G. A. H. Wells

Ovine scrapie is a member of the transmissible spongiform encephalopathies (TSEs), a heterogeneous family of fatal neurologic disorders characterized by deposition of an abnormal isoform (prion protein [PrP] PrP-Sc) of a cellular sialoglycoprotein in neural tissue. PrP-Sc is detectable in some lymphoid tissues of infected sheep months or years before development of clinical disease. Detection of PrP-Sc in these tissues is the basis for live-animal testing. In this study, we characterize the performance of a preclinical diagnostic test for ovine scrapie based on a monoclonal antibody (MAb)-based immunohistochemistry assay of nictitating membrane ("third eyelid")-associated lymphoid tissue. The results of third eyelid immunohistochemistry assay agreed with the scrapie status of the sheep for 41 of 42 clinical suspects with confirmed scrapie and 174 of 175 sheep without scrapie. Third eyelid sampling agreed with the scrapie status for 36 of 41 clinically normal sheep positive for PrP-Sc immunostaining of brain tissue, including 27 sheep with positive biopsy specimens that progressed to clinical disease with confirmed scrapie 3 to 20 months after biopsy. The assay used MAb F89/160.1.5, which binds to residues 142 to 145 of ovine PrP. This antibody can be used in combination with MAb F99/97. 6.1, which binds to residues 220 to 225. One or both MAbs in this cocktail recognize PrP sequences conserved in most mammalian species in which natural TSEs have been reported. Immunohistochemistry assay of routinely formalin-fixed lymphoid tissues with a cocktail of pan-specific MAbs is a practical, readily standardized live-animal and preclinical test for ovine scrapie.

Physicians and surgeons have long recognized that septic illness may be accompanied by abnormal brain functions; however, no systematic, comprehensive study has been done to define the clinical and laboratory features of the syndrome of sepsis-associated encephalopathy. We undertook such a prospective study in a tertiary care hospital and found that of 69 patients with fever and microbial cultures, 32 had marked brain dysfunction, 17 showed mild encephalopathy, and 20 were clinically nonencephalopathic. Severe cases showed obtundation and paratonic rigidity while milder cases showed confusion, inappropriate behavior, inattention, disorientation, and writing errors. There were no focal neurological deficits. The following factors correlated with the severity of brain dysfunction: adult respiratory distress syndrome; fatal outcome; certain types of EEG abnormality; axonal peripheral neuropathy; elevated peripheral white blood cell count; elevated serum levels of alkaline phosphatase, bilirubin, creatinine, phosphate, potassium, and urea; reduced blood pressure and reduced serum albumin level. Our data suggest that brain functions fail with dysfunction of other organs in septic illness. Pathogenetic mechanisms are discussed. The brain dysfunction should be regarded as potentially reversible, even in severely encephalopathic cases. Prompt control of the infection is the most important measure in controlling the encephalopathy and in preventing the increased mortality found with severely encephalopathic patients.

Bovine spongiform encephalopathy (BSE), defined originally from its characteristic neuropathology, retains a place of particular interest in the scrapie-like or prion disease group, presenting uniquely an example of such diseases occurring as a nationwide food-borne epidemic in Great Britain. Comprehensive monitoring of the epidemic, both pathologically and epidemiologically, has facilitated our present understanding of the disease. BSE presents the classical neuropathological features of the transmissible spongiform encephalopathies. Although particularly similar to natural scrapie of sheep, BSE has, unlike scrapie, a stereotypic lesion profile from which it has been concluded that host and agent factors, including probably the strain of agent, which influence the profile, are constant in this disease. Neuronal loss in BSE may make an important but hitherto inapparent contribution to functional deficits. Preliminary ultrastructural studies have confirmed light microscopic features of brain changes in BSE but have as yet not established significant new findings. Immunohistochemical studies of PrP accumulation reveal distinctive forms and distributions of immunolabelling, confirming features reported previously in experimental models of scrapie, including perineuronal and perineuritic "synapse-like" reactivity. The histopathological diagnosis of BSE, validated on a single section of the medulla for the statutory diagnosis of large numbers of cases, is supplemented where necessary by fibril (SAF) examination which performs similarly to the histological diagnosis in the majority of cases. Epidemiological studies of BSE have supported the pathological findings that there is no detectable variation in susceptibility within the cattle population. The detailed monitoring of the epidemic has revealed the expected effects on the incidence as a result of statutory measures intended to prevent food-borne exposure after July 1988. The main effect has been a reduction in the national incidence during 1993 which has been continued into 1994. Analytical studies have not revealed any means of transmission, other than the food-borne source, capable of maintaining the epidemic in Great Britain. An international comparison of risk factors for the occurrence of BSE indicates that an epidemic of similar magnitude outside the British Isles is unlikely.

The infectivity in tissues from cattle exposed orally to the agent of BSE was assayed by the intracerebral inoculation of cattle. In addition to the infectivity in the central nervous system and distal ileum at stages of pathogenesis previously indicated by mouse bioassay, traces of infectivity were found in the palatine tonsil of cattle killed 10 months after exposure. Because the infectivity may therefore be present throughout the tonsils in cattle infected with BSE, observations were made of the anatomical and histological distribution of lingual tonsil in the root of the tongue of cattle. Examinations of tongues derived from abattoirs in Britain and intended for human consumption showed that macroscopically identifiable tonsillar tissue was present in more than 75 per cent of them, and even in the tongues in which no visible tonsillar tissue remained, histological examination revealed lymphoid tissue in more than 90 per cent. Variations in the distribution of the lingual tonsil suggested that even after the most rigorous trimming of the root of the tongue, traces of tonsillar tissue may remain.