch to what we are having
the procedure for, but to categorically state at this present time of scientific
knowledge;
-
- snip...
-
- "Gastro-intestinal endoscopy is unlikely to be a
vector for the transmission of sporadic CJD as infected tissue is not encountered
during the procedure. No special precautions are necessary during or after
the procedure and the endoscope should be cleaned and disinfected in the
normal thorough way.4"
-
- snip...
-
- but, to categorically state this, in my opinion, is not
only wrong, but potentially very dangerous to the future of human health...TSS
-
- SHORT REPORT
-
- Creutzfeldt-Jakob disease 38 years after diagnostic use
of human growth hormone
-
- E A Croes, G Roks, G H Jansen, P C G Nijssen, C M van
Duijn ...............................................................
-
- J Neurol Neurosurg Psychiatry 2002;72:792-793
-
- A 47 year old man is described who developed pathology
proven Creutzfeldt-Jakob disease (CJD) 38 years after receiving a low dose
of human derived growth hormone (hGH) as part of a diagnostic procedure.
The patient presented with a cerebellar syndrome, which is compatible with
iatrogenic CJD. This is the longest incubation period described so far
for iatrogenic CJD. Furthermore, this is the first report of CJD after
diagnostic use of hGH. Since the patient was one of the first in the world
to receive hGH, other cases of iatrogenic CJD can be expected in the coming
years.
-
- Prion diseases are potentially transmissible. Human to
human transmission was first reported in 1974, when a 55 year old woman
was described who developed symptoms of Creutzfeldt-Jakob disease (CJD)
18 months after a corneal transplant.1 Since then, transmission has been
reported after stereotactic electroencephalographic (EEG) depth recording,
human growth hormone (hGH) and gonadotrophin treatment, and dura mater
transplantation.2-5 More than 267 patients with iatrogenic CJD are known
today and their number is growing.6 The most important iatrogenic cause
of CJD is still contaminated cadaveric hGH. Exposure to contaminated hGH
occurred before 1985, when recombinant growth hormone became available.
In a recent study, incubation periods in 139 patients with hGH associated
CJD were found to range from 5-30 years, with a median of 12 years.6 One
of the factors influencing incubation time is genotype on polymorphic codon
129 of the prion protein gene.7 The incubation time is significantly shorter
in people who are homozygous for either methionine or valine on this polymorphism.7
-
- We describe the second patient with hGH related CJD in
the Netherlands. The patient developed the disease 38 years after hGH injections.
To our knowledge, this is the longest incubation period described for any
form of iatrogenic CJD. Further-more, our patient was not treated with
hGH but only received a low dose as part of a diagnostic procedure.
-
- CASE REPORT
-
- This patient presented at the age of 47 years with paraesthesia
in both arms for six months, difficulty with walking for four weeks, and
involuntary movements of mainly the upper extremities of two weeks' duration.
He did not notice any change in cognitive function, although his twin sister
had noticed minor memory disturbances. There was no family history of neurological
disease. During childhood the patient had experienced a growth delay compared
with his twin sister and with the average in the Netherlands. When he was
9 years old, a nitrogen retention test with 6 IU hGH over five days was
performed to exclude growth hormone deficiency. Since the result was not
decisive, a quantitative amino acid test was performed, which measures
30 amino acids during fasting and one, two, and three hours after growth
hormone injection. No abnormal amino acid concentrations were found making
the diagnosis of primordial dwarfism most likely. Therefore, no treatment
with hGH was given.
-
- On neurological examination we found a slight dysarthria
without aphasia. Cranial nerve function was normal. Walking was unstable
and wide based. During movements of the upper extremities myoclonic jerks
were present. Sensation, muscle tone, and strength were normal. Co-ordination
was impaired in all four limbs with a disturbed balance. Tendon reflexes
were brisk at the arms and increased at the legs with a clonus in the ankle
reflex. Plantar responses were both normal. On the mini mental state examination,
the patient scored 30/30. Routine laboratory investigation, thyroid function,
vitamin concentrations (B-1, B-6, B-12, and E), and copper metabolism were
normal. Admission EEG examination showed generalised arrhythmic slow activity
with diffuse spikes and spike waves. EEG examination two months later showed
a further slowing of the rhythm with bilateral diphasic sharp waves but
was not typical for CJD. Cerebral magnetic resonance imaging was normal.
Cerebrospinal fluid examination showed 1 cell/3 µl, normal glucose
and protein concentrations, and a strongly positive 14-3-3 protein test.
The patient was homozygous for methionine on the PRNP codon 129 polymorphism.
On clinical grounds, CJD was diagnosed. Within one month the patient's
condition deteriorated rapidly and because of severe disturbances in coordination
and progressive myoclonus he became bedridden. An eye movement disorder
developed with slow saccadic and dysmetric eye movements. Temperature became
unstable with peaks of 39°C without an infectious focus, for which
a disorder of autoregulation was presumed. Until a very advanced stage,
cognitive function was intact. The patient died five months after admission.
The diagnosis of CJD was confirmed at necropsy. The brain weighed 990 g
and showed clear cortical and cerebellar atrophy. Spongiosis, neuronal
loss, and gliosis were found predominantly in the putamen, caudate nucleus,
and basotemporal and cerebellar cortex; the cerebellum was the most severely
affected of these. Vacuoles ranged from 2-12 µm. No amyloid or Kuru
plaques were found. Immunohistochemical staining (3F4 antibody 1:1000,
Senetek, USA) was clearly positive for prion protein accumulation in a
"synaptic" distribution. Most deposition was found in the stratum
moleculare of the cerebellum.
-
- DISCUSSION
-
- We describe a 47 year old patient who developed pathology
proven CJD 38 years after hGH injections. The patient was never treated
with hGH but received a small dose as part of a diagnostic procedure. The
onset of CJD was signalled by prodromal symptoms of paraesthesia followed
by a rapidly progressive ataxia. The disease presentation and course with
predominantly cerebellar and eye movement disorders are compatible with
iatrogenic CJD caused by hGH treatment.6 8
-
- Growth hormone treatment was first described in 1958
but hGH was not produced on a larger scale from human pituitary glands
until the beginning of the 1960s. In the Netherlands growth hormone extraction
started in 1963 and was soon centrally coordinated. Until 1979 growth hormone
was extracted non-commercially from pituitaries by a pharmaceutical company.
In 1971 commercial products also became available. Our patient was one
of the first to receive hGH in the Netherlands but the origin of this product
was not recorded. A causal relation can therefore not be established with
full certainty, but coincidentally receiving growth hormone and developing
this very rare disease is unlikely. Since the clinical course in this relatively
young patient is in accordance with an iatrogenic cause, we think the probability
is high that the hGH injections explain the development of CJD in this
patient.
-
- The first Dutch patient with hGH related CJD died in
1990. 9 During several periods from 1963 to 1969 she received intramuscular
injections of hGH. During an unknown period the hGH was derived from South
America. At age 39, 27 years after starting the treatment, she developed
an ataxic gait, slurred speech, sensory disorders, and myoclonus, but her
cognitive function remained normal. Postmortem examination of the brain
confirmed the diagnosis of CJD.9 Following the identification of this patient,
a retrospective study was started to trace all 564 registered hGH recipients
who were treated before May 1985. Until January 1995, none of these was
suspected of having CJD.10 Since 1993 prospective surveillance for all
forms of human prion disease has been carried out in the Netherlands and,
apart from the patient described above, a further two patients with iatrogenic
CJD have been identified, who developed the disease after dura mater transplantation.11
-
- An incubation period as long as 38 years had never been
reported for iatrogenic CJD. Huillard d'Aignaux et al7 studied the incubation
period in 55 patients with hGH related CJD in a cohort of 1361 French hGH
recipients. The median incubation period was between 9 and 10 years. Under
the most pessimistic model, the upper limit of the 95% confidence interval
varied between 17 and 20 years. Although the infecting dose cannot be quantified,
it can be speculated that the long incubation period in our patient is
partly explained by the administration of a limited amount of hGH. This
hypothesis is supported by experimental models, in which higher infecting
doses usually produce shorter incubation periods.6 Since our patient was
one of the first in the world to receive hGH, this case indicates that
still more patients with iatrogenic CJD can be expected in the coming years.
Another implication of our study is that CJD can develop even after a low
dose of hGH. This case once more testifies that worldwide close monitoring
of any form of iatrogenic CJD is mandatory.
-
- ACKNOWLEDGEMENTS
-
- We are grateful to M Jansen PhD MD for his search for
the origin of the growth hormone and P P Taminiau MD. CJD surveillance
in the Netherlands is carried out as part of the EU Concerted Action on
the Epidemiology of CJD and the the EU Concerted Action on Neuropathology
of CJD, both funded through the BIOMED II programme, and is supported by
the Dutch Ministry of Health. This surveillance would not have been possible
without the cooperation of all Dutch neurologists and geriatricians. ........................................
-
- Authors' affiliations
-
- E A Croes, G Roks*, C M van Duijn, Genetic Epidemiology
Unit, Department of Epidemiology and Biostatistics, Erasmus University
Medical Centre Rotterdam, PO Box 1738, 3000 DR Rotterdam, Netherlands
-
- P C G Nijssen, Department of Neurology, St Elisabeth
Hospital, PO Box 90151, 5000 LC Tilburg, Netherlands
-
- G H Jansen, Department of Pathology, University Medical
Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, Netherlands
-
- *Also the Department of Neurology, St Elisabeth Hospital
-
- Correspondence to: Professor C M van Duijn, Genetic Epidemiology
Unit, Department of Epidemiology and Biostatistics, Erasmus University
Medical Centre Rotterdam, PO Box 1738, 3000 DR Rotterdam, Netherlands;
vanduijn@epib.fgg.eur.nl
-
- Received 27 December 2001 In revised form 1 March 2002
Accepted 12 March 2002
-
- Competing interests: none declared
-
- REFERENCES
-
- 1 Duffy P, Wolf J, Collins G, et al. Possible person-to-person
transmission of Creutzfeldt-Jakob disease. N Engl J Med 1974;290:692-3.
-
- 2 Bernoulli C, Siegfried J, Baumgartner G, et al. Danger
of accidental person-to-person transmission of Creutzfeldt-Jakob disease
by surgery. Lancet 1977;i:478-9.
-
- 3 Koch TK, Berg BO, De Armond SJ, et al. Creutzfeldt-Jakob
disease in a young adult with idiopathic hypopituitarism: possible relation
to the administration of cadaveric human growth hormone. N Engl J Med 1985;313:731-3.
-
- 4 Cochius JI, Burns RJ, Blumbergs PC, et al. Creutzfeldt-Jakob
disease in a recipient of human pituitary-derived gonadotrophin. Aust NZ
J Med 1990;20:592-3.
-
- 5 Thadani V, Penar PL, Partington J, et al. Creutzfeldt-Jakob
disease probably acquired from a cadaveric dura mater graft: case report.
J Neurosurg 1988;69:766-9.
-
- 6 Brown P, Preece M, Brandel JP, et al. Iatrogenic Creutzfeldt-Jakob
disease at the millennium. Neurology 2000;55:1075-81.
-
- 7 Huillard d'Aignaux J, Costagliola D, Maccario J, et
al. Incubation period of Creutzfeldt-Jakob disease in human growth hormone
recipients in France. Neurology 1999;53:1197-201.
-
- 8 Billette de Villemeur T, Deslys JP, Pradel A, et al.
Creutzfeldt-Jakob disease from contaminated growth hormone extracts in
France. Neurology 1996;47:690-5.
-
- 9 Roos RA, Wintzen AR, Will RG, et al. Een patiënt
met de ziekte van Creutzfeldt-Jakob na behandeling met humaan groeihormoon.
Ned Tijdschr Geneeskd 1996;140:1190-3.
-
- 10 Wientjens DP, Rikken B, Wit JM, et al. A nationwide
cohort study on Creutzfeldt-Jakob disease among human growth hormone recipients.
Neuroepidemiology 2000;19:201-5.
-
- 11 Croes EA, Jansen GH, Lemstra AF, et al. The first
two patients with dura mater associated Creutzfeldt-Jakob disease in the
Netherlands. J Neurol 2001;248:877-81.
-
- re-CJD after diagnostic use of human growth hormone
-
- from a donor sourcing aspect, seems the record keeping
here has a lot to be desired for, let us hope it has improved for recipients
sake.
-
- also, they speak of 'low dose fitting long incubation'.
what about KURU still existing after some 40 years exposure had ceased.
i don't believe in most instances the dose with kuru is low. just something
else to ponder?
-
- TSS
-
- http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12023427&dopt=Abstract
-
- 1: Ann Neurol 1999 Aug;46(2):224-33
-
- Classification of sporadic Creutzfeldt-Jakob disease
based on molecular and phenotypic analysis of 300 subjects.
-
- Division of Neuropathology, Institute of Pathology, Case
Western Reserve University, Cleveland, OH 44106, USA.
-
- snip...
-
- The present data demonstrate the existence of six phenotypic
variants of sCJD. The physicochemical properties of PrP(Sc) in conjunction
with the PRNP codon 129 genotype largely determine this phenotypic variability,
and allow a molecular classification of the disease variants.
-
- snip...
-
- http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10443888&dopt=Abstract
-
- were not all CJDs, even nvCJD, just sporadic, until proven
otherwise?
-
- Terry S. Singeltary Sr., P.O. BOX 42, Bacliff, Texas
77518 USA
-
- http://mailhost.rz.uni-karlsruhe.de/warc/bse-l.html
-
-
- Professor Michael Farthing wrote:
-
- Louise Send this to Bramble (author) for a comment before
we post. Michael
-
- =======================================================
-
- Subj: Reprocessing of Flexible Endoscopes and Endoscopic
Accessories - an International Comparison of Guidelines Date: 9/17/02
3:28:43 AM Eastern Daylight Time From: flounder@WT.NET (Terry S. Singeltary
Sr.) Sender: BSE-L@UNI-KARLSRUHE.DE (Bovine Spongiform Encephalopathy)
Reply-to: BSE-L@UNI-KARLSRUHE.DE (Bovine Spongiform Encephalopathy) To:
BSE-L@UNI-KARLSRUHE.DE
-
- Bovine Spongiform Encephalopathy <BSE-L@UNI-KARLSRUHE.DE>
-
- Reprocessing of Flexible Endoscopes and Endoscopic Accessories
- an International Comparison of Guidelines
-
- Zeitschrift für Gastroenterologie
-
- © Georg Thieme Verlag Stuttgart New York More about
this journal
-
-
- Endoscopic examinations and procedures are essential
for diagnosis and treatment of gastrointestinal diseases. As a result of
poor reprocessing practice microorganisms can be transmitted via endoscope.
The majority of infection transmissions is due to insufficient performance
of cleaning and disinfection disregarding guidelines of societies of gastrointestinal
endoscopy.
-
- A review of the literature and a comparison of European
and American guidelines for reprocessing flexible endoscopes are given.
Differences in the classification of endoscopic devices, on the possibility
of prion transmission, recommendations on staff training and protection,
quality assurance of reprocessing and evidence-based graduation of guidelines
are stressed and discussed. With respect to the procedure of endoscope
reprocessing, differences concerning the cleaning solution to choose, necessity
of thoroughly manual cleaning and brushing of the accessible endoscope
channels (even in the case of subsequent automatic reprocessing endoscopes
in washers-disinfectors), disinfection solution, microbiological quality
of water for final rinsing and rationale for alcohol flush of endoscope
channels for better drying are mentioned.
-
- The need for experimental investigations of the cleaning
and disinfection process is stressed. In contrast to recent guidelines
of European and American societies of gastrointestinal endoscopy, the now
updated recommendations of the Robert Koch-Institute for reprocessing flexible
endoscopes and endoscopic accessories are evidence-based and graduated.
-
-
- Original Article Z Gastroenterol 2002; 40: 531-542 DOI:
10.1055/s-2002-32807 Table of Contents Leitlinien zur Aufbereitung flexibler
Endoskope und endoskopischen Zusatzinstrumentariums im internationalen
Vergleich Reprocessing of Flexible Endoscopes and Endoscopic Accessories
- an International Comparison of Guidelines O. Leiß1, U. Beilenhoff2,
L. Bader3, M. Jung2, M. Exner4 1Fachbereich Gastroenterologie, Deutsche
Klinik für Diagnostik, Wiesbaden 2St. Hildegardis-Krankenhaus, Mainz
3Max von Pettenkofer-Institut der LMU München, München 4Hygiene-Institut
der Universität Bonn, Bonn
-
- Zusammenfassung
-
- Endoskopische Untersuchungen und Eingriffe sind für
Diagnostik und Therapie gastrointestinaler Erkrankungen unverzichtbar.
Durch mangelhaft aufbereitete Endoskope können Mikroorganismen übertragen
werden. Die Mehrzahl der Infektionsübertragungen bei Endoskopie ist
auf unzureichende Reinigungs- und Desinfektionsmaßnahmen unter Missachtung
aktueller Aufbereitungsrichtlinien der Fachgesellschaften zurückzuführen.
-
- In einer Literaturübersicht werden die Leitlinien
europäischer und amerikanischer Fachgesellschaften zur Aufbereitung
flexibler Endoskope verglichen. Es werden Unterschiede in der Klassifikation
des endoskopischen Instrumentariums, in der Bewertung der Prionenproblematik,
in den Anforderungen an Personalschulung und Personalschutz, in der Betonung
qualitätssichernder Maßnahmen und in der wissenschaftlichen
Untermauerung und Graduierung der ausgesprochenen Empfehlungen dargestellt
und diskutiert. Zu Einzelschritten der Aufbereitung werden Unterschiede
hinsichtlich der einzusetzenden Reinigungslösung, der Notwendigkeit
einer manuellen Bürstenreinigung der Endoskopkanäle (auch bei
nachfolgender maschineller Aufbereitung), der Wahl des Desinfektionsmittels,
der mikrobiologischen Qualität des zur Schlussspülung verwendeten
Wassers und der Empfehlung einer Spülung der Endoskopkanäle mit
Alkohol für eine verbesserte Trocknung herausgestellt und kritisch
bewertet.
-
- Es wird offensichtlich, dass experimentelle Untersuchungen
zu Einzelaspekten der Endoskop-Aufbereitung weitgehend fehlen bzw. erst
in jüngster Zeit bearbeitet wurden. Im Gegensatz zu bisherigen Leitlinien
europäischer und amerikanischer Fachgesellschaften zur Endoskop-Aufbereitung
sind die aktualisierten Empfehlungen des Robert Koch-Instituts zur Aufbereitung
flexibler Endoskope und endoskopischen Zusatzinstrumentariums mit der verfügbaren
Evidenz verknüpft und graduiert. Schlüsselwörter
-
- Flexible Endoskope - Aufbereitung - Reinigung - Desinfektion
- Personalschulung - Qualitätssicherung - Mikrobiologische Prüfungen
- Hygiene Abstract
-
- http://www.thieme-connect.com/DOI/DOI?10.1055/s-2002-32807
-
- TSS
-
- http://mailhost.rz.uni-karlsruhe.de/warc/bse-l.html
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