CJD Test Validated
Abstract & commentary
Source: Lemstra AW, et al. 14-3-3 testing in diagnosing Creutzfeldt-Jakob disease. Neurology 2000;55:514-516.
Past studies have brought into question the use of the spinal fluid test for the 14-3-3 protein as a market for Creutzfeldt-Jakob disease (CJD). A new study from The Netherlands is the first to prospectively examine the sensitivity and specificity of the 14-3-3 test in a large series of patients with suspected CJD.
Lemstra and colleagues obtained cerebrospinal fluid (CSF) samples from patients with suspected CJD from various hospitals in The Netherlands over a two-and-a-half year period. A total of 113 cases were collected and categorized based on clinical reports as pathologically confirmed CJD, clinically definite CJD, or possible CJD. The 14-3-3 test was positive in 42 of these samples. This included all of the pathologically confirmed and clinically definite CJD cases, and two of three clinically probable cases. Positives were also seen in patients with disorders other than CJD, including cerebrovascular disease (1/5), encephalopathy (3/7), CNS infection (3/14), malignancies (2/9), and other unspecified disorders (1/14). The overall sensitivity of the test for CJD in this sample was 97%, and specificity was 87%.
Lemstra et al examined all cases in which the 14-3-3 test was positive to identify features that might distinguish true CJD cases from false positives. In all true positive CJD cases, CSF total protein and cell counts were normal. Five of the false-positive cases had significant elevations in these CSF parameters. In two cases, positive neuroimaging studies suggested etiologies other than CJD that could account for the elevation in 14-3-3, namely recent stroke and CNS malignancy. The conclusion fostered by these findings is that the clinical use of the 14-3-3 test can be enhanced by taking into account the results of neuroimaging and routine studies of CSF.
Commentary
CJD is fortunately a rare disorder, although its devastating prognosis warrants consideration in all cases of rapidly progressive dementia. Although brain biopsy can be diagnostic, it is risky for both patient and surgeon. The 14-3-3 test is sensitive to sporadic and familial CJD, as well as the more recently discovered uncommon variant forms (Zerr I, et al. Ann Neurol 2000;48:323-329). The 14-3-3 protein is normally expressed in neurons and, as a consequence, a variety of conditions that lead to neuronal death can transiently or persistently elevate its levels in CSF. The most common culprits in this regard are stroke, CNS infections, and malignancies. This explains why past studies examining the clinical value of the 14-3-3 test have generally reported good sensitivity but less than optimal specificity.
Lemstra et al make the valuable observation that false positives may be reduced by taking into account other clinical information, particularly the results of routine CSF studies and neuroimaging. Other correlates of this disease, including periodic sharp and slow waves on the EEG, hyperintensities in the basal ganglia on MRI, ribbon-like cortical anomalies on diffusion MRI, as well as elevated CSF enolase and S100 protein levels, appear less reliable than the 14-3-3, but can provide supporting evidence for a CJD diagnosis when positive in the appropriate clinical context. As emphasized by Lemstra et al, the 14-3-3 test appears valid and reliable, but must be interpreted in light of the complete clinical picture, including the history and other potentially informative tests. —Norman R. Relkin
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