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Aseptic Meningitis

  • Author: Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS; Chief Editor: Niranjan N Singh, MD, DM  more...
 
Updated: Jun 14, 2016
 

Background

Aseptic meningitis is an illness characterized by serous inflammation of the linings of the brain (i.e., meninges), usually with an accompanying mononuclear pleocytosis. Clinical manifestations vary, with headache and fever predominating. The illness is usually mild and runs its course without treatment; however, some cases can be severe and life threatening.

Aseptic meningitis syndrome is not caused by pyogenic bacteria. Although it is usually caused by certain viruses, it has a number of other etiologies as well, both infectious and noninfectious. Hence, the term aseptic meningitis is no longer synonymous with viral meningitis, although the two are still often used interchangeably.

The epidemiologic setting (e.g., time of year, geographic locale, exposure to insects, diseases prevalent in the local community) and accompanying systemic manifestations may be helpful in making a presumptive diagnosis. However, with a few exceptions, the clinical and laboratory findings accompanying acute viral meningitis are insufficiently distinct to allow an etiologic diagnosis, and distinguishing these disorders from a number of nonviral diseases may be difficult.

Treatment varies with the cause. No specific pharmacologic treatment is available for most cases of viral meningitis; these patients are managed with supportive therapy, which includes analgesics, antinausea medications, intravenous fluids, and prevention and treatment of complications.

Viral infection

Overall, viral infection is the most common form of aseptic meningitis, and enteroviruses are the most common viral cause. Enteroviruses are small, nonenveloped RNA viruses of the picornavirus family with various serotypes. More than 50 subtypes have been linked with meningitis. Coxsackieviruses and echoviruses, which are enteroviruses, account for approximately half of cases of aseptic meningitis.

Certain enteroviruses (e.g., coxsackievirus B5, echovirus 6, 9, and 30) are more likely to cause meningitis outbreaks, while others (coxsackie A9, B3, and B4) are mostly endemic.[1, 2, 3] The incidence of infections from enteroviruses increases in the summer and early fall. Transmission occurs by hand-to-mouth contact and to a lesser extent by respiratory and fecal routes.

Herpesviruses, both herpes labialis (HSV-1) and genital herpes (HSV-2), can cause meningitis in children and especially infants. Varicella-zoster virus, another herpesvirus, causes encephalitis but only in immunocompromised persons.

Mumps was a common cause of aseptic meningitis in the United States until mumps vaccination came into use. In several countries, mumps virus remains a common pathogen in aseptic meningitis. It is spread by respiratory secretions, with increased incidence in the spring.

Aseptic meningitis from HIV occurs mostly at the time of seroconversion. HIV spreads to the meninges hematogenously, while rabies, polio, and herpesviruses are neurotrophic (i.e., spread through neurons).

Aseptic meningitis from arboviruses follows geographic and seasonal patterns determined by the life cycle of arthropod vectors, animal reservoirs, and their contact with human subjects. Eastern equine encephalitis virus (EEEV) usually is observed in Atlantic and Gulf regions, whereas western equine encephalitis virus (WEEV) is prevalent in the western part of the United States. WEEV is responsible for more aseptic meningitis cases than EEEV.

Approximately 15% of St Louis encephalitis virus (SLEV) infections result in meningitis. In children, this incidence is as high as 60%. SLEV infection can occur in both rural and urban areas. In the rural setting, the infection from SLEV tends to follow the same pattern as WEEV infection. Conversely, in urban settings, outbreaks tend to be more explosive.

Approximately 18% of people infected with Colorado tick fever develop meningitis. This disease primarily occurs in the Rocky Mountain region, which is the habitat of Dermacentor andersoni ticks whose bite transmits the virus.

Infection with Venezuelan equine encephalitis virus initially leads to influenza-like illness in most people. Only 3% of infected persons are known to develop acute meningitis. This virus has spread into Florida and some southwestern states. LCMV, an arenavirus, is an extremely rare cause of meningitis. Transmission of LCMV infection occurs by contact with dust or food contaminated by excreta of rodents. Cases tend to be more common in the winter. Human infections have been seen in both laboratory and home settings.

Brucellosis

Brucellosis is an infection with a bacterium of one of the Brucella species, usually Brucella abortus (cattle), Brucella melitensis, Brucella ovis (sheep, goats), Brucella suis (pigs), or rarely Brucella canis (dogs). Its distribution is worldwide, but it is most common in the Mediterranean regions, Africa, the Middle East, India, Central Asia, Mexico, and Central and South America.

Persons at highest risk of brucellosis are those who work with animals that are infected, such as veterinarians and ranchers, and persons who consume raw milk or cheeses made with raw milk. Brucellosis also may be transmitted to humans if they are exposed inadvertently to live brucellosis vaccine by a needlestick or other accident.

The incidence in the United States is fewer than 0.5 cases per 100,000 population.

Drug-induced aseptic meningitis

The incidence of drug-induced meningitis (DIAM) is unknown. Many antimicrobials can cause the disorder (e.g., trimethoprim-sulfamethoxazole, ciprofloxacin, cephalexin, metronidazole, amoxicillin, penicillin, isoniazid). Other drugs that have been associated with DIAM include NSAIDs, ranitidine, carbamazepine, vaccines against hepatitis B and mumps, immunoglobulins, radiographic agents, and muromonab-CD3.

DIAM may recur with re-exposure to the offending agent. Green et al reported a case of lamotrigine-induced aseptic meningitis, with a second episode on rechallenge with lamotrigine.[5]

The pathogenic mechanisms of DIAM are diverse and presumably differ from drug to drug. There are two proposed mechanisms: direct meningeal irritation by the intrathecal drug and hypersensitivity reactions to the drug (type III and IV). In type III hypersensitivity reactions, the drug or its metabolite forms a complex with antibodies in the serum, in turn activating the complement cascade. In type IV reactions, T helper cells, after previous sensitization, are recruited to the site of inflammation.[6]

DIAM from muromonab (OKT3) is believed to be mediated, at least in part, by cytokine release. Why such reactions are confined selectively to the CSF compartment is unclear.

Aseptic meningitis—along with cerebral vasospasm or ischemic encephalopathy—has been reported with intravenous immunoglobulin (IVIg) therapy.[7] Jarius et al strongly suggest that in vivo activation of TNF-alpha–primed neutrophils by atypical antineutrophil cytoplasmic antibodies (ANCAs) of IVIg may contribute to these side effects.[8]

Aseptic meningitis in systemic disease

Patients with systemic lupus erythematosus are especially susceptible to aseptic meningitis. In these patients, the disorder is often precipitated by drugs.

Vogt-Koyanagi-Harada syndrome

The exact etiology of this condition remains uncertain. Originally, the Vogt-Koyanagi syndrome was described independently of the Harada syndrome. However, the clinical manifestations of both overlap sufficiently to justify their combination into a single entity.

Behçet syndrome

The cause of Behçet syndrome remains uncertain. CNS manifestations occur in 18% of patients with Behçet syndrome.

Mollaret meningitis

Mollaret meningitis is a recurrent disorder whose causative agent remains unknown. However, recent data suggest that herpes simplex virus (HSV-2 and, less frequently, HSV-1) may cause some if not most cases.

Iatrogenic aseptic meningitis

Patients have developed febrile meningeal syndromes shortly after undergoing embolization of cerebral aneurysms with hydrogel-coated coils.[9]

Postoperative aseptic meningitis was first described by Cushing in 1925,[10] though the mechanisms remain unclear.

Go to Meningitis, Meningococcal Meningitis, Staphylococcal Meningitis, Haemophilus Meningitis, Viral Meningitis, and Tuberculous Meningitis for more complete information on these topics.

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Etiology

Aseptic meningitis may be caused by viruses, bacteria, fungi, parasites, drugs, systemic diseases, and miscellaneous other conditions.

Viral causes include the following:

  • Enteroviruses - coxsackievirus, echovirus, poliovirus
  • Herpes simplex virus (HSV) types 1 and 2 (HSV-1, HSV-2)
  • Varicella-zoster virus
  • Arboviruses
  • Epstein-Barr virus
  • HIV
  • Influenza virus types A and B
  • Mumps virus
  • Coloradotick fever virus
  • Lymphocytic choriomeningitis virus (LCMV)
  • Rabies

Bacterial causes are as follows:

  • Partially treated bacterial meningitis
  • Parameningeal infection
  • Endocarditis
  • Mycoplasma pneumoniae
  • Mycobacterium tuberculosis
  • Ehrlichiosis - monocytic, granulocytic
  • Borrelia burgdorferi
  • Treponema pallidum
  • Brucella species

Fungal causes are as follows:

  • Cryptococcus neoformans
  • Histoplasma capsulatum
  • Coccidioides immitis
  • Blastomyces dermatitides

Parasites that can cause aseptic meningitis are as follows:

  • Toxoplasma gondii
  • Taenia solium (cysticercosis)

Drugs that can cause aseptic meningitis include the following:

  • Nonsteroidal anti-inflammatory drugs (NSAIDs)
  • Antimicrobials (e.g., trimethoprim-sulfamethoxazole, amoxicillin, isoniazid)
  • Muromonab-CD3 (Orthoclone OKT3)
  • Azathioprine
  • Intravenous immunoglobulin
  • Intrathecal methotrexate
  • Intrathecal cystine arabinoside
  • Vaccines
  • Allopurinol

Systemic diseases that can cause aseptic meningitis include the following:

  • Sarcoidosis
  • Leptomeningeal cancer
  • Posttransplantation lymphoproliferative disorder
  • Systemic lupus erythematosus
  • Wegener granulomatosis
  • CNS vasculitis
  • Behçet disease
  • Vogt-Koyanagi-Harada syndrome

Miscellaneous causes include the following:

  • Arachnoiditis
  • Migraine
  • Postinfectious syndromes
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Epidemiology

Frequency

Viral meningitis is a relatively common disorder. In Olmsted County, Minnesota, the incidence of viral meningitis was 10.9 per 100,000 person-years from 1950 to 1981, with most cases occurring in the summer months.[4] The incidence of aseptic meningitis has been reported as 11 per 100,000 person-years, compared with a rate of 8.6 per 100,000 for bacterial meningitis. In the United States, a specific cause is usually identifiable in 10-15% of cases of meningitis.

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Prognosis

Aseptic meningitis is usually a benign disease. Rates of morbidity and mortality are low, except among neonates. Most patients experience full recovery in 5-14 days after onset of symptoms. Fatigue, light-headedness, and asthenia may persist for months in some cases, however.

Complications

Seizures sometimes can complicate meningitis. Encephalitis may develop in some patients. The most common sequela following mumps meningoencephalitis is sensorineural deafness. Hydrocephalus from aqueductal stenosis has been reported as a late sequela of mumps meningitis and encephalitis in children.

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Contributor Information and Disclosures
Author

Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS Professor Emeritus of Neurology and Psychiatry, Clinical Professor of Medicine, Clinical Professor of Family Medicine, Clinical Professor of Neurosurgery, State University of New York Upstate Medical University; Neuroscience Director, Department of Neurology, Crouse Irving Memorial Hospital

Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS is a member of the following medical societies: American College of International Physicians, American Heart Association, American Stroke Association, American Academy of Neurology, American Academy of Pain Medicine, American College of Forensic Examiners Institute, National Association of Managed Care Physicians, American College of Physicians, Royal College of Physicians, Royal College of Physicians and Surgeons of Canada, Royal College of Surgeons of England, Royal Society of Medicine

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Glenn Lopate, MD Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Consulting Staff, Department of Neurology, Barnes-Jewish Hospital

Glenn Lopate, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, Phi Beta Kappa

Disclosure: Nothing to disclose.

Chief Editor

Niranjan N Singh, MD, DM Associate Professor of Neurology, University of Missouri-Columbia School of Medicine

Niranjan N Singh, MD, DM is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Headache Society

Disclosure: Nothing to disclose.

Additional Contributors

Norman C Reynolds, Jr, MD Neurologist, Veterans Affairs Medical Center of Milwaukee; Clinical Professor, Medical College of Wisconsin

Norman C Reynolds, Jr, MD is a member of the following medical societies: American Academy of Neurology, Association of Military Surgeons of the US, International Parkinson and Movement Disorder Society, Sigma Xi, Society for Neuroscience

Disclosure: Nothing to disclose.

References
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  2. Martinez AA, Castillo J, Sanchez MC, Zaldivar Y, Mendoza Y, Tribaldos M, et al. Molecular diagnosis of echovirus 30 as the etiological agent in an outbreak of aseptic meningitis in Panama: May-June 2008. J Infect Dev Ctries. 2012 Dec 15. 6(12):836-41. [Medline].

  3. Pabbaraju K, Wong S, Chan EN, Tellier R. Genetic characterization of a Coxsackie A9 virus associated with aseptic meningitis in Alberta, Canada in 2010. Virol J. 2013 Mar 22. 10:93. [Medline]. [Full Text].

  4. Nicolosi A, Hauser WA, Beghi E, Kurland LT. Epidemiology of central nervous system infections in Olmsted County, Minnesota, 1950-1981. J Infect Dis. 1986 Sep. 154(3):399-408. [Medline].

  5. Green MA, Abraham MN, Horn AJ, Yates TE, Egbert M; Sharma A. Lamotrigine-induced aseptic meningitis: a case report. International Clinical Psychopharmacology. May, 2009. 24(3):159-161.

  6. Jolles S, Sewell WA, Leighton C. Drug-induced aseptic meningitis: diagnosis and management. Drug Saf. 2000 Mar. 22(3):215-26. [Medline].

  7. Bhatt GC, Sharma T. Aseptic meningitis following intravenous immunoglobulin therapy of common variable immunodeficiency. J Pediatr Neurosci. 2012 Sep. 7(3):242-3. [Medline]. [Full Text].

  8. Jarius S, Eichhorn P, Albert MH, Wagenpfeil S, Wick M, Belohradsky BH. Intravenous immunoglobulins contain naturally occurring antibodies that mimic antineutrophil cytoplasmic antibodies and activate neutrophils in a TNFalpha-dependent and Fc-receptor-independent way. Blood. 2007 May 15. 109(10):4376-82. [Medline].

  9. Im SH, Han MH, Kwon BJ, Jung C, Kim JE, Han DH. Aseptic meningitis after embolization of cerebral aneurysms using hydrogel-coated coils: report of three cases. AJNR Am J Neuroradiol. 2007 Mar. 28(3):511-2. [Medline].

  10. Ross D, Rosegay H, Pons V. Differentiation of aseptic and bacterial meningitis in postoperative neurosurgical patients. J Neurosurg. 1988 Nov. 69(5):669-74. [Medline].

  11. Hiwatani Y, Miwa H, Kondo T. Aseptic meningitis as a rare manifestation of saho syndrome. Neurology. Nov. 2008. 71(20):1645-1647.

  12. Dubos F, Korczowski B, Aygun DA, Martinot A, Prat C, Galetto-Lacour A, et al. Serum Procalcitonin Level and Other Biological Markers to Distinguish Between Bacterial and Aseptic Meningitis in Children: A European Multicenter Case Cohort Study. Archives of Pediatrics & Adolescent Medicine. Dec. 2008. 162(12):1157-1163.

  13. Lee BE, Davies HD. Aseptic meningitis. Curr Opin Infect Dis. 2007 Jun. 20(3):272-7. [Medline].

  14. Bishara J, Hadari N, Shalita-Chesner M, Samra Z, Ofir O, Paul M. Soluble triggering receptor expressed on myeloid cells-1 for distinguishing bacterial from aseptic meningitis in adults. Eur J Clin Microbiol Infect Dis. 2007 Jul 4. [Medline].

  15. The management of neurosurgical patients with postoperative bacterial or aseptic meningitis or external ventricular drain-associated ventriculitis. Infection in Neurosurgery Working Party of the British Society for Antimicrobial Chemotherapy. Br J Neurosurg. 2000 Feb. 14(1):7-12. [Medline].

  16. Zarrouk V, Vassor I, Bert F, Bouccara D, Kalamarides M, Bendersky N. Evaluation of the management of postoperative aseptic meningitis. Clin Infect Dis. 2007 Jun 15. 44(12):1555-9. [Medline].

 
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