| Summary: | Background: Sporadic Creutzfeldt-Jakob disease (sCJD) is an invariably fatal spongiform encephalopathy that has a worldwide incidence of approximately 1/1,000000 per year. Prospective surveillance has been in place in the UK since 1990, coordinated by the National CJD Surveillance Unit (NCJDSU). Accurate surveillance of CJD is important not only in detecting changes in patterns of disease and predicting trends but also in instituting protective public health measures. Aims of the study: To define circumstances where making a clinical diagnosis of sCJD is potentially problematic. To explore ways of improving diagnostic accuracy and enhancing surveillance in these settings. Methodology: Clinically "atypical" cases of sCJD were defined according to specific criteria (young, long duration, certain focal features at onset) and identified by retrospective case-file review of all 485 pathologically-proven cases (1990-2002). Comparisons were made with a consecutively selected "Core group" of "typical" sCJD (n=133). Cases identified only at autopsy, cases finally classified as "Possible sCJD" (according to internationally agreed criteria) and initially suspect but pathologically proven non-cases were also identified and analysed. Results and conclusions: Twenty four per cent of all pathologicallly confirmed sCJD cases were "atypical". For each "atypical" subgroup, relatively distinct phenotypic characteristics were identified when compared with the Core group. Long duration cases were associated with early depression and personality change, more psychiatric features and infrequent cerebellar or extrapyramidal features. Young cases had less ataxia at onset and more psychiatric symptoms and involuntary movements. Cases presenting with predominantly cerebellar features were associated with a higher prevalence of visual disturbance and sensory symptoms and a longer illness duration. Those with a pure visual onset had a shorter duration with less cerebellar or extrapyramidal features. Amongst "atypical" cases (with the exception of pure visual onset cases) the electroencephalogram was diagnostically less sensitive and where positive was associated with short disease duration and increased age at onset. Visual onset cases were associated with genotype MM at codon 129 of the prion protein gene. Nineteen per cent of sCJD cases were referred after autopsy, of these about one third were not diagnosed whilst alive. Alzheimer's disease (AD) was the most likely alternative diagnosis in pathologically proven non-cases except when disease duration was less than six months, where paraneoplastic/neoplastic disease was commonest. Diagnostic accuracy is likely to improve with a greater understanding of the range of disease presentation, evolution and differential diagnoses along with the targeted use of diagnostic tests. The referral of unusual cases should be encouraged. In view of the declining autopsy rates in the U.K. it is particularly important that accuracy in clinical diagnosis is pursued.
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