Progress Report from the National Prion Disease Pathology Surveillance Center

An Update from Stephen M. Sergay, MB, BCh & Pierluigi Gambetti, MD

April 10, 2008


April 3, 2008

Dear Member:

Once again we are writing to thank you for your continued support in enhancing surveillance of prion diseases in the United States and to bring you up to date on the National Prion Disease Pathology Surveillance Center (NPDPSC).

In large part because of your support, the number of cases examined by biopsy, autopsy and 14-3-3 protein determination has increased significantly over the years (see Tables 1 and 2). We are now able to establish a definitive diagnosis of prion disease in an estimated 60–70% of the cases in the United States, a percentage which exceeds that in even some major surveillance centers. In addition, we receive from you cerebrospinal fluid (CSF) for 14-3-3 determination, a surrogate protein which is helpful in the diagnosis of prion disease, probably in most if not all cases of suspected Creutzfeldt-Jakob disease (CJD). We are making constant efforts to reach our goal of at least 80% definitively diagnosed cases.

The major obstacle to our further increasing the autopsy rate remains the inadequate reporting of suspected cases of CJD to the NPDPSC or to the State Health Department, which in turn would notify us. Since you are the one likely to request the 14-3-3 test on these cases, please include in your request the information needed to contact you, which we will do if the test proves positive. If your institution uses a referral laboratory to send us the CSF, please provide your name, phone, and fax numbers to the lab, which will in turn submit it to us along with the sample. If this information is missing in the request accompanying the CSF sample (as it happens in about 30% of the cases), we will be unable to contact the caregiving physician. Having your contact information would also allow us to send results directly to you, thus reducing turnaround times.

If you suspect CJD in a case, but do not plan to request the 14-3-3 test, please nevertheless notify us of this suspected case; because we try to contact the caregiving physician in all cases of suspected prion disease in order to offer support in discussions with the families regarding autopsy, whenever such discussions are deemed appropriate. According to our data, families refuse autopsy in fewer than 10% of cases. In fact, they generally wish to have the autopsy carried out but may be unaware that it is free of charge. Therefore, if you notify us of every case of suspected prion disease, we believe that our 80% goal can be achieved.

Most of you may be aware that the usefulness of the 14-3-3 test is limited because of the large number of tests whose results are ambiguous. Accordingly, we are working to supplement or replace the 14-3-3 test with the CSF tau protein test, which will eliminate or very much reduce the number of ambiguous test results while increasing the overall accuracy of diagnosis.

The importance to public health in the U.S. of timely diagnosis and monitoring of human prion diseases is unquestionable. Here are some compelling reasons for this:

  1. Prion surveillance in cattle has been reduced by 90% (from about 470,000 to 40,000 in the U.S. in 2007 out of about 35 million cattle slaughtered). Termination of human prion surveillance would therefore remove the second line of surveillance, thereby eliminating prion surveillance in the U.S. entirely. This development would be extremely worrisome in view of recent reports that precautions to limit the spread of the prion infectious agent may not have been followed in some slaughter houses in the U.S.
  2. Cattle affected with bovine spongiform encephalopathy (BSE) continue to be discovered in Canada, which has more rigorous BSE surveillance than the U.S. At the same time, Canada imposes few limitations in the trade of potentially prion-infectious cattle with the U.S.
  3. There has been increased occurrence and recognition in the U.S. of chronic wasting disease (CWD), an endemic prion disease affecting elk and deer, as well as uncertainties concerning CWD's transmissibility to humans.
  4. Atypical forms of BSE have emerged which, although rare, appear to be more virulent than the classical BSE that causes vCJD.

These facts make it very clear that careful monitoring of human prion diseases is crucial, because currently it is the only means of rigorous prion surveillance which can promptly detect human exposure to BSE and CWD in the U.S. should it occur. The mission of the NPDPSC is precisely to facilitate and expedite this surveillance.

However, in order to accomplish its mission, the NPDPSC must examine as many cases as possible by analysis of frozen and fixed tissue, which is the only way to accurately identify and classify prion diseases. This requires that an autopsy be performed. Our free-of-charge autopsy coordination service provides assistance in arranging and paying for autopsies, body transportation, and shipment of brain tissues. Results are reported to the senders (see Table 3 for turnaround times). It is also important that when requested, the patient's clinical history be sent to the NPDPSC along with autopsy and biopsy tissues so that each case can be better diagnosed and reported to CDC.

Again, we thank you very much for your continued help in reporting to our Center all cases of possible prion disease. If you have any concerns or questions, please call the NPDPSC at 216-368-0587 or e-mail at The website is

Pierluigi Gambetti, MD
Director, National Prion Disease Pathology Surveillance Center

Stephen M. Sergay, MB, BCh
President, American Academy of Neurology

Table 1

Year Total Referrals2 Prion Disease Sporadic Familial Iatrogenic vCJD
1996 or earlier 42 32 25 4 0 0
1997 115 68 56 9 0 0
1998 93 53 45 7 1 0
1999 114 69 61 8 0 0
2000 151 103 89 14 0 0
2001 209 117 108 9 0 0
2002 258 146 119 22 2 0
2003 274 176 132 41 0 0
2004 335 184 155 21 0 13
2005 349 194 147 39 1 0
2006 385 193 151 31 0 14
2007 357 200 144 21 0 0
Totals 26825 15356 1232 226 4 2

Listed based on the year of death or, If not available, on year of referral; 2 Cases with suspected prion disease for which brain tissue and/or blood (in familial cases) were submitted; 3 Disease acquired in the United Kingdom; 4 Disease acquired in Saudi Arabia; 5 Includes 11 cases in which the diagnosis is pending, and 18 inconclusive cases; 6 Includes 26 cases with type determination pending (2 from 2006, 24 from 2007), and 45 cases with adequate tissue to establish the diagnosis of prion disease, but not the type; in all these cases, vCJD could be excluded.

Table 2

Table 3

Test on biopsy tissue Turnaround times
Western Blot (WB) of the prion protein (PrP). (Establishes presence and type of scrapie PrP; frozen tissue required) 3–5 business days
Histology and PrP immunohistochemistry (IHC). (Establish presence and distribution of scrapie PrP on fixed tissue) 4 business days
14-3-3 determination in CSF 5 business days
Test on autopsy tissue Turnaround times
WB of PrP 14 business days
Histology and IHC of PrP 21 business days
PrP gene sequencing. (Identifies mutations and codon 129 genotype needed for precise prion disease type diagnosis) 4–8 weeks (biopsies and autopsies)
Summary report with prion disease type diagnosis based on all above tests 6–10 weeks (biopsies and autopsies)