Creutzfeldt-Jakob disease

Creutzfeldt-Jakob disease (CJD) surveillance relies on autopsy and neuropathologic evaluation. The 1990-2000 CJD autopsy rate in California was 21%. Most neurologists were comfortable diagnosing CJD (83%), but few pathologists felt comfortable diagnosing CJD (35%) or performing autopsy (29%). Addressing obstacles to autopsy is necessary to improve CJD surveillance.

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Transmissible spongiform encephalopathies (TSEs) are rare, progressively fatal, neurodegenerative illnesses. Human TSEs include classic Creutzfeldt-Jakob disease (CJD) and the recently described variant CJD associated with eating bovine spongiform encephalopathy--infected cattle products in Europe (1). The recent identification of bovine spongiform encephalopathy in the United States underscores the importance of maintaining enhanced surveillance to monitor for the possible occurrence of variant CJD in this country (2,3).

In California, CJD is not reportable. Since 1999, the California CJD Surveillance Project of the California Emerging Infections Program, a collaboration of the California Department of Health Services and the U.S. Centers for Disease Control and Prevention, has conducted enhanced surveillance for classic and variant CJD. Methods include review of state mortality data and follow-up investigation of CJD-related deaths that occur in persons <55 years of age, since >98% of cases of variant CJD in the United Kingdom have occurred in this age group. As part of this enhanced surveillance, medical records for 33 deceased California residents <55 years old from 1996 through 2003 have been investigated with criteria for CJD developed by the World Health Organization and Centers for Disease Control and Prevention; none met the criteria for variant CJD.

Currently, pathologic review of brain tissue obtained by biopsy or autopsy is the only means of confirming a diagnosis of CJD. Autopsy remains the preferred method for obtaining tissue, as brain biopsy can result in serious complications (e.g., brain hemorrhage or abscess formation) and may not yield adequate amounts of tissue for analysis. The main role of brain biopsy is to exclude other, potentially treatable conditions (4).

In this article, we describe results from analysis of California mortality data from 1990 through 2000. We also summarize responses generated from a statewide survey of neurologists and pathologists regarding the challenges to diagnosing CJD and variant CJD, including obtaining autopsy in suspected cases.

The Study

Data from the 1990-2000 Death Public Use File (underlying cause of death only) and 1990-1999 Multiple Cause-of-Death Data (underlying or contributing causes of death) were obtained from the Center for Health Statistics, California Department of Health Services (5). Deaths among California residents with an International Classification of Diseases, 9th Revision, code 046.1 or 10th Revision, code A81.0 listed anywhere on the death record were included in our analysis. Both data files included report of autopsy as a variable, with the exception of the Multiple Cause-of-Death Data for 1997 to 1999, when autopsy performance was not recorded. Statistical analysis was performed by using SAS software (SAS Institute, Cary, NC).

From July to December 2002, questionnaires regarding experience with diagnosing CJD were sent to 1,241 California neurologists identified as members of the American Academy of Neurology and 574 pathologists identified as members of the California Society of Pathologists and the American Association of Neuropathologists. Approval was obtained from the Committee for the Protection of Human Subjects of the State of California.

Review of mortality data identified 263 CJD-related deaths in California from 1990 through 2000. Of these, 244 were identified from the 19901999 Multiple Cause-of-Death Data, and an additional 19 deaths were identified from the 1990 2000 Death Public Use File. A total of 42 (16%) cases identified by the Multiple Cause-of-Death Data were not detected in the Death Public Use File. Overall, 26 (10%) of the 263 CJD-related deaths were in persons <55 years of age. Only two deaths occurred in persons <30 years of age. The overall autopsy rate, which for 1997 to 2000 only includes autopsies performed on persons for whom CJD was recorded as the underlying cause of death, was 53 (21%) of 251 persons: 11 (44%) of 25 persons <55 years of age, and 42 (19%) of 226 persons [greater than or equal to] 55 years of age. For two deaths, autopsy performance was not recorded.

Of 1,241 questionnaires mailed to neurologists, 428 (34%) were completed, including 310 (25%) from respondents involved in patient care. Responses regarding the neurologists' experience with diagnosing CJD and performing autopsy are summarized in Tables 1 and 2. Most neurologists (83%, 255/307) felt comfortable clinically recognizing classic CJD. More than one third (36%, 74/207) had not considered arranging for autopsy in their CJD patients, although most reported access to histopathologic services (75%, 223/297). The most commonly cited barrier to obtaining autopsy was family reluctance to give consent (79%, 192/242).

Of 574 questionnaires mailed to pathologists, 284 (49%) were completed. Tables 1 and 2 summarize the responses. Thirty-five percent (96/273) and 15% (40/274) of pathologists were comfortable recognizing the neuropathologic features of classic CJD and variant CJD, respectively. Infection control concerns (77%, 143/185), lack of experience (62%, 69/111), and institutional limitations (53%, 111/210) were cited as major obstacles to autopsy performance, and less than half of respondents reported that confirming the diagnosis of CJD (47%, 92/197) or ruling out variant CJD (45%, 87/193) was an important reason to pursue autopsy.

Conclusions

Our analysis suggests that autopsy rates for CJD in California are low. The results of our surveys, which attempted to discern the reasons for this low rate, imply that both neurologists and pathologists have similar perceptions of the value of obtaining histopathologic evaluation for CJD but for different reasons. Most neurologists appeared to be comfortable clinically diagnosing CJD, with more than one third reporting they had never considered pursuing autopsy for CJD cases. In contrast, pathologists appeared to be less comfortable making a histopathologic diagnosis, indicating that autopsy performance was limited by infection control concerns, lack of experience with CJD cases, and institutional restrictions.

Our results have some limitations. Approximately 10% of CJD cases may have atypical signs and symptoms that can obscure the diagnosis. To the extent that these cases are misdiagnosed and not autopsied, they could contribute to overestimation of the autopsy rate. On the other hand, death certificate analysis can be an insensitive indicator of the true rate of autopsy, and autopsy performance information was unavailable for 1997 to 2000 from the Multiple Cause-of-Death Data. Both factors could lead to possible underestimation of the true autopsy rate. Given that some CJD cases will have had confirmatory brain biopsy or strongly suggestive clinical features and diagnostic studies, the autopsy rates cited may apply mostly to patients for whom a satisfactory antemortem diagnosis could not be made. Interpreting survey results is limited by the low response rate; neurologists and pathologists who are experienced in diagnosing CJD may be more likely to respond, which would introduce bias.

The public health benefits of performing autopsy on patients with suspected CJD should not be underestimated. Autopsy and histopathologic analysis remain important ways to confirm a diagnosis of CJD and help define the usual occurrence of subtypes of classic CJD, thereby facilitating the recognition of emerging TSEs (1,6,7). Autopsy rates for nonforensic deaths have declined dramatically during the past 40 years, with national hospital rates currently <5%, possibly resulting in missed diagnoses of the actual cause of death in 8% to 25% of cases (8-11). The reasons for the decline are multifaceted and include escalating cost of autopsy borne by hospitals and county medical examiners, lack of direct reimbursement, fear of litigation, and increasing reliance on modern technology to determine a diagnosis antemortem (10).

Our survey results suggest that infection control concerns play a role in low autopsy rates for CJD, whether because of fears about the risk of acquiring CJD from handling contaminated tissue or because of liability considerations at the institutional level. More realistically, brain autopsy can be performed safely as long as CJD-specific infection control guidelines are strictly followed (12-13). Nonetheless, concerns about potentially acquiring CJD through autopsy procedures should be acknowledged and recognized as an opportunity to address proper infection control techniques.

Enhancing surveillance for variant CJD and other emerging prion diseases will require educating neurologists and pathologists, addressing the perceived obstacles to obtaining autopsy, and encouraging the use of available resources that provide expertise and technical assistance in evaluating CJD. For example, brain tissue can be submitted to the National Priori Disease Pathology Surveillance Center (NPDPSC) in Cleveland, Ohio, for free state-of-the-art diagnostic testing (14). The availability of a national center of expertise may facilitate obtaining tissue evaluation; since the inception of NPDPSC, the number of referrals to the facility has more than doubled, from 104 in 1997 to 265 in 2002, and the number of TSE cases confirmed from those referrals increased from 60 in 1997 to 151 in 2002 (14). Regional academic institutions, such as the University of California, San Francisco, Memory and Aging Center, can also provide expertise and assistance with diagnostic testing. Such resources are vital to maintaining vigilance for cases of CJD and potentially emerging human TSEs, such as variant CJD or possibly a human form of chronic wasting disease in the United States.

Acknowledgments

We gratefully acknowledge Laura Dalla Betta, Stephen DeArmond, Michael Geschwind, Ryan Maddox, Jennifer Martindale, Bruce Miller, Gretchen Rothrock, James Sejvar, and Mark Starr for their invaluable advice and support.

References

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(3.) Centers for Disease Control and Prevention. Preliminary investigation suggests BSE-infected cow in Washington state was likely imported from Canada [monograph on the Internet]. 2003 Dec 29 [cited 2004 Jul 10]. Available from: http://www.cdc.gov/ncidod/diseases/cjd/bse_washington.htm

(4.) Will RB, Alpers MP, Dormont D, Schonberger LB, Tateishi J. Infectious and sporadic prion diseases. In: Prusiner SB, editor. Prion biology and disease. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 1999. p. 465-507.

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(6.) U.K. Creutzfeldt-Jakob Disease Surveillance Unit. Investigations undertaken in possible CJD cases [monograph on the Internet]. 2002 Oct 15 [cited 2004 Jul 10]. Available from: http://www.cjd. ed.ac.uk/investigations.htm

(7.) Fatal degenerative neurologic illnesses in men who participated in wild game feasts--Wisconsin, 2002. MMWR Morb Mortal Wkly Rep. 2003;52:125-7.

(8.) Burton EC. The autopsy: a professional responsibility in assuring quality of care. Am J Med Qual. 2002;17:56-60.

(9.) The autopsy as an outcome and performance measure [monograph on the Internet]. File inventory, evidence report/technology assessment no. 58. AHRQ publication no. 03-E002. Rockville (MD): Agency for Healthcare Research and Quality; 2002 Oct [cited 2004 Jul 10]. Available from: http://www.ahrq.gov/clinic/autopinv.htm

(10.) Brooks JP, Dempsey J. How can hospital autopsy rates be increased? Arch Pathol Lab Med. 1991;115:1107-11

(11.) Hasson J, Schneiderman H. Autopsy training programs: to right a wrong. Arch Pathol Lab Med. 1995;119:289-91.

(12.) WHO infection control guidelines for transmissible spongiform encephalopathies: report of a WHO consultation [monograph on the Internet]. Geneva: World Health Organization; 1999 Mar 26 [cited 21104 Jul 10]. Available from: http://www.who.int/emcdocuments/tse/whocdscsraph2003c.html

(13.) Questions and answers regarding Creutzfeldt-Jakob disease infection control practices [monograph on the Internet]. Atlanta; Centers for Disease Control and Prevention: 2003 May 21 [cited 2004 Ju1 10]. Available from: http://www.cdc.gov/ncidod/diseases/cjd/cjd_inf_ctrl_qa.htm

(14.) National Prion Disease Pathology Surveillance Center [homepage on the Internet], [cited 2004 Jul 10]. Available from: www.cjdsurveillance.com

Dr. Louie served as project clinician for the California Creutzfeldt-Jakob Disease Surveillance Project, a joint collaborative project of the California Department of Health Services and the Centers for Disease Control and Prevention. Her research interests include the study of emerging infectious diseases.

Janice K. Louie, * ([dagger]) Shilpa S. Gavali, * Ermias D. Belay, ([double dagger]) Rosalie Trevejo, ([dagger]) Lucinda H. Hammond, * Lawrence B. Schonberger, ([double dagger]) and Duc J. Vugia * ([dagger])

* California Emerging Infections Program, Richmond, California, USA; ([dagger]) California Department of Health Services, Berkeley, California, USA; and ([double dagger]) Centers for Disease Control and Prevention, Atlanta, Georgia, USA

Address for correspondence: Janice K. Louie, California Emerging Infections Program, California Department of Health Services, 2151 Berkeley Way, Room 716, Berkeley, CA 94704, USA; fax: 510-883-6015; email: jlouie@dhs.ca.gov

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