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Tick-borne encephalitis (TBE) in Germany and clinical course of the disease
J~
InU. Med. Microbial. 291, Suppl. 33,58-61 (2002) © Urban & Fischer Verlag http://www.urbanfischer.de/journalslijmm
M
original article Tick-borne encephalitis (TBE) in Germany and clinical course of the disease Reinhard Kaiser* Department of Neurology, Municipal Hospital, Pforzheim, Germany
Abstract Between 1991 and 2000 about 1500 patients fell ill in Germany (Baden-Wuertternberg, Bavaria, Hesse) after infection with the tick-borne encephalitis (TEE) virus. Detailed clinical and epidemiological data of TEE were available from 850 patients. A biphasic course of the disease occurred in 75 % of patients. TEE presented as meningitis in 400 patients (47 %), as meningoencephalitis in 356 (42 %) and as meningoencephalornyelitis in 93 (11 %). Nine of the patients (l %) died from TEE. Five hundred and ninety three patients (70 %) had noticed a tick bite and the first symptoms occurred, on average, seven days later. The most frequent neurological symptoms were an impairment of consciousness (31 %), ataxia (18%) and paresis of the extremities (15%) and cranial nerves (11 %). Laboratory investigations revealed leukocytosis in the peripheral blood in 74 % of the patients, elevation of the sedimentation rate in 91 %, increased Cereacrive protein in 82 %, pleocytosis in the CSF of all patients tested, damage of the blood-CSF-barrier in 79 %, abnormalities in EEG in. 77% and abnormalities in MRI in 18 %. In general, adolescents up to 14 years of age had a more favourable course of the disease than adults. In view of the severity of the illness and the high frequency of sequelae, active immunisation against TEE is recommended for all subjects living in and travelling to areas of risk. Regarding the higher risk of severe manifestations of TEE in the elderly patients and the higher risk of failure of immunisation in this population, vaccination against TEE is more important in elderly subjects than in very young persons. Prevention of TEE by post exposure prophylaxis with hyperimmunoglobulins is less effective and should therefore not be performed.
Introduction Tick-borne encephalitis (TBE) is caused by an RNA virus belonging to the family Flaviviridae. Based on antibody adsorption experiments, peptide mapping and nucleotide sequencing, three different subtypes of TBE-virus have been identified (Heinz and Kunz, 1981; Heinz and Kunz, 1982; Mandl ct aI., 1988; Pletnev er aI., 1990). The western subtype is endemic in large parts of northern, central and eastern Europe, while the eastern subtypes can be found in the European and
Asian regions of the Commonwealth of Independent States (former Soviet Union) (WHO, 1986; Anonymous, 1997). In Germany, TBE is prevalent in Baden\X!uerttemberg, Bavaria and South Hesse (Roggendorf, 1996; Anonymous, 1997; Kaiser, 1999). During the years 1991 to 2000, about 1483 cases ofTBE were reported in Germany with a mean incidence in BadenWuerttemberg of 1.2/100,000 inhabitants per year and a case fatality rate of 1 % (Kaiser, 1996). In 1994 a dramatic increase of TBE-virus infections occurred in the area of Freiburg (southern Germany).
* Corresponding author: Reinhard Kaiser, Stadt. Klinikum Pforzheim, Kanzlerstralie 2-6, 75175 PIorzheim, Germany, Phone: 00497231969602, Fax: 00497231969911, E-mail: [email protected] 1438-4221/01/291/8-000 S 15.00/0
Clinical course of TBE in Germany With regard to the lack of information regarding the risks associated with and the outcome of TBE-virus infection a prospective study to investigate the clinical course, prognosis and epidemiology of TBE in Germany was undertaken. Results of this study support a policy of active immunisation against TBE for all subjects who stay in or travel to areas of risk and are likely to be exposed to ticks.
Patients and methods Patient population This prospective multicentre study was performed in Baden\Vuerttemberg,a federal Land in southern Germany, between 1994 and 2000. Data from patients were recorded by departments of Neurology (n =25), Internal Medicine (n =101) and Paediatrics (n = 14) in Baden-Wuerttemberg as well as 50 diagnostic laboratories and 40 health authorities which were invited to participate in this study. Data was acquired by means of a questionnaire. In addition, the clinicians were asked to send an anonymous record of the patients, which included laboratory data. Patients were asked to give their informed consent. Data were made anonymous to satisfy the German data protection law. TBE was diagnosed by the demonstration of specific IgM and IgG activity in the serum by routine serological tests (Roggendorf et al., 1981). In patients recently immunised with TBE vaccine, CNS infection was diagnosed by demonstration of intrathecally produced viral TBE IgM activity. Definition of areas of riskfor TBE-virus infection According to the recommendations of a national conference on tick-borne diseases held in Freiburg in March 1998, the areas of risk in Germany for TBE-virus infection are defined as administrative districts with at least five cases of TBE within five years (Kaiser, 1998).
Statistics Independent samples were analysed by means of the r-test and Levene's test for equality of variances. The frequency of positive findings was examined by the chi2-test. The significance level considered was 1 % (P::5 0.01).
Results Epidemiological data Between 1994 and 2000 a total of 850 patients fell ill after infection with TBE-virus in Baden-Wuerttemberg and South Hesse. Most of the infections were acquired within the valleys of the black forest and in the vicinity of Lake Constance. Out of 850 individuals, 596 (70 %) had noticed a tick bite before admission. In 765 patients (90 %) infection took place during leisure time activity and only 85 (10 %) had professions associated with outdoor activ-
59
ities (forest workers, farmers). No obvious association between geographical region and the severity of the disease could be found. Admissions to hospital of patients with TBE were between March and December in each year, but two thirds of infections were acquired between June and August. On average twice as many men as women fell ill but the mean age of male (45 ± 19 years) and female patients (43 ± 21 years) did not differ. 11 % (n = 95) were children and adolescents up to 14 years.
Clinical presentation A biphasic course of illness with a prodromal period occurred in 635 patients (75 %). The first stage of illness, characterised by fever, headache and sometimes malaise, upper respiratory andlor abdominal symptoms, lasted a median of 4 days (range 1-7). Thereafter, most of the patients recovered for a median of 7 days (range 3-21). Of the 850 patients, 400 (47 %) presented with meningitis, 356 (42 %) with meningoencephalitis and 93 (11 %) with meningoencephalomyelitis. Patients with meningoencephalitis mostly suffered from an impairment of consciousness, ataxia and paresis of the cranial nerves and the limbs. Impairment of consciousness was a frequent finding in patients with meningoencephalitis and encephalomyelitis, but patients with men ingoencephalomyelitis were more severely affected. Flaccid paresis of the extremities (:5 315) was the most prominent feature in all patients with meningoencephalomyelitis; forty patients (43 %) suffered from either mono- or tetraparesis and 13 patients (15%) from paraparesis of the lower extremities. In meningoencephalitis, paresis of the extremities was less frequent (monoparesis 7 %, hemiparesis 6 %), less serious (> 315) and mostly transitory of a few days duration. A similar pattern was observed with pareses of the cranial nerves which were more severe and relatively more frequent in patients with meningoencephalomyelitis. In patients with meningoencephalitis most pareses of the cranial nerves were transitory for three to ten days, except for hearing impairment, dysphagia and dysarthria which persisted for longer periods. Twelve patients with meningoencephalomyelitis were continuously ventilated either to the present time (n = 2, ventilation for 4 to 7 years) or until death (n = 10; 1-52 weeks after onset of the disease). Tremor of the limbs mostly occurred as intention tremor (n =20) and less frequently as resting tremor (n = 8). Other neurological symptoms occurred with a frequency of less than 3 %.
laboratory findings on admission to hospital TBE-virus-specific IgM-antibodies in serum were present in 847/850 patients with TBE (99 %); in three
60
R. Kaiser
patients the diagnosis was established as the result of a significant rise of IgG antibodies in serum, and an accompanying increase of antibody avidity three weeks after the first testing. All patients revealed IgGantibodies against TBE-virus after a maximum of two weeks following admission to hospital. Examination of the peripheral blood revealed leukocytosis (> 10,000/~tl) in 224/302 patients (74%) and elevation of the sedimentation rate in 223/245 patients (91 %) and of Cereactive protein in 127/155 patients (82 %). The frequency and the extent of abnormal values did not correlate with the diagnosis or prognosis of TBE . Pleocytosis in the cerebrospinal fluid (CSF) was a general finding in all patients; the median cell count was 60/~ll with a range from 6 to 1200/~ll. Impairment of the blood-CSF-barrier was demonstrated in 304/380 patients (80 %) studied. Abnormal values of total protein in the CSF were detected more frequently in patients with meningoencephalornyelitis (88 %, P = 0.021) and meningoencephalitis (82 %, P = 0.025) than in patients with meningitis (71 %). Additionally, patients with meningitis had lower levels of total protein in the CSF than patients with other manifestations.
Electro-encephalogram (EEG) and magnetic resonance imaging (MRI) Of 214 patients who were examined by EEG, 165 (77%) presented with abnormalities (diffuse slowing and/or intermittent focal abnormalities). The frequency of abnormal EEG findings was similar in patients with meningoencephalitis (91 %) and meningoencephalomyelitis (96%). MRI studies were carried out on 102 patients and 18 showed abnormal findings. Of 64 patients with meningoencephalitis and 25 with meningoencephalomyelitis, 11 (17 %) and 7 (28 %), respectively, showed abnormalities on MRI. The MRI was unremarkable in 13 patients with meningitis. In 15/18 patients the findings were confined to the thalamus, in three patients further lesions were detected in the cer ebellum, brain-stem, and caudate nucleus. One of these three patients was under immunosuppression with ciclosporin and corticosteroids following renal transplantation and two patients had received specific immunoglobulins intramuscularly after the notion of the tick bite.
Discussion The diagnosis of TBE is derived from epidemiological (a stay in an area of risk for TEE, facultative history of a tick bite) and clinical data (biphasic course of disease, neurological symptoms with ataxia being most indica-
tive for this infection), and the demonstration of TBEspecific IgM and IgG-antibodies in the serum. In gen eral, there is an intrathecal synthesis of TBE-specific IgM- and/or IgG-antibodies in the CSF, at the latest three weeks after admission to hospital (Kaiser and Holzmann, 2000). Although this latter criterion is the most specific serological method of confirming the diagnosis, the presence of sp ecific IgM-antibodies in the serum is generally considered to be adequate evidence of TBE (Roggendorf et al., 1981 b). The patients of the present study are assumed to have been infected by the western subtype of TBE-virus, as the eastern subtype has not as yet been isolated from ticks or patients in western Europe. The frequent presence of signs of inflammation in serum (leukocytosis, elevation of the sedimentation rate and of C-reactive protein) is noteworthy, as it should not be forgotten that these findings associated with headache, fever and meningism are highly indicative of bacterial meningitis. A predominance of neutrophilic cells over lymphocytes in the CSF would also support such a presumptive diagnosis, and consequently, most of the patients were treated with antibiotics, at least until the TBE serology was found to be positive. The most obvious feature of TBE, not only in patients, but also in experimentally infected monkeys, is ataxia, followed by paresis or paralysis of one or more limbs (Duniewicz, 1976; Kock er aI., 1992; Gunther et al., 1997). These and other neurological symptoms of TBE can be explained by the affinity of the TEE-virus for certain regions of the central nervous system. Post mortem examination of the brain and spinal cord from patients with a lethal course of TBE and from monkeys who were infected experimentally with the TBE-virus show similar findings (Grinschgl, 1955). \'<'hile there are numerous reports on the clinical picture of TBE, there is little information available on the convalescent phase or on the risk of contracting permanent damage. Follow-up data of patients with TEE have only been published in three studies. In the first study, which was done retrospectively, the frequency of sequelae was nearly 36 % (40/112 patients) (Haglund et al., 1996). In the second prospective study of 85 patients with TEE and 64 patients with meningoencephalitis of other viral aetiology (controls), the frequency of sequelae was significantly higher (40%) in patients with TBE than in the controls (Gunther et al ., 1997). In the last study, about 27 % of the patients suffered from sequelae (Kaiser, 1999). A lower frequency of sequelae reported in the latter study probably reflects the selection of assessment criteria and the fact that mental disorders were not intensely investigated.
Clinical course of TBE in Germany
References Anonymous. Risikogebiete der Friihsommer-Meningoenzephalitis in Europa. Epidemiologisches Bulletin 47, 293294 (1997). Duniewicz, M.: Clinical picture of Central European tickborne encephalitis. MMW 118, 1609-1612 (1976). Grinschgl, G.: Virus meningo-encephalitis in Austria. Clinical features, pathology, and diagnosis. Bull. World Health. Org. 12,535-564 (1955) . Gunther, G., Haglund, M., Lindquist, L., Forsgren, 1'.1., Skolden berg, B.: Tick-bone encephalitis in Sweden in relation to aseptic meningo-encephalitis of other etiology: a prospective study of clinical course and outcome. ]. Neurol. 244,230-238 (1997). Haglund, 1'.1., Forsgren, 1'.1., Lindh, G., Lindquist, L.: A toyear follow-up study of tick-borne encephalitis in the Stockholm area and a review of the References: need for a vaccination strategy. Scand.]. Infect. Dis. 28, 217-224 (1996). Heinz, EX., Kunz, C: Homogeneity of the structural glycoprotein from European isolates of tick-borne encephalitis virus: comparison with other f1aviviruses. J. Gen. Virol. 57,263-274 (1981) . Heinz, EX., Kunz, C: Molecular epidemiology of tick-borne encephalitis virus: peptide mapping of large non-structural proteins of European isolates and comparison with other flaviviruses.] . Gen. Virol. 62,271-285 (1982). Kaiser, R.: lick-borne encephalitis in southwestern Germany. Infection, 24, 398-399 (1996).
61
Kaiser, R.: Friihsommermeningoenzephalitis und Lyme-BorreIiose - Pravention vor und nach Zeckenstich. DMW 123, 847-853 (1998). Kaiser, R.: The clinical and epidemiological profile of tickborne encephalitis in southern Germany 1994-98: A prospective study of 656 patients. Brain 122,2067-2078 (1999). Kaiser, R., Holzmann, H.: Laboratory findings in tick-borne encephalitis - correlation with clinical outcome. Infection 28, 78-84 (2000). Kock, T., Stiinzner, D., Freidl, W., Pierer, K.: Clinical aspects of early summer meningoencephalitis in Styria. Nerven. arzt 63, 205-208 (1992). Mandl, C W., Heinz, EX., Kunz, C: Sequence of the structural proteins of tick-borne encephalitis virus (western subtype) and comparative analysis with other flaviviruses. Virology 166, 197-205 (1988) . Pletnev, A. G., Yarnshchikov, V. E, Blinov, V.M.: Nucleotide sequence of the genome and complete amino acid sequence of the polyprotein of tick-borne encephalitis virus. Virology 174, 250-263 (1990). Roggendorf, 1'.1.: Epidemiology of tick-borne encephalitis virus in Germany. Infection 24,465-466 (1996) . Roggendorf, 1'.1., Heinz, E, Deinhardr, E, Kunz, C: Serological diagnosis of acute tick-borne encephalitis by demonstration of antibodies of the IgM class. J. Med. Virol. 7, 41-50 (1981). WHO: Tick-borne encephalitis and haemorrhagic fever with renal syndrome in Europe. Report on a \VHO meeting. EURO Rep. Stud. 1-79 (1986).
InU. Med. Microbial. 291, Suppl. 33,58-61 (2002) © Urban & Fischer Verlag http://www.urbanfischer.de/journalslijmm
M
original article Tick-borne encephalitis (TBE) in Germany and clinical course of the disease Reinhard Kaiser* Department of Neurology, Municipal Hospital, Pforzheim, Germany
Abstract Between 1991 and 2000 about 1500 patients fell ill in Germany (Baden-Wuertternberg, Bavaria, Hesse) after infection with the tick-borne encephalitis (TEE) virus. Detailed clinical and epidemiological data of TEE were available from 850 patients. A biphasic course of the disease occurred in 75 % of patients. TEE presented as meningitis in 400 patients (47 %), as meningoencephalitis in 356 (42 %) and as meningoencephalornyelitis in 93 (11 %). Nine of the patients (l %) died from TEE. Five hundred and ninety three patients (70 %) had noticed a tick bite and the first symptoms occurred, on average, seven days later. The most frequent neurological symptoms were an impairment of consciousness (31 %), ataxia (18%) and paresis of the extremities (15%) and cranial nerves (11 %). Laboratory investigations revealed leukocytosis in the peripheral blood in 74 % of the patients, elevation of the sedimentation rate in 91 %, increased Cereacrive protein in 82 %, pleocytosis in the CSF of all patients tested, damage of the blood-CSF-barrier in 79 %, abnormalities in EEG in. 77% and abnormalities in MRI in 18 %. In general, adolescents up to 14 years of age had a more favourable course of the disease than adults. In view of the severity of the illness and the high frequency of sequelae, active immunisation against TEE is recommended for all subjects living in and travelling to areas of risk. Regarding the higher risk of severe manifestations of TEE in the elderly patients and the higher risk of failure of immunisation in this population, vaccination against TEE is more important in elderly subjects than in very young persons. Prevention of TEE by post exposure prophylaxis with hyperimmunoglobulins is less effective and should therefore not be performed.
Introduction Tick-borne encephalitis (TBE) is caused by an RNA virus belonging to the family Flaviviridae. Based on antibody adsorption experiments, peptide mapping and nucleotide sequencing, three different subtypes of TBE-virus have been identified (Heinz and Kunz, 1981; Heinz and Kunz, 1982; Mandl ct aI., 1988; Pletnev er aI., 1990). The western subtype is endemic in large parts of northern, central and eastern Europe, while the eastern subtypes can be found in the European and
Asian regions of the Commonwealth of Independent States (former Soviet Union) (WHO, 1986; Anonymous, 1997). In Germany, TBE is prevalent in Baden\X!uerttemberg, Bavaria and South Hesse (Roggendorf, 1996; Anonymous, 1997; Kaiser, 1999). During the years 1991 to 2000, about 1483 cases ofTBE were reported in Germany with a mean incidence in BadenWuerttemberg of 1.2/100,000 inhabitants per year and a case fatality rate of 1 % (Kaiser, 1996). In 1994 a dramatic increase of TBE-virus infections occurred in the area of Freiburg (southern Germany).
* Corresponding author: Reinhard Kaiser, Stadt. Klinikum Pforzheim, Kanzlerstralie 2-6, 75175 PIorzheim, Germany, Phone: 00497231969602, Fax: 00497231969911, E-mail: [email protected] 1438-4221/01/291/8-000 S 15.00/0
Clinical course of TBE in Germany With regard to the lack of information regarding the risks associated with and the outcome of TBE-virus infection a prospective study to investigate the clinical course, prognosis and epidemiology of TBE in Germany was undertaken. Results of this study support a policy of active immunisation against TBE for all subjects who stay in or travel to areas of risk and are likely to be exposed to ticks.
Patients and methods Patient population This prospective multicentre study was performed in Baden\Vuerttemberg,a federal Land in southern Germany, between 1994 and 2000. Data from patients were recorded by departments of Neurology (n =25), Internal Medicine (n =101) and Paediatrics (n = 14) in Baden-Wuerttemberg as well as 50 diagnostic laboratories and 40 health authorities which were invited to participate in this study. Data was acquired by means of a questionnaire. In addition, the clinicians were asked to send an anonymous record of the patients, which included laboratory data. Patients were asked to give their informed consent. Data were made anonymous to satisfy the German data protection law. TBE was diagnosed by the demonstration of specific IgM and IgG activity in the serum by routine serological tests (Roggendorf et al., 1981). In patients recently immunised with TBE vaccine, CNS infection was diagnosed by demonstration of intrathecally produced viral TBE IgM activity. Definition of areas of riskfor TBE-virus infection According to the recommendations of a national conference on tick-borne diseases held in Freiburg in March 1998, the areas of risk in Germany for TBE-virus infection are defined as administrative districts with at least five cases of TBE within five years (Kaiser, 1998).
Statistics Independent samples were analysed by means of the r-test and Levene's test for equality of variances. The frequency of positive findings was examined by the chi2-test. The significance level considered was 1 % (P::5 0.01).
Results Epidemiological data Between 1994 and 2000 a total of 850 patients fell ill after infection with TBE-virus in Baden-Wuerttemberg and South Hesse. Most of the infections were acquired within the valleys of the black forest and in the vicinity of Lake Constance. Out of 850 individuals, 596 (70 %) had noticed a tick bite before admission. In 765 patients (90 %) infection took place during leisure time activity and only 85 (10 %) had professions associated with outdoor activ-
59
ities (forest workers, farmers). No obvious association between geographical region and the severity of the disease could be found. Admissions to hospital of patients with TBE were between March and December in each year, but two thirds of infections were acquired between June and August. On average twice as many men as women fell ill but the mean age of male (45 ± 19 years) and female patients (43 ± 21 years) did not differ. 11 % (n = 95) were children and adolescents up to 14 years.
Clinical presentation A biphasic course of illness with a prodromal period occurred in 635 patients (75 %). The first stage of illness, characterised by fever, headache and sometimes malaise, upper respiratory andlor abdominal symptoms, lasted a median of 4 days (range 1-7). Thereafter, most of the patients recovered for a median of 7 days (range 3-21). Of the 850 patients, 400 (47 %) presented with meningitis, 356 (42 %) with meningoencephalitis and 93 (11 %) with meningoencephalomyelitis. Patients with meningoencephalitis mostly suffered from an impairment of consciousness, ataxia and paresis of the cranial nerves and the limbs. Impairment of consciousness was a frequent finding in patients with meningoencephalitis and encephalomyelitis, but patients with men ingoencephalomyelitis were more severely affected. Flaccid paresis of the extremities (:5 315) was the most prominent feature in all patients with meningoencephalomyelitis; forty patients (43 %) suffered from either mono- or tetraparesis and 13 patients (15%) from paraparesis of the lower extremities. In meningoencephalitis, paresis of the extremities was less frequent (monoparesis 7 %, hemiparesis 6 %), less serious (> 315) and mostly transitory of a few days duration. A similar pattern was observed with pareses of the cranial nerves which were more severe and relatively more frequent in patients with meningoencephalomyelitis. In patients with meningoencephalitis most pareses of the cranial nerves were transitory for three to ten days, except for hearing impairment, dysphagia and dysarthria which persisted for longer periods. Twelve patients with meningoencephalomyelitis were continuously ventilated either to the present time (n = 2, ventilation for 4 to 7 years) or until death (n = 10; 1-52 weeks after onset of the disease). Tremor of the limbs mostly occurred as intention tremor (n =20) and less frequently as resting tremor (n = 8). Other neurological symptoms occurred with a frequency of less than 3 %.
laboratory findings on admission to hospital TBE-virus-specific IgM-antibodies in serum were present in 847/850 patients with TBE (99 %); in three
60
R. Kaiser
patients the diagnosis was established as the result of a significant rise of IgG antibodies in serum, and an accompanying increase of antibody avidity three weeks after the first testing. All patients revealed IgGantibodies against TBE-virus after a maximum of two weeks following admission to hospital. Examination of the peripheral blood revealed leukocytosis (> 10,000/~tl) in 224/302 patients (74%) and elevation of the sedimentation rate in 223/245 patients (91 %) and of Cereactive protein in 127/155 patients (82 %). The frequency and the extent of abnormal values did not correlate with the diagnosis or prognosis of TBE . Pleocytosis in the cerebrospinal fluid (CSF) was a general finding in all patients; the median cell count was 60/~ll with a range from 6 to 1200/~ll. Impairment of the blood-CSF-barrier was demonstrated in 304/380 patients (80 %) studied. Abnormal values of total protein in the CSF were detected more frequently in patients with meningoencephalornyelitis (88 %, P = 0.021) and meningoencephalitis (82 %, P = 0.025) than in patients with meningitis (71 %). Additionally, patients with meningitis had lower levels of total protein in the CSF than patients with other manifestations.
Electro-encephalogram (EEG) and magnetic resonance imaging (MRI) Of 214 patients who were examined by EEG, 165 (77%) presented with abnormalities (diffuse slowing and/or intermittent focal abnormalities). The frequency of abnormal EEG findings was similar in patients with meningoencephalitis (91 %) and meningoencephalomyelitis (96%). MRI studies were carried out on 102 patients and 18 showed abnormal findings. Of 64 patients with meningoencephalitis and 25 with meningoencephalomyelitis, 11 (17 %) and 7 (28 %), respectively, showed abnormalities on MRI. The MRI was unremarkable in 13 patients with meningitis. In 15/18 patients the findings were confined to the thalamus, in three patients further lesions were detected in the cer ebellum, brain-stem, and caudate nucleus. One of these three patients was under immunosuppression with ciclosporin and corticosteroids following renal transplantation and two patients had received specific immunoglobulins intramuscularly after the notion of the tick bite.
Discussion The diagnosis of TBE is derived from epidemiological (a stay in an area of risk for TEE, facultative history of a tick bite) and clinical data (biphasic course of disease, neurological symptoms with ataxia being most indica-
tive for this infection), and the demonstration of TBEspecific IgM and IgG-antibodies in the serum. In gen eral, there is an intrathecal synthesis of TBE-specific IgM- and/or IgG-antibodies in the CSF, at the latest three weeks after admission to hospital (Kaiser and Holzmann, 2000). Although this latter criterion is the most specific serological method of confirming the diagnosis, the presence of sp ecific IgM-antibodies in the serum is generally considered to be adequate evidence of TBE (Roggendorf et al., 1981 b). The patients of the present study are assumed to have been infected by the western subtype of TBE-virus, as the eastern subtype has not as yet been isolated from ticks or patients in western Europe. The frequent presence of signs of inflammation in serum (leukocytosis, elevation of the sedimentation rate and of C-reactive protein) is noteworthy, as it should not be forgotten that these findings associated with headache, fever and meningism are highly indicative of bacterial meningitis. A predominance of neutrophilic cells over lymphocytes in the CSF would also support such a presumptive diagnosis, and consequently, most of the patients were treated with antibiotics, at least until the TBE serology was found to be positive. The most obvious feature of TBE, not only in patients, but also in experimentally infected monkeys, is ataxia, followed by paresis or paralysis of one or more limbs (Duniewicz, 1976; Kock er aI., 1992; Gunther et al., 1997). These and other neurological symptoms of TBE can be explained by the affinity of the TEE-virus for certain regions of the central nervous system. Post mortem examination of the brain and spinal cord from patients with a lethal course of TBE and from monkeys who were infected experimentally with the TBE-virus show similar findings (Grinschgl, 1955). \'<'hile there are numerous reports on the clinical picture of TBE, there is little information available on the convalescent phase or on the risk of contracting permanent damage. Follow-up data of patients with TEE have only been published in three studies. In the first study, which was done retrospectively, the frequency of sequelae was nearly 36 % (40/112 patients) (Haglund et al., 1996). In the second prospective study of 85 patients with TEE and 64 patients with meningoencephalitis of other viral aetiology (controls), the frequency of sequelae was significantly higher (40%) in patients with TBE than in the controls (Gunther et al ., 1997). In the last study, about 27 % of the patients suffered from sequelae (Kaiser, 1999). A lower frequency of sequelae reported in the latter study probably reflects the selection of assessment criteria and the fact that mental disorders were not intensely investigated.
Clinical course of TBE in Germany
References Anonymous. Risikogebiete der Friihsommer-Meningoenzephalitis in Europa. Epidemiologisches Bulletin 47, 293294 (1997). Duniewicz, M.: Clinical picture of Central European tickborne encephalitis. MMW 118, 1609-1612 (1976). Grinschgl, G.: Virus meningo-encephalitis in Austria. Clinical features, pathology, and diagnosis. Bull. World Health. Org. 12,535-564 (1955) . Gunther, G., Haglund, M., Lindquist, L., Forsgren, 1'.1., Skolden berg, B.: Tick-bone encephalitis in Sweden in relation to aseptic meningo-encephalitis of other etiology: a prospective study of clinical course and outcome. ]. Neurol. 244,230-238 (1997). Haglund, 1'.1., Forsgren, 1'.1., Lindh, G., Lindquist, L.: A toyear follow-up study of tick-borne encephalitis in the Stockholm area and a review of the References: need for a vaccination strategy. Scand.]. Infect. Dis. 28, 217-224 (1996). Heinz, EX., Kunz, C: Homogeneity of the structural glycoprotein from European isolates of tick-borne encephalitis virus: comparison with other f1aviviruses. J. Gen. Virol. 57,263-274 (1981) . Heinz, EX., Kunz, C: Molecular epidemiology of tick-borne encephalitis virus: peptide mapping of large non-structural proteins of European isolates and comparison with other flaviviruses.] . Gen. Virol. 62,271-285 (1982). Kaiser, R.: lick-borne encephalitis in southwestern Germany. Infection, 24, 398-399 (1996).
61
Kaiser, R.: Friihsommermeningoenzephalitis und Lyme-BorreIiose - Pravention vor und nach Zeckenstich. DMW 123, 847-853 (1998). Kaiser, R.: The clinical and epidemiological profile of tickborne encephalitis in southern Germany 1994-98: A prospective study of 656 patients. Brain 122,2067-2078 (1999). Kaiser, R., Holzmann, H.: Laboratory findings in tick-borne encephalitis - correlation with clinical outcome. Infection 28, 78-84 (2000). Kock, T., Stiinzner, D., Freidl, W., Pierer, K.: Clinical aspects of early summer meningoencephalitis in Styria. Nerven. arzt 63, 205-208 (1992). Mandl, C W., Heinz, EX., Kunz, C: Sequence of the structural proteins of tick-borne encephalitis virus (western subtype) and comparative analysis with other flaviviruses. Virology 166, 197-205 (1988) . Pletnev, A. G., Yarnshchikov, V. E, Blinov, V.M.: Nucleotide sequence of the genome and complete amino acid sequence of the polyprotein of tick-borne encephalitis virus. Virology 174, 250-263 (1990). Roggendorf, 1'.1.: Epidemiology of tick-borne encephalitis virus in Germany. Infection 24,465-466 (1996) . Roggendorf, 1'.1., Heinz, E, Deinhardr, E, Kunz, C: Serological diagnosis of acute tick-borne encephalitis by demonstration of antibodies of the IgM class. J. Med. Virol. 7, 41-50 (1981). WHO: Tick-borne encephalitis and haemorrhagic fever with renal syndrome in Europe. Report on a \VHO meeting. EURO Rep. Stud. 1-79 (1986).