CNS Infections: Meningitis & Encephalitis

Author: Michael T. Fitch, M.D., Ph.D. Wake Forest School of Medicine

Chapter Editor: Al’ai Alvarez, MD, Stanford University

Last update: 2019


Case Study

Mr. Jones is a 29-year-old male who presents to your Emergency Department with chief complaints of fever, headache, and neck stiffness.  His initial recorded temperature is 103º F and on examination he is somnolent and difficult to arouse, he is unable to answer your questions, and he has a positive Brudzinski’s sign.


Objectives

  1. List the classic triad of meningitis.
  2. Interpret CSF findings typical for viral or bacterial meningitis.
  3. Recognize the limitations of classically described signs and symptoms of CNS infection
  4. Compare empiric medications recommended for patients with differing ages and risk factors

Introduction

Bacterial meningitis and viral encephalitis are life-threatening causes of infection and inflammation within the central nervous system (CNS).  Patients may present to the Emergency Department (ED) in an early stage of illness when the diagnosis is challenging due to the presence of common non-specific signs and symptoms.  Emergency Medicine (EM) physicians are challenged to quickly identify patients who need urgent diagnostic testing and treatment.

Before antibiotics became available at the beginning of the 20th century, bacterial meningitis was nearly 100% fatal.  Morbidity and mortality remain high even with appropriate and timely treatment of bacterial infections within the CNS with broad-spectrum antibiotics.  Meningitis can affect patients of any age, but those at the extremes of age or those who are immunosuppressed are at increased risk.  An accurate diagnosis and timely administration of antibiotics and other adjunctive therapies are important for patients with suspected bacterial disease.

Meningitis is an inflammatory process of the membranes that surround the brain and spinal cord.  It is classified as bacterial meningitis when caused by a bacterial pathogen, the most common of which are encapsulated organisms. These pathogens may enter the CNS by violating the blood-brain barrier after an upper airway infection with mucosal involvement, or via the bloodstream when a patient has bacteremia.  CNS inoculation can also occur after trauma, surgery, or a contiguous infection such as sinusitis or otitis media.  The most common pathogens causing acute bacterial meningitis are Streptococcus pneumoniae and Neisseria meningitidis. Changes in epidemiology have mirrored vaccination practices in adults and children against H. influenzae, S. pneumoniae, and N. meningitidis. Routine childhood vaccination against Haemophilus influenza type b has helped decrease this pathogen as a common cause of meningitis, and use of the pneumococcal vaccine may be reducing the rate of disease in adults. Listeria monocytogenes as a cause of meningitis is more common in patients over the age of 50, infants less than 3 months old, and immunocompromised or pregnant individuals. 

Meningitis is referred to as aseptic meningitis when a CNS inflammatory response is due to any other cause besides a bacterial infection. Aseptic meningitis can be a side effect of some medications, a result of an autoimmune disease process, or caused by a non-bacterial infection.  Most cases of aseptic meningitis are caused by a virus such as enteroviruses and echoviruses which are the most common overall cause of meningitis. Mycobacterial infections can also cause aseptic meningitis. 

Encephalitis is an infection of the brain parenchyma causing inflammation within the CNS and is most often the result of a viral infection of brain tissue.  It can be caused by a variety of viral pathogens, and infection by herpes simplex virus (HSV) is the most treatable cause of encephalitis.   In the acute setting, it can be difficult to distinguish encephalitis from severe cases of bacterial meningitis, as patients’ signs and symptoms may be similar.

Patients diagnosed with meningitis or encephalitis have a broad differential diagnosis for the specific underlying causes of the inflammatory responses within the CNS.  Life threatening causes include bacterial meningitis or viral encephalitis from a variety of potential pathogens.  Aseptic meningitis can be caused by drugs, rheumatologic conditions, viruses, parasitic infections, fungal infections, malignancy, HIV, HSV, syphilis, Lyme disease, Rocky Mountain Spotted Fever, Ehrlichiosis, or autoimmune diseases.


Initial Actions and Primary Survey

Patients with suspected CNS infection who are ill appearing should be promptly evaluated observing appropriate universal precautions. Close monitoring and empiric treatment should rapidly be undertaken. Patients with rapidly declining consciousness, ongoing seizures, or airway compromise should have appropriate critical care interventions completed immediately.  Prioritize evaluation and stabilization of airway, breathing, and circulation as with any critically ill patient.  When bacterial meningitis is a likely diagnosis, administer empiric antibiotics after a prompt lumbar puncture (LP), or after blood cultures are drawn if there is an anticipated delay in obtaining cerebrospinal fluid (CSF). In the Emergency Department, the specific causative pathogen is typically uncertain when a patient initially presents, and therefore broad empiric antimicrobial coverage is recommended when bacterial meningitis is suspected.

Consider the diagnosis of encephalitis in patients with suspected CNS infection that is accompanied by altered mental status or a focal neurologic deficit. Administer antiviral therapy when HSV encephalitis is suspected as a cause for encephalitis.


Presentation

Patients diagnosed with meningitis have been classically described as having a triad of findings:

  1. Fever
  2. Neck stiffness
  3. Altered mental status

However, studies have shown that all three of these features are present together in less than half of adult patients who are diagnosed with bacterial meningitis.  Many early symptoms of meningitis are nonspecific, such as headache, fever, nausea and vomiting, and neck pain, which can make for a diagnostic challenge as these are also symptoms of many other clinical conditions. Patients with CNS infections may also experience confusion, altered mental status, or seizure as the disease progresses.  

Patients at the extremes of age and those who are immunocompromised can be particularly challenging to diagnose, as they may have vague symptoms, more subtle presentations, and may lack the presence of a fever early in the course of illness. Infants may present with nonspecific symptoms such as irritability, lethargy, poor feeding, rash, or a bulging fontanelle.  Seizures may be a presenting symptom in up to one-third of pediatric patients with bacterial meningitis.  Geriatric patients may present with confusion or altered mental status. 

The clinical presentation of patients with encephalitis can be similar to patients with meningitis, including fever, headache, and neck stiffness.  A clinical suspicion for the diagnosis of encephalitis is often raised by the presence of altered mental status or neurologic findings in patients in whom a CNS infection is diagnosed.

Physical Examination

Fever is a common physical exam findings for a patient with an acute CNS infection, although this finding is not universally present.

Classically described meningeal signs on physical examination may include:

  • Nuchal rigidity - severe neck stiffness due to meningeal irritation
  • Kernig’s sign - flexing the hip and extending the knee to elicit pain in the back and the legs
  • Brudzinski’s sign - passive flexion of the neck elicits flexion of the hips

These physical examination findings are concerning for a CNS infection when they are present, but because of relatively poor sensitivities their absence cannot be relied upon exclusively but should be interpreted in the overall clinical context.   Petechiae and purpura are classically associated with meningococcal meningitis, however these skin findings can be present with other causes of bacterial meningitis and bacteremia or may be absent.  Altered mental status and focal neurologic findings in a patient with suspected CNS infection raises concerns for encephalitis as a possible diagnosis.


Diagnostic Testing

A prompt lumbar puncture (LP) is the preferred diagnostic procedure in patients with suspected bacterial meningitis or encephalitis.

While neuroimaging is not required in all patients in whom a CNS infection is being evaluated, consider a CT scan of the brain before LP in patients with any of the following: 

  • Altered mental status
  • New onset seizures
  • Immunocompromised state
  • Focal neurologic signs
  • Papilledema.  

In these circumstances, the goal of neuroimaging is to identify patients with possible contraindications to LP such as an occult mass from infection or brain tumor, signs of brain shift or herniation, or alternative diagnoses. 

When performing an LP to assess for possible CNS infection, clinicians typically collect four tubes each containing about 1mL of CSF.  Common initial CSF laboratory studies include:

  • Cell count and differential
  • Protein
  • Glucose
  • Gram’s stain and bacterial culture

Additional CSF studies may be ordered for immunocompromised patients, or if the initial laboratory results are suggestive of a CNS infection. 

These other laboratory studies may include:

  • PCR for HSV or other viral pathogens
  • Antigen testing (bacterial or cryptococcal)
  • Fungal testing and/or culture

Patients being evaluated for possible CNS infections often have other laboratory studies completed such as a complete blood count (CBC), serum glucose and electrolytes, serum urea nitrogen (BUN) and creatinine.  Most laboratory studies are nonspecific for meningitis or encephalitis.  When empiric antibiotics are to be given for suspected CNS infection, consider drawing blood cultures beforehand as another avenue for identifying bacterial pathogens.

An LP result revealing an elevated number of white blood cells in the CSF is diagnostic for meningitis or encephalitis.  It remains a challenge to then determine whether the cause of such a CNS inflammatory response is caused by a bacterial infection, viral infection, or other etiology. 

CSF results suggestive of bacterial meningitis include the following: 

  • Positive Gram’s stain
  • Glucose less than 40 mg/dL or ratio of CSF/blood glucose less than 0.40
  • Protein greater than 200 mg/dL
  • WBC greater than 1000/mL
  • Greater than 80% polymorphonuclear neutrophils
  • Elevated opening pressure during LP (pressure reading obtained in lateral decubitus position)

See Table 1 for examples of classically described CSF findings in bacterial, viral, and fungal meningitis.  While these general guidelines may be helpful to broadly characterize CSF findings in many cases, several studies have demonstrated that no single laboratory finding can accurately categorize the cause of CSF pleocytosis in all patients.

Table 1: Classically described CSF findings suggestive of bacterial, viral, or fungal meningitis.

CSF findings

Bacterial

Viral

Fungal

Opening Pressure

Elevated

Normal

Elevated

White Blood Cell count*

1,000-10,000

< 300

< 500

Neutrophils

>80%

1% – 50%

1% – 50%

Glucose

Reduced

Normal

Reduced

Protein

Elevated

Normal

Elevated

Gram’s Stain

Bacteria

Nothing

Nothing

*There can be considerable overlap in CSF white blood cell counts between the various causes of meningitis, and cell counts should be interpreted in the context of other CSF findings and individual patients’ clinical presentations.

CSF studies for patients with encephalitis will lead to similarly abnormal results with increased numbers of white blood cells in the CSF, generally with a lymphocytic predominance.  Results may also reveal increased numbers of red blood cells in the CSF due to neuronal cell death leading to edema, hemorrhage, and necrosis when encephalitis is present.


Treatment

For patients with suspected bacterial meningitis, begin empiric broad-spectrum intravenous antibiotic therapy and arrange for admission to the hospital. Patients with severe disease may require ICU level care depending on the clinical circumstances.  Consult with local infectious disease specialists for guidance when selecting empiric therapy, and for local recommendations for neonates and infants with suspected CNS infections. Empiric treatment for neonates in many circumstances includes ampicillin and gentamycin, although changes in resistance patterns may in some circumstances replace gentamycin with cefotaxime.  For children and adults less than 50 years old, consider beginning an empiric regimen of a third generation cephalosporin (cefotaxime or ceftriaxone) plus vancomycin. For patients with risk factors for Listeria monocytogenes infection (age 50 years and older, age less than 3 months, pregnant women, alcohol abuse, immunocompromised state), consider adding ampicillin to the selected empiric antibiotic coverage regimen. The treatment for most cases of encephalitis is supportive care. HSV is the only cause of encephalitis with a specific treatment, and intravenous acyclovir is recommended for patients suspected to have this source of infection.

Adjunctive corticosteroid treatment started before or concurrently with the first dose of antibiotics may decrease mortality and neurologic sequelae for some subsets of patients with bacterial meningitis, particularly patients in high-income countries with suspected pneumococcal meningitis. Consider intravenous dexamethasone every 6 hours for 4 days in adults and children 6 weeks of age and older when it is initiated before or at the same time antibiotics are given. 

In patients with likely meningitis who will undergo a CT scan of the brain prior to LP, obtain blood cultures and begin empiric therapy prior to CT to avoid additional delays.

Admit patients with CSF findings concerning for bacterial meningitis to the hospital for IV antibiotics and further evaluation. It is important that patients with bacterial meningitis be placed in droplet precautions if there is concern for meningococcal meningitis to prevent further spread of the disease. If confirmed, patient contacts should be given prophylactic antibiotics.

Patients with encephalitis will also require inpatient care. Some well-appearing patients with findings consistent with viral meningitis may be suitable for outpatient treatment with careful return precautions and close outpatient follow-up plans in place. However, hospital observation is a reasonable option in circumstances when the diagnosis is unclear after emergency evaluation and bacterial meningitis remains a concern..

When diagnostic testing results suggest that a CNS infection is not present, additional inpatient or outpatient evaluation may be appropriate to identify an alternative diagnosis as appropriate for the clinical circumstances.


Pearls and Pitfalls

  • Patients who are very young, very old, or immunocompromised may present with atypical signs and symptoms.
  • The classic triad of meningitis has been described as fever, neck stiffness, and altered mental status. All three of these are present together in less than half of adult patients with bacterial meningitis, but the absence of all three makes the diagnosis of meningitis unlikely.
  • When the diagnosis of bacterial meningitis is likely, treat with broad-spectrum empiric antibiotics and consider adjunctive treatments while awaiting the results of diagnostic studies.
  • Administer empiric antibiotics while waiting for a CT scan prior to an LP if meningitis is a likely diagnosis.  In these circumstances, draw blood cultures and administer appropriate antibiotics and adjunctive treatments before the LP.
  • Consider the diagnosis of HSV encephalitis in patients with concerns for CNS infection who have focal neurologic findings, altered mental status, and/or elevated numbers of red blood cells in the CSF.  Administer IV acyclovir in addition to the empiric antimicrobial regimen.
  • Initial CSF laboratory findings do not always yield classic results, so consider empiric treatment for possible bacterial meningitis (and/or HSV encephalitis)  when CSF results are inconclusive.

Case Study Resolution

On your initial evaluation of Mr. Jones, you are immediately concerned about a high likelihood of a central nervous system infection.  You begin empiric treatment that includes antibiotics for possible bacterial meningitis with intravenous ceftriaxone, vancomycin, and adjunctive dexamethasone after drawing blood cultures.  A broad workup is undertaken to identify a suspected source of infection. You order a CT scan of the brain because of his profound altered mental status, but the images identify no contraindications to lumbar puncture. Initial CSF results from the LP show a WBC of 659 with 85% neutrophils, no RBCs, normal glucose levels, elevated protein levels, and a negative Gram’s stain. You add on an HSV PCR that comes back negative, and therefore do not begin any empiric treatment with acyclovir.  You contact the intensive care unit to admit the patient for close monitoring and continued treatment of suspected bacterial meningitis.


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