Clinical Diagnosis of Creutzfeldt-Jakob Disease
Abstracts & Commentary
Sources: Poser S, et al. How to improve the clinical diagnosis of CJD. Brain 1999;122:2345-2351; Puoti G, et al. Sporadic CJD: Concurrence of different types of PvPsc in the same brain. Neurology 1999;53:2173-2176; Dickson WD, Brown N. Multiple prion types in the same brain. Is a molecular diagnosis of CJD possible? Neurology 1999;53: 1903-1904.
The transmissible spongiform encephalopathies (TSEs) include several different disorders, each caused by different prion proteins and show relatively distinct disease patterns. Most are sporadic but some are inheritable, others can be iatrogenic, and recently some appear to have been transmitted to humans from cows suffering from bovine spongiform encephalopathy. (See Scott MR, et al. Proc Natl Acad Sci U S A 1999;96: 15137-15142.) Hereditary forms are rare and consist of familial Creutzfeldt-Jakob disease (CJD), the Gerstman-Straussler-Sheinker syndrome, and fatal familial insomnia (FFI). Iatrogenic examples from the past include transfer of the prions by corneal transplants, reuse of deep brain electrodes previously used for EEG recordings, or dura mater obtained post-mortem from CJD patients. Several years ago, a miniepidemic of CJD occurred from injecting children with pituitary growth hormone obtained from CJD cadavers. No such person-to-person transmittal has been reported during recent years.
Sporadic CJD is a relatively rare disorder with a yearly incidence of a little more than one case per million per year. The actual occasion of sporadic CJD lacks a completely satisfactory explanation. Dickson and Brown, however, point out that the gene exists on the short arm of chromosome 20 and, in early life, generates the normal prion gene, termed PrP. They state, ’Missence, deletion and duplication of the normal gene at codon 129 of Cr 20 influence expression, both inherited and, apparently, sporadic.” Whether this is the ultimate, correct conclusion, time will tell.
In keeping with the above comments, Puoti and colleagues have identified two distinctly different molecular types of prion disease-specific protein (PrPsc) in five out of 15 patients dying from sporadic CJD. As Dickson and Brown point out, it may soon be possible to identify CJD exactly by tissue molecular identification. Meanwhile, noninvasive clinical diagnoses of CJD based on the clinical phenotype and supporting laboratory tests have become progressively more accurate.
Poser and colleagues have established in Gottingen, Germany, a national surveillance unit for notification of patients having possible/probable CJD. During three years (1993-96) 364 cases were reported, all accompanied by family consent for procedures. When possible, all patients had research-level, scalp-recorded EEGs, CT, and/or MRI studies and expressed mini-mental scores of less than 24. CSF samples, single or successive, were performed in most patients with emphasis on the presence or absence of the 14-3-3 protein im-munoassay (source: Santa Cruz Biotech, Santa Cruz, CA). Cases were classified as probable, possible, or not CJD. Six patients were excluded from further analysis because of having a genetic prion disease.
The clinical diagnosis of CJD is usually not difficult. As the table indicates, the disease begins insidiously with either clinically recognized early dementia, unilateral signs of a combination of striatum-engendered hypertonia, cortico spinal motor dysfunction, and/or myoclonus. Routine laboratory findings or CT scans have little diagnostic value, except to rule out neoplasms or inflammatory disease of the brain. EEG findings of periodic sharp waves or MRI-identified hyperintensity of the basal ganglia strongly support the clinical diagnosis.
The predictive table turned out to be remarkably accurate and, as the reader can see, includes only a limited but important group of clinical signs that derive from the known autopsy diagnoses. The 14-3-3 marker gave a false-positive response mostly when patients had a continued inflammatory reaction of the CNS but the number of negative errors is not given.
Regrettably, the incidence of the 14-3-3 spinal fluid is not precisely indicated in Poser et al’s ultimate predictions prior to autopsy. Among 193 patients who were classified as probable CJD on the basis of clinical findings and laboratory data, about half (95) were autopsied. Only five were misdiagnosed as CJD by the presence of the 14-3-3 positively. Four of these turned out to have Alzheimer’s disease and one had a primary CNS lymphoma. Fifty-four patients fulfilled the clinical criteria of CJD but lacked the specific sharp waves as EEGs. Of these, half had CJD at autopsy but Poser et al omit saying whether they had typical MRI changes. Most illnesses such as Hashimoto’s encephalitis (identified by anti-thyroid antibodies) or Alzheimer’s disease, identified by NINCDS, were omitted in advance from the study.
One hundred eleven patients were not clinically diagnosed even as possible CJD. Two turned out to have CJD, but the required galloping dementia was not apparent (one had become aphasic at 3 months). Both, however, had the 14-3-3 protein in the CSF.
| Table | ||
| Clinical and Laboratory Diagnostic Features of CJD* | ||
| Rapid, progressive dementia in less
than two years. (No evidence of vascular, inflammatory, or other encephalitis) At least two of the following somatic abnormalities must exist: 1. Myoclonus: 2. Visual and/or cerebellar ataxia; 3. Pyramidal and/or extrapyramidal signs; akinetic mutism |
||
| Laboratory signs | Sensitivity | Specificity |
| EEG: periodic sharp | 65% | 86% |
| waves (n = 256) | ||
| MRI: basal ganglia | 67% | 93% |
| hyperintense (n = 213) | ||
| 14-3-3 protein in CSF (n = 289) | 95% | |
| *Adapted from Poser S, et al. Brain 1999;122:2345-2351. | ||
Commentary
Poser et al’s report is useful and provides a helpful clinical protocol that usually will lead the neurologist directly to an accurate diagnosis of CJD. Certain lapses, however, reduce the imperative value of their report. They cite the evidence that MRI brings out basal ganglia enhancement in CJD and is apparently a little more informative than the EEG in strengthening the clinical diagnosis taken together. Unfortunately, however, they omit calculating the compound probability of EEG and MRI in accurately diagnosing CJD. Furthermore, although they highly praise the 14-3-3 protein as a diagnostic tool for CJD, they don’t emphasize to the reader: a) the knowledge that the protein is nonspecific for CJD; b) how specifically is it related, overall, to the individual autopsy findings, both positive or negative; and c) how often does it miss the diagnosis. Cornell-New York Presbyterian Hospital has also used the 14-3-3 protein test developed by Santa Cruz Biotech. We have not always found it positive in morphologically diagnosed cases of CJD. The test nonspecifically reacts to CNS inflammatory illnesses. It appears in early stages of such illnesses but declines as they subside, usually disappearing by two to three weeks after onset. By contrast, the molecule usually appears relatively low in the CSF early during the course of CJD but gradually rises as CJD progressed.
MRL Reference Laboratory (10703 Progress Way, Cypress, CA 90630; 800-445-4032) can process the 14-3-3 test. For the interested reader, a well-written, short, up-to-date, and comprehensive description of the fundamental biology of the prion diseases can be found in the article, ’Prion protein and the transmissible spongiform encephalopathy diseases” (Chesebro B. Neuron 1999; 24:503-506). fp
Creutzfeldt-Jakob disease has an incidence of one per million of the population, yet clinical diagnosis is usually not difficult for neurologists. Which combination of tests has the highest probability of diagnostic accuracy?
a. Two of four physical abnormalities plus EEG usually is specific.
b. EEG is better than MRI.
c. MRI is equal to the 14-3-3 in sensitivity.
d. The presence of the 14-3-3 protein is the best clinical test when physical signs suggest the illness.
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