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Borrelia crocidurae meningoencephalitis, West Africa.
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MedLine Citation:
PMID:  23347436     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Borrelia crocidurae-associated relapsing fever is endemic to West Africa and is considered benign. We report 4 patients with B. crocidurae-associated neurologic symptoms; 2 of their cases had been misdiagnosed. Frequency and severity of this disease could be underestimated; molecular methods and serodiagnostic tests for Lyme disease might be helpful in its detection.
Authors:
Sandrine Goutier; Elisabeth Ferquel; Claudine Pinel; Annick Bosseray; Bruno Hoen; Gérard Couetdic; Amina Bourahoui; Claire Lapostolle; Hervé Pelloux; Martine Garnier; Natacha Sertour; Isabelle Pelloux; Patricia Pavese; Muriel Cornet
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Emerging infectious diseases     Volume:  19     ISSN:  1080-6059     ISO Abbreviation:  Emerging Infect. Dis.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-25     Completed Date:  2013-07-01     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  9508155     Medline TA:  Emerg Infect Dis     Country:  United States    
Other Details:
Languages:  eng     Pagination:  301-4     Citation Subset:  IM    
Affiliation:
Grenoble Teaching Hospital, Grenoble, France. sandrinegoutier@hotmail.com
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MeSH Terms
Descriptor/Qualifier:
Adult
Borrelia / genetics*
Ceftriaxone / therapeutic use
Child
Doxycycline / therapeutic use
Endemic Diseases*
Female
France
Humans
Male
Meningoencephalitis / drug therapy,  epidemiology,  microbiology*
Middle Aged
Molecular Diagnostic Techniques
Polymerase Chain Reaction
RNA, Bacterial / genetics
RNA, Ribosomal, 16S / genetics
Relapsing Fever / drug therapy,  epidemiology,  microbiology*
Senegal / epidemiology
Sequence Analysis, DNA
Travel
Chemical
Reg. No./Substance:
0/RNA, Bacterial; 0/RNA, Ribosomal, 16S; 564-25-0/Doxycycline; 73384-59-5/Ceftriaxone
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Journal Information
Journal ID (nlm-ta): Emerg Infect Dis
Journal ID (iso-abbrev): Emerging Infect. Dis
Journal ID (publisher-id): EID
ISSN: 1080-6040
ISSN: 1080-6059
Publisher: Centers for Disease Control and Prevention
Article Information
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Print publication date: Month: 2 Year: 2013
Volume: 19 Issue: 2
First Page: 301 Last Page: 304
PubMed Id: 23347436
ID: 3559064
Publisher Id: 12-1325
DOI: 10.3201/eid1902.121325

Borrelia crocidurae Meningoencephalitis, West Africa Alternate Title:Borrelia crocidurae Meningoencephalitis
Sandrine Goutier1
Elisabeth Ferquel1
Claudine Pinel
Annick Bosseray
Bruno Hoen
Gérard Couetdic
Amina Bourahoui
Claire Lapostolle
Hervé Pelloux
Martine Garnier
Natacha Sertour
Isabelle Pelloux
Patricia Pavese
Muriel Cornet
Author affiliations: Grenoble Teaching Hospital, Grenoble, France (S. Goutier, C. Pinel, A. Bosseray, H. Pelloux, I. Pelloux, P. Pavese, M. Cornet);
Pasteur Institute, Paris, France (E. Ferquel, M. Garnier, N. Sertour), Joseph Fourier University, Grenoble (C. Pinel, H. Pelloux, M. Cornet);
Besançon Teaching Hospital, Besançon, France (B. Hoen, G. Couetdic);
Argenteuil Hospital, Argenteuil, France (A. Bourahoui);
Laennec Hospital, Quimper, France (C. Lapostolle)
Correspondence: Address for correspondence: Sandrine Goutier, Service de Médecine Interne, Groupe Hospitalier Mutualiste de Grenoble, 8 Rue du Docteur Calmette, 38028 Grenoble Cedex 1, France; email: sandrinegoutier@hotmail.com

Tick-borne relapsing fever (TBRF) is caused by several Borrelia species that are transmitted through the bites of Ornithodoros ticks (1). TBRF is an acute febrile illness characterized by multiple recurrences of nonspecific signs and symptoms, including fever, headache, myalgia, and arthralgia. Neurologic complications might occur, particularly related to B. hispanica, B. crocidurae, B. duttoni, and B. turicatae infections (27). Conventional diagnosis is made by microscopic detection of spirochetes in blood samples collected during acute febrile episodes and by direct examination of the cerebral spinal fluid (CSF) of patients with neurologic manifestations. Recently, molecular methods have been shown to be more reliable for Borrelia spp. detection in blood and CSF (3,8). B. crocidurae is endemic to West Africa; in Senegal, the rising incidence of infections reported recently has been associated with climate change (1,9). We report 3 cases of meningitis and 2 cases of encephalitis in 4 persons among a total of 11 consecutive travelers who returned from West Africa to France with B. crocidurae infections.


The Study

Persons included in our study had clinical signs and symptoms of meningitis or encephalitis, or both, and were selected from the 11 patients with cases of B. crocidurae TBRF that were reported to and confirmed by the National Reference Center for Borrelia (NRCB) in France during 2009–2011. The NRCB is the reference laboratory responsible for the epidemiologic surveillance of TBRF in France. Clinical meningitis or encephalitis was defined as previously reported (2). Borrelia species were detected in Giemsa-stained thin blood smears by microscopy and quantitative buffy coat analysis (Becton Dickinson, Le Pont de Claix, France) when available (4).Borrelia spp. were detected and identified by using 16SrRNA PCR and subsequent sequencing as described (8). We tested serum and CSF samples with standardized antibody assays for detection of Borrelia spp. that cause Lyme disease (Table).

Among the 11 TBRF cases reported to NRCB during the 3-year study, we identified 4 (36%) cases of clinical meningitis or encephalitis, or both. The epidemiologic, clinical, and laboratory findings and the treatment of the 4 patients are documented in the Table. Three of the 4 patients were adult men, 26–57 years of age, and 1 was a 7-year-old girl. None of the patients were immunocompromised. They were all given appropriate antimalarial chemoprophylaxis. Patients 1 and 4 experienced their first febrile episode in Africa and were empirically treated with antimalarial drugs without biological confirmation of Plasmodium infection.

At the time of admission to health care facilities, all patients had fever and headache. Patients 2, 3, and 4 had signs of meningitis, including neck stiffness; patients 2 and 4 also had phonophobia and photophobia. Patients 1 and 4 had encephalitis with drowsiness which for patient 4 was accompanied by cerebellar syndrome (dysarthria and dysmetria). All patients except patient 3 underwent computed tomography scanning of the brain; no abnormality was detected. The 2 patients with encephalitis were examined by magnetic resonance imaging; in patient 4, a predominant positive contrast of the cerebellum leptomeninges on the right side was observed.

For all patients, 16S rRNA PCR and sequencing identified B. crocidurae (8) in blood samples. Laboratory analysis of the 4 CSF samples showed a lymphocytic pleocytosis, high protein concentrations, and a glucose value within reference range (Table). The molecular methods applied to CSF samples confirmed neurologic B. crocidurae infection in patients 1, 2, and 3. Serum samples collected from patients 1 and 4 at the time of diagnosis were tested by using Lyme disease serodiagnostic assays. ELISA detected substantial levels of IgM and IgG in samples from both patients; 1 was confirmed by Western blot analysis. The CSF sample from patient 4 showed a low level of IgG (Table).

All cases were treated with doxycycline or ceftriaxone, or both (Table). In all patients, fever resolved within 3 days of the beginning of the appropriate treatment, and the outcomes were favorable. No Jarisch-Herxheimer reaction was observed.

B. crocidurae–associated TBRF is an emerging disease that is considered to be benign (1,9). However, the series of infections reported here suggest that severe neurologic complications, notably, meningitis and encephalitis, occur more frequently than previously thought and could be particularly common in travelers who acquired this infection in West Africa. For the patients we studied, the earliest neurologic signs occurred during the second febrile episode, confirming previous studies reporting the onset of neurologic complications after the first episode (2). However, facial palsy, often considered to be among the main clinical signs and symptoms of neuroborreliosis caused by TBRF-associated Borrelia species, was not observed in these patients (2). A similar clinical manifestation described in a recent case report of B. crocidurae encephalitis is entirely consistent with our observations (3).

Functional and experimental studies have focused on the capacity of TBRF-associated Borrelia species to cross the blood–brain barrier and to persist in the brain (2–7,10,11). These studies have established B. crocidurae as the most neurotropic species, an observation consistent with this and other case series and case reports. In animal models, this feature has been associated with the presence of vascular microemboli in the brain of infected animals and the particular ability of B. crocidurae to form and bind to erythrocyte rosettes, a phenomenon also involved in cerebral malaria pathogenesis. Erythrocyte aggregation might prevent host–pathogen interactions and thereby protect the spirochetes from the specific immune response (10,12,13).

The rather high frequency and severity of neurologic complications associated with B. crocidurae infection raise the problem of distinguishing it from cerebral malaria, because the areas of endemicity of these 2 diseases largely coincide (1,9). Indeed, relapsing fever is frequently misdiagnosed as malaria, as it was for 2 of the patients we studied, who were initially treated with antimalarial drugs (14). In this context, quantitative buffy coat analysis that can effectively detect each pathogen in blood might be of particular interest (4). In addition, our study confirms the usefulness of molecular methods applied to blood and CSF samples to confirm Borrelia infection (3,8). The negative result obtained by PCR of CSF from patient 4 could have been the consequence of inappropriate storage of the sample at high room temperature for 72 hours before analysis.

Lyme disease serodiagnostic testing of serum and CSF samples might be helpful. Indeed, cross-reacting IgG and IgM were detected by ELISAs and in Western blot assays. Because Lyme disease is endemic to France, our results could have been caused by the actual detection of B. burgdorferi sensu lato antibodies, although none of the patients had a known history of Lyme disease.

No specific recommendations have been proposed for the treatment of patients with TBRF neuroborreliosis. Erythromycin and penicillin have been reported to be ineffective (5,6). In our series, all patients were prescribed either ceftriaxone or doxycycline, or both (Table), resulting in successful treatment of the disease. Thus, from the literature and our own experience, we suggest that TBRF with neurologic involvement should be treated with ceftriaxone or doxycycline for at least 21 days.


Conclusions

Our study highlights the frequent occurrence of meningitis or encephalitis in patients with B. crocidurae TBRF acquired in West Africa. The clinical and radiologic manifestations suggest that this infection could be more severe than previously thought. Consequently, travelers returning from West Africa with febrile neurologic disorders should be tested immediately for biological confirmation of Borrelia infection through blood and CSF analyses, including molecular methods.


Notes

Suggested citation for this article: Goutier S, Ferquel E, Pinel C, Bosseray A, Hoen B, Couetdic G, et al. Borrelia crocidurae meningoencephalitis, West Africa. Emerg Infect Dis [Internet]. 2013 Feb [date cited]. http://dx/doi.org/10.3201/eid1902.121325

1These authors contributed equally to this work.

Acknowledgments

We thank Laurence Courdavault, Patrick Plésiat, Ian Dorval, Jacques Croizé, and the technicians of the biology laboratory of the Centre Hospitalier d’Argenteuil for their help with diagnostic confirmation and for providing samples from the patients. We also thank Olivier Epaulard for his insightful comments on the manuscript.

Dr Goutier is an infectious disease specialist at the Groupe Hospitalier Mutualiste in Grenoble, France. Her research interests include clinical infectious diseases, antimicrobial drugs resistance, and epidemiology of nosocomial pathogens.


References
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3. . BottieauE, VerbruggenE, AubryC, SocolovschiC, VliegheE. Meningoencephalitis complicating relapsing fever in traveler returning from Senegal.Emerg Infect Dis. Year: 2012;18:697–810.3201/eid1804.11177122469185
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Tables
[TableWrap ID: T1] Table  Epidemiologic, clinical, and laboratory findings and treatment for 4 patients with Borrelia crocidurae meningitis, or encephalitis, or both*
Characteristic and treatment Patient 1 Patient 2 Patient 3 Patient 4
Demographic factor
Age, y/sex 36/M 57/M 7/F 26/M
Country of origin/of residence Senegal/France France/France France/France Senegal/France
Travel country Senegal Senegal Senegal Senegal
Travel dates Mar–May 2009 May 2010 Feb–May 2011 Aug–Sep 2011
Travel duration, d 53 15 15 35
Travel accommodation Family house Hotel Hotel Family house
Arthropod or insect bite report No Yes No No
Individual vector protection No No No No
First suspected diagnosis†/presumptive treatment Malaria/quinine Sinusitis Gastroenteritis Malaria/piperaquine
Symptoms
Oral temperature >38.5°C Yes Yes Yes Yes
Chills No No Yes Yes
Total no. febrile episodes/no. before diagnosis 2/1 4/2 6/5 2/1
Length of acute febrile episodes, d 2–8 2–6 2 2 to 6
Afebrile periods between febrile episodes, d 15 2–15 2–13 34
Asthenia/anorexia/weight loss Yes/no/no Yes/yes/yes‡ Yes/no/no Yes/no/no
Headache Yes (severe) Yes Yes (severe) Yes (severe)
Myalgia No No No Yes
Photophobia, phonophobia No Yes No Yes
Neck stiffness No Yes Yes Yes
Cerebellar syndrome No No No Yes
Drowsiness Yes No No Yes
Imaging results
Brain CT scan Normal Normal ND Normal
Brain MRI Normal ND ND Abnormal
Serologic results
Leukocytes, g/L 4.7 15.8 13.0 8.4
Hemoglobin, g/L 134 139 115 131
Platelets, g/L 245 273 295 103
C-reactive protein, mg/L 103 4 57 150
Creatinine, μmol/L 107 76 42 99
Borrelia spp. detection, Giemsa-stained blood smear
Quantitative buffy coat ND ND ND +
ELISA anti–B. murgdorferi (titer)
Enzygnost Lyme IgG link VlsE Siemens# +(11.3) ND ND +(19)
Enzygnost Lyme IgM Siemens# +(3.7) ND ND +(1.21)
Western blot anti–B. burgdorferi
Bioadvance IgG anti VlsE/p41/p83/p21** +/−/–/+ ND ND ND
Euroimmun IgG anti–p17/p19/p21/p25/p30/p31/ p39/p83/VlsE†† ND ND ND −/−/−/−/−/−/– /‡‡ /‡‡
Meridian IgM garinii/afzelii/p41/p39/p17 ND ND ND ND
Bioadvance IgM anti p25/p83** +/+ ND ND ND
16 rRNA PCR Borrelia/identification +/B. crocidurae +/B. crocidurae +/B. crocidurae +/B. crocidurae
CSF test results
Leukocytes, cells/mm3 405 217 258 156
% Lymphocytes 94 80 90 84
Erythrocytes, cells/ mm3 0 7 12 5
Protein, g/L 0.66 1.38 0.39 0.44
Glucose, mmol/L 3.1 2.7 2.69 2.9
Chloride, mmol/L 114 113 117 115
Lactate, mmol/L ND ND 1.5 2.2
Direct examination (Gram stain)
Conventional bacterial culture
16 rRNA PCR Borrelia/Identification +/B. crocidurae +/B. crocidurae +/B. crocidurae
ELISA anti-B. burgdorferi
IgG enzygnost lyme IgG link VlsE Siemens ND ND ND +¶¶
IgM enzygnost lyme IgM Siemens ND ND ND
Treatment (daily dose/total d) Ceftriaxone
(2 g/21) Doxycycline (100 mg 2×d/10) Ceftriaxone (2 g/14) Doxycycline (100 mg 2×d/21), ceftriaxone (2 g/15)

*CT, computed tomography; MRI, magnetic resonance imaging; ND, not done; +, positive; –, negative; CSF, cerebrospinal fluid.
†First suspected diagnosis was not biologically confirmed.
‡7 kg in 3 wk.
§Second sample was positive.
¶First sample was positive after review prompted by the quantitative buffy coat result.
#Siemens, Erlangen, Germany.
**Bio-Advance, Bussy Saint Martin, France.
††Euroimmun Medizinische Labordiagnostika AG, Lübeck, Germany.
‡‡Ambiguous.
§§Meridian Bioscience, Paris, France.
¶¶At 12-fold dilution (low level).



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Keywords: Keywords: Borrelia crocidurae, Borrelia meningitis, encephalitis, spirochete, molecular diagnosis, bacteria, tick-borne relapsing fever, Ornithodoros ticks, Lyme disease, West Africa.

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