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 abnorm al isoform of cellular prion protein (PrPSc), which is the principal consti tuent of prions. Prions replicate in lymphoreticular tissues before neuroin vasion, suggesting that lymphoreticular biopsy samples may allow early diag nosis by detection of PrPSc 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 l ymphoreticular 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 fro m neurological and normal controls. Tonsil biopsy sampling was done on 20 p atients with suspected prion disease. Tissues were analysed by western blot to detect and type PrPSc, by PrP immunohistochemistry, or both. Findings All lymphoreticular tissues obtained at necropsy from patients wit h neuropathologically confirmed variant CJD, but not from patients with oth er prion diseases or controls, were positive for PrPSc. In addition, PrPSc typing revealed a consistent pattern (designated type 4t) different from th at 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 hi ghly consistent with, a diagnosis of variant CJD and negative in all patien ts subsequently confirmed to have other diagnoses. Interpretation We found that if, in the appropriate clinical context, a ton sil biopsy sample was positive for PrPSc, variant CJD could be diagnosed, w hich obviates the need for a brain biopsy sample to be taken. Our results a lso show that variant CJD has a different pathogenesis to sporadic CJD.