More Tests for Prion Disorders
ABSTRACTS & COMMENTARY
Sources: de Silva R, et al. Single photon emission computed tomography in the identification of new variant Creutzfeldt-Jakob disease: Case reports. BMJ 1998;316:593-594; Otto M, et al. Diagnosis of Creutzfeldt-Jakob disease by measurement of S100 protein in serum: Prospective case-control study. BMJ 1998;316:577-582.
Concern about prion-related disorders has increased in the wake of the bovine spongiform encephalopathy outbreak in Great Britain and continuing reports of sporadic cases of variant Creutzfeldt-Jakob disease (vCJD) in Europe. Improved methods for clinical detection of CJD and vCJD are desirable, and several new approaches are currently under study.
Electroencephalographic abnormalities can be helpful in recognizing CJD, but they are frequently absent in vCJD. As an alternative to EEG, de Silva and colleagues carried out single photon emission computed tomography (SPECT) brain perfusion studies in two patients who were subsequently proven by autopsy to suffer from vCJD. They found that SPECT was abnormal in these patients even in the absence of EEG abnormalities. The two patients studied were women, aged 28 and 34, respectively, whose initial symptoms included progressive ataxia, behavioral abnormalities, and myoclonus. Both died less than two years from onset of symptoms. In each case, repeated EEG studies failed to document periodic complexes, although background slowing was found in one case. MRIs were normal, but SPECT perfusion imaging revealed decreased left temporoparietal blood flow in one case and diffuse cortical hypoperfusion in the other. The authors suggest that SPECT may be a useful adjunct for the evaluation of suspected cases of vCJD.
In another study focusing on the diagnosis of conventional CJD, Otto and colleagues examined the utility of measuring serum levels of the S100 protein. Cerebrospinal fluid tests, such as measurement of 14-3-3 protein (see Neurology Alert 1996;15(3):19), have facilitated antemortem diagnosis of CJD and are reported to have greater than 90% sensitivity and specificity for CJD. Unfortunately, 14-3-3 measurement cannot be carried out on blood and currently requires collection of CSF by lumbar puncture. The S100 protein has previously shown some promise as a putative CSF marker for CJD but had not previously been studied in serum. S100 is an acidic, calcium-binding protein produced predominantly by the activated astroglia found in the brain of patients with CJD throughout the course of the disorder. Among 108 patients with definite or probable CJD, Otto et al found that the median serum concentration of the S100 protein was 395 pg/mL (SD, 387 pg/mL), significantly greater than in other neurologic and psychiatric disorders (median = 109, SD = 177 pg/mL). Using a cutoff of 213 pg/mL, sensitivity of S100 measurements for CJD was 77.8% and specificity was 81.1%. Notably, the survival time of patients with CJD appeared to correlate with the S100 concentration in serum.
COMMENTARY
The finding that SPECT can be abnormal in vCJD before periodic complexes develop on EEG may be of some interest in evaluating a young patient with unusual neurobehavioral symptoms. Antemortem diagnosis of CJD has usually been made in the past by brain biopsy. Brain biopsy is still warranted when suspicion of CJD is high but diagnostic tests are equivocal and when other potentially treatable etiologies are suspected. When brain biopsy is contemplated, perfusion imaging with SPECT or PET may help to guide the choice of biopsy site by providing an indication of region most likely to contain spongiform pathology. The SPECT findings reported in vCJD by de Silva et al imply that perfusion imaging might also be used in this way in the context of vCJD. However, the perfusion abnormalities are not specific for vCJD. Thus, a negative SPECT does not rule out vCJD, and a positive SPECT is not specific for vCJD.
Based on the report by Otto et al, measurement of S100 protein in serum is not sufficiently sensitive or specific to serve as a primary diagnostic test for CJD, although it could conceivably be used as a diagnostic adjunct in the future. Since S100 levels also increase after head trauma and could conceivably be elevated after other insults to the brain, caution must be exercised in interpreting positive results in the setting of acute cerebral injury. Serum S100 determinations are not widely available from clinical testing laboratories at this time, and, until further studies are carried out, their use as a diagnostic or prognostic indicator for CJD is not recommended. -nrr
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