**6. Clinical manifestations of TBEV infection**

due to oral virus transmission are reported from Eastern Europe and Baltic states [29, 30]. A few cases of laboratory-acquired TBEV infections have been documented [31]. Vertical transmission, person-to-person transmission including breast-feeding, and transmission through

TBE is a seasonal disease; most cases occur in the warm period of the year (usually between April and November) which correlates with the period of the highest tick activity and with increased exposure during this time period [32]. In Central Europe, a two‐peak distribution of TBE cases can be seen, first in June and July, and second in September and October, whereas in the regions where *I. persulcatus* is widespread, cases as a rule occur in May and June [11]. In all age groups men are affected more frequently than women. The highest notification rate is in the 45–64 year‐old age group, followed by the over 65‐year olds [20, 33]. On an average, 10–20% of all reported cases of TBE occur in children, with the lowest incidence in those less than 3 years of age [34, 35]. It should be pointed out that due to its unspecific clinical presentation, TBE in children is often missed and is diagnosed as aseptic meningitis of unknown etiology [36, 37].

TBE represents a potential risk for nonvaccinated travelers traveling to countries with high endemic foci and therefore should be included in the differential diagnosis of the CNS infections in case of an appropriate epidemiological history also in patients living outside endemic areas. The risk depends on the season of travel, duration of stay as well as on travel style (degree of unprotected outdoor exposure). In the different endemic areas, the risk for infec-

After the bite of an infected tick TBEV replication occurs locally. Dendritic cells (Langerhans cells) are considered to be the most important cells for local viral replication and to transport the virus to the regional lymph nodes where further replication takes place. After release into the bloodstream the virus disseminate to other organs, in particular to the reticulo-endothelial system (mainly bone marrow, spleen, and liver) where the virus continue to multiply and maintain viremia for few days. During the viremic phase (which clinically matches to the initial phase of TBE) the virus probably reaches the brain [38, 39]. The precise mechanism of viral passage through the blood-brain barrier is unclear, but depends on the presence of viremia. Four possible routes have been postulated: (i) peripheral nerves, (ii) highly susceptible olfactory neurons (especially relevant in laboratory infections by aerosols), (iii) transcytosis through vascular endothelial cells of brain capillaries, and (iv) diffusion of the virus between capillary endothelial cells. The primary targets of TBEV infection in central nervous system

TBEV in CNS induces inflammation with inflammatory cell infiltration, activation of microglia, and neuronal degeneration. The exact mechanism of tissue destruction is unclear, but Ružek and coworkers demonstrated that inflammatory reaction mediated by CD8+ T cells significantly contributes to neuronal damage [40]. Limited data are available on the role of

blood transfusion have not been reliably described in humans.

26 Meningoencephalitis - Disease Which Requires Optimal Approach in Emergency Manner

tion after a single tick bite varies from 1:200 to 1:1000 [21].

are neurons. Rarely, oligodendrocytes are infected [38].

cytokines and chemokines.

**5. Pathogenesis and pathology**

Seroepidemiological studies have demonstrated that TBEV infection is often asymptomatic. The exact proportion of such cases is not known, because those with mild clinical presentation may not be diagnosed, but data suggest rates between 70 and 98% [42–44].

Time interval from a tick bite to the beginning of the illness is usually 7–14 days, but it may be as short as 2 days and as long as 4 weeks. After alimentary route of infection, there is regularly a shorter incubation period of 3–4 days [30, 32, 45].

In at least three‐quarters of patients who develop CNS involvement, the disease caused by the European virus subtype has a biphasic course [46–48]. The initial phase corresponds to the viremia and usually presents with nonspecific systemic signs and symptoms; the most common are moderate fever (99%), fatigue (63%), general malaise (62%), headache and body pain (arthralgia and myalgia) (54%) [47]. In this phase, which lasts 2–7 days, there are no signs or symptoms of CNS involvement; cerebrospinal fluid (CSF) examination reveals normal findings. After an improvement or even an asymptomatic interval of about 1 week duration (range 1–21 days) the second phase presents as meningitis, meningoencephalitis, or meningoencephalomyelitis in 54, 37, and 9% of adult patients [49]. The far most frequent clinical manifestation of TBE in children is meningitis [34]. Fever in the second phase is typically 1–2°C higher than the peek temperature in the first phase and is of longer duration [12, 50].

In some patients the disease course is monophasic: they may either have CNS involvement or a febrile illness with headache with symptoms subsiding without developing into the second phase (i.e., the initial phase of TBE without subsequent CNS involvement), named abortive form of TBE or "febrile headache" [12, 32, 50, 51].
