Tick-borne viral encephalitis in adults: clinical guidelines

List of Abbreviations

IVIG – intravenous immunoglobulins

WHO – World Health Organization

TBEV – tick-borne encephalitis virus

GCS – Glucocorticosteroids

DEET – diethyltoluamide

DNA – deoxyribonucleic acid

Dr. Med. Sci. – Doctor of Medical Sciences

EIA – enzyme immunoassay

Cand. Med. Sci. – Candidate of Medical Sciences

CT – computed tomography

TBE — tick-borne encephalitis

PT – physical therapy

Ministry of Health of the Russian Federation – Ministry of Health of the Russian Federation

ICD – International Classification of Diseases

NSAIDs – nonsteroidal anti-inflammatory drugs

Complete blood count (CBC)

PCR – polymerase chain reaction

NT – neutralization test

RNA – ribonucleic acid

LP – lumbar puncture

US – ultrasound examination

CNS – central nervous system

EEG – electroencephalography

IgG – immunoglobulin G

IgM – immunoglobulin M

Th1 – type 1 T-helper lymphocytes

TBEV – Tick-borne encephalitis virus

Terms and Definitions

Alimentary mechanism of infection transmission – a mechanism of infection transmission in which the pathogen enters a susceptible organism through the mouth, mainly through the consumption of raw milk from cows and goats (alimentary route).

Viremia – a medical term denoting a condition in which viruses enter the bloodstream and can spread throughout the body.

Incubation period – the time interval from the moment the pathogen enters the body until the onset of disease symptoms.

Cerebrospinal fluid (Latin: *liquor cerebrospinalis*, spinal fluid, CSF) – fluid that constantly circulates in the cerebral ventricles, cerebrospinal fluid pathways, and the subarachnoid space of the brain and spinal cord.

Vector-borne mechanism of infection transmission – a mechanism of infection transmission in which the infectious agent is present in the circulatory system and lymph, and is transmitted through the attachment of specific and non-specific vectors: blood-sucking arthropods (insects or ticks). It is necessary for the vector to transmit the pathogen directly from the source of infection to a susceptible organism.

Encephalitis (Latin: *encephalitis* – inflammation of the brain) – a group of diseases characterized by inflammation of the brain.

Natural focal diseases are a clearly defined group of diseases characterized by specific features of the epidemic process. These are diseases of wild animals whose pathogens possess polypathogenicity and can be transmitted to humans, causing illness.

Natural focus of disease – a territory of a specific landscape where susceptible warm-blooded vertebrates, the pathogen, and vectors are present, and where, under favorable environmental factors, the circulation of the pathogen takes place. Natural foci exist independently of humans. A natural focus may contain pathogens of several diseases, as well as various species of animals susceptible to these diseases.

Anthropurgic foci (human-made) are foci acting as components of natural foci in areas developed by humans within cities, villages, and other settlements.

Virusophory (vector infection rate) – a quantitative expression of the virus infection rate in a vector population over a given period of time.

Isolates (microbiol.) – a culture of viruses or other microorganisms isolated from a specific source.

Cytokines – a group of polypeptide mediators involved in the formation and regulation of the body's defense responses (interleukins, interferons, colony-stimulating factors, chemokines, transforming growth factors, etc.). The main properties of cytokines that unite them into an independent regulatory system include pleiotropism and interchangeability of biological action, the predominantly inducible nature of synthesis, the absence of antigenic specificity of action, self-regulation of production, and the formation of a cytokine network.

Microglia – a specialized type of glial cells in the central nervous system that perform phagocytic functions and play an important role in the immune response and the maintenance of homeostasis in the brain.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Tick-borne encephalitis – a natural focal viral infection characterized by fever, intoxication, and damage to the gray matter of the brain (encephalitis) and/or the meninges of the brain and spinal cord (meningitis and meningoencephalitis) [1].

Human infection occurs via a vector-borne route through the attachment of virus-carrying ticks. Alimentary transmission of the infection is possible through the consumption of raw milk and dairy products from infected goats and cows [2].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Tick-borne encephalitis virus (TBEV) belongs to the genus *Flavivirus* (group B), which is part of the Togaviridae family within the ecological group of arboviruses [3–5].

According to modern concepts, within the nosoarea, there are three main subtypes of TBEV—the causative agent of this infection: Far Eastern, European (or Western), and Siberian. In recent years, two more putative TBEV subtypes have been described: Baikal and Himalayan. Genotypes 4 and 5 are represented not by groups, but by single strains—178-79 and 886-84. All strains of this group were isolated in Eastern Siberia, in areas where severe forms of TBE are registered, and they meet the criteria for isolation into separate genotypes established on the basis of the degree of genomic differences. According to literature data, genotype 1 (Far Eastern subtype) is found everywhere in the territory of the Russian Federation, but predominates in the Far East. In Europe outside the Russian Federation, genotype 1 strains have not been detected. Genotype 2 strains (European subtype) are detected mainly in foreign Europe, the Central and Northwestern parts of Russia, the Altai, the Urals, and rarely in Eastern Siberia; they are not found in the Far East. The most genetically heterogeneous and geographically widespread is the Siberian genotype. The Siberian subtype of the TBE virus differs from the Far Eastern and European subtypes by the presence of the amino acid leucine (Leu, or L) at position 206 of the E gene. At position 234 of the E gene, strains of the Siberian genotype also have marker amino acids: histidine (His, or H) or glutamine (Gln, or Q), which divides them into two subgroups (Asian and Eastern European) with prototype strains Vasilchenko and Zausaev. It has been established that the Siberian subtype of TBEV has been stably circulating in Eastern European regions since 1943, and in the Urals and Siberia since 1960 [6, 20].

TBEV virions are spherical in shape with a diameter of 50–60 nm. The internal component is the nucleocapsid. It is surrounded by an outer lipoprotein envelope in which spikes are embedded, consisting of a glycoprotein with hemagglutinating properties. The nucleocapsid contains single-stranded RNA [5].

The virus persists for a long time at low temperatures (optimal regime minus 60°C and below), tolerates lyophilization well, remains viable in a dried state for many years, but is rapidly inactivated at room temperature. Boiling inactivates it within 2 minutes, and in hot milk at 60°C, the virus dies within 20 minutes. Formalin, phenol, alcohol and other disinfectants, as well as ultraviolet radiation, also have an inactivating effect.

TBEV is most often transmitted by ticks of the species I. persulcatus and I. ricinus. In some foci, TBEV is transmitted by H. concinna, D. silvarum, D. pictus ticks, etc. [10]. It is believed that up to 14 more tick species are carriers of the virus in nature, but their epidemic role is small [5, 9]. The main reservoir of the virus in nature is its main vectors—ixodid ticks [10]. The possibility of transovarial transmission of TBEV maintains a constant level of virus-carrying capacity in these arthropods. An additional natural reservoir of the virus consists of the hosts of infected ticks: numerous rodents (field mouse, chipmunk, hare, etc.), other wild and domestic animals, and birds. In nature, the virus is maintained by constant circulation through a closed chain: ticks – hosts (animals) – ticks [5]. Human infection with TBEV is a biological dead end, since the virus is not transmitted further to another organism and exits natural circulation [7, 11].

TBE is characterized by a strict spring-summer seasonality of morbidity, associated with the seasonal activity of the vectors [7, 11, 12].

Human infection with TBEV occurs during the blood-sfeeding of hungry virus-carrying ticks. Sexually mature individuals (imagoes) are of the greatest epidemiological importance in the transmission of TBEV to humans, while the nymphal stage of metamorphosis of ixodid ticks is of lesser importance. Upon full engorgement, while feeding on reservoir hosts, the female ixodid tick increases in size by 80–120 times. It has now been proven that TBEV replication occurs in the body of feeding vectors; therefore, the virus infection rate of ticks removed from the population is always higher than that of ticks removed from forest biotopes of endemic regions [13]. Blood-feeding of males usually lasts several hours and sometimes goes unnoticed. TBEV transmission can occur in the first few minutes of a virus-carrying tick attaching to a human.

The alimentary route of infection is also observed when consuming raw, virus-containing milk from infected goats, cows, and sheep [3, 11].

Removal of the tick while preserving the "cement plug" containing the virus apparently does not completely eliminate the transmission of infection. When a tick attaches, the virus replicates at the site of introduction (in vascular endothelium, subcutaneous tissue), and a local limited inflammatory reaction develops (hyperemia, edema, tissue necrosis). During the local reaction, vasodilation occurs, facilitating the spread of viruses [4, 9].

12–18 hours after attachment, the virus enters the bloodstream; this is the first wave of viremia, which is short-lived and called resorptive. Then the virus penetrates into the tissues of the reticuloendothelial system (RES), where it multiplies. This corresponds to the incubation period of the disease (there are no clinical manifestations) [9].

Dissemination of the virus in the body occurs via lymphogenic, hematogenous, and perineural pathways. The onset of meningeal and meningoencephalitic syndromes occurs during hematogenous spread of the pathogen, while poliomyelitic syndromes occur via lymphogenic spread. Damage to the nervous system is possible via centripetal neural spread of the virus through the olfactory tract without a viremic stage.

TBEV is tropic to many body tissues, but its preferred localization is the nervous system. The wide dispersion of the virus throughout the CNS leads to a rapid development of an inflammatory process in the nervous system, with a certain concentration in the brainstem and the cervical spinal cord.

The meninges may act as a barrier along the path of viral progression. The blood-brain barrier (BBB) plays a crucial protective role. Currently, the morphological organization of the BBB, including several levels of cellular systems, has been theoretically and experimentally substantiated. The first level is a dual-membrane layer of endothelial cells, the second is the basement membrane with fibrillar and cellular components (pericytes), and the third is the astrocytic sleeve, covering 85–90% of the BBB surface and formed by astrocyte processes. The BBB endothelium separates the blood and the neural tissue of the brain, which differ both morphologically and functionally [9].

When overcoming protective barriers, the virus can affect:

– the meninges;

– the cerebral cortex;

– the basal ganglia;

– the cerebellar cortex;

– the motor nuclei of the medulla oblongata;

– the pons;

– the most intense damage occurs in the motor neurons of the spinal cord.

Thus, when multiple CNS structures are affected, morphologically TBE represents a panencephalomyelitis (affecting all levels of the CNS) [5].

It is hypothesized that the heterogeneity of the antigenic properties of TBEV subtypes may determine the predominance of a particular pathway of entry into the CNS. The replication process of TBEV in the CNS occurs predominantly in nerve cells, both in neurons and glial cells. Viral reproduction is accompanied by the breakdown and reduction of cell organelles and cytoplasmic vacuolization, which is subsequently followed by cell destruction with the release of organelles and the virus into the intercellular space. In addition to cytopathic mechanisms of neuronal death, virus-induced apoptosis is also observed [14, 15, 16].

A leading role in the chain of pathophysiological processes is played by pathogen-induced reactions that implement immune and inflammatory mechanisms. In response to the introduction of the virus, cellular immunity systems are triggered, during which macrophages, natural killers, and antigen-specific cytotoxic T-lymphocytes are activated, and cytokines are released in response to the antigen. Upon activation of humoral immunity, antibodies are synthesized by B-lymphocytes in blood plasma in response to the appearance of foreign antigens [9, 17-19].

In TBE, specific antibodies are produced very early, but they cannot cross the blood-brain barrier, and viral persistence may continue.

Cellular immunity (T-lymphocytes, including type 1 and type 2 T-helper cells) plays the primary protective role. On this basis, T-helper cells have been termed the "conductors of the immune response". Type 1 T-helper cells (Th1) produce (secrete) IL-2, gamma-interferon (γ-IFN), and other pro-inflammatory cytokines with antiviral activity. Cytokines secreted by Th1 cells activate macrophages, which, upon activation, also produce pro-inflammatory cytokines, enhancing the inflammatory process, which contributes to the destruction of intracellular pathogens.

An active cell-type immune reaction leads to the elimination of the virus. However, on the other hand, the virus leads to damage of lymphoid tissue and suppression of defense mechanisms. Thus, a secondary immunodeficiency is formed, against the background of which the inflammatory reaction in the CNS progresses [7].

Early imbalance in Th1/Th2 cytokine production, directed toward Th2 cytokines, is a serious prerequisite for the formation of pronounced immunosuppression, which leads to the development of focal forms of TBE [19]. Studies by Doctor of Medical Sciences E.A. Kvetkova also noted that TBE in the acute period of the disease is in most cases accompanied by pronounced T-cell deficiency, the depth of which directly correlates with the severity of the clinical course [18].

Thus, immunogenesis determines the differences in the forms of the clinical course of TBE; therefore, prognostically unfavorable factors include T-lymphocyte deficiency, prolonged circulation of IgM class antibodies, and the absence or low titer of IgG class antibodies. After recovering from the disease, immunity persists, the duration of which depends on many factors, in particular, the patient's immune status.

In the pathogenesis of the chronic course, two main processes are important: viral persistence with the preservation of pathogen replication against the background of virus-induced or genetically determined immune mechanism disorders, and the development of reactive and autoimmune processes. Molecular biology methods have proven the integration of the TBEV genome into the brain cell genome and its long-term persistence for many years. TBEV exhibits pantropic properties and persists in the same parts of the CNS and lymph nodes where it multiplies in the initial period during the visceral and neural phases of pathogenesis. Currently, viral persistence has been proven against the background of pronounced humoral immunity, which is based on the mechanism of disruption of the final stages of virion assembly and impairment of the natural seroconversion mechanism. The prolonged presence of the virus generally forms a latent course of infection occurring without replication and cytopathic effects. The preservation and spread of TBEV in the patient's CNS occur as a result of its replication, during the division of infected cells, and via intercellular contacts. Currently, the ability of strains belonging to two subtypes (Siberian and Far Eastern) to cause a chronic process has been proven [6, 20].

1.3 Epidemiology of the Disease or Condition

In 2022, the incidence rate of TBE in the Russian Federation increased by almost 2 times compared to the previous year, reaching 1.34 per 100,000 population (in 2021 – 0.69 per 100,000 population). The disease was registered in 48 constituent entities, with 60 deaths, which is 43 more than in 2021 [21]. The bulk of cases occur in the Ural, West Siberian [22], and East Siberian regions. These regions account for 93% of all TBE cases in the Russian Federation. Recently, TBE cases have also begun to be detected among the population of previously safe areas regarding this infection, such as the Penza, Yaroslavl, and Magadan Oblasts, Kamchatka Krai, the Komi Republic, and other territories. Recently, the incidence of TBE has been more frequently registered among the urban population. The distribution range of TBE vectors has expanded to urban areas (parks, public gardens, cemeteries, new residential areas). The number of patients with chronic TBE is still not officially registered [11].

Of the total number of TBE patients, up to 75–80% are urban residents, whose infection occurs in anthropurgic foci (suburban areas) during trips for household reasons related to gathering mushrooms and berries, work and recreation in nature, and country dachas. Tick bites in humans can occur not only in the forest but also at home. Ticks are brought into the house on work clothes, with pets, bouquets of wildflowers, etc. Ticks may also crawl between passengers in city transport. Recently, the increase in TBE incidence in Russia is likely associated not only with the growth of the non-immune urban population frequently contacting nature, but is also explained to some extent by the increase in the infection rates of ticks with the virus [11].

1.4 Features of Coding the Disease or Condition

A84 Tick-borne viral encephalitis

А84.0 Far Eastern tick-borne encephalitis [Russian spring-summer encephalitis]

А84.1 Central European tick-borne encephalitis

А84.8 Other tick-borne viral encephalitis

А84.9 Tick-borne viral encephalitis, unspecified

1.5 Classification of the disease or condition

There is no universally accepted clinical classification of TBE. The "Methodological Guidelines for the Clinic, Diagnosis, and Treatment of Tick-Borne Encephalitis" contain the latest revision of the classification of the acute period of TBE, along with the Methodological Guidelines "On the Laboratory Diagnosis of Tick-Borne Encephalitis" and "On the Epidemiology and Prevention of Tick-Borne Encephalitis".

The classification of the acute period of TBE is presented by A.P. Jerusalimsky in the form of the following clinical forms [17]:

1. Febrile;

2. Meningeal;

3. Meningoencephalitic (focal or diffuse);

4. Polioencephalitic;

5. Polioencephalomyelitis;

6. Poliomyelitic;

7. Biphasic course indicating the form of the second wave.

Comments: We believe that the polyradiculoneuritic form, previously included in the TBE classification, is currently more likely attributable to tick-borne borreliosis, which is widespread in the Russian Federation. From a modern perspective, the classification could be supplemented by the inclusion of the inapparent form of TBE. This form, referred to in the literature as latent or subclinical, is defined by the absence of clinical manifestations accompanied by the detection of viral RNA in the blood via PCR, viral antigen, or specific antibodies via ELISA. This exact form occurs in the vast majority of primarily infected individuals, determining the main pathway of "pro-epidemicization" and immunity formation. Sometimes undetected forms of the infection may result in prolonged viral persistence with the subsequent development of a primary and secondary progressive course. The rationale for identifying the inapparent form of the disease is supported by the possibility of specific prevention and the prediction of an unfavorable TBE course.

All clinical manifest forms are generally divided into focal and non-focal. Non-focal forms include the febrile and meningeal forms, while focal forms include meningoencephalitic, polioencephalitic, polioencephalomyelitis, and poliomyelitis forms. Depending on the severity, mild, moderate, and severe forms are distinguished; depending on the course, acute, progressive, and chronic forms are identified.

Among the numerous classifications of chronic TBE, the most comprehensive one that reflects all variants of its course is the classification by K.G. Umansky, V.N. Kovalenko, A.V. Subbotin, and E.P. Dekonenko (1984).

Classification of chronic forms of tick-borne viral encephalitis [1, 23, 24]

1. Clinical forms

1.1. Hyperkinetic (syndromes: Kozhevnikov's epilepsy, myoclonus-epilepsy, hyperkinetic);

1.2. Amyotrophic (syndromes: poliomyelitis, encephalopoliomyelitis, disseminated encephalomyelitis, amyotrophic lateral sclerosis);

1.3. Rare syndromes not belonging to forms 1.1 and 1.2.

2. Syndrome severity

2.1. Mild (ability to work preserved);

2.2. Moderate (disability group 3);

2.3. Severe (disability groups 1 and 2).

3. Time of onset of the chronic process

3.1. Initial progressive (direct continuation of acute TBE);

3.2. Early progressive (occurs within the first year after acute TBE);

3.3. Late progressive (occurs a year or more after acute TBE);

3.4. Spontaneous progressive (occurs without a distinct acute TBE).

4. Nature of the course of chronic TBE

4.1. Relapsing;

4.2. Continuously progressive;

4.3. Abortive.

5. Stages of the disease

5.1. Initial;

5.2. Escalation (progression);

5.3. Stabilization;

5.4. Terminal.

1.6 Clinical presentation of the disease or condition

Clinical manifestations of TBE are characterized by marked polymorphism, which is due to the neurotropic, viscerotropic, and angiotropic properties of the virus and its ability to undergo prolonged persistence [25, 26].

The disease is characterized by an acute, sometimes sudden onset with a rapid increase in general infectious, cerebral, meningeal, and less frequently focal symptoms, as well as a sequential manifestation of pathological symptoms (staging).

Staging corresponds to the following phases of disease development in the acute stage [4]:

• first – stage of infection;

• second – incubation period;

• third – prodromal period;

• fourth – febrile period;

• fifth – early convalescence period;

• sixth – recovery period.

The propensity of TBEV for prolonged persistence determines the development of chronic progressive forms of the disease.

Incubation (post-exposure) period (from the moment of tick attachment to the onset of the disease) ranges from 1 to 35 days, in most cases 7-12 days [4, 27]. There is a clear correlation between the duration of the incubation period, the clinical form, and the severity of the TBE course. The shorter the incubation period, the more severe the disease course [7, 17]. A longer incubation period is recorded in patients who received tick-borne encephalitis immunoglobulin for post-exposure prophylaxis**.

In some patients, the onset of the disease is preceded by a short prodromal period manifested by weakness, malaise, body aches, and headache [4]. In most cases, the prodromal period goes unnoticed. The disease begins acutely with the appearance of chills, severe headache, dizziness, fever up to 38-39˚C, nausea, and vomiting [27]. Simultaneously, pain occurs in the neck, back, lumbar region, and limbs. Fibrillation and fascicular twitching in isolated muscle groups may also be observed during this period. Almost concurrently, general muscle weakness appears, along with a sensation of numbness, most commonly in a single limb without visible signs of motor disorders. Typical signs of meningeal irritation appear in the form of nuchal rigidity and Kernig's sign. Autonomic dysfunctions are very characteristic of the initial period, manifested by rapid changes in skin color, hyperhidrosis, persistent diffuse dermographism, skin hydrophilicity, pulse lability, and blood pressure fluctuations. Bradycardia at the onset of the disease is more typical of a severe disease course [7, 17].

Patients are apathetic, sluggish, drowsy, and lethargic. Some patients experience abdominal pain and short-term diarrhea. The tongue is often coated with a thick white plaque. In the initial period of TBE, this complicates differential diagnosis with acute intestinal infections.

High fever usually lasts for 5-8 days, subsiding completely by days 8-10, sometimes followed by low-grade fever for 2-3 weeks. The febrile period can be significantly shorter – up to 2-3 days, which is characteristic of a milder disease course. In some patients, predominantly with alimentary infection, a two-wave fever is observed. In these cases, the first wave is characterized by a rise in temperature for 2-3 days, followed by a period of apyrexia lasting from 3 to 10 days, after which a second wave occurs, distinguished by a recurrent temperature rise to higher figures than in the first wave and lasting up to 5-10 days. In most cases, the second wave runs a more severe course due to CNS involvement. In the most severe forms of TBE, the disease may begin with sudden loss of consciousness, delirium, severe psychomotor agitation, convulsive syndrome, or a generalized or focal epileptic seizure [7, 17].

Febrile form

The development of the febrile form is due to the viscerotropic properties of the virus. This form occurs in 30-50% of cases. A sudden temperature rise to 38-39˚C, general malaise, and other intoxication symptoms make this form of TBE similar to a number of infectious diseases. Sometimes intoxication is accompanied by meningism phenomena, while inflammatory changes in the cerebrospinal fluid are absent. Fever lasts from 1 to 6 days. This form of the disease has the most favorable course and prognosis, and generally ends in complete recovery. However, some patients may experience persistent asthenovegetative syndrome after discharge [4, 17].

The diagnosis is established based on epidemiological data, the presence of general infectious manifestations of the disease, and laboratory confirmation.

Meningeal form

In the structure of TBE morbidity, the meningeal form accounts for 50-60%. The clinical picture is characterized by a combination of leading syndromes inherent in acute meningitis: intoxication syndrome, meningeal syndrome, hypertension syndrome, and changes in the cerebrospinal fluid. The initial manifestations of this form are almost indistinguishable from those observed in the febrile form [4]. In a single-wave course, the meningeal syndrome develops on days 1-5 of fever; in a two-wave course, it may already occur during the first temperature wave and intensify during the second. The severity of meningeal symptoms depends on the severity of the disease. The clinical picture typically features headache of varying intensity and localization, eye pain, nausea, and vomiting. From the first days of the disease, nuchal rigidity and Kernig's sign are detected. In some patients, consciousness disturbances appear in the form of somnolence and psychomotor agitation, and focal symptoms are also possible in the form of facial asymmetry, slight tongue deviation, mild failure to abduct the eyeball outward, hyperactive tendon reflexes, and anisoreflexia, which indicate the progression of CNS damage and the development of encephalitis. The meningeal symptom complex regresses by days 8-20, but may persist for up to 2 months and be accompanied by prolonged cerebraphenia and intracranial hypertension [4, 7, 17].

Cerebrospinal fluid changes are characterized by an elevated intracranial pressure ranging from 250 to 300 mm H₂O, alongside inflammatory changes typical of serous meningitis. Pleocytosis is predominantly lymphocytic, ranging from several tens to several hundred cells, most commonly between 30 and 600 per µL [4]. In the first days of the disease, pleocytosis is mixed or neutrophilic, but by the end of the 1st week, it becomes lymphocytic. Protein levels are moderately elevated, up to 0.66 g/L. Glucose levels are normal. In rare cases, hyperglycorrhachia and hypochlorhydrachia are observed. Cerebrospinal fluid normalization occurs by the 3rd–5th week, though pathological changes may occasionally persist for several months.

Focal neurological symptoms are caused by alterative-exudative and degenerative-proliferative changes distributed throughout the nervous system, associated with the pathogenic action of TBEV. The motor neurons of the anterior horns of the spinal cord, motor nuclei of the medulla oblongata, cerebral cortex, and cerebellum are most intensely affected. Focal forms account for a relatively small proportion of all disease cases and are combined with meningeal syndrome in the majority of cases. These forms are typically accompanied by a pronounced intoxication syndrome and autonomic disorders. Symptoms of focal involvement appear early—on days 1–4 of fever in a single-wave course, and on days 1–3 of the second wave in a two-wave course. Unlike other neuroinfections (e.g., poliomyelitis, West Nile fever, etc.), the neurological symptoms of TBE may progress for 5–7 days or more, and in cases of early progressive onset, for an indefinitely long time with continuous or periodic remissions [17, 25].

Mingoencephalitic form

The meningoencephalitic form of TBE is one of the most severe presentations of TBE. It can manifest with either diffuse or focal brain damage. In diffuse meningoencephalitis, toxic-infectious, cerebral, and seizure symptoms predominate, along with varying degrees of consciousness impairment, up to coma. In rapidly progressing coma and status epilepticus, a fatal outcome may occur on days 2–4 of the disease [4, 17, 25].

Focal meningoencephalitis is distinguished by the development of motor disorders: spastic hemiparesis, hyperkinesia, ataxia, and akinetic-rigid syndrome. Unlike peripheral motor disorders, central paresis recovers completely or with minor deficits by the end of the acute period. The most severe cases are those in which hemiparesis is accompanied by continuous local myoclonus, gradually spreading from the distal extremities (most commonly the hands) to the proximal segments, and then to the face and the entire paretic half of the body. Myoclonic jerks periodically increase sharply, escalating into a local or generalized epileptic seizure. In rare cases, amyostatic syndrome develops, presenting as hypomimia and bradycardia, with subsequent regression over 4–6 weeks [4, 17].

In some cases, the sole manifestation of the meningoencephalitic form may be cerebellar disorders, clinically manifested by dizziness, vomiting, nystagmus, ataxia, muscle weakness, and intention tremor [17].

The outcome of the meningoencephalitic form includes residual effects such as psychiatric disorders, prolonged cerebropenia, and impaired memory and intellect. Kozhevnikov's epilepsy may also develop.

Polioencephalitic form

The clinical presentation of this form is driven by primary involvement of the brainstem and cranial nerve nuclei, along with the cerebellum and its connections.

Clinical features of this TBE variant include the frequent appearance of cerebellar disorders and bulbar syndrome, characterized by dysarthria, dysphagia, and dysphonia. Lingual fibrillations and nasolalia may occur. Speech becomes nasal and indistinct, and the voice becomes hoarse. Swallowing is accompanied by choking and the regurgitation of liquids through the nose. Examination reveals unilateral or bilateral soft palate paresis. Oculomotor impairments are less common, presenting as gaze bradykinesia, gaze paresis, convergence insufficiency, anisocoria, and horizontal nystagmus [17].

Involvement of the dorsal nuclei of the vagus nerve poses an immediate threat to life [7]. Disorders associated with this lesion are accompanied by marked central respiratory disturbances with rhythm changes (Cheyne-Stokes respiration), vascular collapse, and acute heart failure, which are the primary causes of death. Fatal outcomes typically occur in the first days of the illness. In cases where vital centers are not involved in the pathological process, the prognosis is relatively favorable, although a progressive course is also characteristic of this form. Asthenic syndrome may sometimes persist for a long time, up to a year [17].

The polioencephalitic form of TBE rarely occurs in isolation; it is more frequently combined with the poliomyelitic form.

Poliomyelitic form

This develops as a result of selective damage to the gray matter of the anterior horns of the spinal cord, specifically the motor neurons of its cervical and upper thoracic segments [1]. This localization of damage determines the clinical picture typical for TBE, characterized by flaccid paralysis of the neck muscles and predominantly the proximal shoulder girdle and upper extremities. Involvement of the neck muscles makes it impossible to hold the head in an upright position. This syndrome, known as "dropped head" syndrome, is a pathognomonic symptom of this form of TBE. With this localization of spinal cord damage, the muscles of the diaphragm, innervated by the phrenic nerve originating from motor neurons in the anterior horns at the level of the 4th cervical spinal segment, are frequently paralyzed. Combined involvement of the neck muscles and the diaphragm leads to peripheral respiratory failure, posing a serious threat to life. Clinically, diaphragmatic paralysis manifests as rapid, shallow breathing with paradoxical inward movement of the abdomen during inspiration and retraction of the lower intercostal spaces. Motor disorders exhibit all the features characteristic of anterior horn spinal cord lesions and are characterized by atonia, decreased or absent deep tendon and periosteal reflexes, and early-onset, severe muscle atrophy. Paralysis of the shoulder girdle and neck muscles is frequently asymmetrical. In some cases, alongside anterior horn involvement, symptoms indicating involvement of the posterior and lateral horns at the same level appear—specifically, segmental sensory disturbances affecting pain and tactile modalities. Developing on days 1–4 of the first febrile wave or days 1–3 of the second wave, motor disorders in the neck and shoulder girdle muscles may progress over several days and occasionally up to two weeks, accompanied by the characteristic general infectious and autonomic syndromes described above. It is in this form of TBE that the most pronounced manifestations of the prodromal period are observed, featuring recurrent fibrillary and fascicular twitching of the neck, limb, and intercostal muscles, as well as sudden, transient weakness in a limb followed by the development of flaccid paralysis [4, 7].

The course of the disease is invariably severe, with general improvement occurring very slowly, often without full recovery of motor functions and with persistent muscle atrophy. A progressive disease course is frequently associated with this clinical form.

Polioencephalomyelitis form

This form is characterized by a very severe clinical course and high mortality. The clinical picture comprises features typical of both the polioencephalitic and poliomyelitic variants of TBE. In this variant, cranial nerve involvement plays a predominant role. The severity of these lesions, combined with cardiac and respiratory paralysis, determines the outcome of the neuroinfection. In rare cases, a picture of panencephalomyelitis may develop, featuring total multilevel involvement of all cranial nerve nuclei, seizure syndrome, and ataxia. The disease proceeds with high fever for 7–8 days, followed by prolonged subfebrile temperatures and varying degrees of impaired consciousness. The acute period lasts 4–6 weeks. Regression of flaccid paralysis is prolonged and incomplete, with transition into a chronic progressive form being most common. Mortality reaches 20–30%.

Tick-borne encephalitis with a two-wave course

This distinct variant of acute infection begins abruptly with chills, headache, nausea, vomiting, dizziness, limb pain, sleep disturbances, and autonomic dysfunction, and is characterized by a biphasic fever. The first febrile wave lasts 3–7 days and has a mild course. Mild meningeal signs are observed. Cerebrospinal fluid changes are absent [7, 23].

The first wave is followed by a period of apyrexia lasting 7–14 days. The second wave of fever begins just as acutely as the first. Nausea, vomiting, mild meningeal symptoms, and focal CNS signs appear. The development of meningeal and meningoencephalitic forms without gross focal motor deficits and with a quite favorable outcome is most characteristic of this TBE variant [11, 23].

Chronic (progressive) course of tick-borne viral encephalitis

There are still many controversial issues regarding terminology, classification, and the frequency of chronization in the theory of chronic TBE [23]. Based on the timing of chronization, the primary-progressive form (first diagnosed in the absence of any acute TBE form in the anamnesis) and the secondary-progressive form (as a direct continuation of any acute TBE form or later after the manifest stage) are distinguished [1, 23].

Most often, the progressive course develops in the first year after the acute period, sometimes within the first 2–6 months [23]. Transformation into a chronic form may also occur much later, after 5, 15, or even 19 years. The chronic course develops more frequently in young individuals. According to some data, the cause of such transformation is the prolonged persistence of the TBE virus, while others attribute it to autoimmune processes in the CNS [23]. Factors that may trigger progression include intercurrent infections, closed craniocerebral injuries, alcoholism, etc. [7].

Examples of TBE diagnosis formulation:

• Tick-borne encephalitis, febrile form, moderate severity.

• Tick-borne encephalitis, meningoencephalitic form, right-sided hemiparesis, severe course. Cerebral edema-swelling. Prolonged artificial lung ventilation.

• Tick-borne encephalitis, poliomyelitic form, flaccid upper monoparesis on the left, flaccid paresis of neck muscles, severe grade.

• Tick-borne encephalitis, meningoencephalopoliomyelitic form with the development of bulbar syndrome, cranial nerve palsies, neck muscle paralysis, tetraplegia, severe course. Cerebral edema-swelling.

• Tick-borne encephalitis, meningoencephalopoliomyelitic form, severe grade, chronic course. Left-sided hemiparesis syndrome. Symptomatic focal epilepsy. Hyperkinetic syndrome.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis of tick-borne viral encephalitis

Diagnosis of TBE is carried out based on epidemiological and clinical anamnesis data, clinical examination, laboratory and special diagnostic methods, and is aimed at determining the nosology and clinical form, severity of the condition, identifying complications, and indications for therapy.

2.1 Complaints and Anamnesis

2.2 Physical Examination

2.3 Laboratory Diagnostics

2.3.1 Non-specific laboratory diagnostics

2.3.2 Specific laboratory diagnostics

Comments: repeat the assay dynamically 10–14 days after the first one in case of a negative result for the determination of class G antibodies (IgG) to TBEV in the blood to assess seroconversion.

Comments: the virological research method is the most reliable, but rather labor-intensive, which is why it is available in virological laboratories of major research institutions. Blood serum or a 10% suspension of blood clot in saline, as well as cerebrospinal fluid, are subject to virological investigation.

2.3.3 Special laboratory diagnostics

Comments: the general clinical biochemical blood test does not provide specific information, but the detected deviations have certain prognostic value and influence the choice of medications and/or their dosage regimens.

2.4 Instrumental Diagnostics

Comment: lumbar puncture is performed within the first 24 hours from the establishment of a probable TBE diagnosis in the absence of contraindications. TBE is characterized by lymphocytic pleocytosis (in the first days of the disease, pleocytosis may be mixed or neutrophilic), elevated protein up to 0.66 g/L, and normal glucose levels [4].

Lumbar puncture can only be performed in the absence of contraindications; if present, the procedure is carried out after patient stabilization and relief of cerebral edema.

Predictors of severe TBE course: high pleocytosis combined with a predominance of polynuclear cells, and blood-CSF barrier dissociation [28, 29, 30].

Comments: follow-up lumbar puncture in dynamics is performed on days 7–10.

Comment: thickening of the optic nerve with its sheaths is observed in intracranial hypertension, and as it progresses, increasing nerve thickness and blurred outlines are visualized, which correlates with ophthalmological signs of cerebral edema. Serial monitoring of optic nerve thickness allows for evaluating the efficacy of therapy aimed at normalizing intracranial pressure and reducing cerebral edema.

Comments: funduscopic examination via ophthalmoscopy reveals indirect signs of intracranial hypertension and cerebral edema.

Comments: EEG is recommended for patients with meningoencephalitic or multi-focal TBE during the acute period of the disease. Assessing the severity of bioelectrical activity disorders of the brain allows for indirectly estimating signs of cerebral edema; focal changes in bioelectrical activity indicate focal brain lesions; detection of epileptiform activity patterns enables the initiation or adjustment of anticonvulsant therapy. The presence on the EEG of marked disorganization of the background rhythm, frequent paroxysms of slow-wave and epileptiform activity is characteristic of a progressive TBE course with the development of Kozhevnikov's epilepsy and may serve as a prognostically unfavorable symptom.

Comment: MRI changes in TBE are represented by foci of inflammatory demyelination. Such MRI patterns as inflammatory lesions in the basal ganglia and, particularly, in the thalamus are characteristic of TBE. The localization of lesions aids in differential diagnosis with encephalitis of other etiologies, specifically herpes simplex virus type 1/2 encephalitis. Their detection helps determine the location and extent of CNS involvement. The detection of acute inflammatory demyelination lesions assists in differential diagnosis with non-inflammatory CNS lesions. The acute period of the disease is characterized by single or multiple hyperintense inflammatory foci on T2-weighted images, in severe cases with perifocal edema and subsequent development of generalized or focal cerebral atrophy during the convalescence period and disease outcomes.

Comment: if brain MRI is unavailable, brain MSCT is performed for all patients with focal forms of TBE.

Comments: pulse oximetry is a simple and reliable screening method for identifying patients with hypoxemia who require respiratory support and for evaluating its efficacy. In patients with signs of acute respiratory failure (ARF) (SpO₂ less than 90%), it is advisable to study the acid-base balance and blood gases, determining blood partial pressure of oxygen (PaO₂), blood carbon dioxide tension (PaCO₂), blood hydrogen ion concentration (pH), blood bicarbonate level (HCO₃), and blood lactic acid level.

Comments: certain ECG changes (e.g., QT interval prolongation) require attention when assessing the cardiotoxicity of certain prescribed drugs.

2.5 Other Procedures

2.5.1. Differential diagnostics

Differential diagnosis of TBE is carried out with three groups of diseases: other vector-borne infections transmitted by ixodid ticks; infectious diseases with an acute onset and pronounced general infectious manifestations; and diseases accompanied by damage to the nervous system.

The differential diagnosis of TBE is presented in Appendix A3.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

Comments: the organization of clinical nutrition for TBE patients during inpatient treatment in medical organizations is carried out in accordance with the orders of the Russian Ministry of Health dated August 5, 2003, No. 330 "On measures to improve clinical nutrition in healthcare institutions of the Russian Federation", dated June 21, 2013, No. 395n "On approval of clinical nutrition standards", and dated September 23, 2020, No. 1008n "On approval of the procedure for providing patients with clinical nutrition".

3.1. Etiotropic treatment

Etiotropic treatment includes the use of interferons, specific immunoglobulins (ATC code: J06BB), ribonuclease, and systemic antiviral drugs (ATC code: J05). To achieve maximum effectiveness, their prescription as early as possible is required [6, 36, 37, 40, 41, 42, 43, 64].

Comments: in the Russian Federation, tick-borne encephalitis immunoglobulin** containing specific antibodies against TBEV in titers of 1/80-1/160 has been used for therapeutic purposes for a long time. However, its effectiveness currently remains insufficient, and the necessity of its use is debatable. There is evidence of worsening the course of TBE when using tick-borne encephalitis immunoglobulin**. Therefore, the drug can be used only at the viremia stage, since it does not cross the blood-brain, tissue, and cell barriers. In focal forms, especially with brainstem lesions, there is a high risk of progression of immunopathological reactions. An objective criterion for viremia is the detection of TBEV RNA in the blood by PCR.

When using tick-borne encephalitis immunoglobulin** in the treatment of TBE, the presence of contraindications must be strictly taken into account.

In early diagnosis, good results are provided by the use of interferon preparations (Immunostimulants, ATC code: L03A) and other immunostimulants (ATC code: L03AX).

Comments: in meningeal forms, the use of tick-borne encephalitis immunoglobulin** in combination with interferon alfa-2b** is inappropriate, since proteins with a molecular weight from 12.3-13.7 to 45-150 kDa are unable to cross the blood-brain barrier, enter eukaryotic cells and extracellular virions; therefore, their potential effect is limited to the surfaces of infected cells [6, 36].

Interferon alfa-2b** lyophilizate for the preparation of suspension for oral administration in febrile and meningeal forms of TBE, dosing according to instructions [64]. In the febrile form in the presence of viremia (detection of TBEV RNA in the blood by PCR) in combination with tick-borne encephalitis immunoglobulin**. In meningeal and focal forms #Interferon alfa-2b** 500 thousand - 1 million IU intramuscularly 1-2 times a day for a course of up to 10 days [6, 43, 66, 71].

Comments: the drug #ribavirin** is an acyclic nucleoside, a guanosine analogue. It is widely used as an antiviral agent in the treatment of hemorrhagic fever with renal syndrome (monotherapy), other flavivirus infections (hepatitis C in combination with recombinant interferon alfa-2b**), in non-randomized studies on the treatment of West Nile fever, yellow fever, and dengue fever. Members of the Flaviviridae family share a similar antigenic structure, common virion morphology, and replication strategy [80]. It is advisable to use #ribavirin** in combination with interferon alfa-2b**[79].

Comments: the treatment course, according to the instructions, consists of 12 injections of the drug with an interval of 48 hours (every other day); a single dose is 250-500 mg (1-2 ampoules).

Comments: Ribonuclease 25-30 mg 6 times a day intramuscularly; the use of ribonuclease is discontinued 2 days after achieving apyrexia.

In severe meningeal and focal forms of TBE, it is advisable to combine Ribonuclease with interferon alfa-2b**, which have antiviral activity.

Ribonuclease should be prescribed taking into account the contraindications specified in the medication instructions for use.

Comments: in patients without foci of bacterial infection, the prescription of systemic antibacterial drugs is not indicated. Systemic antibacterial drugs should be prescribed only upon clinical and laboratory confirmation of a comorbid bacterial process, in the case of a mixed infection of tick-borne encephalitis and ixodid tick borreliosis [6, 43].

3.2. Pathogenetic treatment

The scope and duration of the course of pathogenetic and symptomatic therapy, as well as the choice of drugs and doses, depend on the severity of TBE.

Comments: infusion therapy for TBE patients is carried out with solutions affecting the water-electrolyte balance (ATC: B05BB) and irrigation solutions (ATC: B05C). The volume of infusion therapy is calculated based on the sum of physiological needs and pathological losses and is carried out to maintain normovolemia. Infusion therapy utilizes 0.9% sodium chloride solution**, dextrose solution**, solutions affecting the water-electrolyte balance: Potassium chloride + Sodium acetate + Sodium chloride**, meglumine sodium succinate** as an antihypoxant [56-60].

When symptoms of intracranial hypertension develop, the volume of infusion therapy is similar, but combination with a carbonic anhydrase inhibitor, "loop" diuretics (ATC code: C03C) and/or osmotic diuretics (ATC code: B05BC, Solutions with osmotic diuretic action) is possible. When symptoms of brain edema-swelling develop, solutions affecting the water-electrolyte balance are prescribed together with drugs having a colloid-osmotic effect (ATC code: B05AA, Blood substitutes and plasma protein fractions - human albumin**).

Comments: in the acute period of the disease, it is advisable to use the combined drug #Inosine + Nicotinamide + Riboflavin + Succinic acid**, which has a multifactorial effect. The drug exerts antihypoxic, membranoprotective, and energy-correcting effects; its use in the complex therapy of neuroinfections is due to the compensation of tissue hypoxia, detoxification, and reduction of lipid peroxidation [4, 7]. The antioxidant, antihypoxic, and cytoprotective properties of the drug disrupt pathological events associated with CNS metabolism depression, the development of respiratory and circulatory hypoxia leading to profound disorders of tissue metabolism, altering acid-base balance, reducing the activity of the free-radical defense system and lipid peroxidation activation, and preventing cytolysis and cell death. The drug has an anti-ischemic effect, improves coronary and cerebral blood flow, limits the necrosis zone, and improves metabolic processes in the CNS, restoring consciousness, reflex disorders, and sensory disturbances [73-75]. The drug is prescribed in the acute period of the disease. The method of treatment consists of slow intravenous drip administration of 10 ml of #Inosine + Nicotinamide + Riboflavin + Succinic acid** in 200 ml of 5% dextrose solution** or 0.9% sodium chloride solution** once a day for 7 days. The administration rate is 3–4 ml/min.

Comments: in case of severe pain syndrome (severe headache, myalgia, bone ache), the prescription of Diclofenac** or Ketoprofen** is possible.

Comments: one of the complications of a severe course of tick-borne encephalitis is the development of cerebral edema and convulsive syndrome, which serves as an indication for transferring the patient to mechanical ventilation, including, when indicated, mechanical ventilation via temporary tracheostomy placement.

Comments: in cerebral edema, the administration of glucocorticoids is indicated, preferably dexamethasone**. In cerebral edema, an initial dose of 10 mg is administered IV, followed by 4 mg every 6 hours until symptoms resolve (usually within 12–24 hours). After 2–4 days, the dose is tapered, and the use of dexamethasone** is gradually discontinued over 5–7 days. For acute cerebral edema, short-term intensive therapy is performed: for adults, the loading dose is 50 mg IV, then on days 1–3, 8 mg is administered every 2 hours; on day 4, 4 mg every 2 hours; on days 5–8, 4 mg every 4 hours, after which the daily dose is reduced by 4 mg/day until complete withdrawal.

Comments: IVIG #Normal human immunoglobulin** is prescribed to patients with tick-borne encephalitis by decision of a medical commission.

Comment: it is possible to prescribe Ipidacrine as an anticholinesterase agent (ATX code: N06DA05) at a dose of 20 mg 2–3 times a day for 2–6 months in the presence of organic CNS lesions accompanied by motor and/or cognitive impairments.

Comments: nootropic drugs (ATX codes: N06BX, N07AX, N07XX) are prescribed from the acute period and thereafter regularly in courses during the periods of early and late convalescence. Choline alphoscerate** should be administered intravenously by drip or intramuscularly slowly in a daily dose of 1000 mg in 2 divided doses; for intravenous administration, the contents of one ampoule (4 ml) are diluted in 100 ml of 0.9% sodium chloride solution, infusion rate 60–80 drops per minute; the course of therapy is 10 days. Ethylmethylhydroxypyridine succinate** is recommended to be administered parenterally (IV drip or bolus) at a dose of 200–500 mg 1–2 times a day for 14 days, then intramuscularly at 100–250 mg per day for the subsequent 2 weeks.

Comments: the dose, route, and frequency of administration of deep sedation drugs are determined individually by the anesthesiologist-intensivist based on the clinical picture of the disease, comorbid pathology, weight, and in accordance with the dosing guidelines in the drug instructions.

3.3. Enteral nutrition

Comments: calculation and type of nutrition in accordance with clinical guidelines for nutritional support

3.4. Parenteral nutrition

Comments: calculation and type of nutrition in accordance with clinical guidelines for nutritional support.

3.5. Respiratory support

Comments: performed in accordance with clinical guidelines for respiratory support.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

For passive gymnastics – Recommendation grade C (Level of Evidence – 4).

For massage – Recommendation grade C (Level of Evidence – 5).

5. Prevention and Dispensary Observation

5.1 Specific prevention

Comment: an individual is considered vaccinated against TBE if they have received a completed vaccination course and 1 (or more) revaccination(s). Vaccination against TBE is carried out year-round in accordance with medical indications.

Vaccine prophylaxis is carried out according to 2 schedules: the standard (primary) or emergency schedule. The standard specific prophylaxis schedule includes 2 vaccinations, which should be administered during the autumn-spring period (November–March) with an interval ranging from 1 to 7 months depending on the vaccine. Then, after 5–12 months (depending on the vaccine), the first revaccination must be performed. A three-dose administration constitutes a completed vaccination course. This is followed by long-term revaccinations – once every 3 years or more.

With the emergency, or accelerated, vaccination schedule, the interval between the 1st and 2nd vaccination is reduced to 2 weeks.

Thus, revaccination is performed 1 year after the 2nd vaccination, and subsequently, within the framework of personalized healthcare for the population based on the detected degree of immunological protection of those vaccinated against TBE and the duration of post-vaccination protective immunity, revaccination of each patient should be carried out according to an individual schedule at an ELISA antibody titer of 1:400 – 1:100, no more frequently than once every 3 years.

The indicator of vaccine prophylaxis efficacy is the titer of specific antibodies determined by ELISA, neutralization test, and their avidity. The lower threshold of the protective IgG antibody titer in ELISA is 1:400; an IgG antibody titer of 1:100 is the lower threshold of immunological memory at which the vaccination course can be continued. This level of specific antibodies is able to provide protection for patients at early stages of infection immediately after the bite of a tick containing TBEV.

• Rapid elimination of TBEV (after 1–2 days) can occur in vaccinated individuals with antibody titers greater than 1:400.

• With an antibody titer of 1:800 and higher, the near and long-term revaccinations may be postponed under the control of immune status levels.

• The vaccination course can be carried out throughout the year, including the summer period (epidemic season), but no later than 2 weeks before visiting the TBE focus.

• Currently, there is a change in the circulating TBEV subtypes in the Eurasian region, with the dominance of up to 70–100% of the Siberian genetic type of TBEV in certain endemic areas. All domestic vaccines are developed based on Far Eastern TBEV strains (genotype 1, strain no. 205, Sofyin strain), while foreign ones are based on European subtype strains (genotype 2, strains "Neudoerfl" and K-23). The vaccines have demonstrated high protective properties against 3 TBEV genotypes. The obtained results of evaluating the specific activity (immunogenicity) of vaccines for TBE prevention (ATC group J07BA – Vaccines for viral encephalitis) indicate differences in protective properties against strains of different genotypes, and the predominance of homologous protection against strains matching the vaccine strains in genotype [48, 49].

Currently, the following domestic vaccines used for the prevention of tick-borne encephalitis are registered in the Russian Federation:

• Tick-borne encephalitis vaccine** (ATC code: J07BA01), TBEV strain No. 205 obtained by its propagation in a suspended culture of chicken embryo cells, adsorbed on aluminum hydroxide.

• Tick-borne encephalitis vaccine** (ATC code: J07BA01), TBEV Sofyin strain obtained by propagation in a primary chicken embryo cell culture and inactivated with formalin.

• Tick-borne encephalitis vaccine** (ATC code : J07BA01), TBEV Sofyin strain obtained by propagation in a primary chicken embryo cell culture, adsorbed on aluminum hydroxide.

Comment: the multi-vector action of specific antibodies differs in their pre- and post-exposure applications. For prophylaxis, it is better to use high-titer tick-borne encephalitis immunoglobulin** (titer not less than 1:160). Full protection of cells against TBEV in an experimental prophylactic schedule is achieved only at a high antibody concentration (320 IU/mL), which can be achieved in individuals vaccinated against TBE [50].

Comment: contraindications should be considered when prescribing the drug. The use of iodophenazone is advisable for individuals who have contraindications to vaccination and the use of tick-borne encephalitis immunoglobulin** prescribed for the specific prevention of TBE; individuals who have previously completed a full course of TBE vaccination, as an additional preventive measure; when patients seek medical help at later stages (later than 3–4 days) after a tick bite, when the administration of tick-borne encephalitis immunoglobulin** is not indicated; when laboratory testing of the tick is not possible. Pre-exposure use of the drug is permissible during periods of stay in areas associated with potential tick bites [43, 52, 53].

5.2 Non-specific prevention

5.3 Clinical follow-up (dispensary observation)

Comments: dispensary monitoring of patients is carried out jointly with a neurologist. The frequency of follow-up, additional diagnostic methods, therapeutic and rehabilitation measures are determined by the neurologist together with other specialists according to clinical indications. The grounds for discharging a patient from dispensary follow-up are full recovery of working capacity, satisfactory general well-being, and the absence of focal neurological signs along with normalization of laboratory and instrumental test results.

Comments: if IgM persists in blood serum by ELISA 6 months after discharge, the patient must be referred to an infectious diseases hospital to rule out a chronic course of TBE.

6. Organization of Medical Care

Comments: in focal forms of tick-borne encephalitis, discharge of the patient from the hospital is carried out no earlier than 21 days of illness, following clinical recovery and normalization of the main cerebrospinal fluid parameters [4].

7. Additional Information

Possible outcomes and their characteristics (Table 1) [4, 6, 17]

Table 1. Possible outcomes and their characteristics

Criteria for Evaluating the Quality of Medical Care

Quality of care criteria for patients with tick-borne encephalitis

References

Appendix A1. Working Group Composition

1. Gorelov A.V. - Academician of the RAS, Professor, Deputy Director for Scientific Work, Central Research Institute of Epidemiology of Rospotrebnadzor, Head of the Department of Infectious Diseases and Epidemiology, Russian University of Medicine of the Ministry of Health of the Russian Federation.

2. Konkova-Reidman A.B. - Doctor of Medical Sciences, Associate Professor, Head of the Department of Infectious Diseases, South Ural State Medical University of the Ministry of Health of the Russian Federation.

3. Minoranskaya N.S. - Doctor of Medical Sciences, Associate Professor, Professor of the Department of Infectious Diseases and Epidemiology with the Course of Postgraduate Education, Krasnoyarsk State Medical University named after Prof. V.F. Voino-Yasenetsky of the Ministry of Health of the Russian Federation.

4. Barsukova D.N. - Candidate of Medical Sciences, Associate Professor of the Department of Infectious Diseases, South Ural State Medical University of the Ministry of Health of the Russian Federation.

5. Pozdnyakova L.L. - Candidate of Medical Sciences, Chief Infectious Disease Specialist of the Novosibirsk Region, Chief Medical Officer of City Clinical Infectious Hospital No. 1, Novosibirsk Region.

6. Ulyanova Ya.S. - Candidate of Medical Sciences, Deputy Chief Medical Officer for Medical Affairs, City Clinical Infectious Hospital No. 1, Novosibirsk Region.

7. Burmistrova T.G. - Honored Doctor of the Russian Federation, Head of Department No. 7, City Clinical Infectious Hospital No. 1, Novosibirsk Region.

8. Krasnova E.I. - Doctor of Medical Sciences, Professor, Head of the Department of Infectious Diseases, Novosibirsk State Medical University of the Ministry of Health of the Russian Federation.

9. Prorova V.V. - Candidate of Medical Sciences, Associate Professor of the Department of Infectious Diseases, Novosibirsk State Medical University of the Ministry of Health of the Russian Federation.

10. Sizikova E.A. - Clinical Pharmacologist, City Clinical Infectious Hospital No. 1, Novosibirsk Region.

11. Tomilin V.V. - Head of the Department of Internal Quality Control and Safety of Medical Activities, City Clinical Infectious Hospital No. 1, Novosibirsk Region.

12. Smirnova M.M. - Infectious Disease Physician, Expert of the Department of Quality Control and Safety of Medical Activities, City Clinical Infectious Hospital No. 1, Novosibirsk Region.

13. Agletdinov E.F. - Doctor of Medical Sciences, Deputy General Director for Scientific Work, Vector-Best JSC.

14. Lyakh O.V. - Deputy Chief Medical Officer for Clinical Expert Work, City Clinical Infectious Hospital No. 1, Novosibirsk Region.

15. Schukin M.M. - Anesthesiologist-Resuscitator, Department of Anesthesiology and Intensive Care, City Clinical Infectious Hospital No. 1, Novosibirsk Region.

16. Chulanov V.P. - Doctor of Medical Sciences, Professor, Deputy Director for Scientific Work and Innovative Development, National Medical Research Center for Phthisiopulmonology and Infectious Diseases of the Ministry of Health of the Russian Federation.

17. Esaulenko E.V. - Doctor of Medical Sciences, Professor, Head of the Department of Infectious Diseases in Adults and Epidemiology, St. Petersburg State Pediatric Medical University of the Ministry of Health of the Russian Federation.

18. Novak K.E. - Candidate of Medical Sciences, Associate Professor, Department of Infectious Diseases in Adults and Epidemiology, St. Petersburg State Pediatric Medical University of the Ministry of Health of the Russian Federation.

19. Usenko D.V. - Doctor of Medical Sciences, Head of the Educational Center, Leading Researcher of the Clinical Department of Infectious Pathology, Central Research Institute of Epidemiology of Rospotrebnadzor.

There is no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Infectious diseases physicians;

2. General practitioners;

3. General practitioners (family physicians).

Table P1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table P2. Level of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table P3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

These clinical guidelines were developed taking into account the following regulatory legal documents:

1. Federal Law No. 323-FZ dated November 21, 2011 "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation".

2. Federal Law No. 326-FZ dated November 29, 2010 "On Compulsory Medical Insurance in the Russian Federation".

3. Order of the Ministry of Health and Social Development of Russia No. 541n dated July 23, 2010 "On Approval of the Unified Qualification Handbook of Positions of Managers, Specialists and Employees, Section 'Qualification Characteristics of Employee Positions in Healthcare'".

4. Resolution of the Chief State Sanitary Doctor of the Russian Federation No. 4 dated January 28, 2021 "On Approval of Sanitary Rules and Norms SanPiN 3.3686–21 'Sanitary and Epidemiological Requirements for the Prevention of Infectious Diseases' (XX. Prevention of tick-borne viral encephalitis).

5. Federal Guidelines for the Use of Medicines (Formulary System). Issue XIV - M.: "Echo", 2013: 980 p.

6. Order of the Ministry of Health of Russia No. 330 dated August 5, 2003 "On Measures to Improve Therapeutic Nutrition in Healthcare Institutions of the Russian Federation".

7. Order of the Ministry of Health of Russia No. 395n dated June 21, 2013 "On Approval of Therapeutic Nutrition Norms".

8. Order of the Ministry of Health of Russia No. 1008 dated September 23, 2020 "On Approval of the Procedure for Providing Patients with Therapeutic Nutrition".

9. Resolution of высокую the Chief State Sanitary Doctor of the Russian Federation No. 28 dated May 28, 2007 "On Additional Measures for the Prevention of Tick-Borne Viral Encephalitis".

10. Letter of Rospotrebnadzor No. 02/1775-2024-32 dated February 5, 2024 "On the List of Territories Endemic for Tick-Borne Viral Encephalitis in 2023".

Table A4. Severity criteria for the febrile form of TBE

Table A5. Severity criteria for the meningeal form of TBE

Table P6. Differential diagnosis

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Tick-borne encephalitis is a natural focal viral infection characterized by fever, intoxication, and damage to the gray matter of the brain (encephalitis) and/or the membranes of the brain and spinal cord (meningitis and meningoencephalitis).

Human infection occurs via the vector-borne route following a tick bite. Alimentary transmission of the infection is possible when consuming raw milk and dairy products from infected goats and cows.

The main vectors of the tick-borne encephalitis virus are ixodid ticks, blood-sucking arthropods of the family Ixodidae (Acari). They are widespread everywhere. Typical habitats of ixodid ticks are mixed, coniferous, and deciduous forests with dense undergrowth, well-developed grass cover, and a litter of fallen rotting leaves, where there are no direct sun rays and the temperature does not exceed 200°C.

It should be remembered that ticks live not only in forests, but also in parks and garden plots. Ticks can also be found in cities: on lawns, in the grass along roadsides. Ticks can be brought home by animals; on branches, on country or forest flower bouquets, brooms, or grass; on clothing worn while walking in the forest. At home, a tick can bite any family member, even several days later.

The best way to prevent tick-borne encephalitis is protection against tick bites.

When are ticks most dangerous?

Ticks become active from April to September—until the first frosts. The peak of activity occurs in May–July, but tick bites are possible from April to October. When the soil warms up to 5–7 °C, the first victims of tick attachment begin to seek help.

What is the risk of a tick bite?

Once on a person, a tick crawls under clothing and attaches itself most often in the area of the neck, chest, armpits, scalp, and sometimes in the groin area. A tick bite results in human infection with tick-borne encephalitis. Human infection occurs during tick attachment. The latent (incubation) period lasts 7–12 days, less often up to 30 days. The duration of the incubation period depends on a number of factors: human susceptibility and body resistance, and the degree of tick infestation.

The disease can develop in several ways:

• the febrile form of the disease proceeds with a high body temperature, severe headache, muscle pain, general toxic symptoms, and no nervous system involvement;

• another form of the disease is characterized by the development of meningitis or encephalitis with the appearance of high fever, severe headaches with vomiting, and brain damage, for example, in the form of impaired vision, hearing, difficulty swallowing, or speech impairment;

• the third form of the disease development proceeds with the development of nervous system damage in the form of limb paralysis.

Few people are able to feel the moment of a tick bite, as the tick effectively numbs the bite site, so there is always a risk of missing this fact. During a prolonged stay in the forest, self-examinations and mutual examinations must be carried out. Particular attention should be paid to hairy parts of the body, skin folds, auricles, axillary, and inguinal regions.

It has been proven that in search of an open place to bite, a tick crawls on clothing from the bottom up. Therefore, trousers must be tucked into boots, and the shirt into trousers. Cuffs of sleeves must fit snugly around the wrists. Shoulders and neck must be covered. A headwear is mandatory. To repel ticks, treat your clothing with repellents. The repellent packaging must bear a label confirming its effectiveness against ticks.

What to do if a tick bite has occurred?

If an attached tick is found, you should contact a medical institution as soon as possible for its removal in order to further test the tick for virusophoricity, depending on the result of which the issue of the feasibility of emergency specific prevention of tick-borne encephalitis by administering tick-borne encephalitis immunoglobulin** should be resolved.

If it is not possible to seek help at a medical institution, the tick should be immediately removed independently. There are several methods for removing ticks, differing in the types of tools used. It is most convenient to remove the tick with curved tweezers or a clamp. The tick must be grasped as close to the proboscis as possible, gently pulled up, rotating around its axis until it is extracted. Sharp movements are unacceptable, as the probability of its rupture is high.

Alternatively, the tick can be removed using a thread, which should be tied as close to the tick's proboscis as possible and extracted by rocking it to the sides and pulling it upwards.

It is possible to remove the tick by hands. You should grasp the tick with your fingers as close to the skin as possible; wearing gloves is recommended in this case. It is also necessary to pull and rotate the tick. It is important to prevent crushing the tick. If tick removal is performed without gloves, hands must be thoroughly washed afterwards. The wound must be treated with an antiseptic.

Tick removal must be carried out with caution, without squeezing its body, as this may squeeze out the tick's contents along with pathogens into the wound. It is important not to rupture the tick during removal - the part remaining in the skin can cause inflammation and suppuration. At the same time, it should be borne in mind that if the tick's head is torn off, the infection process may continue, since a significant concentration of the tick-borne encephalitis virus is present in the salivary glands and ducts.

If during the extraction of the tick its head is torn off, which looks like a black dot, the bite site must be treated with alcohol, and then the head should be removed with a sterile needle.

It is unacceptable to apply ointment dressings to an attached tick or to use oil solutions.

After tick removal, the skin at the bite site must be treated with antiseptics (alcoholic iodine solution, alcohol, alcoholic brilliant green solution, etc.). Applying a bandage is generally not required.

Hands and tools must be thoroughly washed after tick removal.

When removing a tick, one should not:

– apply dressings soaked in caustic liquids (ammonia, gasoline, etc.) to the bite site;

– cauterize the tick;

– allow sharp movements during its extraction;

– apply various compresses to the tick bite site;

– allow the tick to be crushed.

The removed tick should be placed in a small hermetically sealed container with a moist environment (a cotton swab moistened with water) and delivered to the laboratory to test the tick for the presence of tick-borne infection pathogens, including tick-borne encephalitis virus RNA.

Prevention of tick-borne encephalitis is carried out in two directions: routine vaccination and emergency immunoprophylaxis with tick-borne encephalitis immunoglobulin**.

Emergency immunoprophylaxis is carried out during the first 72 hours after the tick bite.

Nonspecific prevention measures consist of preventing tick bites, namely:

- avoiding visiting tick habitats (forest biotopes with tall grass, bushes) during the tick-borne infection epidemic season; hikers should stick to trails;

- using repellents containing DEET or permethrin;

- wearing light-colored clothing with long sleeves and trousers, tucking the latter into long socks; wearing a headwear;

- during the stay in the forest and upon return, it is recommended to carry out self- and mutual examinations;

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Glasgow Coma Scale

Russian title: Glasgow Coma Scale

Original title: Glasgow Coma Scale

Source: Teasdale G.M., Jennett B., 1974

Piradov M.A., Suponeva N.A., Ryabinkina Yu.V., Gnedovskaya E.V., Ilyina K.A., Yusupova D.G., et al. Glasgow Coma Scale (GCS): Linguocultural adaptation of the Russian-language version. N.V. Sklifosovsky Journal of Emergency Medical Care.

2021;10(1):91–99. https://doi.org/10.23934/2223-9022-2021-10-1-91-99

Type: rating scale

Indication: for assessing the severity of impaired consciousness and coma.

Content:

Key (interpretation):

The initial Glasgow Coma Scale score correlates with the severity of cerebral injury and prognosis.

The scale consists of three tests assessing eye-opening, verbal, and motor responses. A specific number of points is awarded for each test. The eye-opening test ranges from 1 to 4 points, the verbal response test from 1 to 5 points, and the motor response test from 1 to 6 points.

Thus, the Glasgow Coma Scale is an important criterion for assessing the level of consciousness. Each individual response is scored in points, and the level of consciousness is expressed as the sum of points for each parameter. The lowest score is 3 points, and the highest is 15 points. A score of 8 points or lower is defined as a coma.

A scale score of 3–5 points is prognostically extremely unfavorable, especially if combined with dilated pupils and the absence of the oculocephalic reflex.

Appendix G2. SOFA score

Original name: Sequential Organ Failure Assessment (SOFA) Russian name: SOFA scale

Source (official developer website, validation publication): https://pubmed.ncbi.nlm.nih.gov/29443733/

Tee Y.S., Fang H.Y., Kuo I.M., Lin Y.S., Huang S.F., Yu M.C. Serial evaluation of the SOFA score is reliable for predicting mortality in acute severe pancreatitis. Medicine (Baltimore). 2018 Feb; 97(7): e9654. doi: 10.1097/MD.0000000000009654.

Type (underline):

- rating scale

- index

- questionnaire

Indication: determination of organ dysfunction

¹ - Adrenergic and dopaminergic agents (ATC code: C01CA)

Key (interpretation):

PaO2 in mmHg. FiO2 from 0.21 to 1.00.

Adrenergic agents (Adrenergic and dopaminergic agents, ATC code: C01CA) were used for at least 1 hour. Dosage is in mcg/kg per minute. 0 is the most optimal parameter, 4 is the most abnormal parameter.

Data must be collected and evaluated once daily throughout the patient's stay in the intensive care unit.

Mean (systemic) arterial pressure is calculated using the formula: MAP = (SBP + 2DBP) / 3.

The SOFA index equals the sum of all six parameters.