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Tick-borne encephalitis (TBEV) in the dog

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  • Disciplina: Parassitologia
  • Specie: Cane

Tick-borne encephalitis (TBE) is an infection caused by an arbovirus called TBEV (Tick-Borne Encephalitis Virus). Arboviruses belong to different viral families that share the characteristic of being transmitted by arthropod vectors such as mosquitoes (Class Insecta) and ticks (Class Arachnida).1

TBEV belongs to the family Flaviviridae, genus Flavivirus; the genre includes about 70 different viruses.1 Flaviviruses transmitted by mosquitoes of the genus Aedes spp. and Culex spp. (mosquito-borne flaviviruses) include the viral species of the Japanese encephalitis group (Japanese Encephalitis Virus, Murray Valley Encephalitis Virus, St. Louis Encephalitis Virus, West Nile and Kunjin viruses), the viral species of the yellow fever group (Yellow Fever Virus and Wesselbron Virus) and finally of the Dengue virus group (Dengue haemorrhagic fever virus).1 The flaviviruses prevalently transmitted by ticks of the genus Ixoides spp. are the TBEV (with its European, Far Eastern and Siberian serotypes),2 the sheep encephalomyelitis virus (Louping Ill Virus)3 and the Powassan Virus.1 Flaviviruses are a cause of disease in humans and in other warm-blooded animals; the course of the disease is from acute to chronic and major gastrointestinal and/or neurological symptoms may be present.1

TBEV was first discovered by Schneider in Austria in 1931 as the virus responsible for "serous meningitis" in humans;4 the virus is endemic in central Europe, where it is known as TBE (Tick Borne Encephalitis) or FSME (Frühsommer-Meningoenzephalitis), and is considered responsible for neurological disorders in different regions of central Europe;5 the disease is characterized by the presence of neurological sequelae in approximately 40-50% of affected patients.6 In Italy, the situation is little known,7 however outbreaks in humans have been reported especially in the northeastern part of the country5,8and a case has been described in a dog returning from Hungary.9

The purpose of this article is to focus on the current understanding of TBEV, on the resulting clinical symptoms, its course in companion animals, clinicopathological laboratory findings, magnetic resonance imaging and pathologic findings. Furthermore, the Author will report on the experience gained with regard to prevention, treatment and long-term prognosis in dogs with tick-borne encephalitis (TBE).

 

AETIOPATHOGENESIS

The TBE virus is a spherical, neurotropic flavivirus, about 40-60 nm in diameter and surrounded by a phospholipid envelope. It contains a positive (infectious), single-stranded RNA that replicates in the cytoplasm.2 The RNA encodes a single polyprotein which is subsequently cleaved into three structural proteins and seven non-structural ones.2 The structural proteins are: protein C or capsid protein, protein M or membrane protein, and protein E, an envelope glycoprotein which determines its antigenicity2 and neuroinvasivity.10 The non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5) are responsible for the replication of viral RNA and for its cleavage.10 The virus takes its final form via budding from the endoplasmic reticulum.2

Virions are stable in an alkaline environment of pH 7-9; they are inactivated by an acid pH andtemperatures above 40°C and are labile to lipid solvents, ultraviolet light, ionic and non-ionic detergents, such as tripsin.1

Three subtypes of TBVE have been reported: the European, Far Eastern and Siberian. The three groups are distinguished in view of their morbidity, but have a 95% antigenic similarity which determines a strong cross-reactivity and cross-protection.11 The subtypes can be distinguished one from the other only by means of seroneutralization assays.1 Moreover, three additional serovariants of the European TBVE are present: A, B and Bavarian.

 

EPIDEMIOLOGY

The European TBEV virus is highly endemic in Central Europe. Clinical human cases of the disease are reported every year, as it is a notifiable disease in many European countries.12 In northern Europe, TBEV extends from the southern coasts of Sweden (where it is expanding) to Norway and Denmark; in the west it extends to Alsace-Lorraine; in the south to Switzerland, Austria, Greece and Turkey and in the east to Poland and the Balkan countries (Fig. 1. Regions of TBE risk 2013 BAXTER.) The Far Eastern subtype is present from the Urals to Japan and China. The Siberian subtype is present in Finland and Siberia (Fig. 2. Distribution of TBEV).

A map concerning the situation in Italy was made in 2009, correlating the number of confirmed human cases of TBE13 (Fig. 3. TBE in Italian Provinces) to the 1.0-2.5% prevalence of TBEV RNA in Ixodes ricinus ticks in the provinces of Veneto and Trentino Alto Adige;14 in 2012 a map on the annual incidence of TBE per 100,000 inhabitants was released by the European Centre for Disease Prevention and Control (Fig. 4. TBE incidence).5 Moreover, as an additional piece of information, in 2010, TBE antibodies were not detected in the sera of Forestry workers in the Lazio Region.15

 

The epidemiology of TBE is closely related to its natural vectors (ticks) and to the definitive hosts (such as mice, red deer and wild boar). Domestic ruminants may also serve as reservoirs, while horses and domestic canids, like humans, are dead-end (incidental) hosts. The typical course of TBE is biphasic, with peak incidence during the months of April/May and September/October, closely associated with the peak activity of the nymphs and larvae of Ixodesspp. In Europe, Ixodesricinus is the main vector of the European TBE virus (Dermatocentor and Rhipicephalus may also be involved); Ixodes persulcatus is the main vector of the Far Eastern and Siberian subtype; and Ixodes ovatus is the probable vector in Japan162 (Fig. 5. Tick distribution map).

Ticks can become infected through a blood meal (females) or through the uptake of extracellular fluid and of dermal cells (males) from the reservoir host. TBEV spreads among ticks via transtadial (larva, nymph, adult) or transovarial (adult, eggs) transmission, or by direct (by feeding on viraemic subjects) and indirect (feeding of non-infected ticks on skin areas in which simultaneously other infected ticks are feeding) contagion.1,16 Since males of Ixoides spp. survive a few years, they ultimately also serve as reservoirs.1 The definitive hosts of TBEV consist of a broad range of vertebrates that live in forested areas of central Europe, such as the wood mouse (Apodemus spp.), in which forms of asymptomatic viraemia are present and in which TBEV may also actively replicate itself in dermal cells.17 Roe deer (Capreolus capreolus) and domestic ruminants are poor amplifiers and rarely transmit the virus. Dogs, equines and humans are dead-end hosts and do not seem to be responsible for the transmission of the disease, despite the presence of a strong viraemia.16 The transmission through unpasteurized cow, goat or sheep milk is documented as responsible for human cases of foodborne TBE in endemic regions17 (Fig. 6. Diagram of the life cycle of TBEV).

In Europe, the seroprevalence of European TBEV in asymptomatic dogs as well as in wild or farm animals is not clear. In Greece, in the period 1977-1978, between 0.97 and 8.6% of dog sera tested positive for TBEV.18 In dogs around Zurich (Switzerland), positivity is found in 30% of the canine population.19 In Austria, in 1999, 24% of dogs resulted seropositive.20 In southern Norway, in 2004, 16.4% of dogs tested positive.21 In Denmark, the seroprevalence in dogs on the island of Bornholm is of 4.8%.22 In the surroundings of Leipzig (Germany), in 2014, the seroprevalence was of 2.8%. In Poland, the overall seropositivity stands at 12%, with a peak of 25% in the district of Mazowiecki, where TBEV is endemic in humans.23 The seroprevalence of TBEV in Italian dogs is currently unknown.

In horses, in the region of Marbug-Biedenkopf (Germany), in 2006, the seroprevalence was of 2.9%,24 while in Bavaria, in 2013, it amounted to 20-30% of the horses tested.25 In Austria, in 2011, the seroprevalence in horses stood at 26.1%.26

In farm animals, in Hungary, in 2009, the presence of an active outbreak of TBE was confirmed in the northeastern part of the country, with26.5% of the cattle resulting positive, as well as 7% of the sheep, while no horse resulted positive.27 In eastern Poland, the seroprevalence in cattle is of 4.7%, 16.8% in wild boar, and 11.6% in roe deer; the highest prevalence is observed in wild boar in the district of Chlem (35.7%).28 In Lithuania, in 2005, the overall prevalence tested in sheep was of 1.5%.29

 

PATHOGENESIS AND ANATOMOPATHOLOGICAL FINDINGS

TBEV infection can occur through two main routes: the bite of an infected tick or food-borne via ingestion of unpasteurized milk from viraemic animals. In our companion animals, tick-bite transmission is definitely the most common. The virus, spilled into the dermis through the regurgitation of endolymph during the tick’s meal, determines a first infection of dendritic or Langerhans cells, where it replicates.6 From here, the virus then reaches the tributary lymph node and the circulatory system via the lymphatic ducts.

The initial viraemia is associated with the presence of the virus in B and T cells.6 In humans, this viraemic stage is associated with general malaise and flu-like clinical signs; in the dog, objective findings during this phase are often lacking.20 The initial viraemic state is followed by an asymptomatic phase that lasts about 4-10 days.6,20 This phase is characterized by an increase in IgM and IgG, with neuroinvasion occuring in around 30% of infected subjects.6,10 Neuroinvasion occurs both through the penetration of the immune cells into the central nervous system as well as through the retrograde transport of the virus by means of motor fibres; trans-synaptic transmission is also possible, so as to elude the intrinsic immune system of the central nervous system.10 The neurotropism for particular nuclei of the medulla oblongata as well as for motor neurons, in the ventral horns of the spinal cord, explains the typical CNS symptomatology, characterized by a combination of meningitis and/or poliomyelitis and/or poliomyeloradiculitis and/or encephalitis.6,20

The histopathological findings, similar to those of other infections caused by flaviviruses,10 are characterized by: perivascular cuffing with lymphocytes, macrophages and some plasma cells; lymphohistiocytic meningitis; neuronophagia with microgliosis; neuronal karyorrhexis; microgliosis extended to the region that surrounds the fourth ventricle; but also the hippocampus, cerebral cortex, the basal ganglia, thalamus and medulla oblongata are affected in an important way.6,30,31The spinal cord is also extensively affected by meningitis; perivascular cuffing, neuronophagia with consequent axonopathy, microgliosis and the presence of Wallerian-likemyelin degeneration can be found especially in motor neurons of the ventral horn.30,31 The detection of infectious RNA in outbreaks of encephalitis and poliomyelitis is somewhat difficult in view of the very rapid viral clearance.2,6,20,30,31

 

CLINICAL SIGNS AND MRI FINDINGS

In the dog, similarly to humans, the clinical signs of TBEV infection are biphasic and four neurological courses are possible.20,30,32,33

The most common of these is the asymptomatic form, in which the dog only presents seroconversion not associated with overt symptoms; there is then a hyperacute form, which is often fatal within the first week, even in the absence of seroconversion; finally, there are the acute and chronic forms of the infection, which are correlated with the severity of the clinical symptoms.20

In humans,and in the dog, the incubation period of the disease ranges from 4 to 28 days, on average 4-7 days.6.34 The initial viraemia is associated with a flu-like prodromal phase, with temperature rise, lethargy, nausea and gastrointestinal symptoms which are however reported by the owner only in 10% of cases.30,35 In the experience of the Author, in 25% of cases owners report the presence of ticks in the month prior to the onset of symptoms.36 In the initial stages, viral RNA may be detected in the blood, and it is possible to detect the presence of leucopenia, thrombocytopenia and of a slight increase in liver enzymes with, however, the absence of specific antibodies.6 This phase, which continues for a few days, is then followed by an asymptomatic phase of variable duration (2-10 days in humans).6

The neurological form20,35 is accompanied by the presence of symptoms such as fever (60%), altered state of consciousness (54%) and neck hyperalgesia (21%). Dogs may often exhibit mild vestibular ataxia, proprioceptive deficits, altered menace response, marked weakness of the neck (a quite frequent finding in the experience of the Author), reduced reflexes, especially of the forelimbs. In rare cases (12%), the onset may be characterized by single seizures or, even less frequently, by status epilepticus (around 5%). A breed predisposition has been reported for the Rottweiler.20,33In the case series of the Author the frequency in the Rottweiler and Newfoundland is high, as in the case series described by Reiner.33

In most cases, clinicopathological findings detect peripheral leukopenia or leukocytosis.35 Cerebrospinal fluid analysis reveals an elevated cell count in 100% of cases (9-56.666 cells/µl, normal <4 cells/µL). Activated lymphocytes (70%), mononuclear cells (24%) and neutrophils (6%) are normally found in the cerebrospinal fluid cytology. Total proteins are elevated in 90% of cases. In all cases in which the cerebrospinal fluid is drawn during the acute/chronic form of the disease, immunoglobulins for TBEV may be detected. While the detection of immunoglobulins for TBEV in the serum is not strictly correlated with the presence of the disease,19,37 their detection in the cerebrospinal fluid is strongly suggestive of an ongoing infection.20,37,33 Should the disease be detected in subjects residing outside areas known to be endemic and who have not spent holiday periods in such areas, a positive ELISA should always be confirmed with a serum neutralization test (currently the gold standard for confirmation of the serological diagnosis).37

Electrophysiological findings are correlated with the clinical symptoms. In most subjects with flaccid paralysis a spontaneous muscle activity with fibrillation potentials and positive sharp waves may be detected. In the presence ofmarked neuromuscular weakness the neck muscles are often involved. These findings are present already 4-5 days after the onset of the first signs of the disease. Motor nerve conduction examinations detect the presence of a temporal dispersion of the M-wave and a general slowdown in nerve conduction velocity associated with an alteration of the F-wave. This to underline the primary involvement of the lower motor neurons and of the ventral nerve roots and the consequent demyelination observed in histological preparations.

In humans, magnetic resonance imaging (MRI) allows the detection of definite signs of injury in only 15-30% of cases.6.38 In the dog, the percentage is similar (in the experience of the Author) and the likelihood of detecting anatomical alterations is probably directly related to the duration of the symptomatology. The most common neuroimaging signs are a generally symmetrical T2 hyperintensity compared to the rest of the parenchyma and T1 hypointensity relative to the rest of the parenchyma in sequences of the thalami31.38 and ventral horns of the spinal cord, especially in the cervical spine31,38 (Figs. 7a and b, 8). There is no contrast uptake by these lesions, or only minimally by the meninges.

The clinical course varies, but in the first week the mortality rate is high;20,36 overall, 52% of the dogs survive.36 The complete remission of lower motor neuron signs can take up to 6 months-1 year.20,36 The presence of cranial nerve paralysis or of vestibular ataxia is associated with a greater probability of cure.36 Long-term neurological sequelae, such as muscle weakness (persistent neck flexion or accentuated lordosis of the back), reluctance to move and proprioceptive deficits are observed in just under half of survivors (45%).36 These neurological sequelae are similarly present also in humans.6

 

TREATMENT

Therapies are ineffective; the use of corticosteroids has no impact on prognosis6,20,33,36 and their administration may in fact  even worsen the neurogenic muscular atrophy, delaying a possible improvement. In the experience of the Author, the necessary measures to be taken are the use of non-steroidal anti-inflammatory drugs to lower the body temperature, the use of antibiotics in case of concomitant infections (such as aspiration pneumonia, cystitis, dermatitis), regular physiotherapeutic activity, bladder catheterization or manual emptying three to four times a day, associated with constant nursing care to ensure that TBEV-infected subjects may regain a good quality of life as fast as possible.

In the experience of the Author,dogs regain autonomy in the management of major organ functions in the first 2-4 weeks.

In subjects with seizures, the use of anti-epileptic medications is always necessary and to be maintained for the entire life of the subject. In rare cases, suspension of the anti-epileptic medication can be attempted in the first year after diagnosis, but the data available to the Author are not such to recommend this practice in all subjects. In the dog, anti-TBEV IgG antibodies remain in the blood for at least 9 months,20 and in large animals for even up to 28 months.39

 

PREVENTION

The most successful prevention strategy consists in reducing tick infestation. In Austria, the regular use of repellent agents has not currently resulted in a real reduction in the incidence of the infection in dogs;40 however, based on our current state of knowledge, the regular and appropriate use for these products is the only approach available. Several TBEV vaccines are present on the market for human use; none of these have ever been experimented in the dog. Some experimental studies have been performed in sheep, goats and horses, with induction of an immune response.39 Unfortunately, no study has been done on the actual protective efficacy of these vaccines against street viruses.

 

CONCLUSIONS

In the dog, TBEV infection is often asymptomatic, just as in humans. When it occurs, it is characterized by the acute onset and the progression of neurological signs. These are often associated with a form of encephalitis and a progressive flaccid-type paralysis. The prognosis, in spite of what was known until about ten years ago, is not necessarily poor. 52% of the animals survive and regain an acceptable quality of life. As in humans, neurological sequelae are common. When dealing with a dog with symptoms of encephalitis and who visited an endemic area for TBEV in the prior month, the finding of typical MRI lesions and the detection of seroneutralizing antibodies in the cerebrospinal fluid may confirm the clinician’s suspected diagnosis.

 

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