Creutzfeldt-Jakob Disease: How to Best Diagnose It
Abstract & Commentary
By Joseph E. Safdieh, MD, Assistant Professor of Neurology, Weill Medical College, Cornell University. Dr. Safdieh reports no financial relationships relevant to this field of study.
Synopsis: Sporadic Creutzfeldt-Jakob disease (CJD) has multiple subtypes, and the subtype has an effect on the sensitivity of commonly utilized diagnostic tests in the workup of CJD.
Sources: Head MW, Ironside JW. Sporadic Creutzfeldt-Jakob disease: Further twists and turns in a convoluted protein. Brain. 2006;129:2238-2240.
As a group, prion diseases are relentlessly progressive and ultimately fatal neurodegenerative diseases. However, the time course, symptomatology, and sensitivity of diagnostic studies vary between different patients affected with the sporadic form of Creutzfeldt-Jakob disease (sCJD). It seems that there are multiple clinical variants of sCJD, and the clinical manifestations depend both on the configuration of the abnormal prion protein and the prion protein gene. There are 2 physio-chemical forms of the abnormal prion protein known as type 1 and type 2. These 2 types are distinguished by their N-terminus and by their gel mobility of the prion after treatment with a proteolytic enzyme, proteinase K.
Codon 129, of the prion protein gene, plays a key role in determining the clinical form as well. Patients may be homozygous for methionine, homozygous for valine, or heterozygotes. A classification system proposed by Gambetti contains 6 subtypes of sCJD: MM1, MV1, VV1, MM2, MV2 and VV2.1 An alternative classification system proposed by Collinge further subdivides the MM1 group into short and long duration subtypes based on chemical properties. In the paper by Cali and colleagues,1 a series of experiments were performed suggesting that differentiation of the MM1 subgroup is not justified. They argue that the subdivision proposed by Collinge was an artifact of laboratory conditions, specifically pH.
The article by Collins and colleagues2 is a prospective study over a 10-year period, with a total of 2451 patients with definite sCJD, all from Europe or Australia.2 The study assessed the influence of age at onset, duration of illness, prion protein gene codon 129 polymorphism, and molecular subtype (type 1 or type 2) on the diagnostic sensitivity of EEG, brain MRI, and CSF 14-3-3 assay. EEG was considered positive when it contained sustained periodic sharp wave complexes typically seen in sCJD. Brain MRI was considered positive when high signal was present in the putamen and caudate nucleus on T2-weighted images. Overall, the median age of onset of CJD was 67 years. VV1 patients were significantly younger at onset. The median duration of illness was 5 months. Two-thirds of patients had the more common MM genotype, and two-thirds of the prion proteins were type 1.
Overall, the CSF 14-3-3 assay was the most frequently positive investigation, with 88.1% sensitivity. However, it was much less sensitive in the uncommon MV2 and MM2 subtypes. Overall sensitivity of EEG was 58.4%. The EEG was most sensitive in MM1 subtype patients, with sensitivity of 72.8%. This is the most common subtype of sCJD. Sensitivity of EEG decreased significantly over the duration of the disease. Additionally, older patients more frequently demonstrated positive EEG findings. Positive MRI was seen in only 39.1% of cases where the test was done. The likelihood of a positive MRI was higher in MV and VV subtypes, in contrast to EEG. However, Head and colleagues acknowledge that this may be an underestimate of MRI sensitivity given recent advances in technology, especially diffusion-weighted imaging.
Commentary
As with most neurological disorders, the diagnosis of CJD is usually made at the bedside with a comprehensive neurological history and examination. Because of the rarity of this disease, the utility of diagnostic tests has not been well established. The study by Collins et al is the largest to date, and it sheds light on the sensitivity of the 3 most commonly used diagnostic tests in the evaluation of CJD. Clearly, the CSF 14-3-3 protein assay is highly sensitive. The study does not address the specificity of this protein assay, which is not as high as the sensitivity. However, in the proper clinical context, a positive CSF 14-3-3 protein is quite helpful. EEG is more sensitive early in the course of CJD. As the disease progresses, the periodic sharp wave complexes in the EEG become less frequent as the overall pattern of EEG becomes slower and more disorganized. The sensitivity of MRI in this study is quite low. However, with newer technology, it is likely that the sensitivity of MRI will be higher. Additionally, in the less common and less clinically characteristic VV2 and MM2 subtypes, MRI demonstrates higher sensitivity. These subtypes have traditionally been more difficult to diagnose, and it seems that the diagnosis may become easier with modern, high-field MRI imaging.
References
1. Cali I, et al. Classification of sporadic Creutzfeldt-Jakob disease revisited. Brain. 2006;129:2266-2277.
2. Collins SJ, et al. Determinants of diagnostic investigation sensitivities across the clinical spectrum of sporadic Creutzfeldt-Jakob disease. Brain. 2006;129:2278-2287.
Sporadic Creutzfeldt-Jakob disease (CJD) has multiple subtypes, and the subtype has an effect on the sensitivity of commonly utilized diagnostic tests in the workup of CJD.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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