New AAN Guideline on Diagnosis of Sporadic Creutzfeldt-Jakob

Megan Brooks

September 21, 2012

September 21, 2012 — When sporadic Creutzfeldt-Jakob disease (CJD) is strongly suspected in a patient with rapidly progressive dementia, clinicians should order cerebrospinal fluid (CSF) testing for protein 14-3-3, a new evidence-based guideline from the American Academy of Neurology (AAN) recommends.

The guideline, "Diagnostic Accuracy of CSF 14-3-3 Protein in Sporadic Creutzfeldt-Jakob Disease," was published September 19 in Neurology.

The authors are Taim Muayqil, MBBS, from King Saud University, Riyadh, Saudi Arabia; Gary Gronseth, MD, from University of Kansas Medical Center in Kansas City; and Richard Camicioli, MD, from University of Alberta, Edmonton, Canada.

They note that sporadic CJD is a rare and universally fatal disease estimated to occur in about 1 person per million worldwide annually. Affected individuals typically present with rapidly progressing dementing illness in their 60s or 70s, although the "wide spectrum" of clinical manifestations makes diagnosis difficult.

Subject of Debate

The test for the presence of protein 14-3-3 in the CSF of patients suspected of having sporadic CJD has been the subject of much debate, the authors point out. Initial studies showed the test to be "quite sensitive and specific in an appropriate clinical setting, particularly that of rapidly progressive cognitive decline." However, subsequent studies questioned the sensitivity of the test.

The new guideline is based on a review of 9 class II studies involving 1849 people suspected of having sporadic CJD who had CSF analysis for protein 14-3-3. It concludes that the 14-3-3 protein assay can be useful when the probability of the person having CJD is between 20% and 90%.

"If the physician considers the likelihood of (CJD) is extremely low or extremely high, then testing for 14-3-3 protein would not be useful regardless of the result," Dr. Muayqil said in a statement.

Although it remains "an imperfect test," the 14-3-3 protein assay is probably "moderately accurate" in diagnosing sporadic CJD, the guideline states.

Table. Estimated Diagnostic Accuracy of the 14-3-3 Protein Assay

Measure Estimated Diagnostic Accuracy (95% Confidence Interval)
Sensitivity (%) 92 (89.8 - 93.6)
Specificity (%) 80 (77.4 - 83.0)
Likelihood ratio 4.7
Negative likelihood ratio 0.10


The guideline writers caution that the test "lacks the diagnostic accuracy either to include a CJD diagnosis as a possibility or to rule out CJD." In addition, "[i]t is important to realize that the test will not importantly change the probability of CJD in patients who are unlikely to have CJD to begin with," they write. "A positive result in such patients should not distract the investigator from considering a different dementing illness, or more important, a reversible cause of dementia."

The authors say the value of the 14-3-3 assay will largely depend on a clinician's judgment of the pretest probability of CJD for an individual patient. "Such judgments will reasonably consider the rarity of CJD (incidence 1 per million per year), the practice setting (community hospital vs tertiary referral center), the patient's clinical presentation, and the results of already obtained ancillary tests such as head MRI [magnetic resonance imaging]."

The guideline also notes that imaging studies are emerging as valuable tools in diagnosing CJD, with evidence that diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) MRI sequences are more useful than electroencephalography. The sensitivity and specificity of DWI and FLAIR in diagnosing CJD were 91% to 92.3% and 93.8% to 95%, respectively.

Future Research Needs

The guideline also notes that efforts to standardize the definition of a positive 14-3-3 result and validate it in well-designed cohort studies would be helpful. Issues yet to be resolved include the question of which specific isoform (beta or gamma) of protein 14-3-3 is most useful and the need for standardization of the norms for the laboratory technique used (enzyme-linked immunosorbent assay or Western blot).

Also, "Investigation for the presence of a combination of multiple biomarkers such as t-tau, p-tau, S-100, or NSE [neuron-specific enolase] in the CSF is needed in addition to, or in lieu of, protein 14-3-3."

Integration of the recent advancement in MRI technology and DWI with CSF studies examining the presence or absence of protein 14-3-3 or another biomarker is also needed, the guideline authors write.

Finally, the authors say further study on the value of CSF biomarkers in subgroups of patients based on demographic characteristics, time of presentation, duration of illness, specific causes of prion disease, and genetic factors is needed.

The guideline was developed with financial support from the American Academy of Neurology. None of the authors received reimbursement, honoraria, or stipends for their participation in its development.

Neurology. Published online September 19, 2012. Abstract