clinical presentation of viral meningitis

Viral Meningitis

• Symptoms and Signs |
• Diagnosis |
• Treatment |
• Key Points |

(See also Overview of Meningitis .)

Viral meningitis is sometimes used synonymously with aseptic meningitis. However, aseptic meningitis usually refers to acute meningitis caused by anything other than the bacteria that typically cause acute bacterial meningitis. Thus, aseptic meningitis can be caused by viruses, noninfectious conditions (eg, drugs, disorders), fungi, or, occasionally, other organisms (eg, Borrelia burgdorferi in Lyme disease, Treponema pallidum in syphilis).

Unlike bacterial meningitis, viral meningitis usually spares the brain parenchyma. (Parenchyma is affected in viral encephalitis or meningoencephalitis.)

Causes of Viral Meningitis

Viral meningitis usually results from hematogenous spread, but meningitis due to herpes simplex virus type 2 (HSV-2) or varicella-zoster virus can also result from reactivation of latent infection. Recurrent attacks of viral meningitis in women are usually due to HSV-2.

The most common cause of viral meningitis is

Enteroviruses

For many viruses that cause meningitis (unlike the bacteria that cause acute bacterial meningitis ), incidence is seasonal (see table Common Causes of Viral Meningitis ).

Common Causes of Viral Meningitis

Zika virus and Chikungunya virus are uncommon causes of meningitis, but these viruses should be considered in people who have traveled to endemic areas if they develop symptoms that suggest meningitis.

Occasionally, meningitis, usually accompanied by encephalitis , develops in patients with COVID-19 . Rarely, meningitis in COVID-19 patients is due to coinfection by another virus (eg, varicella-zoster virus).

Symptoms and Signs of Viral Meningitis

Viral meningitis, like acute bacterial meningitis , usually begins with symptoms that suggest viral infection (eg, fever, myalgias, gastrointestinal or respiratory symptoms), followed by symptoms and signs of meningitis (headache, fever, nuchal rigidity). Manifestations tend to resemble those of bacterial meningitis but are usually less severe (eg, nuchal rigidity may be less pronounced). However, findings are sometimes severe enough to suggest acute bacterial meningitis. Because brain parenchyma is spared, delirium, confusion, seizures, and focal or global neurologic deficits are absent.

Diagnosis of Viral Meningitis

Cerebrospinal fluid (CSF) analysis (cell count, protein, glucose)

Polymerase chain reaction (PCR) of CSF and sometimes IgM

Sometimes PCR and/or culture of blood, a throat swab, nasopharyngeal secretions, or stool

Diagnosis of viral meningitis is based on analysis of CSF obtained by lumbar puncture (preceded by neuroimaging if increased intracranial pressure or a mass is suspected). Typically, protein is slightly increased but less than that in acute bacterial meningitis (eg, West Nile virus meningitis . Glucose is usually normal or only slightly lower than normal. Other findings include pleocytosis with a lymphocytic predominance. Nonetheless, no combination of findings in CSF cells, protein, and glucose can rule out bacterial meningitis. Bacterial meningitis is eventually ruled out if no bacteria grow in CSF cultures. However, if a patient with bacterial meningitis took antibiotics (ie, was partially treated) before blood cultures and lumbar puncture, CSF findings may resemble those of viral meningitis; thus, if patients were partially treated, empirical antibiotic treatment for bacterial meningitis may be warranted even though viral meningitis is suspected.

CSF viral culture is insensitive and not routinely done. PCR can be used to detect some viruses in CSF ( enteroviruses and herpes simplex , herpes zoster , West Nile viruses); a multiplex film-array PCR panel can be used to rapidly screen for multiple bacteria and viruses. Measurement of IgM in CSF is more sensitive than PCR in diagnosing suspected West Nile virus or other arboviruses .

Patients with HSV-2 meningitis may have enlarged mononuclear cells (Mollaret cells) in the CSF. HSV-2 meningitis often recurs (called Mollaret meningitis) .

Viral serologic tests, PCR, or culture of samples taken from other areas (eg, blood, a throat swab, nasopharyngeal secretions, stool) may help identify the causative virus.

Pearls & Pitfalls

Treatment of Viral Meningitis

Supportive measures

If patients appear seriously ill and if acute bacterial seems possible (even if viral meningitis is suspected), appropriate antibiotics and corticosteroids are started immediately (without waiting for test results) and continued until bacterial meningitis is ruled out (ie, no bacteria grow in CSF cultures).

Viral meningitis usually resolves spontaneously over weeks or, occasionally (eg, in West Nile virus meningitis or lymphocytic choriomeningitis ), months. Treatment is mainly supportive.

herpes simplex meningitis and can be used to treat herpes zoster meningitis

Pleconaril is only modestly efficacious for meningitis due to enteroviruses and is not available for routine clinical use.

Patients with HIV meningitis are treated with antiretroviral drugs .

Viral meningitis begins with symptoms typical of a viral illness, followed by headache, fever, and nuchal rigidity, but is rarely as severe as acute bacterial meningitis.

Enteroviruses are the most common cause, usually causing infection during summer or early autumn.

CSF findings (usually lymphocytic pleocytosis, near normal glucose, and slightly increased protein) cannot exclude acute bacterial meningitis.

Treat patients for acute bacterial meningitis until that diagnosis is ruled out.

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Viral meningitis

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• Theory  
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Viral meningitis must be distinguished from bacterial meningitis, which is associated with significant morbidity and mortality and requires urgent treatment including prompt antibiotics.

Treat all patients with suspected meningitis in line with guidelines on bacterial meningitis until the diagnosis of bacterial meningitis is excluded or deemed unlikely. See Bacterial meningitis in adults and Bacterial meningitis in children .

No specific treatment has been proven to be beneficial for viral meningitis.

If testing identifies a viral pathogen, stop any empirical antibiotics or corticosteroids that have been started, give the patient supportive care as needed, and prioritise discharging the patient from hospital if they are well enough.

Viral meningitis is inflammation of the meninges caused by a variety of different viruses and is the most common cause of aseptic meningitis.

History and exam

Key diagnostic factors.

• presence of risk factors
• photophobia
• neck stiffness
• nausea and vomiting

Other diagnostic factors

• Kernig's sign
• Brudzinski's sign

Risk factors

• infants and young children
• young adults
• older people
• summer and autumn
• exposure to mosquito or tick vector
• unvaccinated for mumps
• use of swimming pools and ponds
• immunosuppression
• exposure to rodents

Diagnostic investigations

1st investigations to order.

• blood cultures
• FBC and differential
• C-reactive protein (CRP)
• serum procalcitonin
• serum urea, creatinine, and electrolytes
• blood gases
• blood glucose
• CSF microscopy
• CSF Gram stain
• CSF bacterial culture
• CSF protein
• CSF glucose
• CSF lactate
• CSF, stool and throat swab PCR for viral pathogens
• HIV serology/HIV reverse transcriptase (RT)-PCR

Investigations to consider

• CT/MRI head scan

Emerging tests

• CSF procalcitonin

Treatment algorithm

Suspected meningitis, unknown aetiology, confirmed viral meningitis, recurrent viral meningitis, contributors, expert advisers, john williams, mrcp, dtm&h.

Infectious Diseases Consultant

The James Cook University Hospital

Middlesbrough

Disclosures

JW declares that he has no competing interests.

Acknowledgements

Dr John Williams would like to gratefully acknowledge Dr David Chadwick, a previous contributor to this topic.

Peer reviewers

Alex alexiou, mbbs, bsc, dch, frcem, dip imc rcsed.

Consultant in Emergency Medicine

Royal London Hospital

Consultant, Physician Response Unit

Barts Health NHS Trust/London Air Ambulance

AA declares that he has no competing interests.

Fiona McGill, MRCP, DTMH, DipHIVMed

Clinical Lecturer

Institute of Infection and Global Health

University of Liverpool

FM is on the Meningitis Research Foundation’s Medical Advisory Group, has lectured on national and international events on meningitis and has developed a review for ‘clinical medicine’ on viral meningitis and encephalitis.

Tannaz Aliabadi-Oglesby

Lead Section Editor, BMJ Best Practice

TAO declares that she has no competing interests.

Rachel Wheeler

RW declares that she has no competing interests.

Adam Mitchell

Drug Editor, BMJ Best Practice

AM declares that he has no competing interests.

Julie Costello

Comorbidities Editor, BMJ Best Practice

JC declares that she has no competing interests.

Differentials

• Bacterial meningitis (adults)
• Bacterial meningitis (children)
• Encephalitis
• A guide to utilization of the microbiology laboratory for diagnosis of infectious diseases: 2018 update by the Infectious Diseases Society of America and the American Society for Microbiology
• The UK joint specialist societies guideline on the diagnosis and management of acute meningitis and meningococcal sepsis in immunocompetent adults

Patient information

Meningitis and septicaemia

Lumbar puncture

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About Viral Meningitis

• Meningitis is an inflammation (swelling) of the protective membranes covering the brain and spinal cord.
• A bacterial or viral infection can cause the swelling.
• Viral meningitis is the most common type of meningitis.
• Most people get better on their own without treatment, but it can be very serious.

Many viruses can cause meningitis. Leading U.S. causes include:

• Arboviruses, such as West Nile virus
• Herpesviruses
• Influenza virus
• Lymphocytic choriomeningitis virus
• Measles virus
• Mumps virus
• Non-polio enteroviruses (most common)

Herpesviruses include:

• Epstein-Barr virus
• Herpes simplex viruses
• Varicella-zoster virus (which causes chickenpox and shingles )

People with viral meningitis usually start having typical meningitis symptoms .

When to seek emergency care‎

Risk factors.

Anyone can get viral meningitis; however, the following factors can increase someone's risk.

Children younger than 5 years old are at increased risk for viral meningitis.

Babies younger than 1 month old are most likely to have severe illness if they get viral meningitis.

Medical conditions

People with a weakened immune system are at increased risk for getting viral meningitis and having severe illness. Diseases, some medications (such as chemotherapy), and recent organ or bone marrow transplantations can weaken the immune system.

Close contacts aren't likely to develop meningitis‎

How it spreads.

The table below summarizes the most common ways these viruses spread. Visit specific CDC websites for more detailed information.

• Spread through specific animal exposures, including bites, urine, or feces
• Spread by sharing respiratory or throat secretions (saliva or spit) through close contact
• Spread by items contaminated with those secretions
• Spread through coughing, sneezing, or talking
• Don't require close contact
• Spread through contact with fluid from blisters
• Spread through contact with other body secretions (feces, nasal mucus)
• Spread by items contaminated with those secretions (diapers

Limit virus exposure and spread

Many daily healthy habits can help prevent viral infections:

• Wash your hands often, especially after changing diapers or using the toilet
• Avoid close contact, such as touching and shaking hands, with people who are sick
• Clean and disinfect frequently touched surfaces
• Stay home when sick and keep sick children out of school

Vaccination

Vaccines can protect against some diseases that can lead to viral meningitis:

• Chickenpox vaccines
• Influenza vaccines
• Measles and mumps vaccines
• Shingles vaccines

Other prevention tips

Avoid bites from mosquitoes and other insects that carry diseases that can infect humans.

Avoid contact with wild mice. Take precautions when handling pet rodents like mice, hamsters, or guinea pigs.

Testing and diagnosis

There are laboratory tests for meningitis .

Treatment and recovery

In most cases, there's no specific treatment for viral meningitis. Most people with mild viral meningitis usually get better on their own within 7 to 10 days.

People who develop severe illness, or are at risk for developing severe illness, may need hospital care.

Antiviral medicines

Antiviral medicine may help people with meningitis caused by viruses such as herpesvirus and influenza.

Bacteria, viruses, parasites, and fungi can all cause meningitis.

For Everyone

Health care providers.

• Patient Care & Health Information
• Diseases & Conditions

Meningitis is an infection and inflammation of the fluid and membranes surrounding the brain and spinal cord. These membranes are called meninges.

The inflammation from meningitis typically triggers symptoms such as headache, fever and a stiff neck.

Most cases of meningitis in the United States are caused by a viral infection. But bacteria, parasites and fungi also can cause it. Some cases of meningitis improve without treatment in a few weeks. Others can cause death and require emergency antibiotic treatment.

Seek immediate medical care if you suspect that you or someone in your family has meningitis. Early treatment of bacterial meningitis can prevent serious complications.

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Early meningitis symptoms may be similar to the flu. Symptoms may develop over several hours or over a few days.

Possible symptoms in anyone older than the age of 2 years include:

• Sudden high fever.
• Stiff neck.
• Severe headache.
• Nausea or vomiting.
• Confusion or trouble concentrating.
• Sleepiness or trouble waking.
• Sensitivity to light.
• No appetite or thirst.
• Skin rash in some cases, such as in meningococcal meningitis.

Signs in newborns

Newborns and infants may show these signs:

• High fever.
• Constant crying.
• Being very sleepy or irritable.
• Trouble waking from sleep.
• Being inactive or sluggish.
• Not waking to eat.
• Poor feeding.
• A bulge in the soft spot on top of the baby's head.
• Stiffness in the body and neck.

Infants with meningitis may be hard to comfort. They may even cry harder when held.

When to see a doctor

Seek immediate medical care if you or someone in your family has meningitis symptoms, such as:

• Severe headache that doesn't go away.

Bacterial meningitis is serious and can cause death within days without prompt antibiotic treatment. Delayed treatment also increases the risk of permanent brain damage.

It's also important to talk to your health care provider if you've been exposed to someone with meningitis. That may include a family member or someone you live or work with. You may need to take medicines to prevent getting an infection.

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Meningitis is an infection and inflammation of the fluid and three membranes (meninges) protecting the brain and spinal cord. The tough outer membrane is called the dura mater, and the delicate inner layer is the pia mater.

Viral infections are the most common cause of meningitis. That's followed by bacterial infections and, rarely, fungal and parasitic infections. Because bacterial infections can lead to death, learning the cause is essential.

Bacterial meningitis

Bacteria that enter the bloodstream and travel to the brain and spinal cord cause bacterial meningitis. But bacterial meningitis also can occur when bacteria directly invade the meninges. This may be caused by an ear or sinus infection, a skull fracture, or — rarely — some surgeries.

Several strains of bacteria can cause bacterial meningitis, most commonly:

• Streptococcus pneumoniae. This bacterium is the most common cause of bacterial meningitis in infants, young children and adults in the United States. It more commonly causes pneumonia or ear or sinus infections. A vaccine can help prevent this infection.

Neisseria meningitidis. This bacterium causes a bacterial meningitis called meningococcal meningitis. These bacteria commonly cause an upper respiratory infection but can cause meningococcal meningitis when they enter the bloodstream. This is a highly contagious infection that affects mainly teenagers and young adults. It may cause local epidemics in college dormitories, boarding schools and military bases.

A vaccine can help prevent infection. Even if vaccinated, anybody who has been in close contact with a person with meningococcal meningitis should receive an oral antibiotic to prevent the disease.

• Haemophilus influenzae. Haemophilus influenzae type b (Hib) bacterium was once the leading cause of bacterial meningitis in children. But new Hib vaccines have greatly reduced the number of cases of this type of meningitis.
• Listeria monocytogenes. These bacteria can be found in unpasteurized cheeses, hot dogs and lunchmeats. People who are pregnant, newborns, older adults and people with weakened immune systems are most susceptible. During pregnancy, listeria can cross the placenta. Infections in late pregnancy may be fatal to the baby.

Viral meningitis

Viral meningitis is usually mild and often clears on its own. Most cases in the United States are caused by a group of viruses known as enteroviruses. They're most common in late summer and early fall. Viruses such as herpes simplex virus, HIV , mumps virus, West Nile virus and others also can cause viral meningitis.

Chronic meningitis

Chronic meningitis — one that's long-lasting — can be caused by slow-growing organisms such as fungi and Mycobacterium tuberculosis. They invade the membranes and fluid surrounding the brain. Chronic meningitis develops over two weeks or more. Symptoms are similar to acute meningitis, which is a sudden, new case. They include headache, fever, vomiting and mental cloudiness.

Fungal meningitis

Fungal meningitis isn't common in the United States. It may mimic acute bacterial meningitis. It's often contracted by breathing in fungal spores that may be found in soil, decaying wood and bird droppings.

Fungal meningitis isn't spread from person to person. Cryptococcal meningitis is a common fungal form of the disease. It affects people with weakened immune systems, such as from AIDS . It can cause death if not treated with an antifungal medicine. Even with treatment, fungal meningitis may come back.

Parasitic meningitis

Parasites can cause a rare type of meningitis called eosinophilic meningitis. Parasitic meningitis also can be caused by a tapeworm infection in the brain or cerebral malaria. Amoebic meningitis is a rare type that is sometimes contracted through swimming in fresh water and can quickly become life-threatening.

The main parasites that cause meningitis typically infect animals. People are usually infected by eating foods contaminated with these parasites. Parasitic meningitis isn't spread between people.

Other meningitis causes

Meningitis also can result from noninfectious causes. They include chemical reactions, drug allergies, some types of cancer and inflammatory diseases such as sarcoidosis.

Risk factors

Risk factors for meningitis include:

• Skipping vaccinations. Risk rises for anyone who hasn't completed the recommended childhood or adult vaccination schedule.
• Age. Most cases of viral meningitis occur in children younger than age 5 years. Bacterial meningitis is common in those under age 20.
• Living in a community setting. College students living in dormitories, personnel on military bases, and children in boarding schools and child care facilities are at greater risk of meningococcal meningitis. This is probably because the bacterium is spread through the respiratory route, and spreads quickly through large groups.
• Pregnancy. Pregnancy increases the risk of an infection caused by listeria bacteria, which also may cause meningitis. The infection increases the risk of miscarriage, stillbirth and premature delivery.
• Weakened immune system. AIDS , alcohol use disorder, diabetes, use of immunosuppressant drugs and other factors that affect your immune system increase the risk of meningitis. Having a spleen removed also increases risk. People without a spleen should get vaccinated to lower the risk.

Complications

Meningitis complications can be severe. The longer you or your child has the disease without treatment, the greater the risk of seizures and permanent neurological damage, including:

• Hearing loss.
• Memory problems.
• Learning disabilities.
• Brain damage.
• Trouble walking.
• Kidney failure.

With prompt treatment, even people with severe meningitis can have good recovery.

Common bacteria or viruses that can cause meningitis can spread through coughing, sneezing, kissing, or sharing eating utensils, a toothbrush or a cigarette.

These steps can help prevent meningitis:

• Wash your hands. Careful hand-washing helps prevent the spread of germs. Teach children to wash their hands often, especially before eating and after using the toilet, spending time in a crowded public place or petting animals. Show them how to thoroughly wash and rinse their hands.
• Practice good hygiene. Don't share drinks, foods, straws, eating utensils, lip balms or toothbrushes with anyone else. Teach children and teens to avoid sharing these items too.
• Stay healthy. Maintain your immune system by getting enough rest, exercising regularly, and eating a healthy diet with plenty of fresh fruits, vegetables and whole grains.
• Cover your mouth. When you need to cough or sneeze, be sure to cover your mouth and nose.
• If you're pregnant, take care with food. Reduce your risk of a listeria infection by cooking meat, including hot dogs and deli meat, to 165 degrees Fahrenheit (74 degrees Celsius). Avoid cheeses made from unpasteurized milk. Choose cheeses that are clearly labeled as being made with pasteurized milk.

Vaccinations

Some forms of bacterial meningitis are preventable with the following vaccinations:

• Haemophilus influenzae type b vaccine (Hib). The World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) recommend this vaccine for children starting at about 2 months of age. The vaccine also is recommended for some adults, including those who have sickle cell disease or AIDS and those who don't have a spleen.
• Pneumococcal conjugate vaccine (PCV15 or PCV20). These vaccines are part of the CDC recommended routine vaccination schedule for children younger than 2 years. They also are part of the recommended vaccine schedule for children age 2 through 18 who are at high risk of pneumococcal disease.
• Pneumococcal polysaccharide vaccine (PPSV23). Older children and adults who need protection from pneumococcal bacteria may receive this vaccine. The CDC recommends the PPSV23 vaccine for all adults older than 65; for younger adults and children age 2 and older who have weak immune systems or chronic illnesses such as heart disease, diabetes or sickle cell anemia; and for anyone who doesn't have a spleen.

Meningococcal conjugate vaccine (MenACWY). The CDC recommends that a single dose be given to children ages 11 to 12, with a booster shot given at age 16. If the vaccine is first given between ages 13 and 15, the booster is recommended between ages 16 and 18. If the first shot is given at age 16 or older, no booster is necessary.

This vaccine also can be given to children between the ages of 2 months and 10 years who are at high risk of bacterial meningitis or who have been exposed to someone with the disease. It's also used to vaccinate healthy but previously unvaccinated people who have been exposed in outbreaks.

• Serogroup B meningococcal vaccine (MenB). The CDC recommends this vaccine for adults and children 10 years and older who are at increased risk of meningococcal disease. They include adults and children with sickle cell disease, who have a damaged spleen or who have had their spleen removed. They also include people with the rare immune disorder called complement component deficiency or who take certain medicines. This vaccine may be recommended if you're in a population that's having an outbreak of serogroup B meningococcal disease.
• Meningitis and encephalitis fact sheet. National Institute of Neurological Disorders and Stroke. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Meningitis-and-Encephalitis-Fact-Sheet. Accessed Oct. 10, 2022.
• Bacterial meningitis. Centers for Disease Control and Prevention. https://www.cdc.gov/meningitis/bacterial.html. Accessed Oct. 20, 2022.
• Ferri FF. Meningitis, bacterial. In: Ferri's Clinical Advisor 2023. Elsevier; 2023. https://www.clinicalkey.com. Accessed Oct. 21, 2022.
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• Fungal meningitis. Centers for Disease Control and Prevention. https://www.cdc.gov/meningitis/fungal.html. Accessed Oct. 20, 2022.
• Ferri FF. Meningitis, viral. In: Ferri's Clinical Advisor 2023. Elsevier; 2023. https://www.clinicalkey.com. Accessed Oct. 21, 2022.
• Loscalzo J, et al., eds. Acute meningitis. In: Harrison's Principals of Internal Medicine. 21st ed. McGraw Hill; 2022. https://accessmedicine.mhmedical.com. Accessed Oct. 10, 2022.
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• Recommended immunization schedules for children and adolescents aged 18 years or younger, United States, 2020. Centers for Disease Control and Prevention. https://www.cdc.gov/vaccines/schedules/hcp/imz/child-adolescent.html. Accessed Oct. 20, 2022.
• Recommended adult immunization schedule for adults aged 19 or older, United States, 2020. Centers for Disease Control and Prevention. https://www.cdc.gov/vaccines/schedules/hcp/imz/adult.html. Accessed Oct. 20, 2022.
• Meningococcal vaccination: What everyone should know. Centers for Disease Control and Prevention. https://www.cdc.gov/vaccines/vpd/mening/public/index.html. Accessed Oct. 26, 2022.
• Sexton D, et al. Approach to the patient with chronic meningitis. https://www.uptodate.com/contents/search. Accessed Oct. 25, 2022.
• Tunkel A. Aseptic meningitis in adults. https://www.uptodate.com/contents/search. Accessed Oct. 25, 2022.
• Di Pentima C. Viral meningitis: Management, prognosis, and prevention in children. https://www.uptodate.com/contents/search. Accessed Oct. 25, 2022.
• Parasitic meningitis. Centers for Disease Control and Prevention. https://www.cdc.gov/meningitis/parasitic.html. Accessed Oct. 26, 2022.
• Kobayashi M, et al. Use of 15-valent pneumococcal conjugate vaccine among U.S. Children: Updated recommendations of the advisory committee on immunization practices – United States, 2022. MMWR Morbidity and Mortality Weekly Report. 2022; doi:10.15585/mmwr.mm7137a3.
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Viral meningitis and encephalitis: an update

Affiliations.

• 1 Wisconsin Institute of Medical Research, University of Wisconsin-Madison, Madison, Wisconsin.
• 2 Professor of Medicine, Section of Infectious Diseases, UT Health McGovern Medical School, Houston, Texas, USA.
• PMID: 37093042
• DOI: 10.1097/QCO.0000000000000922

Purpose of review: The most common infectious etiologies of meningitis and encephalitis are viruses. In this review, we will discuss current epidemiology, prevention, diagnosis, and treatment of the most common causes of viral meningitis and encephalitis worldwide.

Recent findings: Viral meningitis and encephalitis are increasingly diagnosed as molecular diagnostic techniques and serologies have become more readily available worldwide but recent progress in novel antiviral therapies remains limited. Emerging and re-emerging viruses that have caused endemic or worldwide outbreaks or epidemics are arboviruses (e.g., West Nile virus, Japanese encephalitis, Tick borne encephalitis, Dengue, Zika, Toscana), enteroviruses (e.g., Enterovirus 71, Enterovirus D68), Parechoviruses, respiratory viruses [e.g., severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza, metapneumoviruses, measles, mumps], and herpes viruses [e.g., herpes simplex virus (HSV) type 1 (HSV-1), HSV-2, human herpes (HV) 6, varicella zoster virus (VZV)]. Future efforts should concentrate in increasing availability for those viruses with effective vaccination [e.g., Japanese encephalitis, Tick borne encephalitis, varicella zoster viruses, SARS-CoV-2, influenza], prompt initiation of those with encephalitis with treatable viruses (e.g., HSV-1, VZV), increasing the diagnostic yield by using novel techniques such as metagenomic sequencing and avoiding unnecessary antibiotics in those with viral meningitis or encephalitis.

Summary: We review the current epidemiology, clinical presentation, diagnosis, and treatment of the common causative agents of viral meningitis and encephalitis worldwide.

Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.

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• Author: Shikha S Vasudeva, MBBS; Chief Editor: Michael Stuart Bronze, MD  more...
• Sections Meningitis
• Practice Essentials
• Pathophysiology
• Epidemiology
• Patient Education
• Physical Examination
• Complications
• Approach Considerations
• Blood Studies
• Cultures and Bacterial Antigen Testing
• Syphilis Testing
• Serum Procalcitonin Testing
• Lumbar Puncture and CSF Analysis
• Neuroimaging
• Laboratory Studies
• Imaging Studies
• CSF Lactate
• CSF TNF- alpha,IL-1 and cytokines
• Treatment of Subacute Meningitis
• Treatment of Bacterial Meningitis
• Treatment of Viral Meningitis
• Treatment of Fungal Meningitis
• Treatment of Tuberculous Meningitis
• Treatment of Syphilitic Meningitis
• Treatment of Parasitic Meningitis
• Treatment of Lyme Meningitis
• Consultations
• Long-Term Monitoring
• Treatment of Noninfectious Meningitis
• Treatment of Recurrent Meningitis
• Treatment of Other Causes of Recurrent Meningitis
• Medication Summary
• Sulfonamides
• Tetracyclines
• Carbapenems
• Fluoroquinolones
• Antibiotics, Miscellaneous
• Glycopeptides
• Aminoglycosides
• Penicillins, Amino
• Penicillins, Natural
• Cephalosporins, 3rd Generation
• Antivirals, CMV
• Antivirals, Other
• Antifungals, Systemic
• Antituberculous Agents
• Vaccines, Inactivated, Bacterial
• Corticosteroids
• Diuretics, Osmotic Agents
• Diuretics, Loop
• Anticonvulsants, Hydantoins
• Anticonvulsants, Barbiturates
• Anticonvulsants, Other
• Questions & Answers
• Media Gallery

Meningitis is a condition characterized by inflammation in the meninges and subarachnoid space, which can be caused by infections, underlying medical conditions, or medication reactions. The severity and onset of symptoms can vary. [ 1 , 2 ]

Signs and symptoms

The classical triad of bacterial meningitis consists of the following [ 1 , 2 ] :

Nuchal rigidity (neck stiffness)

Less than half of patients have all three classical signs [ 3 , 4 ] ; other symptoms can include nausea, vomiting, photalgia (photophobia), sleepiness, confusion, irritability, delirium, and coma. Patients with viral meningitis may have a history of preceding systemic symptoms (eg, myalgias, fatigue, or anorexia).

The history should address the following [ 1 , 2 , 5 ] :

Epidemiologic factors and predisposing risks such as mosquito bites ( West Nile virus in endemic months, June-October in the United States)

Exposure to a sick contact (small children with febrile illness)

Previous medical treatment and existing conditions

Geographic location and travel history

Season and temperature ( enterovirus and West Nile virus in the summer and fall; herpes simplex virus type 2 year round)

Acute bacterial meningitis in otherwise healthy patients who are not at the extremes of age presents in a clinically obvious fashion; however, subacute bacterial meningitis often poses a diagnostic challenge.

General physical findings in viral meningitis are common to all causative agents. Enteroviral infection is suggested by the following:

Contact with small children with febrile illnesses

Symptoms of pericarditis, myocarditis, or conjunctivitis

Syndromes of pleurodynia, herpangina, and hand-foot-and-mouth disease

See Acute Pericarditis , Myocarditis ,  Viral Conjunctivitis , Pleurodynia , Herpangina , and Hand-foot-and-mouth Disease .

Infants may have the following:

Bulging fontanelle (if euvolemic)

Paradoxic irritability (ie, remaining quiet when stationary and crying when held)

High-pitched cry

The examination should evaluate the following:

Focal neurologic signs

Signs of meningeal irritation

Systemic and extracranial findings

Level of consciousness

In chronic meningitis, it is essential to perform careful general, systemic, and neurologic examinations, looking especially for the following:

Lymphadenopathy

Papilledema

Meningismus

Cranial nerve palsies

• Other focal neurologic signs

Patients with aseptic meningitis syndrome usually appear clinically nontoxic, with no vascular instability. They characteristically have an acute onset of meningeal symptoms, fever, and CSF pleocytosis that is usually prominently lymphocytic.

See Clinical Presentation for more detail.

The diagnostic challenges in patients with clinical findings of meningitis are as follows [ 1 , 2 , 6 , 7 ] :

Early identification and treatment of patients with acute bacterial meningitis

Assessing whether a treatable CNS infection is present in those with suspected subacute or chronic meningitis

Identifying the causative organism

Blood studies that may be useful include the following [ 1 , 7 ] :

Complete blood count (CBC) with differential

Serum electrolytes

Serum glucose (which is compared with the CSF glucose)

Blood urea nitrogen (BUN) or creatinine and liver profile

In addition, the following tests may be ordered [ 1 , 7 ] :

Blood, nasopharynx, respiratory secretion, urine or skin lesion cultures or antigen/polymerase chain reaction (PCR) detection assays

Syphilis testing

Serum procalcitonin testing

Lumbar puncture and CSF analysis

Neuroimaging (CT of the head or MRI of the brain)

See Workup for more detail.

Initial measures include the following [ 1 ] :

Shock or hypotension – Crystalloids

Altered mental status – Seizure precautions and treatment (if necessary), along with airway protection (if warranted)

Stable with normal vital signs – Oxygen, IV access, and rapid transport to the emergency department (ED)

Treatment of bacterial meningitis includes the following [ 1 ] :

Prompt initiation of empiric antibacterial therapy as appropriate for patient age and condition

After identification of the pathogen and determination of susceptibilities, targeted antibiotic therapy as appropriate for patient age and condition

Steroid (typically, dexamethasone) therapy

In certain patients, consideration of intrathecal antibiotics

The following systemic complications of acute bacterial meningitis must be treated [ 1 ] :

Hypotension or shock

Hyponatremia

Cardiac arrhythmias and ischemia

Exacerbation of chronic diseases

Most cases of viral meningitis are benign and self-limited, but in certain instances, specific antiviral therapy may be indicated, if available.

Other types of meningitis are treated with specific therapy as appropriate for the causative pathogen, as follows [ 1 ] :

Fungal meningitis - Cryptococcal (amphotericin B, flucytosine, fluconazole), Coccidioides immitis (fluconazole, amphotericin B, itraconazole), Histoplasma capsulatum (liposomal amphotericin B, itraconazole), or Candida (amphotericin plus 5-flucytosine)

Tuberculous meningitis (isoniazid, rifampin, pyrazinamide, ethambutol, streptomycin)

Parasitic meningitis (amebic [ Naegleria fowleri ] or acanthamebic) - Variable regimens

Lyme meningitis (ceftriaxone; alternatively, penicillin G, doxycycline, chloramphenicol)

See Treatment and Medication for more detail.

Infections of the central nervous system (CNS) can be categorized into two main groups: those that mainly affect the meninges (such as meningitis) and those that mainly affect the parenchyma (such as encephalitis). [ 1 ]

The 3 layers of membranes that enclose the brain and spinal cord. [ 1 ]

Dura mater - A hard outer membrane

Arachnoid mater - A lacy, weblike middle membrane

Pia mater – Is firmly attached to spinal cord and has rich blood supply

Subarachnoid space - A fragile fibrous inner layer that houses numerous blood vessels supplying the brain and spinal cord, located between the arachnoid mater and pia mater.

Arachnoid and pia mater are called leptomeninges

Meningitis is inflammation of leptomeninges including subarachnoid space leading to a constellation of signs and symptoms and presence of inflammatory cells in CSF.

Pachymeningitis is inflammation of dura mater that usually is manifested by thickening of the intracranial dura mater on radiology

Other definitions

• Acute meningitis is defined as onset of symptoms of meningeal inflammation over the course of hours to several days [ 1 ]

Chronic meningitis is defined as at least 4 weeks of symptoms of inflammation of meninges [ 8 ]

Aseptic meningitis refers to a syndrome consistent with signs and symptoms of meningeal inflammation but with negative routine CSF cultures (See Aseptic Meningitis .)

Recurrent meningitis is defined as at least 2 episodes of signs and symptoms of meningeal inflammation with associated CSF findings separated by a period of full recovery. [ 9 ]

In most cases, meningitis is caused by an infectious agent  that has colonized or established a localized infection in various parts of the body such as the skin, nose and throat, respiratory tract, gastrointestinal tract, or genitourinary tract. [ 1 ] The organism is able to invade the submucosa at these sites by bypassing the host's defenses (eg, physical barriers, local immunity, and phagocytes, or macrophages).

An infectious agent (such as a bacterium, virus, fungus, or parasite) can access the CNS and cause meningeal disease through any of the following three major pathways [ 1 ] :

Invasion of the bloodstream (eg, bacteremia, viremia, fungemia, or parasitemia) leading to subsequent hematogenous seeding of the CNS

Utilizing a retrograde neuronal pathway (eg, olfactory and peripheral nerves), as seen with organisms like Naegleria fowleri or Gnathostoma spinigerum

Direct contiguous spread through methods such as sinusitis, otitis media, congenital malformations, trauma, or direct inoculation during intracranial manipulation

Invasion of bloodstream, subsequent seeding

The most common mode of spread for many pathogens is through invasion of the bloodstream and subsequent seeding. [ 1 ] This pathway is characteristic of meningococcal, cryptococcal, syphilitic, and pneumococcal meningitis. On rare occasions, meningitis can result from invasion via septic thrombi or osteomyelitic erosion from infected neighboring structures. Meningeal seeding also can occur through direct bacterial inoculation during trauma, neurosurgery, or instrumentation. In newborns, meningitis can be transmitted vertically, involving pathogens that have colonized the maternal intestinal or genital tract, or horizontally, from nursery staff or caregivers at home.

Progressing from nearby infections such as otitis media, mastoiditis, or sinusitis, the expansion of bacteria into the brain's outer layers is a frequent occurrence. [ 1 ] The potential avenues for bacteria to travel from the middle ear to the meninges include the following:

The bloodstream

Existing tissue planes (eg, posterior fossa)

Fractures in the temporal bone

The oval or round window membranes within the inner ear's labyrinths

The protective barrier created by the meninges shields the brain from the immune system, but in cases of meningitis, this defense can be breached, enabling bacteria to infiltrate and cause infection. The body's effort to combat the infection may exacerbate the situation by causing blood vessels to become leaky, leading to brain swelling and diminished blood flow. [ 1 ]  Severe bacterial meningitis can break through the pial barrier, causing extensive brain damage. The sustained inflammatory response in meningitis is fueled by factors like bacterial replication, increased inflammatory cells, and disruptions in membrane transport, resulting in alterations in the composition of cerebrospinal fluid, including changes in cell count, pH, lactate, protein, and glucose levels.

Exudates spread throughout the cerebrospinal fluid, primarily affecting the basal cisterns, leading to the following consequences [ 1 ] :

Cranial nerve damage (such as cranial nerve VIII, which can result in hearing loss)

Blockage of CSF flow (resulting in obstructive hydrocephalus)

Triggering of vasculitis and thrombophlebitis (resulting in localized brain ischemia)

Intracranial pressure and cerebral fluid

Meningitis can lead to increased intracranial pressure (ICP) due to various factors such as interstitial edema, cytotoxic edema, and vasogenic edema. [ 1 ] This can result from mechanisms like obstructed CSF flow, toxic factors released by bacteria and neutrophils, and increased permeability of the blood-brain barrier. Left untreated, the cycle of decreasing CSF, worsening cerebral edema, and rising ICP can continue, potentially causing complications like vasospasm, thrombosis, and systemic hypotension (septic shock) leading to systemic complications or diffuse central nervous system ischemic injury and ultimately, death.

Cerebral edema

The influx of plasma components into the subarachnoid space and impaired venous outflow contribute to increased cerebrospinal fluid (CSF) viscosity, leading to interstitial edema. [ 1 ] Bacterial byproducts, activated cells, and neutrophils lead to cytotoxic edema. This accumulation of fluids and cellular elements causes various types of cerebral edema, resulting in elevated intracranial pressure and reduced cerebral blood flow. Anaerobic metabolism, elevated lactate, and low glucose levels in the CSF may occur. Inadequately controlled, this process can lead to transient neuronal dysfunction or permanent injury if not effectively treated.

Cytokines and secondary mediators in bacterial meningitis

Advancements in understanding the pathophysiology of meningitis have shed light on the crucial roles of various cytokines (eg, tumor necrosis factor alpha [TNF-α] and interleukin [IL]-1), chemokines (IL-8), and proinflammatory molecules in pleocytosis and neuronal damage during bacterial meningitis episodes.

Patients with bacterial meningitis typically exhibit heightened levels of cytokines such as TNF-α, IL-1, IL-6, and IL-8 in their CSF. [ 1 ] These molecules are believed to play key roles in triggering the inflammatory cascade in meningitis through interactions with pattern-recognition receptors like Toll-like receptors (TLRs).

Among these cytokines, TNF-α and IL-1 are particularly notable for their involvement in the inflammatory process. [ 1 ] TNF-α, derived from cells like monocyte-macrophages and astrocytes, and IL-1, produced by activated mononuclear phagocytes, are prominently detected in the CSF of bacterial meningitis patients. Secondary mediators like IL-6, IL-8, nitric oxide, prostaglandins, and platelet activation factor are thought to amplify the inflammatory response synergistically or independently.

This cascade of events can lead to vascular endothelial injury, increased blood-brain barrier permeability, and the influx of blood components into the subarachnoid space. [ 1 ] Neutrophils then are attracted to the area, crossing the damaged blood-brain barrier and contributing to the pronounced neutrophilic pleocytosis seen in bacterial meningitis.

Genetic predisposition to inflammatory response

In cases of bacterial meningitis, the inflammatory response triggers the recruitment of an excessive number of neutrophils to the subarachnoid space. These activated neutrophils release harmful substances such as oxidants and metalloproteins, which can damage brain tissue.

Pattern recognition receptors, particularly TLR A4 (TLRA4), activate the MyD88-dependent pathway, leading to the overproduction of proinflammatory mediators. Dexamethasone is used to mitigate the cellular toxicity caused by neutrophils. Ongoing research is focused on developing strategies to inhibit TLRA4 and other proinflammatory receptors through genetically engineered suppressors. [ 1 ]

Acute Bacterial Meningitis

Bacterial meningitis is characterized by a pyogenic inflammatory response in the meninges and subarachnoid cerebrospinal fluid (CSF), caused by bacterial infection. It typically presents with a sudden onset of meningeal symptoms and an increase in neutrophils in the CSF. Without prompt treatment, bacterial meningitis can result in lifelong disability or even death. [ 1 , 10 , 11 ]  Depending on age and general condition, patients with acute bacterial meningitis present acutely with signs and symptoms of meningeal inflammation and systemic infection of less than 24 hours’ (and usually >12 hours’) duration.

Bacterial meningitis typically occurs when bacteria enter the meninges through the bloodstream, with colonization of the nasopharynx being a common source in cases where the infection is not clearly identified. Many bacteria that cause meningitis, such as Neisseria meningitidis and Streptococcus pneumoniae , often are present in the nose and throat without causing symptoms.

Certain respiratory viruses may weaken mucosal defenses, making it easier for bacterial agents to enter the bloodstream. Once in the blood, these pathogens must evade immune responses, including antibodies, complement-mediated bacterial killing, and neutrophil phagocytosis.

Subsequently, the bacteria can spread to different parts of the body, including the central nervous system (CNS). The specific mechanisms by which these infectious agents reach the subarachnoid space are not fully understood. Inside the CNS, the pathogens can thrive as immune defenses, such as immunoglobulins, neutrophils, and complement factors, are limited in this region. The uncontrolled presence and replication of these infectious agents can trigger the inflammatory cascade seen in meningitis.

The specific infectious agents that are involved in bacterial meningitis vary among different patient age groups, and the meningeal  inflammation may evolve into the following conditions:

Ventriculitis

Abscess formation

Some of the bacteria associated with bacterial meningitis include the following [ 11 , 12 ] : 

Acinetobacter  spp

Capnocytophaga canimorsus 

Coagulase negative Staphylococcus

Cutibacterium acnes

Enterococcus  spp

Escherichia coli

Fusobacterium necrophorum

Haemophilus influenzae

Klebsiella pneumoniae

Listeria monocytogens

Pasteurella multocida

Pseudomonas aeruginosa

Salmonella  spp

Staphylococcus aureus

Stenotrophomonas maltophilia

Streptococcus agalactiae

Streptococcus pneumoniae

Streptococcus pyogenes

Viridans streptococci

Table 1. Most Common Bacterial Pathogens on Basis of Age and Predisposing Risks [ 1 , 13 ] (Open Table in a new window)

Some of the more common bacterial pathogens causing meningitis are elaborated below, but any bacteria is capable of causing meningitis

H influenzae meningitis

H influenzae  is a small, pleomorphic, gram-negative coccobacillus that is frequently found as part of the normal flora in the upper respiratory tract. The organism can spread from one individual to another in airborne droplets or by direct contact with secretions. Meningitis is the most serious acute manifestation of systemic infection with  H influenzae . 

In the past,  H influenzae  was a major cause of meningitis, and the encapsulated type b strain of the organism (Hib) accounted for most cases. Since the introduction of the Hib vaccine in the United States in 1990,  H influenzae  meningitis is rare in the United States and Western Europe, where use of the vaccine is common. In areas where the vaccine is not widely used, H influenza is a common cause of meningitis, particularly in children aged 2 months to 6 years. [ 11 ]

The isolation of  H influenzae  in adults suggests the presence of an underlying medical disorder, such as the following:

Paranasal sinusitis

Otitis media

CSF leak after head trauma

Functional or anatomic asplenia

Hypogammaglobulinemia

(See Haemophilus Meningitis .)

Listeria monocytogenes  meningitis

Listeria monocytogenes , a small gram-positive bacillus, accounts for 3% of bacterial meningitis cases and is associated with one of the highest mortality rates at 20%. [ 14 ] Widely distributed in nature, this pathogen has been found in the stool of 5% of healthy adults, with most infections believed to be food-related. [ 11 ]

Known as a common food contaminant, L monocytogenes has a recovery rate of up to 70% from raw meat, vegetables, and various food products. Outbreaks of listeriosis have been linked to the consumption of contaminated items such as coleslaw, milk, cheese, and alfalfa tablets.

Groups at risk include the following:

Pregnant individuals

Infants and children

Elderly individuals (>60 years)

Patients with alcoholism

Adults who are immunosuppressed (eg, steroid users, transplant recipients, or persons with AIDS)

Individuals with chronic liver and renal disease

Individuals with diabetes

Persons with iron-overload conditions (eg, hemochromatosis or transfusion-induced iron overload)

Meningitis caused by gram-negative bacilli

Aerobic gram-negative bacilli include the following [ 1 , 9 ] :

Serratia marcescens

P aeruginosa

Salmonella  species

Gram-negative bacilli can cause meningitis in certain groups of patients.  E coli  is a common agent of meningitis among neonates. Other predisposing risk factors for meningitis associated with gram-negative bacilli include the following:

Neurosurgical procedures or intracranial manipulation

Immunosuppression

• >p?High-grade gram-negative bacillary bacteremia

Disseminated strongyloidiasis

Disseminated strongyloidiasis has been reported as a classic cause of gram-negative bacillary bacteremia, as a result of the translocation of gut microflora with the  Strongyloides stercoralis  larvae during hyperinfection syndrome.

Meningococcal meningitis

N meningitidis  is a gram-negative diplococcus that is carried in the nasopharynx of otherwise healthy individuals. It initiates invasion by penetrating the airway epithelial surface. [ 1 ]  The precise mechanism by which this occurs is unclear, but recent viral or mycoplasmal infection has been reported to disrupt the epithelial surface and facilitate invasion by meningococcus. 

Most sporadic cases of meningococcal meningitis (95-97%) are caused by serogroups B, C, and Y, whereas the A and C strains are observed in epidemics (< 3% of cases).  N meningitidis  is one of the leading causes of bacterial meningitis in children and young adults, but the incidence has decreased with use of the conjugate meningococcal vaccine. [ 1 , 15 ]

Risk factors for meningococcal meningitis include the following:

Deficiencies in terminal complement components (eg, membrane attack complex, C5-C9), which increases attack rates but is associated with surprisingly lower mortality rates

Properdin defects that increase the risk of invasive disease

Antecedent viral infection, chronic medical illness, corticosteroid use, and active or passive smoking

Crowded living conditions, as is observed in college dormitories (college freshmen living in dormitories are at highest risk) and military facilities, which has been reported in clustering of cases

(See Meningococcal Meningitis .)

Staphylococcal meningitis

Staphylococci are gram-positive cocci that are part of the normal skin flora. Meningitis caused by staphylococci is associated with the following risk factors [ 11 , 16 ] :

Neurosurgery

Head trauma

Presence of CSF shunts

Infective endocarditis and paraspinal infection

S epidermidis  is the most common cause of meningitis in patients with CNS (ie, ventriculoperitoneal) shunts.

Pneumococcal meningitis

S pneumoniae ,  a gram-positive coccus, is the most common bacterial cause of meningitis in middle-aged adults and the elderly. [ 1 , 11 , 17 ]  In addition, it is the most common bacterial agent in meningitis associated with basilar skull fracture and CSF leak. It may be associated with other focal infections, such as pneumonia, sinusitis, or endocarditis (as, for example, in Austrian syndrome, which is the triad of pneumococcal meningitis, endocarditis, and pneumonia).

S pneumoniae  is a common colonizer of the human nasopharynx; it is present in 5-10% of healthy adults and 20-40% of healthy children. It causes meningitis by escaping local host defenses and phagocytic mechanisms, either through choroid plexus seeding from bacteremia or through direct extension from sinusitis or otitis media.

Patients with the following conditions are at increased risk for  S pneumoniae  meningitis:

Hyposplenism

Multiple myeloma

Glucocorticoid treatment

Defective complement (C1-C4)

Diabetes mellitus

Renal insufficiency

Malnutrition

Chronic liver disease

Streptococcus agalactiae meningitis

Streptococcus agalactiae  (group B streptococcus [GBS]) is a gram-positive coccus that inhabits the lower GI tract. It also colonizes the female genital tract at a rate of 5-40%, which explains why it is the most common agent of neonatal meningitis (associated with 70% of cases). Routine testing and treatment of pregnant females for GBS has led to a decrease in neonatal meningitis with this organism. [ 11 ]

Predisposing risks in adults include the following:

Hepatic failure

Renal failure

Corticosteroid treatment

In 43% of adult cases, however, no underlying disease is present.

Viral meningitis

Viral meningitis typically is less severe than acute bacterial meningitis and may present with fever and myalgias before progressing to typical meningitis symptoms including headache and nuchal rigidity. Delirium, confusion, and neurological deficits usually are absent due to the preservation of brain tissue. [ 18 ]

Various viruses, such as adenovirus, astrovirus, and enteroviruses, can cause meningitis, with different modes of transmission and seasonal patterns. [ 19 , 20 ] Herpesviruses, including Epstein-Barr virus and cytomegalovirus, as well as HIV, can also lead to meningitis in certain populations. Arthropod-borne viruses like West Nile virus and St Louis encephalitis virus can cause aseptic meningitis syndrome. Other pathogens such as Lymphocytic choriomeningitis virus and mumps virus may also be responsible for aseptic meningitis. Travelers returning from Mediterranean countries during the summer should be aware of Toscana virus meningitis or encephalitis. Diagnosing these viral infections may involve performing paired serologies and CSF PCR. [ 21 , 22 , 23 , 24 , 25 , 26 ]

Please see Viral Meningitis  and Aseptic Meningitis .)

Aseptic Meningitis

Aseptic meningitis, although sometimes used interchangeably with viral meningitis, generally describes acute meningitis resulting from pathogens other than the typical bacteria responsible for acute bacterial meningitis; it is one of the most common infections of the meninges. Although viruses are the most common cause of aseptic meningitis, it also can be caused by bacteria, fungi, and parasites. [ 1 ]  Partially treated bacterial meningitis accounts for a large number of meningitis cases with a negative microbiologic workup. 

In many cases, a cause of meningitis is not apparent after initial evaluation, and the disease therefore is classified as aseptic meningitis. These patients characteristically have an acute onset of meningeal symptoms, fever, and CSF pleocytosis that is usually prominently lymphocytic.

When the cause of aseptic meningitis is discovered, the disease can be reclassified according to its etiology. If appropriate diagnostic methods are performed, a specific viral etiology is identified in 55-70% of cases of aseptic meningitis. However, the condition also can be caused by bacterial, fungal, mycobacterial, and parasitic agents.

If, after an extensive workup, aseptic meningitis is found to have a viral etiology, it can be reclassified as a form of acute viral meningitis (eg, enteroviral meningitis or herpes simplex virus [HSV] meningitis). [ 27 ]

(See  Aseptic Meningitis .)

Table 2. Infectious Agents Causing Aseptic Meningitis [ 1 , 28 ] (Open Table in a new window)

See Meningitis in HIV .

Subacute and Chronic Meningitis

Chronic meningitis is a constellation of signs and symptoms of meningeal irritation associated with CSF pleocytosis that persists for longer than 4 weeks. [ 8 ]

Chronic meningitis can be caused by a wide range of infectious and noninfectious etiologies (see Table 3 below). [ 8 ]

Table 3. Causes of Chronic Meningitis  [ 8 ] (Open Table in a new window)

Acanthamoeba  and  Balamuthia  cause granulomatous amebic encephalitis, which is a subacute opportunistic infection that spreads hematogenously from the primary site of infection (skin or lungs) to the CNS and causes an encephalitis syndrome. These cases can be difficult to distinguish from culture-negative meningitis. [ 8 ]

Angiostrongylus cantonensis,  the rat lungworm, can cause eosinophilic meningitis (pleocytosis with more than 10% eosinophils) in humans. The adult parasite resides in the lungs of rats. Its eggs hatch, and the larval stages are expelled in the feces. The larvae develop in the intermediate host, usually land snails, freshwater prawns, and crabs. Humans acquire the infection by ingesting raw mollusks. [ 8 ]

Baylisascaris procyonis  is an ascarid parasite that is prevalent in the raccoon populations in the United States and rarely causes human eosinophilic meningoencephalitis. Human infections occur after accidental ingestion of food products contaminated with raccoon feces. [ 8 ]

Blastomyces dermatitidis  is a dimorphic fungus that has been reported to be endemic in North America (eg, in the Mississippi and Ohio River basins). It also has been isolated from parts of Central America, South America, the Middle East, and India. Its natural habitat is not well defined. Soil that is rich in decaying matter and environments around riverbanks and waterways have been demonstrated to harbor  B dermatitidis  during outbreaks and are thought to be risk factors for acquiring the infection. [ 8 ]

Inhalation of the conidia establishes a pulmonary infection. Dissemination may occur in certain individuals, including those with underlying immune deficiency (eg, from HIV or pharmaceutical agents) and extremes of age, and may involve the skin, bones and joints, genitourinary tract, and CNS. Involvement of the CNS occurs in fewer than 5% of cases.

Borrelia burgdorferi , a tick-borne spirochete, is the agent of Lyme disease, the most common vector-borne disease in the United States. Meningitis may be part of a triad of neurologic manifestations of Lyme disease that also includes cranial neuritis and radiculoneuritis. Lyme disease meningitis typically is associated with a facial palsy that can be bilateral. As many as 8% of children and some adults with Lyme disease develop meningitis. [ 1 ]

Brucellae are small gram-negative coccobacilli that cause zoonoses as a result of infection with  Brucella abortus, Brucella melitensis, Brucella suis,  or  Brucella canis.  Transmission to humans occurs after direct or indirect exposure to infected animals (eg, sheep, goats, or cattle). Direct infection of the CNS occurs in fewer than 5% of cases, with most patients presenting with acute or chronic meningitis. [ 8 ]

Persons at risk for brucellosis include individuals who had contact with infected animals or their products (eg, through intake of unpasteurized milk products). Veterinarians, abattoir workers, and laboratory workers dealing with these animals also are at risk. [ 8 ]

Candida  species are ubiquitous in nature. They are normal commensals in humans and are found in the skin, the GI tract, and the female genital tract. The most common species is  Candida albicans,  but the incidence of non- albicans  candidal infections (eg,  Candida tropicalis ) is increasing, including species with antifungal resistance (eg,  Candida krusei  and  Candida glabrata ). [ 8 ]

Involvement of the CNS usually follows hematogenous dissemination. The most important predisposing risks for acquiring disseminated candidal infection appear to be iatrogenic (eg, the administration of broad-spectrum antibiotics and the use of indwelling devices such as urinary and vascular catheters). Prematurity in neonates is considered a predisposing risk factor as well. Infection also may follow neurosurgical procedures, such as placement of ventricular shunts. [ 16 , 8 ]

Coccidioides immitis  is a soil-based, dimorphic fungus that exists in mycelial and yeast (spherule) forms. Persons at risk for coccidioidal meningitis include individuals exposed to the endemic regions (eg, tourists and local populations) and those with immune deficiency (eg, persons with AIDS and organ transplant recipients). [ 8 ]

Cryptococcus neoformans  is an encapsulated, yeastlike fungus that is ubiquitous. It has been found in high concentrations in aged pigeon droppings and pigeon nesting places. The 4 serotypes are designated A through D, with the A serotype causing most human infections. Onset of cryptococcal meningitis may be acute, especially among patients with AIDS. [ 8 ]

Numerous cases occur in healthy hosts (eg, persons with no known T-cell defect) [ 8 ] ; however, approximately 50-80% of cases occur in immunocompromised hosts. At particular risk are individuals with defects of T-cell–mediated immunity, such as persons with AIDS, organ transplant recipients, and other patients who use steroids, cyclosporine, and other immunosuppressants. Cryptococcal meningitis also has been reported in patients with idiopathic CD-4 lymphopenia, Hodgkin disease, sarcoidosis, and cirrhosis.

Gnathostoma spinigerum,  a GI parasite of wild and domestic dogs and cats, may cause eosinophilic meningoencephalitis. Humans acquire the infection after ingesting undercooked infected fish and poultry. [ 8 ]

Histoplasma capsulatum  is one of the dimorphic fungi that exist in mycelial and yeast forms. It usually is found in soil and occasionally can cause a chronic meningitis. The preferred means of making the diagnosis is CSF histoplasma antigen detection. [ 8 ]

M tuberculosis  is an acid-fast bacillus that causes a broad range of clinical illnesses that can affect virtually any organ of the body. It is spread through airborne droplet nuclei, and it infects one third of the world’s population. Involvement of the CNS with tuberculous meningitis usually is caused by rupture of a tubercle into the subarachnoid space.

Tuberculous meningitis  always should be considered in the differential diagnosis of patients with aseptic meningitis or chronic meningitis syndromes, especially those with basilar meningitis, symptoms of more than 5 days’ duration, or cranial nerve palsies. If tuberculous meningitis is suspected, antituberculosis therapy, with or without steroids, should be empirically started. [ 8 ]  (See Tuberculous Meningitis .) [ 29 ]

Sporothrix schenckii  is an endemic dimorphic fungus that often is isolated from soil, plants, and plant products. Human infections are characteristically lymphocutaneous. Extracutaneous manifestations of sporotrichosis may occur, though meningeal sporotrichosis, which is the most severe form, is a rare complication. AIDS is a reported underlying risk factor in many described cases and is associated with a poor outcome. [ 8 ]

Treponema pallidum  is a slender, tightly coiled spirochete that is usually acquired by sexual contact. Other modes of transmission include direct contact with an active lesion, passage through the placenta, and blood transfusion (rare). [ 8 ]

Infection with free-living amoebas is an infrequent but often life-threatening human illness, even in immunocompetent individuals.  N fowleri  is the only species of  Naegleria  recognized to be pathogenic in humans, and it is the agent of primary amebic meningoencephalitis (PAM). The parasite has been isolated in lakes, pools, ponds, rivers, tap water, and soil. [ 8 ]

Infection occurs when a person is swimming or playing in contaminated water sources (eg, inadequately chlorinated water and sources associated with poor decontamination techniques). The  N fowleri  amebas invade the CNS through the nasal mucosa and cribriform plate. [ 30 ]

PAM occurs in 2 forms. The first is characterized by an acute onset of high fever, photophobia, headache, and altered mental status, similar to bacterial meningitis, occurring within 1 week after exposure. Because it is acquired via the nasal area, olfactory nerve involvement may manifest as abnormal smell sensation. Death occurs in 3 days in patients who are not treated. The second form, the subacute or chronic form, consists of an insidious onset of low-grade fever, headache, and focal neurologic signs. Duration of illness is weeks to a few months. [ 30 ]

Noninfectious Meningitis

Noninfectious meningitis can be attributed to various factors such as noninfectious disorders, drugs, or vaccines, resulting in subacute or chronic presentations. The symptoms of noninfectious meningitis, which include headache, fever, and nuchal rigidity, are similar to those observed in other forms of meningitis. Although the severity and duration of symptoms may vary, noninfectious meningitis typically is less severe compared to acute bacterial meningitis. [ 31 ]

Recurrent Meningitis

Recurrent meningitis usually is caused by bacteria, viruses, or noninfectious conditions. [ 9 ]

Recurrent viral meningitis

Recurrent viral meningitis most often is caused by Herpes simplex virus type 2 (HSV-2; also known as Mollaret meningitis)

In cases where HSV-2 is the identified cause, patients may experience recurrent episodes marked by symptoms like fever, nuchal rigidity, and lymphocytic pleocytosis in cerebrospinal fluid (CSF). Each bout typically lasts for 2 to 5 days before spontaneously resolving. Patients also exhibit additional neurological deficits, including altered sensorium, seizures, and cranial nerve palsies, suggesting a diagnosis of meningoencephalitis.

Whenever feasible, addressing the root cause is a key aspect of treatment. Acyclovir is the recommended treatment for Mollaret meningitis, with most patients achieving complete recovery.

Recurrent acute bacterial meningitis

Acute bacterial meningitis may recur if it arises from an unresolved congenital or acquired defect in the skull base or spine. If the defect is a result of an injury, meningitis may manifest years later.

Rarely, recurrent bacterial meningitis (usually due to  Streptococcus pneumoniae  or  Neisseria meningitidis ) results from a  deficiency in the complement system . Treatment is the same as that used in patients without complement deficits. Vaccination against  S. pneumoniae  and  N. meningitidis  (given according to Centers for Disease Control and Prevention [CDC] recommendations for patients with complement deficits) may reduce likelihood of infection.

Recurrent bacterial meningitis is treated with antibiotics and dexamethasone.

Other recurrent meningitides

Acute meningitis secondary to nonsteroidal anti-inflammatory drugs (NSAIDs) or other drugs may recur when the causative drug is used again.

Meningitis caused by rupture of a brain cyst may also recur.

Additional Causes of Meningitis

Congenital malformation of the stapedial footplate has been implicated in the development of meningitis. Head and neck surgery, penetrating head injury, comminuted skull fracture, and osteomyelitic erosion infrequently may result in direct implantation of bacteria into the meninges. Skull fractures can tear the dura and cause a CSF fistula, especially in the region of the frontal ethmoid sinuses. Patients with any of these conditions are at risk for bacterial meningitis. [ 1 ]

Epidemiology of Bacterial Meningitis

Bacterial meningitis affects around 4,100 individuals annually in the United States causes 500 deaths, equating to an overall annual incidence rate of 1.33 cases per 100,000 people. [ 32 ] The incidence of meningitis varies globally, with developing nations experiencing rates up to 10 times higher than developed countries due to limited access to preventive measures. In the United States, there is a higher reported incidence of meningitis among Black individuals compared with White and Hispanic populations. [ 33 ]

During 1998 to 2007, there was a 31% decrease in meningitis incidence in the United States, attributed to vaccination programs. The introduction of the Hib conjugate vaccine for infants in the early 1990s led to a 55% reduction in bacterial meningitis rates, with reported cases of invasive H influenzae disease in children under 5 dropping significantly. Whereas these reductions have been significant in developed nations, the impact has been less profound in developing countries where Hib vaccination is not as widespread. [ 14 ] The implementation of pneumococcal vaccines and universal screening for group B streptococcus in pregnant women has further lowered the incidence of meningitis among young children; however, the burden of bacterial meningitis has shifted to impact older adults.

Since 1988, the incidence of H influenzae meningitis in the Netherlands has decreased significantly due to the implementation of Hib vaccination. The incidence of N meningitidis meningitis also has decreased, mainly due to the MenC vaccination. However, S pneumoniae has become the most common pathogen causing bacterial meningitis, with interventions being less effective compared to those for H influenzae . The use of conjugate vaccines has led to a decline in meningitis cases in non-vaccinated populations. Overall, although there have been significant reductions in meningitis cases in preschool and school-aged children, rates remain high in infants, older adults, and the elderly. [ 34 ]

Table 4. Changing Epidemiology of Acute Bacterial Meningitis in United States*  [ 14 ]         (Open Table in a new window)

Table 5. Changing Epidemiology of Bacterial Meningitis Since Introduction of Conjugate Vaccines in The Netherlands [ 34 ] (Open Table in a new window)

Epidemiology of Aseptic and Viral Meningitis

Viruses are the major cause of aseptic meningitis. In the United States, enteroviral meningitis affects about 75,000 individuals annually, representing more than half of all cases of meningitis. [ 32 ]

Aseptic meningitis has a reported incidence of 10.9 cases per 100,000 person-years. It occurs in individuals of all ages but is more common in children, especially during summer. No racial differences are reported. [ 35 ]  

Viral meningitis was the most prevalent form of meningitis in patients aged 16 years and older, followed by bacterial cases and those with unknown causes in a multicenter prospective observational study in England. The research emphasized the significance of early lumbar puncture in determining the specific cause and reducing hospital stays. Patients diagnosed with viral meningitis experienced a considerable loss in quality-adjusted life-years. [ 36 ]

Nonpolio Enteroviruses (NPEVs) include the coxsackieviruses, echoviruses, and newer numbered EVs (a total of 67 distinct serotypes). In the United States alone, the NPEVs cause an estimated 10 to 15 million symptomatic infections annually. [ 35 ]   [ 37 ]

(See  Aseptic Meningitis  and  Viral Meningitis .)

Patients with bacterial meningitis who present with an impaired level of consciousness, hypotension, or seizures are at increased risk for neurologic sequelae or death. [ 19 ]

In bacterial meningitis, several risk factors are associated with death and with neurologic disability. [ 1 ] A risk score has been developed and validated in adults with bacterial meningitis. This score includes the following variables, which are associated with an adverse clinical outcome:

Increased heart rate

Lower Glasgow Coma Scale score

CSF leukocyte count lower than 1000/μL

Gram-positive cocci on CSF Gram stain

Bacterial meningitis can result in severe neurologic complications in up to 30% of survivors, [ 12 ] underscoring the crucial importance of vigilant monitoring to detect and address these issues promptly. Mortality rates vary across age groups, with the highest fatalities seen in infants, decreasing in midlife, and rising again in older age groups, leaving 1 in 10 cases fatal and 1 in 7 survivors facing significant disabilities like deafness or brain injury.

A comprehensive review spanning nearly a century and multiple countries highlighted key pathogens like Neisseria meningitidis , Streptococcus pneumoniae , and Haemophilus influenzae in causing meningitis episodes. The overall case fatality ratio has shown a progressive decline, with Listeria monocytogenes and pneumococci associated with higher mortality rates. [ 38 ] Notably, S pneumoniae meningitis has a fatality rate of 19-26%, [ 39 ] and Haemophilus influenzae type b (Hib) cases in children range from 3-6% fatality. Older individuals face elevated risks. [ 40 ]

Increases in meningococcal disease cases, particularly due to serogroup Y infections, have prompted public health alerts to raise awareness and advocate for preventive measures. Timely vaccination and medical attention are vital in managing these serious bacterial infections, which can lead to long-term complications such as brain damage and coma, with up to 30% of survivors experiencing neurological sequelae. Ensuring vigilant monitoring and immediate intervention remains paramount in mitigating the impacts of bacterial meningitis. [ 41 ]  (See  Meningococcal Meningitis .)

Serious complications include the following:

Hearing loss

Cortical blindness

Other cranial nerve dysfunction

Muscular hypertonia

• Multiple seizures

Mental motor impairment

Focal paralysis

Subdural effusions

Hydrocephalus

Cerebral atrophy

Risk factors for hearing loss after pneumococcal meningitis are female sex, older age, severe meningitis, and infection with certain pneumococcal serotypes (eg, 12F). [ 42 ]  Delayed complications include the following:

Decreased hearing or deafness

Delayed cerebral thrombosis [ 43 ]

Other cranial nerve dysfunctions

Intellectual deficits

Waterhouse-Friderichsen syndrome

Peripheral gangrene

Seizures are a common and significant complication of meningitis, occurring in about one fifth of patients, with a higher incidence (40%) in those younger than 1 year. Half of patients experiencing seizures may have recurrent episodes, leading to adverse outcomes such as diffuse CNS ischemic injury or systemic complications.

The prognosis for patients with meningitis caused by opportunistic pathogens heavily depends on the host's immune function, requiring many survivors to undergo lifelong suppressive therapy post-recovery. In viral meningitis cases without encephalitis, the mortality rate is less than 1%. However, individuals with deficient humoral immunity, like agammaglobulinemia, facing enteroviral meningitis may encounter fatal outcomes. Fortunately, patients with viral meningitis typically have a favorable recovery prognosis, with poorer outcomes seen in those at the extremes of age (under 2 or over 60 years) and individuals with significant comorbidities or underlying immunodeficiency.

Patients and parents of young children should be educated about the benefits of vaccination in preventing meningitis. Vaccination against N meningitidis is recommended for all US college students.

Close contacts of patients with known or suspected N meningitidis or Hib meningitis may require education regarding the need for prophylaxis. All contacts should be instructed to come to the emergency department immediately at the first sign of fever, sore throat, rash, or symptoms of meningitis. Rifampin prophylaxis only eradicates the organism from the nasopharynx; it is ineffective against invasive disease.

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• Pneumococcal meningitis in a patient with alcoholism. Courtesy of the CDC/Dr. Edwin P. Ewing, Jr.
• Acute bacterial meningitis. This axial nonenhanced computed tomography scan shows mild ventriculomegaly and sulcal effacement.
• Acute bacterial meningitis. This axial T2-weighted magnetic resonance image shows only mild ventriculomegaly.
• Acute bacterial meningitis. This contrast-enhanced, axial T1-weighted magnetic resonance image shows leptomeningeal enhancement (arrows).
• Chronic mastoiditis and epidural empyema in a patient with bacterial meningitis. This axial computed tomography scan shows sclerosis of the temporal bone (chronic mastoiditis), an adjacent epidural empyema with marked dural enhancement (arrow), and the absence of left mastoid air.
• Subdural empyema and arterial infarct in a patient with bacterial meningitis. This contrast-enhanced axial computed tomography scan shows left-sided parenchymal hypoattenuation in the middle cerebral artery territory, with marked herniation and a prominent subdural empyema.
• Table 1. Most Common Bacterial Pathogens on Basis of Age and Predisposing Risks [ 1 , 13 ]
• Table 2. Infectious Agents Causing Aseptic Meningitis [ 1 , 28 ]
• Table 3. Causes of Chronic Meningitis  [ 8 ]
• Table 4. Changing Epidemiology of Acute Bacterial Meningitis in United States*  [ 14 ]        
• Table 5. Changing Epidemiology of Bacterial Meningitis Since Introduction of Conjugate Vaccines in The Netherlands [ 34 ]
• Table 6. Other Exposures and Organisms Associated with Meningitis
• Table 7. CSF Findings in Meningitis by Etiologic Agent [ 7 , 51 ]
• Table 8. Comparison of CSF Findings by Type of Organism
• Table 9. Recommended Empiric Antibiotics for Suspected Bacterial Meningitis, According to Age or Predisposing Factors [ 69 ]
• Table 10. Specific Antibiotics and Duration of Therapy for Acute Bacterial Meningitis [ 70 , 91 , 93 ]

Contributor Information and Disclosures

Shikha S Vasudeva, MBBS Assistant Professor of Internal Medicine, Virginia Tech Carilion School of Medicine; Assistant Professor of Internal Medicine, Edward Via Virginia College of Osteopathic Medicine; Infectious Disease Consultant, Department of Medicine, Veterans Affair Medical Center Shikha S Vasudeva, MBBS is a member of the following medical societies: Infectious Diseases Society of America Disclosure: Nothing to disclose.

Michael Stuart Bronze, MD David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha , American College of Physicians , American Medical Association , Association of Professors of Medicine , Infectious Diseases Society of America , Oklahoma State Medical Association , Southern Society for Clinical Investigation Disclosure: Nothing to disclose.

Rodrigo Hasbun, MD, MPH Associate Professor of Medicine, Section of Infectious Diseases, University of Texas Medical School at Houston Disclosure: Received research grant from: Biofire<br/> Speaker for Biofire.

Suur Biliciler, MD Neuromuscular Fellow, Department of Neurology, Baylor College of Medicine

Disclosure: Nothing to disclose.

Timothy S Brannan, MD Director, Department of Neurology, Jersey City Medical Center; Professor, Department of Neurology, Seton Hall School of Graduate Medical Education

Robert Cavaliere, MD Assistant Professor of Neurology, Neurosurgery and Medicine, Ohio State University College of Medicine

Sidney E Croul, MD Director of Neuropathology, Professor, Department of Pathology and Laboratory Medicine, Medical College of Pennsylvania Hahnemann University

Francisco de Assis Aquino Gondim, MD, MSc, PhD Associate Professor of Neurology, Department of Neurology and Psychiatry, St Louis University School of Medicine

Francisco de Assis Aquino Gondim, MD, MSc, PhD is a member of the following medical societies: American Academy of Neurology , American Association of Neuromuscular and Electrodiagnostic Medicine , and Movement Disorders Society

Alan Greenberg, MD Director, Associate Professor, Department of Internal Medicine, Jersey City Medical Center, Seton Hall University

Alan Greenberg, MD is a member of the following medical societies: Alpha Omega Alpha and American College of Physicians

Ronald A Greenfield, MD Professor, Department of Internal Medicine, University of Oklahoma College of Medicine

Ronald A Greenfield, MD is a member of the following medical societies: American College of Physicians , American Federation for Medical Research , American Society for Microbiology , Central Society for Clinical Research , Infectious Diseases Society of America , Medical Mycology Society of the Americas , Phi Beta Kappa , Southern Society for Clinical Investigation , and Southwestern Association of Clinical Microbiology

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J Stephen Huff, MD Associate Professor of Emergency Medicine and Neurology, Department of Emergency Medicine, University of Virginia School of Medicine

J Stephen Huff, MD is a member of the following medical societies: American Academy of Emergency Medicine , American Academy of Neurology , American College of Emergency Physicians , and Society for Academic Emergency Medicine

Lutfi Incesu, MD Professor, Department of Radiology, Ondokuz Mayis University School of Medicine; Chief, Neuroradiology and MR Unit, Department of Radiology, Ondokuz Mayis University Hospital, Turkey

Lutfi Incesu, MD is a member of the following medical societies: American Society of Neuroradiology and Radiological Society of North America

Uma Iyer, MD Resident Physician, Department of Neurology, State University of New York Upstate Medical Center

Pieter R Kark, MD, MA, FAAN, FACP Instructor in Palliative Care, The Lifetime Healthcare Companies

Michael R Keating, MD Associate Professor of Medicine, Chair, Division of Infectious Diseases, Department of Medicine, Mayo Clinic College of Medicine

Michael R Keating, MD is a member of the following medical societies: American College of Physicians , American Medical Association , American Society for Microbiology , American Society of Transplantation , Infectious Diseases Society of America , and International Immunocompromised Host Society

Anil Khosla, MBBS, MD Assistant Professor, Department of Radiology, St Louis University School of Medicine, Veterans Affairs Medical Center of St Louis

Anil Khosla, MBBS, MD is a member of the following medical societies: American College of Radiology , American Roentgen Ray Society , American Society of Neuroradiology , North American Spine Society , and Radiological Society of North America

John W King, MD Professor of Medicine, Chief, Section of Infectious Diseases, Director, Viral Therapeutics Clinics for Hepatitis, Louisiana State University Health Sciences Center; Consultant in Infectious Diseases, Overton Brooks Veterans Affairs Medical Center

John W King, MD is a member of the following medical societies: American Association for the Advancement of Science , American College of Physicians , American Federation for Medical Research , American Society for Microbiology , Association of Subspecialty Professors, Infectious Diseases Society of America , and Sigma Xi

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Marjorie Lazoff, MD is a member of the following medical societies: Alpha Omega Alpha , American College of Emergency Physicians , American Medical Informatics Association , and Society for Academic Emergency Medicine

Glenn Lopate, MD Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Director of Neurology Clinic, St Louis ConnectCare; 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 , and Phi Beta Kappa

Disclosure: Baxter Grant/research funds Other; Amgen Grant/research funds None

Joseph Richard Masci, MD Professor of Medicine, Professor of Preventive Medicine, Mount Sinai School of Medicine; Director of Medicine, Elmhurst Hospital Center

Joseph Richard Masci, MD is a member of the following medical societies: Alpha Omega Alpha , American College of Physicians , Association of Professors of Medicine , and Royal Society of Medicine

C Douglas Phillips, MD Director of Head and Neck Imaging, Division of Neuroradiology, New York Presbyterian Hospital, Weill Cornell Medical College

C Douglas Phillips, MD is a member of the following medical societies: American College of Radiology , American Medical Association , American Society of Head and Neck Radiology , American Society of Neuroradiology , Association of University Radiologists , and Radiological Society of North America

Tarakad S Ramachandran, MBBS, FRCP(C), FACP Professor of Neurology, Clinical Professor of Medicine, Clinical Professor of Family Medicine, Clinical Professor of Neurosurgery, State University of New York Upstate Medical University; Chair, Department of Neurology, Crouse Irving Memorial Hospital

Tarakad S Ramachandran, MBBS, FRCP(C), FACP is a member of the following medical societies: American Academy of Neurology , American Academy of Pain Medicine , American College of Forensic Examiners , American College of International Physicians, American College of Managed Care Medicine , American College of Physicians , American Heart Association , American Stroke Association , Royal College of Physicians , RoyalCollegeofPhysicians and Surgeons of Canada , Royal College of Surgeons of England , and Royal Society of Medicine

Disclosure: Abbott Labs None None; Teva Marion None None; Boeringer-Ingelheim Honoraria Speaking and teaching

Raymund R Razonable, MD Consultant, Division of Infectious Diseases, Mayo Clinic of Rochester; Associate Professor of Medicine, Mayo Clinic College of Medicine

Raymund R Razonable, MD is a member of the following medical societies: American Medical Association , American Society for Microbiology , Infectious Diseases Society of America , and International Immunocompromised Host Society

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 , Movement Disorders Society , Sigma Xi , and Society for Neuroscience

Robert Stanley Rust Jr, MD, MA Thomas E Worrell Jr Professor of Epileptology and Neurology, Co-Director of FE Dreifuss Child Neurology and Epilepsy Clinics, Director, Child Neurology, University of Virginia School of Medicine; Chair-Elect, Child Neurology Section, American Academy of Neurology

Robert Stanley Rust Jr, MD, MA is a member of the following medical societies: American Academy of Neurology , American Epilepsy Society , American Headache Society , American Neurological Association , Child Neurology Society , International Child Neurology Association , and Society for Pediatric Research

Prem C Shukla, MD Associate Chairman, Associate Professor, Department of Emergency Medicine, University of Arkansas for Medical Sciences

Manish K Singh, MD Assistant Professor, Department of Neurology, Teaching Faculty for Pain Management and Neurology Residency Program, Hahnemann University Hospital, Drexel College of Medicine; Medical Director, Neurology and Pain Management, Jersey Institute of Neuroscience

Manish K Singh, MD is a member of the following medical societies: American Academy of Neurology , American Academy of Pain Medicine , American Association of Physicians of Indian Origin , American Headache Society , American Medical Association , and American Society of Regional Anesthesia and Pain Medicine

Niranjan N Singh, MD, DNB Assistant Professor of Neurology, University of Missouri-Columbia School of Medicine

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Mark S Slabinski, MD, FACEP, FAAEM Vice President, EMP Medical Group

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James G Smirniotopoulos, MD Professor of Radiology, Neurology, and Biomedical Informatics, Program Director, Diagnostic Imaging Program, Center for Neuroscience and Regenerative Medicine (CNRM), Uniformed Services University of the Health Sciences

James G Smirniotopoulos, MD is a member of the following medical societies: American College of Radiology , American Roentgen Ray Society , American Society of Head and Neck Radiology , American Society of Neuroradiology , American Society of Pediatric Neuroradiology , Association of University Radiologists , and Radiological Society of North America

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

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Florian P Thomas, MD, MA, PhD, Drmed Director, Spinal Cord Injury Unit, St Louis Veterans Affairs Medical Center; Director, National MS Society Multiple Sclerosis Center; Director, Neuropathy Association Center of Excellence, Professor, Department of Neurology and Psychiatry, Associate Professor, Institute for Molecular Virology, and Department of Molecular Microbiology and Immunology, St Louis University School of Medicine

Florian P Thomas, MD, MA, PhD, Drmed is a member of the following medical societies: American Academy of Neurology , American Neurological Association , American Paraplegia Society , Consortium of Multiple Sclerosis Centers , and National Multiple Sclerosis Society

Frederick M Vincent Sr, MD Clinical Professor, Department of Neurology and Ophthalmology, Michigan State University Colleges of Human and Osteopathic Medicine

Frederick M Vincent Sr, MD is a member of the following medical societies: Alpha Omega Alpha , American Academy of Neurology , American Association of Neuromuscular and Electrodiagnostic Medicine , American College of Forensic Examiners , American College of Legal Medicine , American College of Physicians , and Michigan State Medical Society

Amir Vokshoor, MD Staff Neurosurgeon, Department of Neurosurgery, Spine Surgeon, Diagnostic and Interventional Spinal Care, St John's Health Center

Amir Vokshoor, MD is a member of the following medical societies: Alpha Omega Alpha , American Association of Neurological Surgeons , American Medical Association , and North American Spine Society

Cordia Wan, MD Adult Neurologist, Kaiser Permanente Hawaii, Kaiser Permanente Southern California

Cordia Wan, MD is a member of the following medical societies: American Academy of Neurology

Eric L Weiss, MD, DTM&H Medical Director, Office of Service Continuity and Disaster Planning, Fellowship Director, Stanford University Medical Center Disaster Medicine Fellowship, Chairman, SUMC and LPCH Bioterrorism and Emergency Preparedness Task Force, Clinical Associate Progressor, Department of Surgery (Emergency Medicine), Stanford University Medical Center

Eric L Weiss, MD, DTM&H is a member of the following medical societies: American College of Emergency Physicians , American College of Occupational and Environmental Medicine , American Medical Association , American Society of Tropical Medicine and Hygiene , Physicians for Social Responsibility , Southeastern Surgical Congress , Southern Association for Oncology , Southern Clinical Neurological Society , and Wilderness Medical Society

Lawrence A Zumo, MD Neurologist, Private Practice

Lawrence A Zumo, MD is a member of the following medical societies: American Academy of Neurology , American College of Physicians , American Medical Association , and Southern Medical Association

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• Meningococcemia
• Complement Deficiency
• Rapid Review: Paroxysmal Nocturnal Hemoglobinuria
• Meningococcal Meningitis
• Fast Five Quiz: Do You Know Current Vaccination Recommendations?
• Pediatric Asplenia
• A 30-Year-Old With a Full-Body Rash, Vomiting, and Confusion
• Timing the New Meningococcal Disease Shots
• EU OKs Meningococcal Disease Vaccine
• US CDC Alerts Healthcare Providers Of Increase in Meningococcal Disease

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In this section

Meningitis and encephalitis

Acute meningococcal disease  

Febrile child   Afebrile seizures   

• Symptoms at presentation can be non-specific, so early diagnostic consideration, investigation and empiric treatment is needed
• Prompt investigations (including lumbar puncture), together with early antibiotic administration, gives the best outcomes in bacterial meningitis
• Herpes Simplex Virus (HSV) encephalitis should be considered in any child with encephalopathy
• Aciclovir should be given to children with encephalitis of uncertain aetiology
• Meningitis is inflammation of the meninges surrounding the brain and spinal cord
• Encephalitis is inflammation of the brain parenchyma
• Making a clinical distinction between meningitis and encephalitis is important as the common causative pathogens differ, however initial empiric management often covers both
• Bacterial meningitis is a medical emergency which requires empiric antibiotic treatment without delay. A high index of suspicion for meningitis is needed in any unwell child, particularly if there is altered mental state or no clear focus
• Presentation of bacterial meningitis can vary from fulminant (hours) to insidious (days) and can be altered by recent treatment with antibiotics
• It is difficult to distinguish viral from bacterial meningitis clinically; children with meningitis should be treated with empiric antibiotics until the cause is confirmed
• Unrecognised HSV encephalitis is a devastating illness with significant morbidity and mortality, however treatment with aciclovir can lead to a full recovery
• Vaccines have significantly reduced the incidence of bacterial meningitis ( Haemophilus influenzae type B (HiB) vaccine, Pneumococcal Conjugate Vaccine, Meningococcal ACWY)

Red flag features in Red

• Defer if there are focal neurological signs, markedly reduced GCS, cardiovascular compromise or coagulopathy
• Urgent CSF  microscopy and biochemistry (preferably with simultaneous blood glucose)
• Based on clinical presentation and initial CSF results consider further investigations eg multiplex or specific PCR testing for enterovirus, parechovirus,  Neisseria meningitidis ,  Streptococcus pneumoniae  or Herpes simplex virus (HSV)
• FBE (may be normal), Glucose, Serum sodium, Blood cultures
• Consider venous gas, coagulation studies if shock or coagulopathy suspected
• Consider LFTs, metabolic and toxicology testing if non-infective cause of encephalopathy is suspected
• encephalitis
• focal neurological signs
• signs of raised intracranial pressure (ICP)
• diagnostic uncertainty (eg to look for a mass)
• Is not routine in meningitis but is used to look for complications eg abscess, thrombosis
• Normal head CT does not exclude raised ICP and should not influence the decision to perform an LP
• MRI will provide more detailed information to guide diagnosis, but may require general anaesthetic
• EEG may be helpful in suspected encephalitis

Antibiotics must not be delayed for more than 30 minutes after the decision to treat is made Antimicrobial recommendations may vary according to local antimicrobial susceptibility patterns; please refer to local guidelines Suggested antibiotic regimen, if local guidelines not available:

• Current evidence for steroids in bacterial meningitis in children is mixed, but does suggest that steroids may reduce the risk of hearing loss
• Steroids are not recommended in neonates due to possible effects on neurodevelopment
• Give the first dose of IV dexamethasone just before or with the first dose of antibiotics. If giving the first dose of IV dexamethasone after initial antibiotic administration, this should ideally be done within 4 hours and not more than 12 hours after starting antibiotics.

Ongoing management

• All seizures in the setting of meningitis or encephalitis should be treated immediately
• Consult the fluid management in meningitis/encephalitis guideline to assist with fluid balance (restriction is often required)
• Head circumference <2 yo
• Vital signs including HR and BP
• Electrolytes, urea, creatinine and blood glucose
• Isolation: droplet precautions in first 24 hours of admission
• Chemoprophylaxis for contacts

Directed treatment* Antimicrobial recommendations may vary according to local antimicrobial susceptibility patterns; please refer to local guidelines Suggested antibiotic regimen, if local guidelines not available:

* consider Infectious Diseases consultation for those with organisms resistant to first line therapy or with immediate hypersensitivity to penicillins/cephalosporins Notification

• All cases of presumed or confirmed N meningitidis and HiB should be notified to the Health Department immediately
• Confirmed S pneumoniae is notifiable within 5 days
• Follow state guidelines

Complications

• Persistent fever after 4–6 days of treatment consider:
• nosocomial infection
• subdural effusion or empyema
• cerebral abscess or parameningeal foci of ongoing infection
• inadequate treatment
• Hearing impairment
• Neurodevelopmental impairment
• Multi-organ involvement due to primary pathogen or secondary to septic shock (eg hepatic or cardiac)
• Venous sinus thrombosis
• Seizures, subsequent epilepsy
• Permanent focal neurological deficit
• Hydrocephalus
• All children with encephalitis or bacterial meningitis should have a formal audiology assessment 6–8 weeks after discharge (earlier if concerns)
• Neurodevelopmental progress should be monitored in outpatients
• Consider investigating for complement deficiency if the child has had >1 episode of meningococcal disease

Consider consultation with local paediatric team 

• All children with suspected encephalitis or bacterial meningitis
• All children with concern for non-infectious encephalopathy

Consider transfer when

• Haemodynamic or respiratory instability
• Altered conscious state or focal neurological signs
• Child requiring care above the level of comfort of the local hospital
• Complications of meningitis or encephalitis or poor response to treatment

For emergency advice and paediatric or neonatal ICU transfers, see Retrieval Services

Consider discharge when 

Children can complete IV treatment through HITH services if available once haemodynamically stable, afebrile and decision made regarding directed treatment

Parent information sheet

Lumbar Puncture Meningitis Meningococcal infection

Additional notes

Kernig sign:

• Child is supine
• One hip and knee are flexed to 90 degrees by the examiner
• The examiner then attempts to passively extend child’s knee
• Positive if there is pain along spinal cord, and/or resistance to knee extension

Brudzinski sign:

• Child is supine with legs extended
• The examiner grasps child’s occiput and attempts neck flexion
• Positive if there is reflex flexion of child’s hips and knees with neck flexion  

Last Updated March, 2020

Reference List

• Beaman, M 2018 Community acquired acute meningitis and encephalitis: a narrative review , Medical Journal of Australia, viewed February 2020, < https://www.mja.com.au/journal/2018/209/10/community-acquired-acute-meningitis-and-encephalitis-narrative-review >
• Britton, P et al 2015, Consensus guidelines for the investigation and management of encephalitis, Medical Journal of Australia, viewed February 2020 < https://www.mja.com.au/system/files/issues/202_11/bri01042.pdf >
• Brouwer MC et al 2015, Corticosteroids for bacterial meningitis , Cochrane Library viewed February 2020 < https://www.cochrane.org/CD004405/ARI_corticosteroids-bacterial-meningitis >
• Muller M 2019, Pediatric bacterial meningitis , Emedicine Medscape, viewed February 2020 < https://emedicine.medscape.com/article/961497-overview#a6 >
• National Institute for Health and Care Excellence 2015, Meningitis (bacterial) and meningococcal septicaemia in under 16s: recognition, diagnosis and management , NICE, viewed February 2020 < https://www.nice.org.uk/guidance/cg102/chapter/Introduction >
• New South Wales Ministry of Health 2014, Infants and Children: Acute management of bacterial meningitis , NSW Health, viewed February 2020 < https://www1.health.nsw.gov.au/pds/ActivePDSDocuments/GL2014_013.pdf >
• Ogunlesi TA et al 2015, Use of corticosteroids for treatment of the newborn with bacterial meningitis , Cochrane library, viewed February 2020 < https://www.cochrane.org/CD010435/NEONATAL_use-corticosteroids-treatment-newborn-bacterial-meningitis >
• Perth Children’s Hospital 2018, Meningitis guideline , viewed February 2020, < https://pch.health.wa.gov.au/For-health-professionals/Emergency-Department-Guidelines/Meningitis >
• Starship Child Health 2018, Meningitis guideline , viewed February 2020,  < https://www.starship.org.nz/for-health-professionals/starship-clinical-guidelines/m/meningitis/ >
• Therapeutic Guidelines 2019, Antibiotic , viewed February 2020< https://tgldcdp.tg.org.au/viewTopic?topicfile=meningitis >
• Le Saux N 2018, Guidelines for the management of suspected and confirmed bacterial meningitis in Canadian children older than one month of age, Canadian Paediatric Society, viewed February 2020, < https://www.cps.ca/en/documents/position/management-of-bacterial-meningitis >
• Hardarson HS 2018, Acute viral encephalitis in children: Clinical manifestations and diagnosis; Pathogenesis, incidence and etiology, Treatment and prevention, UpToDate, viewed February 2020

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Clinical features and prognostic factors in adults with viral meningitis

Pelle trier petersen.

Department of Pulmonary and Infectious Diseases, Nordsjællands Hospital, 3400 Hillerød, Denmark

Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark

Jacob Bodilsen

Department of Infectious Diseases, Aalborg University Hospital, 9000 Aalborg, Denmark

Department of Clinical Medicine, Aalborg University, 9000 Aalborg, Denmark

Micha Phill Grønholm Jepsen

Lykke larsen.

Department of Infectious Diseases, Odense University Hospital, 5000 Odense, Denmark

Merete Storgaard

Department of Infectious Diseases, Aarhus University Hospital, 8200 Aarhus, Denmark

Birgitte Rønde Hansen

Department of Infectious Diseases, Hvidovre Hospital, 2650 Hvidovre, Denmark

Jannik Helweg-Larsen

Department of Infectious Diseases, Rigshospitalet, 2100 Copenhagen, Denmark

Lothar Wiese

Department of Medicine, Sjællands University Hospital, 4000 Roskilde, Denmark

Hans Rudolf Lüttichau

Department of Infectious Diseases, Herlev Hospital, 2730 Herlev, Denmark

Christian Østergaard Andersen

Department of Clinical Microbiology, Hvidovre Hospital, 2650 Hvidovre, Denmark

Henrik Nielsen

Christian thomas brandt, associated data.

Data are only available with permission from the Danish health and legal authorities.

Clinical features applicable to the entire spectrum of viral meningitis are limited, and prognostic factors for adverse outcomes are undetermined.

This nationwide population-based prospective cohort study included all adults with presumed and microbiologically confirmed viral meningitis in Denmark from 2015 until 2020. Prognostic factors for an unfavourable outcome (Glasgow Outcome Scale score of 1–4) 30 days after discharge were examined by modified Poisson regression.

In total, 1066 episodes of viral meningitis were included, yielding a mean annual incidence of 4.7 episodes per 100 000 persons. Pathogens were enteroviruses in 419/1066 (39%), herpes simplex virus type 2 in 171/1066 (16%), varicella-zoster virus in 162/1066 (15%), miscellaneous viruses in 31/1066 (3%) and remained unidentified in 283/1066 (27%). The median age was 33 years (IQR 27–44), and 576/1066 (54%) were females. In herpes simplex virus type 2 meningitis, 131/171 (77%) were females. Immunosuppression [32/162 (20%)] and shingles [90/149 (60%)] were frequent in varicella-zoster virus meningitis. The triad of headache, neck stiffness and hyperacusis or photophobia was present in 264/960 (28%). The median time until lumbar puncture was 3.0 h (IQR 1.3–7.1), and the median CSF leucocyte count was 160 cells/µl (IQR 60–358). The outcome was unfavourable in 216/1055 (20%) 30 days after discharge. Using unidentified pathogen as the reference, the adjusted relative risk of an unfavourable outcome was 1.34 (95% CI 0.95–1.88) for enteroviruses, 1.55 (95% CI 1.00–2.41) for herpes simplex virus type 2, 1.51 (95% CI 0.98–2.33) for varicella-zoster virus and 1.37 (95% CI 0.61–3.05) for miscellaneous viruses. The adjusted relative risk of an unfavourable outcome was 1.34 (95% CI 1.03–1.75) for females. Timing of acyclovir or valacyclovir was not associated with the outcome in meningitis caused by herpes simplex virus type 2 or varicella-zoster virus.

In summary, the outcome of viral meningitis was similar among patients with different aetiologies, including those with presumed viral meningitis but without an identified pathogen. Females had an increased risk of an unfavourable outcome. Early antiviral treatment was not associated with an improved outcome in meningitis caused by herpes simplex virus type 2 or varicella-zoster virus.

In a nationwide study of 1066 Danish adults with viral meningitis, Petersen et al. report that incomplete recovery persists in one in five patients 30 days after discharge. Female patients in particular have an increased risk of an unfavourable outcome, whereas the type of virus is not associated with the prognosis.

Introduction

Viruses are the leading cause of meningitis in adults in the western world, and enteroviruses (EVs), herpes simplex virus type 2 (HSV-2) and varicella-zoster virus (VZV) constitute the most common pathogens. 1-3 The aetiology, however, remains unidentified in 50–60% of patients with presumed viral meningitis. 4 , 5 Although viral meningitis is often considered a benign disease, incomplete recovery is observed in a substantial proportion of patients. 1 , 6-9 In addition, the prognosis of presumed viral meningitis without an identified pathogen is unclear, which may cause concern among patients and physicians and lead to unnecessary examinations and prolonged treatment and hospitalization. 1 Moreover, the benefit of antiviral treatment with acyclovir in meningitis caused by HSV-2 or VZV is unproven. As most previous studies on viral meningitis have been restricted to small study populations, selected pathogens or laboratory data incapable of discriminating between meningitis and encephalitis, clinical data applicable to the entire spectrum of the disease are limited. Here, we present clinical features and prognostic factors of all adults hospitalized for viral meningitis with and without an identified pathogen in Denmark from 2015 until 2020.

Materials and methods

Design, setting and participants.

This nationwide population-based prospective observational cohort study was based on the Danish Study Group of Infections of the Brain (DASGIB) database. The DASGIB database has previously been described and contains data on prospectively included episodes of CNS infections hospitalized at the departments of infectious diseases in Denmark since 1 January 2015. 10 Viral meningitis was defined as a clinical presentation consistent with viral meningitis (e.g. headache, neck stiffness, hyperacusis or photophobia, fever) combined with either: (i) detected viral DNA/RNA in the CSF; (ii) CSF leucocyte count >10 cells/µl and positive intrathecal synthesis of antibodies specific for herpes simplex virus type 1 (HSV-1), HSV-2 or VZV; (iii) CSF leucocyte count >10 cells/µl and detected DNA from HSV-1, HSV-2 or VZV from skin lesions or positive serology of a neurotropic virus; or (iv) CSF leucocyte count >10 cells/µl and no other diagnosis considered more likely at last follow up (i.e. categorized as presumed viral meningitis without an identified pathogen). In the present study, we included all episodes of viral meningitis in adults (≥18 years) in the DASGIB database hospitalized between 1 January 2015 and 31 December 2019. Patients with encephalitis (fulfilment of the diagnostic criteria for infectious encephalitis proposed by the International Encephalitis Consortium 11 ) were not included, and patients with herpes zoster oticus were excluded. We have previously used the DASGIB database for studies on HSV-2 meningitis 12 and enteroviral meningitis 13 separately. Eleven episodes of enteroviral meningitis in patients aged 15–18 years included in the study on enteroviral meningitis were not included in the present study. Conversely, 11 episodes of enteroviral meningitis were retrospectively identified through quality control of the database and only included in the present study. The DASGIB database was approved by the Danish Health and Medicines Authority (record nos. 3-3013-2579/1 and 3-3013-3168/1). Danish legislation does not require consent from patients in this type of study.

Data on clinical features were obtained from medical records during hospitalization and registered in an online database using the Research Electronic Data Capture (REDCap) software. Immunosuppression was alcohol abuse, intravenous substance abuse, organ transplantation, cancer, diabetes mellitus, asplenia, HIV infection, primary immunodeficiency, prednisolone >7.5 mg/day or other immunosuppressive therapy.

Outcomes were categorized using the Glasgow Outcome Scale (GOS) (1, death; 2, vegetative state; 3, severe disability; 4, moderate disability; 5, good recovery) and assessed at discharge, and at follow-up visits 30, 90 and 180 days after discharge. In case of missing values, the last observation was carried forward if patients had a good recovery (GOS score of 5) at the most recent contact. An unfavourable outcome was defined as a GOS score of 1–4.

Statistical methods

Mean and standard deviation (SD) or median and interquartile range (IQR) were reported for quantitative variables. Counts and percentages were reported for categorical variables. Data were compared using the χ 2 test, Fisher's exact test or a Mann-Whitney U-test. Annual incidences were calculated by dividing the number of episodes of viral meningitis by the total adult Danish population of each study year. Population data were obtained from Statistics Denmark. 14 Multiple ln-linear regression was used to assess associations between brain imaging prior to lumbar puncture (yes, no) and admission directly to a department of infectious diseases (yes, no) and time from admission until lumbar puncture (ln-hours). A referral diagnosis of CNS infection (yes, no) was included as a covariable. To obtain easily interpretable parameters of differences in the probability of an unfavourable outcome 30 days after discharge between potential prognostic factors, a modified Poisson regression was used to estimate crude and adjusted relative risks (RRs) with 95% confidence intervals (95% CI). 15 Potential prognostic factors and their classifications were prespecified and based on general knowledge and previous research, 16 , 17 and constituted age (18–30, 31–50, ≥51 years), sex (male, female), immunosuppression (yes, no), duration of symptoms until admission (0–1, ≥2 days), the triad of headache, neck stiffness and hyperacusis or photophobia (yes, no), CSF leucocyte count (0–100, 101–500, ≥501 cells/µl), CSF protein (0.0–0.5, 0.6–1.0, ≥1.1 g/l), aetiology (unidentified pathogen, EVs, HSV-2, VZV, miscellaneous viruses) and treatment with dexamethasone for acute bacterial meningitis (yes, no). The analysis was repeated post hoc stratified according to aetiology, except for miscellaneous viruses due to a limited number of episodes. As the occupational dimension of the GOS can most reliably be assessed in patients with work or study before the event, 18 a subgroup analysis was done in patients with premorbid full-time occupations. A subgroup analysis using only GOS scores that had not been carried forward was also done. Modified Poisson regression was used to estimate RRs of an unfavourable outcome 30 days after discharge for time until treatment with acyclovir or valacyclovir (≤8, 8–16, ≥17 h from admission) in meningitis caused by HSV-2 or VZV. The analysis was adjusted for all previously described factors as well as aetiology (HSV-2, VZV). Post hoc , patients were stratified according to immune status, and associations between time until acyclovir or valacyclovir and outcome were examined with χ 2 test or Fisher's exact test. A P -value <0.05 was considered statistically significant, except in comparisons of signs and symptoms among aetiologies where a Bonferroni adjusted significance level of 0.005 was used. SAS Enterprise Guide v.7.11 was used for all statistical analyses.

Data availability

A total of 1120 episodes of presumed and microbiologically confirmed viral meningitis in adults were identified in the DASGIB database ( Supplementary Fig. 1 ). Next, episodes with herpes zoster oticus ( n = 54) were excluded, leaving 1066 episodes of viral meningitis in 1045 individuals for further analyses. EVs were detected in 419 (39%) of 1066 episodes, HSV-2 in 171 (16%) of 1066 episodes and VZV in 162 (15%) of 1066 episodes ( Fig. 1 ). Eleven miscellaneous viruses were detected in 31 (3%) of 1066 episodes, whereas a pathogen was not identified in the remaining 283 (27%) of 1066 episodes. In the 5-year study period, the total mean annual incidence of presumed and microbiologically confirmed viral meningitis was 4.7 episodes (SD 1.3) per 100 000 persons, with an annual variation from 3.1 to 6.1 episodes due to fluctuation in episodes of enteroviral meningitis ( Fig. 2 ).

Aetiologies of viral meningitis in adults.

Annual incidences of viral meningitis in adults .

The referral diagnosis was CNS infection in 435 (47%) of 917 episodes, and 474 (45%) of 1065 episodes were admitted directly to a department of infectious diseases ( Table 1 ). The median age was 33 years (IQR 27–44) in the total study population and 46 years (IQR 27–69) in VZV meningitis ( Table 2 ). Females constituted 576 (54%) of all 1066 episodes and 131 (77%) of 171 episodes of HSV-2 meningitis. Immunosuppression was present in 83 (8%) of all 1066 episodes, 32 (20%) of 162 episodes of VZV meningitis and 6 (19%) of 31 episodes of meningitis caused by miscellaneous viruses. In enteroviral meningitis, prodromal gastrointestinal or respiratory symptoms were reported in 66 (17%) of 385 episodes and 60 (16%) of 384 episodes, respectively. In viral meningitis of all other causes, prodromal gastrointestinal or respiratory symptoms were reported in 67 (11%) of 606 episodes and 81 (13%) of 601 episodes, respectively. Shingles were present in 90 (60%) of 149 episodes of VZV meningitis. At admission, headache was reported in 1005 (95%) of 1061 episodes, a history of fever in 691 (71%) of 971 episodes and hyperacusis or photophobia in 660 (67%) of 987 episodes. Neck stiffness was found in 371 (36%) of 1028 episodes and was most frequent in HSV-2 meningitis [92 (57%) of 162 episodes]. The triad of headache, neck stiffness and hyperacusis or photophobia was present in 264 (28%) of 960 episodes. At least two of four classic signs and symptoms of viral meningitis (headache, neck stiffness, hyperacusis or photophobia and a history of fever or measured fever) were present in 835 (87%) of 955 episodes and were less frequent in VZV meningitis [105 (74%) of 142 episodes] than in enteroviral meningitis [361 (94%) of 383 episodes; P < 0.001] and HSV-2 meningitis [138 (92%) of 150 episodes; P < 0.001]. At least two classic signs and symptoms were also less frequent in meningitis without an identified pathogen [211 (82%) of 257 episodes] than in enteroviral meningitis ( P < 0.001) and HSV-2 meningitis ( P = 0.003).

Management and treatment of adults with viral meningitis

Quantitative data are presented as median (IQR) and categorical data are presented as n / N (%). ID = infectious diseases; ITS = intrathecal synthesis.

Clinical features of adults with viral meningitis

Quantitative data are presented as median (IQR) and categorical data are presented as n / N (%).

Including presumed viral meningitis without an identified pathogen.

Glasgow Coma Scale (GCS) score <15 for <24 h.

Triad of headache, neck stiffness and hyperacusis or photophobia.

Signs and symptoms were headache, neck stiffness, hyperacusis or photophobia and a history of fever or measured fever.

The median c-reactive protein was 5 mg/l (IQR 2–15) at admission, and 1010 (97%) of 1036 episodes had a c-reactive protein <100 mg/l ( Table 2 ). The median CSF leucocyte count was 160 cells/µl (IQR 60–358) in the total population and 374 cells/µl (IQR 162–670) in HSV-2 meningitis ( Supplementary Fig. 2 ). Among 38 patients with a CSF leucocyte count ≥1000 cells/µl, meningitis was caused by HSV-2 ( n = 20), EVs ( n = 11), VZV ( n = 3), unidentified pathogen ( n = 3) and Toscana virus ( n = 1). The median CSF neutrophil percentage was 7 (IQR 1–31) in the total study population and 24 (IQR 6–55) in enteroviral meningitis ( Supplementary Fig. 2 ).

Brain imaging was done in 544 (51%) of 1066 episodes during admission, of which 16 (3%) had new intracranial pathological findings ( Table 1 ). The radiological diagnoses comprised benign brain tumours ( n = 6), brain cysts ( n = 5), brain infarction ( n = 3), brain haemorrhage ( n = 1) and brain oedema ( n = 1). The median time from admission until brain imaging was 2.8 h (IQR 1.5–7.5). Brain imaging preceded lumbar puncture in 408 (39%) of 1058 episodes. A lumbar puncture was done in all episodes. The median time from admission until lumbar puncture was 3.0 h (IQR 1.3–7.1). The median time from admission until lumbar puncture was shorter in episodes admitted directly to a department of infectious diseases [2.0 h (IQR 0.9–4.7)] than in those admitted elsewhere [3.9 h (IQR 1.8–11.2); P < 0.001] and longer in episodes where brain imaging preceded lumbar puncture [6.2 h (IQR 3.6–15.2)] than in those where it did not [1.7 h (IQR 0.9–3.5); P < 0.001]. In multiple ln-linear regression, admission directly to a department of infectious diseases was associated with a 28% (95% CI: 16–39) decrease in time to lumbar puncture, whereas brain imaging prior to lumbar puncture was associated with a 184% (95% CI: 140–235) increase.

At least one dose of acyclovir or valacyclovir was administered in 743 (70%) of 1060 episodes ( Table 1 ). In meningitis caused by HSV-2 or VZV, acyclovir or valacyclovir was administered in 321 (96%) of 333 episodes at a median time from admission of 6.4 h (IQR 2.7–18.0) and with a median duration of treatment of 10 days (IQR 7–14). The route of administration was exclusively oral in 35 (11%) of 321 episodes, exclusively intravenous in 45 (14%) of 321 episodes and a combination of oral and intravenous in 241 (75%) of 321 episodes. The median length of hospitalization was 3 days (IQR 1–5), and within 30 days of discharge, 93 (9%) of 1037 episodes were readmitted. Causes of readmission were headache ( n = 38, 41%), post-dural puncture headache ( n = 21, 23%), non-CNS infections ( n = 8, 9%), other neurological symptoms ( n = 7, 8%) and miscellaneous ( n = 19, 20%).

An unfavourable outcome was observed in 216 (20%) of 1055 episodes 30 days after discharge, of which only three episodes had a GOS score of <4 ( Table 3 ). At 180 days after discharge, an unfavourable outcome was observed in 62 (6%) of 957 episodes.

Outcome assessed on the GOS in adults with viral meningitis

Data are presented as n (%). GOS scores of 5 were carried forward for 121 (11%) of 1055 episodes at 30 days after discharge, 597 (59%) of 1010 episodes at 90 days after discharge and 779 (81%) of 957 episodes at 180 days after discharge.

Prognostic factors for an unfavourable outcome 30 days after discharge were examined by modified Poisson regression. Using meningitis without an identified pathogen as the reference, the adjusted RR of an unfavourable outcome was 1.34 (95% CI: 0.95–1.88) for enteroviral meningitis, 1.55 (95% CI 1.00–2.41) for HSV-2 meningitis, 1.51 (95% CI: 0.98–2.33) for VZV meningitis and 1.37 (95% CI: 0.61–3.05) for meningitis caused by miscellaneous viruses ( Table 4 ). In two subgroup analyses restricted to episodes with premorbid full-time occupation or where GOS scores had not been carried forward, the adjusted RR for HSV-2 meningitis was 1.78 (95% CI: 1.06–2.98) and 1.56 (95% CI: 1.01–2.39), respectively ( Supplementary Table 1 ).

Prognostic factors for an unfavourable outcome (GOS score of 1–4) 30 days after discharge in adults with viral meningitis

Owing to missing values, 922 episodes were used in the adjusted analysis.

Adjusted for all prognostic factors listed in the table.

The adjusted RR of an unfavourable outcome 30 days after discharge was 1.34 (95% CI: 1.03–1.75) for females compared with males ( Table 4 ). In analyses stratified according to the aetiology, the adjusted RR for females was 2.35 (95% CI: 1.27–4.33) in meningitis without an identified pathogen, 1.39 (95% CI 0.93–2.08) in enteroviral meningitis, 0.91 (95% CI: 0.47–1.79) in HSV-2 meningitis and 0.96 (95% CI: 0.52–1.77) in VZV meningitis ( Fig. 3 ).

Stratified analyses of sex-based differences in unfavourable outcome (GOS score 1–4) 30 days after discharge in adults with viral meningitis . a Stratified analyses were adjusted for age (18–30, 31–50, ≥51 years), sex (male, female), immunosuppression (yes, no), triad of headache, neck stiffness and hyperacusis or photophobia (yes, no), CSF leucocyte count (0–100, 101–500, ≥501 cells/µl), CSF protein (0.0–0.5, 0.6–1.0, ≥1.1 g/l), and treatment with dexamethasone for bacterial meningitis (yes, no). The number of episodes used in adjusted analyses were 251 in unidentified pathogen, 369 in EVs, 140 in HSV-2, 140 in VZV and 922 in all viral meningitis.

The association between timing of antiviral treatment and an unfavourable outcome 30 days after discharge was examined by modified Poisson regression among patients with meningitis caused by HSV-2 or VZV. Using administration of acyclovir or valacyclovir ≤8 h from admission as the reference, the adjusted RR of an unfavourable outcome was 0.61 (95% CI: 0.30–1.23) for administration between 8 h and 16 h and 0.86 (95% CI: 0.51–1.43) for administration ≥17 h ( Supplementary Table 2 ). When stratified according to immune status, post hoc testing did not disclose any associations between time until acyclovir or valacyclovir and outcome in either immunocompetent or immunosuppressed patients ( Supplementary Table 3 ).

The nationwide study design allowed us to estimate incidences of viral meningitis based on the total adult Danish population. Including presumed viral meningitis without an identified pathogen, the mean annual incidence was 4.7 episodes per 100 000 persons. In a study from the UK, 1 the annual incidence of proven viral meningitis was 2.73 episodes per 100 000 persons, whereas annual incidences of aseptic meningitis in studies from Finland 2 and Sweden 3 were 7.6 and 7.4 episodes per 100 000 people, respectively. In contrast to our study, the Scandinavian studies included patients with verified non-viral aseptic meningitis.

A correct tentative diagnosis based on signs and symptoms is a prerequisite for timely lumbar puncture and appropriate management of viral meningitis. In our study, only one in four patients presented with the triad of headache, neck stiffness and hyperacusis or photophobia, and 1 in 10 patients had less than two of four classic signs and symptoms (triad and fever). Thus, clinicians should remain aware that viral meningitis may present atypically. Still, the median time from admission until lumbar puncture was short in our study compared with a previous study on viral meningitis (3 h versus 13 h). 1 Consistent with other studies, we found that brain imaging before lumbar puncture was a potential amendable factor associated with increased time until lumbar puncture in meningitis. 1 , 19 , 20 In addition, we found that admission directly to a department of infectious disease was associated with decreased time until lumbar puncture.

In agreement with most previous studies, we observed that short-term outcome after viral meningitis was frequently unfavourable but improved during extended follow up. 6 , 21 , 22 Reassuringly, patients with presumed viral meningitis but without an identified pathogen had a similar risk of an unfavourable outcome compared with those with an identified virus. Of interest, the risk of an unfavourable outcome was also not associated with the type of virus, which contrasts with bacterial meningitis, where the prognosis varies between different bacteria. 16 It could be hypothesized that the host immune response rather than the causative pathogen itself is relatively more important for the course of recovery in viral meningitis than in bacterial meningitis, as similarly proposed for some post-infectious syndromes. 23 Correspondingly, viral meningitis is a relatively homogenous disease in terms of demographics, initial presentation and severity and CSF characteristics. Still, unaccounted factors such as serotypes and cross-immunity in enteroviral meningitis, as well as differences between de novo infections and reactivation in HSV-2 meningitis, could have affected our results. In a study from the UK, quality of life 6 weeks after discharge was lower among patients with HSV-2 meningitis than among those with meningitis caused by other viruses. 1 However, a direct comparison with our results is limited due to the different outcome measures (EQ-5D-3L versus GOS).

In our study, female sex was independently associated with an increased risk of an unfavourable outcome 30 days after discharge. However, when the study population was stratified according to aetiology, the sex-based differences were not present in meningitis caused by HSV-2 or VZV. In meningitis without an identified pathogen and in enteroviral meningitis, female sex was associated with an increased risk of an unfavourable outcome, although not statistically significant in the latter strata. In a previous analysis of enteroviral meningitis, we found that female sex was associated with an increased risk of an unfavourable outcome at discharge. 13 Similarly, in an analysis based on combined data from two randomized controlled trials of treatment with pleconaril in enteroviral meningitis, females had a longer time to resolution of headaches during admission. 24 The importance of sex-based differences has also been recognized in other CNS infections, 25 , 26 and an enhanced immune response to certain pathogens among females has been proposed as a theoretical framework for these observations. 27-29 Since unaccounted factors probably remain in our analyses, these results serve as leverage to further explore the impact of sex and gender on the outcome of viral meningitis.

Although Danish guidelines on viral meningitis recommend withholding antiviral treatment until HSV-2 or VZV have been detected, 30 most patients in our study were treated with acyclovir or valacyclovir. In analyses of time until treatment with aciclovir or valaciclovir among patients with meningitis caused by HSV-2 or VZV, early administration was not associated with an improved outcome 30 days after discharge. Similarly, previous observational studies have not found an apparent effect of antivirals in HSV-2 meningitis, 31 , 32 except in immunosuppressed patients, where no or delayed treatment has been linked to complications. 33 , 34 In the present study, time until acyclovir or valacyclovir was not associated with the outcome when examining immunosuppressed patients separately, but the analysis was not adjusted for potential confounders due to the limited number of episodes. Although at risk of residual confounding, these results together indicate that it is safe to withhold antivirals for 1–2 days until a microbiological diagnosis is established in immunocompetent patients without signs or symptoms of encephalitis.

Limitations

First, although the Danish Board of Health requires that adults with CNS infections be managed in specialized departments of infectious disease, some patients might have been admitted elsewhere, which would underestimate incidences and potentially introduce selection bias. Second, a CSF leucocyte count >10 cells/µl was chosen as the cut-off to indicate meningitis if no viral DNA/RNA was detected in the CSF. This may limit the generalizability in the presumed small subpopulation of patients with viral meningitis and lower CSF leucocyte counts. Third, patients without an identified pathogen were included in this study if viral meningitis was otherwise considered the most likely diagnosis, given all available information, including information on the post-discharge course of the disease, which was equal to patients with an identified pathogen. Although the aetiology is not microbiologically confirmed, we believe that it is important to account for this group of patients in research on viral meningitis to cover the entire spectrum of the disease. Fourth, as the completeness of the DASGIB database is ensured by annual searches of ICD-10 code of CNS infections or review of patients with CSF pleocytosis at local sites, 10 a few patients may have been retrospectively identified. Fifth, information on the character of impairments was unavailable for the total study population, but in previous studies on enteroviral meningitis and HSV-2 meningitis, we observed that neurological (headache, photophobia and phonophobia, vertigo and tinnitus), cognitive (concentration and memory difficulties) and more general complaints (fatigue and sleep disturbances) were common. 12 , 13 The GOS used to assess the outcome in the present study was developed to evaluate recovery after brain injury 35 and is—although frequently used 16 , 17 , 36 —not validated for CNS infections. The GOS may be too crude to capture subtle neurocognitive impairments in patients with an otherwise favourable outcome (i.e. ceiling effect). Most patients with an unfavourable outcome had moderate disabilities (GOS score of 4), meaning they could not resume premorbid social or occupational activities. Therefore, the results on prognostic factors were validated by repeating the analysis in patients with premorbid full-time occupations. Sixth, data on long-term outcomes were missing for some patients, which could introduce bias. In Denmark, hospital follow up is usually discontinued if full recovery is achieved 30 days after discharge. Thus, GOS scores of 5 were carried forward if there was no subsequent follow up. Similarly, in the minority of patients without any post-discharge follow up, GOS scores of 5 at discharge were carried forward, assuming that full recovery would most probably persist. Importantly, results on prognostic factors for an unfavourable outcome 30 days after discharge were overall consistent when the analysis was restricted to patients where GOS scores had not been carried forward.

Conclusions

The outcome of viral meningitis was similar among patients with different aetiologies, including those with presumed viral meningitis but without an identified pathogen. Females had an increased risk of an unfavourable outcome, and future studies should explore causes of these sex-based differences. Stressing the need for randomized control trials, nearly all patients with meningitis caused by HSV-2 or VZV received antiviral treatment, but early administration was not associated with an improved outcome.

Supplementary Material

Awad089_supplementary_data, contributor information.

Pelle Trier Petersen, Department of Pulmonary and Infectious Diseases, Nordsjællands Hospital, 3400 Hillerød, Denmark. Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.

Jacob Bodilsen, Department of Infectious Diseases, Aalborg University Hospital, 9000 Aalborg, Denmark. Department of Clinical Medicine, Aalborg University, 9000 Aalborg, Denmark.

Micha Phill Grønholm Jepsen, Department of Pulmonary and Infectious Diseases, Nordsjællands Hospital, 3400 Hillerød, Denmark.

Lykke Larsen, Department of Infectious Diseases, Odense University Hospital, 5000 Odense, Denmark.

Merete Storgaard, Department of Infectious Diseases, Aarhus University Hospital, 8200 Aarhus, Denmark.

Birgitte Rønde Hansen, Department of Infectious Diseases, Hvidovre Hospital, 2650 Hvidovre, Denmark.

Jannik Helweg-Larsen, Department of Infectious Diseases, Rigshospitalet, 2100 Copenhagen, Denmark.

Lothar Wiese, Department of Medicine, Sjællands University Hospital, 4000 Roskilde, Denmark.

Hans Rudolf Lüttichau, Department of Infectious Diseases, Herlev Hospital, 2730 Herlev, Denmark.

Christian Østergaard Andersen, Department of Clinical Microbiology, Hvidovre Hospital, 2650 Hvidovre, Denmark.

Henrik Nielsen, Department of Infectious Diseases, Aalborg University Hospital, 9000 Aalborg, Denmark. Department of Clinical Medicine, Aalborg University, 9000 Aalborg, Denmark.

Christian Thomas Brandt, Department of Medicine, Sjællands University Hospital, 4000 Roskilde, Denmark.

This work was supported by grants from Helsefonden (grant number 21-B-0437), Helen Rudes Fond (grant number 60988), A & J C Tvergaards Fond and Minister Erna Hamiltons Legat for Videnskab og Kunst (grant number 24-2022) to P.T.P.

Competing interests

The authors report no competing interests.

Supplementary material

Supplementary material is available at Brain online.

HILLARY R. MOUNT, MD, AND SEAN D. BOYLE, DO

Am Fam Physician. 2017;96(5):314-322

Patient information : See related handout on meningitis , written by the authors of this article.

Author disclosure: No relevant financial affiliations.

The etiologies of meningitis range in severity from benign and self-limited to life-threatening with potentially severe morbidity. Bacterial meningitis is a medical emergency that requires prompt recognition and treatment. Mortality remains high despite the introduction of vaccinations for common pathogens that have reduced the incidence of meningitis worldwide. Aseptic meningitis is the most common form of meningitis with an annual incidence of 7.6 per 100,000 adults. Most cases of aseptic meningitis are viral and require supportive care. Viral meningitis is generally self-limited with a good prognosis. Examination maneuvers such as Kernig sign or Brudzinski sign may not be useful to differentiate bacterial from aseptic meningitis because of variable sensitivity and specificity. Because clinical findings are also unreliable, the diagnosis relies on the examination of cerebrospinal fluid obtained from lumbar puncture. Delayed initiation of antibiotics can worsen mortality. Treatment should be started promptly in cases where transfer, imaging, or lumbar puncture may slow a definitive diagnosis. Empiric antibiotics should be directed toward the most likely pathogens and should be adjusted by patient age and risk factors. Dexamethasone should be administered to children and adults with suspected bacterial meningitis before or at the time of initiation of antibiotics. Vaccination against the most common pathogens that cause bacterial meningitis is recommended. Chemoprophylaxis of close contacts is helpful in preventing additional infections.

Patients with meningitis present a particular challenge for physicians. Etiologies range in severity from benign and self-limited to life-threatening with potentially severe morbidity. To further complicate the diagnostic process, physical examination and testing are limited in sensitivity and specificity. Advanc`es in vaccination have reduced the incidence of bacterial meningitis; however, it remains a significant disease with high rates of morbidity and mortality, making its timely diagnosis and treatment an important concern. 1

WHAT IS NEW ON THIS TOPIC: BACTERIAL MENINGITIS

In 2015, the Advisory Committee on Immunization Practices gave meningococcal serogroup B vaccines a category B recommendation (individual clinical decision making) for healthy patients 16 to 23 years of age (preferred age 16 to 18 years).

Meningitis is an inflammatory process involving the meninges. The differential diagnosis is broad ( Table 1 ) . Aseptic meningitis is the most common form. The annual incidence is unknown because of underreporting, but European studies have shown 70 cases per 100,000 children younger than one year, 5.2 cases per 100,000 children one to 14 years of age, and 7.6 per 100,000 adults. 2 , 3 Aseptic is differentiated from bacterial meningitis if there is meningeal inflammation without signs of bacterial growth in cultures. These cases are often viral, and enterovirus is the most common pathogen in immunocompetent individuals. 2 , 4 The most common etiology in U.S. adults hospitalized for meningitis is enterovirus (50.9%), followed by unknown etiology (18.7%), bacterial (13.9%), herpes simplex virus (HSV; 8.3%), noninfectious (3.5%), fungal (2.7%), arboviruses (1.1%), and other viruses (0.8%). 5 Enterovirus and mosquito-borne viruses, such as St. Louis encephalitis and West Nile virus, often present in the summer and early fall. 4 , 6 HSV and varicella zoster virus can cause meningitis and encephalitis. 2

Causative bacteria in community-acquired bacterial meningitis vary depending on age, vaccination status, and recent trauma or instrumentation 7 , 8 ( Table 2 9 ) . Vaccination has nearly eliminated the risk of Haemophilus influenzae and substantially reduced the rates of Neisseria meningitidis and Streptococcus pneumoniae as causes of meningitis in the developed world. 10 Between 1998 and 2007, the overall annual incidence of bacterial meningitis in the United States decreased from 1 to 0.69 per 100,000 persons. 1 This decrease has been most dramatic in children two months to 10 years of age, shifting the burden of disease to an older population. 1 Annual incidence is still highest in neonates at 40 per 100,000, and has remained largely unchanged. 1 Older patients are at highest risk of S. pneumoniae meningitis, whereas children and young adults have a higher risk of N. meningitidis meningitis. 1 , 11 Patients older than 60 years and patients who are immunocompromised are at higher risk of Listeria monocytogenes meningitis, although rates remain low. 11

Presentation

Presentation can be similar for aseptic and bacterial meningitis, but patients with bacterial meningitis are generally more ill-appearing. Fever, headache, neck stiffness, and altered mental status are classic symptoms of meningitis, and a combination of two of these occurs in 95% of adults presenting with bacterial meningitis. 12 However, less than one-half of patients present with all of these symptoms. 12 , 13

Presentation varies with age. Older patients are less likely to have headache and neck stiffness, and more likely to have altered mental status and focal neurologic deficits 11 , 13 ( Table 3 11 – 13 ) . Presentation also varies in young children, with vague symptoms such as irritability, lethargy, or poor feeding. 14 Arboviruses such as West Nile virus typically cause encephalitis but can present without altered mental status or focal neurologic findings. 6 Similarly, HSV can cause a spectrum of disease from meningitis to life-threatening encephalitis. HSV meningitis can present with or without cutaneous lesions and should be considered as an etiology in persons presenting with altered mental status, focal neurologic deficits, or seizure. 15

The time from symptom onset to presentation for medical care tends to be shorter in bacterial meningitis, with 47% of patients presenting after less than 24 hours of symptoms. 16 Patients with viral meningitis have a median presentation of two days after symptom onset. 17

Examination findings that may indicate meningeal irritation include a positive Kernig sign, positive Brudzinski sign, neck stiffness, and jolt accentuation of headache (i.e., worsening of headache by horizontal rotation of the head two to three times per second). Physical examination findings have shown wide variability in their sensitivity and specificity, and are not reliable to rule out bacterial meningitis. 18 – 20 Examples of Kernig and Brudzinski tests are available at https://www.youtube.com/watch?v=Evx48zcKFDA and https://www.youtube.com/watch?v=rN-R7-hh5x4 .

Because of the poor performance of clinical signs to rule out meningitis, all patients who present with symptoms concerning for meningitis should undergo prompt lumbar puncture (LP) and evaluation of cerebrospinal fluid (CSF) for definitive diagnosis. Because of the risk of increased intracranial pressure with brain inflammation, the Infectious Diseases Society of America recommends performing computed tomography of the head before LP in specific high-risk patients to reduce the possibility of cerebral herniation during the procedure ( Table 4 ) . 7 , 21 , 22 However, recent retrospective data have shown that removing the restriction on LP in patients with altered mental status reduced mortality from 11.7% to 6.9%, suggesting it may be safe to proceed with LP in these patients. 22

The CSF findings typical of aseptic meningitis are a relatively low and predominantly lymphocytic pleocytosis, normal glucose level, and a normal to slightly elevated protein level ( Table 5 9 ) . Bacterial meningitis classically has a very high and predominantly neutrophilic pleocytosis, low glucose level, and high protein level. This is not the case for all patients and can vary in older patients and those with partially treated bacterial meningitis, immunosuppression, or meningitis caused by L. monocytogenes . 11 It is important to use age-adjusted values for white blood cell counts when interpreting CSF results in neonates and young infants. 23 In up to 57% of children with aseptic meningitis, neutrophils predominate the CSF; therefore, cell type alone cannot be used to differentiate between aseptic and bacterial meningitis in children between 30 days and 18 years of age. 24

CSF results can be variable, and decisions about treatment with antibiotics while awaiting culture results can be challenging. There are a number of clinical decision tools that have been developed for use in children to help differentiate between aseptic and bacterial meningitis in the setting of pleocytosis. The Bacterial Meningitis Score has a sensitivity of 99% to 100% and a specificity of 52% to 62%, and appears to be the most specific tool available currently, although it is not widely used. 25 – 27 The score can be calculated online at http://reference.medscape.com/calculator/bacterial-meningitis-score-child .

Serum procalcitonin, serum C-reactive protein, and CSF lactate levels can be useful in distinguishing between aseptic and bacterial meningitis. 28 – 33 C-reactive protein has a high negative predictive value but a much lower positive predictive value. 28 Procalcitonin is sensitive (96%) and specific (89% to 98%) for bacterial causes of meningitis. 29 , 30 CSF lactate also has a high sensitivity (93% to 97%) and specificity (92% to 96%). 31 – 33 CSF latex agglutination testing for common bacterial pathogens is rapid and, if positive, can be useful in patients with negative Gram stain if LP was performed after antibiotics were administered. This test cannot be used to rule out bacterial meningitis. 7

Because CSF enterovirus polymerase chain reaction testing is more rapid than bacterial cultures, a positive test result can prompt discontinuation of antibiotic treatment, thus reducing antibiotic exposure and cost in patients admitted for suspected meningitis. 34 Similarly, polymerase chain reaction testing can be used to detect West Nile virus when seasonally appropriate in areas of higher incidence. HSV and varicella zoster viral polymerase chain reaction testing should be used in the setting of meningoencephalitis.

INITIAL MANAGEMENT

Prompt recognition of a potential case of meningitis is essential so that empiric treatment may begin as soon as possible. The initial management strategy is outlined in Figure 1 . 7 , 9 Stabilization of the patient's cardiopulmonary status takes priority. Intravenous fluids may be beneficial within the first 48 hours, but further study is needed to determine the appropriate intravenous fluid management. 35 A meta-analysis of studies with variable quality in children showed that fluids may decrease spasticity, seizures, and chronic severe neurologic sequelae. 35 The next urgent requirement is initiating empiric antibiotics as soon as possible after blood cultures are drawn and the LP is performed. Antibiotics should not be delayed if there is any lag time in performing the LP (e.g., transfer to clinical site that can perform the test, need for head computed tomography before LP). 7 , 8 Droplet isolation precautions should be instituted for the first 24 hours of treatment. 23

ANTIMICROBIALS

Before CSF results are available, patients with suspected bacterial meningitis should be treated with antibiotics as quickly as possible. 8 , 22 , 36 , 37 Acyclovir should be added if there is concern for HSV meningitis or encephalitis. Door-to-antibiotic time lapse of more than six hours has an adjusted odds ratio for mortality of 8.4. 37 If CSF results are more consistent with aseptic meningitis, antibiotics can be discontinued, depending on the severity of the presentation and overall clinical picture. Selection of the appropriate empiric antibiotic regimen is primarily based on age ( Table 2 9 ) . Specific pathogens are more prevalent in certain age groups, but empiric coverage should cover most possible culprits. Viral meningitis (non-HSV) management is focused on supportive care.

Treatment of tuberculous, cryptococcal, or other fungal meningitides is beyond the scope of this article, but should be considered if risk factors are present (e.g., travel to endemic areas, immunocompromised state, human immunodeficiency virus infection). These patients, as well as those coinfected with human immunodeficiency virus, should be managed in consultation with an infectious disease subspecialist when available.

Length of treatment varies based on the pathogen identified ( Table 6 7 ) . Intravenous antibiotics should be used to complete the full treatment course, but outpatient management can be considered in persons who are clinically improving after at least six days of therapy with reliable outpatient arrangements (i.e., intravenous access, home health care, reliable follow-up, and a safe home environment). 7

CORTICOSTEROIDS

Corticosteroids are traditionally used as adjunctive treatment in meningitis to reduce the inflammatory response. The evidence for corticosteroids is heterogeneous and limited to specific bacterial pathogens, 38 – 44 but the organism is not usually known at the time of the initial presentation. A 2015 Cochrane review found a nonsignificant reduction in overall mortality (relative risk [RR] = 0.90), as well as a significant reduction in severe hearing loss (RR = 0.51), any hearing loss (RR = 0.58), and short-term neurologic sequelae (RR = 0.64) with the use of dexamethasone in high-income countries. 41 The number needed to treat to decrease mortality in the S. pneumoniae subgroup was 18 and the number needed to treat to prevent hearing loss was 21. 38 , 41 There was a small increase in recurrent fever in patients given corticosteroids (number needed to harm = 16) with no worse outcome. 38 , 41

The best evidence supports the use of dexamethasone 10 to 20 minutes before or concomitantly with antibiotic administration in the following groups: infants and children with H. influenzae type B, adults with S. pneumoniae , or patients with Mycobacterium tuberculosis without concomitant human immunodeficiency virus infection. 7 , 8 , 42 , 45 Some evidence also shows a benefit with corticosteroids in children older than six weeks with pneumococcal meningitis. 45

Because the etiology is not known at presentation, dexamethasone should be given before or at the time of initial antibiotics while awaiting the final culture results in all patients older than six weeks with suspected bacterial meningitis. Dexamethasone can be discontinued after four days or earlier if the pathogen is not H. influenzae or S. pneumoniae , or if CSF findings are more consistent with aseptic meningitis. 46

REPEAT TESTING

Repeat LP is generally not needed but should be considered to evaluate CSF parameters in persons who are not clinically improving after 48 hours of appropriate treatment. Repeating the LP can identify resistant pathogens, confirm the diagnosis if initial results were negative, and determine the length of treatment for neonates with a gram-negative bacterial pathogen until CSF sterilization is documented. 7 , 47

Prognosis varies by age and etiology of meningitis. In a large analysis of patients from 1998 to 2007, the overall mortality rate in those with bacterial meningitis was 14.8%. 1 Worse outcomes occurred in those with low Glasgow Coma Scale scores, systemic compromise (e.g., low CSF white blood cell count, tachycardia, positive blood cultures, abnormal neurologic examination, fever), alcoholism, and pneumococcal infection. 11 – 13 , 16 Mortality is generally higher in pneumococcal meningitis (30%) than other types, especially penicillin-resistant strains. 12 , 48 , 49 Viral meningitis outside the neonatal period has lower mortality and complication rates, but large studies or reviews are lacking. One large cohort study found a 4.5% mortality rate and a 30.9% rate of complications, such as developmental delay, seizure disorder, or hearing loss, for childhood encephalitis and meningitis combined. 50 Tuberculous meningitis also has a higher mortality rate (19.3%) with a higher risk of neurologic disease in survivors (53.9%). 51 A recent prospective cohort study also found that males had a higher risk of unfavorable outcomes (odds ratio = 1.34) and death (odds ratio = 1.47). 52

Complications from bacterial meningitis also vary by age ( Table 7 1 , 11 , 12 , 46 , 53 – 56 ) . Neurologic sequelae such as hearing loss occur in approximately 6% to 31% of children and can resolve within 48 hours, but may be permanent in 2% to 7% of children. 53 – 56 An audiology assessment should be considered in children before discharge. 8 Follow-up should assess for hearing loss (including referral for cochlear implants, if present), psychosocial problems, neurologic disease, or developmental delay. 57 Testing for complement deficiency should be considered if there is more than one episode of meningitis, one episode plus another serious infection, meningococcal disease other than serogroup B, or meningitis with a strong family history of the disease. 57

VACCINATION

Vaccines that have decreased the incidence of meningitis include H. influenzae type B, S. pneumoniae , and N. meningitidis . 58 – 60 Administration of one of the meningococcal vaccines that covers serogroups A, C, W, and Y (MPSV4 [Menomune], Hib-MenCY [Menhibrix], MenACWY-D [Menactra], or MenACWY-CRM [Menveo]) is recommended for patients 11 to 12 years of age, with a booster at 16 years of age. However, the initial dose should be given earlier in the setting of a high-risk condition, such as functional asplenia or complement deficiencies, travel to endemic areas, or a community outbreak. 60 There are also two available vaccines for meningococcal type B strains (MenB-4C [Bexsero] and MenB-FHbp [Trumenba]) to be used in patients with complement disease or functional asplenia, or in healthy individuals at risk during a serogroup B outbreak as determined by the Centers for Disease Control and Prevention. 60

The Advisory Committee on Immunization Practices recently added a category B recommendation (individual clinical decision making) for consideration of vaccination with serogroup B vaccines in healthy patients 16 to 23 years of age (preferred age of 16 to 18 years). 60 , 61 The serogroup B vaccines are not interchangeable, so care should be taken to ensure completion of the series with the same brand that was used for the initial dose.

CHEMOPROPHYLAXIS

Treatment with chemoprophylactic antibiotics should be given to close contacts 7 , 62 , 63 ( Table 8 9 , 14 , 64 – 68 ) . Appropriate antibiotics should be given to identified contacts within 24 hours of the patient's diagnosis and should not be given if contact occurred more than 14 days before the patient's onset of symptoms. 63 Options for chemoprophylaxis are rifampin, ceftriaxone, and ciprofloxacin, although rifampin has been associated with resistant isolates. 62 , 63

This article updates a previous article on this topic by Bamberger . 9

Data Sources: The terms meningitis, bacterial meningitis, and Neisseria meningitidis were searched in PubMed, Essential Evidence Plus, and the Cochrane database. In addition, the Infectious Diseases Society of America, the National Institute for Health and Care Excellence, and the American Academy of Pediatrics guidelines were reviewed. Search dates: October 1, 2016, and March 13, 2017.

The authors thank Thomas Lamarre, MD, for his input and expertise.

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