Diagnosis Prion Diseases

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The dramatic and atypical features of human prion diseases can be recognized readily in classic presentations of the common phenotypes. However, there is a wide range of clinical presentations and prion phenotypes that can make antemortem diagnosis very difficult in some patients. Clinical features that suggest prion disease, ancillary tests that can be of value in supporting a diagnosis of a prion dementia, and pathologic findings that confirm a diagnosis of a prion disease are discussed next.

In sporadic, infectious, and familial CJD, the clinical feature that is most characteristic of a diagnosis of a prion dementia is the rapidly progressive nature of the disorder. Within three to eight months of a patient's first symptoms, most patients develop severe dementia that results in their death in less than 1.5 years (Parchi et al., 1999). In a majority of patients, the initial symptoms are some type of cognitive impairment (e.g., memory loss, confusion, disorientation, intellectual decline), but, commonly, initial symptoms can be changes in vision, balance and gait, movement disorders, or psychiatric symptoms. At some point during the disease course, severe dementia, gait impairment or ataxia, hyperkinetic movement disorders including myoclonus, and behavioral symptoms are seen in most cases. Startle myoclonus is a classic clinical feature often seen in sporadic CJD and is very rare in other common causes of dementia. The average age of onset in sporadic CJD is approximately 61 (onset range 40 to 90 years), but familial CJD, some iatrogenic CJD, and vCJD cases present at a younger age. New variant CJD (vCJD) has been limited to cases in Europe so far, but may spread to other countries. These cases have had a very early age of onset (mean age of onset is 29 years) and frequently have presented with psychiatric symptoms and early sensory symptoms that were often painful (Zeidler et al., 1997).

Few conditions mimic the classic "cortical" presentation of CJD; however, the possibility of viral encephalitis, paraneoplastic limbic encephalitis, and Hashimoto's encephalitis needs to be considered in the right clinical situation because each of these conditions is potentially treatable (Seipelt et al., 1999). While these conditions can resemble CJD clinically, they can be diagnosed by looking for antibodies to thyroglobulin, thyroid peroxi-dase, or paraneoplastic antigens (e.g., antineuronal nuclear antibodies types 1 and 2) and by cerebral spinal fluid (CSF) analysis. Viral encephalitis can be distinguished from CJD by an inflammatory pleocytosis and the detection of viral nucleic acid by polymerase chain reaction in the CSF. Hashimoto's encephalitis patients have antibodies against thyroglobulin and thyroid peroxidase in addition to normal CSF, including 14-3-3 protein analysis. Patients with paraneoplastic limbic encephalitis can be diagnosed by identifying paraneoplastic antibodies.

A familial prion disease is suggested by a family history consistent with autosomal dominant inheritance of an atypical dementia and/or ataxia. However, some patients with familial prion diseases do not have an informative family history (e.g., adopted patient without knowledge of biologic family). The non-CJD presentations of familial prion disease (e.g., GSS and FFI ) are difficult to diagnose without prior tissue confirmation of other family members. When patients present with slowly progressive ataxia without dementia (e.g., GSS), the variety of diseases that cause progressive cerebellar dysfunction need to be considered in the differential diagnosis, including the spinocerebellar atrophies. FFI or thalamic forms of CJD are suspected if intractable insomnia and dysautonomia develop, especially if there is a family history of similar cases. If a familial form of CJD is suspected, prion protein gene analysis is available in research laboratories to look for pathogenic mutations.

Several minimally invasive ancillary tests can provide supportive evidence of prion disease, including electroencephalograms (EEG), spinal fluid analysis for the 14-3-3 protein, and magnetic resonance imaging (MRI ) imaging. The classic EEG pattern seen in CJD is periodic sharp wave complexes (PSWCs). This EEG pattern is present after approximately 12 weeks of symptoms in those who develop the EEG pattern. In late stages of the disease, the pattern may be lost. In sporadic CJD, PSWCs are seen in 60% to 80% of cases (Brown et al., 1986; Zerr et al., 2000). However, in many iatrogenic CJD, vCJD, and genetic CJD cases, PSWCs are absent. Detection of the 14-3-3 proteins in CSF has been described as a useful test to support a diagnosis of a prion disease. In studies of patients with suspected CJD, the test was positive in 93% of probable cases and 95% of definite cases (Zerr et al., 1998). The 14-3-3 proteins are a group of proteins involved in the regulation of protein phosphorylation and are found in the CSF of patients with conditions where significant brain injury is occurring. False positive results have been reported in herpes simplex encephalitis or other viral causes of encephalitis, acute stroke, subarachnoid hemorrhage, and meningeal carcinomatosis due to small cell lung cancer. As with EEG finding, vCJD and genetic forms of prion disease may be less likely to have 14-3-3 proteins in CSF. Finally, MRI imaging of the brain can show two characteristic abnormalities in the brains of patients with prion diseases (Collins, Boyd, Fletcher, Gonzales, et al., 2000). One is symmetric increased signal in the basal ganglia on T-2 and proton-density weighted images. These findings can be asymmetric in some patients and involve other structures including the thalamus, white matter, or cortex. The second MRI finding is high signal changes on diffusion-weighted imaging that may involve deep gray matter structures such as the thalamus and basal ganglia or the cortex, with cortical signal changes often having an asymmetric pattern.

Diagnostic criteria for making a clinical diagnosis of sporadic CJD have been proposed using clinical features and the results of the noninvasive ancillary tests. These criteria are shown in Table 4.1. MRI findings are not included in the diagnostic criteria at this time because the specificity and sensitivity of these imaging abnormalities are not well understood. The clinical phenotype expected in sporadic CJD and the likelihood of noninvasive ancillary tests being positive can be predicted by knowing patients' genotype at codon 129 of the prion protein gene and knowing whether they have type 1 or type 2 PrPSc as determined by the size and glycosylation of the

Table 4.1 Diagnostic Criteria for Sporadic CJD

Definite CJD Neuropathological confirmation at postmortem or by brain biopsy (ideally by confirming the presence of PrPSc in the brain immunochemically). Probable CJD 1. Progressive dementia of less than 2 years duration with at least two of these four features: myoclonus, visual or cerebellar signs, pyramidal or extrapyramidal signs, or akinetic mutism. 2. Typical periodic sharp wave complexes (PSWCs) on EEG or 14-3-3 proteins detectable in the CSF. Possible CJD Clinical features as those for probable CJD, but no PSWCs and CSF negative for 14-3-3 proteins.

From "Recent Advances in the Pre-Mortem Diagnosis of Creutzfeldt-Jakob Disease," by S. Collins et al., 2000, Journal of Clinical Neurosciences, 7, pp. 195-202.

protease-resistant fragment of PrPSc (Parchi et al., 1999; Zerr et al., 2000). Six subtypes are found using this classification. This type of subtyping is not available for most clinicians; however, these results provide insights into which diagnostic tests may be of value in which clinical phenotype. Although data is limited on some of the rare subtypes, at least one of the three noninvasive tests (EEG, 14-3-3 protein, MRI ) is expected to support a diagnosis of sporadic CJD in the majority of cases from all subtypes. In general, the presence of type 2 PrPSc makes it unlikely to have PSWCs on EEG (4% versus 78%), less likely to have 14-3-3 proteins in the CSF (75% versus 96%), but similarly likely to have MRI abnormalities (71% versus 68%).

The definitive diagnosis of a prion protein disease requires a tissue diagnosis. The classic histopathologic autopsy findings of prion diseases are spongiform degeneration, gliosis, and neuronal loss. In some prion diseases, prion protein amyloid plaques are seen, especially in the cerebellum. Prion diseases with prion protein amyloid plaques include Kuru, GSS, vCJD, and sporadic CJD patients that are heterozygous at codon 129 of the prion protein gene (i.e., Met/Val) and have type 2 PrPSc. Most cases of sporadic CJD have diffused pathologic changes in the cortex and subcortical structures such as the basal ganglia and cerebellum. However, the pathology of prion disease can be very focal, including cases with FFI and thala-mic variants of sporadic CJD that preferentially and, at times, exclusively involve thalamic nuclei, GSS, and ataxic variants of sporadic CJD with preferential involvement of the cerebellum.

The pathologic diagnosis of a prion disease is aided and confirmed by the identification of the protease-resistant portion of PrPSc (i.e., PrP 27-30) by immunohistochemical techniques or Western blot. In the past, brain biopsies were performed more frequently in patients with suspected prion disease. However, brain biopsies in patients with suspected prion diseases are uncommon presently because of lack of effective treatments for prion diseases, the difficulty in decontaminating surgical equipment, and the availability of helpful, minimally invasive ancillary tests. It has been found that patients with vCJD have detectable PrP 27-30 in lymphoid tissue, including the tonsils, spleen, and lymph nodes even at early stages of their disease (Collins, Boyd, Fletcher, Gonzales, et al., 2000). Prospective studies of tonsil biopsies in vCJD have found PrP 27-30 in all technically adequate specimens of patients that later were confirmed to have vCJD. Interestingly, similar findings of PrP 27-30 in lymphoid tissue have not been found in any other prion diseases, including sporadic, iatrogenic, and genetic forms of CJD. Thus, tonsil biopsies may play a role in the early and definitive diagnosis of vCJD, but not other forms of prion diseases. Such timely and precise diagnostic procedures may become more important if effective, but potentially toxic, treatments for prion diseases become available.

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