Determinants of diagnostic investigation sensitivities across the clinical spectrum of sporadic Creutzfeldt–Jakob disease

• Published in: Brain (London, England : 1878) England : 1878), 2006-09, Vol.129 (9), p.2278-2287
• Main Authors: Collins, S. J., Sanchez-Juan, P., Masters, C. L., Klug, G. M., van Duijn, C., Poleggi, A., Pocchiari, M., Almonti, S., Cuadrado-Corrales, N., de Pedro-Cuesta, J., Budka, H., Gelpi, E., Glatzel, M., Tolnay, M., Hewer, E., Zerr, I., Heinemann, U., Kretszchmar, H. A., Jansen, G. H., Olsen, E., Mitrova, E., Alpérovitch, A., Brandel, J.-P., Mackenzie, J., Murray, K., Will, R. G.
• Format: Article
• Language: English
• Subjects: 14-3-3 Proteins - cerebrospinal fluid; Adult; Age of Onset; Aged; Aged, 80 and over; Biological and medical sciences; Brain - pathology; Creutzfeldt-Jakob Syndrome - cerebrospinal fluid; Creutzfeldt-Jakob Syndrome - diagnosis; Creutzfeldt-Jakob Syndrome - genetics; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; diagnostic investigation results; Electroencephalography - methods; Female; Genotype; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Humans; Magnetic Resonance Imaging - methods; Male; Medical sciences; Middle Aged; molecular sub-typing; Nervous system (semeiology, syndromes); Neurology; Polymorphism, Genetic - genetics; Prion Proteins; Prions - genetics; Protein Precursors - genetics; Sensitivity and Specificity; sporadic CJD; Time Factors
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awl159

To validate the provisional findings of a number of smaller studies and explore additional determinants of characteristic diagnostic investigation results across the entire clinical spectrum of sporadic Creutzfeldt–Jakob disease (CJD), an international collaborative study was undertaken comprising 2451 pathologically confirmed (definite) patients. We assessed the influence of age at disease onset, illness duration, prion protein gene (PRNP) codon 129 polymorphism (either methionine or valine) and molecular sub-type on the diagnostic sensitivity of EEG, cerebral MRI and the CSF 14-3-3 immunoassay. For EEG and CSF 14-3-3 protein detection, we also assessed the influence of the time point in a patient's illness at which the investigation was performed on the likelihood of a typical or positive result. Analysis included a large subset of patients (n = 743) in whom molecular sub-typing had been performed using a combination of the PRNP codon 129 polymorphism and the form of protease resistant prion protein [type 1 or 2 according to Parchi et al. (Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O, Zerr I, Budka H, Kopp N, Piccardo P, Poser S, Rojiani A, Streichemberger N, Julien J, Vital C, Ghetti B, Gambetti P, Kretzschmar H. Classification of sporadic Creutzfeldt–Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 1999; 46: 224–233.)] present in the brain. Findings for the whole group paralleled the subset with molecular sub-typing data available, showing that age at disease onset and disease duration were independent determinants of typical changes on EEG, while illness duration significantly influenced positive CSF 14-3-3 protein detection; changes on brain MRI were not influenced by either of these clinical parameters, but overall, imaging data were less complete and consequently conclusions are more tentative. In addition to age at disease onset and illness duration, molecular sub-type was re-affirmed as an important independent determinant of investigation results. In multivariate analyses that included molecular sub-type, time point of the investigation during a patient's illness was found not to influence the occurrence of a typical or positive EEG or CSF 14-3-3 protein result. A typical EEG was most often seen in MM1 patients and was significantly less likely in the MV1, MV2 and VV2 sub-types, whereas VV2 patients had an increased likelihood of a typical brain MRI. Overall, the CSF 14-3-3 immunoassay