eMedicine Specialties > Infectious Diseases > CNS Infections

Meningitis: Differential Diagnoses & Workup

Author: Raymund R Razonable, MD, Consultant, Division of Infectious Diseases, Mayo Clinic of Rochester; Associate Professor of Medicine, Mayo Clinic College of Medicine
Coauthor(s): Michael R Keating, MD, Consultant, Assistant Professor of Medicine, Division of Infectious Diseases, Department of Medicine, Mayo Clinic College of Medicine
Contributor Information and Disclosures

Updated: Aug 26, 2009

Differential Diagnoses

Brain Abscess

Other Problems to Be Considered

Noninfectious meningitis, including medication-induced meningeal inflammation
Meningeal carcinomatosis
CNS vasculitis
Stroke
Encephalitis

Workup

Laboratory Studies

The cornerstone in the diagnosis of meningitis is examination of the CSF.

In general, whenever the diagnosis of meningitis is strongly considered, promptly perform a lumbar puncture.

Measure the opening pressure and send the fluid for cell count (and differential count), chemistry (ie, CSF glucose and protein), and microbiology (ie, Gram stain and cultures).

CT scan of the brain may be performed prior to lumbar puncture in some patient groups with a higher risk of herniation. These groups include those with newly onset seizures, an immunocompromised state, signs suspicious for space-occupying lesions (such as papilledema and focal neurologic signs), and moderate-to-severe impairment in consciousness.

Special studies, such as serology and nucleic acid amplification, may also be performed depending on clinical suspicion. There is increasing data to suggest that serum procalcitonin levels can be used as a guide to distinguish between bacterial and aseptic meningitis in children. The results yielded by a serum procalcitonin, combined with other findings, could be helpful in making clinical decisions.¹

Table 5. CSF Picture of Meningitis According to Etiologic Agent

Open table in new window

Bacterial meningitis

• Examination of the CSF in patients with acute bacterial meningitis reveals the characteristic neutrophilic pleocytosis (usually hundreds to a few thousand, with >80% PMN cells). In some cases of L monocytogenes meningitis (25-30%), a lymphocytic predominance may occur. Low CSF WBC count (<20 cells/µL) in the presence of a high bacterial load suggests a poor prognosis.
• The opening pressure (reference range is 80-200 mm H2O) may be elevated, suggesting some form of increased ICP from cerebral edema.
• The CSF glucose (reference range is 40-70 mg/dL) is less than 40 mg/dL in 60% of patients. Obtain a simultaneous blood glucose determination for comparison purposes. Some patients may have elevated blood sugar levels as a result of underlying diabetes mellitus, and the predictive value of the CSF and blood sugar ratio may not be accurate in these circumstances.
• The CSF protein (reference range is 20-50 mg/dL) is usually elevated.
• CSF Gram stain permits rapid identification of the bacterial cause in 60-90% of patients with bacterial meningitis. The presence of bacteria is 100% specific, but the sensitivity for detection is variable. The likelihood of detection is higher in the presence of a higher bacterial concentration and diminishes with prior antibiotic use.
• CSF bacterial cultures yield the bacterial cause in 70-85% of cases. The yield diminishes significantly in patients who have received antimicrobial therapy. In these cases, some experts advocate the use of a CSF bacterial antigen assay. This is a latex agglutination technique that can detect the antigens of HIB, S pneumoniae, N meningitidis, E coli K1, and S agalactiae. Its theoretical advantage is the detection of the bacterial antigens even after microbial killing, as is observed following antibacterial therapy. Others, however, have shown that it may not be better than the Gram stain. It is specific (a positive result indicates a diagnosis of bacterial meningitis), but a negative finding on bacterial antigen test does not rule out meningitis (50-95% sensitivity).
• Obtain blood cultures and appropriate cultures from possible sites of infection. Obtain these promptly and prior to the administration of an antibacterial agent. The utility of these cultures is most evident in cases when the performance of a lumbar puncture is delayed by the need for head imaging (risk for herniation in a patient with focal neurologic deficit or coma) and when antimicrobial therapy is rightfully initiated before the lumbar puncture and neuroimaging tests.

Acute viral meningitis

• The CSF picture of acute viral meningitis is different from the CSF picture of bacterial meningitis.
• The opening pressure is usually within the reference range.
• The CSF cell count is usually in the few hundreds (100-1000 cells/µL) with a predominance of lymphocytes. Some cases of echovirus, mumps, and HSV meningitis may produce a neutrophilic picture early in the course of disease.
• The CSF glucose level is usually within the reference range, but some cases of LCM, HSV, mumps, and polio may cause low CSF glucose levels.
• CSF protein levels may be within the reference range but are usually elevated.
• Virus isolation from the CSF can be performed. It has a sensitivity of 65-70% for enteroviruses. Alternatively, enterovirus isolation from throat and stool viral cultures may also be used to indirectly implicate it as the cause of the meningitis. Mumps viral culture from the CSF has a low sensitivity (30-50%). LCM virus may be cultured in blood early in the disease or later in the urine.
• The use of nucleic acid amplification (eg, PCR) has revolutionized the diagnosis of herpes simplex meningitis. The availability of this technique has confirmed HSV as the cause of the recurrent Mollaret meningitis. This technique has also been applied to the diagnosis of enterovirus infections and the other herpesvirus infections. The PCR assay for enteroviruses has been demonstrated to be substantially more sensitive than culture and is 94-100% specific.
• In addition, the demonstration of a 4-fold rise between acute and convalescent sera traditionally has been used to document meningeal infection with these viral pathogens.

Cryptococcal meningitis

• The diagnosis of cryptococcal meningitis relies on the identification of the pathogen in the CSF.
• The CSF is characterized by a lymphocytic pleocytosis (10-200 lymphocytes), a reduced glucose level, and an elevated protein level.
• The CSF opening pressure may be elevated at times, suggesting increased ICP.
• C neoformans may be cultured from the CSF. Other methods of identification have included India ink preparation and the detection of CSF cryptococcal antigen. India ink has a sensitivity of only 50%, but it is highly diagnostic if positive. Because of the low sensitivity of the India ink preparation, many centers have adapted the use of CSF cryptococcal antigen determination, a test with a sensitivity of greater than 90%. However, the CSF cryptococcal antigen determination is not universally available. In instances when the India ink results are negative but the clinical suspicion for cryptococcal meningitis is high, the CSF specimen may be sent to reference laboratories that can perform CSF cryptococcal antigen determination to confirm the diagnosis. In addition, the titer of the antigen could serve to monitor the response to treatment.
• Obtain blood cultures and serum cryptococcal antigen to determine if cryptococcal fungemia is present.

Other fungal meningitis

• The CSF picture of other fungal meningitis is similar to the CSF picture of cryptococcal meningitis, usually with lymphocytic pleocytosis.
• Eosinophilic pleocytosis has rarely been associated with C immitis meningitis.
• The definitive diagnosis usually relies on the demonstration of the specific fungal agent (eg, H capsulatum, C immitis, B dermatitidis, Candida species) from clinical specimens, including the CSF. This could be in the form of fungal culture isolation (eg, C albicans growth from CSF). More commonly, fungal serology is used in the diagnosis of many cases of fungal meningitis because isolating them from culture has been difficult (eg, presence of histoplasma antigen in the CSF). However, note that the serology for B dermatitidis is not accurate and a negative serology finding does not rule out the diagnosis.

Syphilitic meningitis

• The CSF in syphilitic meningitis is characterized by mild lymphocytic pleocytosis.
• Abnormal CSF protein levels (elevated) and CSF glucose levels (decreased) may be observed in 10-70% of cases.
• Isolating T pallidum from the CSF is extremely difficult and time consuming. The spirochete could be demonstrated using dark-field or phase-contrast microscopy on specimens collected from skin lesions (eg, chancres and other syphilitic lesions).
• The diagnosis is usually supported by the CSF Venereal Disease Research Laboratory (VDRL) test, which has a sensitivity of 30-70% (a negative result on the CSF VDRL test does not rule out syphilitic meningitis) and a high specificity (a positive test result suggests the disease). Always take care to not contaminate the CSF with blood during spinal fluid collection (eg, traumatic tap).
• Perform serologic tests to detect syphilis, such as the nontreponemal (ie, rapid plasma reagent [RPR] or VDRL test) and specific treponemal (ie, fluorescent treponemal antibody absorption [FTA-Abs], Treponema pallidum hemoagglutination [TPHA], microhemagglutination-Treponema pallidum [MHA-TP]) tests to support the diagnosis. These also guide the success of therapy. The titer of the nonspecific treponemal tests decreases and usually reverts back to negative or undetectable levels following treatment.

Lyme neuroborreliosis

• The CSF in patients with Lyme meningitis is characterized by low-grade lymphocytic pleocytosis, low glucose levels, and elevated protein levels. Oligoclonal bands reactive to B burgdorferi antigens may be present.
• Demonstration of the specific antibody to B burgdorferi aids in the diagnosis. Comparison between the antibody response in the CSF and the serum is a helpful diagnostic test. A CSF-to-serum ratio of greater than 1 suggests intrathecal antibody production and neuroborreliosis.
• The culture for B burgdorferi has a low yield.
• The recent availability of the CSF Lyme PCR assay offers a rapid, sensitive, and specific method of diagnosis. This assay is gaining popularity as the method of choice for diagnosis of Lyme meningitis. Findings on blood Lyme PCR are usually negative.

Tuberculosis meningitis

• The CSF of patients with tuberculosis meningitis is characterized by a predominantly lymphocytic pleocytosis, usually in the hundreds.
• The opening CSF pressure is usually elevated.
• A characteristic hypoglycorrhagia (glucose <40 mg/dL) is present, and the protein level is usually elevated, especially if a CSF block is present.
• The demonstration of the acid-fast bacilli (eg, with auramine-rhodamine stain, Ziehl-Neelsen stain, Kinyoun stain) in the CSF is difficult and usually requires a large volume of CSF.
• Meningeal biopsy, with the demonstration of caseating granulomas and acid-fast bacilli on the smear, may prove useful because it has a higher yield than the CSF acid-fast bacilli smear.
• The culture for Mycobacterium usually takes several weeks and may delay definitive diagnosis.
• M tuberculosis detection assays involving nucleic acid amplification have become available and have the advantage of a rapid, sensitive, and specific method of tuberculosis detection.
• The need for mycobacterial growth in cultures remains because this offers the advantage of performing drug susceptibility assays.

Parasitic meningitis

• PAM caused by N fowleri is characterized by a neutrophilic pleocytosis, low glucose levels, elevated protein levels, and red blood cells. Mononuclear pleocytosis may be observed in patients with subacute or chronic forms of PAM. Demonstration of the trophozoites, with the characteristic amoeboid movement, using wet preparations of the CSF has been used for diagnosis. Alternatively, the amoeba could be demonstrated in biopsy specimens.
• Suspect meningitis caused by A cantonensis, G spinigerum, and B procyonis in the presence of exposure, profound peripheral blood eosinophilia, and characteristic eosinophilic pleocytosis. Demonstrating the larva antemortem is usually difficult, and diagnosis relies on clinical presentation and a compatible epidemiological history. Serologic tests may aid in the diagnosis. G spinigerum meningitis may mimic cerebrovascular disease because it may cause cerebral hemorrhage.

Imaging Studies

• Computed tomography scans of the head and magnetic resonance imaging of the brain do not aid in the diagnosis of meningitis. Some patients may show meningeal enhancement, but its absence does not rule out the condition.
• The practice of obtaining CT scans of the head may lead to the unnecessary delay in the performance of diagnostic lumbar puncture and the initiation of antibiotic therapy. The delay in the institution of antimicrobial therapy may be detrimental to the total outcome in these patients. Cerebral herniation following the lumbar tap procedure is rare in individuals with no focal neurologic deficits and no evidence of increased ICP. If it occurs, it usually happens within 24 hours following the lumbar puncture and should always be considered in the differential diagnosis if the patient's neurologic status deteriorates.
• Neuroimaging is indicated in patients with prolonged fever, focal neurologic symptoms and signs, evidence of increased ICP, and suspected basilar fracture. It is also indicated for evaluation of the paranasal sinuses. These studies are helpful in the detection of CNS complications of bacterial meningitis, such as hydrocephalus, cerebral infarct, brain abscess, subdural empyema, and venous sinus thrombosis.

Procedures

• Perform lumbar puncture promptly in all patients whenever a strong clinical suspicion for meningitis exists.
• Neurosurgical procedures are performed in consultation with a neurosurgical service in the presence of severe intracranial hypertension, evidence of paranasal and mastoid infection that requires surgical drainage, skull fractures, foreign body–associated infections (eg, ventriculoperitoneal shunts), or an associated abscess formation.

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