Tick-borne encephalitis : on pathogenesis and prognosis

Abstract: The general aim of the five studies presented in this thesis was to investigate the clinical oucome and prognosis and factors of importance for the pathogenesis of TBE compared to other aseptic meningo encephalitis. In a prospective study 149 patients presenting with clinical symptoms of acute viral meningo-encephalitis between June 1991 and December 1993 were included. Tick-borne encephalitis (TBE) was diagnosed consecutively in 85/149 patients and the other 64 were included as a reference group (non-TBE). The first study showed that the time off work and the time to recovery were significantly longer in TBE than in non-TBE. No lethal cases occurred, but many patients with TBE had protracted neurological dysfunction with decreased memory and concentration, dysphasia or ataxia after 11-13 months (TBE: 40%; 33/83, non-TBE 20%; 13/64). Spinal nerve paralysis persisted in 5/85 (6%,) of the patients with TBE. In the second study the pathophysiology of Tick-borne encephalitis (TBE) the kinetics of neopterin and ,B-2 microglobulin (B-2M) production were measured in sequential cerebrospinal fluid (CSF) and serum samples (TBE n=72, non-TBE n=61). TBE induced a strong intrathecal immune activation indicated by the neopterin and B-2M response. On day 9 and at week 6 the CSF neopterin level was significantly higher in TBE than in non-TBE. The B-2M response in CSF followed the pattern of neopterin. The intensity and duration of neopterin and of B-2M were not correlated to the clinical course. In the third study the kinectics of soluble cytokines IFN-y, IL-10, TNF-a, IL-6, IL-lra and soluble CD8 (sCD8) in CSF and serum and their impact on the pathogenesis were analyzed in 44 patients with TBE and 36 with non-TBE. Intrathecal cytokine synthesis was also studied at single-cell level (n=36) with semi-quantitative indirect immunofluorescence after in vitro priming with anti-CD3 serum antibodies. High initial CSF concentrations of soluble IL-6, IL-lra and sCD8 were detected in all patients. Low concentrations of soluble intrathecal TNF-a levels were found, but production from single CSF leucocytes was detectedy Single CSF leucocytes produced IFN-y and IL- 10, but not IL-6. Lower geometric mean CSF levels of soluble IL-10 were detected in TBE than in non-TBE on days 0-6. Moderate-to-severe TBE patients had significantly lower IL-10 CSF concentrations between days 7 and 18 than patients with meningeal disease. In study four antibody response by IgM, IgG and IgA was demonstrated in serum and CSF in 69, patients from the acute phase up to 11-13 months after onset. Intrathecal antibody production was demonstrated in 84% of the patients after one year (50/52 of CSF-serum sampled in the interval 11-61 days). Patients with dominating encephalitic symptoms showed significantly lower intrathecal IgM activity day 9 after onset. In study five the regional cerebral blood flow (rCBF-scintigraphy; SPECT) was studied in TBE patients (n=73) and non-TBE patients (n=56) in the acute phase of disease and at long-term follow-up. Blood flow disturbances and their localization in the CNS were correlated to clinical course and outcome. Slightly to moderately decreased rCBF was seen in 49% of the TBE patients and 50% of non-TBE after six weeks and in 47% and 46%, respectively, after one year. Reduced rCBF was significantly more common among patients with encephalitis than among those with meningitis. In TBE patients, remaining neurological symptoms at six weeks of disease were associated with worsening of decreased regional cerebral blood flow at one year follow-up. The general conclusions are that TBE in Sweden was associated with a significant morbidity, a post TBE syndrome existing after one year in more than one third of the patients. Neopterin seemed to be a more sensitive indicator of intrathecal T-cell response and inflammatory reaction than B-2M. It is hard to find TBEV RNA in CSF. The TBEV replication is probably inhibited in the CNS at onset of meningo encephalitis, when IgG antibodies are present in CSF. The Th 2 monokine IL- 10 is initially downregulated, and the stimulation of B-cells to produce immunoglobulins is subsequently delayed, leading to reduced antibody levels after the first week of disease. Low IL-10 in CSF aggravates TBE. Capture IgM and IgG assays were superior to indirect ELISA in detcting intrathecal antibody response. Reduction of rCBF was detected in patients with aseptic meningo-encephalitis, more commonly seen in patients with severe disease. Key words: Human, tick-borne encephalitis, viral, meningo-encephalitis, cerebrospinal fluid, PCR, cytokines, immunoglobulin, SPECT, technetium-99m-HMPAO