Tick-borne encephalitis and golden agers: position paper of the International Scientific Working Group on Tick-borne encephalitis (ISW-TBE).

One of the primary goals of the 11th Annual Meeting of the International Scientific Working Group on Tick-borne encephalitis (ISW-TBE) held in 2009 was to develop the first update of the Position Paper on TBE in Golden Agers, summarizing the most essential aspects of the disease in this age group. TBE morbidity has continued to increase in recent years, which is thought to be due to an interplay of social, political, ecological, economic and demographic factors combined with climate changes. Today's golden agers i.e. individuals aged 50 years or above, are healthier and more mobile, lead more active lifestyles and spend more time travelling and performing outdoor leisure activities. This places them at an increased risk of infection. At the same time, increasing age is associated with a quantitative and qualitative decline in innate and adaptive immunity, which is why elderly individuals are more susceptible to infection and severe disease than younger people. Also, their response to vaccination tends to be slower, antibody titres generally reach lower levels and titres tend to decrease earlier than in younger individuals. Evidence is accumulating that this is also the case with TBE vaccination, emphasizing the importance of administering the first TBE booster vaccination no later than 3 years after the completion of primary immunization or at an even shorter interval. Encouragingly, recent data have shown that the field effectiveness of TBE vaccination exceeds 97%, with no significant differences between age groups.

Tick-borne encephalopathies : epidemiology, diagnosis, treatment and prevention.

Tick-borne encephalopathies constitute a broad range of infectious diseases affecting the brain and other parts of the CNS. The causative agents are both viral and bacterial. This review focuses on the current most important tick-borne human diseases: tick-borne encephalitis (TBE; including Powassan encephalitis) and Lyme borreliosis. Rocky Mountain spotted fever (RMSF) and Colorado tick fever (CTF), less common tick-borne diseases associated with encephalopathy, are also discussed. TBE is the most important flaviviral infection of the CNS in Europe and Russia, with 10 000-12 000 people diagnosed annually. The lethality of TBE in Europe is 0.5% and a post-encephalitic syndrome is seen in over 40% of affected patients, often producing a pronounced impairment in quality of life. There is no specific treatment for TBE. Two vaccines are available to prevent infection. Although these have a good protection rate and good efficacy, there are few data on long-term immunity. Lyme borreliosis is the most prevalent tick-borne disease in Europe and North America, with >50 000 cases annually. Localised early disease can be treated with oral phenoxymethylpenicillin (penicillin V), doxycycline or amoxicillin. The later manifestations of meningitis, arthritis or acrodermatitis can be treated with oral doxycycline, oral amoxicillin or intravenous ceftriaxone; intravenous benzylpenicillin (penicillin G) or cefotaxime can be used as alternatives. The current use of vaccines against Lyme borreliosis in North America is under discussion, as the LYMErix vaccine has been withdrawn from the market because of possible adverse effects, for example, arthritis. RMSF and CTF appear only in North America. RMSF is an important rickettsial disease and is effectively treated with doxycycline. There is no treatment or preventative measure available for CTF.

Surveillance of tick-borne encephalitis in Europe and case definition.

The study by Stefanoff et al raises two important questions concerning tick-borne encephalitis (TBE) virus infections. First, the lack of a generally accepted case definition and secondly the quality of national surveillance of TBE cases. Ideally, reported cases should be confirmed and the clinically relevant cases with central nervous system (CNS) disease should be separated from febrile cases without CNS manifestations. The surveillance of TBE in the European countries is not uniform and not always mandatory. Efforts to reach a final diagnosis, especially in less severe cases and in children, varies as well as the awareness of the disease in low endemic regions. The only relevant and stable basis for national surveillance is cases with established CNS disease, although immunity to TBE virus after less severe febrile illness is of interest on individual basis. The ratio of non-CNS disease to CNS disease is generally believed to be about three, but there are regional differences in virulence. Significantly, age related differences are basically unknown.

Tickborne encephalitis in an area of high endemicity in lithuania: disease severity and long-term prognosis.

Of 250 consecutively admitted patients with central nervous system (CNS) infections who were treated during a 1-year period, all 133 patients with tickborne encephalitis (TBE) were included in a prospective follow-up study. TBE presented as mild (meningeal) in 43.6% of patients and as moderate or severe (encephalitic) in 43.6% and 12.8% of patients, respectively. Paralytic disease was observed in 3.8% of the subjects, and cranial nerve injury was observed in 5.3%. One patient died of TBE. Permanent CNS dysfunction after 1 year was found in 30.8% of patients; in 8.5% of all TBE cases, severe disabilities required adjustment of daily activities. Corticosteroid treatment did not seem to improve outcome. A progressive course of TBE was noted in 2 patients. The risk of incomplete recovery was significantly higher among patients with the encephalitic form of TBE (odds ratio, 4.066; 95% confidence interval, 1.848-8.947). In conclusion, TBE is an important pathogen in CNS infection in the Kaunas region of Lithuania, and it causes long-lasting morbidity in one-third of cases.

Acute viral infections of the central nervous system in immunocompetent adults: diagnosis and management.

Patients with viral infections of the central nervous system (CNS) may present with a variety of neurological symptoms, most commonly dominated by either encephalitis or meningitis. The aetiological panorama varies in different parts of the world as well as over time. Thus, virological first-line diagnostics must be adapted to the current epidemiological situation and to the individual patient history, including recent travels. This review focuses on the diagnostics and treatment of viral CNS infections in the immunocompetent host from a Northern European perspective. Effective vaccines are available for viruses such as poliovirus and tick-borne encephalitis virus (TBEV) and for the childhood diseases morbilli (measles), rubella (German measles), parotitis (mumps) and varicella (chickenpox). However, cases do appear due to suboptimal immunization rates. In viral CNS infections, epidemiological surveillance is essential for establishing preventive strategies and for detecting emerging viruses. Knowledge of the possibilities and limitations of diagnostic methods for specific viral CNS infections is vital. A positive cerebral spinal fluid (CSF) polymerase chain reaction (PCR) finding is usually reliable for aetiological diagnosis. The demonstration of intrathecal antibody synthesis is useful for confirming the aetiology in a later stage of disease, hitherto sufficiently evaluated in herpes simplex encephalitis (HSE) and tick-borne encephalitis (TBE). Despite improved virological and differential diagnostic methods, aetiology remains unknown in about half of the cases with suspected viral encephalitis. Antiviral treatment is available chiefly for infections caused by herpesviruses, and acyclovir (aciclovir) is the drug of choice for empirical therapy in suspected viral encephalitis. However, randomized, controlled antiviral trials have only been conducted for HSE, while such studies are lacking in other viral CNS infections. Viral cytolysis and immune-mediated mechanisms may contribute to varying extents to neurological damage. Although the brain damage is believed to depend, to a varying degree, on the intrathecal host immune response, the use of corticosteroids in viral CNS infections is scarcely studied, as is specific treatment for neuroinflammation. Improved antiviral and immunomodulating treatment is desirable. Since neurological sequelae are still abundant, follow-up after severe viral CNS disease must include a neuropsychological assessment and an individually adapted rehabilitation plan.

Tick-borne encephalitis is associated with low levels of interleukin-10 in cerebrospinal fluid.

Tick-borne encephalitis (TBE) is associated with higher morbidity and induces a stronger intrathecal immune activation than most other viral induced meningo-encephalitis. The aim of this study was to investigate cytokine concentrations in cerebrospinal fluid (CSF) and serum in relation to aetiology and clinical course. Cytokines were analysed by Enzyme-linked Immuno Assay (ELISA) from 44 patients with TBE and from 36 patients with aseptic meningo-encephalitis of other aetiology (non-TBE). Significantly increased CSF levels of Interferon-γ (IFN-γ), Interleukin-10 (IL-10), Interleukin-6 (IL-6), Interleukin-1 receptor antagonist (IL-1ra), and soluble CD8 receptor (sCD8) were detected in both cohorts. Tumour necrosis factor-α (TNF-α showed low levels or was not detected in CSF in any group in the acute stage. However, the CSF levels of IL-10 were significantly lower in TBE than in non-TBE cases 0-6 days after onset of encephalitis. The TBE patients with encephalitis had significantly lower IL-10 CSF levels later in the clinical course (day 7-18) than TBE patients with meningeal disease. Increased IFN-γ production, but low IL-10 secretion, may be of pathophysiological significance in TBE.

Vaccine failures after active immunisation against tick-borne encephalitis.

Tick-borne encephalitis (TBE) is a major disease of the central nervous system in Europe and is endemic in Sweden with about 200 notified cases annually. The far most effective protective measure against TBE is active immunisation. The vaccines available today induce a high degree of protection in field studies. However, vaccine failures have occasionally been reported and may be overlooked due to different, and sometimes confusing, antibody kinetics in vaccinees with TBEV infection. In this study, 27 patients with clinical and serological evidences of TBE despite adequate immunisation are presented. Vaccination failure is characterized by a slow, and initially non-detectable, development of the specific TBEV-IgM response, seen together with a rapid rise of IgG and neutralising antibodies in serum. The majority (70%) of the patients were more than 50 years of age, which may implicate a need for a modified immunisation strategy in the elderly.

Serum S-100B protein levels in patients with herpes simplex encephalitis and tick-borne encephalitis--a marker of CNS damage during the initial stage of disease.

BACKGROUND AND PURPOSE: This study was mainly aimed at the comparative analysis of serum S-100B protein in patients with herpes simplex encephalitis (HSE) and tick-borne encephalitis (TBE). S-100B protein is an established biochemical marker of astroglial damage in central nervous system (CNS) injury. METHODS: Serum levels of S-100B were measured using a commercial immunolumino-metric assay (LIA). RESULTS: Patients with HSE (n = 17) had significantly higher levels of S-100B with median 0.351 microg/l (range 0.017-0.636) compared to patients with TBE (n = 15), who had 0.04 microg/l (range 0.001-0.542) (p < 0.001), as well as controls (n = 17) 0.054 (range 0.004-0.214) (p < 0.001). 11/17 patients with HSE had serum S-100B levels above 0.2 microg/l, in contrast to 1/15 patients with TBE and 1/17 of the control patients. The patients with HSE with serum levels below 0.2 microg/l had a mean 3.2 days disease duration, while patients with levels above 0.2 microg/l had 6 days disease duration. CONCLUSIONS: The serum levels of S-100B in the acute stage of disease were significantly higher in patients with HSE than in patients with TBE or controls. A role for the use of serum S-100B in monitoring CNS damage during initial stage of disease in HSE is suggested.

A case of Plasmodium falciparum malaria with an exceptionally long incubation period.

Clinical symptoms of Plasmodium falciparum malaria normally appear within 2 months of transmission. The incubation period is important for deciding whether a febrile illness is associated with a previous stay in a malarial region. This case report shows that P. falciparum malaria can have a prolonged incubation period.

Tick-borne encephalitis--pathogenesis, clinical course and long-term follow-up.

The prospective studies available today confirm the experience gained from several retrospective studies that TBE is a disease with a severe acute clinical course and considerable long-term morbidity. A defined post-encephalitic TBE syndrome exists, causing long-lasting morbidity that often affects the quality of life and sometimes also forces the individual to a change in life-style. The sequelae render high costs for individual patients and the society. Three clinical courses may be identified: one with complete recovery within 2 months, occurring in approximately one fourth of patients, one with protracted, mainly cognitive dysfunction, and one with persisting spinal nerve paralysis with or without other post-encephalitic symptoms. Up to 46% of patients are left with permanent sequelae at long-time follow-up, the most commonly reported residuals being various cognitive or neuropsychiatric complaints, balance disorders, headache, dysphasia, hearing defects, and spinal paralysis. This knowledge enhances the need for continued local epidemiological surveillance of TBE to form a basis for vaccination policies. Even though knowledge of the clinical course of TBE has improved in recent years, there are still several aspects of this disease that warrant further studies. These comprise the clinical picture and prognosis in children, an evaluation of different rehabilitation strategies, and an improved understanding of pathogenic mechanisms to permit the development of antiviral or, maybe more probable, immune modulatory treatment strategies.

Report of the Meningitis Program of the International Scientific Working Group on TBE. Serological screening of patients with viral CNS-infection of unknown etiology in search of undiagnosed TBE cases.

The endemicity of tick-borne encephalitis (TBE) in Europe is changing. Potential undetected or emerging TBEV foci and the risk of underdiagnosis due to a low awareness among the medical community form the background of this retrospective multicenter follow-up study. We investigated the possibility of undiagnosed TBE cases among patients with presumed viral central nervous system (CNS)-infection of unknown etiology. Eight centers in four European countries provided sera and/or cerebrospinal fluid (CSF) samples from 233 individuals. The samples were screened with a commercial TBEV ELISA test system (IgM and IgG). Positive or borderline samples were re-evaluated at the Institute of Virology in Vienna by an in-house ELISA test and a neutralization test (NT). Two previously undiagnosed Swedish TBE patients were verified. Three additional individuals from Swedish centers were IgG ELISA and NT positive. No NT positive individuals were found from France, Belgium or The Netherlands. Nineteen individuals were found IgG TBE ELISA positive, but negative in NT, indicating unspecific reactivity. At least four of those patients were vaccinated against yellow fever. The probable reason for the reactivity seen in these individuals is the well-known cross-reactivity existing among flaviviruses.

Characterisation of human tick-borne encephalitis virus from Sweden.

Viruses of the tick-borne encephalitis (TBE) antigenic complex, within the family Flaviviridae, cause a variety of diseases including uncomplicated febrile illness, meningo-encephalitis and haemorrhagic fever. Different wildlife species act as reservoir hosts with ixodid tick species as vectors. TBE virus (TBEV) causes 40-130 cases confirmed serologically in Sweden each year. Characteristics of TBEV strains circulating in Sweden have not been investigated previously and no viral sequence data has been reported. In the present study, virus strains were isolated from serum of patients with clinical symptoms consistent with acute TBEV infection. Serologic characterisation, using a panel of E-specific monoclonal antibodies and cross-neutralisation tests, indicated that the Swedish strains of TBEV, isolated 1958-1994, all belonged to the Western TBEV subtype, which includes the Austrian vaccine strain Neudoerfl. Genetic analysis of a partial E-sequence confirmed this close relationship: all Swedish TBEV strains belonged to the European lineage of the Western TBEV subtype, which includes the previously characterised strains Neudoerfl, Hypr, and Kumlinge. Further, three Swedish strains showed partial E-sequences identical to that of the Finnish Kumlinge strain, ten Swedish strains formed a well-supported separate cluster, whereas four others did not show any real clustering. No apparent correlation was observed in comparison of clinical parameters with genetic data or geographic origin of the strains.