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Meningitis: Distinguishing the benign from the serious

Aseptic meningitis has a self-limited course, but bacterial meningitis can be lethal. An expeditious diagnostic approach helps to differentiate between the two.

Chris Shelburne, MPAS, PA-C; Michel Statler, MLA, PA-C

Chris Shelburne is a physician assistant in the postgraduate Surgical Residency Program at Johns Hopkins Hospital, Baltimore, Maryland. Michel Statler is associate director and associate professor, Midwestern University physician assistant program, Glendale, Arizona. They have indicated no relationships to disclose relating to the content of this article.

Aseptic meningitis, commonly referred to as viral meningitis, is responsible for 75,000 cases of meningitis and approximately 26,000 to 42,000 hospitalizations each year in the United States.^1,2 Aseptic meningitis has a benign, self-limited course, but it must be distinguished from bacterial meningitis, which is a potentially life-threatening illness. Hospitalization, diagnostic testing, and antibiotics may be required to differentiate aseptic meningitis from bacterial meningitis.

Although the typical case of aseptic meningitis resolves in less than 7 days² with a good prognosis, a majority of patients may still require hospitalization. An outbreak of aseptic meningitis in Rhode Island resulted in hospital admissions for 184 adult and 224 pediatric patients.³ The average hospital stay was 2.5 days; in that time 74% of the patients received at least one dose of antibiotic and 32% underwent CT. The overall financial impact of the 1991 outbreak was calculated to be $500,000.^2,3

Aseptic meningitis most commonly affects infants younger than 1 year and children aged 5 to 10 years, but it can affect persons in any age group. In approximately 90% of cases in which the underlying cause was identified, enteroviruses were the most common pathogen (see Figure 1).^1,4 Incidences of aseptic meningitis in the United States are prevalent during the summer and autumn because of the predominance of enteroviruses during these months.

Although enteroviruses are the most commonly identified cause of aseptic meningitis, other viruses such as herpes simplex virus (HSV), varicella zoster virus (VZV), Epstein-Barr virus, HIV, West Nile virus (WNV), arbovirus, mumps, rabies, and influenza are all possible causes.^5-8 Malignancies, such as acute leukemia and large cell lymphomas, also can cause meningitis by invading the CNS through hematogenous spread.^6,7 Breast cancer, lung cancer, gastrointestinal malignancies, and cancers of unknown etiology can cause meningitis via direct tumor invasion of the meninges, which results in secondary inflammation.⁶ Even though malignancy is an uncommon cause of meningitis, it remains an important part of the differential diagnosis.

A medication reaction should also be considered, even though it is relatively rare. The underlying pathophysiology is thought to be secondary to a delayed hypersensitivity response or secondary to direct irritation of the meninges by the drug itself. NSAIDs, antibiotics, and IV immune globulin can replicate the symptoms of aseptic meningitis. A diagnosis of medication-induced meningitis is usually made by eliminating other causes. Symptoms resolve after discontinuing the offending medication.⁶ A literature search did not include autoimmune disease as a potential cause of aseptic meningitis. However, an additional search from the standpoint of neurologic complications associated with autoimmune diseases indicated that neurologic complications are possible but that aseptic meningitis is one of the least common causes.

PATHOGENESIS

Enteroviruses, usually acquired by fecal-oral contamination, have the ability to gain entrance into a host via mucosal, skin, GI, or GU routes.⁷ Following exposure, the virus passes into the lower GI tract. The viral particles bind to specific receptors on enterocytes and traverse the intestinal lining to reach the Peyer’s patches in the lamina propria, where they replicate.⁴ An initial viremia spreads the virus to other organs such as the liver, spleen, and heart, where additional replication takes place. Further replication leads to a second major viremia associated with the signs and symptoms of enteroviral infection.⁴

Viruses can gain access to the CNS via hematogenous dissemination or neuronal spread. Hematogenous dissemination usually results from the seeding of distant sites such as the endothelial cells of meningeal capillaries with a secondary passage to the subarachnoid space or from direct seeding of the choroid plexus. Enteroviruses are commonly associated with this route after primary replication within the GI tract. Viruses such as rabies, HSV, and VZV gain access to the CNS by traveling in a retrograde fashion from peripheral nerve endings.⁷

SIGNS AND SYMPTOMS

Clinical manifestations vary with the patient’s age and immune status. Common features include the acute onset of fever, generally less than 40°C,^4,7 accompanied by nonspecific constitutional symptoms such as anorexia, fatigue, myalgias, nasal congestion, sore throat, and cough.⁴ A thorough history should include contacts with people who have similar symptoms, recent travel, exposure to mosquitoes (WNV, St Louis encephalitis), exposure to tuberculosis, animal bites (rabies), immunizations (mumps), IV drug use (HIV), and blood transfusions (HIV). Clinicians should elicit a sexual history to determine the risk of HSV and HIV,⁶ review medications to rule out medication-induced meningitis, and perform a general review of systems to look for systemic symptoms associated with malignancy.

Neonates are at a higher risk of systemic illness because of their age, underdeveloped immune systems, and the complications associated with systemic infections such as hepatic necrosis, myocarditis, and necrotizing enterocolitis.⁴ Signs and symptoms of meningitis—bulging fontanel, nuchal rigidity, lethargy, poor feeding, and irritability—are more difficult to assess in neonates than in adults.⁴ A thorough history and a high index of suspicion are key to avoiding a potentially life-threatening event.

Older children frequently complain of fever, headaches, photophobia, and nuchal rigidity.^4,8 The fever pattern may be biphasic, appearing first with nonspecific constitutional symptoms such as fatigue, anorexia, and myalgias.^4,5,8 These symptoms resolve and then reappear with signs of meningeal irritation such as nuchal rigidity, positive Brudzinski’s sign, and/or positive Kernig’s sign.^4,8 Altered states of consciousness such as marked confusion, stupor, and coma; new onset seizure activity; and focal or diffuse neurologic signs such as hemiparesis or papilledema should prompt consideration of other diagnoses such as viral encephalitis, brain abscess, or epidural abscess.⁸

The presence of a rash may help determine the etiology of the virus. A diffuse erythematous, maculopapular rash suggests enterovirus infection; whereas oral or genital erythematous, vesicular lesions suggest HSV infection.^7,8 A vesicular eruption on the palms, soles, and buttocks is indicative of hand-foot-and-mouth disease. The presence of petechiae or a purpuric rash is associated with meningococcal meningitis and suggests a bacterial etiology.⁸

Signs of meningeal irritation are frequently associated with meningitis but are not pathognomonic. A retrospective study assessed 326 patients aged 1 month to 15 years who presented to an emergency department in the Netherlands from 1988 to 1998 with signs of meningeal irritation.⁹ Bacterial meningitis was diagnosed in 30% of the patients, aseptic meningitis in 13%, and non-CNS infections in 57%. No individual sign of meningeal irritation indicated a significantly higher incidence of bacterial meningitis than the other signs. Furthermore, the combination of nuchal rigidity with a positive Kernig’s sign or a positive Brudzinski’s sign was no more accurate than nuchal rigidity alone.⁹

In a prospective study in the United States, nuchal rigidity, Kernig’s sign, and Brudzinski’s sign were assessed for their diagnostic accuracy in predicting meningitis.¹⁰ The results yielded a sensitivity of only 5% for both Kernig’s sign and Brudzinski’s sign and 30% for nuchal rigidity. Therefore these meningeal signs are of little diagnostic value for suspected meningitis.¹⁰

CEREBROSPINAL FLUID ANALYSIS

The diagnostic approach for patients presenting with headache, nuchal rigidity, and fever is of paramount importance because bacterial meningitis is a potentially life-threatening disease. Accordingly, a bacterial cause must be eliminated before a diagnosis of aseptic meningitis can be assumed. Currently, one of the most important tests for diagnosing meningitis is CSF analysis (see Table 1).⁸

Typical CSF analysis indicators of aseptic meningitis include pleocytosis with a WBC count of 100/mm³ to 1,000/mm³, comprised mainly of lymphocytes.^5,11 CSF indicators of bacterial meningitis include pleocytosis with a WBC count of more than 1,000/mm³, comprised mainly of polymorphonuclear cells (PMNs).⁶ CSF analysis appears to make the distinction between aseptic meningitis and bacterial meningitis relatively straightforward; however, ruling out bacterial meningitis on the basis of CSF analysis alone is problematic. Because a high percentage of PMNs suggests a bacterial etiology, some clinicians initiate antibiotic therapy based on this evidence alone. However, a retrospective chart review of 150 patients from the Children’s Hospital of Pittsburgh found a positive predictive value (PPV) of 81% for PMN predominance indicating aseptic disease, but found a PPV of only 19% for PMN predominance indicating bacterial meningitis in the pediatric population.¹² The data suggest that PMN predominance, as a sole criterion, is a poor diagnostic marker of disease type and the use of antibiotics should not be based solely on PMN predominance.

Protein levels vary from 18 to 58 mg/dL depending upon different laboratory reference ranges.¹³ Typical levels in patients with aseptic meningitis are less than 100 mg/dL, primarily because of inflammation caused by the virus; however, bacterial infections cause a more dramatic increase in CSF protein (higher than 400 mg/dL). Although elevated protein levels are indicative of CNS pathology, CSF protein levels are most beneficial when evaluating all the entities of CSF analysis together.¹³

Glucose concentration also differentiates aseptic meningitis from bacterial meningitis.^6,8 Normal CSF glucose concentration is 45 to 80 mg/dL and should be approximately two-thirds of the blood glucose level in healthy persons.¹³ Accordingly, blood glucose should be measured at the same time the lumbar puncture is performed. CSF glucose remains normal in patients with aseptic meningitis but falls to less than 40 mg/dL in patients with bacterial meningitis.⁸ A ratio of CSF glucose to blood glucose is used to determine the presence of bacterial meningitis because hyperglycemia may increase CSF glucose concentration. The normal CSF:blood glucose ratio should be 0.6, which is preserved in aseptic meningitis. A CSF:blood glucose ratio of less than 0.4 is highly predictive of bacterial meningitis.⁸

Gram’s stain may differentiate between aseptic meningitis and bacterial meningitis before CSF culture or enterovirus-polymerase chain reaction (PCR) results become available. Gram’s stain is normally negative with aseptic meningitis and positive with bacterial meningitis.^6,8 Sensitivity varies widely from 60% to 90%,⁸ which could lead to both false positives and false negatives. The reliability of the test depends on the bacterial count. The more bacteria present, the higher the probability that the Gram’s stain will be positive and more likely to be associated with bacterial meningitis.⁸

CSF analysis can help differentiate aseptic meningitis from bacterial meningitis but results may be equivocal. Most patients fall into the indeterminate category because each CSF finding on its own overlaps between aseptic and bacterial disease.⁶ To rule out bacterial meningitis, the Gram’s stain must be negative, the CSF:blood glucose ratio must be 0.6 or higher, and the bacterial culture must be negative. The algorithm “Diagnostic workup for meningitis” outlines a directed approach to ruling in aseptic meningitis while ruling out bacterial meningitis.

ADDITIONAL DIAGNOSTIC STUDIES

Cultures The next step is to obtain cultures of the CSF. Viral and bacterial cultures are the gold standard for diagnosing aseptic meningitis and bacterial meningitis, respectively.^11,14 CSF viral culture is the most sensitive test available. However, the sensitivity of CSF culture for enteroviruses is only 65% to 75% because low concentrations of infectious virus in the CSF produce poor growth of some enterovirus serotypes.^1,2,4 Furthermore, because CSF cultures take 4 to 8 days to produce results, they are usually not available within sufficient time to affect treatment.^2,4,15 Treatment with empiric antibiotics should be initiated immediately pending culture results to avoid the complications associated with bacterial meningitis.¹⁴

Polymerase chain reaction The most sensitive and specific test to rule in aseptic meningitis is reverse-transcription (RT) PCR. The PCR assay is a method in which primers are used to amplify the DNA or RNA of specific virus genomes. The primers are used for reverse transcription of the viral RNA genome combined with PCR of the CSF. PCR has the potential to become the diagnostic procedure of choice for aseptic meningitis because it is reportedly 100% sensitive and 95% specific.^1,4,11,15 RT-PCR can be used as a complementary test to diagnose bacterial meningitis when Gram’s stain and bacterial culture are equivocal. In a study of 54 CSF specimens collected during a summer 2001 outbreak of aseptic meningitis in France, only 52% were positive by cell culture versus 76% by in-house RT-PCR assay.¹⁶

The diagnostic impact of an enterovirus-specific RT-PCR on patient management was investigated in a retrospective chart review of patients at Children’s Hospital of San Diego.¹ The median turnaround time for the enterovirus RT-PCR assay was found to be 33.9 hours, considerably less than the 4 to 8 days for viral culture results.^1,2 When enterovirus- positive results are available before hospital discharge, patients had significantly fewer ancillary tests performed, received IV antibiotics for a shorter period of time, and had shorter hospital stays.¹ This study’s results suggest that an RT-PCR assay could substantially reduce unnecessary diagnostic testing and unnecessary therapeutic interventions.

The RT-PCR assay also differentiates aseptic meningitis from bacterial meningitis when CSF analysis results are equivocal. Currently RT-PCR assays are only performed at reference laboratories and, therefore, obtaining results may take up to 2 weeks. A strong case can be made for reference laboratories to provide RT-PCR results within 48 hours of receiving the specimen.¹¹

Other laboratory tests Systemic signs or symptoms such as fever, weight loss, and nuchal rigidity should lead to additional diagnostic tests including blood culture, urine culture, CBC with differential, ESR, and/or C-reactive protein.¹¹ Abnormal test results may suggest particular etiologies such as an occult malignancy or a systemic infection other than meningitis.^11,17

Imaging Cranial CT or MRI is not required for every patient.⁷ Neuroimaging should be ordered before lumbar puncture if increased intracranial pressure is suspected to avoid the risk of herniation. Findings such as focal neurologic deficit, new onset seizure, papilledema, abnormal level of consciousness, or an immunocompromised state are associated with increased intracranial pressure and are more consistent with bacterial meningitis, encephalitis, or a brain abscess.⁸

TREATMENT

Aseptic meningitis is self-limited, and treatment is usually geared toward managing symptoms. Empiric antibiotics should be administered to patients with fever, headache, and nuchal rigidity prior to lumbar puncture or neuroimaging until a diagnosis of aseptic meningitis is confirmed. Symptomatic treatment may include analgesics, antiemetics, and antipyretics.¹⁸ Aspirin for fever is contraindicated in children and adolescents because of a possible association with Reye’s syndrome.¹⁸ Fluid balance must be monitored to avoid the syndrome of inappropriate antidiuretic hormone with or without brain edema.⁴ Too-rapid correction with IV fluids can lead to subdural and intracerebral hemorrhage, permanent CNS damage, and demyelination syndrome. A rapidly progressive course that requires a more intensive treatment regimen strongly suggests a diagnosis other than aseptic meningitis and should lead to the pursuit of other etiologies.⁴

Specific antiviral treatment targets several steps in the replication cycle of the enterovirus. Pleconaril is an experimental antiviral agent that inhibits viral replication by blocking viral attachment and inhibiting viral uncoating.^8,15,19 Treatment with antivirals is not generally indicated because of the benign course of aseptic meningitis; however, pleconaril has been used on a “compassionate-release” basis to treat patients with life-threatening enterovirus infections or those patients who lack humoral immunity.^7,15,20 A double-blind, placebo-controlled trial of pleconaril in infants with aseptic meningitis caused by an enterovirus infection was conducted to determine the safety and efficacy of the drug.²⁰ The study determined that pleconaril obtained sufficient plasma concentrations to inhibit the majority of enteroviruses. The difficulty encountered in this study was that the drug reached toxic levels by the seventh day of treatment.²⁰ Pleconaril is not currently in active production and has not yet been submitted to the FDA for approval; however, it may be beneficial for immunocompromised persons.⁷ Future studies need to address the potential toxicity of the agent in all age groups.

The prognosis for a full recovery from aseptic meningitis is excellent for children and adults. Most patients have a self-limited illness that lasts approximately 1 week and requires no follow-up.¹⁵ The disease may persist in adolescents and adults for up to several weeks because of a prolonged convalescent stage.² In neonates, however, aseptic meningitis is potentially life-threatening because they have an underdeveloped immune system. For this reason, most neonates with aseptic meningitis are hospitalized. Ten percent of patients with aseptic meningitis may develop a serious complication such as febrile seizures, increased intracranial pressure, encephalitis, or the syndrome of inappropriate antidiuretic hormone secretion.¹⁵

CONCLUSION

Enterovirus infection is the leading cause of aseptic meningitis worldwide and accounts for 90% of all cases. Patients with suspected meningitis present with fever, headache, and nuchal rigidity. CSF analysis should be performed on every patient with suspected aseptic meningitis to rule out life-threatening illness. Typical CSF findings that indicate a diagnosis of aseptic meningitis include pleocytosis, normal glucose and normal to slightly elevated protein levels, and a negative Gram’s stain. Although CSF viral culture is the gold standard for diagnosis, RT-PCR can provide a more rapid and accurate diagnosis. When clinical suspicion of meningitis is high, empiric antibiotics should be started prior to lumbar puncture or neuroimaging until a diagnosis can be confirmed. Aseptic meningitis is a benign and self-limited disease, but the difficulty in differentiating it from bacterial meningitis always presents a medical challenge. Antiviral agents are not currently indicated for the treatment of aseptic meningitis, but research suggests they could be helpful in cases of life-threatening enterovirus infections. JAAPA

ACKNOWLEDGEMENT

The authors would like to express their appreciation to Jim Stoehr, PhD, and Alison Essary, MHPE, PA-C, for their invaluable insights to the editing process.

REFERENCES

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