History (based on Kunz & Heinz, 2003)
The first mention of what was probably tick-borne encephalitis (TBE) occurred in the18th century in parish records on the Aland islands (Finland). The first medical description was published in 1931 by Schneider, who observed in southern Lower-Austria the regular seasonal incidence of a disease that he named “Epidemische akute Meningitis serosa”. The TBE virus (TBEV) was first isolated from humans, mice and ticks in 1937 in the Russian Far East where an unusually high number of human meningoencephalitis cases  had been observed since the early 1930s. More than 10 years ensued before the virus was isolated by Gallia in Czechoslovakia in 1948. Subsequently, the disease was shown to occur in many European countries and, later in northern China and Japan. TBE has been referred to as Russian spring–summer encephalitis (RSSE), Far Eastern encephalitis, Taiga encephalitis, Biphasic milk fever, Central European encephalitis, Kumlinge disease, and Frühsommer-Meningoenzephalitis (FSME). In the first phase of subsequent research, field studies were conducted in Russia, Czechoslovakia, and Austria to elucidate the virus cycle in nature. Several reports have described TBE as one of the most severe of the viral encephalitides in Europe and with approximately 10, 000–12,000 hospitalised cases registered annually, including about 3000 in Europe, it is one of the most frequently occurring flavivirus-encephalitides worldwide. The high morbidity rate of TBE in Austria prompted the development of the first vaccine in a western European country in the mid-1970s and its clinical effectiveness was shown in a mass vaccination campaign leading to a drastic decline of the disease in Austria. Inactivated vaccines are now available for disease prevention  in a large number of  European countries.

Clinical features
Approximately two-thirds of TBEV infections are asymptomatic (Taba et al., 2017). Among the symptomatic cases, about 30% develop signs and symtoms of CNS inflammation. Clinically, European TBE takes a biphasic course in about 75% of patients, with flu-like symptoms during the first phase, a subsequent asymptomatic period without fever, followed by a second phase in which neurological signs and symptoms occur (Kaiser, 2008). The incubation period is about 7–14 days (range 2-28 days) after a tick bite but may be shorter after milk-borne transmission. The first viremic phase usually lasts for 2-7 days and is accompanied by fever, fatigue, headache and muscle pain.  The neurological phase with high fever may occur after an asymptomatic period of 2-10 days, and may include meningitis (50% of patients), meningoencephalitis (40% of patients), myelitis, radiculitis or any combination of these. The most severe form is meningoencephalomyelitis which affects approximately 10% of patients (Kaiser, 2008). Severely affected patients may show altered consciousness and a poliomyelitis-like syndrome leading to long-term disability. Other symptoms include central and peripheral pareses, cranial nerve paralysis, hypo- and hyperkinesias, epileptic attacks, speech disorders, cognitive deficits and psychotic symptoms. The most typical clinical sign is ataxia of the limbs (Kaiser, 2008). The meningitis form has a favourable prognosis, but with encephalitis the illness can be expected to last for weeks, and after myelitis the regression of the symptoms may take years and often remains incomplete. A post-encephalitic syndrome causing long-term morbidity has been identified in 35-58% of patients and may include various cognitive or neuropsychiatric complaints (ie, reduced stress tolerance, impaired ability to memorize), balance disorders, headache, dysphasia, hearing defects, and spinal paralysis. The severity of the disease increases with age and case fatality rate of European TBE is estimated to be 1-4% (Kaiser, 2008).

Biology of the infectious agents
TBEV is a member of the genus Flavivirus, within the family Flaviviridae and occurs in three subtypes, the European virus (previously CEE virus, Central European encephalitis virus, TBEV-Eu), the Far Eastern virus (previously RSSE virus, TBEV-Fe) and the Siberian virus (previously west Siberian virus, TBEV-Sib). TBEV-Eu is closely associated with Ixodes ricinus and TBEV-Fe and TBEV-Sib with I. persulcatus. The infection is transmitted transstadially in the ticks, and transovarial transmission is of limited importance. Larvae are therefore not considered to be an important source of human infections. Although the vectors can feed on a wide range of hosts the animal reservoirs of TBEV are limited. The majority are small mammals such as the rodents.  Birds appear to be incompetent reservoir hosts. Even in the recognised reservoir hosts the viraemic period seems to be short, so that relatively few ticks are infected via this systemic route. Most infections probably arise as a result of co-feeding transmission in which the virus transfers directly from infected to uninfected  ticks feeding in close proximity to each other (Labuda et al., 1993). This mode of transmission is thought to explain the rather patchy distribution of the infection within its geographical range, because the most efficient co-feeding transmission occurs where nymphal and larval tick activity coincides, and this in turn is determined by local climatic conditions (Randolph, 2000). Even within endemic areas the infection may be highly focal, in contrast to Lyme borreliosis. There is considerable debate at present on the possible influence of climate change on TBE incidence. Although increases in incidence have been reported over several years in some countries, part of this increase is probably due to demographic factors and it is not yet clear how climate change will influence the epidemiology of TBE in Europe (Randolph, 2010; Süss, 2011).

Diagnosis
During the first phase of illness, neutropenia, thrombocytopenia, and abnormal liver enzyme levels are observed in 10%-20% of patients. The second phase is characterised by a raised white blood cell count in about 75% of patients, an elevation of C-reactive protein in more than 80% of patients, and of the sedimentation rate in more than 90% of patients. The TBE diagnosis is confirmed by detection of specific  IgM and IgG  in serum, usually by using ELISA techniques.  However,  false positive reactivities with other flaviviruses occur, and a confirmatory test using a neutralization assay is  therefore recommended in cases with such potential exposure (e.g. yellow fever, Dengue, West Nile virus). Although TBE vaccination is considered to be highly effective vaccination failures occur in 1-6% of all TBE cases, especially in elderly patients and in those with incomplete vaccination series (Hanson et al., 2020).  The immunological response in previously vaccinated individuals is characterized by a delayed and/or weak specific IgM response and a rapid increse of IgG antibodies. Serological diagnosis in vaccination breakthrough TBE may be challenging and it is necessary to demonstrate intrathecal synthesis of TBEV-specific antibodies. In contrast to those with a moderate course of disease, patients with severe TBE display higher cell counts in the CSF and lower concentrations of neutralizing antibodies in serum. In severe cases, especially in immunocompromised patients, TBEV may be detected in cerebrospinal fluid (CSF) and PCR can therefore be a useful complementary tool to serology. However, a negative PCR result does not exclude TBE due to limited sensitivity.  Other tick-borne pathogens such as Borrelia burgdorferi sensu lato may also cause infections of the nervous system, and valid differentiation can only be made by serologic tests in both blood and CSF (Kaiser, 2008).

Treatment
No specific therapy for TBE exists and symptomatic treatment of patients is the only therapeutic option. Maintenance of water and electrolyte balance, sufficient caloric intake, and administration of analgesics and antipyretics and, if necessary, anticonvulsive agents are the most important components of effective clinical management of patients. Physiotherapy of paralyzed limbs is essential to prevent muscular atrophy (Kaiser, 2008).

Risk management
General measures to prevent tick bites, such as awareness of tick habitat, appropriate clothing, application of repellents etc can help prevent TBE , but rapid removal of ticks will not have the same impact as in preventing B. burgdorferi s.l, Babesia spp. and Anaplasma phagocytophilum, infection, since TBEV can be transmitted within hours of tick attachment rather than days. However, it is possible to vaccinate against TBE  and this is by far the most effective preventive measure for this disease. Inactivated vaccines are administered by intramuscular injection on three occasions,  preferably starting in the winter months before the tick season (Kaiser, 2008). The second dose is given between 1 and 3 months after the first vaccination, and the third dose between 5 and 12 months after the second vaccination. Rapid immunization schedules are also available and these differ slightly between manufacturers, the second dose being given one or two weeks after the first and the last after a gap of several months. However, inferior vaccine responses have been demonstrated with increasing age and immunosuppressive comorbidities which suggest that an extra priming dose could be beneficial for immunocompromised individuals and for those > 50 years of age (Hansson et al., 2020). In addition to residents, vaccination is recommended for travellers visiting highly endemic areas during the spring and summer months if extensive outdoor activities are expected.

References

1. Hansson, K.E., Rosdahl, A., Insulander, M., Vene, S., Lindquist, L., Gredmark-Russ, S., Askling, HH. 2020. Tick-borne encephalitis vaccine failures: A 10-year retrospective study supporting the rationale for adding an extra priming dose in individuals starting at age 50 years. Clin Infect Dis. 70(2):245-251.
2. Kaiser, R. (2008). Tick-borne encephalitis (TBE) in Germany and clinical course of the disease. Int. J. Med. Microbiol. 291 Suppl 33:58–61.
3. Kunz, C., Heinz, F.X. (2003). Editorial: tick-borne encephalitis. Vaccine 21, S1/1–S1/2.
4. Labuda, M., Jones, L. D., Williams, T., Danielova, V., Nuttall, P. A. (1993). Efficient transmission of tick-borne encephalitis virus between cofeeding ticks. J. Med. Entomol. 30, 295–299.
5. Randolph, S E. (2010). To what extent has climate change contributed to the recent epidemiology of tick-borne diseases? Vet Parasitol. 16792–4.
6. Randolph, S. E., Green, R. M., Peacey, M. F., Rogers, D. J. (2000). Seasonal synchrony: the key to tick-borne encephalitis foci identified by satellite data. Parasitology 121, 15–23.
7. Süss, J. (2011). Tick-borne encephalitis 2010: Epidemiology, risk areas, and virus strains in Europe and Asia—An overview. Ticks and Tick-borne Dis. 2, 2–15.
8. Taba, P., Schmutzhard, E., Forsberg, P., Lutsar, I., Ljostad, U., Mygland, Å., Levchenko, I., Strle, F., Steiner, I. 2017. EAN consensus review on prevention, diagnosis and management of tick-borne encephalitis. Eur J Neurol. 24(10):1214-e61.