Investigation of variant Creutzfeldt-Jakob disease and other human prion diseases with tonsil biopsy samples

Background Prion diseases are associated with the accumulation of an abnormal isoform of cellular prion protein (PrP(Sc)), which is the principal constituent of prions. Prions replicate in lymphoreticular tissues before neuroinvasion, suggesting that lymphoreticular biopsy samples may allow early diagnosis by detection of PrP(Sc) Variant Creutzfeldt-Jakob disease (variant CJD) is difficult to distinguish from common psychiatric disorders in its early stages and definitive diagnosis has relied on neuropathology. We studied lymphoreticular tissues from a necropsy series and assessed tonsillar biopsy samples as a diagnostic investigation for human prion disease. Methods Lymphoreticular tissues (68 tonsils, 64 spleens, and 40 lymph nodes) were obtained at necropsy from patients affected by prion disease and from neurological and normal controls. Tonsil biopsy sampling was done on 20 patients with suspected prion disease. Tissues were analysed by western blot to detect and type PrP(Sc), by PrP immunohistochemistry, or both. Findings All lymphoreticular tissues obtained at necropsy from patients with neuropathologically confirmed variant CJD, but not from patients with other prion diseases or controls, were positive for PrP(Sc). In addition, PrP(Sc) typing revealed a consistent pattern (designated type 4t) different from that seen in variant CJD brain (type 4) or in brain from other CJD subtypes (types 1-3). Tonsil biopsy tissue was positive in all eight patients with an adequate biopsy sample and whose subsequent course has confirmed, or is highly consistent with, a diagnosis of variant CJD and negative in all patients subsequently confirmed to have other diagnoses. Interpretation We found that if, in the appropriate clinical context, a tonsil biopsy sample was positive for PrP(Sc), variant CJD could be diagnosed, which obviates the need for a brain biopsy sample to be taken. Our results also show that variant CJD has a different pathogenesis to sporadic CJD.