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Title: Detection and diagnosis of acute viral encephalitis
Author: Michael, Benedict
ISNI:       0000 0004 6057 7346
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2014
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Introduction Acute viral encephalitis is a severe form of brain inflammation due to sporadic infection, typically with herpes simplex virus, or epidemic/pandemic infections. Epidemiological data are particularly important for pandemic viruses. Although new reporting approaches are often considered, no real-time clinical data collection tool has been developed. These data are dependent on diagnosis of individual cases. However, the aspects of management that result in delays and missed diagnoses are not clear and it is not known if interventions can improve sample collection and diagnosis. Whilst the importance of cytokines and associated mediators is increasingly recognised, signatures associated with specific aetiologies have not been established. Also, it is not known whether these mediators correlate with clinical severity and outcome, or their impact on blood-brain barrier permeability. Methods I undertook a national surveillance study through neurology networks, and investigated alternative notification approaches. I undertook a multicentre cross-sectional study of clinical investigation, studied viral load and assessed the impact of a lumbar puncture pack. I used bead array to assess mediator profiles and assessed the albumin ratio and viral load, in samples from a Health Protection Agency study. I examined profiles with respect to aetiology, disease severity and outcome and compared this with histopathology tissue and a blood-brain barrier model. Results In the context of a pandemic influenza virus, existing mechanisms identified limited cases, and a smartphone application was developed to collect real-time data. Delays in lumbar puncture and sub-optimal sample collection were identified, in association with a lower viral load. A lumbar puncture pack improved sample collection. Mediator profiles differed between those with an infectious versus immune-mediated aetiology, and those of unknown aetiology best reflected infectious; particularly myeloperoxidase, in part relating to neutrophils in cerebrospinal fluid and parenchyma. The interleukin1 antagonists, IL1RA and IL10, were associated with coma and outcome; and IL10 with reduced blood-brain barrier permeability. Adhesion molecules may counteract this, in both clinical samples and the model. Conclusions Current limitations of detection may be augmented with novel real-time technologies. Diagnosis is limited by delayed and sub-optimal sample collection, which can be improved with a simple pack. Mediators profiles may assist in the distinction of infectious from immune-mediated encephalitis, and cytokines that act against IL1 correlated with clinical severity and outcome. This may be more closely associated with outcome than viral load, although this may reflect sample timing. These findings should direct future research to develop approaches for improved diagnostics and adjunctive therapies.
Supervisor: Not available Sponsor: NIHR
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry