A correlative study of the clinical, pathological and biochemical features of sporadic Creutzfeldt-Jakob Disease : 2000-2006

Historically various CJD syndromes have been described with a spectrum of clinical presentations. Sporadic CJD (sCJD) is the most common form of human transmissible spongiform encephalopathy (TSE) and is characterised by accumulation of pathological prion protein (PrP) in the central nervous tissue. Classification criteria have changed with the advent of novel diagnostic tests over the last decade. The subclassification according to the codon 129 genotype and prion protein (PrP) type in the brain has led to the identification of six sCJD subtypes, but whether different phenotypes are related to distinct infectious agent strains remains unclear. In order to assess clinical phenotype in detail, four hundred and fourteen cases of sCJD referred to the NCJDSU and classified using the Rotterdam Criteria (1998) were retrospectively analysed (2000-2006). Seventy-four non-cases (1998-2008) were included for comparative analyses. The number of referrals seen has remained relatively uniform with necropsy performed on 70% of suspect cases. The clinical phenotype is less well defined than previously postulated with marked overlap of clinical symptoms and signs independent of PrP[superscript sc] subtype, PRNP genotype and age of onset. In particular the MM1 and MV1 subtypes are not as clinically matched as previously proposed, with the suggestion that these are two distinct forms. The early development of symptoms and signs however favours a diagnosis of sCJD compared with non-cases and may be a potential diagnostic indicator for sCJD. The utility of investigative tests in sCJD, including the EEG and CSF 14-3-3 have been validated. The additional role of the brain MRI, particularly in atypical subtypes, is also demonstrated. This thesis demonstrates that the current WHO diagnostic criteria for sCJD are of value. However, the inclusion of the results of brain MRI and the time to onset of neurological signs and symptoms may improve diagnostic accuracy and allow identification of atypical phenotypes.