Статья посвящена эпилепсии Кожевникова, одному из наиболее распространенных и по сути патогномоничных проявлений хронического течения клещевого энцефалита. Описаны стадийность в ее развитии, типы течения сформировавшейся кожевниковской эпилепсии, подходы к терапии. В статье представлен уникальный по продолжительности наблюдения случай хронического клещевого энцефалита (ХКЭ) (47 лет от начала заболевания и свыше 30 лет после вакцинотерапии). Показано, что замедленное развитие тяжелой неврологической симптоматики, прогрессирование болезни происходят на фоне дисиммуноглобулинемии. Штамм, выделенный от пациентки, обладал высокой нейровирулентностью для белых мышей, был высоконейроинвазивным, показал принадлежность к сибирскому подтипу вируса клещевого энцефалита. По мере прогрессирования ХКЭ развивался полиштаммовый иммунный ответ и напряженный иммунитет с высокой авидностью антител (через 30-32 года после вакцинотерапии). В неврологическом статусе – характерные постэнцефалитические изменения с элементами кортикальной моторной эпилепсии. Существенного когнитивного дефекта не было выявлено. The article is devoted to Kozhevnikov's epilepsy, one of the most common and, in fact, pathognomonic manifestations of the chronic course of tick-borne encephalitis. The stages in its development, the types of the course of the formed Kozhevnikovskaya epilepsy, and approaches to therapy are described. This material presents a unique case of chronic tick-borne encephalitis (TBE) (47 years from the beginning of the disease and more than 30 years after vaccination). It is shown that the delayed development of severe neurological symptoms and disease progression occur against the background of dysimmunoglobulinemia. The strain isolated from the patient had high neurovirulence for white mice, was highly neuroinvasive, and belong to the Siberian subtype of tick-borne encephalitis virus (TBEV). As TBE progressed, a polystrain immune response and a stressed immune response with high antibody avidity developed (30-32 years after vaccination). In the neurological status – pecular postencephalitic changes with elements of cortical motor epilepsy. No significant cognitive defect was detected.

Relevance.Modern inactivated culture vaccines against tick-borne encephalitis (TBE) with at least 70% of the population living in the natural foci of the FE give a high epidemiological effect. Unresolved issues are the simplification of the cumbersome vaccination scheme, the optimal number of revaccinations, the protective titer of antibodies against the Siberian subtype of the TBE virus dominant in Russia.Goalof this work is to study the state of postvaccinal immunity in the population of the highly endemic area of the Trans-Urals.Materials and methods. 1381 blood serum of the population vaccinated from 3 to 13 times with vaccines was studied: unconcentrated culture inactivated from strain No. 205 of the TBE virus produced by «Virion», Tomsk, «EnceVir» produced by «Microgen», Tomsk, produced by Chumakov Federal Scientific Center for Research and Development of Immuneand-Biological Products of Russian.To identify specific antibodies – IgG, IgM, antigen of TBE virus, sets of reagents of ELISA from «Vector-Best» were used. Neutralizing activity of sera was determined by the index of neutralization index with 4 strains of the Siberian subtype of TBE virus.Results.The immune layer among the vaccinated population in 10 districts of the Kurgan region, which differ in epidemiological tension, ranges from 69.9% to 94.6%. The intensity of humoral immunity varied according to IgG titers in ELISA from 1: 100 – 1: 200 to 1: 3200 (rarely 1: 6400). The duration and intensity of immunity depends on the number of vaccinations and the number of missed remote revaccinations. Preservation and intensity of immunity with reliability P = 95%, higher in persons vaccinated 6–10 times compared with the group of vaccinated 3 times. In persons who had 4–8 booster dose of vaccine, the immunity persisted for 15–19–36 years with an IgG titer of not more than 1: 100. The neutralizing activity of the sera of vaccinated individuals with antibody titers from 1:100 to 1: 6400 was studied for the Siberian subtype of BCE. The degree of protection of the vaccinated population against the doses of the virus found in individual mites is determined. From the doses of the virus, 57% of the vaccinated population are most often found in mites, and from the dose of 105– 8%. Recommendations are proposed on the tactics of revaccination of the population, depending on the level of immunity.

Relevance. Modern inactivated culture vaccines against tick-borne encephalitis (TBE) with at least 70% of the population living in the  natural foci of the FE give a high epidemiological effect. Unresolved  issues are the simplification of the cumbersome vaccination scheme,  the optimal number of revaccinations, the protective titer of  antibodies against the Siberian subtype of the TBE virus dominant in Russia. Goal of this work is to study the state of postvaccinal immunity in the population of the highly endemic area of the Trans-Urals. Materials and methods . 1381 blood serum of the population vaccinated from 3 to 13 times with vaccines was studied: unconcentrated culture inactivated from strain No. 205 of the TBE  virus produced by «Virion», Tomsk, «EnceVir» produced by  «Microgen», Tomsk, produced by Chumakov Federal Scientific Center for Research and Development of Immuneand-Biological Products of  Russian.To identify specific antibodies – IgG, IgM, antigen of TBE  virus, sets of reagents of ELISA from «Vector-Best» were used.  Neutralizing activity of sera was determined by the index of  neutralization index with 4 strains of the Siberian subtype of TBE  virus. Results. The immune layer among the vaccinated population in 10 districts of the Kurgan region, which differ in epidemiological tension, ranges from 69.9% to 94.6%. The intensity of humoral immunity  varied according to IgG titers in ELISA from 1: 100 – 1: 200 to 1:  3200 (rarely 1: 6400). The duration and intensity of immunity  depends on the number of vaccinations and the number of missed  remote revaccinations. Preservation and intensity of immunity with  reliability P = 95%, higher in persons vaccinated 6–10 times  compared with the group of vaccinated 3 times. In persons who had 4–8 booster dose of vaccine, the immunity persisted for 15–19–36 years with an IgG titer of not more than 1: 100. The neutralizing  activity of the sera of vaccinated individuals with antibody titers from 1:100 to 1: 6400 was studied for the Siberian subtype of BCE. The  degree of protection of the vaccinated population against the doses  of the virus found in individual mites is determined. From the doses  of the virus, 57% of the vaccinated population are most often found  in mites, and from the dose of 105– 8%. Recommendations are  proposed on the tactics of revaccination of the population, depending on the level of immunity.

Siberian subtype of TBE virus dominates in the most part of Russia outside of the Far East. Peculiarity of immunity induced by Siberian subtype during disease or inapparent infection and change of immunity after vaccination are described in this article. Protective titre of antibodies and persistence of TBE virus (TBEV) in vaccinated organism are discussed.

Lethal cases of tick-borne encephalitis in previously vaccinated patients have not been described. Modern inactivated vaccines against Tick-borne encephalitis (TBE) are high effective. The TBE cases, preference unfocal forms, are developed in persons with incomplete irregular vaccination. First case of lethal TBE after plural vaccination was described in the Kurgan region, the second case - in the Chelyabinsk region. These very rare unusual cases were studied. Being dominant the Siberian subtype of TBE virus is related with lethal TBE cases in the Chelyabinsk region. Unusual TBE case was developed in patient who had been vaccinated 8 limes with vaccines produced from strains of Far-Eastern TBE subtype («Virion», Tomsk, Chumakov institute, Moscow) and European TBE subtype (Encepur; FSME-Immun). Two years after the last vaccination a focal form of TBE was developed with lethal outcome at 9 th day. Specific antibodies IgM and IgG seroconversion were detected. The TBE virus antigen was detected in brain neurons by immunofluorescent test. Destructed neurons and gliocyles were shown by hystological study in cerebral hemispheres and cerebellum. The Purkinje cells were destructed. Possible reasons of surmounting vaccinal immunity including a genetic difference of vaccine and infection virus strains are discussed.

Chronic tick-borne encephalitis (CTBE) is a severe form of the disease, leading to permanent disability and death. Most cases of CTBE caused Siberian subtype of a virus of tick-borne encephalitis virus (TBEV), dominant in the Russian Federation. The pathogenesis of CTBE associated with persistence of TBEV in the central nervous system and the organs of the immune system. Specific vaccine therapy with using of inactivated full-virion vaccines prevents immunosuppression, leading to activation of persisting tick-borne encephalitis. The article describes various schemes of CTBE vaccinotherapy. Dynamics of humoral immunity in CTBE caused by Siberian subtype of TBEV. In the early stages and during remission antibodies against this subtype are detected. Vaccine therapy increases the level of immunity to all subtypes of TBEV, slowing the progression of the disease. In seronegative status of the patient vaccine therapy is not effective: from the central nervous system of a deceased patient severe strain «Zausaev» was isolated. Mechanisms of high immunity after 30-32 years after vaccine therapy and advantages of vaccine therapy compared with treatment of CTBE using specific immunoglobulin are discussed.

Целью настоящего исследования являлось изучение эпидемиологии клещевого энцефалита (КЭ) в Ярославской области, одном из наиболее эндемичных регионов по данной инфекции в Центральном федеральном округе России. Проведен подробный анализ современной эпидемиологической ситуации по КЭ в Ярославской области с оценкой возможных влияющих на нее факторов в сравнении с таковой за более ранний период наблюдений совместно с рассмотрением некоторых клинических аспектов и изучением этиологии случаев заболевания, в числе которых и летальные случаи. В ходе работы мы столкнулись с рядом наблюдений и научных фактов, которые говорят о необходимости менять сложившееся представление о группах риска, важности изменения подхода к специфической профилактике КЭ и дополнительного изучения тактики лечения пациентов при очаговых формах заболевания.

In the Yaroslavl region (Central Federal District of Russia), endemic of tick-borne encephalitis (TBE), the features of epidemiology of this infection were studied during 1992-2012. Cyclical fluctuations in the incidence of TBE, the lack of the trend to decrease of the incidence were observed, the average annual incidence was 1,6 ± 0,32 per 100 thousand ofpopulation. The prevalence offebrile forms of disease was 62,2%, meningeal forms - 16,3%, the total percentage offocal forms was 13,9%. Manifestations of evolution of TBE were: the increase of the epidemiological significance of anthropogenically transformed natural foci, anthropurgical foci of TBE, until 81% of TBE cases were unvaccinated citizens, the high lethality of 4% and the high frequency of cases of alimentary infection of TBE of 7,8% with lethality of 10,8%. The aethiological agent of 10 lethal cases was Siberian subtype of TBE virus.

1 . VAccINE thERApy OF chRONIc tIcK-BORNE ENcEphALItIS 1 Chumakov Institute of polyomielitis and viral encephalitides of Russian academy of medical sciences, 142782, Moscow, Russia; 2 Aldan central hospital, 678900 Republic Saha (Yakutia), Aldan, Russia. Chronic tick-borne encephalitis (CTBE) is a severe form of the disease, leading to permanent disability and death. Most cases of CTBE caused Siberian subtype of a virus of tick-borne encephalitis virus (TBEV), dominant in the Russian Federation. The pathogenesis of CTBE associated with persistence of TBEV in the central nervous system and the organs of the immune system. Specific vaccine therapy with using of inactivated full-virion vaccines prevents immunosuppression, leading to activation of persisting tick-borne encephalitis. The article describes various schemes of CTBE vaccinotherapy. Dynamics of humoral im- munity in CTBE caused by Siberian subtype of TBEV. In the early stages and during remission antibodies against this subtype are detected. Vaccine therapy increases the level of immunity to all subtypes of TBEV, slowing the progression of the disease. In seronegative status of the patient vaccine therapy is not effective: from the central nervous system of a deceased patient severe strain «Zausaev» was isolated. Mechanisms of high immunity after 30-32 years after vaccinу therapy and advantages of vac- cine therapy compared with treatment of CTBE using specific immunoglobulin are discussed. Key w ords: tick-borne encephalitis; chronic tick-borne encephalitis; Siberian subtype of tick-borne encephalitis virus; persistence; vaccine therapy; immune system; antibodies.

In the Kurgan region, the Siberian subtype of the tick-borne encephalitis virus (TBEV) is dominant. The vaccines prepared from Far-Eastern TBEV subtype are used in this area. Among TBE patients in 2007-2011, 23.79% were vaccinated according to complete or incomplete course. 76.9% of persons were vaccinated with Encevir vaccine, Tomsk. An unusual focal form of TBE with fulminant disease with lethal outcome was developed in a patient who was vaccinated 6 times with heterotype vaccines produced using the strains of the Far-Eastern TBE subtype. inoculation of immunoglobulin in hospital produced aggravation of clinical symptoms, development of convulsions, brain oedema, and respiratory distress syndrome. The disease continues only 55 hours from first symptoms to fatal outcome. Siberian subtype of TBEV was isolated from patient spinal cord (Kurgan-118-2010 strain). Possible mechanisms of this disease are discussed.

In the Kurgan region, the Siberian subtype of the tick-borne encephalitis virus (TBEV) is dominant. The vaccines prepared from Far-Eastern TBEV subtype are used in this area. Among TBE patients in 2007-2011, 23.79% were vaccinated according to complete or incomplete course. 76.9% of persons were vaccinated with Encevir vaccine, Tomsk. An unusual focal form of TBE with fulminant disease with lethal outcome was developed in a patient who was vaccinated 6 times with heterotype vaccines produced using the strains of the Far-Eastern TBE subtype. Inoculation of immunoglobulin in hospital produced aggravation of clinical symptoms, development of convulsions, brain oedema, and respiratory distress syndrome. The disease continues only 55 hours from first symptoms to fatal outcome. Siberian subtype of TBEV was isolated from patient spinal cord (Kurgan-118-2010 strain). Possible mechanisms of this disease are discussed.

Eighteen polytypic tick-borne encephalitis virus (TBEV) strains containing the fragments of E and NS1 protein genes of Siberian and Far Eastern, occasionally Siberian and European subtypes were isolated in the European and Asian parts of the tick-borne encephalitis (TBE) area. They were identified using real-time polymerase chain reaction, hybridization-fluorescence detection with genotype-specific probes, restriction fragment length polymorphism analysis, and E protein sequencing. The polytypic strains were isolated from individual Ixodes persulcatus ticks, their pools, from the blood of patients and the brain of dead patients. The isolation rates of the polytypic strains in the sympathry area of different TBEV subtypes ranged from 4.4% (the Irkutsk Region) to 15.1% (the Yaroslavl Region). In addition to 2 polytypic strains, a strain similar to the TBEV 886-84 strain was isolated. The TBEV subtypes entering into the composition of the polytypic strains show nongenetic interactions, such as neutral replication or competition. The polytypic strains are stable during passages in the cultured pig embryo kidney epithelial cells and on cloning. Mouse brain passage promotes dissociation of polytypic strains. The conditions for the formation of polytypic strains and their role in the etiology of TBE are discussed.

Eighteen polytypic tick-borne encephalitis virus (TBEV) strains containing the fragments of E and NS1 protein genes of Siberian and Far Eastern, occasionally Siberian and European subtypes were isolated in the European and Asian parts of the tick-borne encephalitis (TBE) area. They were identified using real-time polymerase chain reaction, hybridization-fluorescence detection with genotype-specific probes, restriction fragment length polymorphism analysis, and E protein sequencing. The polytypic strains were isolated from individual Ixodes persulcatus ticks, their pools, from the blood of patients and the brain of dead patients. The isolation rates of the polytypic strains in the sympathry area of different TBEV subtypes ranged from 4.4% (the Irkutsk Region) to 15.1% (the Yaroslavl Region). In addition to 2 polytypic strains, a strain similar to the TBEV 886-84 strain was isolated. The TBEV subtypes entering into the composition of the polytypic strains show nongenetic interactions, such as neutral replication or competition. The polytypic strains are stable during passages in the cultured pig embryo kidney epithelial cells and on cloning. Mouse brain passage promotes dissociation of polytypic strains. The conditions for the formation of polytypic strains and their role in the etiology of TBE are discussed.