TICK-BORNE ENCEPHALITIS

Herbert Weissenb ock

Pathology and Forensic Veterinary Medicine, Department of Pathobiology, University of Veterinary Medicine, Vienna, Austria

Tick-borne encephalitis is a flaviviral nervous system disease of humans, which sporadically also affects several animal species and for which wild mammals serve as res­ervoir hosts.

AETIOLOGY

Tick - borne encephalitis virus (TBEV) belongs to the family Flaviviridae, genus Flavivirus. The species of TBEV is grouped into three subtypes: the European, the Far Eastern and the Siberian subtypes¹-²⁶’²⁷). This assignment is based on their shared pathogenicity for humans rather than on genomic similarities. A different classification ofTBEV has been proposed according to genome sequence data, which includes the assignment of tick- borne encephalitis and louping-ill viruses to the same species (TBEV), of which there are four viral types (Louping-ill virus, including Spanish, British and Irish subtypes; Western tick-borne encephalitis virus (W-TBEV); Eastern tick-borne encephali­tis virus (E-TBEV) including far eastern and Siberian sub­types; and Turkish sheep encephalitis virus, including the Greek goat encephalitis virus subtype)(²⁸). Louping-ill has already been described in this chapter.

EPIDEMIOLOGY

The distribution range of W-TBEV is from the Urals in Russia to the Alsace region in France, Scandinavia in the north and parts of the Mediterranean areas along the Adriatic coast to the south. The far eastern subtype is distributed from the Baltic countries to northeastern China and northern Japan, and the Siberian subtype is found in Siberia and the Baltic states. Thus, in parts of the Baltic states the three virus types occur simultaneously. TBEV is not a primary cause of clinical disease in wildlife, but it has a considerable pathogenic potential for humans.

For efficient transmission, the virus must be capable of multiplication within the vector. The vector then carries the pathogen to a range of hosts that play different roles within natural foci. The principal vector of W-TBEV is the tick Ixodes ricinus, and there is an overlap in the dis­tribution pattern of this tick species and W-TBEV. In the European part of Russia and in Asia, I. persulcatus is the most prevalent vector, which is correlated with the pres­ence of the E-TBEV strains.

Reservoir hosts of TBEV are small mammals, such as yellow-necked mice (Apodemus flavicollis) and bank voles (Clethrionomys glareolus). Infected ticks, by the mecha­nism of trans- stadial transmission, remain virus carriers for their entire life and are the most important source of virus. The most relevant transmission event between ticks seems to be co-feeding of several ticks of different devel­opmental stages on one reservoir host. By this mechanism infected tick nymphs are able to transmit the virus to non- infected larvae, which take their blood meal on the same host. Viraemia of the host is not a prerequisite, because the infection occurs by means of infected skin cells. The small mammal hosts have evolution-based adap­tation to the virus and do not develop disease. Indicator hosts of TBEV are humans and wild animals larger than rodents, such as hares (Lepus europaeus), roe deer ( Capreo- lus capreolus), foxes (Vulpes vulpes) and wild boar (Sus scrofa). These species become infected accidentally, and although they are not able to transmit the virus back to feeding ticks, they support virus circulation by enabling the ticks themselves to survive and reproduce. These species become infected with TBEV and show seroconver­sion; thus in endemic areas seroprevalence in large wild mammals can be used as indicators for TBEV transmis­sion within a geographical region. Wild birds are acciden­tal hosts of TBEV.

Transovarial transmission in ticks has been demon­strated experimentally. This, as well as the vertical trans­mission by small mammals to their offspring, does not seem to play a major epidemiological role in the transmis­sion of TBEV. TBEV is mainly transmitted by infected ticks, but transmission by unpasteurized milk or milk products from clinically inapparently infected sheep and goats has been repeatedly described.

Seroprevalence between 14% and almost 50% in small mammals and of 10% in large mammals has been shown in different endemic areas in Austria and Germany. In an endemic area in Russia, viral nucleic acid was recovered by RT-PCR in 58% of investigated Sorex araneus shrews, 44% of Clethrionomus rutilus and 20% of Apodemus agrarius mice³³'.

PATHOGENESIS, PATHOLOGY AND IMMUNITY

Experimentally, the pathogenesis of TBE is characterized by initial viral replication in endothelial cells and macro­phages at the site of the tick bite, followed by transport of the virus to the lymphatic system and viraemia. At this stage, the virus attains access to the nervous system, where it replicates in neurons, leading to their necrosis, and initi­ates an inflammatory response.

Little information is available on the pathology of natural TBE in wild animals.

A euthanized mouflon ( Ovis ammon musimon) found moribund in a hunting reserve in eastern Austria had a severe infestation with I. ricinus and neuropathological examination revealed a marked non-suppurative lep- tomeningoencephalitis, with the most severe inflamma­tory changes in the brainstem. Characteristic histological features were neuronal necroses with accompanying neu- ronophagic areas, diffuse microglial activation and numer­ous lympho-histiocytic perivascular cuffs (Figure 9.6).

A Barbary macaque (Macaca sylvanus) from a group of about 200 animals in a large, outdoor enclosure of a monkey park in a TBE-endemic area in southern Germany

FIGURE 9.6 Severe non-suppurative encephalitis characterized by perivascular cuffs consisting of lymphocytes and monocytes. TBE, mouflon, haematoxylin and eosin.

FIGURE 9.7 TBE viral antigen can be demonstrated as brown reac­tion products in the cytoplasm of neurons and in neuronal processes. Mouflon, IHC.

showed staggering paresis of the hind legs, incoordination and intermittent opisthotonos. Four days after the onset of clinical signs, the animal became comatose and was eutha­nized. Histologic examination of the brain showed moder­ate perivascular inflammatory cuffs and mild diffuse infiltration of brain parenchyma with mononuclear cells in almost all brain areas, including basal ganglia and cerebel­lum. In addition, mild mononuclear inflammatory infil­trates were present in the meninges. Single neuronophagias were also observed. Microglial nodules were not detected. IHC demonstrated viral antigen in several neurons and their processes, including Purkinje cells of the cerebellar cortex and pyramidal neurons of the temporal cortex. Genetic analysis of the entire genome of the isolated TBEV strain showed a typical member ofthe W-TBEV subtype (³⁴).

There are no reports of clinical disease and pathological changes in wild rodents. Experimentally infected labora­tory mice show extensive neuronal necroses and encephalitis.

CLINICAL SIGNS

Clinical disease and death due to TBE have been recorded infrequently in domestic animals (dogs, horses, goat, sheep).

DIAGNOSIS

Diagnostic tests for TBE are comparatively straightforward in dead animals but more challenging in clinical samples from living animals. In dead animals, there are neuropatho- logical findings consistent with an infection with a neu­ronotropic virus, accompanied by the presence of antigen in neurons. In addition, TBEV can be isolated or amplified by RT-PCR from samples of the nervous system. Confir­mation of TBE in animals with transient or no clinical signs depends on the detection of viral genome and, more importantly, of specific antibodies. Viral isolation or RT- PCR from either blood or cerebrospinal fluid (CSF) plays a minor role in TBE diagnostics, because the virus is usually cleared from the blood before the onset of CNS clinical signs. Thus, diagnostic assays are mainly based on the detection of specific antibodies. As a rule, TBEV immunoglobulin M (IgM) and usually TBEV IgG anti­bodies are present in the first serum samples taken when CNS signs become manifest. Intrathecal IgM and IgG antibody response can be detected in CSF, but several days later than in serum. Enzyme immunoassays are usually used for specific serodiagnosis. Also haemagglutination inhibition is widely used, but it measures all antibody classes and requires a rise in antibody titre for definitive diagnosis. Because of high cross-reactivity of the antigenic structure in the flavivirus, possible diagnostic difficulties could arise in areas where other flaviviruses co-circulate (e.g. West Nile virus). In such cases, neutralization tests for the confirmation ofTBEV specificity of the antibodies are needed⁽³⁶⁾.

MANAGEMENT, CONTROL

AND REGULATIONS

The vaccines against TBE are only licensed for use in humans and not for animals.

PUBLIC HEALTH CONCERN

The risk of acquiring TBE is correlated with the likelihood of tick exposure; thus the infection rate in endemic areas is higher in those individuals who have more frequent outdoor activities. The infection rate within the popula­tion of a country in which TBE is endemic can be mark­edly reduced by vaccination programmes. This has been shown in Austria, where a large percentage of inhabitants are vaccinated against TBE.

Apart from Japanese encephalitis virus, TBEV is the encephalitogenic flavivirus with the most severe impact on human health in Europe and Asia. Each year it is respon­sible for several thousands cases of encephalitis in humans, and the fatality rate is significantly higher with the eastern subtypes (up to 20%), than with the western subtype (approximately 1%).