- Viral: enteroviruses (including Coxsackie, echo, Enterovirus 71), HSV (primarily Type 2), arboviruses (West Nile virus, others), LCMV, mumps, influenza, parainfluenza, measles, EBV, CMV, VZV, HHV-6, parvovirus B19, acute HIV infection, Ebola virus.
- Borrelia burgdorferi, rickettsial spp, Leptospiraspp., syphilis, M. tuberculosis, Brucella spp., Mycoplasma pneumoniae, tick-borne relapsing fever (B. turicatae)
- Parameningeal infection (e.g., bacterial sinusitis or otitis)
- Meningitis as a consequence of endocarditis
- Partially treated bacterial meningitis
- Fungal: occasional causes if fungal culture not obtained or lacks organism growth.
- Parasitic: Toxoplasma gondii (more commonly encephalitic), Amoeba spp., T. solium, Angiostrongylus cantonensis
- Recurrent: often due to HSV (formerly called Mollaret’s meningitis); repeated meningitis following exposure to a given medication suggests medication-induced
- Non-infectious causes: carcinomatous (primary or metastatic, lymphoma or leukemia), drug-induced (e.g., TMP-SMX, INH, ibuprofen, allopurinol, immune checkpoint inhibitors), CNS vasculitis, CNS sarcoidosis, Behçet’s syndrome, Fabry disease, vaccines, benign lymphocytic meningitis, HANDL (headache w/ neurological deficits and lymphocytic pleocytosis), intravenous immunoglobulin, Vogt-Koyanagi-Harada syndrome, SLE, granulomatosis with polyangiitis, Sjögren syndrome, Kikuchi-Fujimoto disease.
- The above lists are not entirely comprehensive.
- Annually diagnosed as reason for >36,000 hospitalizations. Most common reason: viral infections w/ enteroviruses as the leading cause (55-90%), seen mostly in summer and fall.
- Member of the picornavirus family, the second most common viral infection in humans after rhinovirus.
- More than 60 serotypes, including Polioviruses, Coxsackieviruses (23 Type A, 6 Type B strains), Echoviruses (28 strains), and newer numbered enteroviruses.
- Infants infected > children > adults.
- Highly contagious by fecal-oral spread (children) or respiratory (adult).
- Incubation 7-10d.
- Only 1/1000 infected develop meningitis.
- Viral shedding can persist for weeks after recovery from infection.
- Clinical: varies with the pathogen and host age and immune status, but typically fever, headache (often more prominent than in bacterial meningitis), photophobia, nausea/vomiting, rash (depending on etiology), diarrhea, flu-like illness, meningeal signs and lethargy without obtundation.
- Review history of travel and exposures: rodents (LCMV, leptospirosis), ticks (Lyme, rickettsial), TB, sexual activity (HSV, acute HIV infection, syphilis), endemic/epidemic (West Nile virus), IDU (acute HIV, endocarditis).
- Other etiologies: drug-induced meningitis (NSAIDs, co-trimoxazole), parameningeal foci (epidural abscess, epidermoid cyst), and malignancy (lymphoma, carcinoma).
- Physical examination: meningismus, cranial nerve palsies, rash (depending on the cause), hand-foot-mouth disease (multiple oral ulcers and papulovesicular rash of palms and soles commonly seen with enterovirus), acute flaccid paralysis (WNV, enteroviruses including polio), genital herpes (>1/3 of primary genital HSV-2 infections in women are accompanied by meningitis; 11% in men).
- CSF: 10 to < 1,000 WBC typical, predominantly lymphocytes or monocytes (PMNs may be seen early in the course, particularly with enteroviruses)
- Elevated protein
- Glucose normal
- Negative culture and gram stain
- High CSF lactate (>35 mg/dL) suggests aseptic > bacterial meningitis.
- CSF: 10 to < 1,000 WBC typical, predominantly lymphocytes or monocytes (PMNs may be seen early in the course, particularly with enteroviruses)
- CT or MRI should not show any acute brain pathology.
- Craniocervical and sinus imaging (MRI or CT) should be considered to rule out parameningeal focus.
- Historically a specific cause was not identified in up to 80+% of cases, but the ability to identify a culprit pathogen is improving with the expanded use of molecular diagnostics.
- Dx studies should include CSF with WBC and differential, protein, glucose, VDRL, Cryptococcal Ag, WNV IgM, Gram stain and culture, fungal stain and culture, AFB smear and culture; PCRs for Enterovirus, HSV, VZV; Lyme serology (if an endemic region), RPR, HIV testing (including RNA given possibility of primary infection). Other tests per suspicions.
- Enterovirus CSF PCR is superior to viral culture.
- Consider WNV IgM (more sensitive than PCR) from serum and CSF and other arbovirus serologies (e.g., Western Equine encephalitis, Eastern Equine encephalitis, St. Louis encephalitis, etc.).
- Suspect w/ CSF WBC < 500/ml with monocyte pleocytosis, protein < 80. Enteroviral PCR is helpful if (+) one can likely stop antibiotics and speed up hospital discharge.
- Mean CSF lymphocyte percentage lower for enteroviral (~50%) than HSV-2 (~95%) or VZV (~98%) meningitis.
- Mean CSF protein is lower for enteroviral (~60) than HSV-2 (~120) or VZV (~130) meningitis.
- Supportive care for most (hydration, electrolyte repletion, pain management).
- Observe for SIADH.
- Seizures are rare.
- A progressive downhill course argues against most purely viral meningitides (although viral meningoencephalitis can be severe).
- Enteroviral meningitis:
- Pleconaril appeared promising, but the drug was not FDA approved and is no longer available for compassionate use.
- Given the evidence of benefit from IV immunoglobulin (IVIG) if given early for severe EV 71 infection in Asia, now used routinely and part of treatment guidelines in Taiwan.
- Agammaglobulinemia with chronic enteroviral meningitis (rare): IVIG, administer 350->400 mg/kg IV q3 weeks to maintain serum IgG >500-800 mg/dL +/- initial intrathecal therapy.
- HSV-2 meningitis: may treat for neurologic sx such as urinary retention or weakness; treatment of immunocompetent persons is not necessary if only meningitis presentation without complication:
- Acyclovir 10 mg/kg IV q8h x 10-14d, can likely switch to valacyclovir 1g PO three times a day with improvement (experience limited).
- Limited data suggest a benefit of a short course of treatment for immunocompromised persons.
- Recurrent HSV-2 meningitis (formerly called Mollaret’s meningitis): prevention is suggested, although little evidence supports this approach.
- Acyclovir 400 mg PO twice daily to three times a day
- Famciclovir 250 mg PO twice-daily
- Valacyclovir 500 mg PO once-daily.
- VZV meningitis: treat if compromised hosts and severe infection: acyclovir 15 mg/kg IV q8h x 10-14d.
- Acute HIV infection: ART (See Acute Retroviral Syndrome)
- Refer to a specific pathogen or diagnosis module.
- Confusion may arise with partially treated bacterial meningitis: may need to conclude empiric therapy for bacterial meningitis or repeat LP in 12h off therapy.
Pathogen Specific Therapy
- For CNS presentations
Isoniazid + Rifampin + Pyrazinamide + Ethambutol. Corticosteroids.
Combinations of first- and second-line agents (consult an expert)
Valacyclovir, acyclovir (oral), foscarnet
Human immunodeficiency virus
Antiretroviral therapy (see Acute Retroviral Syndrome)
IVIG used routinely for severe disease in Asia
Foscarnet, ganciclovir (IV), valacyclovir, famciclovir
Amphotericin B (intrathecal), itraconazole
- Ellis L, Curtis MW, Gunter SM, et al. Relapsing Fever Infection Manifesting as Aseptic Meningitis, Texas, USA. Emerg Infect Dis. 2021;27(10). [PMID:34546167]
Comment: The case report of a patient with tick-borne relapsing fever (Borrelia turicatae) and aseptic meningitis highlights the point that other Borrelia species should be considered for patients with aseptic meningitis, positive tests for B. burgdorferi, and no epidemiologic risk for Lyme disease.
- Shukla B, Aguilera EA, Salazar L, et al. Aseptic meningitis in adults and children: Diagnostic and management challenges. J Clin Virol. 2017;94:110-114. [PMID:28806629]
Comment: Retrospective review of over 500 patients from 2005-2010 highlighted the importance of reprioritizing diagnostic testing to include more significant utilization of molecular diagnostics (as no pathogen is identified in the vast majority of cases without them) and lesser utilization of CNS imaging (which commonly does not add diagnostic value)
- Jarrin I, Sellier P, Lopes A, et al. Etiologies and Management of Aseptic Meningitis in Patients Admitted to an Internal Medicine Department. Medicine (Baltimore). 2016;95(2):e2372. [PMID:26765411]
Comment: Review of 180 patients admitted to IM unit with aseptic meningitis, including 124 without encephalitis. Most with ID diagnosis due to enteroviruses (43%), HSV-2 (17%), and VZV (14%). Significant differences in CSF profiles between enteroviral meningitis and these herpes virus meningitides, including lower CSF protein and lymphocyte percentages.
- Noska A, Kyrillos R, Hansen G, et al. The role of antiviral therapy in immunocompromised patients with herpes simplex virus meningitis. Clin Infect Dis. 2015;60(2):237-42. [PMID:25273082]
Comment: Retrospective, observational review of patients with HSV detected by PCR from CSF. Outcomes were improved in immunocompromised patients who received anti-viral therapy. No difference in rates of neurologic sequelae among immunocompetent patients whether treated or not.
- Sakushima K, Hayashino Y, Kawaguchi T, et al. Diagnostic accuracy of cerebrospinal fluid lactate for differentiating bacterial meningitis from aseptic meningitis: a meta-analysis. J Infect. 2011;62(4):255-62. [PMID:21382412]
A meta-analysis that mainly includes studies from the 1970s and 1980s; argues for using CSF lactate to help distinguish aseptic from bacterial meningitis with 93% sensitivity and 96% specificity. Utility diminished (sensitivity 49%) if antibiotics were administered before LP.
- Ooi MH, Wong SC, Lewthwaite P, et al. Clinical features, diagnosis, and management of enterovirus 71. Lancet Neurol. 2010;9(11):1097-105. [PMID:20965438]
Epidemics of Enterovirus 71 infections have arisen in Asia over the past 10-15 years. Excellent review of the spectrum of clinical manifestations of EV 71 infections, including aseptic meningitis, acute flaccid paralysis, and brainstem encephalitis, as well as differential diagnostic considerations, recommended diagnostic tests, and treatment modalities (admittedly limited mainly to supportive care and consideration of IVIG).
- Dubos F, Korczowski B, Aygun DA, et al. Distinguishing between bacterial and aseptic meningitis in children: European comparison of two clinical decision rules. Arch Dis Child. 2010;95(12):963-7. [PMID:20660523]
Comment: Another study seeks to help distinguish between life-threatening bacterial meningitis versus likely viral causes. This study examined 198 patients presenting with acute meningitis n six European centers. The clinical decision rules used were two: the Bacterial Meningitis Score [BMS--start antibiotics in case of seizure, positive cerebrospinal fluid (CSF) Gram staining, blood neutrophil count ≥10 ×10(9)/l, CSF protein level ≥80 mg/dl or CSF neutrophil count ≥1000 ×10(6)/l); and the Meningitest (start antibiotics in case of seizure, purpura, toxic appearance, PCT level ≥0.5 ng/ml, positive CSF Gram staining or CSF protein level ≥50 mg/dl). Both were 100% sensitive when compared, but the BMS yielded better specificity (52% vs. 36%, p< 0.00000001). Authors conclude that BMS is better when used cautiously in an alogrithm and avoid unnecessary antibiotics.
- Ginsberg L, Kidd D. Chronic and recurrent meningitis. Pract Neurol. 2008;8(6):348-61. [PMID:19015295]
Comment: Review article is most useful for its differential diagnosis of chronic meningitis and the uveo-meningitis syndromes.
- Rodríguez SC, Olguín AM, Miralles CP, et al. Characteristics of meningitis caused by Ibuprofen: report of 2 cases with recurrent episodes and review of the literature. Medicine (Baltimore). 2006;85(4):214-220. [PMID:16862046]
Comment: Case report and literature review for one of the more common causes of drug-induced meningitis. Many of the patients noted in the literature with this syndrome also had pre-existing autoimmune disorders such as SLE.
- Kupila L, Vuorinen T, Vainionpää R, et al. Etiology of aseptic meningitis and encephalitis in an adult population. Neurology. 2006;66(1):75-80. [PMID:16401850]
Comment: A report from Finland finds that adult aseptic meningitis is primarily due to enteroviral infection and HSV-2.
- Worthington MG, Ross JJ. Aseptic meningitis and acute HIV syndrome after interruption of antiretroviral therapy: implications for structured treatment interruptions. AIDS. 2003;17(14):2145-6. [PMID:14502028]
Comment: Besides aseptic meningitis as a presentation of acute retroviral infection, the authors detail a case wherein similar clinical scenarios developed after structured ART interruption.
- Sejvar JJ, Haddad MB, Tierney BC, et al. Neurologic manifestations and outcome of West Nile virus infection. JAMA. 2003;290(4):511-5. [PMID:12876094]
Comment: A prospective study suggests that besides encephalitic presentations, WNV is well capable of causing an aseptic meningitis picture as 5/16 (31%) West Nile seropositive patients only developed meningitis but not encephalitis as a consequence of infection.
- Rotbart HA, O'Connell JF, McKinlay MA. Treatment of human enterovirus infections. Antiviral Res. 1998;38(1):1-14. [PMID:9613999]
Comment: A summary of the evidence behind the use of intravenous immunoglobulin in severe or chronic CNS enteroviral infections. It also reviews the early clinical studies with pleconaril, which has now been shown in a multi-center randomized trial to reduce the duration of headache and hasten the return to school or work in patients with acute meningitis.
- Gómez-Aranda F, Cañadillas F, Martí-Massó JF, et al. Pseudomigraine with temporary neurological symptoms and lymphocytic pleocytosis. A report of 50 cases. Brain. 1997;120 (Pt 7):1105-13. [PMID:9236623]
Comment: Describes a series of patients with HANDL (Headache with neurological deficits and CSF lymphocytosis. Pts with severe headache, temporary neurological deficit and CSF pleocytosis (cells 16-350 WBC, predominantly lymphocytes) and elevated CSF protein that is self-limiting. Most have more than one episode, and there is often a strong migraine history.
- Bergström T, Alestig K. Treatment of primary and recurrent herpes simplex virus type 2 induced meningitis with acyclovir. Scand J Infect Dis. 1990;22(2):239-40. [PMID:2162558]
Comment: The case series included one patient with acute and three with recurrent meningitis associated with recurrent genital lesions. A small sample size, but no further episodes were reported over 1-3 years of follow-up while taking acyclovir continuously or at the first sign of recurrent genital lesions.
- Ramers C, Billman G, Hartin M, et al. Impact of a diagnostic cerebrospinal fluid enterovirus polymerase chain reaction test on patient management. JAMA. 2000;283(20):2680-5. [PMID:10819951]
Comment: Use of enterovirus PCR (typically 97-100% sensitive, 100% specific) in aseptic meningitis studied here prospectively with 137/276 (~50%)peds pts with positive studies. Those pts. all had fewer tests, antibiotics and were discharged faster, suggesting marked economic benefits of the test.
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