A Case of Creutzfeldt-Jakob Disease with Alien Limb Syndrome and Elevated Thyroid Autoantibodies

P03.135] CSF Findings in a Large United States Sporadic CJD Cohort

Michael Geschwind, Aissa Haman, Charles Torres-Chae, Benjamin J. Raudabaugh, Gillian Devereux, Bruce Miller, San Francisco, CA

OBJECTIVE: Determine the CSF profile and the diagnostic sensitivity and specificity of various CSF proteins in a US sCJD cohort (n=196). BACKGROUND: The diagnostic utility of various biomarkers for CJD is controversial. We examined the sensitivity and specificity for various CSF proteins in 800 potential prion cases referred to our center over the past five years. DESIGN/METHODS: Medical records were reviewed and/or patients were evaluated at our center. Data was stored in a secure clinical relational database that was queried for CSF findings, including cell count, protein, IgG index, oligoclonal bands (OCBs), 14-3-3, neuron specific enolase (NSE), Total Tau (T-Tau) in patients with probable or definite sporadic CJD and non-prion rapidly progressive dementias (RPD), most of whom were referred as suspected CJD cases. T-Tau positive if >1300 pg/ml; NSE positive if >35 ng/ml. Probable sCJD diagnosis was based on modifications to WHO 1998 criteria, allowing other focal cortical signs (e.g., aphasia, apraxia, neglect) AND a positive MRI or EEG (14-3-3 not used for diagnosis). RESULTS: 14-3-3 protein (n=131) sensitivity was only 50% (47% for definite; 52% for probable sCJD). NSE (n=34) sensitivity was 59% (65% for definite; 50% for probable sCJD). T-Tau (n=18) was the most sensitive at 72% (78% for definite; 67% for probable sCJD). The specificity of these biomarkers among our CJD and RPD controls (n=68) was 70% for 14-3-3 (n=33), 80% for NSE (n=15), and 100% for T-Tau (n=4). The 14-3-3 had the lowest sensitivity and specificity. CONCLUSIONS/RELEVANCE: Our data is contrary to other published data suggesting high sensitivity and specificity of these proteins for sCJD. DWI MRI has better sensitivity and specificity and should be used in diagnostic criteria. We question the utility of these CSF proteins for CJD diagnosis. A prion-specific test is needed. Supported by: John Douglas French Foundation for Alzheimers Research, the McBean Foundation, NIA K23AG021989-01, NIH-NINDS contract N01-NS-0-2328. Category - Aging and Dementia SubCategory - Clinical

Tuesday, May 1, 2007 4:00 PM

Poster Sessions: HIV and Prion Diseases (4:00 PM-7:30 PM)

The embargo for all abstracts to be presented at the 59th Annual Meeting is in effect until the date and time of the presentation unless otherwise noted on the abstract and/or press release. If there are questions, please contact the AAN media and public relations team.

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http://www.abstracts2view.com/aan2007boston/sessionindex.php?day=2007-05-01&session=PO02-L


Debate Continues as New Studies Support MRI, Not CSF Markers, to Diagnose CJD

Neurology Today 5 June 2007; Volume 7(11); pp 6,10-11 Hurley, Dan

Outline article in brief study protocols experts comment mri as a diagnostic tool references Links View Article PDF

ARTICLE IN BRIEF

1. Two new studies aim to improve diagnosis of Creutzfeldt-Jakob Disease (CJD): one found a low sensitivity and specificity for CSF biomarkers for sporadic CJD; another study found MRI an effective diagnostic tool in a small number of patients with familial CJD.

BOSTON-A new, larger study by a San Francisco neurologist who previously challenged the use of the 14-3-3 protein in CSF for diagnosing sporadic Creutzfeldt-Jakob Disease (CJD) has again found a disappointingly low sensitivity and specificity for the biomarker.

Although the specificity and sensitivity of two other biomarkers, neuron specific enolase (NSE) and Total Tau (T-Tau), proved better than those of 14-3-3, neither were good enough to make them useful in diagnosing CJD, concluded Michael D. Geschwind, MD, PhD, assistant professor of neurology at the Memory and Aging Center of the University of California-San Francisco (UCSF). The findings were presented in a poster session here at the AAN annual meeting in May.

MRI appears to be a more reliable diagnostic tool, Dr. Geschwind said, and that view was supported by another poster at the meeting reporting high sensitivity and specificity for familial CJD with diffusion tensor imaging (DTI).

STUDY PROTOCOLS

Dr. Geschwind and colleagues examined the sensitivity and specificity for CSF in potential prion cases referred to the UCSF center in the past five years. Among 142 patients tested for 14-3-3, the sensitivity was only 49 percent overall - 47 percent for those with a diagnosis of sporadic CJD, and 50 percent for those with probable CJD.

Among the 40 tested for NSE, sensitivity was 63 percent (64 percent for definite CJD; 60 percent for probable CJD). Among the 20 tested for T-Tau, sensitivity was 70 percent (67 percent for definite CJD; 75 percent for probable CJD).

The specificity of the three biomarkers was 66 percent among the 44 controls tested for 14-3-3, 83 percent among the 18 controls tested for NSE, and 100 percent for the four controls tested for T-Tau.

Our data are contrary to other published results suggesting high sensitivity and specificity of these proteins for sporadic CJD, according to Dr. Geschwind and colleagues. We question the utility of these CSF proteins for CJD diagnosis.

EXPERTS COMMENT

But two neurologists who have led other studies with more positive findings said their views remain unchanged - that the biomarkers are a useful, though imperfect, tool for diagnosing CJD.

The data have limitations but also strengths, said Allen J. Aksamit Jr., MD, associate professor of neurology at the Mayo Clinic College of Medicine in Rochester, MN. If you have a select patient group who fit the clinical criteria for CJD and exclude every other possible diagnosis, it's a fairly sensitive and specific test. You use it as a weight to put on one side for or against the diagnosis.

In 2003, Dr. Aksamit espoused a similar view in an Archives of Neurology editorial (60:803-804) accompanying Dr. Geschwind's first paper challenging the clinical value of the 14-3-3 protein for diagnosis of sporadic CJD. In that study, Dr. Geschwind reviewed 32 pathologically confirmed cases on which 14-3-3 testing had been performed; only 17 cases had a positive result, a sensitivity of only 53 percent (Arch Neurol 2003;60:813-816).

Figure. Dr. Allen J. Aksamit Jr.: The data have limitations but also strengths. If you have a select patient group who fit the clinical criteria for CJD and exclude every other possible diagnosis, it's a fairly sensitive and specific test. You use it as a weight to put on one side for or against the diagnosis.

[ Click here to enlarge ] The largest data set published so far on biomarkers in CJD patients comes from a European consortium led by Inga Zerr, MD, a neurologist at Georg-August University in Götingen, Germany. She and colleagues reported last year on 1,859 patients with sporadic, genetic, iatrogenic, and variant CJD and 1,179 controls, finding a sensitivity of 85 percent for 14-3-3, 86 percent for T-Tau, and 93 percent when the results of both tests were combined with S100b and NSE (Neurology 2006;67:637-643).

I am aware that the sensitivity of the tests in Dr. Geschwind's laboratory is lower than we reported and I have discussed this with him on several occasions, Dr. Zerr said in an e-mail. I have no idea why the data are so different.

One possible explanation, she and Dr. Aksamit suggested, is that at UCSF - a referral institution where many patients go for a second opinion - Dr. Geschwind is seeing more patients with slowly progressing disease than in the European group. Dr. Zerr's data showed, as have previous studies, that the sensitivity of the biomarkers is highest in patients with the shortest disease duration.

Another possible reason the two studies have reached such different conclusions is that Dr. Zerr included patients with genetic, iatrogenic, and variant CJD, whereas Dr. Geschwind's group includes only sporadic cases. Different case definitions and different testing methods might also contribute to the different findings.

Figure. Dr. Isak Prohovnik: MRI does seem to have better sensitivity and specificity than the biomarkers. But neither our group nor his [Dr. Geschwind's] have sufficient numbers yet.

[ Click here to enlarge ] In an interview with Neurology Today, Dr. Geschwind said of the European group's findings, I think they may have a selection bias. Every time they publish a study, their sensitivity goes lower and lower. Eventually it will hit ours.

He added in an e-mail, I believe there are occasional cases in which these biomarkers, such as the 14-3-3, total-tau or NSE, may be helpful in diagnosing CJD. The problem is that because these CSF proteins clearly can be elevated in other diseases that clinically mimic CJD, one must be very thorough in ruling out other conditions. Some of these conditions include cancers, neurologic autoimmune (paraneoplastic and non-paraneoplastic) dementias, sarcoid, Hashimoto encephalopathy, and even atypically rapid presentations of other neurodegenerative diseases.

After speaking with Dr. Geschwind in front of his poster, Dr. Aksamit Jr. told Neurology Today: It's all in the selection of the patient population being reviewed, and how high you set the bar for these laboratory tests. If you set the bar high, you'll get higher specificity but lower sensitivity. Our recommendation at Mayo is to set the bar high, to enhance specificity at the expense of sensitivity.

Dr. Aksamit noted, however, that 14-3-3 is no longer being tested at Mayo, because the reagents for a quantitative version of the test, which the institution had preferred over the standard Western blot, are no longer available. Instead, Mayo is testing NSE.

Despite the questions raised by Dr. Geschwind's paper, Dr. Zerr said: I completely agree with Dr. Aksamit that biomarkers in CSF are useful, when tested in the right populations. This is what we always stress when we are talking with physicians: Use CSF in the right differential diagnosis; that is, in dementia.

MRI AS A DIAGNOSTIC TOOL

The one point on which all three neurologists agreed is that MRI seems to be a powerful diagnostic tool. Although MRI is not part of the clinical criteria for CJD yet, said Dr. Zerr, we strongly recommend that neurologists have the MRI done and consider it as an additional test.

Another poster presented at the meeting shared the results of DTI testing on a small group of patients with familial CJD. Isak Prohovnik, PhD, professor of psychiatry and radiology at Mount Sinai School of Medicine in New York City, reported that DTI was abnormal in the basal ganglia of ten of 11 patients, eight of 11 in different cortical areas, and six of 11 in the thalami. No involvement was seen in the brain stem or cerebellum.

When correlated with the clinical findings, DTI was positive for the frontal cortex in eight of nine patients, and for the motor cortex in seven of nine patients. In the basal ganglia, the DTI was positive in 10 patients, although clinical findings were present in only eight. Clinical cerebellar signs were seen in 11 patients and brain-stem signs in seven of the 11, although no positive findings showed up in those regions on either DTI or other MRI sequences.

MRI does seem to have better sensitivity and specificity than the biomarkers, Dr. Prohovnik said, noting that Dr. Geschwind has also used MRI. But neither our group nor his have sufficient numbers yet.

In 2005, Dr. Geschwind co-authored a paper on diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) in CJD, finding them to be 91 percent sensitive, 95 percent specific, and 94 percent accurate (Am J Neuroradiol 26:1551-1562). In 2005, Dr. Zerr was the senior author on a paper published in Brain (128:2026-2033), which concluded that FLAIR and DWI improved the clinical diagnosis and should be incorporated in the World Health Organization's diagnostic criteria for sporadic CJD.

REFERENCES

• Aksamit AJ. Cerebrospinal fluid 14-3-3 protein: Variability of sporadic Creutzfeldt-Jakob disease, laboratory standards, and quantitation.

• Geschwind MD, Martindale BS, Miller BL, et al. Challenging the clinical utility of the 14-3-3 protein for the diagnosis of sporadic Creutzfeldt-Jakob disease.

• Sanchez-Juan P, Green A, Zerr I, et al. CSF tests in the differential diagnosis of Creutzfeldt-Jakob disease.

• Young GS, Geschwind MD, Dillon WP, et al. Diffusion-weighted and fluid-attenuated inversion recovery imaging in Creutzfeldt-Jakob disease: High sensitivity for diagnosis.

• Tschampa HJ, Kellenberg K, Zerr I, et al. MRI in the diagnosis of sporadic Creutzfeldt-Jakob disease: A study on inter-observer agreement.

http://www.aan.com/elibrary/neurologytoday/?event=home.showArticle&id=ovid.com%3a%2fbib%2fovftdb%2f00132985-200706050-00006


CJD USA

*Acquired in UK ** Acquired in Saudi Arabia *** Includes 17 inconclusive and 9 pending (1 from 2006, 8 from 2007. **** Includes 17 non-vCJD type unknown (2 from 1996, 2 from 1997, 1 from 2001, 1 from 2003, 4 from 2004, 3 from 2005, 4 from 2006) and 36 type pending (2 from 2005, 8 from 2006, 26 from 2007).

Notes:

-- Cases are listed based on the year of death when available. If the year of death is not available, the year of sample receipt is used.

-- Referrals: Cases with possible or probable prion disease from which brain tissue or blood in the case of familial disease were submitted.

-- Inconclusive: Cases in which the samples were not sufficient to make a diagnosis.

-- Non-vCJD type unknown are cases in which the tissue submitted was adequate to establish the presence but not the type; in all cases, vCJD could be excluded.

-- Communicated by: Terry S. Singeltary Sr.

[In submitting these data, Terry S. Singeltary Sr. draws attention to the steady increase in the "type unknown" category, which, according to their definition, comprises cases in which vCJD could be excluded. The total of 26 cases for the current year (2007) is disturbing, possibly symptomatic of the circulation of novel agents. Characterization of these agents should be given a high priority. - Mod.CP]

http://www.promedmail.org/pls/askus/f?p=2400:1001:6833194127530602005::NO::F2400_P1001_BACK_PAGE,F2400_P1001_PUB_MAIL_ID:1010,39963


There is a growing number of human CJD cases, and they were presented last week in San Francisco by Luigi Gambatti(?) from his CJD surveillance collection.

He estimates that it may be up to 14 or 15 persons which display selectively SPRPSC and practically no detected RPRPSC proteins.


http://www.fda.gov/ohrms/dockets/ac/06/transcripts/1006-4240t1.htm


http://www.fda.gov/ohrms/dockets/ac/06/transcripts/2006-4240t1.pdf


JOURNAL OF NEUROLOGY

MARCH 26, 2003

RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob

disease in the United States

Email Terry S. Singeltary:

flounder@wt.net

I lost my mother to hvCJD (Heidenhain Variant CJD). I would like to comment on the CDC's attempts to monitor the occurrence of emerging forms of CJD. Asante, Collinge et al [1] have reported that BSE transmission to the 129-methionine genotype can lead to an alternate phenotype that is indistinguishable from type 2 PrPSc, the commonest sporadic CJD. However, CJD and all human TSEs are not reportable nationally. CJD and all human TSEs must be made reportable in every state and internationally. I hope that the CDC does not continue to expect us to still believe that the 85%+ of all CJD cases which are sporadic are all spontaneous, without route/source. We have many TSEs in the USA in both animal and man. CWD in deer/elk is spreading rapidly and CWD does transmit to mink, ferret, cattle, and squirrel monkey by intracerebral inoculation. With the known incubation periods in other TSEs, oral transmission studies of CWD may take much longer. Every victim/family of CJD/TSEs should be asked about route and source of this agent. To prolong this will only spread the agent and needlessly expose others. In light of the findings of Asante and Collinge et al, there should be drastic measures to safeguard the medical and surgical arena from sporadic CJDs and all human TSEs. I only ponder how many sporadic CJDs in the USA are type 2 PrPSc?

http://www.neurology.org/cgi/eletters/60/2/176#535


THE PATHOLOGICAL PROTEIN

Hardcover, 304 pages plus photos and illustrations. ISBN 0-387-95508-9

June 2003

BY Philip Yam

CHAPTER 14 LAYING ODDS

Answering critics like Terry Singeltary, who feels that the U.S. under- counts CJD, Schonberger conceded that the current surveillance system has errors but stated that most of the errors will be confined to the older population.

http://www.thepathologicalprotein.com/


doi:10.1016/S1473-3099(03)00715-1 Copyright © 2003 Published by Elsevier Ltd. Newsdesk

Tracking spongiform encephalopathies in North America

Xavier Bosch

Available online 29 July 2003. Volume 3, Issue 8, August 2003, Page 463

"My name is Terry S Singeltary Sr, and I live in Bacliff, Texas. I lost my mom to hvCJD (Heidenhain variant CJD) and have been searching for answers ever since. What I have found is that we have not been told the truth. CWD in deer and elk is a small portion of a much bigger problem." ...

http://www.thelancet.com/journals/laninf/article/PIIS1473309903007151/fulltext


http://download.thelancet.com/pdfs/journals/1473-3099/PIIS1473309903007151.pdf


Diagnosis and Reporting of Creutzfeldt-Jakob Disease

Singeltary, Sr et al. JAMA.2001; 285: 733-734.

Vol. 285 No. 6, February 14, 2001 JAMA

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

Since this article does not have an abstract, we have provided the first 150 words of the full text and any section headings.

To the Editor: In their Research Letter, Dr Gibbons and colleagues1 reported that the annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable since 1985. These estimates, however, are based only on reported cases, and do not include misdiagnosed or preclinical cases. It seems to me that misdiagnosis alone would drastically change these figures. An unknown number of persons with a diagnosis of Alzheimer disease in fact may have CJD, although only a small number of these patients receive the postmortem examination necessary to make this diagnosis. Furthermore, only a few states have made CJD reportable. Human and animal transmissible spongiform encephalopathies should be reportable nationwide and internationally.

Terry S. Singeltary, Sr Bacliff, Tex

1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323. FREE FULL TEXT

http://jama.ama-assn.org/cgi/content/extract/285/6/733?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=singeltary&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT


http://jama.ama-assn.org/cgi/content/full/285/6/733?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=singeltary&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT


2 January 2000

British Medical Journal

U.S. Scientist should be concerned with a CJD epidemic in the U.S., as well

http://www.bmj.com/cgi/eletters/320/7226/8/b#6117


15 November 1999

British Medical Journal

vCJD in the USA * BSE in U.S.

http://www.bmj.com/cgi/eletters/319/7220/1312/b#5406


APHIS-2006-0041-0006 TSE advisory committee for the meeting December 15, 2006

http://www.regulations.gov/fdmspublic/ContentViewer?objectId=09000064801f3413&disposition=attachment&contentType=msw8


Subject: [Docket No. FSIS-2006-0011] FSIS Harvard Risk Assessment of Bovine Spongiform Encephalopathy (BSE)

http://www.fsis.usda.gov/OPPDE/Comments/2006-0011/2006-0011-1.pdf


[Docket No. 03-025IFA] FSIS Prohibition of the Use of Specified Risk Materials for Human Food and Requirement for the Disposition of Non-Ambulatory Disabled Cattle

9/13/2005

http://www.fsis.usda.gov/OPPDE/Comments/03-025IFA/03-025IFA-2.pdf


Sunday, March 16, 2008

MAD COW DISEASE terminology UK c-BSE (typical), atypical BSE H or L, and or Italian L-BASE

http://bse-atypical.blogspot.com/2008/03/mad-cow-disease-terminology-uk-c-bse.html


SCHOOL LUNCH PROGRAM FROM DOWNER CATTLE UPDATE

http://downercattle.blogspot.com/


Alzheimer's and CJD

http://betaamyloidcjd.blogspot.com/


Friday, March 21, 2008

Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease

Original Paper

http://betaamyloidcjd.blogspot.com/2008/03/association-between-deposition-of-beta.html


TSS