Mats Haglund

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.

A 10-Year Follow-Up Study of Tick-Borne Encephalitis in the Stockholm Area and a Review of the Literature: Need for a Vaccination Strategy

143 people treated for tick-borne encephalitis (TBE) were included in a retrospective follow-up study. Sequelae and epidemiological characteristics in 114 individuals were analysed. The case fatality rate and the prevalence of residual paresis were low, 1.4 and 2.7%, respectively. However, 40 (35.7%) individuals were found to have a postencephalitic syndrome after a median follow-up time of 47 months, and a majority (77.5%) of these were classified as moderate to severe. Various mental disorders, balance and co-ordination disorders and headache were the most frequently reported symptoms. Increasing age was correlated to a longer duration of hospital stay, longer convalescence and increased risk of permanent sequelae. Results from a neuropsychiatric questionnaire showed marked differences between the subjects with sequelae compared to controls. 57% had noticed a tick bite before admission, and 48% were aware of at least one person in their environment who previously had contracted TBE. 79% were permanent residents or visited endemic areas often and regularly. In conclusion, we have found that TBE in the Stockholm area has a low case fatality rate, but gives rise to a considerable number of different neurological and mental sequelae, which justifies vaccination of a defined risk population in endemic areas.

Characterization of tick-borne enchephalitis virus from Latvia

Viruses of the tick‐borne encephalitis (TBE) antigenic complex, within the family Flaviviridae, cause a variety of diseases including uncomplicated febrile illness, encephalitis, meningo‐encephalitis, hemorrhagic fever and chronic disease in humans, domesticated animals or wildlife species. TBE is a serious problem in Latvia with up to a 1,000 patients confirmed serologically annually 1994–1995. No previous data had been reported on the causative agent of TBE in Latvia. In the present study, a virus was isolated from serum of a patient with clinical symptoms of an acute TBE infection. Nucleotide sequence information obtained by direct reverse transcription‐polymerase chain reaction (RT‐PCR) and the serological characteristics of the isolated virus strain, designated TBE‐Latvia‐1‐96, indicated a closer relationship to the Vasilchenko strain, isolated in Novosibirsk (Siberia, Russia), as compared to the western European or far eastern subtypes of TBE viruses. In a mouse neurovirulence assay, a significant difference in survival rates (days) was shown between Latvia‐1‐96 and the western European TBE virus subtype. J. Med. Virol. 60:216–222, 2000.

Intrathecal IgM, IgA and IgG antibody response in tick-borne encephalitis. Long-term follow-up related to clinical course and outcome.

BACKGROUND Tick-borne encephalitis (TBE) of western subtype causes long-term morbidity and is considered a health problem in Scandinavia, eastern and central parts of Europe and Russia. The pathophysiology is not fully elucidated. As TBE RNA is rarely demonstrable in cerebrospinal fluid (CSF) the kinetics of the CSF antibody response to the disease has attracted attention. OBJECTIVES To investigate the intrathecal TBE-specific antibody response and to correlate its intensity and persistence to the clinical course. To compare indirect, commercially-based ELISA methods indexed against albumin ratio or IgG ratio with the capture ELISA method for the establishment of CSF response. STUDY DESIGN The specific IgM, IgG and IgA antibody responses in serum and CSF were analysed in 69 Swedish patients included in a prospective study of TBE from the acute phase up to 11-13 months after onset. RESULTS Antibody response by all three classes was demonstrable in serum and CSF. All methods were useful, but capture technique was the most sensitive and results were easiest to interpret. Peak IgM activity was seen early during the disease and persisted after 6 weeks. Maximum IgG levels were encountered in late convalescent samples (median 6 weeks). Intrathecal antibody production was demonstrable in nearly all patients: in 41% days 0-6, in 97% days 7-19, in 98% days 21-61 and-at lower levels-in 84% of the patients after 1 year (50/52 of CSF-serum sampled in the interval 11-61 days). Day 9 after onset, patients with dominating encephalitic symptoms showed significantly lower intrathecal IgM activity. The persistence of serum and CSF antibodies did not correlate to severity of disease. CONCLUSIONS Capture IgM and IgG assays were superior to indirect ELISA. Low early CSF IgM response correlated to encephalitic symptoms, otherwise the intensity and duration of intrathecal antibody response were of limited value for the prediction of clinical course and long-term outcome.

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.

Multiple sclerosis and optic neuritis: CCR5 and CXCR3 expressing T cells are augmented in blood and cerebrospinal fluid

Abstract. A role for chemokines as mediators of Th1 cell recruitment to the central nervous system (CNS) is probable in MS. Therefore we studied expression of Th1-related CCR5 and CXCR3 chemokine receptors in patients with MS and controls. Patients with untreated MS had elevated percentages of CCR5 and CXCR3 expressing T cells vs. healthy controls (HC) in blood, and vs. other non-inflammatory neurological diseases (OND) patients in CSF. Such elevation was not found in MS patients examined during ongoing treatment with IFN-β. Patients with optic neuritis (ON), a common first manifestation of MS, had elevated percentages of CXCR3 expressing T cells in blood compared with HC, and of CCR5 expressing T cells in CSF compared with OND patients. High chemokine receptor expression may be one prerequisite for Th1 cells to migrate to the CNS. Inhibition of chemokine receptor expression may constitute a potentially important therapeutic effect of IFN-β.

A rapid fluorescent focus inhibition test for detection of neutralizing antibodies to tick-borne encephalitis virus

Tick borne encephalitis (TBE), is endemic in several countries in central and northern Europe, in the Baltic states and in Russia. Vaccination has been shown to lower efficiently the number of cases of this potentially very serious disease. However, the possibility to assess the neutralizing antibody response after clinical disease or vaccination has been hampered by the lack of easy and specific tests. We developed a rapid fluorescent focus inhibition test (RFFIT) and compared it with a standard plaque reduction neutralization test (PRNT) and an hemagglutination inhibition test (HI) for antibody detection in late convalescent sera from 18 patients with a previous clinical and serological diagnosis of TBE. Neutralizing titres obtained with RFFIT were almost identical to those obtained with PRNT, and correlated also well with the HI results. The RFFIT for detection of neutralizing antibodies to TBE-virus has an advantage over the standard PRNT in its easy and rapid performance (results are obtained in 1 vs 7 days), and over the HI in its specificity, since cross-reactions with other flaviviruses are minimized.

Tick-borne encephalitis virus in ticks detached from humans and follow-up of serological and clinical response

The risk of tick-borne encephalitis virus (TBEV) infection after a tick bite remains largely unknown. To address this, we investigated the presence of TBEV in ticks detached from humans in an attempt to relate viral copy number, TBEV subtype, and tick feeding time with the serological and clinical response of the tick-bitten participants. Ticks, blood samples, and questionnaires were collected from tick-bitten humans at 34 primary health care centers in Sweden and in the Åland Islands (Finland). A total of 2167 ticks was received from 1886 persons in 2008-2009. Using a multiplex quantitative real-time PCR, 5 TBEV-infected ticks were found (overall prevalence 0.23%, copy range <4×10(2)-7.7×10(6)per tick). One unvaccinated person bitten by a tick containing 7.7×10(6) TBEV copies experienced symptoms. Another unvaccinated person bitten by a tick containing 1.8×10(3) TBEV copies developed neither symptoms nor TBEV antibodies. The remaining 3 persons were protected by vaccination. In contrast, despite lack of TBEV in the detached ticks, 2 persons developed antibodies against TBEV, one of whom reported symptoms. Overall, a low risk of TBEV infection was observed, and too few persons got bitten by TBEV-infected ticks to draw certain conclusions regarding the clinical outcome in relation to the duration of the blood meal and virus copy number. However, this study indicates that an antibody response may develop without clinical symptoms, that a bite by an infected tick not always leads to an antibody response or clinical symptoms, and a possible correlation between virus load and tick feeding time.

Intrathecal production of neopterin and β2 microglobulin in tick-borne encephalitis (TBE) compared to meningoencephalitis of other etiology

To study the pathophysiology of tick-borne encephalitis (TBE), the kinetics of neopterin and beta 2 microglobulin (beta 2M) production were measured in sequential, cerebrospinal fluid (CSF) and serum samples in 133 patients with aseptic meningoencephalitis (TBE, n = 72; non-TBE, n = 61). Intrathecal production of neopterin was demonstrable in all patients. Neopterin levels in CSF were elevated already at day 2: geometric mean value in TBE 36 nmol/l (range 1-253), in the non-TBE group 29 nmol/l (0.2-96). At day 9 and week 6 the neopterin level was significantly higher in TBE (86 (19-725) and 17 (4-122) nmol/l) than in non-TBE (28 (5-109) and 3 (0.2-58) nmol/l) (p < 0.001). After 1 year CSF levels were within the normal range. The beta 2M response in CSF followed the pattern of neopterin. The intensity and duration of neopterin and beta 2M was not correlated to the clinical course. Neopterin seems to be a more sensitive indicator of intrathecal T-cell response and inflammatory reaction than beta 2M. The results indicate that a long-lasting strong inflammatory reaction is of pathophysiological significance in TBE.

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.