**4. Epidemiology**

The clinical course of acute illness is highly variable. Due to the relatively high proportion of severe cases and a considerable proportion of patients with long-lasting sequelae which may have a significant impact on quality of life, the disease represents high costs for healthcare

Herein we present an overview of TBE, including a short historical outline, basic information on TBEV, and of the epidemiology, pathogenesis, clinical manifestations, diagnosis and treat-

Historically the first mention of the TBE existence dates back to the eighteenth century in Scandinavian church records from Åland Islands. However, the first medical description of disease was given and published in 1931 by the Austrian physician H. Schneider [2]. Six years later, an expedition headed by Zilber in the Russian Far East isolated for the first time the causative agent (TBEV) from humans, mice, and *Ixodes persulcatus* ticks; they determined the etiology of TBE and its vector [3]. In 1939, Pavlovsky confirmed the preliminary hypothesis on the transmission of the TBEV in nature (between ticks and mammals) and proposed the theory of natural foci [4]. In Europe, TBEV was first isolated, from humans and *Ixodes ricinus* ticks, in Czechoslovakia in 1948 by Gallia and colleagues [5]. In the following years, the disease and/or the virus has been identified in many other European countries and, later, also in

TBE is caused by TBEV, a small, neurotropic, lipid‐enveloped spherical RNA virus, the member of genus *Flavivirus*, family *Flaviviridae*. The viral RNA contains records for three structural (E (envelope), prM/M (precursor of membrane or membrane, respectively), and C (capsid)), and seven nonstructural viral proteins (NS1, NS2a, NS2b, NS3, NS4a, NS4b, and NS5). Glycoprotein E is a major viral antigen and is associated with the production of neutralizing antibodies and the induction of protective immunity. It also plays a key role in the viral life cycle mediating the

TBEV occurs in three subtypes named as European, Siberian, and Far-Eastern subtype [1]. They are very closely related, both genetically and antigenically; variation in amino acids sequences between subtypes is 5–6% [8]. In spite of the pronounced genetic similarity of the subtypes the illness caused by individual subtype is not completely equivalent to those due

An important characteristic of the TBEV, which allows them alimentary route of infection, is their ability to maintain at least residual infectivity at acidic pH (above pH 1.42) [9]. TBEV maintains infectivity at very low environment temperatures (even below −70°C). On the contrary, it is heat labile; total inactivation of the virus occurs within 30 minutes at 56°C [10, 11].

binding of virions to cell receptors and subsequent intraendosomal fusion [7].

ment of TBE, as well as on the course and outcome of the disease and its prevention.

24 Meningoencephalitis - Disease Which Requires Optimal Approach in Emergency Manner

system and society.

**2. History**

**3. Etiology**

to the other subtypes.

It can be inactivated by pasteurization [12].

the north of China and northern Japan [6].

TBE arises in an endemic pattern of so‐called natural foci over a large geographical area extending from Central Europe and Scandinavia through the Eurasian continent to North‐ Eastern China and Northern Japan. Over the past few decades, a trend toward both an expansion of the endemic areas and an increase of reported cases have been observed [13, 14]. The increase in the incidence is the result of a complex interrelation of socioeconomic and ecological factors; a part of an increase may also be explained with an increased medical awareness, advanced diagnostics, and improvements in epidemiological surveillance [15, 16].

In Europe and Asia between 10,000 and 15,000 TBE cases are reported per year with pronounced annual fluctuations [17]. The number is very likely underreported mainly due to lack of standardized TBE case definition, the varying diagnostics procedures, and the wide differences in the quality of national surveillance systems.

In 2012, TBE became a notifiable disease at the European Union level. Currently the disease is endemic in 27 European countries; the reporting is mandatory in 18 of them. Two‐thirds of the countries where TBE is a notifiable disease use the European Centre for Disease Prevention and Control case definition [13, 18, 19]. A total of 2560 TBE cases were reported in Europe in 2012 with the overall notification rate of 0.52 cases per 100,000 inhabitants. Countries with the highest reported incidence (>5 cases per 100,000 inhabitants per year) were Estonia (13.35), Lithuania (11.69), Slovenia (7.98), and Czech Republic (5.46) [20].

The main hosts and reservoirs of TBEV in nature are wild vertebrate, in particular small rodents. Ticks act as both virus vectors and reservoir and carry the virus throughout their life. Humans are only accidental hosts and do not play any role in the maintenance of TBEV in nature [21, 22].

Most human infections occur through an infected hard tick bites. At least 11 tick species are capable of transmitting TBEV, but only 2 species are of clinical importance. *I. ricinus* is the principal vector throughout Europe and, therefore, the most important transmitter of the European TBEV subtype, while *I. persulcatus* occurs in regions of Eastern Europe, in Russia, and in far-eastern Asia and is the main vector of the Siberian and Far-Eastern TBEV subtype [21, 23]. The Siberian TBEV subtype is found in Siberia, the Baltics, and northern Finland, whereas the Far‐Eastern TBEV subtype is endemic in far‐eastern Asia and Japan, and also in central and eastern Siberia [13, 22]. In the Baltic States and Finland, where *I. ricinus* overlaps with *I. persulcatus*, all three TBEV subtypes co-circulate [24–26]. The Far-Eastern TBEV was found in *Ixodes ovatus* in Japan in south‐western China, while the European TBEV subtype was detected in *Ixodes nipponensis* ticks in Korea [1, 27].

In Europe, the TBEV prevalence in unfed *I. ricinus* ticks ranges from 0.1 to 5.0% (depending on the geographical location and time of the year) and increases with development stage, whereas in Siberia, the reported proportion of infected adult *I. persulcatus* ticks is up to 40% [13, 21]. In Slovenia, the prevalence of TBEV‐infected ticks was found to be 0.47%; 0.54% in 2005 and 0.43% in 2006 [28]. About 1% of all human TBEV infections are alimentary‐transmitted by consuming contaminated unpasteurized dairy products, especially goat milk [1]. This route of infection has to be considered in cases of local epidemics. The majority of outbreaks 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 blood transfusion have not been reliably described in humans.

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