 |
|
Eye Banking and Screening for Creutzfeldt-Jakob Disease
Arch Ophthalmol. 2001;119:721-726.
ABSTRACT
| |
Objectives To quantify the risk of Creutzfeldt-Jakob disease (CJD) among cornea
donors, evaluate supplemental screening strategies, and address concerns about
the adequacy of current methods of screening tissue donors in the United States.
Methods Reported data on deaths due to CJD and from all causes were used to
estimate the rate of CJD among cornea donors. The impact of increased screening
on risk of CJD and donor supply was evaluated.
Results Only 1.3 of the approximately 45 000 cornea donors in the United
States each year might be expected to have CJD. Most of the estimated risk
(91%) is due to preclinical (asymptomatic) disease and therefore could not
be eliminated by screening for signs or symptoms. If only the highest-risk
age group (60 to 69 years) were screened and specificity were 90%, more than
21 000 otherwise acceptable donors would incorrectly be excluded over
a period of 17.5 years to correctly exclude a single donor with symptomatic
CJD.
Conclusions Currently, the risk of CJD transmission following cornea transplantation
is remarkably low. Screening for symptoms of CJD would have minimal impact
on safety, but would reduce donor supply and likely result in many patients
not receiving needed treatment.
INTRODUCTION
IT HAS BEEN KNOWN since 1974 that Creutzfeldt-Jakob disease (CJD), a
transmissible spongiform encephalopathy, can be transmitted from person to
person through cornea transplantation.1 This
led to the establishment of screening criteria to prevent those with a known
diagnosis of CJD (and more recently those with a family history of CJD) from
being selected as cornea donors.2 Since 1974,
more than 600 000 cornea transplantations have been performed in the
United States without any additional reported cases of transmission of CJD.
Recently, however, several factors have raised concerns about the adequacy
of current screening methods.
In the United Kingdom, a new variant of CJD characterized by a relatively
young age of onset has been identified and linked to the occurrence of bovine
spongiform encephalopathy (mad cow disease).3-8
Because a large number of persons in the United Kingdom had likely been exposed
to the causative agent (prion protein) from ingestion of affected beef or
contact with products from the rendering industry during the 1980s and early
1990s, the possibility could not be dismissed that CJD would occur with increasing
frequency among potential cornea donors. Thus far, no cases of variant CJD
have been reported in the United States. Another factor that has focused attention
on donor screening criteria has been the occurrence of 2 additional possible
cases of transmission of CJD through cornea transplantation. One was reported
from Japan in 1994 and the other from Germany in 1997.9-10
Also, 2 corneas and sclera were transplanted to 3 recipients in the United
Kingdom from a woman who was found at autopsy to have had CJD.11
All 3 recipients underwent surgical removal of the donor tissue several months
after placement, and none has yet developed CJD (approximately 2 years after
removal).
In 1999, Hogan and associates11 suggested
that collection of additional information concerning previous neurologic findings
among potential donors would reduce the risk of transmitting CJD. Also, the
Food and Drug Administration12 has issued a
proposed rule that would require a "donor medical history interview" to identify
cognitive, behavioral, and other possible indications of underlying disease
that would preclude tissue donation. The question remains, however, whether
the benefits of implementing a more stringent screening process would outweigh
the associated costs and the public health consequences of decreased supply
of donor corneas. For this reason, the Eye Bank Association of America commissioned
a committee to review available information on the occurrence and transmissibility
of CJD as it relates to cornea transplantation. The committee's findings form
the basis for this report.
METHODS
DIAGNOSED CJD
The frequency of occurrence of CJD among potential cornea donors in
the United States was estimated from reported information on death rates of
CJD,13 all-cause death rates,14
and population figures by age.15 Holman and
associates13 examined US death records from
1979 through 1994 and reported no statistically significant trend in death
rates of CJD over time. Consequently, we used the average annual age-specific
death rates to calculate expected numbers of deaths due to CJD for the 1997
US population. The total numbers of deaths by age due to all causes were obtained
from the National Vital Statistics Reports for 1997.14
Currently, potential cornea donors with a known diagnosis or family
history of CJD are excluded. Also, the Eye Bank Association of America medical
standards for documentation of cause of death require exclusion of tissue
from potential donors who died of unknown causes or of neurologic disease
of unestablished diagnosis.2 Even with those
safeguards, the possibility exists that a series of errors could potentially
lead to transplantation of tissue from a donor who had the clinical diagnosis
of CJD established before death. However, we are not aware that this has ever
occurred. An additional threat is posed by persons who die of CJD without
ever having had their disease correctly diagnosed. A consensus view of the
authors is that no more than 1% of persons who die of CJD (approximately 2.6
cases per year) are not excluded by current screening criteria. This figure
was used to estimate the frequency among cornea donors of CJD due to persons
who had the diagnosis or died of the disease.
SYMPTOMATIC BUT UNDIAGNOSED CJD
Separate estimates were made of the risk posed by potential donors who
died of causes unrelated to CJD but who had either preclinical disease (the
phase before symptoms of CJD have developed) or symptomatic disease that had
not yet been diagnosed. Survival following onset of symptoms of CJD is generally
no longer than a few months.11 Consequently,
there is a comparatively short period during which a person could potentially
have symptomatic, undiagnosed disease but die of other causes and be selected
as a cornea donor. The mean duration of symptoms before diagnosis (estimated
to be 6 months), age-specific death rates of CJD,13
US population figures,15 and age-specific death
rates based on all causes of death14 were used
to estimate the annual numbers of potential donors with symptomatic (but not
yet diagnosed) CJD. It was assumed that none of those potential donors would
be identified and excluded by current screening criteria.
PRECLINICAL (ASYMPTOMATIC) CJD
There is only limited information concerning the intervals from onset
of preclinical disease to development of symptoms of CJD.16-18
In a recent review of iatrogenic CJD from all causes, including use of contaminated
neurosurgical instruments or intracerebral electroencephalogram electrodes,
placement of human dura mater grafts, treatment with cadaveric human growth
hormone or gonadotropin, and cornea transplantation, Brown and associates18 reported a range of 16 months to 30 years from exposure
to onset of CJD among 267 patients. Johnson and Gibbs17
had previously observed a range of 16 months to 17 years among more than 80
patients who had received dura mater grafts. The interval from onset of preclinical
disease to onset of symptoms (estimated to be 10 years), age-specific death
rates of CJD,13 US population figures,15 and age-specific death rates based on all causes
of death14 were used to estimate the annual
numbers of potential donors who had preclinical CJD. It was assumed that none
of those potential donors would be identified and excluded by current screening
criteria.
CORNEA DONOR DATA
Data from the Eye Bank Association of America concerning the age distribution
of cornea donors in 1998 (the most recent data available) were used to estimate
the proportions of all deceased individuals (potential donors) by age who
meet the selection criteria and become donors.19
Those proportions (cornea donor fractions) were multiplied by the estimated
numbers of deceased individuals who either died of CJD and were not excluded
by the screening criteria or who had preclinical or symptomatic disease. This
provided estimates of the annual numbers of donors by age that could potentially
transmit CJD to cornea recipients.
RESULTS
DIAGNOSED CJD
The average annual age-specific death rates of CJD based on a study
of US death records from 1979 through 1994 are shown in Table 1.13 Approximately 98% of deaths
occurred among persons 45 years or older and 80% among those 60 years or older.
The overall average annual age-adjusted death rate was 0.95 deaths per 1 million
population, and there was no statistically significant trend over time. Age-specific
numbers of deaths due to CJD per 1 million deaths due to all causes peak in
the 60- to 64-year age group at 266.7 and decline substantially among older
groups. Those rates provide an indication of the risk that a deceased person
of any particular age would have had a diagnosis of CJD.
|
|
|
|
Table 1. Creutzfeldt-Jakob Disease (CJD) Deaths and Death Rates and
Deaths Due to All Causes in the United States, 1997
|
|
|
SYMPTOMATIC AND PRECLINICAL CJD
The numbers of persons by age who at any given time would be expected
to be symptomatic but not diagnosed as having CJD are shown in Table 2. Death rates based on all causes of death were used to calculate
the numbers of such persons who would be expected to die each year. Because
of the much longer assumed duration of the incubation period (10 years) than
the symptomatic period (6 months), the estimated frequencies of potential
donors with preclinical disease (incubating CJD) are much greater.
|
|
|
|
Table 2. Expected Annual Deaths Among Patients With Preclinical or
Symptomatic Creutzfeldt-Jakob Disease in the United States
|
|
|
TOTAL CJD RISK AMONG CORNEA DONORS
Although the Eye Bank Association of America does not provide data on
age by 5-year intervals, the estimated proportions of all deceased individuals
who become cornea donors are similar in the age range of 21 to 70 years (Table 3). The age-specific proportions
were used to estimate the annual numbers of cornea donors who might be expected
to have had preclinical or symptomatic disease or to have had the diagnosis
or died of CJD (Table 4). The
overall estimate of 1.3 cornea donors with CJD among the annual total of approximately
45 000 donors in the United States is equivalent to a rate of approximately
1 per 35 000 cornea donors. Most of the estimated risk (approximately
91% of total risk) is due to preclinical disease.
|
|
|
|
Table 3. Estimated Proportions of All Deaths That Yield Donor Corneas
|
|
|
|
|
|
|
Table 4. Estimated Annual Numbers of Cornea Donors Who Died of Creutzfeldt-Jakob
Disease (CJD) or Who Had Preclinical or Symptomatic Disease at the Time of
Death*
|
|
|
IMPACT OF INCREASED SCREENING FOR CJD
The numbers of otherwise suitable donors who might incorrectly be excluded
to correctly exclude a single donor with symptomatic or diagnosed disease
(who without screening based on symptoms would remain in the donor pool) were
calculated for various levels of specificity (Table 5). For these calculations, it was assumed that all potential
donors with a known diagnosis or symptoms of CJD would be identified (ie,
sensitivity would be 100%). If only those in the highest-risk age group of
60 to 69 years were screened and specificity were as high as 90%, tissue from
approximately 21 580 donors would incorrectly be discarded over a period
of 17.5 years to exclude 1 donor with symptomatic or diagnosed disease. The
numbers of otherwise suitable donors not selected (per donor with disease
appropriately excluded) would be much greater if screening were applied to
a broader age range of donors or if the sensitivity of screening were less
than 100%. Moreover, donor exclusion based on age alone would not be an attractive
strategy. If all donors aged 60 to 69 years were excluded, more than 19 000
donors (38 000 corneas) would be eliminated for each case of CJD removed
from the donor pool.
|
|
|
|
Table 5. Estimated Numbers of Otherwise Suitable Donors Incorrectly
Excluded by Screening for Symptoms Suggestive of Creutzfeldt-Jakob Disease
(CJD) per Donor With Disease Correctly Excluded*
|
|
|
COMMENT
SCREENING FOR CJD
Currently, it is not possible to identify and exclude individual potential
donors who had preclinical disease because no laboratory test suitable for
widespread screening is available. Possible strategies to improve safety could
be based on exclusion of potential donors in the age groups at highest risk
or on more intensive efforts to identify the estimated small number of donors
(approximately 1 case among every 368 000 donors) with a known diagnosis
or symptoms of CJD who are missed by current screening methods. Hogan and
associates11 previously suggested the latter
approach. Also, the Food and Drug Administration included a requirement for
a "donor medical history interview" to identify cognitive, behavioral, and
other possible indicators of underlying disease in a recently proposed rule.12
Even if a supplemental screening approach were available that could
identify all potential donors with a known diagnosis or symptoms of CJD (sensitivity
of 100%), it might not be practical to use unless the specificity (proportion
of those without disease who are correctly identified) were sufficiently high.
Frequent clinical features of CJD include cognitive impairment (personality
and behavioral changes, disorientation, and memory loss), myoclonus, cerebellar
dysfunction, speech abnormalities, and visual impairment.11, 16-17
The overlap of symptoms with common age-related findings among elderly people
(eg, mental deterioration) would tend to limit the specificity of screening
based on symptoms suggestive of CJD and lead to large losses of otherwise
suitable cornea donors (Table 5).
Also, the clinical information would not generally be collected by neurologists
or other physicians but by technicians with limited medical training, and
family members and other respondents might have considerable difficulty in
judging and agreeing whether a potential donor had a particular symptom. If
the percentage of persons who die of CJD and are not excluded by current screening
criteria is actually much higher than has been assumed for our analyses (eg,
5% or 10% instead of 1%), it would imply that many patients have clinical
findings and courses that are sufficiently atypical for the diagnosis of CJD
not to be established. The effect of such an assumption would be to increase
the number of donors with CJD, but expansion of screening criteria based on
this possibility would likely further erode the specificity of screening and
not have a favorable cost-to-benefit ratio.
DEMAND FOR DONOR CORNEAS
There are sufficient donor corneas to meet current demand in the United
States, but worldwide demand will far exceed supply for the foreseeable future.
Consequently, loss of donor corneas due to more intensive screening would
have a direct impact on the number of persons who could have their vision
restored by cornea transplantation and for others would likely lengthen the
waiting time for surgical treatment. This view is supported by the recent
initiation of a study sponsored by the National Eye Institute (the Cornea
Donor Study; http://www.nei.nih.gov/neitrials_script/studydtl.asp?id=80) to evaluate outcomes following use of tissue from older cornea donors.
If the results are favorable, the goal will be to increase the supply and
acceptance of tissue from older donors. Also, concerns have been expressed
that growth in the volume of refractive surgical procedures may constrain
future availability of donor corneas. It is important, therefore, that consideration
of new screening requirements take into account the likely impact on supply
of donor corneas and that the supply not be limited unnecessarily.
LEGISLATIVE CONSENT FOR DONOR CORNEA PROCUREMENT
In some states, the law allows for procurement of donor corneas by the
medical examiner or coroner through a legislative consent process that does
not require communication with the next of kin. Although current federal regulations
require a "donor medical history interview," there is an exception for corneas
obtained through legislative consent. The recently proposed rule drafted by
the Food and Drug Administration would eliminate this exception.12
If the donor's next of kin, acquaintances, or primary treating physician must
be interviewed about symptoms suggestive of CJD, the number of donors obtained
through legislative consent will be substantially reduced (possibly by as
much as 90%) because of the difficulty in locating appropriate individuals
to interview during the short time available for procurement following the
frequently sudden, unexpected, and traumatic deaths that are evaluated by
medical examiners and coroners. At present, approximately 10% of all cornea
donors in the United States are obtained through legislative consent. Data
concerning the age distribution of those donors were collected from the Florida
Lions Eye Bank, the Lions Eye Bank of Texas, and Tissue Banks International.
The data show that in 1998 approximately 50% of cornea donors were 40 years
or younger (compared with 15% among all donors). Based on those data, we estimate
that the overall risk of preclinical, symptomatic, and diagnosed CJD in this
subgroup is about 40% less than the estimated preclinical risk alone among
all other donors. This should more than compensate for any potential increase
in risk due to less complete ascertainment of information concerning family
medical history because only about 13% of patients with CJD have a family
history of the disease.16-17 Consequently,
the data support the view that more intensive screening of donors obtained
through legislative consent might actually reduce the level of safety rather
than enhance it because of the loss of a large proportion of those donors.
It should be noted that ethical concerns have been expressed about the process
of obtaining legislative consent, but those concerns do not center on the
issue of risk due to CJD.
TRANSMISSIBILITY OF CJD
For several reasons, our estimate of the annual number of cornea donors
with CJD (Table 4) is greater
than the number of cornea recipients who might be expected to develop the
disease. Data from the Eye Bank Association of America indicate that more
than one third of donated tissue is either not suitable for transplantation
or is used for research or training purposes.19
Also, various biologic factors may influence the likelihood of transmission
even if a recipient were to receive tissue from an affected donor. For example,
genetic homozygosity for methionine at codon 129 (present in approximately
50% of the general population) is overrepresented (80%) in patients with iatrogenic
CJD.18, 20 In addition, attempts
to transmit disease to experimental animals fail for 10% of patients with
the most common form of CJD (sporadic disease).16
In the United States, more than 600 000 donor corneas have been
transplanted without any additional reports of CJD transmission since 1974.
This would require at least 300 000 donors (2 corneas per donor). Using
our overall estimated rate of CJD among donors, it can be calculated that
8.6 of those donors (99% confidence interval, 8.3-9.0) would be expected to
have had preclinical, symptomatic, or diagnosed CJD. Although CJD transmission
to cornea recipients could potentially have occurred and not been identified
or reported, biologic and other factors probably account for much of the lower
than expected rate of disease among recipients. For this reason, we believe
the estimates of otherwise suitable donors who would be excluded by screening
(Table 5) understate the numbers
who would be excluded per case of CJD transmission prevented among cornea
recipients.
CONCLUSIONS
The risk of disease transmission following cornea transplantation is
remarkably low with use of current practices for excluding potential donors
with a known diagnosis or family history of CJD. Our analyses indicate that
increased screening based on signs and symptoms would likely lead to minimal
additional improvement in safety, but would reduce the supply of suitable
cornea donors, particularly young donors obtained through legislative consent,
and result in many patients not receiving needed treatment in a timely manner.
Consequently, we would not recommend such screening. A limitation in addressing
this issue, however, is the lack of data concerning actual experience with
screening for symptoms of CJD, the precise number of cornea recipients who
have received tissue from donors with CJD, the exact level of protection afforded
by biologic and other factors, and the actual number of potential donors with
CJD who are not eliminated by current screening methods. It is possible that
variant CJD could be identified in the United States in the future and pose
a new threat to cornea recipients. In the United Kingdom, variant CJD has
occurred chiefly in adolescents and young adults (mean age, 28 years). However,
preemptive screening or restriction of the supply of young donors before the
occurrence of sufficient cases to document a risk from variant CJD would likely
not be beneficial because the incidence rate of sporadic disease in the United
States is currently much lower among donors younger than 40 years than among
older donors.
AUTHOR INFORMATION
Accepted for publication December 28, 2000.
This work was supported in part by an unrestricted grant from Research
to Prevent Blindness, Inc, New York, NY.
Presented at the annual meeting of the Eye Bank Association of America,
Washington, DC, June 24, 2000, and a meeting of the US Food and Drug Administration's
Transmissible Spongiform Encephalopathies Advisory Committee, Bethesda, Md,
January 18, 2001.
We thank the following individuals for providing data concerning cornea
donors: Patricia Aiken-O'Neill and Joseph Kelly at the Eye Bank Association
of America; Richard Fuller at Tissue Banks International; Mary Anne Taylor,
MS, at the Florida Lions Eye Bank; Mary Beth Danneffel, RN, at the Lions Eye
Bank of Texas at Baylor College of Medicine, Cullen Eye Institute; and Ellen
Heck, MT, MA, at The University of Texas Southwestern Medical Center. Haroutune
Armenian, MD, DrPH, George Bartley, MD, Dwight Cavanagh, MD, Robert Haley,
MD, and Leonard Kurland, MD, DrPH, reviewed the manuscript and provided valuable
suggestions; Donald McIntire, PhD, offered expert statistical assistance.
Corresponding author: Robert H. Kennedy, MD, PhD, MBA, Exponent,
Inc, 149 Commonwealth Dr, Menlo Park, CA 94025.
Robert H. Kennedy, MD, PhD, MBA;
R. Nick Hogan, MD, PhD;
Paul Brown, MD;
Edward Holland, MD;
Richard T. Johnson, MD;
Walter Stark, MD;
Joel Sugar, MD
From the Health Group, Exponent, Inc, Menlo Park, Calif (Dr Kennedy);
Department of Ophthalmology, The University of Texas Southwestern Medical
Center at Dallas (Dr Hogan); The Laboratory of Central Nervous System Studies,
The National Institutes of Neurological Diseases and Stroke, Washington, DC
(Dr Brown); Department of Ophthalmology, The University of Minnesota, Minneapolis
(Dr Holland); Departments of Neurology (Dr Johnson) and Ophthalmology (Dr
Stark), The Johns Hopkins University, Baltimore, Md; and Department of Ophthalmology,
The University of Illinois, Chicago (Dr Sugar). Dr Holland is now with the
Cincinnati Eye Institute and the University of Cincinnati, Cincinnati, Ohio.
REFERENCES
1. Duffy P, Wolf J, Collins G, DeVoe AG, Streeten B, Cowen D. Possible person-to-person transmission of Creutzfeldt-Jakob disease. N Engl J Med. 1974;290:692-693.
2. Eye Bank Association of America. Medical Standards. Washington, DC: Eye Bank Association of America; 1998.
3. Wilesmith JW, Wells GAH. Bovine spongiform encephalopathy. Curr Top Microbiol Immunol. 1991;172:21-38.
PUBMED
4. Will RG, Ironside JW, Zeidler M, et al. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet. 1996;347:921-925.
FULL TEXT
|
ISI
| PUBMED
5. Collinge J, Sidle KCL, Heads J, et al. Molecular analysis of prion strain variation and the aetiology of "new
variant" CJD. Nature. 1996;383:685-690.
FULL TEXT
| PUBMED
6. Hill AF, Desbruslais M, Joiner S, et al. The same prion strain causes vCJD and BSE. Nature. 1997;389:448-450.
FULL TEXT
| PUBMED
7. Brown P. The risk of bovine spongiform encephalopathy ("mad cow disease") to
human health. JAMA. 1997;278:1008-1011.
FREE FULL TEXT
8. Pocchiari M. Early identification of variant Creutzfeldt-Jakob disease [editorial]. BMJ. 1998;316:563-564.
FREE FULL TEXT
9. Uchiyama K, Ishida C, Yago S, Kuramaya H, Kitmoto T. An autopsy case of Creutzfeldt-Jakob disease associated with corneal
transplantation. Dementia. 1994;8:466-473.
10. Heckmann JG, Lang CJG, Petruch F, et al. Transmission of Creutzfeldt-Jakob disease via a corneal transplant. J Neurol Neurosurg Psychiatry. 1997;63:388-390.
FREE FULL TEXT
11. Hogan RN, Brown P, Heck E, Cavanagh HD. Risk of prion disease transmission from ocular donor tissue transplantation. Cornea. 1999;18:2-11.
FULL TEXT
|
ISI
| PUBMED
12. US Food and Drug Administration. Suitability Determination for Donors of Human Cellular
and Tissue-Based Products. Rockville, Md: US Food and Drug Administration; 1999. Docket No.
97N-484S.
13. Holman RC, Khan AS, Belay ED, Schonberger LB. Creutzfeldt-Jakob disease in the United States, 1979-1994: using national
mortality data to assess the possible occurrence of variant cases. Emerg Infect Dis. 1996;2:333-337.
ISI
| PUBMED
14. Deaths: Final Data for 1997. Natl Vital Stat Rep. 1999;47:19.
15. US Census Bureau. Population Estimates for the US, Regions, Divisions,
and States by 5-Year Age Groups and Sex, 1990-1998. Washington, DC: US Census Bureau; 1999.
16. Brown P, Gibbs CJ, Rodgers-Johnson P, et al. Human spongiform encephalopathy: the National Institutes of Health
series of 300 cases of experimentally transmitted disease. Ann Neurol. 1994;35:513-529.
FULL TEXT
|
ISI
| PUBMED
17. Johnson RT, Gibbs CJ. Creutzfeldt-Jakob disease and related transmissible spongiform encephalopathies. N Engl J Med. 1998;339:1994-2004.
FREE FULL TEXT
18. Brown P, Preece M, Brandel JP, et al. Iatrogenic Creutzfeldt-Jakob disease at the millennium. Neurology. 2000;55:1075-1081.
FREE FULL TEXT
19. Eye Banking Statistical Report. Washington, DC: Eye Bank Association of America; 1998.
20. Brown P, Cervenakova L, Goldfarb LG, et al. Iatrogenic Creutzfeldt-Jakob disease: an example of the interplay between
ancient genes and modern medicine. Neurology. 1994;44:291-293.
FREE FULL TEXT
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter
What's this?
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
Qualifications to the Report of a New Case of Creutzfeldt-Jakob Disease in the Recipient of a Corneal Transplant
Hogan et al.
Arch Neurol 2003;60:293-294.
FULL TEXT
Prion Protein Accumulation in Eyes of Patients with Sporadic and Variant Creutzfeldt-Jakob Disease
Head et al.
IOVS 2003;44:342-346.
ABSTRACT
| FULL TEXT
Papillary Adenocarcinoma of the Iris Transmitted by Corneal Transplantation
McGeorge et al.
Arch Ophthalmol 2002;120:1379-1383.
FULL TEXT
Cornea procurement from very old donors: post organ culture cornea outcome and recipient graft outcome
Gain et al.
Br J Ophthalmol 2002;86:404-411.
ABSTRACT
| FULL TEXT
|
