954
in a 4-month-old boy. At the age of five years neurobrucellosis was diagnosed. Cultures of CSF, blood and shunt specimens all yielded Brucella abortus and it was concluded that the infecting organism had entered the shunt and the CSF from the blood stream after septicaemia caused by Brucella abortus. In this case the progressing neurologic signs and symptoms might also have occurred in the absence of a shunt as in most cases of neurobrucellosis. A case of brucellosis complicated by peritonitis and meningitis was described by Diab et al. in 1988 (3), but in this case no shunt was inserted and the abdominal involvement manifested itself before involvement of the central nervous system. An interesting aspect of our case is the unrecognised neurobrucellosis seeding Brucella melitensis from the brain ventricles via the ventriculoperitoneal shunt into the peritoneal cavity. A raised mononuclear cell count plus a rising protein level in the CSF were the only indications of the infectious nature of the condition. In view of these findings the CSF should have been cultured even without suspecting neurobrucellosis although culture still might not have revealed the diagnosis since in 70 % to 90 % of neurobrucellosis cases the CSF is culture negative (4). T h e r e are no signs and symptoms pathognomonic for neurobrucellosis, which can resemble many diseases of infectious as well as non-infectious etiology (1). The disease is incapacitating if not diagnosed but can be cured if recognised; this diagnosis should thus be considered in a patient with chronic intracranial hypertension. Statistically, less than ten cases of brucellosis can be expected annually in Denmark, less than 5 % of these being neurobrucellosis (1): One would thus expect to diagnose neurobrucellosis only a few times every ten years. Our case illustrates the problem of establishing a diagnosis when a disease is of extremely low incidence and the routine diagnostic methods have low sensitivity. As stressed in the literature, the anamnestic exploration is important in neurobrucellosis. If the disease is suspected an E I A to detect Brucella melitensis specific IgG, IgA and IgM can be diagnostic (4). Due to inhibition of degranulation of peroxidase positive granules in polymorphonuclear leucocytes, Brucella melitensis can survive inside phagocytic cells for several months (5, 6). It can also survive in unpasteurised goat milk products for a n u m b e r of months (7). These characteristics of the organism, together with increasing migra-
Eur. J. Clin. Microbiol. Infect. Dis.
tion worldwide, now facilitate spread of Brucella melitensis infection to countries where according to national statistics it is seldom encountered.
H . A n d e r s e n 1. A. M o r t e n s e n 2 I Department of Clinical Microbiology, Herlev Hospital, University of Copenhagen, Herlev Ringvej, DK-2730 Herlev, Denmark. 2 University Clinic of Neurosurgery, Copenhagen County Hospital, Glostrup, Denmark. References 1. Bouza E, de la Torre MG, Parras F, Guerroro A, Rodriguez-Creixems M, Gobernado J: Bruccllar
meningitis. Reviews of Infectious Diseases 1987, 9: 810--822. 2. Puri P, Harvey TW: Colonisation of ventrieuloatrial shunt with Brucella abortus. British Medical Journal 1981, 151: 1754-1755. 3. Diab SM, Araj GF, AI-Asfour A J, AI-Yusuf AR:
Brucellosis: atypical presentation with peritonitis and meningitis. Tropical and Geographical Medicine 1989, 41: 160-163. 4. George FA, Lulu AR, Khaleeb MI, Saadah MA, Shakir RA: ELISA versus routine tests in the diagnosis
of patients with systemic and neurobrucellosis. APMIS 1988, 96: 171-176. 5. Young EJ, Borchert M, Krelzer FL, Musher DM: Phagocytosis and killing of Brucella by human
polymorphnuclear leukocytes. Journal of Infectious Diseases 1985, 151: 682-690. 6. Canning PC, Rolh JA, Deyoe BL: Release of 5'guanosine monophosphate and adenine by Brucella abortus and their role in the intracellular survival of the bacteria. Journal of Infectious Diseases 1986, 154: 464--470. 7. Weber A: Gegenwfirtige Erkenntnisse iiber Epidemiologie, Klinik und Diagnose der Brucellose. Medizinische Welt 1979, 22: 849-853.
Meningoradiculitis due to T i c k b o r n e Encephalitis Virus in France
The tickborne encephalitis virus is a flavivirus causing encephalitis and meningitis which is found in Central Europe, including the French Alsace (1, 2). Other neurological manifestations are rare. Meningoradiculitis after a tick bite is most often related to Lyme disease (3). In this report we describe a case of meningoradiculitis due to tickborne encephalitis virus following a
Vol. 11, 1992
tick bite occurring in an area from which no cases have been reported previously. A 41-year-old French man was referred in September 1991 to our unit with acute meningitis. A detailed anamnesis revealed that the patient had had a tick bite during a picnic in the Col du Donon, a wooded area of the Vosges mountains close to the German border. Six days after the bite, his temperature rose to 39 °C and he complained of asthenia, myalgia, headache and vomiting. The signs and symptoms then disappeared for one week. The immunofluorescence test to detect Lyme disease was negative ten days after the bite. Fifteen days after the first clinical signs and symptoms, the patient was again admitted with fever (40 °C). Questioning and physical examination revealed headache, vomiting, photophobia in association with Kernig and Brudzinski signs, and hypersomnia, but no cranial neuritis, hepatosplenomegaly or lymphadenopathy. Two black, crusted, non-inflammatory lesions one centimeter in diameter, corresponding to two tick bites, were also noted. The leukocyte count was 16,700/mm 3 (neutrophils 80 %), the platelet count 365,000/mm 3, the hemoglobin level 14.3 g/dl and the C-reactive protein level 16 mg/l. Results of tests of liver and kidney function and hemostasis were normal. The cerebrospinal fluid (CSF) was clear and contained 0.60 g/l proteins, 0.65 g/1 glucose, 6.7 g/l chloride and 300/mm 3 leucocytes (75 % lymphocytes, 25 % granulocytes). No pathogen was discovered on culture of CSF, and the Lyme immunofluorescent test was negative in both blood and CSE The patient initially received ceftriaxone (4 g daily i.m.) for SUspected Lyme disease and improved within 48 hours. Four days after being admitted, the patient COmplained of bilateral paresthesia in the C8 dermatome which increased on coughing, and there was areflexia and hypoesthesia to pin prick in the cutaneous distribution of the right C8 dermatome. No paralysis was observed. The neurological disorders improved within 24 hours and the patient recovered fully and was discharged five days later. Ceftriaxone therapy was stopped. The patient had received a yellow fever vaccination ten years previously. Serological tests for arboviruses (hemagglutination-inhibition) 18 days after the first clinical symptoms were negative for alphaviruses (Chikungunia), bunyaviruses (Bunyamvera, Tahyna) and phleboviruses (Sicile). The results of tests for flaviviruses are shown in Table 1. Anti-Langat IgM antibodies
955
were detected in the serum by the immunocapture test and an E I A (4). The serum of our patient neutralised Langat virus in the plaque reduction neutralisation test using PS cell line cultures. The Langat virus belongs to the complex of tickborne encephalitis viruses and is used as an antigen for antibody detection. These results confirmed the diagnosis of tickborne encephalitis, despite the failure to isolate the virus. Detection of immunoglobulin by E I A is more specific for arboviruses than other serologic tests (4). The neutralization test was not performed because no viral strain was available in our laboratory. Cross-reactivity between flaviviruses is frequent, however it is rarely seen with IgM antibodies. The transient presence of anti-Langat IgM antibodies is a very good marker of recent infection. Langat virus is specific for the tickborne encephalitis virus complex (1). Although positivity was seen for the West Nile and Japanese encephalitis viruses the patient had not travelled in areas where these viruses are present, and no IgM antibodies against these viruses were detected. No CSF sample was saved to test for the presence of anti-Langat IgM. Tickborne encephalitis virus is an arbovirus transmitted by Ixodes ricinus (2). The virus was first detected in France in the Alsace in 1971 (5), which at that time was the western limit of a large endemic area extending from the Urals to the Black Forest and Switzerland, and from the Scandinavian countries to Yugoslavia and Greece (6). lxodes ricinus was the single vector and viral dissemination remained stable throughout the following years. The natural reservoir includes ticks and three wild rodents: Apodemus sylwlticus, Apodemus flavicollis and Clethrionornys glareolus (7). However, differences were observed between this and other endemic areas in Eastern Europe. Very few cases of infection with the virus have been reported in France (7), which could be due to the low percentage (around 0.5 %) of potentially infective ticks, the lower virulence of French strains or fewer visits to the forests (7). The first cases were reported twenty years ago in France (5, 8), but no cases have previously been reported in the French Vosges. A seroepidemiological survey should be performed in this geographic area to determine the importance of our findings. The clinical features of this case were similar to those in previous descriptions by European authors, including the biphasic course (9), with a febrile phase (corresponding to viremia) of about
956
Eur. J. Clin. Microbiol. Infect. Dis.
Table 1: Results of testsa to detect antibodies against flaviviruses in a patient with suspected tickborne encephalitis virus infection 18 days, 25 days and 7 months after a tick bite. Langat virus
West Nile virus
Japanese encephalitis virus
Dengue 2 virus
Yellow fever virus
Day 18 IgM IgG
+ "~
(~)b
+b
-
+~
Day 25 IgM IgG
+ +
-(+)b
+b
-
+c
Month 7 IgM IgG
+
(T)b
-
+°
- negative; (+) weakly positive; + strongly positive (> O D of control x 2). a IgM: immunoeapture test and EIA. IgG: EIA. b Cross-reactivity. c Positive due to previous yellow fever vaccination.
one week prior to the onset of headache and fatigue. After an initial improvement of a few days, the second phase begins abruptly with more intense headache, neck stiffness and vomiting. The patient then develops either encephalitis or meningoencephalitis, with or without paralysis. Sequelae are rare and the mortality rate is less than 5 %. Meningoradiculitis has rarely been reported in tickborne encephalitis (9), but it is a well known feature of Lyme disease (3). An increased leucocyte count has been reported during the second phase of the disease (7). Anti-Langat IgM antibodies should be sought in the serum and CSF of patients with unexplained neurological disorders, including meningoradiculoneuritis, occurring within a few days of a tick bite in an endemic area. Tickborne encephalitis should be considered in the differential diagnosis in patients seronegative for Lyme disease.
O. Lortholary 1 B. D u p o n t 1. M. Eliaszewicz 1 A. Chippaux 2 E Rodhain 3 Department of Infectious Diseases and Tropical Medicine, Pasteur Institute Hospital, 209 rue de Vaugirard, 75724 Paris, Cedex 15, France. 2 National Reference Center for Arboviruses, and 3Vectorial Systems Ecology Unit, Pasteur Institute, Paris, France.
References 1. Monath TP: Flavivirus. In: Mandell GL, Douglas RG, Bennett JE: Principles and practice of infectious diseases. John Wiley, New York, 1985, p. 920-923. 2. Hannoun C, Rodhain F: Arboviroses. In: Encyclop6die M6dico-Chirurgicale, Maladies Infectieuses. Editions Techniques, Paris, 1980. 3. Reik L, Steere AC, Bartenhagen NH, Shope RE, Malawista SE: Neurologic abnormalities of Lyme disease. Medicine 1979, 58: 281-294. 4. Le Guenno B: Rapport annuel 1988 du Centre eollaborateur OMS de r6f6rence et de recherche pour les arbovirus. Institut Pasteur, Dakar, 1988, p. 27-30. 5. Hannoun C, Chatelain J, Krams S, Guillon JC: Isolement en Alsace du virus de l'enc6phalite ~ tiques. Comptes Rendus de I'Acad6mie des Sciences de Paris 1971, 272: 766-768. 6. Hannoun C: Les enc6phatites ~ tiques en Europe. M6decine q¥opicale 1980, 40: 510-519. 7. Rodhain F, Woehl-Kremer B, Perre! (2, Wiederkehr JL, Perez C, Hannoun C: Nouvelle observation d'enc6phalite ~ tiques en Alsace. M6decine et Maladies Infectieuses 1987: 35-37. 8. Bastin R, Lapresle C, Frottier J, Hannoun C, Krams S, Lenoir G: Un cas d'enc6phalite ~ tiques observ6 en France avec isolement du virus. Lyon M6dicale 1971, 225: 109-111. 9. Henner K, Hanzal F: Les enc6phalites europ6ennes tiques. Revue de Neurologie 1963, 108: 697-752.
in a 4-month-old boy. At the age of five years neurobrucellosis was diagnosed. Cultures of CSF, blood and shunt specimens all yielded Brucella abortus and it was concluded that the infecting organism had entered the shunt and the CSF from the blood stream after septicaemia caused by Brucella abortus. In this case the progressing neurologic signs and symptoms might also have occurred in the absence of a shunt as in most cases of neurobrucellosis. A case of brucellosis complicated by peritonitis and meningitis was described by Diab et al. in 1988 (3), but in this case no shunt was inserted and the abdominal involvement manifested itself before involvement of the central nervous system. An interesting aspect of our case is the unrecognised neurobrucellosis seeding Brucella melitensis from the brain ventricles via the ventriculoperitoneal shunt into the peritoneal cavity. A raised mononuclear cell count plus a rising protein level in the CSF were the only indications of the infectious nature of the condition. In view of these findings the CSF should have been cultured even without suspecting neurobrucellosis although culture still might not have revealed the diagnosis since in 70 % to 90 % of neurobrucellosis cases the CSF is culture negative (4). T h e r e are no signs and symptoms pathognomonic for neurobrucellosis, which can resemble many diseases of infectious as well as non-infectious etiology (1). The disease is incapacitating if not diagnosed but can be cured if recognised; this diagnosis should thus be considered in a patient with chronic intracranial hypertension. Statistically, less than ten cases of brucellosis can be expected annually in Denmark, less than 5 % of these being neurobrucellosis (1): One would thus expect to diagnose neurobrucellosis only a few times every ten years. Our case illustrates the problem of establishing a diagnosis when a disease is of extremely low incidence and the routine diagnostic methods have low sensitivity. As stressed in the literature, the anamnestic exploration is important in neurobrucellosis. If the disease is suspected an E I A to detect Brucella melitensis specific IgG, IgA and IgM can be diagnostic (4). Due to inhibition of degranulation of peroxidase positive granules in polymorphonuclear leucocytes, Brucella melitensis can survive inside phagocytic cells for several months (5, 6). It can also survive in unpasteurised goat milk products for a n u m b e r of months (7). These characteristics of the organism, together with increasing migra-
Eur. J. Clin. Microbiol. Infect. Dis.
tion worldwide, now facilitate spread of Brucella melitensis infection to countries where according to national statistics it is seldom encountered.
H . A n d e r s e n 1. A. M o r t e n s e n 2 I Department of Clinical Microbiology, Herlev Hospital, University of Copenhagen, Herlev Ringvej, DK-2730 Herlev, Denmark. 2 University Clinic of Neurosurgery, Copenhagen County Hospital, Glostrup, Denmark. References 1. Bouza E, de la Torre MG, Parras F, Guerroro A, Rodriguez-Creixems M, Gobernado J: Bruccllar
meningitis. Reviews of Infectious Diseases 1987, 9: 810--822. 2. Puri P, Harvey TW: Colonisation of ventrieuloatrial shunt with Brucella abortus. British Medical Journal 1981, 151: 1754-1755. 3. Diab SM, Araj GF, AI-Asfour A J, AI-Yusuf AR:
Brucellosis: atypical presentation with peritonitis and meningitis. Tropical and Geographical Medicine 1989, 41: 160-163. 4. George FA, Lulu AR, Khaleeb MI, Saadah MA, Shakir RA: ELISA versus routine tests in the diagnosis
of patients with systemic and neurobrucellosis. APMIS 1988, 96: 171-176. 5. Young EJ, Borchert M, Krelzer FL, Musher DM: Phagocytosis and killing of Brucella by human
polymorphnuclear leukocytes. Journal of Infectious Diseases 1985, 151: 682-690. 6. Canning PC, Rolh JA, Deyoe BL: Release of 5'guanosine monophosphate and adenine by Brucella abortus and their role in the intracellular survival of the bacteria. Journal of Infectious Diseases 1986, 154: 464--470. 7. Weber A: Gegenwfirtige Erkenntnisse iiber Epidemiologie, Klinik und Diagnose der Brucellose. Medizinische Welt 1979, 22: 849-853.
Meningoradiculitis due to T i c k b o r n e Encephalitis Virus in France
The tickborne encephalitis virus is a flavivirus causing encephalitis and meningitis which is found in Central Europe, including the French Alsace (1, 2). Other neurological manifestations are rare. Meningoradiculitis after a tick bite is most often related to Lyme disease (3). In this report we describe a case of meningoradiculitis due to tickborne encephalitis virus following a
Vol. 11, 1992
tick bite occurring in an area from which no cases have been reported previously. A 41-year-old French man was referred in September 1991 to our unit with acute meningitis. A detailed anamnesis revealed that the patient had had a tick bite during a picnic in the Col du Donon, a wooded area of the Vosges mountains close to the German border. Six days after the bite, his temperature rose to 39 °C and he complained of asthenia, myalgia, headache and vomiting. The signs and symptoms then disappeared for one week. The immunofluorescence test to detect Lyme disease was negative ten days after the bite. Fifteen days after the first clinical signs and symptoms, the patient was again admitted with fever (40 °C). Questioning and physical examination revealed headache, vomiting, photophobia in association with Kernig and Brudzinski signs, and hypersomnia, but no cranial neuritis, hepatosplenomegaly or lymphadenopathy. Two black, crusted, non-inflammatory lesions one centimeter in diameter, corresponding to two tick bites, were also noted. The leukocyte count was 16,700/mm 3 (neutrophils 80 %), the platelet count 365,000/mm 3, the hemoglobin level 14.3 g/dl and the C-reactive protein level 16 mg/l. Results of tests of liver and kidney function and hemostasis were normal. The cerebrospinal fluid (CSF) was clear and contained 0.60 g/l proteins, 0.65 g/1 glucose, 6.7 g/l chloride and 300/mm 3 leucocytes (75 % lymphocytes, 25 % granulocytes). No pathogen was discovered on culture of CSF, and the Lyme immunofluorescent test was negative in both blood and CSE The patient initially received ceftriaxone (4 g daily i.m.) for SUspected Lyme disease and improved within 48 hours. Four days after being admitted, the patient COmplained of bilateral paresthesia in the C8 dermatome which increased on coughing, and there was areflexia and hypoesthesia to pin prick in the cutaneous distribution of the right C8 dermatome. No paralysis was observed. The neurological disorders improved within 24 hours and the patient recovered fully and was discharged five days later. Ceftriaxone therapy was stopped. The patient had received a yellow fever vaccination ten years previously. Serological tests for arboviruses (hemagglutination-inhibition) 18 days after the first clinical symptoms were negative for alphaviruses (Chikungunia), bunyaviruses (Bunyamvera, Tahyna) and phleboviruses (Sicile). The results of tests for flaviviruses are shown in Table 1. Anti-Langat IgM antibodies
955
were detected in the serum by the immunocapture test and an E I A (4). The serum of our patient neutralised Langat virus in the plaque reduction neutralisation test using PS cell line cultures. The Langat virus belongs to the complex of tickborne encephalitis viruses and is used as an antigen for antibody detection. These results confirmed the diagnosis of tickborne encephalitis, despite the failure to isolate the virus. Detection of immunoglobulin by E I A is more specific for arboviruses than other serologic tests (4). The neutralization test was not performed because no viral strain was available in our laboratory. Cross-reactivity between flaviviruses is frequent, however it is rarely seen with IgM antibodies. The transient presence of anti-Langat IgM antibodies is a very good marker of recent infection. Langat virus is specific for the tickborne encephalitis virus complex (1). Although positivity was seen for the West Nile and Japanese encephalitis viruses the patient had not travelled in areas where these viruses are present, and no IgM antibodies against these viruses were detected. No CSF sample was saved to test for the presence of anti-Langat IgM. Tickborne encephalitis virus is an arbovirus transmitted by Ixodes ricinus (2). The virus was first detected in France in the Alsace in 1971 (5), which at that time was the western limit of a large endemic area extending from the Urals to the Black Forest and Switzerland, and from the Scandinavian countries to Yugoslavia and Greece (6). lxodes ricinus was the single vector and viral dissemination remained stable throughout the following years. The natural reservoir includes ticks and three wild rodents: Apodemus sylwlticus, Apodemus flavicollis and Clethrionornys glareolus (7). However, differences were observed between this and other endemic areas in Eastern Europe. Very few cases of infection with the virus have been reported in France (7), which could be due to the low percentage (around 0.5 %) of potentially infective ticks, the lower virulence of French strains or fewer visits to the forests (7). The first cases were reported twenty years ago in France (5, 8), but no cases have previously been reported in the French Vosges. A seroepidemiological survey should be performed in this geographic area to determine the importance of our findings. The clinical features of this case were similar to those in previous descriptions by European authors, including the biphasic course (9), with a febrile phase (corresponding to viremia) of about
956
Eur. J. Clin. Microbiol. Infect. Dis.
Table 1: Results of testsa to detect antibodies against flaviviruses in a patient with suspected tickborne encephalitis virus infection 18 days, 25 days and 7 months after a tick bite. Langat virus
West Nile virus
Japanese encephalitis virus
Dengue 2 virus
Yellow fever virus
Day 18 IgM IgG
+ "~
(~)b
+b
-
+~
Day 25 IgM IgG
+ +
-(+)b
+b
-
+c
Month 7 IgM IgG
+
(T)b
-
+°
- negative; (+) weakly positive; + strongly positive (> O D of control x 2). a IgM: immunoeapture test and EIA. IgG: EIA. b Cross-reactivity. c Positive due to previous yellow fever vaccination.
one week prior to the onset of headache and fatigue. After an initial improvement of a few days, the second phase begins abruptly with more intense headache, neck stiffness and vomiting. The patient then develops either encephalitis or meningoencephalitis, with or without paralysis. Sequelae are rare and the mortality rate is less than 5 %. Meningoradiculitis has rarely been reported in tickborne encephalitis (9), but it is a well known feature of Lyme disease (3). An increased leucocyte count has been reported during the second phase of the disease (7). Anti-Langat IgM antibodies should be sought in the serum and CSF of patients with unexplained neurological disorders, including meningoradiculoneuritis, occurring within a few days of a tick bite in an endemic area. Tickborne encephalitis should be considered in the differential diagnosis in patients seronegative for Lyme disease.
O. Lortholary 1 B. D u p o n t 1. M. Eliaszewicz 1 A. Chippaux 2 E Rodhain 3 Department of Infectious Diseases and Tropical Medicine, Pasteur Institute Hospital, 209 rue de Vaugirard, 75724 Paris, Cedex 15, France. 2 National Reference Center for Arboviruses, and 3Vectorial Systems Ecology Unit, Pasteur Institute, Paris, France.
References 1. Monath TP: Flavivirus. In: Mandell GL, Douglas RG, Bennett JE: Principles and practice of infectious diseases. John Wiley, New York, 1985, p. 920-923. 2. Hannoun C, Rodhain F: Arboviroses. In: Encyclop6die M6dico-Chirurgicale, Maladies Infectieuses. Editions Techniques, Paris, 1980. 3. Reik L, Steere AC, Bartenhagen NH, Shope RE, Malawista SE: Neurologic abnormalities of Lyme disease. Medicine 1979, 58: 281-294. 4. Le Guenno B: Rapport annuel 1988 du Centre eollaborateur OMS de r6f6rence et de recherche pour les arbovirus. Institut Pasteur, Dakar, 1988, p. 27-30. 5. Hannoun C, Chatelain J, Krams S, Guillon JC: Isolement en Alsace du virus de l'enc6phalite ~ tiques. Comptes Rendus de I'Acad6mie des Sciences de Paris 1971, 272: 766-768. 6. Hannoun C: Les enc6phatites ~ tiques en Europe. M6decine q¥opicale 1980, 40: 510-519. 7. Rodhain F, Woehl-Kremer B, Perre! (2, Wiederkehr JL, Perez C, Hannoun C: Nouvelle observation d'enc6phalite ~ tiques en Alsace. M6decine et Maladies Infectieuses 1987: 35-37. 8. Bastin R, Lapresle C, Frottier J, Hannoun C, Krams S, Lenoir G: Un cas d'enc6phalite ~ tiques observ6 en France avec isolement du virus. Lyon M6dicale 1971, 225: 109-111. 9. Henner K, Hanzal F: Les enc6phalites europ6ennes tiques. Revue de Neurologie 1963, 108: 697-752.
