OVERVIEW: What every practitioner needs to know

Are you sure your patient has viral meningitis? What are the typical findings for this disease?

  • Fever plus headache in older patients, irritability in young infants

  • Altered mental status and stiff neck, seizures less common

  • Cerebrospinal fluid shows lymphocytic pleocytosis; normal CSF may be seen in neonates with enterovirus or parechovirus meningitis

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The majority of cases occur in summer or early fall, and are caused by nonpolio enteroviruses, usually echoviruses or Coxsackie viruses.

Herpes virus type 2 and arboviruses (West Nile, eastern equine encephalitis, western equine encephalitis, St. Louis encephalitis, California encephalitis, Colorado tick fever) are additional, less frequent causes of viral meningitis or meningoencephalitis.

Parechovirus is now recognized as a pathogen in young infants. Many infants present with a sepsis like illness with high fever; the CSF is generally acellular.

Lymphocytic choriomeningitis virus (LCM), mumps, and poliovirus are rare causes of viral meningitis in the United States. Very rarely, respiratory viruses (adenovirus, influenza, parainfluenza virus) or other herpes viruses (human herpesvirus-6, Epstein-Barr, varicella zoster, cytomegalovirus) have been associated with neurologic manifestations and CSF pleocytosis.

Mumps meningitis should be suspected in an under-immunized or unimmunized child, particularly if he or she has recently traveled outside of the United States. Herpes simplex virus type 2 meningitis may occur in the setting of primary genital herpes; it is most common in adolescent girls. Varicella zoster virus can be associated with meningoencephalitis.

In August, 2014, a large outbreak of enterovirus D-68 respiratory tract infection was noted across the United States. During the time frame of the widespread outbreak, a neurologic illness characterized by acute limb weakness with MRI brain and spinal cord changes limited to gray matter and reminiscent of poliovirus infection was reported. CSF pleocytosis with predominantly lymphocytes was noted in most patients.

What other disease/condition shares some of these symptoms?

Many conditions share symptoms with viral (aseptic) meningitis.

Acute disseminated encephalomyelitis (ADEM) can mimic viral meningitis and should be considered when neurologic symptoms and pleocytosis follow within 2-3 weeks of acute infection or immunization. A demyelinating disease of the CNS termed neuromyelitis optica is associated with recurrent episodes of optic neuritis and myelitis; the etiology is unknown but it has been associated with HIV.

The most common alternative etiologies that mimic viral meningitis are: erhlichiosis, Rocky Mountain spotted fever, Kawasaki disease, and Lyme meningitis.

Other conditions sharing some of these symptoms are: drug-associated aseptic meningitis, central nervous system vasculitis, neoplastic diseases.

What caused this disease to develop at this time?

  • Enteroviruses and parechoviruses are ubiquitous, and person-to-person transmission occurs. Mumps is also transmitted person to person.

  • For West Nile virus, arthropods (usually mosquitoes) transmit infection to humans through bites (cycle of transmission between birds, small mammals and arthropods with humans infected as dead end hosts).

  • HSV-2 is transmitted by direct contact with an infected individual, usually sexual contact.

  • Blood transfusion can be a source of infection with West Nile virus.

  • For lymphocytic choriomeningitis virus, the source is aerosolization of dust or food contaminated with infected rodent secretions.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Cerebrospinal fluid (CSF) findings: pleocytosis with 50-500 cells, typically lymphocytes, protein 40-100 mg/dl, CSF glucose from CSF is generally 50-75% of serum glucose (though low CSF glucose is reported with mumps and LCMV meningitis). Infants with parechovirus meningitis almost always have normal appearing CSF but the virus can be confirmed by PCR.

For enterovirus, parechovirus, or HSV 2, detection by polymerase chain reaction (PCR) on CSF is recommended; viral culture is less sensitive in enteroviral and HSV 2 meningitis and not available for parechoviruses.

CSF PCR is preferred for West Nile or mumps.

By definition, bacterial cultures from blood and CSF are negative.

Blood counts and electrolyte measurements are usually not needed.

Would imaging studies be helpful? If so, which ones?

Imaging studies are rarely necessary but should be considered in the setting of refractory seizures or focal neurologic disease. Infants with parechovirus meningitis may have extensive white matter changes seen on MRI.

Consider an alternative diagnosis if the patient appears toxic, has lowered Glasgow coma score, refractory seizures, requires intensive care, or has focal findings on neurologic exam.

If you are able to confirm that the patient has viral meningitis, what treatment should be initiated?

  • Management is supportive in most cases; enteroviral and parechovirus meningitis is self-limited and usually resolves in 5-7 days.

  • Some patients require intravenous fluids if vomiting.

  • Identification and management of increased intracranial pressure if present

  • Identification and treatment of syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH) if present

  • Management of seizures if present. Infants with parechovirus meningitis may have seizures refractory to therapy and may require multiple anticonvulsants.

  • Treat fever with appropriate dosing of acetaminophen.

  • Pain management as necessary; many older children have severe headache.

  • Pathogen-specific isolation for hospitalized patients: contact precautions for enteroviral and parechoviral disease, droplet precautions for mumps meningitis, standard precautions for West Nile meningitis

  • Specific antiviral therapy is not available or indicated for enteroviral, parechoviral, West Nile, or LCM meningitis.

  • Empiric antibiotics awaiting cultures if diagnosis of viral meningitis is uncertain

  • In all patients, if herpes simplex viral CNS infection is suspected, initiate acyclovir intravenously, but HSV 2 meningitis is usually self-limited and without complications.

  • Doxycycline should be initiated empirically for a child with febrile CNS syndrome in those locales where tick-borne infection is prevalent, especially if tick exposure is confirmed; it is also the drug of choice for Q fever. It is the drug of choice for all age groups and should be initiated empirically if Rocky Mountain spotted fever or ehrlichiosis is suspected.

  • If cranial nerve findings or clinical course suggests possible Lyme meningitis, intravenous ceftriaxone may be administered pending results of antibody testing.

  • If drug hypersensitivity is suspected to be the cause, it is critical to remove the inciting drug.

What are the adverse effects associated with each treatment option?

Acyclovir can cause renal dysfunction and neutropenia. Doxycycline given in doses for treatment of tick borne disease is not associated with dental changes. Ceftriaxone can cause diarrhea or drug fever.

What are the possible outcomes of viral meningitis?

Enteroviral and LCM meningitis has excellent prognosis; generally there are no sequelae in non-neonates.

HSV 2 meningitis, which is a different clinical entity than HSV encephalitis, usually resolves without complications.

Mumps meningitis can result in hearing loss.

West Nile meningitis can lead to permanent neurologic sequelae, but this is much less common in children than in adults.

Fatal disease has been reported with parechovirus type 3 meningitis in infants. However, even in those with severe disease in whom MRI shows extensive white matter changes, the prognosis is generally good.

What causes this disease and how frequent is it?

  • Generally, 0.8-1.0 reported cases per 100,000 population. Enterovirus is the predominant cause of viral meningitis in the United States and is more common in young infants and during the months of June through October. Parechovirus disease similarly occurs in late summer and fall.

  • Other causes of viral meningitis are associated with specific risk factors, including the following:

    Prior blood transfusion, mosquito exposure, infant whose mother was infected during pregnancy or breastfeeding (West Nile Virus)

    Incomplete or no prior immunization (mumps)

    Concurrent genital herpes (HSV-2)

    Geographic locale (West Nile virus)

    Mouse, hamster, guinea pig exposure (LCM)

    Underlying disease and immune status of child (varicella)

  • Tick exposure (suggests alternative diagnosis, i.e., ehrlichiosis, Borrelia burgdorferi, Rickettsia rickettsii)

  • Exposure to domestic farm animals (especially birthing fluids from sheep, goats, cows) may suggest Q fever

How do these pathogens/genes/exposures cause the disease?

  • Person-to-person exposure is most common; fecal-oral and respiratory routes plus mother to infant peripartum transmission are the most common exposures for enteroviruses and parechovirus. Dissemination to the CNS occurs via viremia.

  • HSV2 meningitis results from recrudescence of latent genital HSV 2 infection.

  • West Nile virus causes meningitis through dissemination of the virus following the bite of an infected mosquito; transfusion and organ transplant-associated infection have occurred.

  • Mumps virus disseminates to the CNS as a consequence of respiratory infection.

Other clinical manifestations that might help with diagnosis and management

Retinitis – think West Nile

Flaccid paralysis – think enterovirus 71, poliomyelitis virus, West Nile, EV-D68

Parotitis – think mumps

Rash – some enteroviruses, parechovirus, West Nile, varicella zoster virus, measles

Genital lesions – think HSV 2

What complications might you expect from the disease or treatment of the disease?

Severe sequelae have been reported in neonatal disease caused by enteroviruses and parechovirus type 3 and in those whose presentation includes flaccid paralysis.

Are additional laboratory studies available; even some that are not widely available?

In patients with unusual or persistent symptoms, serologic studies and CSF PCR for human immunodeficiency virus and Epstein-Barr virus may be warranted.

How can viral meningitis be prevented?

Enteroviral infection cannot be prevented except through careful hand hygiene. All children should receive MMR vaccine to prevent mumps. Appropriate mosquito prevention includes protective clothing during active mosquito season and use of DEET products for those over 6 months of age.

What is the evidence?

Tunkel, AR,, Glaser, CA,, Bloch, KC. “The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America.”. vol. 47. 2008. pp. 303-27. (Good evidence for approach to encephalitis in adults.)

Rotbart, HA. “Viral meningitis”. Semin Neurol. vol. 20. 2000. pp. 277-92. (Prognostic data for enteroviral meningitis in children.)

Chang, LY,, Huang, LM,, Gau, SS. “Neurodevelopment and cognition in children after enterovirus 71 infection.”. N Engl J Med. vol. 356. 2007. pp. 1226-34. (Prognostic data for enterovirus 71 meningitis.)

Wolthers, KC,, Benschop, KS,, Schinkel, J. “Human parechoviruses as an important viral cause of sepsis-like illness and meningitis in young children.”. Clin Infect Dis. vol. 47. 2008. pp. 358-63. (One of the first descriptions of clinical manifestations of parechovirus in infants.)

Verboon-Maciolek, MA1,, Groenendaal, F,, Hahn, CD. “Human parechovirus causes encephalitis with white matter injury in neonates.”. Ann Neurol. vol. 64. 2008. pp. 266-73. (Good description of neuroimaging findings in parechovirus disease and good outcome generally even in severe disease.)

Ben-Nathan, D,, Gershoni-Yahalom, O,, Samina, I. “Using high titer West Nile intravenous immunoglobulin from selected Israeli donors for treatment of West Nile virus infection.”. BMC Infect Dis. vol. 9. 2009. pp. 18(Classic article showing efficacy of IVIG in WN paralytic disease.)

Sharp, J,, Harrison, CJ,, Puckett, K. “Characteristics of young infants in whom human parechovirus, enterovirus, or neither were detected in cerebrospinal fluid during sepsis evaluations.”. Pediatr Infect Dis J. vol. 32. 2013. pp. 213-6. (Comparison of enterovirus, parechovirus disease in infants.)

Wootton, SH,, Aguilera, E,, Salazar, L,, Hemmert, AC,, Hasbun, R. “Enhancing pathogen identification in patients with meningitis and a negative Gram stain using the BioFire FilmArray Meningitis/Encephalitis panel.”. Annals of Clinical Microbiology and Antimicrobials.. vol. 15. 2016. pp. 26(Describes CSF PCR panel to detect bacteria [S. pneumoniae, N. meningitidis, S. agalactiae, H. influenzae, L. monocytogenes, E. coli K1], eight viruses [herpes simplex types 1 and 2, human herpesvirus 6, cytomegalovirus, Epstein-Barr virus, enterovirus, parechovirus, varicella zoster virus] and two fungi [Cryptococcus gattii/neoformans)]).

Sejvar, JJ. “Clinical Manifestations and Outcomes of West Nile Virus Infection”. Viruses. vol. 6. 2014. pp. 606-623. (Updated overview of West Nile outcomes.)