International Journal of Infectious Diseases 65 (2017) 107–109Contents lists available at ScienceDirect International Journal of Infectious Diseases journal home page: www.elsevier .com/ locat e/ i j id Short Communication Central nervous system infections in the absence of cerebrospinal fluid pleocytosis Hakan Erdema, Derya Ozturk-Enginb, Yasemin Cagc, Seniha Senbayrakb, Asuman Inanb, Esra d Kazak , Umit Savascia, Nazif Elaldie , Haluk Vahabogluf, Rodrigo Hasbung,* , ID-IRI study group aDepartment of Infectious Diseases and Clinical Microbiology, Gulhane Medical Academy, Ankara, Turkey bDepartment of Infectious Diseases and Clinical Microbiology, Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey cDepartment of Infectious Diseases and Clinical Microbiology, Lutfi Kirdar Training and Research Hospital, Istanbul, Turkey dDepartment of Infectious Diseases and Clinical Microbiology, Uludag University School of Medicine, Bursa, Turkey eDepartment of Infectious Diseases and Clinical Microbiology, Cumhuriyet University School of Medicine, Sivas, Turkey fDepartment of Infectious Diseases and Clinical Microbiology, Medeniyet University, Goztepe Training and Research Hospital, Istanbul, Turkey gDepartment of Infectious Diseases, UT Health McGovern Medical School, Houston, TX, USA A R T I C L E I N F O A B S T R A C T Article history: Received 11 April 2017 Previous multicenter/multinational studies were evaluated to determine the frequency of the absence of Received in revised form 11 October 2017 cerebrospinal fluid pleocytosis in patients with central nervous system infections, as well as the clinical Accepted 12 October 2017 impact of this condition. It was found that 18% of neurosyphilis, 7.9% of herpetic meningoencephalitis, 3% Corresponding Editor: Eskild Petersen, Aar- of tuberculous meningitis,1.7% of Brucella meningitis, and 0.2% of pneumococcal meningitis cases did not hus, Denmark display cerebrospinal fluid pleocytosis. Most patients were not immunosuppressed. Patients without pleocytosis had a high rate of unfavorable outcomes and thus this condition should not be Keywords: underestimated. CSF © 2017 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. Pleocytosis This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by- Leukocyte Meningitis nc-nd/4.0/). EncephalitisIntroduction The normal white blood cell (WBC) count in the cerebrospinal fluid (CSF) of adults is between 0 and 5 106 cells/l (Tunkel, 2015). CSF pleocytosis is important in establishing the diagnosis of central nervous system (CNS) infections such as meningitis, encephalitis, and meningoencephalitis. However, the absence of pleocytosis represents a diagnostic challenge to clinicians when suspecting a CNS infection. Under this particular circumstance, can the possibility of meningitis, encephalitis, or meningoencephalitis be excluded? Accordingly, the examining physician should know the frequency, clinical characteristics, and outcomes of different CNS infections that may present with an absence of CSF pleocytosis. Data on this subject in the literature appear to be very limited.* Corresponding author at: UT Health McGovern Medical School, 6431 Fannin St. 2.112 MSB, Houston, TX 77030, USA. E-mail address: Rodrigo.Hasbun@uth.tmc.edu (R. Hasbun). https://doi.org/10.1016/j.ijid.2017.10.011 1201-9712/© 2017 The Author(s). Published by Elsevier Ltd on behalf of International So license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Methods The Infectious Diseases International Research Initiative (ID- IRI) study group has been performing large multicenter/multina- tional studies since 2008, with studies on tuberculous meningitis (Erdem et al., 2015a; Erdem et al., 2014a), herpetic meningoen- cephalitis (Erdem et al., 2015c), Brucella meningitis (Erdem et al., 2015b), pneumococcal meningitis (Erdem et al., 2014b), and neurosyphilis (Ozturk-Engin et al., 2016). Strengths of all of these studies include the large numbers of patients involved, microbio- logical confirmation for all patients enrolled, and the inclusion of both patients with and without CSF pleocytosis. Additionally, the first three studies are the largest series published to date in the literature: tuberculous meningitis (n = 507), herpetic meningoen- cephalitis (n = 496), Brucella meningitis (n = 294), pneumococcal meningitis (n = 306), and neurosyphilis (n = 141). In this study, the data of ID-IRI studies were investigated to identify patients without CSF pleocytosis (WBC count of 5106 cells/l). Their clinical presentations, laboratory findings, and outcomes were assessed to provide an insight into this particular condition for the treating clinician.ciety for Infectious Diseases. This is an open access article under the CC BY-NC-ND 108 H. Erdem et al. / International Journal of Infectious Diseases 65 (2017) 107–109Results The characteristics of the patients with CNS infections (pneumococcal meningitis, tuberculous meningitis, Brucella men- ingitis, neurosyphilis, herpes simplex virus (HSV) meningoen- cephalitis) without CSF pleocytosis are presented in Table 1. According to the data, 32 of 141 patients (18%) with neurosyphilis, 39 of 496 patients (7.9%) with herpetic meningoencephalitis, 19 of 507 patients (3%) with tuberculous meningitis, five of 294 patients (1.7%) with Brucella meningitis, and one of 306 patients (0.2%) with pneumococcal meningitis did not present with CSF pleocytosis. These 96 patients were included in this study. The mean CSF protein in all five CNS infections was elevated, with some patients also having hypoglycorrhachia (CSF to serum glucose ratio 0.5). The mean CSF protein was higher and the mean CSF to serum glucose ratio was lower in those with tuberculous meningitis than in those with herpetic meningoencephalitis (p < 0.05). The mean age was 49 years in all groups, and 55 (57%) patients were male. Forty (42%) of the patients had a fever and only seven (7.3%) had the classic meningitis triad. A stiff neck was seen more frequently in tuberculous meningitis (63%) than in the other infections. Immunosuppressive conditions that could predispose to the absence of pleocytosis were not detected inTable 1 Characteristics of patients with a CNS infection with no CSF pleocytosis.a Pneumococcal meningitis Tuberculous meningiti ID-IRI study Erdem et al. (2014b) Erdem et al. (2015a) Number 306 507 CSF analysis Pleocytosis absent, n 1 19 Pleocytosis absent, % 0.2% 3% Protein (mg/dl), mean  SD 1446 305.5  457.63b CSF/blood glucose, mean  SD 0.1 0.45 c  0.16 Demographic and clinical parameters Age (years), mean  SD 68 49.15  17.03 Sex, male, n (%) 1 9 (47%) Fever >38 C,  n (%) 38.2 C 13 (68%) Neck stiffness, n (%) () 12 (63%) Headache, n (%) (+) 6 (31%) Mental changes (+) 13 (68%) Classic triadd () 1 (5%) GCS 5 10.13  3.99 Potential immunosuppressive conditions HIV-positive () 2 Diabetes mellitus () () Immunosuppressive drugs () 1 Solid tumor () () Drug addiction () () Number (%) 0 (0) 3 (15.8%) Outcome Sequelae, g n (%) () 6 (31%) Death, n (%) Died 5 (26%) CNS, central nervous system; CSF, cerebrospinal fluid; HSV, herpes simplex virus; ID-IRI Glasgow coma scale score. a Pleocytosis: 6 number of patients with 5 10 leukocytes/l in the CSF. b Mean CSF protein higher compared to HSV meningoencephalitis by analysis of varian neurosyphilis to HSV meningoencephalitis (p > 0.05). c Mean CSF glucose lower compared to HSV meningoencephalitis (p < 0.05). No d meningoencephalitis (p > 0.05). d Classic triad: symptoms of fever, headache, and altered mental status. e One patient had co-existing diabetes and HIV infection. f Immunosuppressive medications (cyclosporine, methotrexate, cyclophosphamid demyelinating polyneuropathy and intestinal adenocarcinoma, pemphigoid, and Takay g Focal neurological deficits, seizures, and hydrocephalus.pneumococcal meningitis or in Brucella meningitis. Furthermore, they were relatively infrequent in neurosyphilis (37%), tuberculous meningitis (15.8%), and herpetic meningoencephalitis (12.8%). A total of 51 (53%) patients had neurological sequelae or died. Discussion This appears to be the largest study evaluating the frequency, clinical characteristics, and outcomes of patients without CSF pleocytosis in five types of CNS infection. Previous studies have described case series of patients without CSF pleocytosis in relation to bacterial meningitis, herpes simplex encephalitis, and enteroviral meningitis (Saraya et al., 2016; Hui Tan et al., 2016; Lin et al., 2016). The lack of CSF pleocytosis in bacterial meningitis is rare, but this can be seen more commonly in viral infections. In this study, the mean values of protein and CSF/blood glucose suggested the probable presence of a CNS infection despite the absence of CSF pleocytosis, stressing the importance of considering the total CSF profile when ruling out a CNS infection. Even though a significant proportion of patients had fever, headache, and altered mental status, only seven of the 96 patients (7.3%) had the classic meningitis triad. In contrast, although neck stiffness was detected in two-thirds of tuberculous meningitis cases, it was seens Brucella meningitis Neurosyphilis HSV meningoencephalitis Erdem et al. (2015b) Ozturk-Engin et al. (2016) Erdem et al. (2015c) 294 141 496 5 32 39 1.7% 22% 7.9% 89.2  363.43 74.9  114.7 77  48.89 0.51  0.89 0.63  0.13 0.68  0.57 55.4  20.27 52.15  14.09 57  20.99 2 (40%) 26 (81%) 17 (44%) 3 (60%) 4 (12%) 19 (49%) 1 (20%) 6 (18%) 6 (15%) 4 (80%) 13 (40%) 22 (56%) 1 (20%) 13 (40%) 33 (85%) 1 (20%) 1 (3%) 4 (10%) 15  2.38 14.26  1.45 11  3.92 () e 7 () () 3 () () () 4f () () 1 () 3 () 0 (0) 12 (37%) 5 (12.8%) 1 (20%) 12 (37%) 15 (39%) () 3 (9%) 8 (21%) , Infectious Diseases International Research Initiative; SD, standard deviation; GCS, ce analysis (p < 0.05). No differences seen when comparing Brucella meningitis and ifferences seen when comparing Brucella meningitis and neurosyphilis to HSV e, and systemic steroids) for kidney transplantation, chronic inflammatory asu arteritis. H. Erdem et al. / International Journal of Infectious Diseases 65 (2017) 107–109 109infrequently in Brucella, herpetic, and syphilitic CNS diseases. The low frequency of meningismus in this study could possibly be explained by the fact that meningeal irritation disappears in the absence of CSF inflammation. Furthermore, tuberculous meningitis had higher rates of hypoglycorrhachia and elevated CSF protein. The absence of pleocytosis was relatively infrequent but not rare in these CNS infections. Patients without CSF pleocytosis appeared to have a high rate of unfavorable outcomes, including sequelae and death. A recent study of 175 children with bacterial meningitis (Lin et al., 2016) identified the lack of CSF pleocytosis as a prognostic factor in the multivariable analysis. The examining clinician should not underestimate the presence of a CNS infection despite the lack of CSF pleocytosis for a patient with a suspicion of meningitis or encephalitis. In particular, other clues related to the clinical presentation or abnormalities in CSF analyses should be carefully considered as a whole, and microbiological clues pointing to a CNS infection should be pursued when necessary. Funding Grant-A-Starr Foundation. Conflict of interest RH is a consultant for bioMérieux and a speaker for Pfizer, Merck, Medicines Company, and BioFire. The remaining authors have no competing interests to declare.Acknowledgements The ID-IRI study group includes all authors in references Erdem et al. (2015a), Erdem et al. (2015b), Erdem et al. (2015c), Erdem et al. (2014b), Ozturk-Engin et al. (2016). References Erdem H, Ozturk-Engin D, Elaldi N, et al. The microbiological diagnosis of tuberculous meningitis: results of haydarpasa-1 study. Clin Microbiol Infect 2014a;20:O600–8. Erdem H, Elaldi N, Oztoprak N, et al. Mortality indicators in pneumococcal meningitis: therapeutic implications. Int J Infect Dis 2014b;19:13–9. 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