Journal of Medical Virology 88:175–179 (2016)
Etiology of Aseptic Meningitis and Clinical Characteristics in Immune-Competent Adults Su-Hyun Han,1 Hye-Yeon Choi,2 Jeong-Min Kim,3 Kwang-Ryul Park,3 Young Chul Youn,3 and Hae-Won Shin3* 1
Department of Neurology, Asan Medical Center, Ulsan University College of Medicine, Seoul, South Korea Department of Neurology, Gangdong Kyung Hee University Hospital, Kyung Hee University College of Medicine, Seoul, South Korea 3 Department of Neurology, Chung-Ang University College of Medicine, Seoul, South Korea 2
Viral meningitis is the most common cause of aseptic meningitis. Use of the polymerase chain reaction (PCR) has increased the ability to determine the etiology of viral meningitis. This study used PCR analysis to evaluate the etiology of aseptic meningitis in 177 previously healthy adults over a 5-year period, as well as analyzing the clinical characteristics, cerebrospinal fluid (CSF) findings, and prognosis according to each etiology. The most frequent cause of aseptic meningitis was enterovirus (EV), followed by varicella zoster virus (VZV). Patients with EV meningitis were significantly younger than those with VZV meningitis. The percentage of lymphocytes in white blood cell counts and protein concentrations in the CSF differed significantly among patients with EV, VZV and meningitis of undetermined etiology. Younger age and lower percentage of lymphocyte and protein level in CSF analysis may be suggestive of EV meningitis. Further prospective studies are warranted to identify the correlations between the clinical characteristics and the etiologies of meningitis. J. Med. Virol. 88:175–179, 2016. # 2015 Wiley Periodicals, Inc.
KEY WORDS:
aseptic meningitis; etiology; cerebrospinal fluid; signs and symptoms
and varicella zoster virus (VZV) have been considered mainly responsible for aseptic meningitis. [Hosoya et al., 1998, 2002]. To date, however, most studies have evaluated the etiology and characteristics of aseptic meningitis in children, with few studies addressing this issue in adults [Kupila et al., 2006; Delerme et al., 2009]. Most patients with meningitis who visit outpatient clinics of neurology departments are adults, suggesting the need to evaluate the etiology, clinical characteristics, and cerebrospinal fluid (CSF) findings in adults. These characteristics may be predictive of the clinical course and prognosis in adults whose initial CSF findings are suggestive of the disease. This study, therefore, evaluated the etiology of aseptic meningitis in previously healthy adults, as well as their etiology-associated clinical symptoms, CSF findings, and prognosis. MATERIALS AND METHODS Patients This study retrospectively analyzed 177 patients who were diagnosed with aseptic meningitis in the neurology department of a single hospital during the 5-year period from March 2008 to February 2013. Aseptic meningitis was defined as acute symptoms and/or signs suggestive of meningitis, including fever, headache and meningeal irritation associated with white blood cell (WBC) counts in the CSF of 5/mm3; accompanied by normal glucose levels and negative bacterial cultures. Patients were excluded if they had symptoms and signs suggestive of encephalitis,
INTRODUCTION Aseptic meningitis, defined as an infectious disease in the central nervous system negative for bacteria, is most frequently due to viral infection Before the development of polymerase chain reaction (PCR) analytic techniques, the causative virus was rarely detected. Use of PCR-based methods has increased the ability to determine the etiology of viral meningitis. Enterovirus (EV), herpes simplex virus (HSV) C 2015 WILEY PERIODICALS, INC.
The authors report no conflicts of interest. Correspondence to: Hae-Won Shin, MD, PhD, Department of Neurology, Chung-Ang University College of Medicine, 24-1, Heukseok-dong, Dongjak-gu, Seoul 156-755, South Korea. E-mail: [email protected] Accepted 25 June 2015 DOI 10.1002/jmv.24316 Published online 20 July 2015 in Wiley Online Library (wileyonlinelibrary.com).
176
Han et al.
including altered consciousness, seizure or focal neurological deficits. Immune-compromised patients with major medical or surgical illnesses were also excluded. Demographic, clinical and laboratory data were obtained from patients’ medical records. Microbiologic Analysis Defined microbiologic tests were performed, according to our hospital guidelines for the diagnosis of CNS infections in adults. CSF samples were assayed by qualitative PCR tests for EV (Seeplex MeningitisV2 ACE Detection kit, Seegene, Inc., Seoul, Korea), HSV-1 (HSV I PCR Kit, Biocore, Seoul, Korea), HSV-2 (HSV II PCR Kit, Biocore, Korea), and VZV (VZV PCR Kit, Biocore, Korea), according to the manufacturers’ instructions. In addition, CSF and serum samples were cultured for virus, and assayed for antibodies against EV, HSV, and adenovirus. Tests for antibodies against Epstein–Barr virus (EBV) and mumps virus were performed when indicated.
the viral antibody assay. The most frequent cause of aseptic meningitis was EV in 68 patients (38.4%), followed by VZV in 25 patients (14.1%). HSV-I and -II were identified in one patient each. In addition, mumps was detected on the viral antibody assay in one patient. Eighty one patients (45.8%) were classified as meningitis due to undetermined etiologies. The mean age was younger in EV compared to VZV (F ¼ 3.963, P ¼ 0.021). Median time from onset of the symptoms to the spinal tapping was 3 days (range; 0–19 days) and median length of hospital stay was 6 days (range; 1–24 days). Thirty-two patients were treated by intravenous acyclovir for mean 7 days (Table I). The frequency of patients with antiviral treatment was significantly different between the subgroups (P < 0.001). The length of the hospital stay was longer in patients with antiviral treatment than those without antiviral treatment (10.8 4.6 days vs. 6.1 3.0 days; P < 0.001). Clinical Characteristics and CSF Findings
Statistical Analysis The etiology of aseptic meningitis in these patients was classified, based on PCR and antibody assays in CSF, into three subgroups: EV, VZV, and undetermined. Age, length of hospitalization, and laboratory findings in the three groups were compared by oneway ANOVA or the Kruskal–Wallis test. Subgroups were compared using the Mann–Whitney U test or Bonferroni post-hoc analysis. Frequency of anti-viral treatment was compared using the x2 test. Statistical significance was defined as P < 0.05, except for subgroup comparison with the Mann–Whitney U test, for which statistical significance was defined as P < 0.017 (0.05/3). RESULTS Demographic Characteristics and Etiologies of Aseptic Meningitis A total of 177 patients were diagnosed with aseptic meningitis during a 5-year period. They consisted of 92 men and 85 women, whose mean age was 32.4 10.8 years (range, 16–74). Of these, 96 patients (54.2%) had viral etiology on the PCR and one did on
Besides the typical symptoms of meningitis, including headache and fever, some patients presented with gastrointestinal symptoms, symptoms of upper respiratory tract infection, and skin rash and facial palsy (Table II); skin rash and facial palsy were concurrently present only in patients with VZV meningitis. Four patients with VZV meningitis developed skin rash, two on the back, and one each on the abdomen and right periauricular area, indicating that 84% of patients with VZV meningitis in this study had symptoms compatible with zoster sine herpete. Median WBC counts in CSF in patients with EV meningitis, VZV meningitis, and meningitis of unknown etiology were 80/mm3 (range, 5–990/mm3), 210/mm3 (range, 8–850/mm3), and 85/mm3 (range, 5–2000/mm3), respectively, but these differences were not statistically significant (P ¼ 0.074). The differential lymphocyte count and protein level in CSF differed significantly among subgroups (P < 0.001; Table III). Post-hoc comparisons of differential lymphocyte count and protein level also showed significant differences among subgroups (P < 0.017). The percentage of lymphocytes in CSF was lower in the
TABLE I. Etiology and Demographics of Patients With Aseptic Meningitis Diagnosed by CSF PCR EV
VZV
Number of the patients (%) 68 (38.4) 25 (14.1) Mean age, years (range) 30.6 (18–55) 37.6 (20–70) Number of female (%) 32 (47.1) 11 (44.0) Time from symptoms onset to spinal t 2 (0–10) 4 (0–19) apping, days, median (range) Hospital stay, days, median (range) 5 (1–17) 7 (3–15) Number of the patients with 1 (1.5) 12 (48) anti-viral treatment (%) J. Med. Virol. DOI 10.1002/jmv
Undetermined etiology HSV-1 HSV-2 Mumps 81 32.5 40 3.5
(45.8) (18–74) (49.4) (0–15)
7 (2–24) 18 (22.2)
Total
1 29 1 1
1 23 1 3
1 28 1 4
177 (100) 32.8 (18–74) 85 (48.0) 3 (0–19)
6 0
14 1
7 0
6 (1–24) 7.1 (4)
Etiology of Aseptic Meningitis in Immune-Competent Adults
177
TABLE II. Clinical Characteristics in Patients With Aseptic Meningitis Number of the patients (%) Symptoms or signs
EV
Headache Fever Nausea Vomiting Dizziness Neck stiffness Brudzinski’s sign Kernig’s sign Sore throat Cough Sputum Rhinorrhea Diarrhea Abdominal pain Skin rash Peripheral type of facial palsy
68 60 49 33 2 36 4 10 6 3 0 3 3 1 0 0
VZV
(100) (88) (72) (49) (3) (53) (6) (15) (9) (4) (0) (4) (4) (1) (0) (0)
23 14 16 8 2 7 3 1 5 2 2 1 3 1 4 1
Undetermined
(92) (56) (64) (32) (8) (28) (12) (4) (20) (8) (8) (4) (12) (4) (16) (4)
82 55 48 33 9 33 7 10 9 6 3 4 1 2 3 1
(99) (68) (60) (41) (11) (41) (9) (12) (11) (7) (4) (5) (1) (3) (4) (1)
V, enterovirus; VZV, varicellar zoster virus.
TABLE III. Comparison of CSF Analysis Between the Subgroups
CSF, median (range) WBC count (/mm3) Percentage of lymphocyte in WBC (%) Protein level (mg/dl) Peripheral blood, mean standard deviation WBC count (/ml) Percentage of neutrophil in WBC (%) Percentage of lymphocyte in WBC (%)
EV
VZV
Undetermined etiology
P value
80 (5–990) 39.5 (3–100) 53.8 (20 –161)
210 (8–850) 99 (82–100) 102 (53–256)
85 (5–2,000) 98 (2–100) 71.5 (19–264)
0.074
Etiology of Aseptic Meningitis and Clinical Characteristics in Immune-Competent Adults Su-Hyun Han,1 Hye-Yeon Choi,2 Jeong-Min Kim,3 Kwang-Ryul Park,3 Young Chul Youn,3 and Hae-Won Shin3* 1
Department of Neurology, Asan Medical Center, Ulsan University College of Medicine, Seoul, South Korea Department of Neurology, Gangdong Kyung Hee University Hospital, Kyung Hee University College of Medicine, Seoul, South Korea 3 Department of Neurology, Chung-Ang University College of Medicine, Seoul, South Korea 2
Viral meningitis is the most common cause of aseptic meningitis. Use of the polymerase chain reaction (PCR) has increased the ability to determine the etiology of viral meningitis. This study used PCR analysis to evaluate the etiology of aseptic meningitis in 177 previously healthy adults over a 5-year period, as well as analyzing the clinical characteristics, cerebrospinal fluid (CSF) findings, and prognosis according to each etiology. The most frequent cause of aseptic meningitis was enterovirus (EV), followed by varicella zoster virus (VZV). Patients with EV meningitis were significantly younger than those with VZV meningitis. The percentage of lymphocytes in white blood cell counts and protein concentrations in the CSF differed significantly among patients with EV, VZV and meningitis of undetermined etiology. Younger age and lower percentage of lymphocyte and protein level in CSF analysis may be suggestive of EV meningitis. Further prospective studies are warranted to identify the correlations between the clinical characteristics and the etiologies of meningitis. J. Med. Virol. 88:175–179, 2016. # 2015 Wiley Periodicals, Inc.
KEY WORDS:
aseptic meningitis; etiology; cerebrospinal fluid; signs and symptoms
and varicella zoster virus (VZV) have been considered mainly responsible for aseptic meningitis. [Hosoya et al., 1998, 2002]. To date, however, most studies have evaluated the etiology and characteristics of aseptic meningitis in children, with few studies addressing this issue in adults [Kupila et al., 2006; Delerme et al., 2009]. Most patients with meningitis who visit outpatient clinics of neurology departments are adults, suggesting the need to evaluate the etiology, clinical characteristics, and cerebrospinal fluid (CSF) findings in adults. These characteristics may be predictive of the clinical course and prognosis in adults whose initial CSF findings are suggestive of the disease. This study, therefore, evaluated the etiology of aseptic meningitis in previously healthy adults, as well as their etiology-associated clinical symptoms, CSF findings, and prognosis. MATERIALS AND METHODS Patients This study retrospectively analyzed 177 patients who were diagnosed with aseptic meningitis in the neurology department of a single hospital during the 5-year period from March 2008 to February 2013. Aseptic meningitis was defined as acute symptoms and/or signs suggestive of meningitis, including fever, headache and meningeal irritation associated with white blood cell (WBC) counts in the CSF of 5/mm3; accompanied by normal glucose levels and negative bacterial cultures. Patients were excluded if they had symptoms and signs suggestive of encephalitis,
INTRODUCTION Aseptic meningitis, defined as an infectious disease in the central nervous system negative for bacteria, is most frequently due to viral infection Before the development of polymerase chain reaction (PCR) analytic techniques, the causative virus was rarely detected. Use of PCR-based methods has increased the ability to determine the etiology of viral meningitis. Enterovirus (EV), herpes simplex virus (HSV) C 2015 WILEY PERIODICALS, INC.
The authors report no conflicts of interest. Correspondence to: Hae-Won Shin, MD, PhD, Department of Neurology, Chung-Ang University College of Medicine, 24-1, Heukseok-dong, Dongjak-gu, Seoul 156-755, South Korea. E-mail: [email protected] Accepted 25 June 2015 DOI 10.1002/jmv.24316 Published online 20 July 2015 in Wiley Online Library (wileyonlinelibrary.com).
176
Han et al.
including altered consciousness, seizure or focal neurological deficits. Immune-compromised patients with major medical or surgical illnesses were also excluded. Demographic, clinical and laboratory data were obtained from patients’ medical records. Microbiologic Analysis Defined microbiologic tests were performed, according to our hospital guidelines for the diagnosis of CNS infections in adults. CSF samples were assayed by qualitative PCR tests for EV (Seeplex MeningitisV2 ACE Detection kit, Seegene, Inc., Seoul, Korea), HSV-1 (HSV I PCR Kit, Biocore, Seoul, Korea), HSV-2 (HSV II PCR Kit, Biocore, Korea), and VZV (VZV PCR Kit, Biocore, Korea), according to the manufacturers’ instructions. In addition, CSF and serum samples were cultured for virus, and assayed for antibodies against EV, HSV, and adenovirus. Tests for antibodies against Epstein–Barr virus (EBV) and mumps virus were performed when indicated.
the viral antibody assay. The most frequent cause of aseptic meningitis was EV in 68 patients (38.4%), followed by VZV in 25 patients (14.1%). HSV-I and -II were identified in one patient each. In addition, mumps was detected on the viral antibody assay in one patient. Eighty one patients (45.8%) were classified as meningitis due to undetermined etiologies. The mean age was younger in EV compared to VZV (F ¼ 3.963, P ¼ 0.021). Median time from onset of the symptoms to the spinal tapping was 3 days (range; 0–19 days) and median length of hospital stay was 6 days (range; 1–24 days). Thirty-two patients were treated by intravenous acyclovir for mean 7 days (Table I). The frequency of patients with antiviral treatment was significantly different between the subgroups (P < 0.001). The length of the hospital stay was longer in patients with antiviral treatment than those without antiviral treatment (10.8 4.6 days vs. 6.1 3.0 days; P < 0.001). Clinical Characteristics and CSF Findings
Statistical Analysis The etiology of aseptic meningitis in these patients was classified, based on PCR and antibody assays in CSF, into three subgroups: EV, VZV, and undetermined. Age, length of hospitalization, and laboratory findings in the three groups were compared by oneway ANOVA or the Kruskal–Wallis test. Subgroups were compared using the Mann–Whitney U test or Bonferroni post-hoc analysis. Frequency of anti-viral treatment was compared using the x2 test. Statistical significance was defined as P < 0.05, except for subgroup comparison with the Mann–Whitney U test, for which statistical significance was defined as P < 0.017 (0.05/3). RESULTS Demographic Characteristics and Etiologies of Aseptic Meningitis A total of 177 patients were diagnosed with aseptic meningitis during a 5-year period. They consisted of 92 men and 85 women, whose mean age was 32.4 10.8 years (range, 16–74). Of these, 96 patients (54.2%) had viral etiology on the PCR and one did on
Besides the typical symptoms of meningitis, including headache and fever, some patients presented with gastrointestinal symptoms, symptoms of upper respiratory tract infection, and skin rash and facial palsy (Table II); skin rash and facial palsy were concurrently present only in patients with VZV meningitis. Four patients with VZV meningitis developed skin rash, two on the back, and one each on the abdomen and right periauricular area, indicating that 84% of patients with VZV meningitis in this study had symptoms compatible with zoster sine herpete. Median WBC counts in CSF in patients with EV meningitis, VZV meningitis, and meningitis of unknown etiology were 80/mm3 (range, 5–990/mm3), 210/mm3 (range, 8–850/mm3), and 85/mm3 (range, 5–2000/mm3), respectively, but these differences were not statistically significant (P ¼ 0.074). The differential lymphocyte count and protein level in CSF differed significantly among subgroups (P < 0.001; Table III). Post-hoc comparisons of differential lymphocyte count and protein level also showed significant differences among subgroups (P < 0.017). The percentage of lymphocytes in CSF was lower in the
TABLE I. Etiology and Demographics of Patients With Aseptic Meningitis Diagnosed by CSF PCR EV
VZV
Number of the patients (%) 68 (38.4) 25 (14.1) Mean age, years (range) 30.6 (18–55) 37.6 (20–70) Number of female (%) 32 (47.1) 11 (44.0) Time from symptoms onset to spinal t 2 (0–10) 4 (0–19) apping, days, median (range) Hospital stay, days, median (range) 5 (1–17) 7 (3–15) Number of the patients with 1 (1.5) 12 (48) anti-viral treatment (%) J. Med. Virol. DOI 10.1002/jmv
Undetermined etiology HSV-1 HSV-2 Mumps 81 32.5 40 3.5
(45.8) (18–74) (49.4) (0–15)
7 (2–24) 18 (22.2)
Total
1 29 1 1
1 23 1 3
1 28 1 4
177 (100) 32.8 (18–74) 85 (48.0) 3 (0–19)
6 0
14 1
7 0
6 (1–24) 7.1 (4)
Etiology of Aseptic Meningitis in Immune-Competent Adults
177
TABLE II. Clinical Characteristics in Patients With Aseptic Meningitis Number of the patients (%) Symptoms or signs
EV
Headache Fever Nausea Vomiting Dizziness Neck stiffness Brudzinski’s sign Kernig’s sign Sore throat Cough Sputum Rhinorrhea Diarrhea Abdominal pain Skin rash Peripheral type of facial palsy
68 60 49 33 2 36 4 10 6 3 0 3 3 1 0 0
VZV
(100) (88) (72) (49) (3) (53) (6) (15) (9) (4) (0) (4) (4) (1) (0) (0)
23 14 16 8 2 7 3 1 5 2 2 1 3 1 4 1
Undetermined
(92) (56) (64) (32) (8) (28) (12) (4) (20) (8) (8) (4) (12) (4) (16) (4)
82 55 48 33 9 33 7 10 9 6 3 4 1 2 3 1
(99) (68) (60) (41) (11) (41) (9) (12) (11) (7) (4) (5) (1) (3) (4) (1)
V, enterovirus; VZV, varicellar zoster virus.
TABLE III. Comparison of CSF Analysis Between the Subgroups
CSF, median (range) WBC count (/mm3) Percentage of lymphocyte in WBC (%) Protein level (mg/dl) Peripheral blood, mean standard deviation WBC count (/ml) Percentage of neutrophil in WBC (%) Percentage of lymphocyte in WBC (%)
EV
VZV
Undetermined etiology
P value
80 (5–990) 39.5 (3–100) 53.8 (20 –161)
210 (8–850) 99 (82–100) 102 (53–256)
85 (5–2,000) 98 (2–100) 71.5 (19–264)
0.074
